Therapy of Idiopathic Membranous Nephropathy - BANTAO Journal

12/07 BJBANTAO JournalOfficial Publication of theBANTAO AssociationIncorporating Proceedings ofthe BANTAO AssociationEditor-in-ChiefAssociate EditorsAli Basci Izmir Dimitar Nenov VarnaMomir PolenakovicSkopjeLjubica DjukanovicBelgradeCharalambos StathakisAthensDeputy EditorsGoce SpasovskiAdrian CovicVeselin NenovSkopjeIasiVarnaEditorial BoardAdalbert Schiller Timisoara Katica Zafirovska SkopjeAleksandar Sikole Skopje Ladislava Grcevska SkopjeAlketa Koroshi Tirana Liliana Garneata BucharestAmira Peco Antic Belgrade Milan Radovic BelgradeCengiz Utas Kayseri Mirela Gherman-Caprioara Cluj-NapokaDaniela Monova Sofia Myftar Barbullushi TiranaDimitrios Goumenos Patra Nada Dimkovic BelgradeDimitris Tsakiris Veria Nina Basic-Jukic ZagrebDragan Ljutic Split Paul Gusbeth-Tatomir IasiEkrem Erek Istanbul Petar Kes ZagrebEvgueniy Vazelov Sofija Rade Naumovic BelgradeFehmi Akcicek Izmir Radoslav Kveder LjubljanaGeorgios Vergoulas Thessaloniki Rafael Ponikvar LjubljanaGultekin Suleymanlar Antalya Sanja Simic-Ogrizovic BelgradeHalima Resic Sarajevo Velibor Tasic SkopjeHuseyin Toz Izmir Vidosava Nesic BelgradeIgor Mitic Novi Sad Visnja Lezaic BelgradeJohn Boletis Athens Vladislav Stefanovic NisKamil Serdengecti Istanbul Sevgi Mir IzmirInternational Advisory BoardAndrzej Wiecek Poland Jorg Vienken GermanyBernd Stegmayr Sweden Jorge Cannata SpainBoleslav Rutkowski Poland Jurgen Floege GermanyClaudio Ponticelli Italy Marc De Broe BelgiumCarmine Zoccali Italy Markus Ketteler GermanyDavid Goldsmith UK Mohamed Daha NetherlandsDimitrios Oreopoulos Canada Norbert Lameire BelgiumFrancesco Locatelli Italy Raymond Vanholder BelgiumHorst Klinkmann Germany Rosanna Coppo ItalyJohn Feehally UK Ziad Massy FrancePublished by: Balkan Cities Association ofNephrology, Dialysis, Transplantation and ArtificialOrgans,Printing: Grafotisok, SkopjeDecember, 2007

BANTAO Journal 2007; 5 (2)I. Editorial FeaturesEditorial reportBJBANTAO JournalThe Fifth-Year Anniversary of the Bantao JournalGoce Spasovski, Momir Polenakovic and Ali Basci............................................................... 1Editorial commentsA Struggle For Kidney Transplantation in a Developing World?Goce Spasovski, Charalambos Stathakis and Ali Basci.......................................................... 2Editorial reviewPast, Present and Future of NephrologyDorhout Mees EJ..................................................................................................................... 3ReviewsTherapy of Idiopathic Membranous NephropathyClaudio Ponticelli.................................................................................................................... 5Investigating Microscopic Haematuria – the Role of Renal BiopsyJohn Feehally .......................................................................................................................... 10Pediatric Renal TransplantationRosanna Coppo, Alessandro Amore, Licia Peruzzi and Roberta Camilla ............................. 14Focal Segmental GlomerulosclerosisDimitrios S Goumenos............................................................................................................ 23Long-Term Outcome of Children with Congenital Abnormalities of the Kidney andUrinary Tract (CAKUT): an Adult PerspectiveGuy H. Neild .......................................................................................................................... 28II. Scientific PapersOriginal ArticlesSerbian Pediatric Chronic Kidney Disease Registry – SPEKIDAmira Peco-Antic, Radovan Bogdanovic, B. Mulic and SPNWG ........................................ 32Hepatocyte Growth Factor, Vascular Endothelial Cell Growth Factor and TumorNecrosis Factor-A Release, During High Flux HaemodialysisFotini Christidou, Argiri Aggelou, Gramati Galaktidou, Stelios Fragidis, Panagiota Veneti,Kostas Sombolos and Theodore Bischiniotis .........................................................................Course of IgA Nephropathy: follow-up of 23 yearsMaja Milovanceva-Popovska, Ladislava Grcevska, Sonja Dzikova, Vesna Ristovska, VladoNikolov, Aleksandar Sikole and Momir Polenakovic .................................................Anti-Telomere Antibodies in Lupus GlomerulonephritisDaniela Monova, Simeon Monov and Trenka Argirova ........................................................ 43Screening for Microalbuminuria in the General Population of Tirana, a Tool to DetectSubjects at Risk for Progressive Renal Failure in an Early PhaseKliti Hoti, Myftar Barbullushi, Genc Burazeri, Edite Sadiku, Leonard Deda, Merita Rroji,Saimir Seferi and Nestor Thereska .........................................................................................Course and Prognosis of Primary Systemic Vasculitidies (PSV) with Renal LesionsDejan Celic, Tatjana Ilic, Igor Mitic, Gordana Strazmester-Majstorovic, Tatjana Djurdjevic-Mirkovic, Dusan Bozic and Slobodan Curic........................................................Steroid induced Psychiatric Syndromes in Patients with Chronic GlomerulonephritisSimeon Monov and Daniela Monova ..................................................................................... 5237394649

BJBANTAO JournalBANTAO Journal 2007: 5 (2):Outcome and Epidemiology of Hospital-Acquired Acute Renal Failure (ARF)–aMulticenter StudyOlga Balafa, Emilios Andrikos, Paraskevi Tseke, Afroditi Tsinta, Efthimios Pappas, ElissavetKokkolou, Georgios Sferopoulos and Michalis Pappas ......................................... 55Continuous Renal Replacement Therapy for Acute Renal Failure in Critically IllPatients and Early Predictive FactorsAlbana Gjyzari, L. Muzi and Santo Morabito..................................................................... 58Renal Artery Stenting in Atherosclerotic Stenosis: Long - Term Follow up of Results inBlood Pressure and Renal FunctionZiakka Stavroula, Dimitrios Poulikakos, Ioannis Karampinis, Evagelos Kapeleris and NicolasPapagalanis ................................................................................................................ 61Lupus Nephritis and Cardiovascular Disorders - Our Clinical ExpirienceMilorad Rabrenovic, Radomir Matunovic, Violeta Rabrenovic, Dragan Jovanovic and ZoranKovacevic..................................................................................................................... 65Paricalcitol in Dialysis Patients with Calcitriol-Resistant SecondaryHyperparathyroidismVasilis Filiopoulos, Ioannis Malegos, Eleni Stefanopoulou and Athina Patrikarea .............. 70Pulse Pressure is Independent Risk Factor of Left Ventricular Hypertrophy in ChronicKidney DiseaseMargarita Gjata, Mihal Tase, Myftar Barbullushi, Zheni Gjergji, Alketa Koroshi and EnverRoshi ............................................................................................................................ 74Prospective Analysis of Factors Influencing the Antibody Response to Hepatitis BVaccine in Hemodialysis PatientsAlexandra Ouzouni, Elena Papadopoulou, Fotini Miari, Theodoros Pliakogiannis, SofiaMademtzoglou, Kiriaki Traianou, Chrisovalantou Giannioti, Fani Papoulidou, MariaKalientzidou and Kalaitzidis Kleonikos ................................................................................. 77Extracorporeal Lithotripsy – Our Experiences Presented in a Retrospective 10-YearStudyD. Savic, Zoran Kovacevic, Dragan Jovanovic and Z. Cukic ................................................ 81Belgrade Hantavirus Infection is Associated With the most Severe Clinical Form ofHemorrhagic Fever with Renal SyndromeKatarina Obrencevic, Dragan Jovanovic, Zoran Kovacevic and Ljiljana Ignjatovic ............. 85Therapeutic Monitoring of Cyclosporine by Determination of C2 and AUC0-4 Levels inthe First Two Years after the Kidney TransplantationNeven Vavic, Ljiljana Ignjatovic, Biljana Draskovic, Rajko Hrvacevic, Zoran Kovacevic,Zoran Paunic and Dragan Jovanovic ...................................................................................... 90Complications in the Kidney Transplanted Patients Previously Treated by PeritonealDialysis - 10-Year Experience in a Single CenterVioleta Rabrenovic, Zoran Kovacevic, Dragan Jovanovic and Ignatovic Ljiljana................. 94III. Clinical ReportsCase reportA Rare Cause of Headache in a Patient with Poststreptococcal AcuteGlomerulonephritisErkan Dervisoglu, Gokhan Erbag, Murat Alemdar and Ahmet Yilmaz ................................. 97IV. VariaAnnouncements

BJBANTAO JournalBANTAO Journal 2007; 5 (2): 1Editorial reportThe Fifth-Year Anniversary of the Bantao JournalGoce Spasovski 1 , Momir Polenakovic 2 and Ali Basci 31 Department of Nephrology, Medical Faculty, University of Skopje, R.Macedonia, 2 Macedonian Academy of Sciences andArts, Skopje, R.Macedonia, 3 Ege University Medical School Nephrology Department, Bornova, Izmir, TurkeyThe BANTAO Journal is the official publication of theBalkan Cities Association of Nephrology, Dialysis,Transplantation and Artificial Organs (BANTAO).Published twice a year it is perceived as a connecting bondbetween the Balkan nephrologists and the members of theBANTAO Association, gathering messages from andbetween our congresses to be shared among us all in thefield of prevention and treatment of kidney diseases.The BANTAO Association was born 1993 in Ohrid but thefirst Congress was held in Varna (1995). The tradition hasbeen established with the following seven successfulcongresses in Struga (1997), Belgrade (1998), Izmir (1999),Thessaloniki (2001), Varna (2003), Ohrid (2005) andBelgrade (2007). Hence, the BANTAO Congress becamenot just a professional but also a cultural phenomenon,discovering that we have many more things in commonthan we previously thought, and that we have the advantageto live and communicate in a world without politicalboundaries.The first BANTAO Journal appeared in 2003 in Varna withProf. D. Nenov as Editor and Dr. V. Nenov as his assistant.Country MKD SRB GR TR BG AL RO BiH Otherspaper (n) 52 50 46 35 21 12 9 7 35At the General Assembly of our BANTAO Association inOhrid 2005, A. Basci (Izmir) was elected Editor in Chiefand G. Spasovski (Skopje) and A. Covic (Iasi) were electedas Deputy Editors. M. Polenakovic (Skopje), D. Nenov(Varna), Lj. Djukanovic (Belgrade) and Ch. Stathakis(Greece) were appointed as associated editors. At theGeneral Assembly in Belgrade 2007 V. Nenov was electedas Deputy Editor in charge for Medline application anddevelopment and maintenance of the web site of ourBANTAO association www.bantao.org. All publishedissues of BANTAO Journal could be found as a free onlinecontent at the same web site.At this small anniversary we are proud to announce 267papers already published in these ten issues of BANTAOJournal. In addition, the majority of publications belong tothe members of BANTAO Association and the individualcontribution per country is presented in the Table below.Based on a continuous improvement on the Journal contentand design and formally the five years of regular biannualissuing, we'll turn on with the application procedure forMedline citation and hopefully we would be successfulwithin the next year.Finally, celebrating the fifth-year anniversary in this issueof BANTAO Journal we do congratulate all the membersand readers and wish a good and successful collaborationon further progress of the Journal.We encourage you to submit your manuscripts to bepublished in the BANTAO Journal and to help its furtherstrengthening and growing in parallel with our BANTAOAssociation!December 2007_____________________Correspodence to: Goce Spasovski, Department of Nephrology, University of Skopje, R. Macedonia;Tel/Fax.: +3892 3231 501; Email: gspas@sonet.com.mk

BANTAO Journal 2007: 5 (2): 2BJBANTAO JournalEditorial commentsA Struggle For Kidney Transplantation in a Developing World?Goce Spasovski 1 , Charalambos Stathakis 2 and Ali Basci 31 Department of Nephrology, Medical Faculty, University of Skopje, R.Macedonia, 2 Transplant Center, Laiko Hospital, Athens,Greece, 3 Ege University Medical School Nephrology Department, Bornova, Izmir, TurkeyAccording to the recent data and scientific evidence there is evenmore kidney disease than had been previously thought. Anannual treatment of end stage renal disease (ESRD) in developedcountries worldwide is increasing for as many as 250.000new cases each year [1], reaching around 1.5 million patientsnowadays. The same trend of ESRD is observed in the developingworld but the vast majority of people could not have the benefitof dialysis and especially transplantation because of the economicand technological inequality between these two worlds.Organ transplantation became a reality in the 20th centuryfascinating the mankind from time immemorial. The advancesin immunology, tissue matching, immunosuppression andsurgical techniques coupled with an early detection and treatmentof rejection and the control of infection have led the organtransplantation as the ultimate therapy for all end stage organfailures with kidney transplantation being among the most successfulones. Although having all prerequisites for a bright futurein fact transplantation became a victim of its own success.Namely, the shortage of donor organs is increasing in parallelwith the increased number of indications for transplanttation.Because of the growing gap between organ supply and demand,many patients die waiting for an organ each year.The economic deprivation in developing countries and the verymodest expenditure on health care translates into poor transplantationactivity, with a rate of less than 10 per millionpopulation (pmp), far below number in contrast to the developedworld at around 50 pmp. Not only the economic constraint butalso a lack of public awareness, education and motivation fororgan donation as well as the low number of organized teams ofurologists, nephrologists and pathologists might have also beenconsidered as additional factors for an insufficient transplantprogram. Donor shortage is assumed as a universal problem thatis even more prominent in regions like the Balkans wherecadaver transplantation has not yet been developed and livingdonor transplantation remains the most frequent procedure. Theintroduction of expanded criteria for living donation includingelderly and marginal donors [2] as well as the ABO incompatibleliving donation [3] could just ameliorate the magnitude of theproblem. Hence, because of the limited chance of receiving akidney transplant for the aforementioned reasons, a lot of desperatedialysis patients procure an unrelated donor kidney transplant("renal commerce") against all medical advice. This type ofrenal paid transplantation formerly from India and nowadaysin Pakistan has been associated with several medical and socialproblems [4]. Many surgical complications and invasiveopportunistic infections increase the morbidity and mortality inthis group of transplant recipients [5, 6]. Expectedly, the oneyear patients and graft survival were found to be as much as85% and 70%, respectively [7]. In summary, the lack ofinformation from the transplanting center regarding both donor_____________________Correspodence to:and recipient and the associated, unacceptable risks on the graftand patient survival in unrelated, paid transplant recipientsreinforce the standpoint that this practice should be abandoned.On the other hand the ethical dilemmas of the paid kidney donorswho purchase the organ for price from $ 1000 - 3000 and the rateof ESRD patients thereafter remain to be elucidated [8]. Besidesthe reforms in the judicial system, the solution for less likely renalcommerce would be to alleviate poverty and to increase education thatis rather difficult measure for implementtation in these countries.The question how to improve the current status in terms ofincreasing number of living and especially cadaveric kidneytransplants in developing countries is rather intriguing. Anincreased attention to the problem throughout public sessions,governmental support in providing the necessary economic,organizational and infrastructural investments, as well asmotivated teams of committed workers might be a few keypoints to start with. As professionals we just have to reinforceour efforts according to the wisdom of Goethe: "Knowing is notenough, we must apply. Willing is not enough, we must do".Conflict of interest statement. None declared.References1. Dirks J: A world perspective on renal care: The challenges ofprevention and treatment. EDTNA ERCA J. 2005; 31: 72-74.2. Ivanovski N, Popov Z, Kolevski P, Cakalaroski K,Stojkovski L, Spasovski G, Zafirovska K. Livingrelated renal transplantation - the use of advanced agedonors. Clin Nephrol 2001; 55: 309-12.3. Spasovski GB: First two ABO-incompatible livingkidney transplantations in the Balkans-should it be aprocedure of choice in a developing country? Int J ArtifOrgans 2007; 30(2): 173-175.4. Canales MT, Kasiske BL, Rosenberg ME. Transplanttourism: outcomes of United States residents who undergokidney transplantation overseas. Transplantation 2006;82(12): 1658-61.5. Ivanovski N, Popov Z, Cakalaroski K, Masin J, SpasovskiG, Zafirovska K Living-unrelated (paid) renal transplantation- ten years later. Transplant Proc 2005; 37(2): 563–564.6. Spasovski G, Masin-Spasovska J, Stavridis S, Saiti S,Lekovski Lj. Pyelo-ureteral necrosis after renal transplantation.Int Urol Nephrol 2008 Jan 18; [Epub ahead of print]7. Popov Z, Dohcev S, Masin J, Spasovski G, Ivanovski O,Lekovski Lj, Ivanovski N. Pakistan – the new “hope” onthe horizon Transpl Int. 2007; 20(s2): 228.8. Rizvi SAH, Naqvi SAA, Hussain Z et al. Renaltransplantation in developing countries. Kidney Int2003; 63(83): S96-S100.Goce Spasovski, Department of Nephrology, University of Skopje, R. Macedonia;Tel/Fax.: +3892 3231 501; Email: gspas@sonet.com.mk

BJBANTAO JournalBANTAO Journal 2007; 5 (2): 3–4Editorial reviewPast, Present and Future of NephrologyDorhout Mees EJVorden The NetherlandsThe aim of science is not to open a gate to endlesswisdom, but to put a limit to endless error.[Berthold Brecht: Life of Galilei]The rapid proliferation of medical science since the lastworld war naturally resulted in its division into specialtiesand subspecialties. Nephrology was a rather late branch ofthis ‘tree of knowledge’. Pioneers like Jan Borst fromAmsterdam and Robert Platt from Manchester did notaccept the term nephrologist. The latter preferred to be a‘nephrophile’ (friend of the kidney). This was in the line ofStarling, who once characterised the kidney as ‘an organalmost endowed with intelligence’. What these and other‘founding fathers’ had in common was their fascination bythe kidneys regulatory functions. An important concept ofBorst was, that hypertension is the result of a derangedkidney function [1]. This concept was later extended by thebrilliant physiologist Arthur Guyton, who was for somereason never popular at nephrological meetings.With the first international congress of nephrology in Evian(1959), stimulated by Jean Hamburger of Paris, nephrology hadcome of age, and today there are dozens of nephrological journalsall over the world, one being the present BANTAO journal.The Evian congress also witnessed the presentation of twopatients with terminal renal insufficiency who had been kept ingood health by intermittent haemodialysis treatment. Inretrospect it seems odd, that this revolutionary concept ofBelding Scribner, that would soon save thousands of lives, wasnot greeted with enthusiasm by the nephrologists. They fearedthat the psychological burden would be too heavy, butparticularly that the financial burden would be prohibitive.However it appeared that high costs are an incentive fordevelopment. Without interest of the industry, dialysistreatment would not have boomed as it did. But at the sametime, intense commercial interest heralded a new era, whereprofit seems to be the aim of all human effort, includingmedicine. One of the consequences is that cheap treatmentsand simple, logical principles are being neglected.With some exaggeration it might be said that the advent ofchronic dialysis also marked a downward trend of nephrologicalscience. Eating from the tree of knowledge can be hazardous.In this case, the serpent was the commerce, the apple easy gains.It is beyond the scope of this editorial to analyze the complicatedinteractions of commercialisation, mass psychology, fashionand indolence. Thus I only will mention here some strikingexamples of ‘scientific’ aberrations that are verging on sheermadness.When the euphoria after the first years of dialysis treatmentwas over, it became evident that the results of this lifesavingmethod lagged far behind expectation. In the US, aNational Cooperative Dialysis Study introduced concept ofthe 'Urea kinetic modeling'. Gotch and Sargent [2] subsequentlyproposed the famous KT/V formula, in which the'dialysance' of the apparatus during the week is related to the'urea distribution volume', a scholarly sounding term, whichfor convenience is usually replaced by body mass.It is amazing how this simplistic concept conquered the dialysisworld as if it was a new evangelic. In this 'mechanistic analysis',the KT/V was promoted to 'a rigorous statistical tool, furtherdetracting the physician's attention from sound judgement'[3]. It is based on two basically wrong ideas: The first is thaturea is an adequate substitute for uremic toxicity, while it is onlya marker. But the second even worse error is the implicit assumptionthat the only task of the kidney is to remove toxic products.However, control of the body fluid volumes is not only anessential task of the kidney, it is also evidently related tocirculation and blood pressure and thus to cardiac morbidity[4]. While good volume control is not easy to assess, bloodpressure is routinely measured in all dialysis centers. Yet, forreasons I can only guess, no opinion leader has incorporatedblood pressure into the ‘adequacy’ concept. A curiousidiomatic usage: 'dialysis dose', has become accepted, as ifdialysis treatment is a drug, of which one only needs to knowhow much has to be 'administered'.Admittedly, the promotion of KT/V has put an end to thedetrimental tendency towards ever shorter dialysis sessions.But increasing KT/V beyond a certain value does not improvethe outcome. The reason is that without restriction of saltconsumption, dialysis patients will remain ‘volume expanded’.If a patient gains 3 to 5 Kg body weight between 2 sessions,this means an excess of 3 to 5 liters extracellular fluid and aproportionate excess of blood volume. It is not amazing thatit is virtually impossible to remove this amount within theshort dialysis period. But even if this were achieved, themean volume during the week would remain above normal.As a result, blood pressure will be elevated and as long asthe cause (overhydration) is not corrected, antihypertensivedrugs will often be ineffective. However some authors whoare not aware of these logical principles have used thenumber of (ineffective) drugs consumed as a measure of the‘severity’ of the hypertension, thus blaming the patient fortheir own ineffectiveness.All this means that a doctor treating dialysis patients shouldnot be a nephrologist, but a ‘metanephrologist’, that is_____________________Correspodence to:Dorhout Mees EJ, Vorden The Netherlands; Email: m.dorhoutmees@tref.nl

4 BANTAO Journal 2007: 5 (2)someone with knowledge of salt and water homeostasis andits relation to the heart.The fact that many doctors in charge of dialysis units arenot aware of these well known physiologic principles hasled to strange aberrations. A group of Dutch nephrologistshas started investigation how to contain the excessive thirstof dialysis patients. Disregarding the evident reason, saltconsumption, they try to decrease drinking by salivasupplements and chewing gum (!)The consequences of all this are serious. Dialysis units arethreatened to become rinsing factories. The fact that in theUSA spontaneous discontinuation of dialysis (hiddensuicide) is among the main causes of death should alarm us.Of course the human factor is also being neglected. Dialysistreatment is no longer a continuing engagement betweendoctor and patient 'for better and worse'. Time to communicatewith the patient is an increasingly scarce commodity.What will be the future? A change in intellectual, social andmoral attitude is not easy to achieve. Predicting the future isnotoriously hazardous. But shaping the future lies in ourown hands. Gabriel Richet once wrote: ‘Moving away fromphysiology sooner or later results in intellectual suicide’.There is too much intellect and common sense in thenephrological community for this to happen.Therefore I am optimistic. It only can become better!Conflict of interest statement.conflict of interest.ReferencesThe author declares no1. Borst JG, Borst-de Geus A. Hypertension explained byStarlings theory of circulatory homeostasis. The Lancet1963; 1: 677.2. Gotch FA, Sargent JA. Mechanistic analysis of NCDS.Kidney Int 1985; 28: 526-534.3. Shaldon S, Koch KM. Are standards and checklistsneeded in uremia therapy? Kidney Int 1985; 28(supl.17): 124-126.4. Dorhout Mees EJ. Cardiovascular aspects of dialysistreatment. Kluwer Medical Publ. 2000.

BJBANTAO JournalBANTAO Journal 2007; 5 (2); 5–9ReviewTherapy of Idiopathic Membranous NephropathyClaudio PonticelliIstituto Auxologico Italiano, Milano, ItalyAbstractWhether and how treating idiopathic membranous nephropathy(IMN) is still a matter of debate. While there is generalagreement that nonnephrotic patients should be givensymptomatic treatment alone, the results of specific therapyaddressed to interfere with direct or indirect causes of renaldamage are controversial. There is no evidence in favour oftherapies based on corticosteroids alone. A few old randomizedcontrolled trials (RCT) reported that alkylating agents,cyclophosphamide and chlorambucil, may increase theprobability of remission, but the prolonged use of these agentsmay cause disquieting adverse effects. RCT showed that atreatment based on alternating corticosteroids and a cytotoxicagent every other month for 6 months may favour remission ofthe nephrotic syndrome (NS) and may protect renal function inthe long-term. More recently, good results have also beenreported with synthetic adrenocorticotropic hormone (ACTH),cyclosporine, tacrolimus, mycophenolate mofetil (MMF), andrituximab. Unfortunately, however, most of the therapeuticalattempts with these drugs have not been tested in controlled,randomized trials and the follow-up in these studies wasgenerally short-time. Attempts of modifying the natural courseof IMN have also been tried in patients with an established renalinsufficiency. A number of patients showed improvement ofproteinuria and renal function after treatments based oncorticosteroids and cytotoxic drugs. However, in mostresponders the values of creatinine clearance did not return tonormal and little information is available about the long-termfollow-up of these patients.Keywords: membranous nephropathy, glomerulonephritis,immunosuppressive therapy, nephrotic syndrome, corticosteroids,cytotoxic drugsIntroductionMembranous nephropathy is a renal disease histologicallycharacterized by the uniform thickening of the glomerularcapillary wall. This is caused by subepithelial deposits ofimmune complexes which appear as granular deposits of IgGwith immunofluorescence and as electron-dense deposits onelectron microscopy. IMN is typically a disease of adults witha peak incidence at between 30 and 50 years of age, althoughthe clinical impression is that the number of elderly patientswith IMN is progressively increasing. The disease may have avariable natural course. A number of untreated patients mayexperience a partial (proteinuria between 0.21 and 2 g per daywith normal renal function) or even complete (proteinuria

6 BANTAO Journal 2007; 5 (2)anticoagulation are superior to the risks [11,12], it seemsthat prophylactic anticoagulation may be advisable incertain circumstances .The decision needs to take intoaccount the nature of the underlying disease, the severity ofthe nephrotic syndrome (as assessed by serum albuminconcentration), preexisting thrombophilic states, and theoverall likelihood of serious bleeding events consequent tooral anticoagulation. The optimal duration of prophylacticanticoagulation is unknown but very likely extends to theduration of the nephrotic state per se [13].Specific therapyThe first therapeutical attempts in IMN were made withcorticosteroids. Retrospective noncontrolled studies providedconflicting conclusions. Three randomized controlledtrials also gave controversial results. An American collaborativestudy [14] randomly assigned 72 patients with IMNand NS to be given alternate-day prednisone (125 mg/48 h for2 months, with an additional 2-month taper) or symptomatictherapy. During the study there were significantly moreremissions in the treated arm but after a mean follow-up of23 months, there was no significant difference between thetwo arms. The mean creatinine clearance declined moresteeply in the control group. This study has been criticizedbecause the patients assigned to the control group had a worseoutcome than usually seen, with 26% of them enteringsevere renal failure or dying within 23 months. The sameprotocol was evaluated in a double-blind RCT organized inthe United Kingdom [15]. All of the 107 patients enrolledwere followed for at least 3 years. No difference was seenbetween the two arms in the mean levels of proteinuria orserum creatinine. In a Canadian study, 158 patients with orwithout NS were assigned to receive symptomatic therapy ofprednisone at a dosage of 45 mg/m2 every other day for 6months [16]. Again there was no difference in meanproteinuria or creatinine clearance between the two groups.Thus, the current evidence speaks against a benefit ofcorticosteroids over symptomatic therapy, at least at the dosesand for the time of administration used in the available RCT.Some small-sized RCTs have prospectively evaluated therole of immunosuppressive agents. Donadio et al. assigned22 patients with MN to receive cyclophosphamide orsupportive therapy for 1 year [17]. There was a trendtoward a greater reduction of proteinuria in treated patients,but the difference was not significant. Cleary the statisticalpower of the study was very weak and the follow-up wasshort. Lagrue et al. randomized 41 patients to receivechlorambucil, or azathioprine or symptomatic therapy for 1year [18]. After two years of follow-up, of 16 patients whoreceived chlorambucil, 9 entered complete remission and 4partial remissions versus 1 patient with partial remission inthe azathioprine-treated group, and 2 with completeremissions plus 1 with partial remission in the placebogroup. However, a few patients given long-term chlorambucilexperienced severe adverse effects includingmalignancy. Murphy et al. [19] randomized 40 patientswith moderate proteinuria either to symptomatic therapyalone or to cyclophosphamide for 6 months plus warfarinand dipyridamole for two years. In spite of the weakstatistical power of the study treated patients showed asignificantly greater reduction of proteinuria and a largernumber of complete or partial remissions when comparedto controls.A different approach consisted in alternating corticosteroidsand cytotoxic drugs. A multicenter Italian RCT assignedpatients with MN and NS to symptomatic therapy or to a 6-month therapy with 3 months of corticosteroids and 3months of chlorambucil [1]. Patients assigned to treatmentwere given an intravenous pulse of methylprednisolone(MPP), 1 g each, for 3 consecutive days, followed by oralprednisone 0.5 mg/kg per day for 27 days, then steroid wasstopped and oral chlorambucil was administered at a doseof 0.2 mg/kg per day for 1 month. At the end of the monthanother cycle of steroids was given, followed by one monthwith chlorambucil, and again by a third cycle with steroidsfollowed by a month with chlorambucil. Therefore thewhole treatment lasted 6 months, 3 with corticosteroids and 3with chlorambucil. The doses of chlorambucil had to behalved if the number of leukoctes was falling below5,000/cmm and chlorambucil had to be stopped if leukocytesfell below 3,000/cmm. Patients were followed for 10 years.At the last follow-up, 92% of treated patients versus 60% ofuntreated patients were alive with kidney function, 61% oftreated patients were without NS (40% being in completeremission) versus 33% of untreated controls (5% in completeremission). The same protocol was compared with a regimenbased on corticosteroids alone (3 intravenous pulses ofmethylprednisolone at months 1, 3 and 5, plus oral prednisone0.5 mg/kg on alternate days for 6 months). The probability ofreaching complete or partial remission was significantlyhigher at 1, 2 and 3 years for patients given the combinedtreatment. At 4 years, 62% of patients given the combinedtreatment and 42% of patients given steroid alone werewithout NS, but due to the smaller number of patients atrisk the difference was not significant [20]. In a third RCT,patients with MN and NS were allocated tomethylprednisolone and chlorambucil, or to the same schedulebut with cyclophosphamide 2.5 mg/kg per day, instead ofchlorambucil. No significant differences were found in theprobability of remission of NS or in the slope of thereciprocal of serum creatinine. However, side effects tendedto be more frequent in the chlorambucil arm [21]. Takingtogether the results of these 3 RCT conducted on apopulation of Italian patients with biopsy-proven MN andNS, selected with the same inclusion and exclusion criteria,out of 174 patients treated with steroids alternated with acytotoxic agent 83% reached a complete or partialremission as a first event and 75% were still in complete orpartial remission after a mean follow-up of 54 months. Theactuarial probability of renal survival at 10 years was 93%,and graft survival censored by death was 98%. However,about 9% of patients had to interrupt treatment because ofadverse effects [22]. Recently a RCT compared the effectof a 6-month course of alternating prednisolone andcyclophosphamide with supportive treatment in adults withnephrotic syndrome caused by IMN. Patients were followedup for 10 years. Of the 47 patients who received theexperimental protocol, 34 (72%) achieved remissioncompared with 16 of 46 (35%) in the control group. The10-year dialysis-free survival was 89 % in the experimentalgroup and 65% in the control group, the likelihood ofsurvival without death, dialysis, and doubling of serumcreatinine were 79% and 44% respectively, all thesedifferences being statistically significant. The incidence of

BANTAO Journal 2007; 5 (2) 7infections was similar in the two groups [23]. A mainconcern with the use of cytotoxic agents is the possibledevelopment of malignancy. The problem is madecomplicated by the fact that patients with IMN have anincreased risk of developing cancer. About 10% of patientswith MN have malignancy at the time of renal biopsy orwithin a year thereafter with a standardized incidence ratio9.8 in men 12.3 in women compared to general population[24]. Moreover, in a Norwegian study the annual incidence ofcancer in patients with a MN was 24/1000/pts/yearsignificantly higher than that observed in the generalpopulation [25]. In our own cumulative experience theincidence of malignancy was 4.5/1000 pts/year similar to thatexpected in a general Caucasian population [21]. In patientsolder than 65 years, noncontrolled studies reported that a 6-month treatment with corticosteroids alternated with acytotoxic agent obtained a rate of response similar to thatobserved in younger adults [26, 27]. However, adverse effectswere more frequent and severe in elderly patients. Therefore,in older patients it is recommended to halve the doses of MPPand of the cytotoxic agent in order to reduce morbidity.A pilot study reported that synthetic adrenocorticotropichormone (ACTH) given for 1 year resulted in completeremission of proteinuria in 7 of 8 patients with MN [28].On the basis of these promising results, we organized asmall RCT comparing the 6-month regimen based onsteroids and a cytotoxic agent alternated every other monthversus parenteral treatment with synthetic ACTH given ata dosage of 1 mg twice a week for 1 year [29]. In the firstgroup, 15 of 16 patients entered complete or partialremission versus 14 of 16 in the second group. Medianproteinuria decreased from 5.1 g/day to 2.1 g/day in thefirst group and from 6.0 g/day to 0.3 g/day in the secondgroup. Although no adverse effects were seen in this trial,caution with such a therapy should be used in elderlypatients and in those previously treated with corticosteroids.A number of noncontrolled studies have reported a goodantiproteinuric effect of cyclosporine. Taken together, theavailable data show that cyclosporine may be effective infavoring the remission of NS in 50%-60% of patients [30].The addition of small doses of prednisone may favourremission. Remission often occurs within 3-4 months, butin a German study, the median time for response was 7months [31]. Cattran et al. [32] conducted a RCT in 51patients with IMN and NS who were randomized to receive6 months of cyclosporine treatment plus low-dose prednisoneor to placebo plus prednisone. All patients werefollowed for one year after the 6 months. Seventy-fivepercent of the treatment group versus 22% of the controlgroup had a partial or complete remission of proteinuria by6 months. Relapses occurred in 43% of the cyclosporineremission group and 40% of the placebo group by one yearafter treatment interruption. Renal insufficiency, defined asdoubling of baseline creatinine, was seen in 2 patients ineach group. Alexopoulos et al. [33] evaluated the efficacyof a 12-month treatment with low-dose cyclosporine aloneor combined with corticosteroids. Patients who respondedwith complete or partial remission were placed on longtermtreatment with lower doses of cyclosporine andprednisolone or cyclosporine alone. After 12 months oftreatment, 26 out of 31 patients in the combination groupand 17 of 20 patients in the monotherapy group hadcomplete or partial remission. Renal function wasunchanged in the two groups. During long-term treatment,relapses were more frequent in the monotherapy group andwere usually associated with blood levels of cyclosporine

8 BANTAO Journal 2007; 5 (2)months, patients with persisting proteinuria >3 g/dayreceived a second course of rituximab. Mean proteinuriadecreased from 13.0 to 5.5 g/day at 12 months. Completeremission was observed in only 3 patients, 5 patients didnot respond at all. Two patients with declining renalfunction entered end-stage renal failre within one year, onepatient died from lung cancer [40].The above-quoted trials have been performed in patientswith normal or subnormal renal function. In patients withdeteriorating renal function a number of investigatorsreported satisfying results also. The best results have beenobtained with a 6-month treatment based on corticosteroidsalternated with chlorambucil [41-44] or with 1-yeartreatment based on the association of cyclophosphamidewith corticosteroids [2,38, 45,46]. A complete or partialremission of NS could be seen in more than 60% of patientsand a similar percentage of patients showed an improvementof renal function. On the basis of these good results, anumber of nephrologists prefer to start an immunosuppressivetreatment only when there is a deterioration ofrenal function, in order to spare the potential toxicity ofimmunosuppression to patients with stable renal function.However, it should be pointed out that in most cases serumcreatinine did not return to normal values in the availablestudies. Moreover limitations of the studies in patients withrenal insufficiency are the lack of RCT, the short-termfollow-ups, and the insufficient information on renalhistology. Of concern, many patients experienced severeside effects, mainly bone marrow toxicity and infection. Toreduce the risk of iatrogenic toxicity we recommended thatthe doses of MPP and cytotoxic agents should be halved inpatients with renal insufficiency [47]. Actually, such anadjustement of therapy proved to minimize the incidenceand severity of side effects while keeping efficacy in astudy [42]. Although a small RCT showed that cyclosporinecould improve proteinuria and slow the decline of creatinineclearance in MN patients with renal insufficiency [48] the useof cyclosporine in patients with renal insufficiency should becautious, being a damaged kidney more vulnerable to thenephrotoxic effects of cyclosporine [49].Conflict of interest statement. Consultant Novartis PharmaItaly.References1. Ponticelli C, Zucchelli P, Passerini P, Cesana B, LocatelliF, Pasquali S, Sasdelli M, Redaelli B, Grassi C, Pozzi C,Bizzarri D, Banfi G. A 10-year follow-up of a randomizedstudy with methylprednisolone and chlorambucil inmembranous nephropathy. Kidney Int. 1995; 48: 1600-4.2. Du Buf-Vereijken PW, Branten AJ, Wetzels JF. Idiopathicmembranous nephropathy: outline and rationale of atreatment strategy. Am J Kidney Dis. 2005; 46: 1012-29.3. Burnstein DM, Korbet SM, Schwartz MM. Membranousglomerulonephritis and malignancy. Am J KidneyDis. 1993; 1: 5-10.4. Ordonez JD, Hiatt RA, Killebrew EJ, Fireman BH. Theincreased risk of coronary heart disease associated withnephrotic syndrome. Kidney Int. 1993; 44: 638-42.5. Bellomo R, Atkins RC. Membranous nephropathy andthromboembolism: is prophylactic anticoagulationwarranted? Nephron. 1989; 63: 249-54.6. O’Callaghan CA, Hicks J, Doll H, Sacks SH, CameronJS. Characteristics and outcome of membranousnephropathy in older patients. Int Urol Nephrol. 2002;33: 157-65.7. Ponticelli C Membranous nephropathy. J Nephrol.2007; 20:268-87.8. Noel LH, Zanetti M, Droz D, Barbanel C. Long-termprognosis of idiopathic membranous glomerulonephritis:study of 116 untreated patients. Am J Med. 1978; 66: 82-90.9. Kida H, Asamoto T, Yokoyama H, Tomosugi N,Hattori N. Long-term prognosis of membranousnephropathy. Clin Nephrol. 1986; 25: 64-9.10. Davison AM, Cameron JS, Kerr DN, Ogg CS,Wilkinson RW. The natural history of renal function inuntreated idiopathic membranous glomerulonephritisin adults. Clin Nephrol. 1984; 2: 61-711. Bellomo R, Atkins RC. Membranous nephropathy andthromboembolism: is prophylactic anticoagulationwarranted? Nephron. 1989; 63: 249-54.12. Sarasin F, Schifferli J. Prophylactic anticoagulation innephrotic patients with idiopathic membranousnephropathy. Kidney Int. 1994; 45: 578-85.13. Glassock RJ. Prophylactic anticoagulation in nephroticsyndrome: a clinical conundrum. J Am Soc Nephrol.2007; 18: 2221-5.14. Collaborative study of the adult idiopathic nephriticsyndrome: a controlled study of short-term prednisonetreatment in adults with membranous nephropathy. NEngl J Med. 1979; 301: 1301-6.15. Cameron JS, Healy MJ, Adu D. The Medical ResearchCouncil Trial of short-term high-dose alternate dayprednisone in idiopathic membranous nephropathywith nephritic syndrome in adults. Q J Med. 1990;274: 133-56.16. Cattran DC, Delmore T, Roscoe J, Cole E, Cardella C,Charron R, Ritchie S. A randomized controlled trial ofprednisone n patients with idiopathic membranousnephropathy. N Engl J Med. 1989; 320: 210-5.17. Donadio JV Jr, Torres VE, Velosa JA, Wagoner RD,Holley KE, Okamura M, Ilstrup DM, Chu CP.Idiopathic membranous nephropathy: the naturalhistory of untreated patients. Kidney Int. 1988; 33:708-15.18. Lagrue G, Bernard D. Bariéty J, Druet P, Guenel J.Traitement par le chlorambucil et l’azathioprine dansles glomerulonephrites primitives: resultats d’uneetude controlée. J Urol Nephrol. 1975; 81: 655-72.19. Murphy BF, McDonald I, Fairley KF, Kincaid-SmithP. Randomized controlled trial of cyclophosphamide,warfarin and dipyridamole in idiopathic membranousglomerulonephritis. Clin Nephrol. 1992; 37: 229-34.20. Ponticelli C, Zucchelli P, Passerini P, Cagnoli L,Cesana B, Pozzi C, Pasquali S, Imbasciati E, Grassi C,Redaelli B, Sasdelli M. A randomized trial of methylprednisoloneand chlorambucil in idiopathic membranousnephropathy. N Engl J Med. 1989; 320: 8-13.21. Ponticelli C, Altieri P, Scolari F, Passerini P,Roccatello D, Cesana B, Melis P, Valzorio B, SasdelliM, Pasquali S, Pozzi C, Piccoli G, Lupo A, Segagni S,Antonucci F, Dugo M, Minari M, Scalia A, Pedrini L,Pisano G, Grassi C, Farina M, Bellazzi R. Arandomized study comparing methylprednisolone plus

BANTAO Journal 2007; 5 (2) 9chlorambucil versus methylprednisolone plus cyclophosphamidein idiopathic membranous nephropathy. J AmSoc Nephrol. 1998; 9: 444-50.22. Passerini P, Ponticelli C. Corticosteroids, cyclophosphamide,and chlorambucil therapy of membranousnephropathy. Semin Nephrol. 2003; 23: 355-61.23. Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, GuptaKL, Joshi K, Sakhuja V. A randomized, controlledtrial of steroids and cyclophosphamide in adults withnephrotic syndrome caused by idiopathic membranousnephropathy. Am Soc Nephrol. 2007; 18: 1899-904.24. Lefaucheur C, Stengel B, Nochy D, Martel P, Hill GS,Jacquot C, Rossert J. Membranous nephropathy andcancer: epidemiologic evidence and determinants ofhigh-risk cancer association. Kidney Int. 2006; 70:1510-7.25. Bjorneklett R, Vikse BE, Svarstad E, Aasarod K,Bostad L, Langmark F, Iversen BM. Long-term risk ofcancer in membranous nephropathy patients. Am JKidney Dis. 2007; 50: 396-403.26. Passerini P, Como G, Vigano E, Melis P, Pozzi C, AltieriP, Ponticelli C. Idiopathic membranous nephropathy inthe elderly. Nephrol Dial Transplant. 1993; 8: 1321-5.27. Rollino C, Basolo B, Roccatello D, Vallero A, Funaro L,Piccoli G. Outcome of membranous glomerulonephritisin the elderly. Contrib Nephrol. 1993; 105: 71-4.28. Berg AL, Arnadottir M. ACTH-induced improvementin the nephrotic syndrome in patients with a variety ofdiagnoses. Nephrol Dial Transplant. 2004; 19: 1305-7.29. Ponticelli C, Passerini P, Salvadori M, Manno C,Viola BF, Pasquali S, Mandolfo S, Messa P. Arandomized pilot trial comparing methylprednisoloneplus a cytotoxic agent versus synthetic adrenocorticotropichormone in idiopathic membranousnephropathy. Am J Kidney Dis. 2006; 47: 233-40.30. Ponticelli C, Villa M. Does cyclosporine have a role inthe treatment of membranous nephropathy? NephrolDial Transplant. 1999; 14: 23-5.31. Fritsche L, Budde K, Farber L, Charisse G, Kunz R,Gaedeke J, Neumayer HH. Treatment of membranousglomerulopathy with cyclosporin A: how muchpatience is required? Nephrol Dial Transplant. 1999;14: 1036-8.32. Cattran DC, Appel GB, Hebert LA, Hunsicker LG,Pohl MA, Hoy WE, Maxwell DR, Kunis CL; NorthAmerica Nephrotic Syndrome Study Group. Cyclosporinein patients with steroid-resistant membranousnephropathy: a randomized trial. Kidney Int. 2001; 59:1484-90.33. Alexopoulos E, Papagianni A, Tsamelashvili M,Leontsini M, Memmos D. Induction and long-termtreatment with cyclosporine in membranous nephropathywith the nephritic syndrome. Nephrol DialTransplant. 2006; 21: 3127-32.34. Goumenos DS, Kalliakmani P, Tsakas S, Sotsiou F,Vlachojannis JG. The remission of nephrotic syndromewith cyclosporin treatment does not attenuate theprogression of idiopathic membranous nephropathy.Clin Nephrol. 2004; 61: 17-24.35. Ambavalanan S, Fauvel JP, Sibley RK, Myers BD.Mechanism of the antiproteinuric effect of cyclosporinein membranous nephropathy. J Am SocNephrol. 1996; 7: 290-8.36. Miller G, Zimmerman R 3rd, Radhakrishnan J, Appel G.Use of mycophenolate mofetil in resistant membranousnephropathy. Am J Kidney Dis. 2000; 36: 250-6.37. Choi J, Eustace JA, Gimenez LF, Atta MG, Scheel PJ,Sothinathan R, Briggs WA. Mycophenolate mofetiltreatment for primary glomerular diseases. Kidney Int.2002; 61: 1098-114.38. Branten AJ, du Buf-Vereijken PW, Vervloet M,Wetzels JF. Mycohenolate mofetil in idiopathic membranousnephropathy: a clinical trial with comparisonto a historic control group treated with cyclophosphamide.Am J Kidney Dis. 2007; 50: 248-56.39. Ruggenenti P, Chiurchiu C, Abbate M, Perna A,Travedi P, Bontempelli M, Remuzzi G. Rituximab foridiopathic membranous nephropathy: who can benefit?Clin J Am Soc Nephrol. 2006; 1: 738-48.40. Fervenza FC, Herzenberg AM, Erickson SB, Dillon JJ,Cosio F, Leung N, Cohen IM, Wochos DN,Haudelevich M, Berstralh E, Cattran DC. Variation inresponse to rituximab in the treatment of idiopathicmembranous nephropathy [IMN]: preliminary resultsat 1 year. J Am Soc Nephrol. 2006; 17: 570A.41. Mathieson PW, Turner AN, Maidment CG, Evans DJ,Rees AJ. Prednisolone and chlorambucil treatment inidiopathic membranous nephropathy with deterioratingrenal function. Lancet. 1988; 2: 869-72.42. Brunkhorst R, Wrenger E, Koch KM. Low-doseprednisolone/ chlorambucil therapy in patients withsevere membranous glomerulonephritis. Clin Invest.1994; 72: 277-80.43. Reichert CJ, Koene KA, Wetzels JF, Huysmans FT,Assman K. Preserving renal function in patientswith membranous nephropathy: daily oral chlorambucilcompared with intermittent monthly pulses ofcyclophosphamide. Ann Intern Med. 1994; 121:328-33.44. Torres A, Dominguez-Gil B, Carreno A, HernandezE, Morales E, Segura J, Gonzalez E, Praga M.Conservative versus immunosuppressive treatmentof patients with idiopathic membranous nephropathy.Kidney Int. 2002; 61: 219-27.45. Bruns FJ, Adler S, Fraley DS, Segel DP. Sustainedremission of membranous glomerulonephritis aftercyclophosphamide and prednisone. Ann Intern Med.1991; 114: 725-30.46. Jindal K, West M, Bear R, Goldstein M. Long-termbenefits of therapy with cyclophosphamide and prednisonein patients with membranous glomerulonephritisand impaired renal function. Am J KidneyDis. 1992; 14: 61-7.47. Ponticelli C. Prognosis and treatment of membranousnephropathy. Kidney Int. 1986; 29: 927-40.48. Cattran DC, Greenwood C, Ritchie S, Bernstein K,Churchill DN, Clark WF, Morrin PA, Lavoie S. Acontrolled trial of cyclosporine in patients with progressivemembranous nephropathy. Canadian GlomerulonephritisStudy Group. Kidney Int. 1995; 47: 1130-5.49. Feutren G, Mihatsch MJ. Risk factors for cyclosporineinducednephropathy in patients withautoimmune diseases. International Kidney BiopsyRegistry of Cyclosporine in Autoimmune Diseases. NEngl J Med. 1992; 326: 1654-60.9

BANTAO Journal 2007; 5 (2) : 10–13BJBANTAO JournalReviewInvestigating Microscopic Haematuria – the Role of Renal BiopsyJohn FeehallyThe John Walls Renal Unit, Leicester General Hospital, Leicester, UKIntroductionThe investigation and management of isolated microscopichaematuria (mH) present a practical challenge tonephrologists. The correct approach to investigation ofpatients presenting in this way, the role of renal biopsy, andthe need for urological evaluation, continue to be debated.There is wide variation in clinical practice.cells may also be helpful in the evaluation of red cellmorphology (see below). The search for other diagnosticparticles, for example urinary casts, is in practice rarelyhelpful in the absence of proteinuria or other symptoms orsigns of kidney disease. Casts are a very uncommon findingin isolated mH.Prevalence of microscopic haematuriaDetection and definition of microscopic haematuriaFor the purpose of this article I will define isolated mH asan abnormal number of erythrocytes in the urine in theabsence of detectable proteinuria with normal GFR andnormal blood pressure.There is no agreement on a working definition of mH.Values of 1-5 red blood cells per high power field on urinemicroscopy, and 1,000-14,000 red blood cells per ml ofurine by cell counting have all been used in the literature. Inclinical practice of course microscopic haematuria is nearlyalways identified by dipstick testing of the urine rather thanurine microscopy. Dipsticks do not detect haematuria butthe presence of haemoglobin in the urine. Dipstick testing isreported to have a sensitivity of 96-100% and a specificity of 65-99% for haematuria. Identification that a patient has significantmH requires that the stick test should be positive (“trace” can beignored because of the great sensitivity of the stick test). Theurine test should be non-menstrual in a female and should becollected at least 24 hours after strenuous exercise or sexualintercourse.A negative stick test with positive urine microscopy occursoccasionally in people taking a large dose of ascorbic acid.There has been uncertainty whether mH detected bydipstick testing should always be confirmed by urinemicroscopy. A positive urine stick test with negative urinemicroscopy can occur with haemoglobinuria andmyoglobinuria, but much more commonly it occurs becauseof red cell lysis when the urine is hypotonic or of relativelyhigh pH, and especially if the urine remains standing beforemicroscopy is undertaken. Urine microscopy is therefore onlyuseful in the investigation of stick-positive mH if the urine isexamined very soon after voiding by an experienced operator.Urine microscopy performed by laboratory technicians afterurine has taken some time to be transported to the laboratory isof little value. This probably explains why at least one studydemonstrated that the likelihood of identifying significantglomerular disease in patients with mH was no higher inthose with positive urine microscopy than those with apositive dipstick alone [1]. Urine microscopy as well asidentifying red______________________Correspodence to:Prevalence of mH increases significantly with age in both menand women, and is more common in women in all age groups.Variations of reported prevalence differ greatly according to ageof study population and definition of haematuria. Theprevalence of a single positive test in the general populationvaries from 2- 20% and of persistent positive tests from 1-13%.Causes of microscopic haematuriaAs well as parenchymal renal disease, other causes ofhaematuria must always be considered in the differentialdiagnosis including infection, renal tract stones, trauma,tumours, and coagulation disorders. In patients with isolatedmH, a major concern is the identification of cancers in the renaland urinary tract. There are data suggesting that over the age of40 years up to 8% of men and 5% of women with isolatedmicroscopic haematuria will have cancer; on the other handbelow the age of 40 the cancer is found in

BANTAO Journal 2007; 5 (2) 11Microscopic haematuria caused by parenchymal renal diseaseCauses of mH identified by abnormal renal imaging includea number of cystic renal diseases, papillary necrosis, medullarysponge kidney, and tuberculosis. When mH occurswith normal renal imaging, it may be occasionally be due tointerstitial nephritis but in practice the most common differentiallies between glomerulonephritis, most commonly IgAnephropathy, and various hereditary nephropathies affectingthe basement membranes including Alport syndrome and thinbasement membrane nephropathy (TBMN).In children with isolated mH, TBMN is the commonestcause of mH reported in 20-50% of cases followed byAlport syndrome (8-40%) and IgAN (8-35%). In adultsIgAN is commonest (12-28%) followed by TBMN (6-42%). 17-62% of adults with isolated mH are reported tohave a normal renal biopsy, but in some series this includedpatients in whom electron microscopy was unavailable, andtherefore evaluation was incomplete. Older people with mHare still likely to have glomerular disease and in one studyup to 10% of patients over the age of 50 years were foundto have parenchymal renal disease on renal biopsy performedwhen urological evaluation did not identify a causefor mH [1]. Although renal disease may be identified, anychance of progressive kidney disease in a relevant timeframe is much smaller in this age group. The distinctionbetween Alport syndrome and TBMN is often straightforwardespecially in Alport patients when the characteristicdeafness is prominent and if the family history isclearly X-linked. It should not be forgotten that Alportsyndrome may occasionally be autosomal recessive andrarely autosomal dominant. TBMN on the other hand istypically autosomal dominant. Emerging data are finding arange of genetic defects in type IV collagen chains in bothAlport syndrome and TBMN with some evidence that theremay be overlap [5]. It is likely that genetic analysis will indue course refine further our understanding of thepathogenesis of these conditions, and eventually provideuseful clinical testing. In practice glomerular morphologyon light microscopy may be entirely normal in the earlystages of both Alport syndrome and TBMN and electronmicroscopy is mandatory for accurate differential diagnosis.Even with EM however, changes in young people with Alportsyndrome (and in female carriers) may not be diagnostic,showing little more than variable GBM thickness, and noneof the architectural disruption with basket-weave patterningseen in more advanced Alport syndrome. Immunostainingfor the alpha chains of type IV collagen can also beinformative [6] but unfortunately specific antibodies forsuch staining are only infrequently available in routinepathology laboratories. In most cases, there is still noworthwhile substitute for electron microscopy in a completeevaluation of a renal biopsy from a patient with mH.Other causes that should always be considered in “unexplained”mH include hypercalciuria which may cause mHin the absence of overt stone disease especially in children[3], and in children and young adults the ”nutcrackersyndrome” in which haematuria occurs only with uprightposture because the left renal vein is compressed betweenthe aorta and the superior mesenteric artery; this is a benigncondition [4]. It is also important to remember that in asignificant proportion of patients no cause will be found forhaematuria.Investigation of microscopic haematuriaUrine microscopyIdentification of red cell morphology by urine microscopyhas been widely discussed as an investigative tool in mH.The presence of dysmorphic erythrocytes, especiallyacanthocytes, is associated with glomerular haematuria [7]and is reported therefore to be a useful early investigationdirecting whether it is appropriate for a patient to have arenal biopsy or to undergo urological evaluation includingcystoscopy. There have been only two studies in whichurine microscopy has been used prospectively to investigatepatients with isolated mH of unknown origin. In thesestudies sensitivity of 60% and specificity of 85% in distinguishingbetween glomerular and non-glomerular haematuriawas reported [8,9]. Urine microscopy is markedlyoperator-dependent; it is clear that nephrologists expert inphase contrast microscopy of urine find it an extremelyvaluable tool, but it is not useful in clinical practice whenundertaken by routine laboratory staff.Renal biopsyRenal biopsy remains a useful diagnostic tool although itsexact role is open to debate. On the one hand proponents ofrenal biopsy in the evaluation of mH argue that it is a safeday case procedure with very low risks; that it will allow aprecise diagnosis, in particular may establish a familydiagnosis avoiding the need for further biopsies in otherfamily members; and that by identifying parenchymal renaldisease, unnecessary urological investigation can beavoided. Furthermore in up to 50% of patients an entirelynormal renal biopsy may be found in which case the patientcan be reassured and discharged. Renal biopsy provides thekind of precise information which is sometimes required byinsurance companies, employers, or immigration authorities.On the other hand those who are more cautious about renalbiopsy argue that it is an invasive procedure; that in the vastmajority of patients with isolated mH the prognosis isexcellent; and that clinical follow up will in any case berequired, and therefore it may be unimportant to make aprecise morphological diagnosis.Available information suggests that in these asymptomatic,normotensive, non-proteinuric individuals with normalrenal function the risks of renal biopsy are extremely low.The incidence of macroscopic haematuria is reported as 2-5%, and significant peri-renal haematoma 2-3%. Infection,nephrectomy or death following a renal biopsy are rarely,and did not occur in most recent series. A further significantrisk of renal biopsy however is that the biopsy is inadequateeither because the number of glomeruli for light microscopicevaluation are insufficient, or because no electronmicroscopy is available.Another argument in favour of renal biopsy rests uponevidence that glomerular disease presenting with isolatedmH is less benign than has previously been thought, anespecially important point since many of these patients areyoung adults in whom lifetime renal risk must beconsidered. These risks are best documented in IgAN: datafrom the Toronto Registry indicates a ten year risk ofdeterioration in renal function of zero in IgAN presentingwith isolated mH [10]. On the other hand a cohort of IgANfrom Hong Kong had a significant risk of proteinuria,11

12 BANTAO Journal 2007; 5 (2)hypertension or renal impairment during a seven yearfollow up (44% had such an event) after presenting withmH and very low grade proteinuria [11]. Three large serieshave followed adults with mH regardless of the exactdiagnosis and report a 5-11% risk of proteinuria overapproximately five years of follow up, and a 13-16% risk ofnew hypertension [9, 12, 13]. On the other hand 17-36% ofpatients in those cohorts had complete regression of mHduring the same follow up period [14-16]. One small studyof individuals with isolated mH and a normal renal biopsyindicated that 60% lost haematuria within ten years.Can non-invasive testing distinguish between TBMN andIgA nephropathy?A family history may be useful. TBMN is characteristicallyautosomal dominant, although in many families there willhave been no systematic urine testing of other familymembers. While in some parts of the world urineabnormalities in relatives of individuals with IgAN arecommon this pattern is not consistent, and in NorthernEurope only a small minority of those with IgAN haverelatives with an abnormal urine test.It is well known that asymptomatic proteinuria occurringwith mH significantly increases the risk of substantialglomerular disease. In one study of patients presenting withmH and proteinuria

BANTAO Journal 2007; 5 (2) 13matter of local healthcare organisation. In the UK it is possibleto delegate much of this follow up to family physicians withclear recommendations about triggers for referral back forspecialist nephrology care. It is always important thatadvice and recommendations given both about referral andfollow up of patients with mH should be realistic andagreed with family physicians. An additional veryimportant point is the need for the patient themselves totake responsibility for the problem. It is unfortunately thecase that many young individuals with isolated mH whofeel entirely well are not easily convinced of the importanceof an annual medical check up. It is still sadly notuncommon that patients identified in this way will be lost tofollow up and will then return years later with proteinuria,hypertension and advancing renal failure which couldundoubtedly have been slowed if not prevented by propermanagement.ConclusionRenal biopsy still plays a crucial role in the precisediagnosis of many patients with isolated microscopichaematuria. Nevertheless thorough evaluation can minimisethe use of renal biopsy and can allow a diagnosis to bereached in a proportion of patients when renal biopsy is notappropriate. The should include a careful family history,thorough age-related evaluation for non-glomerular causes ofhaematuria, and urine examination including measurement ofmicroalbuminuria, although probably only including urinemicroscopy in experienced hands. Even then the purpose ofthe biopsy and the value of the findings should be carefullydiscussed with the patient before proceeding. Finally, localhealth care arrangements and a variety of circumstances(including the availability of electron microscopy) willsignificantly affect renal biopsy policy in this setting.Conflict of interest statement. The author declares no conflictof interest.This article is based on a lecture given at the 8 th BANTAOCongress, Belgrade Serbia 16 th –19 th September 2007.References1. Topham PS, Harper SJ, Harris KPG, Walls J, FeehallyJ. Glomerular disease as a cause of isolated microscopichaematuria. Quart J Med 1994; 87: 329-336.2. Khadra M, Pickard RS, Charlton M et al. Aprospective analysis of 1,930 patients with haematuriato evaluate current diagnostic practice. J Urol 2000;163: 524-527.3. Perrone HC, Ajzen H, Toporovski J, Schor N.Metabolic disturbance as a cause of recurrent haematuriain children. Kidney Int 1991; 39: 707-710.4. Ahmed K, Sampath R, Khan MS. Current trends in thediagnosis and management of renal nutcracker syndrome:a review. Eur J Endovasc Surg 2006; 31: 410-416.5. Thorner PS. Alport syndrome and thin basementmembrane nephropathy. Nephron Clinical Practice2007; 106: c82-c88.6. Kashtan CE, Kleppel MM, Gubler MC.Immunohistologic findings in Alport syndrome.Contrib Nephrol 1996; 117: 142-153.7. Köhler H, Wandel E, Brunck B Acanthocyturia-Acharacteristic marker for glomerular bleeding KidneyInt 1991; 40:115-20.8. Schramek P, Schuster FX, Georgopoulos M, PorpaczyP, Maier M. Value of urinary erythrocyte meprhologyin assessment of symptomless microhaematuria.Lancet 1989; ii: 1316-1319.9. McGregor DO. Lynn KL, Bailey RR, Robson RA,Gardner J. Clinical audit of the use of renal biopsy inthe management of isolated microscopic haematuria.Clin Nephrol 1998; 49: 345-348.10. Bartosik L, Lajoie G, Sugar L, Cattran DC. Predictingprogression in IgA nephropathy. Am J Kidney Dis2001; 38: 728-735.11. Szeto CC, Lai FM, To KF et al. The natural history ofIgA nephropathy among patients with ahematuria andminimal proteinuria. Am J Med 2001;110:434-437.12. Hall CL, Bradley R, Kerr A et al. Clinical value ofrenal biopsy in patients with asymptomatic microscopichaematuria with and without low gradeproteinuria. Clin Nephrol 2004; 62; 267-272.13. Chow KM, Kwan BC, Li PK, Szeto CC. Asymptomaticisolated microscopic haematuria. Quart J Med2004; 97: 739-745.14. Eardley KS, Ferreira MA, Howie AJ et al. Urinaryalbumin excretion: a predictor of glomerular findingsin adults with microscopic haematuria. Quart J Med2004; 97: 297-30.13

BANTAO Journal 2007; 5 (2) : 14–22BJBANTAO JournalReviewPediatric Renal TransplantationRosanna Coppo, Alessandro Amore, Licia Peruzzi and Roberta CamillaNephrology Dialysis and Transplantation Unit, Regina Margherita Hospital, Turin, ItalyAbstractIndications, procedures, complications, pharmacokineticsand outcomes of renal transplantation are different inchildren and adults. Subjects

BANTAO Journal 2007; 5 (2) 15smaller children are not excluded at priory, since en-blockkidney transplantation may be performed. The frequency byage of cadaveric donors (data in Italy during theobservation period 1998 – 2002) is 20% of donors less than5 year-old, 59% of children aged between 6 and 14 yearsand 21% of donors >14 year-old. According to statisticalcalculations in UK data, the donor age 16 yearsold.Children smaller than one year- old unusually enter awaiting list either in USA or in Italy.The incidence of deaths in the waiting list is particularlyhigh for children aged less than 5 years, who have a deathincidence similar to that seen for more than 50 years oldpersons waiting for kidney transplantation. Whereas adultsand elderly patients in waiting list have a higher comorbidity,the mortality of children is relevant.Nephropathies leading to uraemia and need of renaltransplantation in childrenThe primary diagnosis of renal diseases leading to end stagerenal failure (Table 1) differs among various age groups: inchildren < 2 year-old the most common causes of uraemiaare malformative nephro-uropathies (aplasia, severe renalhypo-dysplasia, obstructive uropathy, usually associatedwith abnormal organogenesis) or congenital nephropathies(familiar nephrotic syndrome, as Denis-Drash syndrome, ormetabolic diseases like primary hyperoxaluria) [11,12]. Inthe older age group (2-8 years) the most common arehereditary diseases with longer course (like renalpolycystosis or nephronophthisis) and acquired diseases,like focal and segmental glomerular sclerosis. In olderchildren and particularly in adolescents the acquirednephropathies prevail over congenital forms. In theAmerican black people lupus erythematosus and focal andsegmental glomerular sclerosis are the more frequent causeof chronic renal failure [13,14].Table 1. Primary diagnosis of end stage renal disease inpaediatric recipients%Obstructive uropathy 16Ipo-dysplastic kidneys 16Reflux nephropathy 6Prune - Belly Syndrome 3Nephronophthisis 3Polycystic Kidneys 3Focal segmental glomerulosclerosis 12Chronic Glomerulonephritis 4Congenital Nephrotic syndrome 3Hemolytic Uremic Syndrome 3Others 36A condition peculiar to paediatric renal transplantation isthe presence of associated bladder disorders/hypoplasia (asin case of posterior urethral valve obstructive uropathy),reported in about 20-30% of the cases. In these children themost important problem is, either before the transplantationor after, to reconstruct the “reservoir” of the bladder,making it continent and able to be voided in the lessinvasive way. The improvement of bladder and urethrareconstruction in children with neo- bladder or urethralderivation, has allowed achieving the same survival afterrenal transplantation as in children without these malformations.It has been recently suggested that bladder andurethral reconstruction could be done after a successfulrenal transplantation, which will allow a urine flow able toefficiently rehabilitate the bladder.Choice of living or cadaveric donor“Pre-emptive” transplantation, done before dialysis (in 24%of children in USA, one third of which receiving a livingrelated donation) is far more frequent in USA or inNorthern Europe than in Italy or in Southern Europe. Thewaiting list for cadaveric donor is not accessible in Italy aswell as in most European Countries before entering thechronic dialysis treatment and living donor transplantationsare uncommon before dialysis. Living relatedtransplantations (LRT), used to be very common in USAsince long time, are further increased in these last years:from 1987 to 2002 the percentage of LRT is increased from42% to 57%. Donors are in above 40% of the cases one ofthe parents, but also grandparents are common donors andin the last years the donation from unrelated donors hasincreased [13]. This percentage is higher than adult LRT in15

16 BANTAO Journal 2007; 5 (2)USA, which is already elevated (41% LRT in adults in 2002).The percentage of LRT is inversely proportional to thereceiver’s age: 100% of LRT in babies < 1 year, 60% in those> 1 year and 11 year-old. In ItalyLRT accounted in 1998-2002 for 7.5% of renal transplantationin children, and the donor was always a receiver’s parents,except one case in which the donor was a brother [6].An important aspect to consider is that renal graft functioncould not last for decades and the child could need anotherkidney transplants. A study satellite to the ERA-EDTARegistry investigated, in children that received twosubsequent renal transplants, whether the outcome wasbetter when receiving first LRT or cadaver transplantation(CT). There was no significant statistic difference and thegeneral behaviour of Paediatric Nephrologists in Italy andin Southern Europe is to wait until a cadaver donor isavailable for the first transplantation: in case of failure, theLRT from parents is encouraged. Several variablesinfluence this choice, which should be discussed accordingto individual needs. However, as increase in LRT even aspre-emptive transplantation is likely to further increase alsoin Southern Europe in a next future.Children age at renal transplantation programmingKidney transplantation is exceptional in children under theage of 2 years, also in USA in spite of the pioneeringactivity of the Minneapolis Centre [15] and it represents 5%of all the paediatric transplantations. Most children (80%)receive a renal transplantation when they are >6 year-old.In Italy since 1987 to 1999 the median age of transplantedchildren was 13,7 years and only 7% was under 5 years.More recently, in 1998-2002, an increased transplantationin the younger subjects was reported, as 21% of kidneygrafts were performed in children aged between 0-5 years,33% between 6-12 years and 48% between 16-18 years.Renal transplantation in less than 2 year- old children haslimited indications, since risk for both kidney and recipientsurvival was reported to be too high. Centres that more thanten years ago begun the program of small baby transplantation- subjects < 1 year-old weighting some 6 kg -highlighted an increased risk for death (1 year-survival ofabout 90% for LRT and 79% for CT) and for kidney lossdue to renal vein thrombosis. Complications were particularlyfrequent when donors were small children, eventuallyweighting more than the donor [15]. Results have beenrecently improved [16,17] using low molecular weightheparin, or selecting living adult donors only and using aparticular surgical technique placing the graft not in thecommon extra-peritoneal location, but intra-peritoneallyperforming the vascular anastomosis with vessels largerthan the iliac ones (like aorta, cava). At any rate, the choiceof grafting so young children is exceptional and even inUSA only 18 transplants in children less than 1 year-oldwere registered from 1996 to 2000.There is no definite age-limit for renal transplantation, buttaking into account the life risk and the good resultsobtained with peritoneal dialysis and adequate nutritionalsupport [19] most Centres choose to wait until the childgrows up to put him in the waiting list for transplantation.The risk decreases progressively and after the first year of ageit is severe but not so high to discourage the transplantationand by 18 months of age the transplant success becomeslikely. The risk for children older than 3 years is within theaverage and does not differ from adolescents.The USA Registry NAPRTCS recently reported greatlyimproved results in children younger than 2 years, but wehave to consider that the number of the very young babiestransplanted is extremely limited and related to excellenceCentres, highly specialized in this field [15].In Italy the good outcomes obtained with peritoneal dialysisand the high risk of kidney transplantation in very youngchildren suggest a waiting attitude till the age of 18-24months.Surgical techniqueIn general, renal transplantation is technically similar inchildren and in adults, as anastomoses with the iliac vesselsare performed in extra peritoneal approach. In very smallchildren the kidney is sometimes located in intra peritonealseat, after mobilising the right colon to enlarge the suitablearea, performing a latero-lateral anastomosis with theinferior vena cava and the distal aorta; but this is very rare,like exceptional is the “en-bloc” bilateral renal transplantationat the same time.Extremely rare is the nephrectomy of the native kidneys,unless they would be bigger for severe polycystic kidneydisease where the room for a new kidney is reduced.During the period 1998-2002 in a total of 231 paediatrictransplants, cold ischemia time was very low, less than 20hours in almost the totality of the patients.Immunosuppressive treatments in paediatric renaltransplantationThe basal protocol of immunosuppressive treatment forpaediatric renal transplantation changed in the last years.The NARPTCS reported that the use of polyclonal andmonoclonal antibodies against T cells has almost completelydisappeared: given in 28% and 14% respectively in1997, they are now employed in 4% and 1% respectively.The use of the monoclonal antibodies anti IL-2 receptor(IL-2R) has increased in USA as well as in Italy. TheNAPRTCS report indicates that, among the childrentransplanted in 2003, 38% received basiliximab, 22%daclizumab, 7% anti-thymocytes/anti-lymphocytes and31.7% did not receive any induction therapy, but this lastgroup is going to disappear [3,20].In the years 1998-1993 almost 90% of the childrenregistered in USA, were on maintenance therapy withcorticosteroids (C), azathioprine (AZA) and cyclosporine(CSA). Over the time we assisted to a revolution of thistherapy for the progressive entry of new drugs and nowonly 15% of the children is taking the traditional treatment(C, CSA, AZA). The 2003 NAPRTCS report indicated thatamong children transplanted in 2002 some 42% receivedCSA, 52% tacrolimus (TAC), 67% mycophenolate mofetil(MMF), 19% sirolimus (SIR) and 1% AZA [3,21]. In parallelto the improving of short-term graft survival due to theeffectiveness of the new drugs, particularly when given inassociation, major attention is going to be focused on longtermgraft survival and general wellbeing of the transplantedchildren trying to avoid the therapy side effects.Special aim of paediatric transplantation is to reduce asminimal as possible steroids. The C has been for long time

BANTAO Journal 2007; 5 (2) 17considered unique for rejection prevention, particularly inchildren. Since C selective target is cellular immunity, thisdrug has been considered a “sine qua non” for transplanttherapy. However the severe side effects (increased infectionvulnerability, Cushing’s face, hypertension, dyslipidemia anddiabetes, vascular complications, digestion and emotionaldisorder…) are even worse in children than in adults as Cdepresses the growth velocity. Moreover, this treatment ispoorly accepted particularly in adolescents due to worsening ofthe physical aspect leading to drug self-reduction, and theincreased risk of cardiovascular is unacceptable for apopulation with a long life expectancy like transplantedchildren [27]. Therefore steroids are going to be reduced inmost paediatric protocols, which generally use an inductiontherapy with 10 mg/kg methylprednisolone followed byprednisone at rapidly reduced dosages of 0.12-0.15mg/Kg/day within 6 months from the transplantation.The first approach was to try to stop C after 6 months inchildren with stable renal function, who were on CSA andAZA. The results were at the beginning not favourable foran increase in acute rejections (AR) [20]. More recentlyretrospective analyses on children with strongly indicationsto stop the steroid therapy due to the severe clinicalcontraindications showed that the C stop was related to agood outcome, particularly when TAC was given. In factsome prospective trials with induction therapy by IL-2Rinhibitory followed by TAC and MMF, where the steroidwas stopped by 6 months, showed very good results with asignificant reduction of the side effects of the corticosteroidtherapy and minimal increasing of the AR.On the basis of these encouraging results a prospective trialwith C interruption at 6 months is now ongoing in USA inchildren who failed to show AR in the first 6 months: patientsare randomized to treatment with CSA or TAC associated toSIR.Another ongoing USA protocol completely avoids C thatare substituted by the first six months after transplantation,with daclizumab therapy plus TAC and MMF [21].CSA maintains a large use in the paediatric kidneytransplant. Several studies were focused on pharmacokineticsof CSA in children to identify the best way tomonitor this drug. The area under the curve (AUC 0-4) isthe most precise method to measure the body exposition toCSA. Considering the number of blood samples needed tocalculate AUC which is unsuited to children, investigationswere made to use, like in adults, the CSA bloody levels atthe second hour (C2). When C2 was > 1700 ng/ml afterthree months the 80% of transplanted children didn’t haveAR, versus 60% that presented C2 < 1000 ng/ml. The targetC2 to limit chronic rejection is still under evaluation [23].TAC aroused great interest in paediatric transplantation forthe possible use on mono-therapy, explored by the Pittsburghgroup, allowing the steroid saving, which was cooled by theincreasing of post transplant lymphoproliferative disorders(PTLD) [24], above all in EBV negative children, that receiveda kidney from a EBV positive donor. After a dosage reduction,the results were more satisfying and presently no increasePTLD frequency has been registered for TAC versus otherimmunosuppressive drugs. The dosage generally used is 0.10-0.15 mg/Kg/day, modifying the dosage on basis of TACtrough level, with levels around 10-15 ng/ml in the firstmonth and decreasing to 6-10 ng/ml for maintenance. Thecomparison between TAC and CSA for the prevention ofAR in paediatric kidney transplantation was at thebeginning in favour of TAC plus C and AZA. When AZAwas substituted by MMF the difference between CSA andTAC was no more evident. The follow-up at 2 yearsrevealed some advantage of TAC, but this is still underdiscussion. TAC could be used combined with SIR, and forthe strengthening of the effects, a reduction of the targetlevel is possible. Since the calcineurin inhibitors, eitherTAC or CSA, have similar nephro-/neuro-toxic effects, inUSA ongoing protocols are aimed to avoid calcineurininhibitors using different combinations of C, MMF and SIRin living donor transplants.MMF has had a rapid success in paediatric renaltransplantation, like for adults, often substituting AZA, even ifit is 6-7 times more expensive than the old drug. Even if thereduction by 50% of AR, observed at the beginning in adults,was not confirmed in children, a prospective 3-year study witha combination of MMF/CSA/C showed an important reductionof AR and a graft survival increased to 98% [25]. It is possiblethat MMF, more efficient, could reduce the need for CSA inchildren. The currently most largely adopted dosage is 1200mg/m 2 /day. The curve most predictive for drug expositionconsiders C0, C1 and C4. The dosage is generally modifiedaccording to the clinical immunosuppressive effect. MMFwas reduced in 14% of the case for gastric intolerance. Thenew gastro-resistant formulation needs less adjustment(only in 7%). The MMF blood level measurement provedthat the association with TAC produces levels allowingdosage reduction.SIR is metabolized, as CSA, by Cytochrome P450 and byGlycoprotein P. The simultaneous administration of bothdrugs amplifies levels and effects (SIR increased to 67-85%) allowing a decrease in SA dosage, with likelylimitation of side effects. Assuming SIR 4 hours after CSAthis super effect is reduced, and the simultaneouslyadministration is recommended to reduce drug dosage. Onthe other hand SIR and TAC can be administratedsimultaneously because they do not interfere. The relevantimmunosuppressive effect of SIR enhanced the search forcalcineurin-free protocols [26]. SIR significant decreasedAR incidence, and it is of particular interest both in adultsand children, because of its potential anti-fibrosis effect inchronic allograft nephropathy (CAN). A protocol isongoing in USA to investigate the potential benefit of SIRon chronic rejection in children who previously experiencedAR, randomized in two groups of traditional triple therapyor SIR [27]. In the last years the Italian Paediatric Centresagreed to use protocols, designed in collaboration, with thepurpose to validate the outcomes of the drugs of newgeneration, including induction therapy by anti IL-2R, CSAand MMF, followed by SIR, stopping MMF, in associationwith reduced dosages (50%) of calcineurin inhibitors.Child and transplanted kidney survivalThe innovative introduction of new immunosuppressivedrugs, as well as improvement of surgical procedures andknowledge of infectious and vascular complication led tosignificant progress in children renal transplantationoutcomes. The survival of children after renaltransplantation is generally better than for adults, and 5years after transplantation it is around 99-98% in LRT andCDT respectively for 6 to10 year-old children (Figure 1, 2).17

18 BANTAO Journal 2007; 5 (2)Adolescents have a lower 5-year survival (96-97%respectively). Also the survival of very young recipients (< 5year-old) is worse than the other children age groups [9]. In theItalian Registry for renal transplantation in children, thesurvival of children less than 3 year old was of 97% in 1998-2002 period. No significant differences for patient survival arepresently found in LRT and CT.100806040200Fig. 1. Graft survival at first (black column) ad fifth year (whitecolumn) of living related pediatric kidney transplantation dividedby age groups (2003 Annual Report USA Registry OPTN/SRTR)100806040200Fig. 2. Graft survival at first (black column) ad fifth year (whitecolumn) of cadaveric pediatric kidney transplantation divided byage groups (2003 Annual Report USA Registry OPTN/SRTR)The most important causes of death in children after 10years of transplantation include infections (33%),cardiovascular disease and the neoplasm (Table 2). Morerecent data indicate an increase in mortality due to thebacterial and fungal infections and lymphoprolipherativedisease (PTLD) [24,28].Table 2. Childrens’ mortality 10 years after Renal Transplantation%Infections 33Neoplasms 25Infarction 10Hepatitis 10Stop medications 10Cerebral hemorrhage 2Medullary aplasia 2Others 8Graft survival1-5 yrs 6-10 yrs 11-17 yrs1-5 yrs 6-10 yrs 11-17 yrsOver the last decade the frequency of AR went to a dramaticreduction: the probability of AR by the first 12 months afterrenal transplantation, changed from 70% and 57% for CTand LRT respectively in 1987 to 63% and 49% in 1991 andsettled down to 31% and 27% respectively in 2002. Therelative risk of AR was related to HLA mismatch, the lackof the induction therapy, and the black race [9,29,30].Moreover, also the severity of the rejections decreased anda complete regression of serum creatinine level, observed in52% of children years ago, changed to the present 65%.In 2002 the lost of paediatric grafted kidney due to AR was4% and 6% in LRT and CT respectively. The treatment forAR in 57% of the cases recorded by the NARPTCS registryconsisted in 3 methylprednisone pulses of 20-25 mg/kgevery other day. One third of cases were treated with monopolyclonalantibodies. The reversibility of the AR wasrelated with the age of the child and with the occurrence ofthe episode in the first year after grafting.Also the renal survival has improved: survival at one yearin the USA registry improved in the last 5 years either inCT or LRT. LRT survival changed from 91% to 94%, from1987-95 to 1996-2000; and CT improved in parallel from81% to 93% (p

BANTAO Journal 2007; 5 (2) 19On the opposite, more recent analysis indicates worst results inthe adolescents, where poor drug compliance leads tounexpected results [31]. In 11-17 year- old recipients the 5year-survival is lower not only in comparison with youngerchildren but also in comparison with adults, except for elderlyones (>65 years old). These adolescents have an excellentshort time renal graft survival (at 3 months -1 year), but show aterrible dropping at 3-5 years. The reasons of these awfulresults are not completely clear and it seems that other factorscould be involved beside incompliance. Unexpectedvascular thrombosis and the relapse of the renal disease (asFocal Segmental Glomerular Sclerosis) could be involved.At any rate the adolescents group is presently thatexperiencing the higher renal graft lost.Causes of renal graft loss in childrenSeveral causes, both immunological and not immunological,can lead to graft loss in children. Rejection of thetransplanted organ, with its different expressions, iscertainly the most important factor both in European andUSA case analysis: it accounts for 50-60% of cases, eventhough modern drugs have reduced its incidence.Thanks to new immunosuppressive drugs, the incidence ofAR has been significantly lowered, but the incidence of CAN,which represents, like in adult transplantation, the mostimportant cause of graft loss in long term follow-up, accountingfor 32% of definitive functional losses, is still high.Non immunological causes of graft loss includes vascularthrombosis, responsible for 13% of function losses in theUSA registry and particularly common when the recipientis less than 3 year-old, even more when the donor is smallerthan the recipient. At multivariate analysis several factorsincrease the risk of thrombosis, including previous treatmentwith peritoneal dialysis, second transplantation, donorless than 6 years old, more than 24 hours of cold ischemia,recipient less than 2 year-old.Another important cause of renal graft loss is the recurrenceof the primary disease, in particular focal and segmentalglomerulosclerosis (FSGS), membranoproliferative glomerulonephritis(MPGN) and primary hyperoxaluria [32,33].Recurrence of FSGS in the transplanted kidney is certainlythe most dramatic problem in Paediatric Nephrology.Several registries underline the fact that FSGS incidence isincreasing year by year; being presently FSGS the mostcommon acquired cause of disease in children leading touraemia, dialysis and transplantation. This nephropathy isparticularly common and aggressive in African-Americanchildren. Recurrence is reported in 14-50% and increasesup to 80-100% of the cases at second transplantations, aftera first graft loss due to FSGS recurrence. African-Americanrace, very short history of disease leading to dialysis andpositive result for the search of permeabilizing factor are atparticular risk. Also the histological aspect of widespreadmesangial proliferation associated with FSGS typicallesions is correlated with a higher incidence of recurrence.The role of a living donation by a relative is discussed, alsotaking into account that common advantages of LRT versusCT are not observed in FSGS case analysis. An average ofone third of patients with FSGS looses the transplantedkidney because of rejection, but the outcome is even worsein adolescents: it is not clear whether a pivotal role isplayed by poor compliance, more frequent in this agegroup. None of the proposed therapies reaches unanimousconsent. The most effective reported treatment is presentlyplasmapheresis (5-13 sessions, started as soon as recurrenceis detected, daily for 3 days, then every other day untilproteinuria is lowered to < 0.5 g/day); results are noticedwithin 5-27 days. A refining of plasmapheresis is plasmaadsorption on Protein A-sepharose column [32], which isable to selectively bind and remove a plasmatic fractionendowed with permeability effects on isolated glomeruli.Another approach is cyclosporine given by continuous e.v.infusion 3 mg/kg/day, starting when proteinuria is detectedand pursued until remission or for 3 weeks, and then givenorally to maintain trough levels at 200-300 ng/ml.Remission was obtained using this protocol in 14/17children within 28 days after recurrence and remission andgood renal function were maintained at long term followup.These high doses of cyclosporine are prescribed toovercome the lack of cyclosporine pharmacological effectin dyslipidemic conditions, as in nephritic syndrome due toFSGS recurrence. A combination of high doses ofcyclosporine and plasmapheresis seems to be the most efficientprotocol. Also the association of Cyclophosphamide, 2 mg/kgfor 2 months achieved some positive results. TAC instead hasno effect in these conditions.Membranoproliferative GN recurs in 30% of children, withfunction loss of the transplanted kidney in one third of cases.Recurrence of the dense deposits form (type 2 MPGN) isespecially frequent (88% of cases). Recurrence of atypicalhaemolytic uremic syndrome (not related to intestinal infectionand verotoxin contacts, but induced by mutation of genesencoding for H factor of complement with loss of a naturalinactivator, or mutation of genes that codify for the proteasethat cut Von Willebrand factor – ADAMST), are verycommon.The increased frequency of recurrence in transplanted kidneysof children affected by Systemic Lupus Erithematosus or IgAnephropathy, or GN secondary to Schoenlein-Henochsyndrome is more debated. In particular Schoenlein-Henochsyndrome seems to be prone to recurrence, often limited to thekidney, without systemic symptoms. As far as primaryhyperoxaluria is concerned, since the metabolic defect isoften the missing function of an enzyme produced by theliver, combined transplantation of liver and kidney had beenproposed: the outcome was excellent; instead, in isolatedkidney transplantation, oxalosis recurs in 90% of cases, withfrequent kidney loss.Finally, organs can be lost due to poor compliance toregular assumption of drugs; in relation to this aspect, theAdult Nephrologist, who often takes care on patients who havealready been transplanted in childhood and may not be awareof the severity of the problem during adolescence, plays a keyrole. Adolescents have the lowest kidney survival on long termfollow-up, both in the LTR and CT case analysis; furthermore,they have the lowest percentage of complete functional recoverafter the treatment of an AR episode. Also recurrence of theoriginal disease is worse in adolescents than in youngerchildren. Several factors contribute to poor compliance,mostly the observation that drugs worsen physical aspectsof transplanted kids and despondency deriving from a posttransplantationcourse characterized by many small to bigproblems. All the specialists of the field agree on the factthat improving the outcomes in adolescents represents thegoal for the upcoming years.19

20 BANTAO Journal 2007; 5 (2)Morbidity of the transplanted childThe morbidity of the transplanted child is similar to that ina transplanted adult (Table 4) in respect to the recurrentbacteria and viral infections which is the more relevant, asmore efficient became the immunosuppressive treatment.The new target of the recent therapy is to reduce infections,especially CMV and HBV infections, involved in thepathogenesis of PTLD and with the risk of cancers.Table 4. Morbidity in transplanted patients%Bacterial infections 13Viral infections 16Hypertension50 at 1 year,75 at 3 yearsLymphoms 2Neoplasms 2Post-transplant-lymphoproliferative2disorders (PTLD)PTLD happens in 4.5% of the pediatric renal transplantsand the RR is quadruple in comparison with the adult renaltransplants [34]. In a pediatric Italian study (NITp) theincidence of cancers in renal transplanted children was2.2% in total, mostly were PTLD (1.3%) but also urothelialcarcinoma, Wilms tumor, dysgerminoma, glioma [16]. Thecardiovascular risk is increasingly important [35], due tothe increasing of the follow up in renal transplantedchildren, and echocardiogram is an important screeningexam [36].The growthOne of the most important results of the paediatrictransplant is the effect on the height growth. Above all theaverage height of children at the moment of the transplant isimproved, thanks to the specific supportive therapy for endstagerenal failure in children, (by the correction of anaemia,uremic-osteodystrophy and caloric implementation bynocturnal enteric-nutrition, when the spontaneous introductionis insufficient) and, finally by the use of recombinant growthhormone, during the pre-transplant period, if necessary. Thechildren growth improves after transplant, but not in thefirst year, when the cortico-steroid treatment affects therenewal of growth.Afterwards the recovery of a normal renal function, theimprovement of the uremic-osteodystrophy, the correctionof the anaemia, acidosis and vitamin D production exert apositive effect on the growth recovering the retardationrelated to uraemia [37]. After the first year from thetransplant and especially when it is possible to followprotocols with low or absent steroids, the growth restarts quitewell. The growth after transplants is as better as younger is thechild (< 5 years), instead it is unsatisfactory in teenagers.Comparing the data of children transplanted before thepuberty with those transplanted after, the average growthvelocity increased in the first group from 4.9 to 8 cm /years,with a final average height of 0.8 SD in the first two yearsafter transplant. But even if the peak of the growth velocity atthe puberty is significant higher than normal children, thetotal final height at the puberty is lower in 20% of the cases,due a minor length of the pubertal spurt. The final height is1.3 SD higher in children transplanted before the puberty andonly 0.7 SD higher in teenagers transplanted during thepuberty. With the actual supportive therapy the final height,among the patients transplanted in paediatric age, growth isnormal in 68%, between the mean and – 2SD from the mean.The results as a whole are reasonable but not optimal yet. It isevident that the more the child is close to the stop of the growth,the more it is difficult to obtain significant improvement.A great interest was played by the possibility to improvethe growth by using rhGH, the human recombinant hormone.This therapy was looked with a certain suspect in thepaediatric application for the possibility that a growth factoradministration could be a risk factor for leucosis in apopulation already at risk for the immunosuppressivetreatment and that could stimulate acute rejection. Clinicalstudies did not confirm theses adverse assumptions, so therhGH can be rather safely administrated to transplantedchildren. The results are in general encouraging but thegreat individual variability indicates that it is possible that atransplanted child could stop the rhGH treatment at themoment of the transplant and than, after a slow growth inthe period immediately after the transplant, could startgrowing without rhGH [38,39].The future of the renal transplanted childA very interesting study, made by the Centres who firstlytransplanted a relevant cohort of children (San Franciscoand Paris), reported positive results concerning thereintegration in the work and social world of 296 personswho received a kidney transplantation 25 years before [40].The outcomes were satisfied: 53% worked at full time, only19% were unemployed. The family life was not so differentfrom the average in healthy subjects: 39% was married ordivorced, 18% had children. The 84% thought to be sociallyindependent and 89% felt satisfied. The actual problem forone third of them was the rather short final stature, but it mustbe taken into account that these subjects were children in a pre-GH, pre- erythropoietin and pre-OH3 Vitamin D period.The paediatric renal transplantation needs a careful therapyand scruple periodic visits. The past decade has seensubstantial improvement in this treatment which is onlyway to get a complete rehabilitation for the unfortunatechild who develops a progressive chronic kidney disease.Conflict of interest statement. None declared.References1. Benfield MR, McDonald R, Sullivan EK, et al. The 1997Annual Renal Transplantation in Children Report of theNorth American Pediatric Renal Transplant CooperativeStudy (NAPRTCS). Pediatr Transplant 1999; 3(2): 152-67.2. McDonald R, Ho PL, Stablein DM, et al. Rejectionprofile of recent pediatric renal transplant recipientscompared with historical controls: a report of the NorthAmerican Pediatric Renal Transplant Cooperative Study(NAPRTCS). Am J Transplant 2001; 1(1): 55-60.3. Benfield MR, McDonald RA, Bartosh S, et al. Changingtrends in pediatric transplantation: 2001 Annual Report ofthe North American Pediatric Renal TransplantCooperative Study. Pediatr Transplant 2003; 7(4): 321-35.

BANTAO Journal 2007; 5 (2) 214. Sirchia G, Poli F, Cardillo M, Scalamogna M, RebullaP, Taioli E, Remuzzi G, Nocera A. Cadaver kidneyallocation in the north Italy transplant program on the eveof the new millennium. Clin Transpl 1998: 133-45.5. Sirchia G, Mascaretti L, Poli F, Scalamogna M,Pappalettera M, Pizzi C. Cadaver kidneytransplantation in the north Italy transplant program inthe nineties. Clin Transpl 1995: 241-54.6. Cardillo M, Poli F, Barraco F, De Fazio N, Rossini G,Boschiero L, Nocera A, Rigotti P, Marchini F, ZacchelloG, Zanon G, Sandrini S, Chiaramonte S, Maresca C,Caldara R, Messa P, Berardinelli L, Ambrosini A,Montanaro D, Rampino T, Minetti E, Gotti E, Ghio L,Ginevri F, Albertario F, Scalamogna M. Renaltransplantation. Strategies to prevent organ rejection--the role of an inter-regional reference center. ContribNephrol 2005; 146: 1-10. Review.7. Magee JC, Bucuvalas JC, Douglas G, et al. Pediatrictransplantation. Am J Transplant 2004; 4(suppl.9): 54-71.8. McDonald RA, Smith JM, Stablein D, et al.Pretransplant peritoneal dialysis and graft thrombosisfollowing pediatric kidney transplantation: a NAPRTCSreport. Pediatr Transplant 2003 Jun; 7(3): 204-8.9. Drukker A. Renal transplantation and long-term graftsurvival for all children and adolescents with end-stagerenal failure. Pediatr Transplant 2004 Aug; 8(4): 313-6.10. Lewy JE. Treatment of children in the U.S. with endstagerenal disease (ESRD). Med Arh 2001; 55(4): 201-2.11. Seikaly MG, Ho PL, Emmett L, et al. Chronic renalinsufficiency in children: the 2001 Annual Report of theNAPRTCS. Pediatr Nephrol 2003; 18(8): 796- 804.12. Mitsnefes M, Ho PL, McEnery PT. Hypertension andprogression of chronic renal insufficiency in children:a report of the North American Pediatric RenalTransplant Cooperative Study (NAPRTCS). J Am SocNephrol 2003; 14(10): 2618-22.13. Neu AM, Ho PL, McDonald RA, et al. Chronic dialysisin children and adolescents. The 2001 NAPRTCSAnnual Report. Pediatr Nephrol 2002; 17(8): 656-63.14. Bartosh SM, Fine RN, Sullivan EK. Outcome aftertransplantation of young patients with systemic lupuserythematosus: a report of the North American pediatricrenal transplant cooperative study. Transplantation2001; 72(5): 973-8.15. Khwaja K, Humar A, Najarian JS. Kidney transplantsfor children under 1 year of age - a single-centerexperience. Pediatr Transplant 2003; 7(3): 163-7.16. Groothoff JW, Cransberg K, Offringa M, van de KarNJ, Lilien MR, Davin JC, Heymans HS; Dutch cohortstudy. Long-term follow-up of renal transplantation inchildren: a Dutch cohort study. Transplantation 2004;78(3): 453-60.17. Johnson RJ, Belger MA, Briggs JD, Fuggle SV,Morris PJ; UK Transplant Kidney and PancreasAdvisory Group. Renal transplantation in the UK andRepublic of Ireland. Clin Transpl 2000: 105-13.18. Warady BA. Should the DOQI adequacy guidelines beused to standardize peritoneal dialysis in children?Perit Dial Int 2001; 21 Suppl 3: S174-8.19. Warady BA, Ho M. Morbidity and mortality inchildren with anemia at initiation of dialysis. PediatrNephrol 2003; 18(10): 1055-62.20. Tejani A, Ho PL, Emmett L, et al. Reduction in acuterejections decreases chronic rejection graft failure inchildren: a report of the North American PediatricRenal Transplant Cooperative Study (NAPRTCS). AmJ Transplant 2002 Feb; 2(2): 142-7.21. Neu AM, Ho PL, Fine RN, et al. Tacrolimus vs.cyclosporine A as primary immunosuppression inpediatric renal transplantation: a NAPRTCS study.Pediatr Transplant 2003; 7(3): 217-22.22. Silverstein DM.Risk factors for cardiovascular diseasein pediatric renal transplant recipients. PediatrTransplant 2004; 8(4): 386-93.23. Pape L, Ehrich JH, Offner G. Advantages of cyclosporinA using 2-h levels in pediatric kidney transplantation.Pediatr Nephrol 2004; 19(9): 1035-8.24. Dharnidharka VR, Douglas VK, Hunger SP, et al.Hodgkin's lymphoma after post-transplant lymphoproliferativedisease in a renal transplant recipient.Pediatr Transplant 2004; 8(1): 87-90.25. Pape L, Ehrich JH, Offner G, et al. Long-term followupof pediatric transplant recipients: mycophenolicacid trough levels are not a good indicator for long-termgraft function. Clin Transplant 2004; 18(5): 576-9.26. Flechner SM, Kurian SM, Solez K, Cook DJ, BurkeJT, Rollin H, Hammond JA, Whisenant T, LaniganCM, Head SR, Salomon DR. De novo kidneytransplantation without use of calcineurin inhibitorspreserves renal structure and function at two years. AmJ Transplant 2004; 4(11): 1776-85.27. Lai WJ, Chiang YJ, Chen Y, Chu SH. Is sirolimus asafe alternative to reduce or eliminate calcineurininhibitors in chronic allograft nephropathy in kidneytransplantation? Transplant Proc 2004; 36(7): 2056-7.28. Dharnidharka VR, Stablein DM, Harmon WE. Posttransplantinfections now exceed acute rejection ascause for hospitalization: a report of the NAPRTCS.Am J Transplant 2004; 4(3): 384-9.29. Gipson DS, Ferris ME. A measure of success in kidneytransplantations. Pediatr Transplant 2004; 8(2): 104-5.30. Pape L, Offner G, Ehrich JH, et al. Renal allograftfunction in matched pediatric and adult recipient pairsof the same donor. Transplantation 2004; 77(8): 1191-4.31. Smith JM, Ho PL, McDonald RA. Renal transplantoutcomes in adolescents: a report of the NorthAmerican Pediatric Renal Transplant CooperativeStudy. Pediatr Transplant 2002; 6(6): 493-9.32. Baum MA, Ho M, Stablein D, et al. Outcome of renaltransplantation in adolescents with focal segmental glomerulosclerosis.Pediatr Transplant 2002; 6(6): 488-92.33. Seikaly MG. Recurrence of primary disease in childrenafter renal transplantation: an evidence-based update.Pediatr Transplant 2004; 8(2): 113-9.34. Shroff R, Rees L. the post-trasnplant lymphoproliferativedisorder- literature review. Pediatr Nephrol2004; 19: 369-377.35. Nocera A, Ghio L, Dall'Amico R, Fontana I, CardilloM, Berardinelli L, Zanon GF, Scalamogna M,Zacchello G, Valente U, Ginevri F. De novo cancers inpaediatric renal transplant recipients: a multicentreanalysis within the North Italy Transplant programme(NITp), Italy. Eur J Cancer 2000; 36(1): 80-6.36. Matteucci MC, Giordano U, Calzolari A, Turchetta A,Santilli A, Rizzoni G.Left ventricular hypertrophy,21

22 BANTAO Journal 2007; 5 (2)treadmill tests, and 24-hour blood pressure in pediatrictransplant patients. Kidney Int 1999; 56(4): 1566-70.37. El-Husseini AA, El-Agroudy AE, El-Sayed MF, et al.Treatment of osteopenia and osteoporosis in renaltransplant children and adolescents. PediatrTransplant 2004; 8(4): 357-61.38. Fine RN, Stablein D, Cohen AH, Tejani A, et al.Recombinant human growth hormone post-renal transplantationin children: a randomized controlled studyof the NAPRTCS. Kidney Int 2002; 62(2): 688-96.39. Acott PD, Pernica JM. Growth hormone therapy beforeand after pediatric renal transplant. Pediatr Transplant2003; 7(6): 426-40.40. Bartosh SM, Leverson G, Robillard D, SollingerHWLong-term outcomes in pediatric renal transplantrecipients who survive into adulthood. Transplantation2003; 76(8): 1195-200.

BJBANTAO JournalReviewFocal Segmental GlomerulosclerosisDimitrios S GoumenosDepartment of Internal Medicine - Nephrology, University Hospital of Patras, GreeceBANTAO Journal 2007; 5 (2) : 23–27IntroductionFocal segmental glomerulosclerosis (FSGS) is a commontype of glomerular disease that is responsible for 20-30% ofcases with proteinuria in children and adults [1]. Theetiology of idiopathic FSGS is unknown and it representsone of the leading causes of renal failure, with an increasingincidence over the last few years [2,3]. FSGS, minimalchanges disease and mesangial proliferation are considereddifferent histological patterns of idiopathic nephroticsyndrome [4]. The fact that FSGS was recognised in repeatbiopsies of patients with minimal changes, 10 years afterthe original diagnosis and the presence of steroid-sensitivityin patients with FSGS, as well as steroid-resistance inpatients with no sclerotic changes on adequate biopsies,suggest that FSGS and minimal changes disease mightrepresent one disease [4]. However, the recent observationof parvovirus B19 and SV40 in the glomeruli of FSGSpatients and the different patterns of cyclin-dependentkinase inhibitors expression, in minimal changes and FSGS,suggest that the latter represents a podocyte disease, totallydifferent to minimal changes [4,5]. The disease is classifiedas primary, familial and secondary. Primary FSGS is themost common form, whereas, familial FSGS is alsorecognised in sporadic cases. FSGS is also observedsecondary to reduction of renal mass or glomerularadaptation [reflux nephropathy and morbid obesity] as wellas after HIV infection and heroin abuse (Table 1).Table 1. Classification of FSGSPrimary(idiopathic)FamilialSecondaryA. Reduced renal mass / glomerular adaptationreflux nephropathyrenal dysplasia or unilateral renal agenesiaoligomeganephroniamorbid obesitysickle cell diseaseB. Secondary to hereditary nephropathies (s. Alport)C. HIV-associated nephropathyD. Heroin associated FSGSPathology and histological variantssections showed more widely distributed disease than theobserved in conventional light microscopy [7]. Chronicchanges in the tubulointerstitial area are also common. IgMand C3 complement component are usually identified withimmunofluoresence in the area of hyaline and scar whereaseffacement of foot processes is recognised in the electronmicroscopy. Morphological variants of the disease; FSGSperihilar variant, FSGS not otherwise specified, cellularvariant, tip lesion and collapsing FSGS have beendescribed. Whether these variants represent differences inpathogenesis or severity of podocyte injury or tempos ofhistolopathologic evolution remains unclear [8].Classic FSGS is characterized by the involvement of glomeruli,which are localized in the deeper cortex and juxtamedullaryarea, usually showing a perihilar scar. In many cases, the scarcontains areas of hyalinosis that represent the remnants ofsubendothelial protein exudates in the obliterated capillaries [1].Glomerular tip lesion is characterized by the presence oflesions (widening of capillary loops and foam cells) in thetubular pole of the glomerulus and lack of chronic tubulointerstitialdisease. In repeat biopsies of patients with tiplesion, progression to other variants of FSGS has beendescribed [9].The cellular variant and its extreme form, the collapsingvariant, are characterized by increased number of cells(podocytes) in Bowman’s space. In collapsing glomerulopathy,severe collapses of the glomerular tuft that is surroundedby proliferating podocytes forming a ‘pseudocrescent’,is observed. Most of the proliferating cells overlie collapsedcapillary loops, but in some cases, podocytes that have beendetached from the basement membrane are found free in theBowman’s space [10,11]. Although the mature normalpodocytes are not able to proliferate, podocytes in cellularand collapsing variant of FSGS regress to a fetalmesenchymal phenotype with proliferative capacity. Thepodocyte expression of proliferating cell nuclear antigen(PCNA), cyclin–dependent kinase inhibitor p21 andproliferation marker Ki-67, in cellular and collapsingvariants, denotes a mitotic activity, which is not observed inmature podocytes or in cases with nephrotic syndrome dueto minimal changes or membranous nephropathy [11]. Thisvariant is more common in black and represents the mainlesion of HIV associated nephropathy.The characteristic glomerular lesion is a focal segmentalscar. The term focal means that only some glomeruli in thebiopsy are involved, whereas, segmental refers to theinvolvement of only some lobules of any glomerulus [6].The involved capillaries are obliterated and collapsed,whereas, in some cases, the scar contains areas ofhyalinosis. However, serial three dimensional ultra thinPathogenesisAlthough primary FSGS is considered a disease ofpodocytes, its pathogenesis remains largely unknown.Podocytes seem to have a unique response to injury,resulting in disruption of glomerular barrier and proteinuria.The early events of podocyte injury are characterized by______________________Correspodence to: Dimitrios S. Goumenos, Dept of Internal Medicine - Nephrology, University Hospital of Patras,265 00, Greece; Tel: +30 610 999366; Fax: +30 610 994424; E-mail: dgoumenos@med.upatras.gr

24 BANTAO Journal 2007; 5 (2)alteration of molecular structutre at the slit diaphragm andeffacement of foot processes, followed by re-organizationof the actin cytoskeleton via induction of the podocyte α-actinin-4 molecule [11,12]. This results in perturbation ofthe attachment of podocytes onto the glomerular basementmembrane by α3β1integrin, dystroglycan and podoplanin,leading to denudation of the basement membrane and collapseof the capillary loops. Finally, deposition of hyaline materialand attachment of the parietal epithelial cells to the denudedglomerular basement membrane (GBM) occur with formationof synechiae and glomerular scar. These changes areirreversible and lead to the development of glomerulosclerosisand end-stage renal failure [12].The recurrence of nephrotic syndrome in FSGS patientsafter renal transplantation and its remission after plasmaexchange, the induction of proteinuria in rats with serumfrom patients with recurrent FSGS and the translocation ofpodocin and nephrin from the plasma membrane to thecytoplasm of human podocytes, cultured with plasma fromnephrotic FSGS patients, suggest that glomerularpermeability factors acting to podocytes are present in theplasma of nephrotic FSGS patients. Although the glomerularpermeability factor(s) remain unkown, the induction ofproteinuria in rats by elute from columns coated withstaphylococcal protein A, used in plasma adsorption,suggests that a substance of molecular weight below100,000 is involved [11,13].Familial forms of FSGS are related to mutations of genesencoding nephrin, podocin, α-actinin-4, CD2AP, structuralproteins of the slit diaphragm responsible for the integrityof glomerular barrier. Sporadic forms of the disease havebeen also identified. Nephrin mutations cause a severe formof nephrotic syndrome in newborns, known as ‘Finnishtype’ nephrosis, because of its higher incidence (1 ever8200 births) in Finland. Responsible gene is the NPHS1gene, located on chromosome 19q13. Podocin mutationsare responsible for the appearance of nephrotic syndrome inthe early adulthood, inherited by autosomal recessive typeand for sporadic forms of the disease. The responsible geneis the NPHS2 gene located on chromosome 1q25-31 andthe most common mutation is the R138Q. Mutations of α-actinin-4 gene are located on chromosome 19q and result inthe development of proteinuria in the adolescence or earlyadulthood, inherited by autosomal dominant type leading tochronic renal failure. Mutations of Wilms’ tumor gene thatis involved in activation of nephrin transcription have beenalso implicated in the development of FSGS in the spectrumof certain syndromes (Denys - Drash, Frasiersyndrome). These familial forms of FSGS are steroidresistant and do not usually recur after renal transplantation[11,14].Other causes of podocyte injury, responsible for secondaryforms of the disease, are the presence of hyperfiltration and/orstretch in the glomeruli in remnant kidney model or in morbidobesity and reflux nephropathy, the presence of glomerularischemia in ageing and hypertensive nephrosclerosis, thepodocyte viral invasion in HIV associated nephropathy and thepresence of toxic agents in heroin associated FSGS [11].Clinical presentationThe presenting feature in all patients is proteinuria, whichfrequently results in nephrotic syndrome. Microscopichematuria, arterial hypertension and renal insufficiency areother common manifestations [1,2]. Nephrotic syndrome isobserved in about 75% of adult patients, microscopichematuria in 40%, arterial hypertension in 43% andimpaired renal function in 35% of patients, at presentation.Heavy proteinuria (>10 g/24h) is more frequently observedin patients with cellular or collapsing variant compared toclassic FSGS [1,2]. Nephrotic syndrome of abrupt onset is acommon manifestation of patients with glomerular tiplesion [90% of patients] and the remission rate afteradministration of corticosteroids is between that observedin minimal changes disease (80-90%) and classic FSGS(50-60%) [9].Clinical courseThe clinical course of primary FSGS varies, but it isparticularly poor in patients with persistent nephroticsyndrome, leading to end-stage renal failure (ESRF) morethan 50% of them over 10 years [1,15,16]. Apart fromheavy proteinuria, other parameters related to a poor clinicaloutcome, are the presence of impaired renal function andarterial hypertension at presentation and severe histopathologicalinvolvement with glomerulosclerosis and interstitialfibrosis in the renal biopsy [1,15]. FSGS usually follows anindolent clinical course, in patients with normal renal functionand remission of nephrotic syndrome with immunosuppressivetreatment [1,15,16]. In a large retrospectivestudy, ESRF was observed in 6% and 18% of patients withcomplete and partial remission after administration ofimmunosuppressive drugs and in 45% of patients withpersistent nephrotic syndrome, over a follow-up period of 5years [17]. No difference in the 10-year renal survival ratehas been observed among patients with FSGS variants, whoshowed remission of nephrotic syndrome (more than 80%).However, in patients who do not enter remission, a worse renalsurvival rate has been desribed for patients with collapsingvariant and tip lesion in comparison to the classic form ofFSGS (21 and 25% vs. 49% respectively) [2].TreatmentVarious therapeutic regimens, including corticosteroids, cytotoxicdrus, cyclosporin, ACE ihibitors and mycophenolatemofetil (MMF), have been tried in nephrotic patients, inorder to achieve remission and delay of FSGS progression.The usual therapeutic approach includes a prolonged courseof corticosteroids (more than 16 weeks), that is followed bypartial or complete remission of nephrotic syndrome inabout 50-60% of patients [1,18]. In this regimenprednisolone is given in high doses (1 mg/kg BW/day) for3-4 months and then is gradually tapered to a lower dose. Thisregimen was followed by a higher remission rate, compared tothat observed with shorter duration of treatment (61% vs. 15%respectively) and with long-term preservation of renal functionin 70% of the patients [18]. Others suggest an alternate dayprednisolone regimen (2 mg/kg, max 120 mg/d) that isfollowed by the same remission rate and less side-effects.Since the mean time to remission is 3 months, cases withpersistent nephrotic syndrome after administration of 1mg/kg BW/day of prednisolone for 4 months are consideredas steroid resistant [19]. Patients with impaired renalfunction (serum creatinine >1.3mg/dl) and/or heavy

BANTAO Journal 2007; 5 (2) 25proteinuria (>10g/24h) at presentation, as well as patientswith severe tubulo-interstitial injury and those with cellularvariant of the disease and hypercellulatity in more than 20%of the glomeruli, show more frequently steroid resistance.Familial forms of the disease are also steroid resistant.Although no significant difference in the remission rate ofthe nephrotic syndrome has been described among caseswith FSGS variants with administration of corticosteroids, atrend towards more frequent remission was observed inpatients with glomerular tip lesion [2,9].Cytotoxic drugs, such as cyclophosphamide (2mg/kg/day)or chlorambucil (0.1-0.2mg/kg/day) for 8-12 weeks, havebeen used as initial treatment with steroids in about 20% ofpatients but more commonly in steroid - dependent orfrequently relapsing nephrotic syndrome, as well as, incases resistant to corticosteroids. No additional benefit tothat of corticosteroids has been observed withadministration of cytotoxic drugs as initial treatment.Although most of the available studies with administrationof cytotoxic drugs in FSGS patients are retrospective withshort-term follow-ups, an analysis of these studies showedthat more than 70% of steroid-dependent patients showpersistent remission with cytotoxic drugs [1,18]. In steroidresistant cases, cytotoxics are not particularly effective(remission in 1 mg/kg BW/day is necessaryin order to characterize the situation as steroid resistant[18,19].Others have used CsA in combination to low prednisolonedose as initial treatment, in patients with borderlinediabetes, obesity or osteoporosis, in order to avoid highdoses of corticosteroids [26]. However, not manyrandomized prospective trials are available for the treatmentof idiopathic FSGS. In our recent retrospective analysis, theeffect of immunosuppressive treatment with prednisolonealone (1 mg/kg BW/day) or combination of lowerprednisolone dose (0.5 mg/kg BW/day) with azathioprine(2 mg/kg BW/day) or CsA (3 mg/kg BW/day, in graduallyreduced dose), was compared to that of conservativemanagement [27]. The regimens with lower prednisolonedose were used in obese and borderline diabetic patientsand in patients with bone disease. Deterioration of renalfunction was observed more frequently (35% vs. 8%)among patients treated conservatively whereas theadministration of immunosuppressive drugs was followedby more frequent remissions of the nephrotic syndrome (75vs. 30.7% of patients). Corticosteroids alone were followedby remission in 63% of patients, whereas, combination oflower dose of prednisolone with azathioprine andcyclosporin were followed by remission in 80 and 87% ofpatients, respectively [27]. Although the number of treatedpatients in each subgroup was small, the results of thisstudy show that low-dose of prednisolone and cyclosporinmight be a good choice as initial therapeutic approach,since it is followed by frequent remission of nephroticsyndrome and no serious side-effects. Relapses of thenephrotic syndome after discontinuation of CsA wereobserved in 20% of patients, with the gradual tapering ofCsA [27]. Tacrolimus and sirolimus have been used in asmall number of patients with steroid and/or cyclosporindependent or resistant nephrotic syndrome with goodresults [28, 29]. However, the experien-ce is very limitedand further research is required in particular for sirolimusthat showed nephrotoxicity in some FSGS patients.Mycophenolate mofetil has been used in some patients withfrequently relapsing or resistant to corticosteroids, cytotoxicdrugs and cyclosporin nephrotic syndrome. A reduction ofproteinuria by 50% was observed in more than 40% ofpatients with resistant nephrotic syndrome, along with thepreservation of renal function in patients with progressiverenal insufficiency and a lack of serious side-effects[30,31]. In a recent prospective trial, MMF was noteffective in children with steroid – resistant nephroticsyndrome, but in steroid-dependent cases it was equallyeffective to cyclosporin with less adverse reactions [32].

26 BANTAO Journal 2007; 5 (2)ACE inhibitors and angiotensin II receptor blockers havebeen given in FSGS patients for blood pressure control andreduction of proteinuria. The experience with these drugs islimited since long-term protection is not necessary inpatients who go into remission with immunosuppressivedrugs. However, administration of losartan (50 mg/day), inpatients with nephrotic syndrome resistant to corticosteroidsand cytotoxic drugs, was followed by remission ofproteinuria in some of them [33].Plasma excange and plasma adsorption have been appliedin patients with recurrence of the disease aftertransplantation and they are followed by remission ofproteinuria, via removal of permeability factors [13]. Inprimary FSGS, plasma exchange has been tried in a limitednumber of patients with nephrotic syndrome resistant toimmunosuppressive drugs with rather favorable results inremission of proteinuria [33].In summary, patients with primary FSGS and proteinuria0.5-2 g/24h, who have a favorable outcome, are usuallytreated only by ACE inhibitors. In patients with proteinuriaof nephrotic range and reasonable renal function (serumcreatinine

BANTAO Journal 2007; 5 (2) 27steroid-resistant idiopathic nephrotic syndrome.Kidney Int 1993; 43: 1377-1384.22. Cattran DC, Appel GB, Hebert LA, Hunsicker LG,Pohl MA, Hoy WE, Maxwell DR, Kunis CL. Arandomized trial of cyclosporin in patients withsteroid-resistant focal segmental glomerulosclerosis.North America Nephrotic Syndrome Study Group.Kidney Int 1999; 56: 2220-2226.23. Zietse R, Wenting GJ, Kramer P, Schalekamp MA,Weimar W. Effects of cyclosporin A on glomerularbarrier function in the nephrotic syndrome. ClinScience 1992; 82: 641-650.24. Cattran D, Neogi T, Sharma R, McCaRTHY E, SavinV for the North American Nehrotic Syndrome Group.Serial estimates of serum permeability activity andclinical correlates in patients with native kidney focalsegmental glomerulosclerosis. J Am Soc Nephrol2003; 14: 448-453.25. Ponticelli C and Passerini P. The place of cyclosporinin the management of primary nephrotic syndrome.Biodrugs 1999; 12: 327-341.26. Cattran DC. Cyclosporine in the treatment ofidiopathic focal segmental glomerulosclerosis. SeminNephrol 2003; 23: 234-241.27. Goumenos D, Tsagalis G, El Nahas AM, Shortland JR,Davlouros P, Vlachojannis JG, Brown CB. Theimmunosuppressive treatment of focal segmentalglomerulosclerosis: A five-year follow-up study.Nephron Clin Pract 2006; 104: c75-c82.28. Duncan N, Dhaygude A, Owen J, Cairns TH, GriffithM, McLean AG, Palmer A, Taube D. Treatment offocal and segmental glomerulosclerosis in adults withtacrolimus monotherapy. Nephrol Dial Transplant2004; 19: 3062-3067.29. Tumlin JA, Miller D, Near M, Selvaraj S, Hennigar R,Guasch A. A prospective open – label trial ofsirolimus in the treatment of focal segmentalglomerulosclerosis. J Am Soc Nephrol 2006; 1: 109-116.30. Choi MJ, Eustace JA, Gimenez LF, Atta MG, ScheelPJ, Sothinathan R, Briggs WA. Mycophenolate mofetiltreatment for primary glomerular diseases. Kidney Int2002; 61: 1098-1114.31. Cattran DC, Wang MM, Appel G, Matalon A, BriggsW. Mycophenolate mofetil in the treatment of focalsegmental glomerulosclerosis. Clin Nephrol 2004; 62:405-411.32. Mendizabal S, Zamora I, Berbel O, Sanahuja M,Fuentes J, Simon J. Mycophenolate mofetil insteroid/cyclosporine-dependent/resistant nephroticsyndrome. Pediatr Nephrol 2005; 20: 914-919.33. Usta M, Ersoy A, Dilek K, Ozdemir B, Yavuz M,Gullulu M, Yurtkuran M. Efficacy of losartan inpatients with primary focal segmental glomerulosclerosisresistant to immunosuppressive treatment. JInt Med 2003; 253: 329-334.34. Feld SM, Figueroa P, Savin V, Nast CC, Sharma R,Sharma M, Hirschberg R, Adler SG. Plasmapheresis inthe treatment of steroid-resistant focal segmentalglomerulosclerosis in native kidneys. Am J Kidney Dis1998; 13: 524.

BANTAO Journal 2007: 5 (2) : 28–31BJBANTAO JournalReviewLong-Term Outcome of Children with Congenital Abnormalitiesof the Kidney and Urinary Tract (CAKUT): an Adult PerspectiveGuy H NeildInstitute of Urology and Nephrology, University College London & Renal Unit, UCL Hospitals, London, UKAbstractPaediatric nephrologists know that worldwide ‘congenitalabnormalities of the kidney and urinary tract’ (CAKUT) accountsfor around 50% of renal failure and other, familial diseasesaccount for another 20%. Adult nephrologists probably do notknow that that this generally remains true up to 40-50 years of age.From a review of the current world literature, the majority ofchildren with renal failure are male and median is 61% (range 51-74%); the diagnosis of CAKUT is made in 51%, and the mediantotal of CAKUT plus hereditary disease is 67%. Progressive renalfailure will occur when the final GFR is below 40 ml/min/1.73m2,and is always associated with increasing proteinuria. Angiotensinconvertingenzyme (ACE) inhibitors lower blood pressure andreduce proteinuria in children. The evidence that they significantlyslow renal failure in children is not yet established, whereas inadults ACEI do slow renal failure in CAKUT. There is noevidence that renal outcome is worse when the CAKUT isassociated with bladder failure.Keywords: CAKUT, reflux nephropathy, proteinuria,abnormal bladder function, angiotensin converting enzymeinhibitors, outcomeIntroductionThe scope of this review and the key teaching points can besummarised as:Paediatric nephrologists know that worldwide ‘congenitalabnormalities of the kidney and urinary tract’ (CAKUT)account for around 50% of renal failure and other, familialdiseases account for another 20% (together 70%).Paediatric nephrologists accept that conditions referred to bythe synonyms primary vesico-ureteric reflux, refluxnephropathy, chronic pyelonephritis, chronic atrophicpyelonephritis, are all part of the family of ‘primary renaldysplasia’ (including synonyms - hypoplasia, adysplasia,hypodysplasia). And that urinary tract infection is not theprimary issue.Paediatricians know everything about the outcome of theirpatients up to around 14 years of age; while adult nephrologistsknow everything about their patients from around 16 years (andlittle before).Progressive renal failure in CAKUT is a consequence ofhyper-filtration in the remnant kidneys. (And therefore similarto any other progressive glomerular disease such as diabetes).ACE inhibitors lower blood pressure and reduce proteinuria inchildren – but the evidence that they significantly slow renalfailure is not yet established. Whereas in adults ACEI do slowrenal failure in CAKUT.There is no evidence that outcome is worse when the CAKUT isassociated with bladder failure. Or, conversely, no evidence thatbladder dysfunction is the cause of progressive renal failure inchildren with congenital outflow obstruction (from e.g. posteriorurethral valves).DiscussionCAKUT as a cause of renal failure.In the Table 1, I review and summarise the current worldliterature on the Epidemiology of renal failure in children.Summarising the data from the Table - the median upper agewas 16 (range: upper age 12-22 yrs); the median male majoritywas 61% (51-74%); the median percentage with CAKUT 51%,and the median total of CAKUT plus hereditary disease was 67%.There are three points to make:There is a consensus that worldwide ‘congenital abnormalities ofthe kidney and urinary tract’ (CAKUT) accounts for around 50%of renal failure and other, familial diseases account for 20%(together 70%).The inadequacy of diagnosis coding systems – such as the oldEDTA system which has 7 forms of ‘pyelonephritis’ to choosefrom – coupled with the lack of effort made in reporting toregistries (such as USRDS) means that USRDS data and EDTAdata massively under-report the true situation.China seems to be genuinely different, with glomerulonephritis asthe major cause of renal failure (this may also be true for Nigeria,i.e. sub-Saharan Africa). There is data reported in the Table fromChina and Japan that suggests that CAKUT, particularly thatassociated with bladder outflow obstruction, is much less commonthan in the West and the latter also seems to apply to BlackAfricans.Moving away from the paradigm of chronic infection inthe pathogenesis of renal failure.The idea that ‘scarring’ of the kidneys, leading to irregularasymmetric kidneys, is a primary consequence of reflux andurinary tract infection is no longer tenable. This is reviewed in anaccompanying paper. While this new view seems to be generallyaccepted by paediatricians, I believe that most adultnephrologists have not yet accepted (realised) this.______________________Correspodence to: Guy H Neild, UCL Centre for Nephrology, Royal Free Campus, London, NW3 2QG, UK;Tel: +44 - 0207 794 0500 xtn 3322; Fax: +44 - 0207 830 2125; E-mail: g.neild@ucl.ac.uk

BANTAO Journal 2007; 5 (2) 29PublishyearTable 1. Epidemiology of Paediatric renal failure by countryReference Age Country number % MalesCongenital/+Hereditary2006 (1)

30ml/min1.73m 2 , mean proteinuria 144 mg/mmol (1.7 g/24hrs). Of 78 patients, 36 (46%) developed ESRF, but none of19 with proteinuria less than 50 mg/mmol and only two of18 patients with eGFR above 50 ml/min did so. Renaloutcome between Groups 1 and 2 were similar with noevidence for a difference. A benefit in favour of treatmentwith ACEI was observed above an eGFR of 40 ml/min. Weconcluded that the similar outcome of the two groupssupports the nephrological nature of progressive renalfailure in young men born with abnormal bladders. There isa watershed GFR of 40-50 ml/min at which ACEI treatmentcan be successful at improving renal outcome. All thesefindings were consistent with previous studies.Treatment and natural history – the paediatric perspectiveUntil recently there was little outcome data on primaryreflux nephropathy in children, none on secondary refluxand no outcome studies of the effect of ACEI. This haschanged in the last 2-3 years and is reviewed in anotheraccompanying paper.One recent retrospective single centre review of childrentreated at Great Ormond Street Hospital in London, shouldbe mentioned, however, and its key results summarised[30].176 children were reviewed with CRF secondary to renaldysplasia, reflux nephropathy or renal obstruction with atleast 5 years of follow-up. The development of renalfunction could be separated into three time periods: (1)During the first years of life, 82% of the children showedearly improvement of their kidney function, which lasteduntil a median age of 3.2 years (median improvement 6.3ml/year). (2) From the age of 3.2 years until 11.4 years,53% of the studied children showed a stable kidneyfunction, whereas in 48%, kidney function immediatelystarted to deteriorate. (3) Around puberty, 43% starteddeterioration in kidney function, whereas 57% even afterpuberty showed a stable function. Patients with proteinuria(Ua/Uc >200 mg/mmol) deteriorated faster (-6.5 comparedwith -1.5 ml/min/1.73m 2 per year) than those with Ua/Uc

BANTAO Journal 2007; 5 (2) 31annual report of NAPRTCS. North American PediatricRenal Transplant Cooperative Study. Pediatr Nephrol1998; 12: 328-337.18. Esbjorner E, Berg U, Hansson S. Epidemiology ofchronic renal failure in children: a report from Sweden1986-1994. Swedish Pediatric NephrologyAssociation. Pediatr Nephrol 1997; 11: 438-442.19. Sirin A, Emre S, Alpay H et al. Etiology of chronicrenal failure in Turkish children. Pediatr Nephrol1995; 9: 549-552.20. Deleau J, Andre JL, Briancon S, Musse JP. Chronicrenal failure in children: an epidemiological survey inLorraine (France) 1975-1990. Pediatr Nephrol 1994;8: 472-476.21. Mattoo TK, Al-Mohalhal S, Al-Sowailem A,Mahmood MA. Chronic renal failure in children inSaudi Arabia. Ann Saudi Medicine 1990; 10: 496-499.22. Pistor K, Olbing H, Scharer K. Children with chronicrenal failure in the Federal Republic of Germany: I.Epidemiology, modes of treatment, survival. Arbeitsgemeinschaftfur Padiatrische Nephrologie. ClinNephrol 1985; 23: 272-277.23. Potter DE, Holliday MA, Piel CF et al. Treatment ofend-stage renal disease in children: a 15-yearexperience. Kidney Int 1980; 18: 103-109.24. Brenner BM, Meyer TW, Hostetter TH. Dietaryprotein intake and the progressive nature of kidneydisease: the role of hemodynamically mediatedglomerular injury in the pathogenesis of progressiveglomerular sclerosis in aging, renal ablation, andintrinsic renal disease. N Engl J Med 1982; 307: 652-659.25. Neild GH, Thomson G, Nitsch D et al. Renal outcomein adults with renal insufficiency and irregularasymmetric kidneys. BMC Nephro. 2004; 5: 12.26. Brod J. Chronic pyelonephritis. Lancet 1956; 270:973-981.27. Kincaid-Smith P, Becker G. Reflux nephropathy andchronic atrophic pyelonephritis: a review. J Infect Dis1978; 138: 774-780.28. Zucchelli P, Gaggi R. Reflux nephropathy in adults.Nephron 1991; 57: 2-9.29. Goodship TH, Stoddart JT, Martinek V et al. Longtermfollow-up of patients presenting to adultnephrologists with chronic pyelonephritis and 'normal'renal function. QJM 2000; 93: 799-803.30. Gonzalez CC, Bitsori M, Tullus K. Progression ofchronic renal failure in children with dysplastickidneys. Pediatr Nephrol 2007; 22: 1014-1020.

BANTAO Journal 2007: 5 (2); 32–36BJBANTAO JournalOriginal ArticleSerbian Pediatric Chronic Kidney Disease Registry - SPEKIDAmira Peco-Antic 1 , Radovan Bogdanovic 2 , B. Mulic 3 and SPNWG 41 University Children's Hospital, Belgrade, Serbia, 2 Institute for Mother and Child Health Care, Belgrade, Serbia, 3 MedicalCentre, Novi Pazar, Serbia, 4 Serbian Pediatric Nephrology Working GroupAbstractBackground. The SPEKID Registry is a prospective,population-based registry formed in Serbia in 2000 toprovide current and reliable information concerning pediatricchronic kidney disease (CKD) stage 2 to 5 forplanning pediatric renal replacement treatment and devisingand monitoring strategies for prevention of chronic renalfailure (CRF) in Serbia.Methods. The index cases were defined using the followingcriteria: 1) decreased GFR for at least 3 months; forchildren aged ≥ 1 year less than 90 ml/min/1,73m² and foryounger ones as serum creatinine > mean +2SD; 2) agebelow 19 years at the time of registration, and 3) writteninformed consent for data collection, reporting and storage.The estimated numbers of people “at risk” for the morbidityanalysis, derived from the 2002 state census were 7,5millions of general total population and 1,7 million of thoseyounger than 19 years. All of the Serbian centres potentiallyinvolved in caring for children and adolescents withCRF were invited to report index cases. The children werereported on a prospective basis, but retrospective check-upwas also performed.Results. From January 2000 to December 2006, 205 childrenwere registered. An average age of patients at the time of theregistration was 8.4 years; boys were about 2 years youngerthan girls. Ratio of male to female was 1.97:1. A medianfollow-up of the patients after being registered was 5 years,while 25% of the patients were followed for 7 years. The meanannual incidence of CKD stage 2 to 5 was 10.04 per millionchild population (pmcp), ranging from 6.5 to 19.4 pmcp. Theprevalence increased significantly during the study period,reaching 100.7 pmcp in December 2006. The mean annualincidence of terminal renal failure was 6.0 pmcp, whileaverage point prevalence was 3 times greater. Conclusion.Congenital disorders contributed to more than two third of allcauses of CRF. Eight children died during 7 years of the studyperiod, 4 patients in non-terminal group and 4 patients on renalreplacement therapy. The most common cause of the deathwas due to cardiovascular complications. The probability ofsurvival was 92.9% at 7 years of the follow-up.Keywords: Chronic kidney disease, children, chronic renalfailure, renal replacement therapy, epidemiologyIntroductionfrom well-defined populations are rare [1]. The existingdata from literature are mainly concentrated on renalreplacement tharapy (RRT) and the incidence of pediatricend-stage renal disease (ESRD) is approximated bydeterming the numer of children accepted into dialysis/transplantprograms [2-4]. On that way, the considerablenumber of children with renal impairment is not included asthey reach ESRD in adulthood. Furthermore, ESRDepidemiological data are not sufficient when the emphasisis on ESRD prevention. Although pediatric RRTdramaticaly improved during the last decade, it can bedifficult for pediatric patients with ESRD to acheive normalcognitive, psychological, and physical development andnormal lifestyle. In addition, pediatric RRT is very costlyand kidney transplantation as the treatment of choice is notwithin the reach of the majority of the patients. Recentresearch results make it clear that appropriate therapeuthicintervention at the less advanced stages of renal impairmentcan change the course of CKD to avoid ESRD. With this inmind, prevention should be directed at limiting theprogression of the disease after the existing progressiverenal disease is discovered. Therefore, the Serbian PediatricNephrology Working Group (SPNWG), founded in January2000, established in June 2000 Serbian Pediatric KidneyDisease registry (SPEKID) as a prospective, populationbasedregistry to provide current and reliable informationconcerning CKD for devising and monitoring strategies forprevention of chronic renal failure (CRF) and planningRRT in Serbia. Thus, the secondary objectives were toexamine the epidemiological characteristics, modalities oftreatment and survival of the children with CRF treated inSerbia. Here we report the basic epidemiologic results ofthe first 7 years of SPEKID activity.Patients and methodsThe index cases were defined using the following criteria:1) decreased glomerular filtration rate (GFR) for at least 3months, below 90 ml/min/1,73m² for children aged ≥ 1 yearand for younger ones serum creatinine above mean +2SD;2) age below 19 years at the time of registration, and 3)written informed consent for data collection, reporting andstorage. The staging of registered population was doneaccording to K/DOQI classification of. CKD [5]; stages from2 to 4 were designated as non-terminal renal failure, whileCKD stage 5, (ESRD) was defined as either GFR less than15 ml/min/1.73 m2, or a need for the initiation of kidneyreplacement therapy by dialysis or transplantation. Theestimated number of pediatric population “at risk” for theThe epidemiological reports on non-terminal stages of theprogressive forms of pediatric chronic kidney disese (CKD)______________________Correspodence to: Amira Peco-Antic, University Children's Hospital, Tirsova 10, Belgrade, Serbia;Tel/Fax. ++ 381 11 3612 858; E-mail: amirapecoantic@yahoo.com

BANTAO Journal 2007; 5 (2) 33morbidity analysis derived from the 2002 state census: generaltotal population of around 7,5 millions and 1,7 million ofchildren [6]. All of the Serbian centres potentially involved incaring for children and adolescents with CRF were invited toreport index cases. The children were reported on aprospective basis, but retrospective check-up was alsoperformed. New cases were reported using a standardizedregistration form containing a predefined list of diagnosis.Updating of tha data were done every year.ResultsFrom January 2000 to December 2006, total of 205 childrenwere registered. An average age of patients at the time of theregistration was 8.4 years; mean age of boys as about 7 [8]years (7.8 ± 5.9; range 0-19), and girls were about 2 yearsolder (9.5 ± 4.9; range 0-19). Pre registration mean follow-upof the patients was almost 5 years (4.7; range 0.5-16). Malespredominated in all age groups; ratio of male to female wasabout 1.97:1. A median follow-up of the patients after beingregistered was 5 years, while 25% of the patients werefollowed for 7 years. The majority of the patients (91.5%)were from Serbia, 4.5% were form Republic of Srpska and 4%from Montenegro. The mean annual incidence of CKD stage2-5 was 10.04 per million child population (pmcp), rangingfrom 6.5 to 19.4 pmcp. The prevalence increased significantlyduring the study period, reaching 100.7 pmcp in December2006. Male predominated in incidence as well as in prevalencegroups of patients. Linear trend of prevalence significantlyincreased, while the linear trend of incidence showed slightdecrease (Figure 1). Regression analysis of age adjusted ratesof incidence for boys showed slight decrease except in infants.The regression analysis of age adjusted rates of incidence forgirls showed decrease in all age groups. On the contrary,regression analysis of prevalence of CKD stage 2 to 5documented increases both in boys and in girls.Belgrade, covered all needs for chronic hemodialysis andkidney transplantation, while peritoneal dialysis was alsodone at Institute for Mother and Child Health Care,Belgrade and in the Institute for Children and Youth, NoviSad.Congenital anomalies of kidney and urinary tract (CAKUT)accounted for 64.5 % of all cases and hereditary renalconditions for 16.5%. Therefore, congenital disorderscontributed to more than three fourth of all causes of CRF.Primary glomerular disease was the cause of CRF in 13.5%.Non obstructive pyelonephritis as the cause of CRF was notfound in any of the children. Congenital disorders were morecommon in male than in female patients. When compared thecauses of non terminal renal failure, to those of terminal renalfailure one can notice that rate of CAKUT occurrence,although still remaining on the first place, decreased while thefrequency of the primary glomerular diseases increased. Age atthe diagnosis of primary renal disorder was the highest for thepatients with primary glomerular disease, while that for theCAKUT was about 4 years.The prevalence of the kidney transplantation has been clearlyexpanded from 2000; the chronic hemodialysis has beenslowly decreases in the recent years, while the prevalence rateof peritoneal dialysis was constantly low (Figure 2).10,009,008,007,006,005,004,003,002,001,000,00y = 0,4984x + 1,6817R 2 = 0,371y = -1,1266x + 9,494R 2 = 0,70922000 2001 2002 2003 2004 2005 2006HD Tx Linear (Tx) Linear (HD)120a)10080y = 5,9707x + 54,336R 2 = 0,800330,0025,00y = 1,2857x + 17,026R 2 = 0,56396040200y = -0,9554x + 13,854R 2 = 0,2322000 2001 2002 2003 2004 2005 2006IncidenceLinear (Prevalence)PrevalenceLinear (Incidence)Fig. 1. Linear trend of incidence and prevalence of CKD stage 2-520,0015,0010,005,000,00y = 3,6732x + 1,5237R 2 = 0,9618y = 0,1574x + 0,2279R 2 = 0,48382000 2001 2002 2003 2004 2005 2006HD Tx PDThe mean annual incidence of terminal renal failure was 6pmcp, while average point prevalence was 3 times greater.Male terminal renal failure patients were more numerousthan female ones in incidence and in prevalence groups,although the difference was less prominent than in the nonterminalrenal failure patients.The majority of the patients with CKD stage 5 (57.9%)were from the central part of Serbia, 21% were fromVojvodina, 8.8% from Kosovo, 7% from Republic ofSrpska and 5.3% from Montenegro. Single specializedpediatric RRT centre at University Children’s Hospital,b)Fig. 2. Linear trend of incident (a) and prevalent RRT* (b)*Legend: HD-hemodialysis; Tx - transplantation; PD -periotoneal dialysisFrom 2000 to 2006 linear trend of incidence of dialysistreatment decreased while that of kidney transplantationincreased. However, the prevalence of both of thesetreatments, chronic hemodialysis and transplantation,showed significant increase, especially transplantation,while peritoneal dialysis remained in stable low position.

34 BANTAO Journal 2007; 5 (2)Eight children died during 7 years of the study period, 4patients in non-terminal group and 4 patients on renalreplacement therapy, mostly occuring early after startingRRT (3/4). The most common cause of the death was dueto cardiovascular complications. The probability of survivalwas 92.9% at 7 years of the follow-up (Figure 3).Probabilityof survival100%80%60%40%CensoredSurvival 020%00 1 2 3 4 5 6 7 8YearsFig. 3. Probability of survival of patients with CKD stage 2-5DiscussionThis is the first nation-wide prospective long-term study ofincidence and etiology of pediatric CKD in Serbia. Havingin mind the prevention of CRF at the first place, we definedour target pediatric population as those patients who have atleast mild chronic reduction of the glomerular filtrationrate. The limitation of this study, as well as with allepidemiological studies based on multicenter reportingdata, must be acknowledged, including the possibility thatall data might not have been reported or registered.Incomplete documentation may underestimate CKD due toboth underdiagnosis, and under-referral. The formercorresponds especially to children with CKD stage 2-3 asthey might be unrecognased in time, while the later ispossible for adolescent patients with CKD 5, as they couldhave been dialyzed in adult centers. Recently SPEKID hasimproved by on line reporting and verification the accuracyof the epidemiological data will be done using the capturerecapturemethod.Data regarding the morbidity of CRF in children,commonly encountered in the literature are disappointinglydifferent due to the un-uniform source of information,definition criteria for CRF and disease of selectedclassification. The incidence and prevalence of nonterminalCRF in children in some countries are shown inTable 1 [7-13].Table 1. Incidence and prevalence of pediatric non-terminal CRFCountry Time AgeIncidence Point prevalenceDefinition of CRF(reference) period (years)pmcp*pmcpGermany (7) 1972-1975 0-16 s. Cr >2 mg% 4.4 6.4Swiss (8,9) 1972-1974 0.5-16 s. Cr >2 mg% NA 1976-18,51991- 28France (10) 1975-1990 0-16 s. Cr >2 mg% 10.05 (12.5-7.5) 29.0-54.0Sweden (11) 1978-1985 0.5-16 CsCr

BANTAO Journal 2007; 5 (2) 35patients. Also there is agreement in our data and those fromliterature concerning the causes of CRF in children [17].Hypo/dysplasia with or without associated urologicalmalformations accounts for the majority of CRF in ourpatients as well as in others (41% in Sweeden, 53% inFrance and 57% in Italy), whereas glomerular disease areby far less common (14.5, 22.5 and 6.8%, respectively),than reported in the past [11,18,19]. Overall survival rate ofour patients was quite well. In children younger than twoyears the mortality occured due to comorbid states and/orearly after starting RRT. The survival of transplantedpatients was better than that of dialysis patiens.Table 2. Incidence and prevalence of ESRD pediatric patientsCountry(reference)TimeperiodAge(years)Incidencepmcp*Pointprevalencepmcp*Germany (7) 1972-1977 0-16 4.4-5.4 11.9-22.0Swiss (8,9) 1967-1974 0.5-16 5.6 NAFrance (10) 1975-1990 0-16 5.6-9.1 15.5-37.0Sweden (11) 1978-1985 0.5-16 6.9 12.4-16Sweden (12) 1986-1994 0.5-16 6.4 38USA (14) 1989-1991 0-19 11.0 53.0France (15) 1998 0-17 14.0 NAYugoslavia (16) 1980-1999 0-19 1.6 NASerbia 2000-2006 0-19 6 (1.3-10) 31.6*pmcp, per million child population; NA, not availableConclusionSPEKID data demonstrated an increase in annual incidenceof CRF in infants and increase in the prevalence of CRF inall age groups. Congenital renal malformations were themain cause of CRF in Serbian children. Survival of nonterminaland terminal CRF patients is comparable to thosein the developed countries. Single specialized pediatricRRT centre can meet all needs the Republic of Serbia.Transplantation is the best modality of RRT. Future effortsshould be directed to extend peritoneal dialysis and toimprove pediatric renal transplantation to meet individualneeds of children with ESRD in Serbia.Primary prevention should be directed at avoiding renalinjury through improved and increased prenatal diagnosisand early postnatal care in targeted groups. Secondaryprevention should be aimed at limiting disease progressionafter discovering renal injury. Early detection interventions(urine protein annual screenings, blood pressure control,dietary counselling, renoprotective therapy) may delayrenal deterioration and/or reduce the incidence of renalrelateddeaths in pediatric patientsConflict of interest statement. None declared.Acknowledgements. This article was written on behalf of allthe members of the Serbian Pediatric Nephrology WorkingGroup – SPNWG whose contribution has been essential.Blagojevic Lj (Cacak), Bubalo J (Novi Sad), Danojlic S(Kraljevo), Golubovic E (Nis), Gostovic S (Beograd),Karaklajic D (Pancevo), Kasza Meszaros M (Subotica),Kojic-Maletkovic D (Gornji Milanovac), Kostic M(Beograd), Kovacevic B (Zrenjanin), Kruscic D (Beograd),Malbasic Lj (Zemun), Milosevic-Rudic B (Novi Sad),Milosevski G (Beograd), Milcanovic B (Uzice), MiljkovicP (Nis), Nikolic R (Cuprija), Paripovic D (Beograd),Pavicevic M (Kragujevac), Pejovic B (Beograd), Pejcic I(Beograd), Poznan A (Subotica), Putnik J (Novi Beograd),Radisavljevic S (Cuprija), Ristic N (Smederevska Palanka),Spasojevic B (Beograd), Stajic N (Novi Beograd), Stanic M(Beograd), Stojanovic V (Novi Sad), Djapic M (Novi Sad),Virijevic V (Krusevac), Vujic-Janic A (Kragujevac), SererV (Valjevo), Scekic G (Zemun).References1. Ardissino G, Dacco, Testa S, Bonaudo R,Claris/Appiani A, Taioli E, Marra G, Edefonti A,Sereni F, on behalf of the ItalKid Project. Epidemiologyof the chronic renal failure in children: data fromthe ItalKid Project. Pediatrics 2003; 111: 382-387.2. Mehls O, Rigden S, Ehrich JHH, Berthoux F, JonesEHP, Valderrabano F, on behalf of the EDTA-ERARegistry (1996) Report on management of renal failurein Europe, XXV, 1994. The child-adult interface.Nephrol Dial Transplant (Suppl. 1); 11: 22-36.3. Lerner GR, Bradley A, warady E, Sullivan EK,Alexander SR. Chronic dialysis in children andadolescents. The 1996 annual report of the NorthAmerican Pediatric Renal Transplant CooperativeStudy. Pediatr Nephrol 1999; 13: 404-417.4. U.S. Renal Data System. USRDS 1999 annual datareport. Bethesda, MD: National Institutes of Health,National Institute of Diabetes and Digestive andKidney Disease.5. Hogg RJ, Furth S, Lemley KV, Portman R, SchwartyGJ, Coresh J, Balk E, Lau J, Kausz A, Eknoyan G,Levey S. National Kidney Foundation’s KidneyDisease Outcomes Initiative Clinical PracticeGuidelines for Chronic Kidney Disease in Childrenand Adolescents: Evaluation, Classification, andStratification. Pediatrics 2003; 111: 1416-14216. Final Results of the Census 2002. Communication SN31. 2002; 295 Issue LII7. Pistor K, Obling H, Scharer K. Children with chronicrenal failure in the Federal Republic of Germany: I.Epidemiology, modes of treatment, survival. Arbeitsgemeinschaftfur Padiatrische Nephrologie.

36 BANTAO Journal 2007; 5 (2)8. Leumann EP. Chronic juvenile kidney insufficiency.Results of a Swiss questionnaire. Schweiz MedWochenschr 1976: 106: 244-250.9. Leumann E. Chronic renal failure (CRF) In: PracticalPaediatric nephrology edited by Leumann E, Turi S,Matheova E. Teaching and training Course in pediatricNephrology, Kosice 1993. RESULT Company, Kosice1994.10. Leumann EP. Chronic juvenile kidney insufficiency.Results of a Sweiss questionnaire, Schweiz MedWochenschr 1976; 21: 106:244-50.11. Deleau J, Andre JL, Briancon S, Musse JP. Chronicrenal failure in children: an epidemiological survey inLorraine/France (1975-1990). Pediatr Nephrol 1994;8: 472-476.12. Esbjorner E, Ronson S, Berg U, Jodal U, Linne T.Children with chronic renal failure in Sweden 1978-1985. Pediatr Nephrol 1990; 4: 240-252.13. Esbjorner E, Berg U, Hansson S. Epidemiology ofchronic renal failure in children: a report from Sweeden1986-1994. Pediatr Nephrol 1997; 11: 438-442.14. Lagomarsimo E, Valenzuela A, Cavagnaro F, Solar E.Chronic renal failure in pediatrics 1996. Chileansurvey. Pediatr Nephrol 1999; 13: 288-91.15. United States Renal Data System. Pediatric end stagerenal disease. Am J Kidney Dis 1994; 24;S112-S127.16. Jungers P, Choukroun G, Robino C, et al.Epidemiology of end-stage renal disease in Ile-deFrance area: a prospective study in 1998. Nephrol DialTransplant 2000; 15: 2000-6.17. Peco-Antic A, Popovic-Rolovic M, Jovanovic O,Marsenic O, Babic D, Kostic M, Kruscic D, Culic D,Trajkovic D. 20 years' experience in the treatment ofchildren with terminal renal insufficiency inYugoslavia. Srpski Arhiv 2001; 128 (11-12): 363-9.18. Ardissino G. Epidemiology of chronic renal failure. InCochat P (eds) ESPN Handbook, Medcom, Lyion,France, p 369-372.19. Dacco V, Testa S, Claris-Appiani A, et al. Naturalhistory of renal function in childhood chronic renalinsufficiency. J Am Soc Nephrol 1998; 9: 145A.31. Fivus BA, Jabs K, Neu Am, et al. Chronic renal insufficiencyin children and adolescents: the 1996 annualreport of NAPRITCS. Pediatr Nephrol 1998; 12: 328-37.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 37–38Original ArticleHepatocyte Growth Factor, Vascular Endothelial Cell Growth Factorand Tumor Necrosis Factor - a Release During High Flux HaemodialysisFotini Christidou¹, Argiri Aggelou¹, Gramati Galaktidou², Stelios Fragidis³, Panagiota Veneti³,Kostas Sombolos³ and Theodore Bischiniotis²¹Renal Unit of Chalkidiki’s General Hospital, ²Symeonidio Research Centre “Theagenio” Cancer Hospital Thessaloniki,3 G. Papanikolaou General Hospital, Thessaloniki, GreeceAbstractBackground. The aim of this study was to compare the effectof low molecular weight heparin (LMWH) on circulatinglevels of hepatocyte growth factor (HGF), vascular endothelialcell growth factor (VEGF) and tumor necrosis factor-a (TNFa)during high flux haemodialysis session.Methods. We studied 12 haemodialysis patients (62, 6 ±13, 2 years), who were on HD for 19-218 months with highflux filters. Following washout of the filter with normalsaline, HD was started with zero hyperfiltration and withoutheparin. LMWH enoxaparin, was administered 10 min fromthe beginning of HD. HD was continued without hyperfiltrationfor 10 more minutes. Four blood samples wereevaluated: at the beginning of the HD session (t 0), 10 and20 mins (t 10, t 20) from the beginning and 5 min after HDwas completed (t - post).Results. Compared to t0 HGF levels, t10 HGF serum levelswere not altered. Following heparin administration a significantincrease in HGF serum levels was noted. Compared tot10 HGF levels, the t20 levels were also significantly increased(p

38 BANTAO Journal 2007; 5 (2)post samples were differed statistically for HGF and TNF-avalues, but not for VEGF values (p

BJBANTAO JournalBANTAO Journal 2007: 5 (2) : 39–42Original ArticleCourse of IgA Nephropathy: follow-up of 23 yearsMaja Milovanceva-Popovska 1 , Ladislava Grcevska 1 , Sonja Dzikova 1 , Vesna Ristovska 1 , Vlado Nikolov 1 ,Aleksandar Sikole 1 and Momir Polenakovic 1, 21 Clinic of Nephrology, Medical Faculty, University ”Ss Cyril and Methodius”, 2 Macedonian Academy of Sciences and Arts,Skopje, R.MacedoniaAbstractBackground. IgA nephropathy (IgAN) accounts for 11.8%of primary glomerulonephritides (GN) in R. Macedonia.IgAN presents with variable onset and shows unpredictableoutcomes.Methods. To evaluate the association of risk factors withthe progression of IgAN to renal failure we examined eightypatients diagnosed by renal biopsy (RB). We used H. S.Lee’s grading system to score the severity of histologicalinvolvement. Baseline clinical and demographic data werereviewed. Patients were followed-up from 6 to 276 months.Male: female ratio was 58:22; the mean age was 36.65±8.83years. The date when patients underwent their firsthaemodialysis or their last visit was defined as an end-point.Independent samples t-tests or one-way analysis of variance(ANOVA) were used to compare the differences in meansbetween groups. Kaplan-Meier survival curves and Coxregression models were used to analyze the time coursefrom renal biopsy to end points.Results. The largest subclasses were grade I and II, with 31patients each. All patients with grade IV and V (after 6-48months), five patients grade I (after 60-144 months), fourpatients grade II (after 48-84 months), and 7 patients fromgrade III (after 24-108 months) entered ESRD. Macrohematuriahad 32; microhematuria had 48 patients. Meanproteinuria was 1.68±0.99 g/day and the mean serum creatininewas 148.02±68.76 μmol/l. By multivariate analysisusing the Cox regression model, grades, renal insufficiencyand significant proteinuria were independent prognosticfactors for progressive renal disease. At the end of followup,grades were significantly related to serum creatinine,proteinuria, hypertension and progressive renal disease.Conclusions. Renal biopsy remains the most powerfulpredictor for renal outcome. Determining the patient whomight develop ESRF over time based on clinical andhistological renal findings remains a challenge.Keywords: IgA nephropathy, follow-up, renal prognosis,histological gradingIntroductionIdiopathic IgA nephropathy (IgAN), the most prevalentprimary glomerulonephritis (GN) in the world, accounts for11.8% of all forms of primary GN in Macedonia [1,2]. Thedifferences between countries are due to the length of thefollow-up period, the geographic variability and differencesin disease prevalence (Italy 21%, Nederland 13%, Spain15%, Check Republic 21%, China 31%), different histologicalcriteria of classification, different indications of biopsy. It ispossible that the potential differences in the progression of thedisease are due to therapy and what is the means of “naturalcourse”. All patients in the present study were not ontreatments modulating immune and inflammatory injury.IgAN is an immune-complex-mediated GN first describedby Berger and Hinglais in 1968, morphologically characterizedby IgA deposition in the glomerular mesangium [3].It occurs predominantly in young people and presents withvariable onset and shows different outcomes [4]. Initially itwas believed to be a benign and non-progressive disease butnow days IgAN is the second or third most common primaryGN to terminate in ESRD in many of the world’s registries.In Europe as a whole, approximately 24% of histologicalexamined patients have IgAN as cause of ESRD [5].Complete remission is also reported in 5 to 30% of cases. [6].The aim of the present study was to examine the associationsof the previously identified factors (demographic, clinical,laboratory, and histological parameters) at the time of renalbiopsy with the progression to renal failure in our population.Patients and methodsEighty Macedonian Caucasians with biopsy-proven IgANwere enrolled in retrospective follow-up study. Patients agedolder than 15 years at presentation were considered adults.Patients who suffered from systemic diseases (Systemic lupuserithematodes, Henoch-Schönlein purpura, Diabetes mellitus,collagen disease, and chronic liver disease) or had previoustreatment with steroids or immunosuppressants were excluded.The parameters were evaluated at the time of renal biopsy (theinitial values), and at the last outpatient check-up. Baselineclinical and demographic data were taken into considerationfor each patient: age, sex, microscopic or macroscopic hematuria,24-h proteinuria, systolic and diastolic blood pressure(sBP, dBP) and renal function (serum creatinine concentration,sCr). Patients with hypertension (BP>130/90 mmHg) ex novoat first observation and those on hypertensive pharmacologicaltreatment were considered as hypertensive. Patients werefollowed up for 6 to 276 months. An end-point was defined asthe date when patients underwent their first haemodialysis ortheir last visit of follow-up.Percutaneous renal biopsies were taken using a TruCutneedle; two specimens were taken for each renal biopsy, forlight microscopy (minimum of 8 glomeruli) and forimmunofluorescence study. The indications for renal biopsy______________________Correspodence to: Maja Milovanceva-Popovska, Department of Nephrology, Medical Faculty, Vodnjanska 17,1000 Skopje, Republic of Mecedonia; Tel. + 389 2 3147 268; E-mail: majamil@freemail.com.mk

40 BANTAO Journal 2007; 5 (2)were persistent microscopic hematuria, proteinuria >0.5g/dayand unexplained renal impairment. All specimens werereviewed by a single pathologist unaware of the patients’clinical condition. IgAN was diagnosed by the typicalappearance of mesangial proliferative GN on light microscopywith predominant mesangial IgA deposition with C3deposition on immunofluorescence microscopy.Meadow [7] and H. S. Lee’s [8] grading system were used forscoring the severity of histological involvement. Grade I:normal glomeruli without crescents/segmental lesions. GradeII: 50-75%glomeruli, with IIIb. Grade V: >50% glomeruli showingproliferation, with crescents/segmental lesions/global sclerosisin >75% glomeruli, with IIIb.Data analysisAll numerical data are expressed as mean±SD. The differencesin means between groups were compared by t-test and onewayanalysis of variance (ANOVA). Post hoc analysis wasperformed by the Bonferroni’s method. The effect ofprognostic factors was studied as stratifying variable withunivariate analysis by log-rank test. Multivariate survivalanalysis was performing using the Cox proportional hazardregression method to identify independent factors. Renalsurvival was estimated by the Kaplan-Meier method. A valueof P1g/day; 21% showednephritic range proteinuria of ≥3.5 g/day. The mean serumcreatinine was 148.02±68.76 μmol/l. Renal insuffici-ency (sCrlevel of 132 μmol/l) was observed in 14%. Arterialhypertension was found in 35%. 60% (48 patients) hadmicroscopic and 40% (32 patients) had macroscopichematuria. The clinical features at the time of biopsy areshown in Table 1.Table 1. Clinical data in relation to glomerular grades at the time of biopsy in patients with IgA nephropathyGlomerular grades F P †I II III IV Vn (%) 31 (38.7) 31 (38.7) 12 (15) 3 (3.7) 3 (3.7)Age (years) 26±10 30±11 31±12 44±0 47±8 4.4 < 0.003*Sex (M:F) 25:6 24:7 6:6 2:1 1:2 NS #sCr (μmol/l) 68±19 85±31 121±78 177±84 228±118 13.3 < 0.001*Proteinuria (g/24h) 1.1±1 1.6±1.3 1.5±1.3 2.5±2.3 2.3±1 1.8 NS*Microscopic Hematuria (n [%]) 19 (61) 19 (61) 6 (50) 1 (33) 3 (100) NS #Macroscopic Hematuria (n [%]) 12 (39) 12 (39) 6 (50) 2 (67) 0 (0) NS #Systolic BP 129±17 130±19 145±19 148±19 177±12 6.6 < 0.001*Diastolic BP 85±10 82±18 93±15 97±15 103±6 2.7 < 0.05*Values represent mean ± SD. NS not significant. BP, blood pressure† Data are compared with *ANOVA or # chi square testYounger age was significantly related to lower histologicalgrades (P

BANTAO Journal 2007; 5 (2) 411Cumulative Renal Survival0,80,60,40,200 12 24 36 48 60 72 84 96 108 120 132 144MonthsFig. 1. The Kaplan-Meier renal survival curve of 80 patients with IgA nephropathy.The renal survival was 97.5% at 1 year, 77.5% at 5 yearsand 61.5% at 10 years. The Kaplan-Meier survival curve isshown in Figure 1.With multivariate analysis, renal impairment at presentation,proteinuria >1g/day and high histological gradingwere associated with worse renal survival (data notshowen). Patients with serum creatinine >132 μmol/l atpresentation ended with renal dead in the first 60 months.According to multivariate analysis, using the Coxproportional hazard regression model, systolic (P1g/day and histologicalgrading at presentation were the major predictors of renalsurvival. The prevalence of patients presenting with arterialhypertension and significant proteinuria increased duringthe follow-up. The prevalence of decreased renal function,present in 14% of the patients at the onset of the disease,had risen to 33.75% by the end of follow-up. These dataconfirm that the prognosis of IgAN is not as good as wasinitially described. The present study confirms that IgANoccurs at a young age, predominately in males (72.5%);moreover microscopic hematuria is the presenting symptomin 60% of cases. These results are similar to other reports[6]. In the present study, higher glomerular grades wereassociated with arterial hypertension, higher sCr levels andolder age at the time of biopsy. These findings are inagreement with previous reports on IgA [6,10,11]. We donot exclude the possibility that age affects the prognosis inIgAN. The presence of renal failure at the time of diagnosishas been reported as an unfavorable prognostic factor.D’Amico et al. reported that there is a ‘point of no-return’,when the patients gets sCr above 3 mg/dl [9]. Over thislimit the functional decline presents a rapid acceleration. Amore recent Komatsu and collaborative German study haveconfirmed these findings [15]. Once renal failure occurs,the evolution to ESRF is practically predictable. We founda little percentage of patients with advanced phases ofIgAN and increased Cr level at the time of biopsy. Thepossible explanation for this is the patients' early referral tothe nephrologists. In general all the studies consider

42 BANTAO Journal 2007; 5 (2)proteinuria values >1g/day as the most significant riskfactor for progression [12]. Patients with nephrotic-rangeproteinuria >3.5g/day were found to have a yearly loss ofrenal function of 9 ml/year. IgA nephropathy ischaracterized by microscopic and macroscopic hematuriabut results from the authors regarding the recurrent bouts ofmacroscopic hematuria as predictor are conflict [6].We observed that higher glomerular grades were related tothe occurrence of hypertension and higher levels of sCr atthe end of follow-up. Grade IV and V; in particular, weremost significantly associated with loss of renal function andprogression. The Lee’s classification system estimatestubulointerstitial damage with increasing severity in twogrades (IV and V). Tubulointerstitial lesions are consideredas indicator of chronic and irreversible renal damage, unlikecrescents or proliferative lesions that may regress.Tubulointerstitial injury strongly and directly correlateswith renal outcome in IgAN, similar to most otherglomerular diseases [6,16,17]. The strong independentpredictors of progression are the severity of glomerularsclerosis and interstitial fibrosis.Adverse clinical features at presentation include hypertension,proteinuria, and renal failure. But, none of the features thatmark a poor prognosis are specific to IgAN [18]. A betterunderstanding of the pathogenesis of IgAN may contributein development more specific therapeutical approaches[19,20]. Recent years there are a lot of studies abouttherapeutic intervention in IgAN. Because the treatmentremains a dilemma (who is high-risk patient, who should betreated, what is the best therapy for one patient) we believethat the renal biopsy in patients with microscopichaematuria and proteinuria is mandatory to prevent renalfailure as the main focus of the therapy.ConclusionIn conclusion, our long-term follow up confirms that thatIgAN occurs at a young age, predominately in males andmicroscopic hematuria is the presenting symptom.Histological features at renal biopsy with higher glomerulargrades are associated with arterial hypertension, higher sCrlevels and older age at the time of biopsy. Increasingevidence now confirm that the prognosis of IgAN is not asgood as was initially believed.Conflict of interest statement. None declared.References1. D’Amico G. The commonest glomerulonephritis in theworld. Q J Med 1987; 64: 707-727.2. Polenakovic HM, Grcevska L, Dzikova S. Theincidence of biopsy-proven primaryglomerulonephritis in the Republic of Macedonialong-termfollow-up. Nephrol Dial Transplant 2003;18: 26-27.3. Berger J, Hinglais N. Les deposits intercapillariesd’IgA-IgG. J Urol Nephrol 1968; 74: 964-965.4. Schena FP. A retrospective analysis of the naturalhistory of primary IgA nephropathy worldwide. Am JMed 1990; 89: 209-215.5. Valderrabano F, Berthoux FC, Jones EH, Mehls O.Report on management of renal failure in Europe,XXV, 1994 end-stage renal disease and dialysis report.The EDTA-ERA registry, European Dialysis andTransplant Association. Nephrol Dial Transplant1996; 11: S2-21.6. D’Amico G. Natural history of idiopathic IgAnephropathy: role of clinical and histological prognosticfactors. Am J Kidney Dis 2000; 36: 227-237.7. Meadow SR, Glasgow EF, White RHR, MoncrieffMW, Cameron JS, Ogg CS. Schoenlein-Henochnephritis. Q J Med 1972; 41: 241-258.8. Lee HS, Koh HI, Lee HB, Park HC. IgA nephropathyin Korea: a morphological and clinical study. ClinicalNephrology 1987; 27: 131-140.9. D’Amico G, Ragni A, Gandini E, Fellin G. Typicaland atypical natural history of IgA nephropathy inadult patients. Contrib Nephrol 1993; 104: 6-13.10. Li PKT, Ho KKL, Szeto CC, Yu LM, Lai F MacM.Prognostic Indicators of IgA nephropathy in theChinese-clinical and pathological perspectives.Nephrol Dial Transplant 2002; 17: 64-69.11. Ikee R, Kobayashi S, Saigusa T, Namikoshi T,Yamada M, Hemmi N, Imakiire T, Kikuchi Y, SuzukiS, Miura S. Impact of hypertension and hypertensionrelatedvascular lesions in IgA nephropathy. HypertensRes 2006; 29; 15-22.12. Usui J, Yamagata K, Kai H, Outeki T, Yamamoto S,Muro K, Hirayama A, Yoh K, Tomida C, Hirayama K,Suzuki S, Kobayashi M, Nogata M, Koyama.Heterogeneity of prognosis in adult IgA nephropathy,especially with mild proteinuria or mild histologicalfeatures. Intern Med 2001; 40: 697-702.13. Bennett WM, Kincaid-Smith P. Macroscopichematuria in mesangial IgA nephropathy: correlationwith glomerular crescents and renal dysfunction.Kidney Int 1983; 23: 393-400.14. Polenakovic M, Grcevska L, Polenakovic H,Josifovska T. The importance of clinicopathologicalpresentation in the evaluation of the survival ofpatients with IgA nephropathy. Acta medica Croatica1994; Zagreb, 48:15-20.15. Komatsu H, Fujimoto S, Sato Y, Hara S, Yamada K,Morita S, Eto T. "Point to no return [PNR]" inprogressive IgA nephropathy: significance of bloodpressure and proteinuria management up to PNR. JNephrol 2005; 18: 690-695.16. Daniel L, Saingra Y, Giorgi R, Bouvier C, Pellissier J-F, Berland Y. Tubular lesions determine prognosis ofIgA nephropathy. Am J Kidney Dis 2000; 35: 13-20.17. Polenakovic M, Grcevska L. Development of renalfailure in IgA nephropathy. The importance ofinterstitial infiltration and deposition of fibrinogen.Renal Failure 1994; 16: 511-523.18. Barratt J, Feehally J. Treatment of IgA nephropathy.Kideny Int 2006; 69: 1934-1938.19. Appel GB, Waldman M. The IgA nephropathytreatment dilemma. Kidney Int 2006; 69: 1939-1944.20. Barratt J, Feehally J. Treatment of IgA nephropathy.Kidney Int 2006; 69: 1934-1938.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 43–45Original ArticleAnti-Telomere Antibodies in Lupus GlomerulonephritisDaniela Monova 1 , Simeon Monov 1 and Trenka Argirova 21 Department of Internal Diseases, Medical University – Sofia, 2 Department of Biochemistry - Sofia University, Sofia, BulgariaAbstractBackground. Differentiating Systemic lupus erythematosus(SLE) from other autoimmune rheumatic diseases andundifferentiated connective tissue diseases may be difficult.Diagnosing SLE early and more accurately is important forpatient education and for the institution of appropriatetreatment to reduce morbidity. The aim of this study is toinvestigate the prevalence and diagnostic significance ofantibodies against telomeric DNA in SLE and otherautoimmune rheumatic diseases, and to make comparisonswith five conventional anti-DNA or anti-nuclear antibody(ANA) assays.Methods. Antibodies to telomeres, which are highlyrepetitive sequences of DNA (TTAGGG/CCCTAA) at theend of eukaryotic chromosomes, were measured by anenzyme linked immunosorbent assay (ELISA) in 225patients with SLE and 108 with other autoimmunerheumatic diseases (96 rheumatoid arthritis, 12 mixedconnective tissue disease). Other assays used were twocommercial ELISA assays for anti-dsDNA using calfthymus as antigen, Crithidia luciliae immunofluorescenceand immunofluorescence using Hep-2 cells for ANA.Results. The prevalence of anti-telomere in SLE was 58,67%, versus 5,21 % in rheumatoid arthritis and 25 % in mixedconnective tissue disease. Specificity of anti-telomere forSLE was 90,6 %, positive and negative predictive valuewere 94,2 % and 45,8 %, respectively. Other anti-dsDNAassays had low sensitivities. The association of antitelomerewith a history of nephritis in patients with SLEwas stronger (P=0,005) than the other assay. Thecorrelations between the different assays were good(P

44 BANTAO Journal 2007; 5 (2)by radioimmunoassay and immunofluorescence werepresent in 97 (43,11 %) and 65 (28,9 %) of patients with SLE,respectively. ANA, by immunofluorescence using Hep-2 cellsas antigen, was present in 141 (62,67 %) of SLE patients.There isn’t correlation between the presence of anti-telomereantibodies and histological type of lupus nephritis.Table 1. Histological type of lupus nephritisHistological type of lupus nephritisNumber (%)of patientsMinimal mesangial lupus nephritis 21 (11,93 %)Mesangial proliferative lupus nephritis 31 (17,61 %)Focal lupus nephritis 14 (7,95%)Diffuse lupus nephritis 68 (38,64 %)Membranous lupus nephritis 42 (23,86 %)Specificity of anti-telomere for SLE was 90,6 %, sensitivitywas 58,4%, PPV and NPV were 94,2 % and 45,8 %,respectively. The most sensitive assays were anti-dsDNAby ELISA (Shield) – 66,2 % and ANA byimmunofluorescence (73,1%), but their specificities werelower (63,5 % and 44,1 %), respectively. The combinationof anti-telomere and anti-dsDNA had high sensitivity (81,2%) and an acceptable specificity (66,2%). SLE patientswith a history of nephritis, confirmed (176 patients) byrenal biopsy (Table 1), had higher concentrations of antitelomereantibodies than patients without nephritis(P=0,005). The associations of other tests were alsostatistically significant (Table 2). Anti-telomere antibodiesalso correlated with SLEDAI score (r=0,389, p=0,006). Thecorrelation coefficients between the different assays aresummarized in Table 3. In general, anti-telomere antibodiescorrelated well with the ELISA assays (r 1 = 0,8021 and r 2 =0,6362) and less well with other tests. ANA and Crithidiaimmunofluorescence had the lowest correlations with othertests.Table 2. Associations of the antibody assays with a history of lupus nephritisANTIBODY ASSAYP - VALUEAnti-telomere 0,005Anti-dsDNA (Shield Diagnostics) < 0,010Anti-dsDNA (Inova Diagnostics) < 0,010Radioimmunoassay < 0,010Chrithidia luciliae < 0,050Antinuclear antibodies < 0,010Table 3. Correlation coefficients of the tests among study patientsANTIBODY ASSAY Anti-telomere Anti-dsDNA (Shield) Anti-dsDNA (Inova) RIA Chithidia luciliae ANAAnti-telomere 1,000 0,8021 0,6362 0,7607 0,3084 0,4423Anti-dsDNA (Shield) 1,000 0,7853 0,4528 0,3206 0,4825Anti-dsDNA (Inova) 1,000 0,4792 0,3101 0,4536RIA 1,000 0,4988 0,4675Chithidia luciliae 1,000 0,2987ANA 1,000DiscussionAn ideal diagnostic test would be sensitive, specific, and havea high PPV and NPV. Increases in sensitivity lead to decreasesin specificity and vice versa. We found that the ELISA assayfor anti-telomeric DNA antibodies was a sensitive and highlyspecific test for SLE. The most sensitive test was ANA byimmunofluorescence, followed by anti-dsDNA and antitelomere.To counterbalance that D. J. Walace et al. ascertainthat anti-telomere was more sensitive than anti-dsDNA by theFarr assay [4]. Anti-telomere was clearly more specific thanthe first two tests. The highest sensitivities were reached byANA together with either anti-telomere or anti-dsDNA.The prevalence of anti-telomere in SLE and other autoimmunerheumatic diseases in our study was similar to other publishedvalues [3,4,7]. D. J. Walace et al. reported that anti-telomereantibody was present in 49% of 220 patients with SLE and E.M. Salonen et al. – in 60% of 305 patients with SLE [4,7]. Wefound a strong correlation of anti-telomere with nephritis,suggesting that the test could be used as an aid for assessingthe activity of SLE.In contrast to D. J. Wallace et al. (35% of SLE patients withnephritis and 21% of patients without nephritis were antitelomerepositive) we found that anti-telomere antibodiespositivity correlated with disease activity score as assessed bySLEDAI [4]. Further longitudinal studies with larger numbersof patients are needed to evaluate whether anti-telomere relatesto the activity of SLE.Why should the anti-telomere assay be better than other antinativeDNA antibody assays? Quantitative immunochemicalstudies in patients with active diseases are needed in whichtelomeric DNA is compared with ordinary dsDNA and withsingle stranded DNA in absorption and cross competitionexperiments with SLE sera.ConclusionsWe found that the ELISA assay for anti-telomeric DNAantibodies was a sensitive and highly specific test for SLE. Themost sensitive test was ANA by immunofluorescence,followed by anti-dsDNA and anti-telomere. Anti-telomere wasclearly more specific than the first two tests.Conflict of interest statement. None declared.References1. Egner W. The use of laboratory tests in the diagnosisof SLE. J Clin Pathol 2000; 53: 113-124.

BANTAO Journal 2007; 5 (2) 452. James K, Meek G. Evaluation of commercial enzymeimmunoassays compared to immunofluorescence anddouble diffusion for autoantibodies associated withauto-immune diseases. Am J Clin Pathol 1992; 97:559-565.3. Salonen EM, Wallace DJ, Metzger A, et al. Antitelomereantibodies are highly specific for SLE.Arthritis Rheum 1998; 41 (suppl 9): 247.4. Wallace DJ, Salonen EM, Avaniss-Aghajani E, et al.Anti-telomere antibodies in systemic lupus erythematosus:a new ELISA test for anti-DNA with potentialpathogenetic implications. Lupus 2000; 9: 328-332.5. Tan EM, Cohen AS, Fries JF, et al. The 1982 revisedcriteria for the classification of systemic lupuserythematosus. Arthritis Rheum 1982; 25: 1271-1277.6. Gladman D, Ginzler E, Goldsmith C, et al. Thedevelopment and initial validation of the SystemicLupus International Collaborating Clinics/AmericanCollege of Rheumatology Damage Index for SLE.Arthritis Rheum 1996; 39: 363-369.7. Salonen E, Miettinen A, Walle T, et al. Anti-telomereantibodies in systemic lupus erythematosus [SLE]: acomparison with five antinuclear antibody assays in430 patients with SLE and other rheumatic diseases.Ann Rheum Dis 2004; 63: 1250-1254.

BANTAO Journal 2007; 5 (2) : 46–48BJBANTAO JournalOriginal ArticleScreening for Microalbuminuria in the General Population of Tirana, a Toolto Detect Subjects at Risk for Progressive Renal Failure in an Early PhaseKliti Hoti 1 , Myftar Barbullushi 1 , Genc Burazeri 2 , Edite Sadiku 3 , Leonard Deda 4 , Merita Rroji 1 ,Saimir Seferi 1 and Nestor Thereska 11 Service of Nephrology Dialysis Transplantation, University Hospital Center “Mother Teresa”, Tirana, Albania, 2 Departmentof Public Health, Faculty of Medicine, Tirana; 3 Service of Internal Medicine, University Hospital Center “Mother Teresa”,Tirana, Albania, 4 Department of Pharmacology, Faculty of Medicine, TiranaAbstractBackground. We conducted a cross-sectional study inTirana, the capital of Albania, in 2005-2006 which aimed toexamine the relationship between urinary albumin excretion(UAE) and other risk factors in the general population.Methods. The sample consisted of 807 individuals: 210men (26%), 597 women (74%). Overall mean age was 37.6± 11.3 years. All participants were invited to undergo urineand blood tests, physical examination and a short interview.For each individual, albuminuria was measured with dipstick andbased on the values of urinary albumin excretion (UAE: mg/24h),participants were classified into 4 groups: 0 to 15 (normal), 15 to30 (high-normal albuminuria [HNA]), 30 to 300 (MA), and >300(macroalbuminuria).Results. The prevalence of proteinuria for each group wasrespectively 69.5% (561 subjects), 19.3% (156 subjects),9.3% (75 subjects) and 1.9% (15 subjects). There wasevidence of a positive correlation of proteinuria with bothdiastolic and systolic blood pressure, which was statisticallysignificant for the third grade of proteiuria and partly forthe second grade. Furthermore, there was evidence of positivecorrelations of proteinuria with body mass index andtotal cholesterol level for the third and the fourth grade.Conversely, there was no correlation with glicemia.Conclusion. Our findings indicate that screening formicroalbuminuria may be a useful tool, either alone or incombination with screening for hypertension and hypercholesterolaemia,to identify subjects at risk for progressive renalfailure. Dipstick urinalysis is a simple, noninvasive test forthe detection of proteinuria, often a marker of unsuspectedchronic renal disease.Keywords: End-stage renal failure; general population;microalbuminuria; screening, urinary albumin excretionIntroductiongeneralized atherosclerosis [1]. CKD has a complexinterrelationship with cardiovascular diseases. There is an inverserelationship between initial renal function and subsequent risk ofdeath and complications from c-v disease [2]. Same correlation as,diabetes and impaired glucose intolerance are also risk factors forrenal disease and cardiovascular disease. Unfortunately, most ofthese patients are referred to the nephrologists only at a time whenrenal function is closeto the level where dialysis is required, that iswhen not much can be expected of conservative renoprotectivetreatments [3].Therefore, it is imperative for screening and prevention programsto detect and then treat people with kidney disease as well thosewith diabetes, hypertension, and cardiovascular disease.Albuminuria is a known risk factor for progression of renaldisease. In addition it’s also risk factor for cardiovascular events inpts with diabetes or kidney disease [4].However, the relevance of urinary albumin excretion as arisk indicator in the general population is controversial.The aim of this study was to early identify the subjects fromgeneral population with risk to develop CKD and toexamine the relationship between urinary albumin excretion(UAE) and other risk factors in the general population suchas age, systolic blood pressure (SBP) and diastolic bloodpressure (DBP), total cholesterol, glomerular filtration rate(GFR), glicemia and body mass index (BMI).Patients and methodsStudy design: a cross-sectional study was carried out in2005-2006 in Tirana, Albania.Study population: sampling was conducted based onpopulation lists provided by the National Institute of Statisticsin Tirana, the capital city of Albania. Sampling frameconsisted of all individuals (both men and women) residing inTirana aged 25-55 years. Based on the population lists, wedrew an age- and sex-stratified sample of 1000 individuals(70% women, 30% men) in selected age-groups (25-35 years:250 women and 100 men; 36-45 years: 225 women and 100men; 46-55 years: 225 women and 100 men). Of 1000individuals targeted for recruitment, 83 (8.3%) could not belocated, whereas 61 (6.1%) refused to participate. A further49 individuals were partially examined, but did not provideinformation on several covariates and, therefore, wereexcluded from the analysis. The final study populationChronic kidney diseases (CKD) are now in pandemicproportions and are one of the causes of morbidity andmortality worldwide. The global prevalence of CKD israpidly increasing, particularly in the developing world,mainly due to changing patterns of disease from intrinsicrenal disease to systemic diseases that damage the kidney,such as diabetes, predominantly type II, hypertension and______________________Correspodence to: Kliti Hoti, Service of Nephrology Dialysis Transplantation, University Hospital Center “MotherTeresa”, Rr. “Dibres”, No. 370, Tirana, Albania; Tel. +355682020275; E-mail: klitihoti@gmail.com

BANTAO Journal 2007; 5 (2) 47consisted of 807 individuals: 210 men (26%), 597 women(74%). Overall mean age was 37.6 ± 11.3 years.Data collection: all participants were invited to undergo urineand blood tests, physical examination (measurement of bloodpressure, weight and height) and a short interview. For eachindividual, albuminuria was measured with dipstick and basedon the values of UAE (mg/24h), participants were classifiedinto 4 groups: 0 to 15 (normal), 15 to 30 (high-normal albuminuria[HNA]), 30 to 300 (MA), and >300 (macroalbuminuria). Weused analytic strip Bayer 10 SG. The dipstick procedures wereconducted by trained laboratory technicians at the UniversityHospital Center in Tirana. GFR was estimated using Cockroft-Gault formula. Definition of hypertension was based on valuesof both systolic and diastolic blood pressure (Joint NationalComity 7). Analysis included data on socio-demographic andsocioeconomic factors and other major risk factors for CKDincluding body mass index.The study was approved by the Albanian Committee ofMedical Ethics. Participants gave written consent after beinginformed about the aim and procedures of the study.Statistical analysis: the prevalence of albuminuria and 95%confidence intervals (CIs) were estimated. Pearson’s correlationcoefficients of microalbuminura with hypertension werecalculated and statistical significance was tested.ResultsAll examined patients were divided into the followinggroups according to levels of proteinuria: 1-Gr (normal), 2-Gr (15-30 mg), 3-Gr (31-300mg) and 4-Gr >300mg. Theprevalence of proteinuria for each group was respectively69.5% (561 subjects), 19.3% (156 subjects), 9.3% (75subjects) and 1.9% (15 subjects). The overall prevalence ofproteinuria is presented in Table 1. Almost 70% of participants(N=561) exhibited normal values of proteinuria, whereas 2%(N=15) displayed values of more than 300 mg.Table 1. Prevalence of proteinuria (mg/24h) in arepresentative sample of Albanian adults (N=807)Proteinuria Number Percentage1-Gr (normal) 561 69.5%2-Gr (15-30 mg) 156 19.3%3-Gr (31-300mg) 75 9.3%4-Gr (>300mg) 15 1.9%Total 807 100%Correlations of proteinuria with systolic and diastolic bloodpressure, body mass index, total cholesterol level andglicemia are presented in Table 2. There was evidence of apositive correlation of proteinuria with both diastolic andsystolic blood pressure, which was statistically significant forthe third grade of proteinuria and partly for the second grade.It must be noted that the number of individuals in the fourthgroup (>300 mg/24h) was rather small (N=15) and, therefore,results were not statistically significant notwithstanding thestrength of the correlation coefficients with either systolicblood pressure (r = 0.38) or diastolic blood pressure (r =0.41). Furthermore, there was evidence of positivecorrelations of proteinuria with body mass index and totalcholesterol level for the third and the fourth grade. Conversely,there was no correlation with glicemia (Table 2).Table 2. Correlations of proteinuria with selected risk factors for chronic kidney diseaseVariableProteinuria1-Gr(normal)2-Gr(15-30 mg)3-Gr(31-300mg)4-Gr(>300mg)Systolic blood pressure 0.18 (0.46)* 0.26 (0.17) 0.32 (0.01) 0.38 (0.13)Diastolic blood pressure 0.21 (0.13) 0.31 (0.01) 0.28 (0.03) 0.41 (0.11)Body Mass Index 0.07 (0.52) 0.13 (0.32) 0.27 (0.06) 0.34 (0.04)Total cholesterol 0.12 (0.71) 0.18 (0.22) 0.27 (0.19) 0.39 (0.09)Glicemia 0.08 (0.67) 0.14 (0.54) 0.09 (0.34) 0.16 (0.23)* Correlation coefficients and p-values (in parenthesis)0.450.40.350.30.250.20.150.10.0500.180.260.320.380.210.310.280.410.070.130.270.340.120.180.270.390.160.140.080.09SBP DBP BMI Cholesterol GlicemiaFig. 1. Correlations of proteinuria with selected risk factorsfor chronic kidney disease1-Gr2-Gr3-Gr4-GrDiscussionIt is now more than 40 years since Keen et al. had reportedan increase in urinary albumin excretion in “newly detectedhyperglycemics”. The term microalbuminuria, however,first appeared in the medical literature in 19801, by Vibertiand Svensen, to describe UAE below the detection limits ofa standard dipstick [5]. In diabetes it has been shownclearly that subjects with microalbuminuria have anenhanced risk of developing progressive renal failurecompared with subjects with a normal albumin excretion[6]. The same can be concluded for essential hypertension.Bigazzi et al. [7] showed that the fall in GFR in patientswith essential hypertension over a mean follow-up period of7 years was greater in those with microalbuminuria at thestart than in those with a normal albumin excretion at thestart.

48 BANTAO Journal 2007; 5 (2)Recently was showed that microalbuminuria occursfrequently even in the general population, in subjectswithout diabetes and hypertension. Moreover, there isevidence that, as in diabetes, already modestly increasedlevels of albumin excretion are associated with a decreasedGFR in patients with essential hypertension and in nondiabeticnon-hypertensive subjects [8]. Finally, microalbuminuriais associated with an enhanced risk forcardiovascular mortality and probably also with anenhanced risk for progressive renal failure not only indiabetic patients but also in hypertensive and in nondiabetic,non-hypertensive subjects [9]. In addition, the useof UAE as a screening tool is made more feasible by moresensitive assays that are more commercially available andthat appear to be reliable even in the lower ranges [10].Ironically, patients with chronic renal failure and persistentproteinuria may remain minimally symptomatic until renalfunction is severely impaired, with the eventual need forend-stage renal disease (ESRD) management (dialysis ortransplantation).We found at general population a significant correlation ofmicroalbuminuria (Table 1) with both systolic and diastolicblood pressure, a significant correlation with TotalCholesterol, a correlation with Glicemia and BMI (Table 2)in a representative sample of adults in Tirana (Albania), atransitional country in Southeast Europe, these data arecomparable with Prevend, Okinava. Our findings suggestthat subclinical abnormalities in the kidneys or vascularendothelium may precede the progression of kidneydamage. Based on these results, treatment of albuminuria inindividuals may offer a cost-effective benefit to preventcardiovascular and renal disease.ConclusionThis large prospective cohort study, in Tirana (Albania),leads us to conclude that screening for microalbuminuriamay be an excellent tool, either alone or in combinationwith screening for hypertension and hypercholesterolaemia,to identify subjects at risk for progressive renal failure.Dipstick urinalysis is a simple, noninvasive test for thedetection of proteinuria, often a marker of unsuspectedchronic renal disease (other analyses available on multipledipstick urine tests are not considered in this study).Conflict of interest statement. None declared.References1. Li P, Weening J, Dirks J, et al. A report withconsensus statements of the International Society ofNephrology 2004 Consensus Workshop on Preventionof Progression of Renal Disease, Hong Kong, June 29,2004. Kidney Int 2005; 67 (Suppl 94): 2-27.2. Hillege HL, Fidler V, Diercks GF, et al. Urinaryalbumin excretion predicts cardiovascular and noncardiovascularmortality in the general population.Circulation 2002; 106: 1777-1782.3. Parving H-H, Lewis JB, Ravid M, Remuzzi G,Hunsicker LG: Prevalence and risk factors for microalbuminuriain a referred cohort of type II diabeticpatients: A global perspective. Kidney Int 2006; 69:2057-2063.4. Rossert JA, Wauters JP. Recommendations for thescreening and management of patients with chronickidney disease, Overview in Europe. Nephrol DialTransplant 2002; 17 (Suppl 1): 19-28.5. Kent DM, Jafar TH, Hayward RA, et al. Progressionrisk, urinary protein excretion, and treatment effects ofangiotensin-converting enzyme inhibitors in nondiabetickidney disease. J Am Soc Nephrol 2007;18:1959-1965.6. Mogensen CE. Microalbuminuria predicts clinical proteinuriaand early mortality in maturity-onset diabetes.N Engl J Med 1984; 310: 356-360.7. Bigazzi R, Bianchi S, Baldari D, Campese VM.Microalbuminuria predicts cardiovascular events andrenal insufficiency in patients with essential hypertension.J Hypertens 1998; 16: 1325-1333.8. Hillege HL, Janssen WMT, Bak AA et al. Microalbuminuriais common, also in a nondiabetic,nonhypertensive population, and an independentindicator of cardiovascular risk factors andcardiovascular morbidity. J Int Med 200; 249: 519-526.9. Hillege HL, Fidler V, Diercks GF, van Gilst WH, deZeeuw D, van Veldhuisen DJ, Gans RO, Janssen WM,Grobbee DE, de Jong PE; Prevention of Renal andVascular End Stage Disease (PREVEND) StudyGroup: Urinary albumin excretion predicts cardiovascularand noncardiovascular mortality in thegeneral population. Circulation 2002; 106: 1777–1782.10. Iseki K. Screening for renal disease - what can be learnedfrom the Okinawa experience. Nephrology DialysisTransplantation 2006; 21: 839-843.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 49–51Original ArticleCourse and Prognosis of Primary Systemic Vasculitidies (PSV) with RenalLesionsDejan Celic, Tatjana Ilic, Igor Mitic, Gordana Strazmester-Majstorovic, Tatjana Djurdjevic-Mirkovic,Dusan Bozic and Slobodan CuricClinic of Nephrology and Clinical Immunology, Clinical Center of Vojvodina, Novi Sad, SerbiaAbstractBackground. Vasculitidies represents heterogeneous groupof diseases characterised with the destructive inflammationin and around blood vessel wall which can cause ischemiaof tissues and organs supplied by the affected vessels.Methods. We conducted prospective-retrospective study inwhich we included 62 patients. Thirty two patients havehad primary systemic vasculitis (PSV) with renal lesions.Sixteen of them were ANCA positive and 16 were ANCAnegative. We also followed 30 patients with PSV withoutrenal lesions. The follow up of patients was two years fromthe time of diagnosis of PSV. We followed serumcreatinine, creatinine clearence, 24h-proteinuria, as well aserythorocyte sedimentation rate (ESR), C-reactive protein(CRP) and fibrinogen. We also scored the activity ofvasculitis with Birmingham Vasculitis Activity Score(BVAS). The diagnosis of PSV was established on the basisof Chapell Hill international consensus criteria.Results. After two years of follow up patients with PSVwithout renal lesions showed better course and prognosisthan patients with PSV with renal lesions. This was largelydue to statistically lower number of affected organs in theformer group. We didn`t found any significant difference inthe course and prognosis beetween ANCA positive andANCA negative patients with vasculitis and renal lesions.Patients with PSV and renal lesions that had more than 50%of crescents on kidney biopsy specimens had significantlyworse kidney function at the begining and at the end offollow up, as well as a higher value of persistent activityindex (BVAS.2) of vasculitis at the end of follow up comparingwith the patients who had less than 50% crescents or nocrescents at all at the kidney biopsy material. Patients with P-ANCA positive vasculitidies have had significantly higherdegree of BVAS.1 at the begining of follow up andsignificantly higher degree of BVAS.2 at the end of follow up.Conclusions. The prognosis of vasculitis is largelyconnected with the number of the affected organs with thevasculitis process. Percutaneous kidney biopsy have tremendousprognostic importance in the vasculitis with renallesions. Patients with pANCA positive vasculitidies hadhigher levels of activity according to BVAS probablybecause of the smoldering type of their disease.Key words: glomerulonephritis, kidney diseases, prognosis,severity of illness index, vasculitisIntroductionVasculitidies represents heterogeneous group of diseasescharacterised with destructive inflammation in and aroundblood vessel walls. As a consequence of this inflammatoryprocess lumen of the blood vessels can become compromisedwhich can lead to ishemia of the dependent tissuesand/or organs. Etiopathogenesis of different forms ofvasculitides is incompletely understood with combinedeffects of genetic and environmental factors. Clinical presentationof vasculitidies varies, in large part due to thediameter of the involved blood vessel. Respectively,involvement of the large blood vessel can be presented withclaudication of the extremities, murmurs over the involvedvessel, aortic dilatation, assimetric blood pressure, etc.;involvement of the medium sized blood vessels can bepresented with skin nodules, skin ulcerations, mononeuritismultiplex, gangrene of the digits, while involvement of thesmall blood vessels (arterioles, capilaries and venules) canbe presented with purpura, glomerulonephritis, alveolarhemorrhage, uveitis, etc. Prognosis of the vasculitidiesdepends on the type of vasculitis, the spectrum of theinvolved organs, the time elapsed from the first simptomsof the disease to the correct diagnosis and on the treatment.Nowadays, the treatment pallette is very wide, withcorticosteroids and cyclophospha-mide that serves as a standardimmunosupressive therapy for more than 30 years [1,2] throughdrugs like azatioprine and methotrexate to the whole newgeneration of drugs that first found their place in solid organtransplantation and hematology/oncology such as mycophenolatmofetil, etanercept [3], deoxipergualin [4] and rituximab [5-7].The aims of the study were to determine difference between thecourse and prognosis of patients with PSV with renal lesions andthose patients with PSV without renal lesions, also to determinedifference in course and prognosis of ANCA positive andANCA negative patients with PSV and renal lesions, and finallyto explore the difference between the two groups of patientsaccording to type of ANCA (pANCA or cANCA).Patients and methodsWe conducted prospective-retrospective study whichincluded 62 patients. Thirty two patients (group 1) withprimary systemic vasculitis (PSV) with renal lesions, 16______________________Correspodence to: Dejan Celic, Mise Dimitrijevica 1a, Novi Sad, Serbia;Fax. +38121540715; 063388164; E-mail: cellia@NSpoint.net

50 BANTAO Journal 2007; 5 (2)ANCA positive (8 pANCA positive and 8 cANCA positive)and 16 ANCA negative patients, and 30 patients with PSVwithout renal lesions (group 2). The study included patientsthat were treated at the Clinical center in Novi Sad betweenyear 2000 and 2006 and the diagnosis of PSV was establishedaccording to Chapel Hill consensus conference criteria[8]. In the group of patients with PSV with renal lesions(n=32) 8 patients were diagnosed as Wegener`s granulomatosis(WG), 11 as microscopic polyangiitis (MPA), 5patients were diagnosed as poliarteritis nodosa (PN), 4patients as kryoglobulinemic vasulitis (KV), 3 patients asHenoch-Schönlein purpura (HSP) and one patient wasdiagnosed as Churg-Strauss syndrome (CSS). In the groupof patients with PSV without renal lesions (n=30) 15patients were diagnosed as leokocytoclastic vasculitis(LCKV), 6 patients were diagnosed as having KV, and 3patients were diagnosed as having HSP, gigantocellularvasculitis (GCV) and vasculitis of the central nervoussystem, respectively. The follow up of the patients was twoyears from the time of diagnosis.We have followed serum creatinine, creatinine clearance,24h-proteinuria, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and fibrinogen that was measuredwith standard methods. Percutaneous needle biopsy of thekidney was performed in the whole group (n=32) with renallesions at the time of admission to our institution andestablished clinically visible renal impairment. Theobtained material was examined with light and immunofluorescentmicroscopy. We also used BirminghamVasculitis Activity Score (BVAS) and its modification forWegener`s granulomatosis to evaluate activity of thevasculitis in every patient [9,10]. For the determination ofANCA we used "Euroimmun-Medizinische Labordiagnostika"AG commercial kits with starting titer of mentioned antibodiesof 1:10.Observed parameters were continous or discontinousvariables. The categorisations of the variables are presentedthrough average values and standard deviations. Distributionof the patients was presented with Student`s T-test.Fisher`s test was used for evaluation of the intensities ofobserved variables.ResultsIn the overall structure of patients we have observed aslight preponderance of female gender (58,1% vs. 41,9%)that was largely due to the higher incidence of LCKV infemales of our population. There was no singificantdifference notified beetween the two groups according tothe age of patients and the duration of simptoms of thedisease before the diagnosis was established (Table 1).Table 1. Average age of patients and average duration ofsimptoms before the establishment of diagnosis of vasculitisNephritisNephritisT+ N=32– N=30Age of patients 61,91 ± 9,8 NS 56,33 ±15,01Days before the 67,31 ± 86,49 NS 38 ± 48,99diagnosisThere was a significant difference in the number of theaffected organs beetween the two groups favouring the groupwith PSV and renal lesions (4,19 ± 1,2 vs 1,3 ± 0,53; p

BANTAO Journal 2007; 5 (2) 51complaints (malaise, fatigue, loss of apetite and bodyweight) that sometimes make the definite diagnosis hard toestablish. Statistically significant difference in theparameters of kidney function beetween the two basicgroups of patients at the begining and at the end of thestudy was straightforward because first group wascomprised of patients with PSV with renal lesions andsecond one of patients with PSV without renal lesions.Significant differences beetween these two groupsaccording to the acute phase reactants and BVAS can beexplained with a significantly higher number of the affectedorgans in the group with PSV and renal lesions in contrastto the group with PSV without renal lesions (4,19 ± 1,2 vs1,3 ± 0,53; p

BANTAO Journal 2007; 5 (2) : 52–54BJBANTAO JournalOriginal ArticleSteroid induced Psychiatric Syndromes in Patients with ChronicGlomerulonephritisSimeon Monov and Daniela MonovaDepartment of Internal Medicine, Medical University - Sofia, BulgariaAbstractBackground. The occurrence of psychiatric symptoms inassociation with the clinical use of corticosteroids has beendocumented since the introduction of steroids as therapeuticagents over 50 years ago. There are some studies in theliterature which address limited aspects of this problem, butthere are no adequately controlled comprehensive studies ofthe psychiatric effects of steroid therapy in patients withchronic glomerulonephritis.Methods. We reviewed case records at the Clinic ofInternal Disease and Therapy and Clinic of Rheumatology,previous case reports and other sources of information inthe literature in order to improve our understanding of thesedisorders.Results. Our findings indicate that severe psychiatricreactions occur in approximately 2% of steroid-treatedpatients, and the large proportion of these patients haveaffective and/or psychotic symptoms. None of our patientshad a past history of psychiatric illness unrelated to steroidtherapy. Psychiatric disturbances usually occur early in thecourse of steroid therapy (1 to 76 days). Female sex,systemic lupus erythematosus and high doses of prednisolone(only two of the patients with significantpsychiatric syndromes had been receiving less than 40mg/24 h of prednisolone before the onset of symptoms)may be risk factors for development of the steroid-inducedpsychiatric syndrome. The duration of symptoms rangedfrom 2 to 48 days, with a mean of 18 days, irrespectively ofthe treatment. 20 of our cases had a complete recovery fromtheir steroid-induced psychiatric syndrome.Conclusion. Patients with delirium have a significantlyshorter duration of symptoms than patients who developedan affective syndrome. Treatment with steroid-taper,neuroleptics or electroconvulsive therapy with regard to theclinical status is generally effective in these patients.Keywords: adverse psychiatric effects, corticosteroids,chronic glomerulonephritisIntroductionAlthough it is well-established that psychiatric symptomscan develop in association with the administration ofcorticosteroids, the nature of this relationship is poorlyunderstood. Early reports consisted of detailed descriptionof individual cases [1,2] and these observations andconclusions have sometimes been uncritically reproducedin the reviews of the literature. Sometimes, others havecited the options reported in the previous reviews, which inturn based their conclusions on the clinical observations ofthe early authors [3]. On the other hand, a few authors wereintrigued whether corticosteroids cause psychiatric adverseeffects at all [3, 4]. A recent meta-analysis of randomizedcontrolled trials has provided a firm confirmation that it isquite possible [5]. The association of corticosteroidtreatment with depressive and manic syndromes isrelatively well documented, although, there is a need foradditional prospective studies in various clinicalpopulations and settings under the use of corticosteroids.Thus, the frequency and severity of these disturbanceswithin specific populations can be more clearly elucidated.A search in the Medline and psycINFO databases(conducted to find clinically relevant articles on psychiatricside effects from corticosteroids) with search terms likeglomerulonephritis, corticosteroid, prednisone, mania,depression, and psychosis occuring during corticosteroidtherapy ascertain the fact that there are only a fewpublished articles about psychiatric side effects ofcorticosteroids in patients with glomerulonephritis.In an attempt to find additional information about theincidence and other aspects of steroid-induced psychiatricsyndromes, we studied the adverse effects of corticosteroidsin the patients with chronic glomerulonephritis.Patients and methodsReview of the case records (365) at the Clinic of InternalDisease and Therapy and Clinic of Rheumatology from1985 through 2005 revealed 21 cases of psychiatricsyndromes. 7 of them (P

BANTAO Journal 2007; 5 (2) 53characteristics including the psychiatric symptomatology,response to the treatment and the outcome.The following statistical methods were applied: parametricStudent’s t-test and Fisher’s exact test for nominalvariables, correlation analysis (daily dose/type ofsyndromes; age/development of steroid-induced psychiatricsyndromes and others) and variation analysis to determinethe independent factors related with psychiatric syndromes.Continuous data are presented as mean (±SD) andcategorical data as number (percentage). For all analyses pvalues less than or equal to 0,05 were consideredstatistically significant.ResultsWe studied 356 patients (195 female, 161 male; mean age45,7±9,6 years) with glomerulonephritis (207 of them withlupus glomerulonephritis) without previous history ofpsychiatric illness unrelated to steroid therapy (Table 1).Oral prednisolone was the most frequently (354 patients)administered therapy. Intravenous methylprednisolone wasgiven to 287 patients for corticosteroid pulse therapy at adose of 500 mg or 1g/24 h for 3 consecutive days. Ourfindings indicate that psychiatric reactions (7 - severepsychiatric reactions and 14 - mild isolated psychiatricsyndromes) occur in 21 of steroid-treated patients withglomerulonephritis (20 female, 1 male; mean age 34,1±6,2years), and all being with affective and/or psychoticsymptoms (Table 2). Corticosteroids can provoke bothmania (6 patients – 28,57%) and depression that clinicallyappear opposite to each other. Underlying medical diseasein 14 of these patients was Systemic lupus erythematosus(mesangial proliferative lupus nephritis – 5 patients, focallupus nephritis – 1 patient, diffuse lupus nephritis – 6patients, membranous lupus nephritis – 2 patients). Thepresence and severity of individual symptoms varied duringthe course of the illness. Depression (8 patients - 38,1%) isthe most common psychiatric disturbance. Two (9,52 %) ofthe patients had delirium characterized by a clouding ofconsciousness, disorientation, changes in psychomotoractivity and rapid fluctuations in symptoms. Five (23,81 %)of the cases suffered from a psychotic disorder withoutevidence of a significant mood change or features of adelirium.Table 1. Biopsy parameters in patients with chronicglomerulonephritisCharacteristicsFemale gender 195Age (years) 45,7 ± 9,6Biopsy parameters in patients with lupus N of patientsnephritisMinimal mesangial lupus nephritis 16Mesangial proliferative lupus nephritis 28Focal lupus nephritis 17Diffuse lupus nephritis 99Membranous lupus nephritis 47Activity index 9,5 ± 2,3Chronicity index 2,4 ± 1,7Biopsy parameters in patients with chronicglomerulonephritis [non-lupus]Minimal change nephropathy 11Focal segmental glomerulosclerosis 8Mesangiocapillary glomerulonephritis 5Mesangial proliferative (IgA)25glomerulonephritisDiffuse proliferative glomerulonephritis 58Membranous nephropathy 42Table 2. Distribution of types of steroid-induced psychiatric syndromesPSYCHIATRICSYNDROMETOTAL (%) TYPE OF CHRONIC GLOMERULONEPHRITISDepression 8 (38,1 %) SLE. Mesangial proliferative lupus nephritis - 2 patientsSLE. Diffuse lupus nephritis – 2 patientsDiffuse proliferative glomerulonephritis (non-lupus) - 3 patientsMembranous nephropathy – 1 patientMania 6 (28,57 %) SLE. Mesangial proliferative lupus nephritis - 1 patientSLE. Diffuse lupus nephritis – 1 patientSLE. Focal lupus nephritis – 1 patientSLE. Membranous lupus nephritis - 1 patientMesangiocapillary glomerulonephritis (non-lupus) - 2 patientsPsychosis 5 (23,81 %) SLE. Mesangial proliferative lupus nephritis -1 patientSLE. Diffuse lupus nephritis – 2 patientsSLE. Membranous lupus nephritis - 1 patientDiffuse proliferative glomerulonephritis (non-lupus) - 1 patientsDelirium 2 (9,52 %) SLE. Diffuse lupus nephritis – 1 patientSLE. Mesangial proliferative lupus nephritis – 1 patientThe duration of treatment with steroids before the onset ofpsychiatric symptoms ranged from 1 to 76 days. 33,33 % ofthe cases developed symptoms during the first week oftreatment, 71,43 % - within the first 2 weeks, and 95,24 % -within 6 weeks of the initiation of steroid therapy. Only twopatients with significant psychiatric syndromes receivedless than 40 mg/24 h of prednisolone before the onset ofsymptoms.The duration of symptoms ranged from 2 to 48 days, with amean of 18 days, irrespective of treatment. 20 of our caseshad a complete recovery from their steroid-inducedpsychiatric syndrome. Patients with a delirium have asignificantly shorter duration of symptoms than do patientswho develop an affective syndrome. There were nostatistically significant differences in duration of symptomsamong the depressive, manic or psychotic groups.

54 BANTAO Journal 2007; 5 (2)Treatment with steroid-taper, neuroleptics orelectroconvulsive therapy, based on the clinical picture, wasgenerally effective in these patients. Despite the smallnumber of subjects in this study, we could not observerecurrences unrelated to corticosteroid treatment inpsychotic disorder patients.DiscussionCorticosteroids can affect various psychiatric functions,including mood, cognition, and thought, and can inducedifferent psychiatric syndromes based on the patient’svulnerability. Changes in mood or affect, such as mildeuphoria or depression are the most frequently seenpsychiatric symptoms [7,8,9].It is widely accepted that affective symptoms are the mostprominent clinical features in “steroid psychosis” [10,11].Lewis and Smith [12] reported in 1983 that there wereseven mania, one depression and two psychosis in theiroriginal series. They also cited 60 mood disorders and 11psychoses from their review of the literature. Ling at al.[10] found 45 patients with mood disorder and 9 with acutepsychosis. Some previous reports of steroid psychosis [3]also demonstrated a higher incidence of depression thanmania.Female sex, systemic lupus erythematosus and high dosesof prednisolone may be risk factors for the development ofa steroid-induced psychiatric syndrome. Age does notappear to be a risk factor for the development of steroidinducedpsychiatric syndromes. Adverse psychiatricreactions to steroid therapy usually occur early in the courseof treatment. This time clustering of psychiatric symptomsmay be due to the dose-response effect of steroids andconsequently it may reflect the prescribing pattern forsteroids; that is, frequently administered an initial largedose and the subsequent tapering of the daily dose. Thedose-response effect of prednisone on the induction ofpsychiatric symptoms was most clearly demonstrated in theBoston Collaborative Drug Surveillance Project where 676patients on prednisone therapy were evaluated for thedevelopment of acute psychiatric syndromes [13]. Theseinvestigators found significantly increased incidence ofpsychiatric disturbances associated with an increase in theaverage daily dose of prednisolone. The evidence from ourpatients also supports this dose-response effect: only two ofthe patients with significant psychiatric syndromes receivedless than 40 mg/24 h of prednisolone before the onset ofsymptoms.Our data are quite similar to those reported in a review ofliterature over 45 years ago [14,15]. These similaritiessuggest that the overall incidence of these disorders werenot changed in despite of the differences in the type ofsteroids used, or other changes in prescribing practices.ConclusionIn summary, combining our case reports with those in theliterature, we were unable to find any significant correlationbetween the type of glomerulonephritis and the averagedaily dose of corticosteroids, the duration of treatmentbefore the onset of symptoms, the duration of symptoms ortype of psychiatric syndrome. Continuous support bypsychiatrists and their close cooperation with otherphysicians will contribute for an improved quality of life ofpatients undergoing long-term corticosteroid treatment.Finally, physicians should carefully monitor patients forpsychiatric and cognitive side effects of corticosteroid use.Conflict of interest statement. None declared.References1. Clark LD, Bauer W, Cobb S, et al. Preliminaryobservations on mental disturbances occurring inpatients under therapy with cortisone and ACTH. NEngl J Med 1952; 246: 205-216.2. Goolker P, Schein J. Psychic effects of ACTH andcortisone. Psychosom Med 1953; 15: 589-613.3. Patten SB, Neutel CI. Corticosteroid-Induced AdversePsychiatric Effects. Incidence. Diagnosis andManagement. Drug safety 2000; 22 (2): 111-112.4. Mitchell DM, Collins JV. Do corticosteroids reallyalter mood. Postgrad Med J 1984; 60: 467-470.5. Conn HO, Poynard T. Corticosteroids and peptic ulcer:metaanalysis of adverse events during steroid therapy.J Intern Med 1994; 236: 619-632.6. American Psychiatric Association. Diagnostic andstatistical manual of mental disorders. 4 th ed.Washington: American Psychiatric Association, 1994.7. Brown ES, Chandler PA. Mood and Cognitive ChangesDuring Systemic Corticosteroid Therapy. Prim. CareCompanion. J Clin Psychiatry 2001; 3(1): 17-21.8. Brown ES, Vera E, Frol AB, Woolston DJ, Johnson B.Effect of chronic prednisone therapy on mood andmemory. J Affect Disord 2007; 99(1-3): 279-283.9. Wada K, Yamada N, Sato T, et al. Corticosteroidinducedpsychotic and mood disorders: diagnosisdefined by DSM-IV and clinical pictures.Psychosomatics 2001; 42(6): 461-466.10. Ling MHM, Perry PJ, Tsuang MT. Side effects ofcorticosteroid therapy. Arch Gen Psychiatry 1981; 18:471-477.11. Broun ES, Suppes T. Mood symptoms duringcorticosteroid therapy: a review. Harv Rev Psychiatry1998; 5: 239-246.12. Lewis D, Smith R. Steroid-induced PsychiatricSyndromes. J Affective Disorders 1983; 3: 319-332.13. The Boston Collaborative Drug Surveillance Program.Acute adverse reactions to prednisone in relation todosage. Clin Pharmacol Ther 1972; 13: 694-698.14. Guze SB. The occurrence of psychiatric illness insystemic lupus erythematosus. Amer J Psychiat 1967;123: 1562-1570.15. Smyth CJ, Black RL, Demartini FE, et al. Rheumatismand arthritis - review of American and Englishliterature of recent years. Ann Intern Med 1960; 53: 1-365.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 55 –57Original ArticleOutcome and Epidemiology of Hospital-Acquired Acute Renal Failure(ARF) - a Multicenter StudyOlga Balafa, Emilios Andrikos, Paraskevi Tseke, Afroditi Tsinta, Efthimios Pappas, Elissavet Kokkolou,Georgios Sferopoulos and Michalis PappasNephrology Unit, General Hospital “Hatzikosta”, Ioannina, GreeceAbstractBackground. ARF is a common hospital clinical entitywith varying mortality rates in different reports (25-40%).Aim of this study was to determine the epidemiology ofARF in Greece; to characterize etiology, management andoutcome of ARF in hospitalized patients (except intensivecare unit [ICU] patients).Methods. Prospective multi-center study of patients withARF from September 2005 to 15 December 2005 (exceptICU patients). ARF was defined as serum creatinine >1.44mg/dl ±daily urine output 0.72 mg/dl inpatients with known renal failure.Results. 30 hospitals participated in the study. 504 patients(age: 69.26±14.26) presented with ARF. The majority of thesepatients were male (60%) and 46% had normal renal functionprior to admission. 71% and 37.5 % had a history ofhypertension and diabetes respectively. Medical causes ofARF were almost 77.3%; volume depletion was thecommonest of these (47.4%). Sepsis accounted for 6% of ARFcauses. Post operative ARF accounted for 34% of the surgicalcauses. The length of hospital stay was 9 days (range 1-90days). 21.75% of the patients finally died.Renal replacement therapy (RRT) was required in 34% of thecohort. Intermittent hemodialysis was the most commonlyperformed modality (83%). Peritoneal dialysis was performedin only 3 cases.Independent risk factors for mortality were age (hazard ratioper year increase 1.02, p=0.003) and daily urine output(hazard ratio per liter/day increase 0.58, p=0.003). In Coxregression analysis RRT, diabetes, hypertension and preexistingrenal failure were not found statistically significantrisk factors for mortality.Conclusion. Mortality rate for patients with ARF in hospitalzedpatients in Greece is comparable to rates referred in otherreports. In our study, only age and urine output were statistiallysignificant mortality risk factors.Keywords: Acute renal failure, hospital, mortality rate,dialysisIntroductionAcute renal failure (ARF) is a syndrome characterized by asudden deterioration in renal function of several hours toseveral weeks duration resulting in the failure of the kidneyand electrolyte homeostasis [1]. ARF may complicate a hostof diseases that for purposes of diagnosis and managementare conveniently divided into three categories: (a) diseasescharacterized by renal hypoperfusion in which the integrityof renal parenchymal tissue is preserved (prerenal azotemia,prerenal ARF), (b) diseases involving renal parenchymaltissue (intrarenal azotemia, intrinsic renal ARF) and (c)diseases associated with acute obstruction of the urinary tract(postrenal azotemia, postrenal ARF). Most acute intrinsic renalazotemia is caused by ischemia or nephrotoxins and isclassically associated with acute tubule necrosis (ATN) [2].ARF is a common hospital clinical entity, an independentrisk factor for mortality and is associated with a significantprolongation in length of hospital stay [3,4]. The incidenceand mortality rate of ARF vary extremely in the numerousstudies in the literature because of different definitions ofARF, different populations studied (ICU patients, community-acquiredARF, hospital acquired ARF), differentcountries and so on [5,6]. Despite this difficulty, it has beenpossible to detect notable variations in the epidemiology ofARF during the past few decades. The absolute incidenceof ARF has increased, while associated mortality rate hasremained relatively static [5,7]. This lack of improvement inoutcome despite significant advances in supportive care mayreflect a reduction in the percentage of isolated ARF combinedwith an increase in ARF complicating sepsis.We prospectively studied the etiology and outcome of adultpatients with ARF in our country. We also aimed to establish thedemographic characteristics of such patients and the differenttreatments used.Patients and methodsDuring a three month period (from September 2005 to 15December 2005) we prospectively studied all patients with ARFoccurring in tertiary hospitals in Greece (except ICU patients).ARF was defined as serum creatinine >1.44 mg/dl ± dailyurine output 0.72 mg/dl in patients with knownrenal failure. We used a questionnaire including a number ofvariables and information; demographic questions, date ofadmission and discharge, original disease, initial admission tohospital, etiology of ARF, use of drugs, prior to admissionmedical history, clinical situation at the first visit, dialysisneeds and techniques etc. All the cases were recorded byone or two nephrologists in each hospital.to excrete nitrogenous waste products and to maintain fluid______________________Correspodence to: Olga Balafa, Ioanninon 18, Anatoli, Ioannina-45500, Greece; Tel. 00302651080406;Fax. 00302651080395; E-mail:balageg@otenet.gr

56 BANTAO Journal 2007; 5 (2)All the questionnaires were sent to our office in our clinicand entered in a database and then analyzed with a statisticalprogram (Stata, version 8). Survival analysis was performedusing Kaplan Meier survival curves. Cox regression analysiswas performed to estimate hazard ratios for continuousvariables, under the assumption of proporionality. Variablesstatistically significant in univariate Cox analysis wereincluded in multivariate Cox models and stepwise procedurewas used to identify independent mortality risk factors.Results30 tertiary hospitals participated in the study. 504 patients(mean age: 69.26±14.26) presented with ARF. The majorityof these patients were male (60%). Mean age of womenwas 71.6± 12.95, while the analogue of the men was67.7±14.95. 46% of the patients had normal renal functionprior to admission, while 71% and 37.5 % had a history ofhypertension and diabetes respectively. Medical causes ofARF were almost 77.3%; volume depletion was thecommonest of these (47.4%) whilst ATN accounted for25%. Sepsis comprised 6% of ARF causes whileglomerulonephritis was responsible for ARF only in 10 cases(0.02%). Post operative ARF accounted for 34% of thesurgical causes (55% of these were due to prostaticobstruction). The length of hospital stay was 9 days (range1-90 days). 21.75% of the patients finally died. Patientsabove 72 years old had 64% higher mortality risk comparedto those below 72 (hazard ratio 1.64, p=0.0014).Survival probability0.00 0.25 0.50 0.75 1.00Survival probability0.00 0.25 0.50 0.75 1.00Kaplan-Meier survival estimates, by AGE1 11 21 31 41 51 60Time of hospitalization (in days)AGE = age721 11 21 31 41 51 60Time of hospitalization (in days)Diuresis = diuresis550mL/dFig. 1. Kaplan-Meier survival survival estimates by; A) age(hazard ratio per year increase 1.02, p=0.003); B) daily urineoutput (hazard ratio per liter/day increase 0.58, p=0.003)BRenal replacement therapy (RRT) was required in 34% ofthe cohort. Intermittent hemodialysis was the mostcommonly performed modality (83%). Peritoneal dialysiswas performed in only 3 cases. Nephrologists and dialysisunit personnel were responsible for the RRT treatments inalmost all cases.Independent risk factors for mortality were age (hazardratio per year increase 1.02, p=0.003) and daily urine output(hazard ratio per liter/day increase 0.58, p=0.003) (Figure1). In Cox regression analysis RRT, diabetes, hypertensionand pre-existing renal failure were not found statisticallysignificant risk factors for mortality.DiscussionThis is the first multicenter prospective study of ARFepidemiology in our country. Designing this study, we hadto confront with all the already known problems ofepidemiological studies. First of all, which definition ofARF we should use? We decided to use the definition byBellomo and Ronco[8] because of its simplicity andaccuracy (RIFLE criteria were not widely used by the timeour study was designed) [9].There are many problems with the design of most of theclinical studies that examine the efficacy of several therapeuticinterventions on the outcome of ARF. Measurementof the effect of treatment interventions in ARF iscomplicated by our inability to accurately define the onsetand resolution of ARF beyond the heterogeneous nature ofthe patient population, variations in technical resources andexpertise among treatment centers, and the timing of renalreferral. In our country severe ARF is usually treated indialysis units and only patients requiring ventilation areadmitted to ICU. Moreover nephrology consultation is acommon policy for other hospital departments. For all thesereasons we decided to exclude the ICU patients realizingthe quite different severity, co-morbidity conditions andtreatment decisions in these patients.The male predominance in ARF patients is something welldocumented in most studies [10,11] but it has not beencommented on. Probably the high incidence of prostaticobstruction (55% of the surgical causes of ARF) could be apossible explanation.Prerenal ARF was the most frequent cause of ARF in ourhospitals. In Western countries etiology of ARF haschanged dramatically the last decades: ATN and prerenalcauses outnumber surgical and obstetrical causes outsideICU [4,12-14]. In ICU patients septic shock is thecommonest cause of ARF (40-50%) and this answers forthe high ICU mortality noticed in recent epidemiologicalstudies [15-17]. We should emphasize the small percentageof glomerulonephritis- induced ARF (only 10 cases). Lianoet al. had also referred similar percentages in their study[4].Despite the disappointing ARF mortality rates (>50%) mostmeta-analysis reveal [7], most agree that ICU highmortality is responsible for the unchanged ARF mortalityduring the last decades [15]. Nevertheless mortality rate forpatients with ARF in hospitalized patients outside ICU inGreece (almost 22%) is comparable –even better-to ratesreferred in other reports-20-40% [4,6] The mean duration ofARF hospital stay was 9 days, a bit longer than other studies[18, 19].

BANTAO Journal 2007; 5 (2) 57In our study, only age and urine output were statisticallysignificant mortality risk factors. Age seems to be a riskfactor in almost all studies. It is a fact that elderly patientswith ARF have greater risk for death than younger [13,20-22]. Moreover anuria or oliguria are associated with pooroutcome, a finding conforming with other studies [11-13,23-26]. Quite the opposite, risk factors such as need fordialysis proved not to be significant in our statisticalanalysis. Finally the percentage of patients needed dialysis(one in three) is comparable to that referred in Liano et al. [4].On the contrary conventional hemodialysis (vs continuoustechniques) was the commonest choice in our patients (80%),while in other studies continuous RRT is preferred [4,27,28].This prospective multicenter hospital-based study haslimitations; it is nephrology unit-based and lacks unique ARFseverity scores. However it highlights the basicepidemiological characteristics of ARF in a tertiary hospital ina developed country. Moreover it indicates the improvementachieved treating patients with ARF as the mortality rateseems better than that referred in older epidemiologicalstudies.Conflict of interest statement. None declared.References1. Schrier RW, Wang W, Poole B, Mitra A. Acute renalfailure: definitions, diagnosis, pathogenesis, andtherapy. J Clin Invest 2004; 114: 5.2. Lameire N, Van Biesen W, Vanholder R. Acute renalfailure. Lancet 2005; 365: 417.3. Fischer MJ, Brimhall BB, Lezotte DC, et al.Uncomplicated acute renal failure and hospitalresource utilization: a retrospective multicenteranalysis. Am J Kidney Dis 2005; 46: 1049.4. Liano F, Pascual J. Epidemiology of acute renalfailure: a prospective, multicenter, community-basedstudy. Madrid Acute Renal Failure Study Group.Kidney Int 1996; 50: 811.5. Lameire N, Van Biesen W, Vanholder R. Thechanging epidemiology of acute renal failure. Nat ClinPract Nephrol 2006; 2: 364.6. Liano F, Pascual J. Outcomes in acute renal failure.Semin Nephrol 1998; 18: 541.7. Uchino S. The epidemiology of acute renal failure inthe world. Curr Opin Crit Care 2006; 12: 538.8. Bellomo R. Defining, quantifying, and classifyingacute renal failure. Crit Care Clin 2005; 21: 223.9. Bellomo R, Kellum JA, Ronco C. Defining andclassifying acute renal failure: from advocacy toconsensus and validation of the RIFLE criteria.Intensive Care Med 2007; 33: 409.10. Turney JH, Marshall DH, Brownjohn AM, et al. Theevolution of acute renal failure, 1956-1988. Q J Med1990; 74: 83.11. Pascual J, Liano F. Causes and prognosis of acuterenal failure in the very old. Madrid Acute RenalFailure Study Group. J Am Geriatr Soc 1998; 46: 721.12. Biesenbach G, Zazgornik J, Kaiser W, et al.Improvement in prognosis of patients with acute renalfailure over a period of 15 years: an analysis of 710cases in a dialysis center. Am J Nephrol 1992; 12: 319.13. Druml W, Lax F, Grimm G, et al. Acute renal failurein the elderly 1975-1990. Clin Nephrol 1994; 41: 342.14. Turney JH, Ellis CM, Parsons FM. Obstetric acuterenal failure 1956-1987. Br J Obstet Gynaecol 1989;96: 679.15. Uchino S, Kellum JA, Bellomo R, et al. Acute renalfailure in critically ill patients: a multinational,multicenter study. Jama 2005; 294: 813.16. Bagshaw SM, Laupland KB, Doig CJ, et al. Prognosisfor long-term survival and renal recovery in criticallyill patients with severe acute renal failure: apopulation-based study. Crit Care 2005; 9: R700.17. Ostermann ME, Chang RW. Prognosis of acute renalfailure: an evaluation of proposed consensus criteria.Intensive Care Med 2005; 31: 250.18. Liangos O, Wald R, O'Bell JW, et al. Epidemiologyand outcomes of acute renal failure in hospitalizedpatients: a national survey. Clin J Am Soc Nephrol2006; 1: 43.19. Shusterman N, Strom BL, Murray TG, et al. Riskfactors and outcome of hospital-acquired acute renalfailure. Clinical epidemiologic study. Am J Med 1987;83: 65.20. Macias-Nunez JF, Lopez-Novoa JM, Martinez-Maldonado M. Acute renal failure in the aged. SeminNephrol 1996; 16: 330.21. Kohli HS, Bhaskaran MC, Muthukumar T, et al.Treatment-related acute renal failure in the elderly: ahospital-based prospective study. Nephrol DialTransplant 2000; 15: 212.22. Xue JL, Daniels F, Star RA, et al. Incidence andmortality of acute renal failure in Medicarebeneficiaries, 1992 to 2001. J Am Soc Nephrol 2006;17: 1135.23. Sural S, Sharma RK, Singhal M, et al. Etiology,prognosis, and outcome of post-operative acute renalfailure. Ren Fail 2000; 22: 87.24. Barretti P, Soares VA. Acute renal failure: clinicaloutcome and causes of death. Ren Fail 1997; 19: 253.25. Chertow GM, Soroko SH, Paganini EP, et al.Mortality after acute renal failure: models forprognostic stratification and risk adjustment. KidneyInt 2006; 70: 1120.26. Obialo CI, Okonofua EC, Tayade AS, Riley LJ.Epidemiology of de novo acute renal failure inhospitalized African Americans: comparingcommunity-acquired vs hospital-acquired disease.Arch Intern Med 2000; 160: 1309.27. Bagshaw SM, Mortis G, Godinez-Luna T, et al. Renalrecovery after severe acute renal failure. Int J ArtifOrgans 2006; 29: 1023.28. Cole L, Bellomo R, Silvester W, Reeves JH. Aprospective, multicenter study of the epidemiology,management, and outcome of severe acute renal failurein a "closed" ICU system. Am J Respir Crit Care Med2000; 162: 191.

BANTAO Journal 2007; 5 (2) : 58–60BJBANTAO JournalOriginal ArticleContinuous Renal Replacement Therapy for Acute Renal Failure in CriticallyIll Patients and Early Predictive FactorsAlbana Gjyzari 1 , L. Muzi 2 and Santo Morabito 21 Dept. of Nephrology, UHC “Nënë Tereza”, Tirana, Albania, 2 Dept. of Clinical Sciences, Div. of Nephrology, Umberto IHospital, "La Sapienza" University, Rome, ItalyAbstractBackground. Acute renal failure (ARF) requiring renalreplacement therapy (RRT) in critically ill patients isassociated with high mortality and continuous renalreplacement therapy (CRRT) is one of modalities to treat it.The aim of this study was to investigate the efficacy ofCRRT, the outcome and early predictive factors of patientswith Multiple Organ Dysfunction Syndrome (MODS) andARF treated with CRRT.Methods. This study was a prospective observational studyconducted between October 05 and March 06. We collecteddata on all patients admitted in the cardiovascular ICU,Umberto I Hospital, “La Sapienza” University whodeveloped ARF after cardiovascular interventions and weretreated with CRRT. In addition to demographics, wecollected: severity of illness (APACHE II), severity of illness(SOFA score), 24-48 hour from the start of CRRT treatment.Clinical outcomes assessed were, mortality, recovery of renalfunction, cardiovascular stability, complications of therapy,hemodynamic instability. We analysed the presence of Coma(GCS

BANTAO Journal 2007; 5 (2) 59clinical conditions has been related to a worse outcome inARF patients: mechanical ventilation [10], low perfusionstatus [10,11,12], sepsis [10,11,12], jaundice [10], coma[10], oliguria [10,11,12,8]. Several scoring systems forassessment of organ dysfunction and morbidity have beenused on ARF patients in ICU. The ICU prognostic scoreAPACHE II was developed in a population of 5030 ICUpatients treated in the United States and published in 1985[13]. The SOFA score is a simple, but effective method todescribe organ dysfunction/failure in critically ill patients [14].The aim of this study was to investigate the efficacy of CRRT,the outcome and early predictive factors of patients withMODS and ARF treated with CRRT.Patients and methodsThis study was a prospective observational study conductedbetween October 05 and March 06. We collected data on allpatients admitted in the cardiovascular ICU, Umberto IHospital, “La Sapienza” University, Roma, who developedARF after cardiovascular interventions and were treatedwith CRRT. In addition to demographics, we collected: severityof illness (APACHE II), severity of illness (SOFA score), 24-48hour from the start of CRRT treatment. Clinical outcomesassessed were, mortality, recovery of renal function,cardiovascular stability, complications of therapy, hemodynamicinstability. We analysed the presence of Coma (GCS

60 BANTAO Journal 2007; 5 (2)ConclusionsMany critically ill patients with ARF severe enough torequire RRT are hypercatabolic and hemodinamicallyunstable. They frequently have large obligate fluidrequirements owing to intravenous medicationadministration and parenteral alimentation. CRRT is shownto reduce significantly the incidence of complicationscommonly observed with intermittent HD in critically illARF patients [2]. This study showed once again theimportant advantages that CRRT provided when used inthis patients: Hemodynamic stability, slow and steady urearemoval, good control of electrolyte balance and acid basehomeostasis, gradual fluid removal and unrestrictedinfusion of parenteral nutrition and drugs. The survivalbenefit of continuous therapy was not aim of this study. Forthat purpose a control group will be provided maybe inother studies. Acute renal failure requiring renalreplacement therapy in critically ill patients is associatedwith high mortality till 90% [7]. The presence of one of thefollowing clinical conditions in ARF patients: mechanicalventilation, low perfusion status, sepsis, jaundice, coma, isassociated with a mortality of about 70% to 80%. A wideagreement has been established; the higher the number oforgans in failure, the higher the mortality. This highmortality rate found in our study (63.3%) is comparable toother studies [12,5,8]. In our study the presence of Coma(survival rate 13.3%) and Oliguria (survival rate 21%)(Figure 1), were found to be the most important predictivefactors. Coma [10] and oliguria [10,11,12] as risk factorsassociated with high mortality have been reported in otherstudies. Among the general ICU scores, APACHE II is theone that is used worldwide in the ARF setting [15].Although the information referring to the use of SOFAscore in ARF is scarce some studies using SOFA seemhopeful [16,11]. Our study demonstrated that SOFA scoreis a better prognostic estimator for ARF than APACHE IIscore.Accurate scoring systems are needed to stratify patientsenrolled in clinical trials and also to allow physicians tomake informed treatment decisions.Conflict of interest statement. None declared.References1. Bellomo R, Ronco C, Mehta RL. Nomenclature forcontinuous renal replacement therapies. Am J KidneyDis 1996; 28(suppl 3): S2-7.2. Ronco C. Continuous renal replacement therapies forthe treatment of acute renal failure in intensive carepatients. Clin Nephrol 1993; 40: 187-98.3. Kramer P, Wigger W, Riege Y. Arteriovenoushemofiltration: a new and simple method for treatmentof overhydrated patients resistant to diuretics. Klin.Wochenschr 1977; 55: 1121.4. Kierdorf HP, Sieberth HG. Continuous renalreplacement therapies versus intermittent hemodialysisin acute renal failure. What do we know? Am J KidneyDis 1998; 28: S90.5. Kellum JA, Angus DC, Johnson JP, et al. Continuousversus intermittent renal replacement therapy: a metaanalysis.Intensive Care Med 2002; 28: 29-37.6. Mehta RL, McDonald B, Gabbai FB, et al. Arandomized clinical trial of continuous versusintermittent dialysis for acute renal failure. Kidney Int2001; 60: 1154–1163.7. Bellomo R, Ronco C, Kellum JA, et al. Acute renalfailure-Definition, outcome measures, animal models,fluid therapy and information technology needs: TheSecond International Consensus Conference of theAcute Dialysis Quality Initiative (ADQI) Group. CritCare 2004; 8: R204-R212.8. Metnitz PG, Krenn CG, Steltzer H, et al. Effect ofacute renal failure requiring renal replacement therapyon outcome in critically ill patients. Crit care med2002; 30(9): 2051-2058.9. Druml W: Prognosis of acute renal failure 1975-1995.Nephron 1996; 73: 8-15.10. Liano F, Gallego A, Pascual J, et al. Prognosis ofacute tubular necrosis: an extended prospectivelycontrasted study. Nephron 1993; 63: 21-31.11. De Mendonca A, Vincent JL, Suter PM, et al. Acuterenal failure in the ICU: risk factors and outcomeevaluation by SOFA score. Intensive Care Med 2000;26: 915-921.12. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJM.Acute renal failure in intensive care units – Causes,outcome, and prognostic factors of hospital mortality:a prospective multicenter study. Crit Care Med 1996;24: 192–198.13. Knaus WA, Draper EA, Wagner DP, Zimmerman JE:APACH II score: A severity of disease classificationsystem. Crit Care Med 1985; 13(10): 818-829.14. Vincent JL, de Mendonça A, Cantraine F, et al. Use ofthe SOFA score to assess the incidence of organdysfunction/failure in intensive care units: results of amulticenter, prospective study. Crit Care Med 1998;26: 1793-1800.15. Liano F, Solez K, Eliahou H, et al. Acute RenalFailure Scoring. In: Ronco C, Bellomo R, eds: CriticalCare Nephrology. Dordrecht: Kluwer AcademicPublisher; 1998; 1535-1545.16. Gainza FJ, Mavnat E. et al. Estudio prospectivo ymulticéntrico del insuficienza renal agudo connecesidad de tratamiento sustitutivo nel pacientescriticos. Nefrologia 1998; 18(suppl 3): 25.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 61–64Original ArticleRenal Artery Stenting in Atherosclerotic Stenosis:Long-Term Follow up of Results in Blood Pressure and Renal FunctionZiakka Stavroula, Dimitrios Poulikakos, Ioannis Karampinis, Evagelos Kapelerisand Nicolas PapagalanisNephrology Department of Red Cross Hospital, Athens, GreeceAbstractBackground. Atherosclerotic renal artery stenosis (RAS) isa known cause of hypertension and renal impairment. Therole of revascularisation in the treatment of RAS has beendebated. Our aim was to identify those patients withatheromatous RAS more likely to have improvement inblood pressure and/or renal function following renal PTAwith stent placement in a long-term follow-up.Methods. The long-term effects of percutaneous transluminalangioplasty (PTA) with stent placement wereassessed in 30 hypertensive patients in 33 renal arteries (18male, 12 female). All patients had atheromatous renal arterydisease (17 unilateral artery stenosis 8 bilateral and 5 in asolitary kidney). Twenty five (83.3%) patients had renalimpairment with serum creatinine > 124 μmol/L and in 16there was ostial lesion. Blood pressure and serum creatininewere estimated before PTA and at the end of follow up.Results. During 47.5±35.4 months follow-up (4 years) therewas a significant reduction in systolic and diastolic BP(20.6/8.3 mm Hg, p

62 BANTAO Journal 2007; 5 (2)patients (83.3%) had serum creatinine > 124 μmol/L (meanserum creatinine 278.2±140.5 μmol/L). Hypertension wasconsidered cured if diastolic blood pressure was 90 mmHgor less without treatment, and improved if diastolic pressurewas less than 90mmHg after administration of an equal orreduced dose of medication. Hypertension was alsoconsidered improved if diastolic pressure was > 90mmHgand < 110mmHg, associated with a fall of at least 15mmHgwhilst on the same or reduced antihypertensive therapy.Hypertension was considered unchanged if the above twocriteria were not fulfilled [6-7]. The renal function wasconsidered improved if serum creatinine fell by 20 %compared to the pre PTA level, and worsened if increasedby 20% or more. During follow-up, one patient had furtherrenal angiography due to strong clinical suspicions ofrestenosis.Statistical analysisResults are expressed as mean±SD, or as percentages whereappropriate. Comparison between paired variables such asblood pressure or serum creatinine levels was performed withpaired-t-test. The un-paired t-test was used to compare themeans between groups. To determine the statistical significanceof the differences (pre and post PTA) between groups,we used the Mann-Whitney rank-sum test. A p value of lessthan 0.05 was considered as statistically significant.ResultsThe clinical and demographic data of patients who underwentrenal PTA are shown in Table 1. Our resultsdemonstrate that in follow-up period after renal PTA, out of30 patients, hypertension was completely cured in 1 (3.4%)patients, improved in 21(68.9%) and failed to improve in 8patients (27.5%), (Table 2). In the group as a whole therewas a significant reduction in both systolic and diastolicBP: 20.6/8.3 mm Hg, p

BANTAO Journal 2007; 5 (2) 63them was with completely regulated hypertension and 3(60%) with improved blood pressure control. Four of them(80%) had improved serum creatinine.The reduction in both SBP and DBP was statisticallysignificant in patients of that group (p 150 μmol/L) who had PTA andstent implantation to a stenosis in a solitary kidney serumcreatinine improved or stabilised in all but six patients led toreturn. Similar results were also reported by other investigators[13]. This can be explained by the fact that in stenosis in asingle functioning kidney there is haemodynamicallysignificant reduction to renal flow with resultant retentionof sodium and water.In our study, in bilateral renal artery disease there was alarger fall in blood pressure following renal PTA whencompared to unilateral disease, and a greater number ofpatients had improved serum creatinine.In patients with renal impairment there was a smallerimprovement in blood pressure control and a decrease inserum creatinine following PTA when compared to patientswith normal renal function (3.0 % and 20.0%, respectively).This is explained by the fact that hypertension in patientswith renal failure has multiple aetiologies and is maintainedas long as the renal damage is not reversible.

64 BANTAO Journal 2007; 5 (2)More importantly, however, in 64% of patients with renalimpairment (mean Cr: 278, 2±140 μmol/L), serum creatinineimproved or remained stable in 24% and 40% respectivelyduring follow-up. This shows the efficacy of this procedureeven in patients with at least moderate to severe renalfailure [14]. This finding is clinically important, becauseatheromatous renovascular disease is a common cause ofend stage renal failure accounting for 7.5-27% of patientsolder than 50 years undergoing renal dialysis [15-16]. Stentrestenosis is a result of myointimal hyperplasia and isusually smooth and concentric, involving the proximal andmiddle portions of the stent. Restenosis seems to be a majorproblem, occurring in 20%-38% of the cases after 1 year or16% reported during short-time follow-up by otherinvestigators [17-18]. The incidence of restenosis is higherin ostial lesions and with the use of the articulated Palmazstent the percentage of restenosis is about 11% [19].Our restenosis rate (3%) was considerably lower than thosein other studies; in one patient with stenosis in ostial lesion.Angiographic follow-up is required only in this patientwhere there was strong suggestion of restenosis. We wereaware of the risk of missing subjects but it was difficult topropose that annual follow-up intrarterial angiography.Cholesterol embolisation is a well-known complication ofboth aortography and renal angioplasty as a complication ofstent placement from 1987 [20]. According to the literaturethis happens in 3-6% of patients [21]. This complicationwas observed in two (6.6%) patients in our series.ConclusionOur results clearly demonstrate that renal PTA withstenting leads to a long term improvement in bloodpressure, and an improvement or stabilisation of renalfunction in a large number of hypertensive patients. Theseeffects are more evident in patients with atheromatous renalartery stenosis in a single functioning kidney and in thosehypertensive patients who present with bilateral stenosis. Itis suggested therefore that hypertensive patients withatheromatous renal artery stenosis with or without mild tomoderate impairment in renal function, or signs of sodiumand water retention in the absence of overt cardiac disease,should be considered for renal artery revascularisation(PTA) with stent replacement. It seems that, at least onethird of them will have a benefit in renal function and moreof them better control of blood pressure for a long term.Conflict of interest statement. None declared.References1. Rudnick KV, Sackett DL, Hirts S, et al. Hypertensionin a family practice. Can Med Assoc J 1977; 117: 492-7.2. Scoble JE, Maher ER, Hamilton G, et al. Atheroscleroticrenovascular disease causing renal impairment a case fortreatment. Clinical Nephrology 1989; 31: 119-122.3. Pickering TG, Devereux RB, James GD, et al.Recurrent pulmonary oedema in hypertension due tobilateral renal artery stenosis: treatment by angioplastyor surgical revascularisation. Lancet 2:1988; 551-552.4. Missouris CG, Buckenham T, Vallance PJT, et al.Renal artery stenosis masquerading as congestive heartfailure. Lancet 1993; 341: 1521-1522.5. Missouris CG, Belli AM, MacGregor GA, et al.Apparent heart failure: a syndrome caused by renalartery stenosis. Heart 2000; 83(2): 152-5.6. Harden PN, MacLeod MJ, Rodger RSC, et al. Effectof renal-artery stenting on progression of renovascularrenal failure. Lancet 1997; 349: 1133-36.7. Saddekni S, Sniderman KW, Hilton S, et al. Percutaneoustransluminal angioplasty of non atheroscleroticlesions. Am J Roentgenol 1980; 135: 975-82.8. Baert AL, Wilms G, Amery A, et al. Percutaneoustransluminal renal angioplasty: initial and long-termfollow-up in 202 patients. Cardiovasc Intervent Radiol1990; 13: 22-28.9. Hayes JM, Risius B, Novick AC, et al. Experience withpercutaneous transluminal angioplasty for renal arterystenosis at the Clevelant Clinic. J Urol 1988; 139: 488-492.10. Canzanello VJ, Millan VG, Spiegal JE, et al. Percutaneoustransluminal renal angioplasty in management ofatherosclerotic renovascular hypertension: results in 100patients. Hypertension 1989; 13: 163-172.11. Pickering TG, Sos TA, Saddekni, et al. Renal angioplastyin patients with azotaemia and renovascular hypertension.J Hypertens 1986; 4(Suppl 6): S667–669.12. Shannon HM, Gillespie IN, Moss JG, et al. Salvage ofthe solitary Kidney by insertion of a renal artery stent.AJR 1998; 171: 217-222.13. Kimm PK, Spriggs DW, Rutecki GW, et al.Transluminal angioplasty in patients with bilateral renalartery stenosis or renal artery stenosis in a solitarykidney. AJR 1989; 153: 1305-1308.14. Dorros G, Jaff M, Mathak L, et al. Multicenter Palmazstent renal artery stenosis revascularization registryreport: follow up of 1058 successful patients. CatheterCardiov Interv 2002; Feb: 55(2): 182-8.15. Chabova V, Schirger A, Stanson AW, et al. Outcomesof atherosclerotic renal artery stenosis managed withoutrevascularization. Mayo Clinn Proc 2000; May; 75(5): 435-6.16. Van Ampting JM, Penne EL, Beek FJ, et al.Prevalence of atherosclerotic renal artery stenosis inpatients starting dialysis. Nephrol Dial Transplant2004; Jan: 19(1): 260-1.17. Van de Ven PJG, Kaatee R, Beutler JJ, et al. Arterialstenting and balloon angioplasty in ostial atheroscleroticrenovascular disease: a randomised trial. Lancet 1999;353: 282-86.18. Nolan BW, Schermerhorn ML, Powell RJ, Rowell E,et al. Restenosis in gold-coated renal artery stents. JVasc Surg 2005; 42(1): 40-6.19. Blum U, Krumme B, Flugel P, et al. Treatment of ostialrenal artery stenosis with vascular endoprostheses afterunsuccessful balloon angioplasty. N Engl J Med 1997;336: 459-65.20. Dean RH, Callis JT, Smith BM, et al. Failedpercutaneous transluminal renal angioplasty: experiencewith lesions requiring operative intervention. J VascSurg 1987; 6(3): 301-7.21. Muller-Hulsbeck S, Frahm C, Behm C, et al. Lowprofilestent placement with the monorail technique fortreatment of renal artery stenosis: midterm results of aprospective trial. J Vasc Interv Radiol 2005; 16(7): 963-71.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 65–69Original ArticleLupus Nephritis and Cardiovascular Disorders - Our Clinical ExpirienceMilorad Rabrenovic 1 , Radomir Matunovic 2 , Violeta Rabrenovic 3 , Dragan Jovanovic 3 and ZoranKovacevic 31 Department of Treatment, 2 Clinic of Cardiology, 3 Clinic of Nephrology, Military Medical Academy, Belgrade, SerbiaAbstractBackground. The aim of this study was to evaluate mostcommon cardiovascular complications in our LN pts.Methods. We investigated 44 LN pts with cardiacmanifestation to conclude which of these are more frequent.In order to achieve the aim of this study, we carried outnoninvasive cardiac procedures including measurement ofbiochemical markers of cardiac function, electrocardiography,echocardiography, computer tomography andmagnetic resonance imaging of the heart as well as invasivecoronarography in some patients.Results. Some forms of pericarditis were found in 39/44pts, substantial pericardial effusion in 3, and 18 pts withpericarditis sicca. Except pericarditis, we identified Libman-Sacks verrucous endocarditis in 3 pts, then other non-specificvalvular involvement such as prolapsus with some degree ofregurgitation in 27 patients and thickening or degenerativedysfunction in 14 cases. Occurrence of thrombosis in thecoronary arteries and the heart valve as well as intramyocardialvasculopathy in the form of the secondary anti-phospholipidsyndrome was reported in 8 patients. Myocardial infarctiondeveloped due to inflammatory changes in coronary arteries(coronaritis) was identified in one of those patients.Tachycardia is the most common rhythm irregularity but,we found cardiac conduction defects during myocarditis in6 pts who were also indicated for the therapy due to themetabolic and electrolyte dysbalance.Concluson. The most common cardiac disorders caused byLN which were detected in our group of patients were formsof pericarditis, valvular thickening and regurgitation while theclassic endocarditis or myocarditis was found to be rare.Keywords: Lupus nephritis, complications, pericarditis,endocarditis, tachycardiaIntroductionSistemic lupus erithemathodes (SLE) is a syndrome withmultifactorial etiology characterized by inflammationaffecting almost all or a part the human body. Fifty yearsago, mortality rate was 50% but, nowadays, it is assessedthat, by careful monitoring of this disease, the 10-yearsurvival period is 90% [1-4]. Once the disease affects thekidneys, we are dealing with lupus nephritis (LN) which isby itself considered a clinical entity. The deterioration ofthe general condition of the body affects the cardiovascularprocesses the information from the internal environmentand external surroundings and transmits the responses backto all the organs, tissues and systems. The response thusprocessed at the level of cardiovascular system leads tonormal, faster or slower heart beating, to narrowing orweakening of the vascular system accompanied by an increaseor decrease in the arterial pressure to the possible variousparadoxical reactions in tissues and organs. As the genesis ofthe cardiovascular diseases is not uniform, the manifestation ofthe same is neither uniform nor predictable.The main morphologic lesion in SLE is diffuse microvasculitisand the cardiac involvement in various forms is found duringthe autopsy [5-7]. But the development of cardiovascularcomplications is less perceived and very often concealed bysymptoms and signs indicating involvement of otherorgans, particularly, the kidneys. While there has beensome improvement in the SLE survival pattern achieved bythe immunosuppressive therapy [7,8] the recent studiesindicate the significance of cardiovascular diseases as themost serious cause of death [9-13].Pathophysiologically, SLE is characterized by pancarditisaffecting the pericardium, myocardium, endocardium andcoronary arteries. In the autopsy findings, pericarditis wasreported in 43% out of 100% of cases (in 62% on average),myocarditis in 8% out of 78% of cases (in 40% onaverage), but they usually were not diagnosed clinically.Libman-Sacks lesions were detected in 25% out of 100% ofcases (in 43% on average) while infectious endocarditis wasidentified in 1,1% - 4,9% of clinical autopsies [11]. Thecoronary disease results from arteritis and may bepharmacologically or surgically treated. In cases of the heartvalve defects, surgical treatment is applied but surgicalmortality rate in SLE is 25% higher. Aortic insufficiency andmitral regurgitation are considered the most common valvulardefects, although aortic and mitral valve stenosis is included.Hypertension was reported in 14-69 %, while the heart failurein 5-55% of cases [11-13]. What left to be done is to assess towhat extent the improved diagnosis and the treatment of theSLE cardiovascular manifestations would improve thesurvival pattern in those patients.Having in mind everything mentioned so far, there is agreat amount of research work to be done with respect tothe genesis, pathomorphology and, clinical but also casualmanifestations of the cardiovascular system in lupusnephritis. Our experience in treating cardiac complicationsin 44 cases was presented in this study.The aim of our study was to determine the frequency ofclinical cardiovascular disorders in patients with lupussystem as well. The neuroendocrine system collects and______________________Correspodence to: Milorad Rabrenovic, Military Medical Academy, Crnotravska 17, Belgrade, Serbia;Tel. + 38164 8743014; E-mail: kaca3110@infosky.net

66 BANTAO Journal 2007; 5 (2)nephritis and their eventual significance for the follow-upmonitoring, treatment and prognosis as well.Patients and methodsDirect or indirect signs of cardiovascular abnormalitieswere seen in 51 out of 92 reported SLE patients treated atthe Military Medical Academy in the period from 1986 to2006. Lupus nephritis was diagnosed in 44 out of 58patients with SLE and cardiovascular manifestations. Datawere gathered retrospectively from both the existingdatabase of patients examined and treated on an inpatientbasis and, the database of patients ambulatory monitored. Indealing with these patients, a multidisciplinary approachwas used. All the patients were adequately treated andobserved for the period of 4 years. According to theobjectives established in this study, the involvement of thecardiovascular system was determined on the basis ofnoninvasive and invasive cardiac diagnostic methods whilethe clinical studies were the base for determining othercardiovascular disorders. The data gathered from all noninvasivecardiovascular procedures including measurementof biochemical specific markers of the heart function suchas cardiospecific enzymes, troponin, brain natriureticpeptide-BNP, electrocardiography, echocardiography,computer tomography and magnetic resonance of the heartas well as from invasive coronarography performed in somepatients were thoroughly assessed. The cause of death wasestablished on the basis of clinical or autopsy reports.ResultsPatient outcome: Out of 44 patients 39 were female and 5male patients. The average age was 33,2 (Table 1). Duringthe 4-year observation period, 28 patients maintained agood health condition and 16 died (12 from cardiac causes,1 from a non-cardiac cause while for the last 3 patients wehad no information).Table 1. Heart function in patients with Lupus nephritis andcardiovascular disturbances estimated by echocardiograficejection fractionFunctional state of heart by echocardiografic ejectionfruction in our patientsGeneral aspects X SDNumber of patients 44Male/female 39/5Age (years) 33,2 ±17,11Ejection fraction of heart 53,43 ±9,37%We estimated cardiac condition of all our patients byappropiate diagnostic procedures (Table 2). Only in 2 out of44 patients there were not clinical, but positive diagnosticresults for cardiac disturbances.Table 2. Assessment of clinical state by different diagnostic proceduresPresence of cardiac clinical manifestation and diagnostic approach in patients withLupus nephritisExaminationOut ofPTSSTATUS44 ptsNUMBERPERCENTClinical presentation 44 positive 42 42/44 95(100%) negative 2Resting ECG 32 normal 32 12/32 37(73%) abnormal 12Ambulatory ECG (Holter) 6 normal 2 4/6 66(13%) abnormal 4Echocardyography44 normal 13 31/44 70(TTE,TOE)(100%) abnormal 31CT / MRI 8 normal 4 4/8 80(18%) abnormal 4Cardiac catheterisation 3 normal 0 3/3 100(7%) abnormal 3Coronary angiography 2 normal 0 2/2 100(4%) abnormal 2Cardiospecific enzyme 19 normal 7 12/19 63(43%) abnormal 12TTE - transthoracic echo, TOE - transoeseophageal echo, CT - computer tomography, MRI -magnetic resonance imagingAmong the general clinical manifestations characteristic fordysfunction of the heart, the following were identified(Table 3).Abnormalities in normal rhythmic pattern out of whichtachycardia is the most common manifestation reported in33/34 cases.Cardiac conduction defect is more severe form of disorderof the normal heart function and is usually associated withmyocarditis. The more severe abnormalities were detectedin 6 patients while one was indicated for the insertion of anartificial pacemaker due to high atrioventricular blocking ofthe II degree.Valvular defects: Valvular defects were reported in 29patients. Echocardiographically recorded morphologicchanges in the form of Libman-Sacks endocarditis wereidentified in 3 patients. The most frequently reported defectwas non-specific thickening of valves (in 27/29 patients).Thickening of valves free of any signs of endocarditis wasseen in 14 patients with mitral valve prolapse.Haemodynamically substantial damage of valvularstructures wasn’t found in any of those patients.

BANTAO Journal 2007; 5 (2) 67Table 3. Presents of different cardiac conditions and cardiac state in our group of patientswith Lupus nephritis and cardiac disordersCardiac conditionsRhythm andconductiondisturbancesOut of44 pts34(77%)Clinical statusN ofpatients%Tachycardia 33/34 97Arrythmias 11/34 32Conduction defect 6/34 17,6Valvular defects 29 Thickening of valve 27/29 93(66%) Prolapsus 14/29 48,2LS-endocarditis 3/29 10,3Pericarditis 27 Pericarditis sicca 18/27 66,6(61%) Pericardial effusion 9/27 33,3Cardiac tamponade 1/27 3,7Myocarditis 4 (9%) Myocardiopatia 4/4Cardiomiopathy 4 (9%) Heart failure 4/4IHD and trombosis 3 (7%) Coronary sindroma 2/3PTS-patients, CVD-cardiovascular disease, IHD-ishaemic heart diseasePericarditis: 39 patients complained of the chest pains and/or dyspnea what was believed to result from the affectionof pericarditis associated with the disease activity duringthe initial examination of the patient or relapsing period asit was seen in 13 patients. The definite diagnosis couldn’tbe established due to the serologic tests being initiallyseronegative. But the successive serologic tests found to beseropositive in a certain number of patients revealed othercharacteristic signs typical for lupus nephritis. Pericarditiswas diagnosed in 27 patients. Substantial pericardialeffusion was detected in 3 of those 27 pts and a form ofpericarditis sicca identified in 18 pts. In 2 cases, thediagnostic punction of pericardium was performed as wellas a biopsy to exclude tuberculosis or some other causes ofpericarditis. All the patients receiving steroide therapyresponded quite well to it.Myocarditis: Endomyocardial biopsy wasn’t performed todiagnose the myocarditis. But in 4 patients that diagnosiswas established on the basis of electrocardiograpic changes,echocardiography and serologic tests. The mentionedpatients responded promptly to the steroid therapy whileazathioprine was introduced into the therapy of one patient.Pulmonary hypertension: The progressive dyspneaaccompanied by generalized edema at the time when thedisease was well controlled with steroids was disclosed intwo cases. The diagnosis of primary pulmonary hypertensionwas established by catherisation of the heart and thepulmonary angiography. One of those two patients wasn’tin the evidence any more while the other one died from theheart failure.Cardiomyopathy and coronary artery disease: One patientwith clinical manifestations of the chest pains andcharacteristic electrocardiographic changes was diagnosedas having the acute myocardial infarction developed whilethe disease was in remission and treated with steroids. Thatpatient wasn’t in the evidence any more.By applying the mentioned diagnostic methods and byusing computed tomography and magnetic resonanceimaging as well, substantial cardiomyopathy was identifiedin 4 patients. Three of them died while the fourth was not inthe evidence any more. In one of those who died, focalmyocardial necrosis and fibrous scar accompanied byintramural stenosis of coronary arteries was found.DiscussionCardiovascular disorders in SLE may be a part of clinicalmanifestations but may considerably be involved in theoccurrence of complications associated with the affection ofother organs or systems particularly if it’s the case of renalfailure in LN. However, it may be considered thatcardiovascular defects, either relating to functional ordiagnosed morphologically organic defects, maysubstantially affect the further course of disease and itsprognosis [5]. The most common forms of the cardiovasculardiseases are pericarditis, valvular degeneration such asvalvular thickening and regurgitation, while classicendocarditis and myocarditis were rarely seen [6]. In theearly stage of the disease, the acute myocardial infarctionmay develop due to the inflammatory changes in thecoronary arteries (coronaritis), particularly, in youngwomen. Our study indicated that the clinical pericarditiswas the most common cardiac complication occurring inLN. Lupus pericarditis is the most often associated with thedisease activity. It is known that infectious causes ofpericarditis might occur in patients in remission. Treatmentwith steroids and immunosuppressive drugs may create theopportunity for the development of opportunistic infectionsbut, it may also mask their signs. Therefore, it is proposedto have the pericardium aspirant carefully analyzed eachtime, taking into account the culture analysis [13]. Thediagnostic punction of the pericardium was performed inpatients with effusion, but the constrictive pericarditis wasdetected in patients after the long evolution of the disease.As pericarditis, myocarditis is also associated with thedisease activity and responds well to the steroid therapy[12]. The most significant results of the latest studies onSLE and LN indicate the increase in number of patientswith changes in coronary blood vessels thought to be theunderlying causes of mortality [14-17].Pulmonary hypertension may also be associated with LN,but cases described in the literature are isolated [8-10]. Onthe basis of autopsy findings, it was determined thatvasculitis affecting the pulmonary vasculature occuredmore often than it was clinically identified [9,10].

68 BANTAO Journal 2007; 5 (2)Abnormalities in normal rhythmic pattern may occurregardless of the stadium of the underlying disease. Sinustachycardia is the most common manifestation of thecardiovascular system. The mentioned disorders reflectingeither organic or functional defects are reported.Contrary to rhythm irregularity, cardiac conduction defectsare most often the result of the existing myocarditis andusually develop due to metabolic and electrolyte dysbalancebut may also be caused by the already introducedpharmacotherapy including antimalarial drugs particularly[14,15].The changed lipid status, a high index of the diseaseactivity, the existence of other diseases (hypertension, renalfailure,) premature menopause and partially the ‘lupusfactor’ including chronic inflammation, anti-phospholipidantibodies as well as chronic treatment with steroids [14-17] are involved in the genesis of systemic changes incoronary vessels in SLE and LN.The development of acute myocardial infarction in onerelatively young female patient was attributed to the antiphospholipidsyndrome and vasculitis related changes incoronary blood vessels.Prognosis of cardiomyopathy is, due to the simple or complexcardiovascular changes bad in those patients and the developeddisease usually results in cardial death.Primary cardiomyopathy is reported in a very small numberof patients while the secondary often results from eithervalvular defects or myocarditis [18].There are no precise information in the literature on thecorrelation that may exist between the occurrence ofcardiovascular diseases and the presence of dsDNA, on theconcentration of complements and the presence of aCLantibodies.Biological survival pattern indicates that cardiovasculardiseases are the underlying cause of mortality in thepatients with the long-lasting evolution of lupus [19].Cardiac manifestations inevitably led to the lethal outcomebefore. It happened that they were diagnosed only duringthe autopsy. Recently, cardiovascular manifestations areoften mild or even asymptomatic. The use ofechocardiography and other sophisticated and noninvasivediagnostic methods allows us to identify abnormalities ofthe heart, particularly mild forms of pericarditis, valvulardefects or other forms of myocardial dysfunction, in a largenumber of cases. Timely diagnosis and the treatment ofcardiovascular diseases may prevent certain undesirableeffects and play a great part in the successful treatment ofthe disease. Therefore, a periodical echocardiography ishighly recommended in the SLE patients.ConclusionOur study shown that cardiovascular complications weresubstantially present in the SLE and LN patients. The mostcommon were pericarditis, valvular defects such asthickening of valvular apparatus and regurgitation, whilethe classic endocarditis and myocarditis were found to bemore rare.Treatment of the SLE patients requires, due to the highincidence of cardiovascular diseases in SLE and /or LNpatients, a wide range of clinical and laboratory analysesthat should serve as the valid standards of SLE andcardiovascular diseases treatment. Periodical examinationsof the cardiovascular system by noninvasive techniques arerequired, even if no visible symptoms of the affection areobserved.It is necessary to conduct further studies as to confirm ourobservation and, if possible, to set the optimal treatmentregimen.Conflict of interest statement. None declared.References1. Stoll T, Stucki G, Malik J, Pyke S and Isenberg DA.Association of the Systemic Lupus InternationalCollaborating Clinics / American College ofRheumatology Damage Index with measures of diseaseactivity and health status in patients with systemic lupuserythematosus. J Rheumatol 1997; 24: 309–13.2. Mandell B. Cardiovascular involvement in systemiclupus erythematosus. Sem Arthritis Rheum 1987; 17:120–41.3. Tucker LB, Menon S, Schaller JG and Isenberg DA.Adult- and childhood-onset systemic lupuserythematosus: a comparison of onset, clinical features,serology and outcome. Br J Rheumatol 1995; 34: 866–72.4. Vaishnaw AK and Walport MJ. Systemic lupuserythematosus. In Connective Tissue Diseases eds J.F.Belch and R.B Zurier, Chapman and Hall, London,1995, pp. 17–50.5. Doherty NE, Siegel RJ. Cardiovascular manifestationsof systemic lupus erythematosus. Am Heart J 1985;110(6): 1257-65.6. Humphries EM. The cardiac lesions of acutedisseminated lupus erythematosus. Ann Intern Med1948; 28: 12-14.7. Baldwin DS, Gluck MC, Lowenstein J, Gallo GR. Lupusnephritis: clinical course as related to morphologic formsand their transitions. Am J Med 1977; 62: 12-30.8. Nair SS, Askari AD, Popelka LG et al. Pulmonaryhypertension and systemic lupus erythematosus. ArchIntern Med 1980; 40: 109-11.9. Santini D, Fox D, Kloner RA et al. Pulmonaryhypertension in systemic lupus erythematosus:haemodynamics and effect of vasodilator therapy. ClinCardiol 1980; 3: 404-11.10. Fayemi A.Pulmonary vascular disease in systemiclupus erythematosus. Am J Clin Pathol 1976; 284.11. Gross L.Cardiac lesion in Libman-Sacks disease withconsideration of its relationship to acute diffuse lupuserythernatosus. Am J Pathol 1940; 16: 375-407.12. Wijetunga M, Rockson S. Myocarditis in systemiclupus erythematosus. Am Heart J 2002; 113(5): 419-23.13. Jacobson EJ, Reza MJ.Constrictive pericarditis insystemic lupus erythematosus.Arth Rheum 1978;21:972-4.14. Logar D, Kveder T, Rozman B, Dobovisek J. Possibleassociation between anti-Ro antibodies and myocarditisor cardiac conduction defects in adults with systemiclupus erythematosus. Ann Rheum Dis 1990;49(8): 627-9.15. Donadio JV Jr, Holley KE, Ferguson RH, DstrupDM.Treatment of diffuse proliferative lupus nephritis

BANTAO Journal 2007; 5 (2) 69with prednisone and combined prednisone andcyclophosphamide. N Engl J Med 1978; 229: 1151-55.16. Urowitz MB, Bookman AAM, Koehler BE et al. Thebimodal mortality pattern of systemic lupuserythematosus. Am J Med 1976; 60: 221-5.17. Rosner S, Guizler EM, Diamond HS et al. Amulticenter study of outcome in systemic lupuserythematosus. Arthr Rheum 1982; 25: 612-7.18. Doria A, Iaccarino L, Sarzi-Puttini P, Atzeni F, TurrielM, Petri M. Cardiac involvement in systemic lupuserythematosus. Lupus 2005; 14(9): 683-6.19. E Galve, J Candell-Riera, C Pigrau, G Permanyer-Miralda, H Garcia-Del-Castillo, and J Soler-Soler.Prevalence, morphologic types, and evolution of cardiacvalvular disease in systemic lupus erythematosus NewEngl J Med 1988; 319(13): 817-823.

BANTAO Journal 2007; 5 (2) : 70–73BJBANTAO JournalOriginal ArticleParicalcitol in Dialysis Patients with Calcitriol - Resistant SecondaryHyperparathyroidismVasilis Filiopoulos 1 , Ioannis Malegos 2 , Eleni Stefanopoulou 1 and Athina Patrikarea 21 Dialysis Unit, General Clinic ‘Timios Stavros’, Athens, Greece,2 Renal Unit, General Hospital of Elefsina, ‘Thriasion’, Athens, Greeceexcessive iPTH suppression and resultant hypercalcemia.AbstractMean doses of paricalcitol decreased significantlythroughout the course of therapy while maintaining acceptableBackground. Clinical studies in dialysis patients with iPTH suppression. Six patients experienced episodes of severesecondary hyperparathyroidism (SHPT) showed that paricalcitolhypercalcemia (Ca > 12 mg/dl or 3 mmol/L), mainly within(19-nor-1a, 25-dihydroxyvitamin D 2 ), a vitamin D the first 2 months and when iPTH levels decreased rapidly toanalog, suppresses parathyroid hormone (PTH) levels as less than 150 pg/ml. All these episodes were successfullyeffectively as intravenous calcitriol without resulting in managed by dietary counseling, phosphate-binder adjustmentsignificant increases in serum Ca and P. The aim of the and paricalcitol dose reduction. Ten patients developed severepresent study is to investigate whether paricalcitol could hyperphos-phatemia (P > 6,5 mg/dl or 2,1 mmol/L); 6 patientsprovide long-term control of moderate to severe SHPT in responded adequately to the dietary manipulation andhemodialysis patients considered resistant to intravenous phosphate binders, but 4 patients had repeated episodes. Threecalcitriol/alfacalcidol therapy. We also assess the incidence patients did not respond adequately to paricalcitol therapy andof hypercalcemia and hyperphosphatemia during treatment were switched on cinacalcet therapy.with paricalcitol in this group of patients.Conclusion. Paricalcitol is effective in controlling SHPT inMethods. Thirty-one stable hemodialysis patients of mean patients resistant to calcitriol therapy with minimal impactage 54±10 with persistent intact PTH (iPTH) levels of 600 on calcium and phosphorus homeostasis.pg/ml or greater for at least 6 months despite treatment withintravenous alfacalcidol were included into the study. All Keywords: Calcitriol/alfacalcidol, paricalcitol, hemodialysis,patients underwent hemodialysis three times weekly. hypercalcemia, hyperphosphatemia, sec. HyperparathyroidismParicalcitol was administered intravenously 3 times perweek at the end of hemodialysis session. Therapy with Introductionparicalcitol was not initiated until a patient’s serum P level Severe renal osteodystrophy, resulting from poorlywas less than 6,5 mg/dl (2,1 mmol/L). Nutritional controlled secondary hyperparathyroidism, is a potentiallycounseling and phosphate binders (calcium acetate and/or disabling disease and causes significant morbidity insevelamer) were used for phosphate control. The initial patients with chronic renal failure [1,2]. Decreased renaldose of paricalcitol in mcg per hemodialysis session was production of calcitriol (1,25 vitamin D 3 ), hypocalcemiacalculated according to the formula: iPTH/100. Subsequent and hyperphospha-temia are the major contributing factorsdoses were titrated according to serum levels of iPTH, Ca to the development of secondary hyperparathyroidism [3,4].and P. The follow-up of the patients was 12-18 months. The administration of calcitriol has a direct inhibitory effectDuring the study serum levels of Ca and P were measured on the parathyroid gland; directly by suppressing theevery month and iPTH every 1-3 months. The serum Ca synthesis of parathyroid hormone (PTH) messenger RNA atconcentration was corrected according to the formula: total the transcription level and indirectly by both increasing theCa + 0,8 × (4 – serum albumin).serum calcium concentration and by increasing theResults. Mean iPTH levels (baseline mean 933±294 pg/ml) sensitivity of PTH suppression to calcium [5].decreased rapidly during the first months of therapy and Medical management of secondary hyperparathyroidismthis decrease reached statistical significance already by the relies on the control of hyperphosphatemia and adequatefirst month of treatment with paricalcitol. Mean iPTH levels dosing of calcitriol or one of the newer vitamin D analogues.reached the designated target range (100-300 pg/ml) by Phosphorus control is accomplished by phosphorus restrictedmonth 5 (mean 242±199 pg/ml). Mean Ca and P levels did diets and the use of oral phosphate binders. Intravenousnot change significantly over the 14 months of paricalcitol calcitriol has a proven efficacy in the severe cases of secondarytherapy. The baseline mean Ca level of 9,3±0,8 mg/dl (2,3±0,2 hyperparathyroidism [6]. Serum calcium concentrations,mmol/L) increased to 9,7±0,9 mg/dl (2,4±0,2 mmol/L) (P = however, are increased via vitamin D-enhanced intestinal0,86) and P level increased from 6,1±0,9 mg/dl (1,9±0,3 calcium absorption, which occasionally results in hypercalcemia[7]. Calcitriol, especially in conjunction with calcium-mmol/L) to 6,4±1,3 mg/dl (2,0± 0,4 mmol/L) (P = 0,77) after14 months of therapy. The initial dose of paricalcitol containing phosphate binders, greatly increases the risk for(iPTH/100) was less than previously recommended to avoid______________________Correspodence to: Vasilis Filiopoulos, MD, General Clinic, Dialysis Unit ‘Timios Stavros’, Athens, Greece;E-mail: filiopoulos1970@hotmail.com

BANTAO Journal 2007; 5 (2) 71hypercalcemia, hyperphosphatemia, and increased calciumphosphorus(Ca×P) product as well as the development ofadynamic bone disease [8,9]. These disturbances, in turn,can result in soft tissue and vascular calcification, whichcontributes to an increased mortality and cardiovascularmorbidity [10]. At the same time the above mentionedadverse events limit the use and effectiveness of calcitriol.Thus, current clinical practice is focused on developingtherapies that do not cause increased body burden ofcalcium and phosphorus. This has included the use of noncalciumcontaining phosphate binders, as well as vitamin Danalogues that has less calcemic and phosphatemic effect.One such analogue, 19-nor-1α, 25-dihydroxyvitamin D 2(paricalcitol), was approved for clinical use in hemodialysispatients in 1998. Preclinical and clinical studies withparicalcitol demonstrated significant PTH suppression withonly mild effects on serum calcium and phosphorus levels[11-13]. A recent double-blinded, randomized multicentercomparative study suggested that paricalcitol provides atherapeutic advantage to calcitriol because it reduced PTHconcentration more rapidly and with fewer sustained episodes ofhypercalcemia and increased Ca×P product than calcitriol [14].The aim of the present study was to investigate whetherparicalcitol could provide long-term control of moderate tosevere SHPT in hemodialysis patients considered resistantto intravenous calcitriol/alfacalcidol therapy. We alsoassessed the incidence of hypercalcemia andhyperphosphatemia during the treatment with paricalcitol inthis group of patients.Patients and methodsThirty-one stable hemodialysis patients with mean age of54±10 with persistent intact PTH (iPTH) levels of 600pg/ml or greater for at least 6 months despite treatment withintravenous alfacalcidol were included into the study. Allpatients evaluated came from the same dialysis unit thatrepresents a dialysis population of approximately 250patients. Informed consent was obtained from all patientsbefore entering the study.All patients were dialyzed three times 4 hours per weekwith a calcium dialysate concentration of 2,5 mEq/l.Paricalcitol was administered intravenously 3 times perweek at the end of hemodialysis session. Therapy withparicalcitol was not initiated until a patient’s serum P levelwas less than 6,5 mg/dl (2,1 mmol/L). Nutritionalcounseling and phosphate binders [calcium acetate andsevelamer] were used for the phosphate control. The initialdose of paricalcitol in mcg per hemodialysis session wascalculated according to the formula: iPTH/100. However,the recommended paricalcitol dosing (iPTH/80) accordingto our previous experience, resulted in an unacceptablyrapid suppression of iPTH and frequent hypercalcemicepisodes.The initial paricalcitol dose was maintained for a minimumof 4 weeks. Subsequent doses were titrated according toserum levels of iPTH, Ca and P. The follow-up of thepatients was 12-18 months. During the study serum levelsof Ca and P were measured every month and iPTH every 1-3 months. iPTH was measured by means of an intacthormone radioimmunoassay. The serum Ca concentrationwas corrected according to the formula: total Ca + 0,8× (4 –serum albumin).If a patient’s serum calcium concentration level increasedto greater than 11 mg/dl (2,7 mmol/L), paricalcitol dosewas decreased by approximately 30%. Paricalcitol waswithheld if serum calcium levels increased to greater than 12mg/dl (3 mmol/L) or symptomatic hypercalcemia wassuspected. Paricalcitol was also withheld if serum phosphoruslevels increased to greater than 7,5 mg/dl (2,4 mmol/L) orcalcium-phosphorus product was greater than 75. When calciumlevels decreased to 10 mg/dl (2,5 mmol/L) or less, phosphoruslevels decreased to 6,5 mg/dl [2,1 mmol/L] or less, or calciumphosphorusproduct decreased to 65 or less, paricalcitol therapywas restarted. The designated target was to correct iPTH levelsto a range of 100-300 pg/ml.Student’s t-test was used for statistical analysis ofbiochemical data before, during and after therapy.Statistical significance threshold was set at 0,05. Results areexpressed as mean ± SD.ResultsThirty-one patients with end-stage renal disease onmaintenance hemodialysis therapy with moderate to severesecondary hyperparathyroidism were included into thestudy. Demographic data for patients are listed in Table 1.Before entering the study, all patients were treated withintravenous alfacalcidol for at least 6 months, butalfacalcidol failed to control secondary hyperparathyroidism.Just before alfacalcidol therapy was discontinued,the mean iPTH level was 933±294 pg/ml.Table 1. Demographics and Baseline characteristicsSexMen 15Women 16AgeMean 54±10Range 25-75Duration of hemodialysisRange (years) 2-10Baseline iPTH (pg/ml)Mean 933±294Range 610-1850Baseline calcium (mg/dl) 9,3±0,8(mmol/L) 2,3±0,2Baseline phosphorus (mg/dl) 6,1±0,9(mmol/L) 1,9±0,3Recruited patients had experienced hypercalcemia (Ca >11,5 mg/dl or 2,8 mmol/L), hyperphosphatemia (P > 6,5mg/dl or 2,1 mmol/L), or both during the previous 6 monthsof therapy with alfacalcidol. Twenty patients (64%)experienced repeated episodes of hyperphosphatemia, 16patients repeated episodes of hypercalcemia (52%) and 15patients (48%) experienced both before being converted toparicalcitol therapy. Patients were followed up for 12-18months. Twenty-eight patients were evaluated for the full14 months of paricalcitol therapy.Mean iPTH levels (baseline mean 933±294 pg/ml)decreased rapidly during the first months of therapy andthis decrease reached statistical significance already by thefirst month of treatment with paricalcitol. Mean iPTH levelsreached the designated target range (100-300 pg/ml) bymonth 5 (mean 242±199 pg/ml). Mean iPTH levels at 6, 12,

72 BANTAO Journal 2007; 5 (2)and 16 months of paricalcitol treatment were statisticallylower than mean iPTH levels at baseline (p< 0,001). Figure1 shows mean iPTH levels over the 18 months ofparicalcitol therapy.PTH (pg/ml)Fig. 1. Mean iPTH levels throughout the study in paricalcitoltreatedpatientsMean Ca and P levels did not change significantly over the 14months of paricalcitol therapy. The baseline mean Ca level of9,3±0,8 mg/dl (2,3±0,2 mmol/L) increased to 9,7±0,9 mg/dl(2,4±0,2 mmol/L) (P = 0,86) and P level increased from6,1±0,9 mg/dl (1,9±0,3 mmol/L) to 6,4±1,3 mg/dl (2,0±0,4mmol/L) (P = 0,77) after 14 months of therapy. Figures 2 and3 show the variations of mean Ca, P and Ca×P throughout thestudy. The initial dose of paricalcitol (iPTH/100) was less thanpreviously recommended to avoid excessive iPTH suppressionand resultant hypercalcemia. Mean doses of paricalcitoldecreased significantly throughout the course of therapy whilemaintaining acceptable iPTH suppression.1210864201 3 5 7 9 11 13 15 17Fig. 2. Mean Ca and P responses over time in paricalcitol-treatedpatients70605040302010090080070060050040030020010001 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18Months1 3 5 7 9 11 13 15 17Fig. 3. Mean Ca×P responses over time in paricalcitol-treatedpatientsSix patients experienced episodes of severe hypercalcemia(Ca > 12 mg/dl or 3 mmol/L), mainly within the first 2months and when iPTH levels decreased rapidly to less than150 pg/ml. All these episodes were successfully managedCaPby dietary counseling, phosphate-binder adjustment andparicalcitol dose reduction. Ten patients developed severehyperphosphatemia (P > 6,5 mg/dl or 2,1 mmol/L), 6patients responded adequately to dietary manipulation andphosphate binders, but 4 patients had repeated episodes.Three patients did not respond adequately to paricalcitoltherapy, their iPTH levels remained greater than 900 pg/mland are now on cinacalcet. One of the patients withpersistent hyperphosphatemia is now also on cinacalcet.DiscussionThe present study evaluated 31 patients with persistentmoderate to severe secondary hyperparathyroidism that didnot respond to intravenous alfacalcidol and were convertedto paricalcitol therapy. In summary, paricalcitol wassuccessful in controlling secondary hyperparathyroidismover a long-term period in patients resistant to alfacalcidoltherapy with minimal impact on calcium and phosphorushomeostasis.The initial dose of paricalcitol (iPTH/100) was less thanpreviously recommended because, according to ourexperience, higher doses of paricalcitol resulted inexcessive iPTH suppression and subsequent hypercalcemia.It seems that lower doses of paricalcitol cause more gradualdecrease in iPTH levels and thus severe hypercalcemicepisodes are avoided. The dramatic iPTH suppression mostlikely induced a state of the low bone turnover that resultedin hypercalcemia.The maintenance dose of paricalcitol was also dictated bythe severity of secondary hyperparathyroidism. Paricalcitoldose decreased gradually as iPTH levels decreased butanyway the dose was lower in patients with an initial iPTHlevel between 600-800 pg/ml. Patients with more severesecondary hyperparathyroidism require greater doses ofparicalcitol, which may reflect the severity of parathyroidhyperplasia in these patients.Among the patients recruited in our study, six patientsdeveloped severe hypercalcemia (Ca > 12 mg/dl or 3mmol/L), mainly within the first 2 months and when iPTHlevels decreased rapidly to less than 150 pg/ml. iPTHvalues after 2 months of paricalcitol therapy had decreasedto 175±75 pg/ml in this group of hypercalcemic patients.All these episodes of hypercalcemia were successfullymanaged by dietary counseling, phosphate-binder adjustmentand paricalcitol dose reduction. After the maintenance doseof paricalcitol is established, the incidence of hypercalcemiaappears to be negligible. Over the 1-year period only oneepisode of mild hypercalcemia (Ca 10,8 mg/dl or 2,7mmol/L) occurred.Ten patients experienced severe hyperphosphatemia (P >6,5 mg/dl or 2,1 mmol/L) mostly due to a lack ofcompliance with dietary phosphorus restrictions andinappropriate phosphorus-binder use, 6 patients respondedadequately to dietary manipulation and phosphate binders,but 4 patients had repeated episodes that necessitatedtemporary or definitive discontinuation of paricalcitoltherapy. One of these patients with persistenthyperphosphatemia is now also on cinacalcet.Three patients did not respond adequately to paricalcitoltherapy and are now on cinacalcet. Parathyroidectomy wasnot performed in any patient at least up to now.______________________Correspodence to: Vasilis Filiopoulos, MD, General Clinic, Dialysis Unit ‘Timios Stavros’, Athens, Greece;E-mail: filiopoulos1970@hotmail.com

BANTAO Journal 2007; 5 (2) 73The results of our study are consistent with that of previousclinical studies, which demonstrated that paricalcitolprovides profound PTH suppression and at the same timedoes not cause significant increases in serum Ca or P 12-14 .However, our study was designed to evaluate theeffectiveness and safety of paricalcitol specifically inpatients considered to be resistant to calcitriol/alfacalcidoltherapy. This subgroup of patients is deemed to have severesecondary hyperparathyroidism and therefore the role ofparicalcitol in these difficult-to-manage patients is ofparticular interest. Additionally, the experience in this areais - according to our knowledge - limited.In conclusion, paricalcitol is effective in controllingpersistent moderate to severe secondary hyperparathyroidismin patients resistant to intravenous alfacalcidoltherapy with minimal impact on calcium and phosphoruslevels. This control was appreciated over a period of up to18 months. The administered dose of paricalcitol was lessthan previously recommended in order to avoid excessiveiPTH suppression and resultant hypercalcemia. Ourexperience shows that dose adjustment after the first monthof therapy is mandatory because of the rapid iPTHsuppression afforded by paricalcitol.Acknowledgements. The authors thank all nursing staff ofthe dialysis unit at General Clinic ‘Timios Stavros’ for theirvaluable help throughout the present study.Conflict of interest statement. None declared.References1. Hruska KA, Teitelbaum SL: Renal osteodystrophy. NEngl J Med 1995; 333: 166-174.2. Sherrard DJ, Hercz G, Pei Y, et al. The spectrum ofbone disease in end-stage renal failure-an evolvingdisorder. Kidney Int 1993; 43: 436-442.3. Slatopolsky E, Delmez JA: Pathogenesis of secondaryhyperparathyroidism. Am J Kid Dis 1994; 23: 229-236.4. Slatopolsky E, Finch J, Denda M, et al. Phosphorusrestriction prevents parathyroid gland growth: Highphosphorus directly stimulates PTH secretion in vitro.J Clin Invest 1996; 97: 2534-2540.5. Brown AJ, Dusso A, Slatopolsky E: Vitamin D. Am JPhysiol 1999; 277: F157-F175.6. Malberti F, Surian M, Cosci P: Effect of chronicintravenous calcitriol on parathyroid function and setpoint of calcium in dialysis patients with refractorysecondary hyperparathyroidism. Nephrol DialTransplant 1992; 7: 822-828.7. Delmez JA, Tindira C, Grooms P, et al. Parathyroidhormone suppression by 1,25-dihydroxyvitamin D, arole for increased sensitivity to calcium. J Clin Invest1989; 83: 1349-1355.8. Delmez JA, Slatopolsky E: Hyperphosphatemia: itsconsequences and treatment in patients with chronicrenal disease. Am J Kidney Dis 1992; 19: 303-317.9. Cannata AJB: Adynamic bone and chronic renalfailure: an overview. Am J Med Sci 2000; 320: 81-84.10. Goodman WG, Goldin J, Kuizon BD, et al. Coronaryartery calcification in young adults with end stagerenal disease undergoing dialysis. N Engl J Med 2000;342: 1478-1483.11. Slatopolsky E, Finch J, Ritter C, et al. A new analog ofIV calcitriol, 19-nor-1, 25-(OH) 2 D 2 suppressesparathyroid hormone secretion in uremic rats in theabsence of hypercalcemia. Am J Kidney Dis 1995; 26:852-860.12. Martin KJ, Gonzalez EA, Gellens M, et al. 19-Nor-1-α-25-dihydroxyvitamin D 2 (paricalcitol) safely andeffectively reduces the levels of intact PTH in patientson hemodialysis. J Am Soc Nephrol 1998; 10: 1427-1432.13. Lindberg J, Martin KJ, Gonzalez EA, et al. A longterm,multicenter study of the efficacy and safety ofparicalcitol in end-stage renal disease. ClinicalNephrology 2001; 56: 315-323.14. Sprague SM, Llach F, Amdahl M, et al. Paricalcitolversus calcitriol in the treatment of secondaryhyperparathyroidism. Kidney Int 2003; 63: 1483-1490.

BANTAO Journal 2007; 5 (2) : 74–76BJBANTAO JournalOriginal ArticlePulse Pressure is Independent Risk Factor of Left Ventricular Hypertrophyin Chronic Kidney DiseaseMargarita Gjata 1 , Mihal Tase 1 , Myftar Barbullushi 2 , Zheni Gjergji 2 , Alketa Koroshi 2 and Enver Roshi 31 Service of Internal Medicine and HTA, 2 Service of Nephrology and Hemodialysis, 3 Department of Public HealthUniversity Hospital Centre “Mother Teresa” Tirana, AlbaniaAbstractBackground. The aim of the study was to evaluate therelations between pulse pressure (PP), hypertension andanemia with left ventricular hypertrophy (LVH).Methods. The risk factors and prevalence of LHV wereevaluated in 111 patients with CRF.Results. LVH was diagnosed in 81,9 % of all patients. Theprevalence of hypertension was 72,6%. Anemia was present inall patients.Of the variables tested lower levels of hemoglobin, systolicblood pressure (SBP) and PP predicted the occurrence of LVH.Conclusions. This study has shown a strong associationbetween chronic kidney disease (CKD) and LVH in predialysis patients.Pulse pressure, SBP and anemia play an important role in thedevelopment of left ventricular hypertrophy in CKD patients.Keywords: anemia, hypertension, left ventricular hypertrophy,pulse pressureIntroductionCardiovascular complications are the leading cause of deathin patients with end-stage renal disease (ESRD), accountingfor 43-52% of deaths in these patientsLVH is a frequent occurrence in patients with CKD and isan important adverse prognostic indicator [1,2].Increased systolic blood pressure has been suggested as anindependent predictor of left ventricular hypertrophy and itsprogression over time [2].Anemia is an important determinant of cardiac hypertrophy,and is a frequent finding in uremic patients [3]. Anemia, inthe long term, can be associated with progressive LVdilation, new-onset cardiac failure, and death [12].Increased PP is associated with the increase of systolicblood pressure (SBP) and decrease in diastolic bloodpressure (DBP) [4] PP reflects stiffness of the large arteriesand increases with age [5,6]. Increasingly, PP is recognizedas an independent predictor of myocardial infarction,congestive heart failure, and cardiovascular death, even inhypertensive patients who undergo successfulantihypertensive drug therapy, especially in olderindividuals [7]. Patients with CKD show higher PP valuesthan control subjects with normal renal function [5].Several studies have shown that PP is a reliable prognosticfactor for mortality and cardiovascular disease inpredialysis, replacement therapy and renal transplantpatients [8].The aim of our study was to evaluate the relations betweenpulse pressure, hypertension and anemia with leftventricular hypertrophy.Patients and methodsThe study is trans-sectional. We studied 111 in the predialysisstages of CDK. The mean age was 42±16,3. The patients weredevised in 4 groups according to the K/DOQI classificationbased on glomerular filtration (GFR). The first group ofpatients (26 patients) presented second stage of CKD (GFR60-89,9 ml/min). The second group (30 patients) presentedthird stage of CKD (GFR 30–59,9 ml/min). The third group(32 patients) was at 4 th stage of CDK (GFR 15-29,9 ml/min)and the fourth group (23 patients) presented 5 th stage of CKD(GFR 140 mmHg and diastolic blood pressure (DBP) > 90 mmHg.All patients were under antihypertensive therapy. Pulse pressurewas calculated as a difference between SBP and DBP.Anemia has been considered as a level of hemoglobin 110 g/m 2 for females. Cardiacmass was calculated using Reichek and Devereux formula.Statistical analysisData are expressed as the mean ± SD. Spearman correlationwas used to assess the relationship between LVMI and thevariables (SBP, DBP, hemoglobin, pulse pressure). P value of< 0,05 was considered to be statistically significant. Statisticalanalysis was performed using the computer software SPSS 8.0.ResultsLVH was diagnosed in 81,9 % of all patients. Theprevalence of hypertension was 72,6%. Anemia was presentin all patients. The group with second stage of CKD had an______________________Correspodence to: Margarita Gjata, University Hospital Center “Mother Teresa”, Rruga Dibres 370, Tirana, Albania;E-mail: mresuli@yahoo.com

BANTAO Journal 2007; 5 (2) 75average of Hb 8.6±1.2 mg/dl, SBP 160.3±16 mmHg, DBP93.2±7 mmHg, Pulse pressure 67.1±6 mmHg and LVMI135.40±55g/m². The group with third stage of CKDpresented with Hb 8.2± 1.8 mg/dl, SBP 162.4±18 mmHg,DBP 92.4±10 mmHg, Pulse pressure 69.7±8 mmHg andLVMI 145±18 g/m². The group with fourth stage of CKDpresented with Hb 7.8±1.2 mg/dl, SBP 148.0±21mmHg,DBP 91.8±12 mmHg, Pulse pressure 56.8±12 mmHg andLVMI 160±32.75 g/m². The group with fifth stage of CKDpresented with Hb 7.3 ± 1.5 mg/dl, SBP 160.9±12 mmHg,DBP 84.1±9.6 mmHg, Pulse pressure 76,9±0,8 mmHg andLVMI 190±56 g/m². The average data for all groups wereHb 7.9±1.4 mg/dl, SBP 157.9±17 mmHg, DBP 90.4±12.15mmHg, Pulse pressure 65.1±6.7 mmHg and LVMI157.5±44 g/m².The data for the studied parameters are presented in Table 1.Table 1. Clinical, laboratory and echocardiography parameters by renal functionParametersGFR 60-89,9 ml/min(n=26)GFR 30–59,9ml/min(n=30)GFR 15-29,9ml/min(n=32)GFR

76 BANTAO Journal 2007; 5 (2)correlation between LVMI and DBP, otherwise the 4 thgroup shows a strong correlation with SBP and PP. Whenanalyzed separately none of the groups demonstrates anycorrelation between lower levels of Hb and LVMI.In contrast, when all the patients were analyzed, it resultedwith strong inverse correlation between levels of Hb andLVMI. On the other hand, it resulted also with a strongpositive correlation between SBP and PP with LVMI.We assumed this controversially data are result of the smallnumber of patients for each group, and when we analyzed asignificant number of patients the correlations emergedclearly.Anemia in our study resulted as an independent predictor ofLVH. The presence of anemia contributes to volumeoverload, which may be the basic player in installing LVH.The analysis of data shows also that PP and SBP werepredictors of LVH. Our patients presented a highprevalence of SBP; that is also accompanied with wideningof PP, therefore peripheral resistance may have played asignificant role in LVH observed in our patients.To consider the relations of these variables with LVH,especially in early stages of CKD, studies with largernumber of patients are required.ConclusionThis study has shown a strong association between CKDand LVH in pre dialysis patients. The patients were anemicand presented a high prevalence of hypertension. In ourstudy pulse pressure, SBP and anemia are importantpredictor factors for development of left ventricularhypertrophy. Different studies have shown that control ofhypertension and anemia lead to a decrease of LVHprevalence.The effect of PP reduction on LVH in CKD remains to bedetermined. Therefore, more evidences are necessary toevaluate the role of PP reduction as a therapeutic target inthe treatment of patients with CKD.Conflict of interest statement. None declared.References1. London GM: Left ventricular hypertrophy: Why doesit happen? Nephrol Dial Transplant 2003; 18 (Suppl8): viii, 2 –6.2. Levin A, Singer J, Thompson CR, Ross H, Lewis M:Prevalent left ventricular hypertrophy in thepredialysis population: Identifying opportunities forintervention. Am J Kidney Dis 1996; 27: 347 –354.3. Weiner DE, Tighiouart H, Vlagopoulos PT, et al.Effects of anemia and left ventricular hypertrophy oncardiovascular disease in patients with chronic kidneydisease. J Am Soc Nephrol 2005; 16:1803-1810.4. Carmine Zoccali. Arterial pressure components andcardiovascular risk in end-stage renal disease. NephrolDial Transplant 2003; 18: 249-252.5. Gema Fernandez-Fresnedo, Emilio Rodrigo, AngelLuis Martin de Francisco, Saturnino Sanz de Castro,Olga Castañeda and Manuel Arias.Role of PulsePressure on Cardiovascular Risk in Chronic KidneyDisease Patients. J Am Soc Nephrol 2006; 17: 246-249.6. Klassen PS, Lowrie EG, Reddan DN, Delong ER,Coladonato JA, Szczech LA, Lazarus JM, Owen WF:Association between pulse pressure and mortality inpatients undergoing maintenance haemodialysis.JAMA 2002; 287: 1548 –1555.7. Celentano A, Palmieri V, Di Palma Esposito N, et al.Relations of pulse pressure and other components ofblood pressure to preclinical echocardiographicabnormalities. J Hypertens. 2002; 20: 531–537.8. London G, Guerin A, Pannier B, et al. Increasedsystolic pressure in chronic uremia. Role of arterialwave reflections. Hypertension 1992; 20: 10–191997:30:428–435.9. Harnett JD, Kent GM, Barre PE, et al. Risk factors forthe development of left ventricular hypertrophy in aprospective cohort of dialysis patients. J Am SocNephrol 1994; 4:1486–1490.10. Parfrey PS, Foley RN, Harnett JD, et al. Outcome andrisk factors for left ventricular disorders in chronicuremia. Nephrol Dial Transplant 1996; 11: 1277–1285.11. Silberberg J, Barre PE, Prichard SS, et al. Impact ofleft ventricular hypertrophy on survival in end-stagerenal disease. Kidney Int 1989; 36: 286–290.12. Drueke TB, Locatelli F, Clyne N, et al. Normalizationof hemoglobin level in patients with chronic kidneydisease and anemia. N Engl J Med 2006; 355: 2071-2084.13. Deferrari and Roberto Pontremoli. Pulse pressure andsubclinical cardiovascular damage in primaryhypertension. Nephrol Dial Transplant 2002; 17:1779-1785.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 77–80Original ArticleProspective Analysis of Factors Influencing the Antibody Responseto Hepatitis B Vaccine in Hemodialysis PatientsAlexandra Ouzouni, Elena Papadopoulou, Fotini Miari, Theodoros Pliakogiannis, Sofia Mademtzoglou,Kiriaki Traianou, Chrisovalantou Giannioti, Fani Papoulidou, Maria Kalientzidouand Kalaitzidis KleonikosDepartment of Nephrology, General Hospital of Kavala, GreeceAbstractBackground. Patients on maintenance hemodialysistypically show a suboptimal immune response to hepatitisB (HB) virus vaccination compared to the non-uremicpopulation. The aim or our study was the identification offactors implicated in the vaccine response of ourhemodialysis patients.Methods. We studied prospectively 63 hemodialysispatients who were seronegative for HB (37 males, 26females). Their mean age was 62.2±11.28 years (range 35-80) and hemodialysis. Duration 55.96±50.1 months (range6-225) fourteen of them (22.2%) were diabetics. Ourpatients followed a four-dose vaccination schedule (0, 1, 2and 6 months) with 40 μg of a recombinant DNA HBvaccine. The antibody response was determined 1 monthafter the fourth dose of vaccination by assessing the titre ofantiHBs antibodies (ab). Immune response was defined assufficient when the antiHBs ab level was ≥ 12 mIU/ml.During the 6-month vaccination period we also monitoredmonthly and time-averaged Kt/V, residual renal function(RRF), BMI, serum creatinine, albumin, transferrin, ferritin,CRP, iPTH and the dose of erythropoietin and Vitamin Dthat they received.Results. An optimal immune response was achieved in 34patients (54%, responders) (antiHBs: 295.95±341.67mIU/ml), whereas 29 patients (46%, non-responders)showed a suboptimal response (antiHBs: 1.98±2.92mIU/ml) (p=1.75x10 -5 ). There was a statistically significantnegative correlation between the antiHBs ab titre and BMI(r=-0.28, p=0.024). A significant difference was also foundbetween the BMI of responders and non-responders asgroups (24.8±5.5 vs. 27.2±4.5, p=0.02). Grouping ourpatients according to the existence of diabetes, age (cut off60 years), and hemodialysis efficiency (Kt/V≥1.2) wefound a statistically significant difference in the antiHBs abtitre between diabetics and non-diabetics (8.43±12.3 vs.200.2±317.7 mIU/ml, p=0.03), younger and older patients(262±365.09 vs. 84.36±189.1 mIU/ml, p=0.0145) and patientswith efficient and inefficient hemodialysis (234.71±337.1 vs.79.14±200.99 mIU/ml, p=0.032). Treatment with vitamin Danalogues, RRF and hypoalbuminemia were not found to beimplicated in the immune response of our patients.______________________Correspodence to:Conclusions. It seems that increased BMI; diabetes;advanced age and inefficient hemodialysis impaired theimmune response to HBV vaccination of our hemodialysispopulation. Future studies should be conducted toinvestigate the need for tailored vaccination schedules forthis hemodialysis subpopulations.Keywords: antibody response, hemodialysis patients,hepatitis B, vaccination.IntroductionPatients on maintenance hemodialysis are at high risk ofinfection with hepatitis B virus (HBV) despite segregation,universal precautions, vigorous vaccination protocols andthe widespread use of erythropoetin leading to the reducedneed for blood transfusions. At the same time hemodialysispatients typically show a suboptimal immune response toHB virus vaccination compared to the non-uremic population[1]. Protective antibody levels develop only in 60%of the hemodialysis population [2,3]. Many factors may beimplicated in this suboptimal immune response such asuremia per se, altered renal metabolism of immunologicalactive protein, the specific effect of renal replacementtherapy, malnutrition, chronic inflammation, inefficientdialysis, age, race, diabetes mellitus and many more [4-15].Moreover factors like insufficient vaccine dosing or omitting adose may lead to suboptimal antibody production inhemodialysis patients [2-16]. In this context the aim or ourstudy was the identification of factors implicated in the vaccineresponse of our hemodialysis population.Patients and methodsFrom a cohort of 112 hemodialysis patients from our unitwe studied prospectively 63 who were seronegative for HB(37 males, 26 females). An unsuccessful attempt forvaccination for HB was performed in 21 of the 63 patientsincluded in the study. Positive patients for hepatitis B(HBeAg and anti-HBc) and those with a sufficient anti-HBstiter from former anti-HB vaccination, acute inflammatorystatus, malignancy and decompensated chronic liver diseasewere excluded. In addition, patients with autoimmunedisease and patients which received immuno-suppressantsOuzouni Alexandra, Nephrology Department, General Hospital of Kavala, Amerikanikou ErythrouStaurou 113, 65001 Kavala, Greece; Tel.: 00302510292034; Fax: 00302510292034;E-mail: alouzouni@mail.gr

78 BANTAO Journal 2007; 5 (2)in the last three months were also excluded. The prevalenceof hepatitis B and hepatitis C infection in unit is 2.67% (3patients) and 7,15% (8 patients) respectively. Thedemographic and laboratory characteristics of our studypopulation are shown in Table 1.The laboratory values are the mean value of the six monthsobservation period. The Mean age of our patients was62.2±11.28 years (range 35-80) and hemodialysis duration5.96±50.1 months (range 6-225). Fourteen (22.2%) of ourpatients were diabetics. Our patients followed a four-dosevaccination schedule with 40 μg of a recombinant DNA HBvaccine administered by deltoid intramuscular injection attime 0, 1, 2 and 6 months. We chose to use this vaccinationschedule recommended by the U.S. Food and DrugAdministration for Preventing Transmission of InfectionsAmong Chronic Hemodialysis Patients because of the higherprotective antibody response obtained (86%) in correlationwith the three dose schedule (64%) recommended by theEuropean best practice Guidelines [17,18].Table 1. Demographic and laboratory characteristics of ourhemodialysis patientsParametersValuesPatients Number 63Males 37Females 26Male/Female ration 1.42Age (years) 62.2±11.28Time on HD* (months) 55.96±50.1Diabetics n=14 (22.2%)Time-averaged Kt/V 1.56±1.08RRF* (ml/min) 5.41±5.36BMI* (kg/m2) 26.03±4.13Serum creatinine (mg/dl) 9.53±2.48Serum albumin (g/L) 3.47±0.44Serum transferrin (g/L) 1.81±0.53Serum ferritin (mg/dl) 675.92±511.84CRP* (mg/dl) 1.05±1.41iPTH* (pg/ml) 187.21±171.31Erythropoietin dose (IU/week) 4790±3450* HD: hemodialysis, RRF: residual renal function, BMI:body mass index, CRP: C reactive protein, iPTH: intactparathormonThe antibody response was determined 1 month after thefourth dose of vaccination by assessing the titre of antiHBsantibodies (ab). AntiHBs titers were measured in plasmasamples by enzyme immuneassay (Abbott LaboratoriesUSA). The immune response was defined as sufficientwhen the antiHBs ab level was ≥12 mIU/ml. Those withlevels 12-100 mIU/ml were termed “poor responders”,whereas those with levels >100 mIU/ml were termed “goodresponders”. During the 6-month vaccination period wealso monitored monthly time-averaged Kt/V, residual renalfunction (RRF), BMI, serum creatinine, albumin,transferrin, ferritin, CRP, iPTH and the dose oferythropoietin and Vitamin D that they received.Statistical analysisResults are reported as mean ± SD. Statistical significancewas calculated for differences between means by use of anunpaired t-test. Correlation between variables wasperformed by the Pearson correlation test. A P value of lessthan 0.05 was considered significant.ResultsAn optimal immune response was achieved in 34 patients(54%, responders) (antiHBs: 295.95±341.67 mIU/ml),whereas 29 patients (46%, non-responders) showed asuboptimal response (antiHBs: 1.98±2.92 mIU/ml)(p=1.75x10-5). In the responder group 20 patients (59%)had an antibody titre of antiHBs > 100mIU/ml (goodresponders) and 14 patients (41%) had an antibody titre ofantiHBs 12-100mIU/ml (poor response). There was astatistically significant negative correlation between theantiHBs ab titre and BMI (r=-0.28, p=0.024). A significantdifference was also found between the BMI of respondersand non-responders as groups (24.8±5.5 vs. 27.2±4.5,p=0.02). (Figure 1).BMI27,52726,52625,52524,52423,524,8p 60 years 84.36Kt/V < 1.2 79.14Kt/V > 1.2 234.71respondersnonrespondersP0.030.01350.032

BANTAO Journal 2007; 5 (2) 79DiscussionIn our series, the percentage of patients responding to theHB vaccine was 54% which is similar to the resultsobtained in other groups [2,3]. This percentage is lowerthan in the general population despite using a doublevaccination dose, reflecting the immune deficiency ofpatients with chronic renal failure. Many factors impinge onthe effectiveness of a vaccine. Not only the potency of thevaccine is important, but also patient characteristics. Alongwith uremia, malnutrition, obesity, diabetes mellitus,increased age, seropositivity for antibody against hepatitisC, impaired T-cell receptor expression and HLA DR3,DR7, DQ2 have been associated with poor response ofhemodialysis patients to HBV vaccine [2-12,14,15].Conversely, there is evidence that Epo therapy improvesresponse rates [13]. But it is worth mentioning that there isgreat controversy in the literature about the factors whichare implicated in the antibody response of the hemodialysispopulation.In our study we found a better antibody response in thegroup with lower BMI. In one study Chow KM et al foundan inadequate anti HBs response in obese hemodialysispatients, which could in part be attributed to a low vaccinedose, so it could be assumed that obese patients are in needof an even higher vaccine dose or maybe the dose should becalculated according to body weight [2].We also found a better antibody response in the nondiabeticgroup, consistent with the findings of the previousstudy [2]. However another study of Eardley et al did notconfirm this finding in this paper the existence of diabetesmellitus did not affect response rates to the HB vaccine inhemodialysis patients [8]. We also found that patients in theyounger age-group had a better respond rate to thevaccination schedule than our older patients, the samefinding was also previously reported by other studies[2,5,9,12]. However other studies did not confirm anassociation between age and antibody response to the HBvaccine in HDpts [8,11]. Our study showed also a betterimmune response to vaccination in patients with higherKt/V consistent with the findings of Kovacic V et al andIbrahim S et al [10,11], a finding not confirmed by otherstudies [8,9,12].Despite the limitations of the present study, that is thelimited number of patients and the heterogeneous studypopulation, as there was an attempt for vaccination againstHBV in some of our patients in the past, our findings are ofclinical relevance as some of the factors influencing theantibody response could be modifiable. So maybe there is needfor a dose adjustment of the vaccine dose according to bodyweight in patients with a high BMI and diabetes mellitus.Another option is to vaccinate our patients at an early stage ofchronic kidney disease before dialysis is started in an attemptto achieve a better antibody response at a younger age.Moreover optimizing the hemodialysis dose could also leadto a better immune response to the HB vaccination.ConclusionsIn conclusion, it seems that increased BMI; diabetesmellitus; advanced age and inefficient hemodialysisimpaired the immune response to HBV vaccination of ourhaemodialysis population. However since there is greatcontroversy in the literature about the factors which areimplicated in the antibody response of hemodialysispatients it seems that there is need of a systemic review ofthe literature and meta-analysis of clinical trials, moreoverfuture studies should be conducted to investigate the needfor tailored vaccination schedules for specific hemodialysissubpopulations.Conflict of interest statement. None declaredReferences1. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ.The risk of transfusion transmitted viral infection. NEngl J Med 1996; 334: 1685-90.2. Chow KM, Law MC, Leung CB, Szeto CC, Li PK.Antibody response to hepatitis B vaccine in end stagerenal disease patients. Nephron Clin Pract 2006;103(3): c89-93.3. Stevens CE, Alter HJ, Taylor PE, et al. Dialysisvaccine trial study group. Hepatitis B vaccine indialysis receiving hemodialysis. Immunogenicity andefficacy. N Engl J Med 1984; 311: 496-501.4. Dumann H, Meuer S, Koehler H. Hepatitis Bvaccination and interleukin 2 receptor expression inchronic renal failure. Kidney Int 1990; 38: 1164-68.5. Fabrizi F, Martin P, Dixit V, Bunnapradist S, Dulai G.The effect of age on immunological response to hepatitisB vaccine in end-stage renal disease. Meta analysis. AlimPharm & Therap 2004; 20(10): 1053-1062.6. Fabrizi F, Dixit V, Dunnapradist S, Martin P. Thedialysis mode and immunological response to hepatitisB virus vaccine in dialysis population. Meta-analysis.Alim Pharm & Therap 2006; 23(8): 1105-1112.7. Stachowski J, Pollok M, Barth C, Maciejewski J,Baldamus CA. Non-responsiveness to hepatitis Bvaccination in hemodialysis patients: association withimpaired TCR/CD3 antigen receptor expression regulatingco-stimulatory processes in antigen presentation andrecognition. Nephrol Dial Transplant 1994; 9: 144-152.8. Eardley KS, Jones H, Osman H, Smith S. Efficacy ofthe accelerated hepatitis B vaccination schedule usedin hemodialysis patients post-exposure to virus: asingle-center experience. Nephrol. Dial Transplant2002; 17(11): 1982-1987.9. Peces R, de la Torre M, Alkazar R, Urra JM.Prospective analysis of the factors influencing antibodyresponse to hepatitis B vaccine in hemodialysispatients. Am J Kidney Dis 1997; 29(2): 239-45.10. Kovacic V, Sain M, Vukman V. Efficient hemodialysisimproves the response to hepatitis B virusvaccination. Intervirology 2002; 45(3): 172-6.11. Ibrahim S, el Din S, Bazzal I. Antibody level afterhepatitis B vaccination in hemodialysis patients: impactof dialysis adequacy, chronic inflammation, localendemicity and nutritional status. J Nati Med Assoc 2006;98(12): 1953-7.12. Fernandez E, Betrin MA, Gomez R, Montolin J.Response to the hepatitis B virus vaccine in hemodialysispatients: influence of malnutrition and itsimportance as a risk factor for morbidity and mortality.Nephrol Dial Transplant 1996; 11: 1559-1563.

80 BANTAO Journal 2007; 5 (2)13. Hassan K, Shternberg L, Alhaj M et al. The effect oferythropoietin therapy and hemoglobin levels on theimmune response to Engerix B vaccination in chronickidney disease. Ren Fail 2003; 25(3): 471-8.14. Girndt M, Sester U, Sester M, Kaul H, Koehler H.Impaired cellular immune function in patients withend-stage renal failure. Nephrol Dial Transpland1999; 14: 2807-2810.15. Kara IH, Yilmaz ME, Suner A, Kodiroglu AK,Isikoglu B. The evaluation of immune responses thatoccur after HBV infection and HBV vaccination in hemodialysispatients. Vaccine 2004; 22(29-30): 3963-7.16. Peces R, Laures AS. Persistence of immunologicmemory in long-term hemodialysis patients andhealthcare workers given hepatitis B vaccine: role ofbooster dose on antibody response. Nephron 2001;89(2): 172-6.17. U. S. Food and Drug Administration. Recommendationsfor Preventing Transmission of infectionsAmong Chronic Hemodialysis Patients. 2001; 50(RR05): 1-43.18. European best practice Guidelines. Section VI.Hemodialysis-associated infection. VI.6 Preventionand management of HBV, HCV and HIV in HDpatients. Nephrol Dial Transplant 2002; 17: 78-81.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 81–84Original ArticleExtracorporeal Lithotripsy - Our Experiences Presented in a Retrospective10 - Year StudyD. Savic, Zoran Kovacevic, Dragan Jovanovic and Z. CukicMilitary Medical Academy, Clinic for Nephrology, Belgrade – SerbiaAbstractBackground. Extracorporeal shock-wave lithotripsy (ESWL)is a therapeutic method of a recent date which, thanks to thesophisticated technology, enables the disintegration of acalculus in the urinary system by electromagnetic wavesgenerated outside the human body which penetrate the body,in most cases, without serious affecting any tissues or organs.This procedure is a method of choice for all the cases of calculiof 2 to 3 and more centimeters in diameter identified in theurinary tract, and which along with endourological methodshas completely eliminated the need for using surgical methods.The performance of the procedure on an outpatient basis,minimal invasion and being relatively painless without analgosedation,with a minor percentage of probable complications,and an average duration of about 20 min, render to aconsideration of a convenient and harmless procedure. Morethan 86% of cases were a complete success and, by combiningthis method with some of the endoprocedures, a success maybe achieved in almost 99% of the cases. Thus the number ofpatients with a calculus requiring by a surgical procedure hasbeen reduced to a minimum. The mentioned statistical data canbe compared with not only the data from the world literature,but the percentage of successfulness is even higher in relationto larger and more well-known healthcare centers in the world.Methods. 25.321 of patients who underwent extracorporeallithotripsy in the period from 1996-2006 wereretrospectively analyzed. Almost 92% of patients of theaverage age of 42, predominantly men (the ratio was52:48%) were treated on an ambulatory basis. This ratio hasbeen by time equalized and, in the last three years, theurinary tract calculosis has been seen in women more thanin men. According to the topographic anatomy, calculosisoccurs almost equally in the right and left kidney, out ofwhich more than one third is seen in the kidney pelvic, upto 16% in the calyx of the lower and 12% in the calyx ofthe upper top of the kidney and 14% in the proximalurethra, while all the other regions are ignorable.Results. Percentage ratio of the numbers of repeatedtreatments was 60% in the first, 20% in the second and 20%in all other cases but, thanks to the introduction ofsophisticated therapeutic approaches in the recent period,that percentage has changed in favor of successfulness ofthe first treatments and amounted up to 70%. As forcomplications, the most common were lumbal pains in 48%of cases and macroscopic hematuria in 43% of cases, thensteinstrasse in 18% of patients while the percentage of allthe other complications was minor.Conclusion. The procedure has recently undergone someconsiderable technical-technological modifications. Thediagnostic-therapeutic approach has in many ways changed,as well as the number of early detected calculosis includingthe growing number of children. Therefore, dealing with thisproblem does not involve only the therapeutic procedure butalso the comprehensive metabolic diagnostic procedure,prevention and observation of the patients, which will, in thenext study, certainly result in a considerable change of thementioned correlations to the mutual benefit.Key words: nephrolithiasis, urolithiasis, calculosis, ESWL,extracorporeal lithotripsy, Shock Wave, complications.IntroductionMore than 15% of today's world population suffers fromurinary tract calculosis. There is not a single country, ethnicpopulation, or age group that is spared from this problem[1-6,9,15]. However, once inevitable surgical procedure hasbeen replaced by extracorporeal lithotripsy (ESWL) andendourological procedures; while evaluation of lifestyle,habits, nutrition, biomineral composition and metabolismdisorders is gaining in its importance in prevention of relapsesthat occur in even 80% (50-100%) of the cases today [9,15].Urinary tract calculosis occurs in all the parts, butcalculosis of calyx, pyelon, ureter and calcificates inparenchyma make up 97% of the cases, while only 3% of itoccurs primarily in the urinary bladder and urethra. Thedecision on application of a concrete treatment procedure inorder to eliminate the calculosis is determined bylocalization, size, structure, consistency, surface appearanceand the period of calculus persistence, as well aspermeability of the pyelo-calyx system and ureter and thepossibility of spontaneous elimination [6,9,15].Extracorporeal shock wave lithotripsy (ESWL) is a semiinvasive therapeutic method of a recent date, which thanksto advanced and sophisticated technological procedures,enables disintegration of the calculus in the kidney andurinary canals by electromagnetic waves generated outsidethe human body, which penetrate the body, in most cases,without serious affecting any tissues or organs [7,10-13].This method is suitable for all calculi in urinary systemfrom 0.5 to 3 cm in diameter or even bigger. In combinationwith endourological methods, it has almost completelyeliminated the need for surgical removal of the stone fromthe urinary system. The advantages of ESWL method arethat it is practically noninvasive, very safe and relatively______________________Correspodence to: D. Savic, Nephrology Clinic, Military Medical Academy, Crnotravska 17, Belgrade, Serbia;Tel.+381113670784

82 BANTAO Journal 2007; 5 (2)painless and possible complications are very rare andalmost by a rule of a mild nature. The procedure lasts 20 to30 minutes on average, and it is performed on anambulatory basis, after which the patient goes home.During and after the procedure, the application of narcoanalgo-sedationis not necessary [7-13].The Department for ESWL at the Military Medical Academystarted working in the beginning of 1989 using the apparatus"Siemens - Lithostar ® ", and in the middle of 1998, thelithotripter "Storz – Modulith SLX ® " came into use. Until 2006,more than 25,000 patients were treated at this Department. Theyoungest patient to have undergone the extracorporeallithotripsy was 3.5 and the oldest was 95 years old.Patients and methodsThis is a retrospective study of 25,321 of patients whounderwent extracorporeal lithotripsy in the period from 1996-2006. In diagnostics, differential diagnostics and indication ofESWL, we used detailed anamnestic data, objective status,echotomographic findings, intravenous urography, dynamicscintigraphy and if necessary CT, MScCT and MR, dependingon a particular case. Almost 92% of the patients were treated onan ambulatory basis and only a small number was treated on astationary basis (elderly people, synergism of severe diseases,bilateral hydronephrosis, complicated urolithiasis, one functionalkidney, coagulation disorders...). All the patients with indicationsfor ESWL were treated regardless of their age. Theyoungest patient was only 3.5 while the oldest was 95 years old.The lithotripter "Siemens - Lithostar®" was used in treatment of1/5 of the patients, while 4/5 of the patients were treated usingthe lithotripter "Storz – Modulith SLX®", due to technicalreasons. Localizations of the stones was performed with RTGscopy(minimal conditions of generator only 15 kw power) andintegrate multifrecvental inline ultrasound localization system.The number of the applied shock waves per a treatment variedfrom a few hundred to 4,000 (due to acquirements), at afrequency of 60 to 120 shock waves per a minute (subject to thepatients respiratory flicks). The applied shock wave powervaried in the range from 14 to 20 kV, depending on a particularcase. Positioning of the calculi in the kidney and pyelon wasperformed with patients in the supine position, while thepositioning of the calculi in the medium and distal ureter and inthe bladder was performed in the abdominal decubitus position.In most cases analgo-sedation was not used, except in patientswith extremely low pain threshold, when Tramadol p.o. 50 –100mg was administered. The average duration of the treatmentwas 20 minutes. Immediately upon the completion of thetreatment, the follow up ultrasonography of the abdomen wasperformed, and the regular follow up examination wasscheduled for 5-7 days or sooner if needed. Further evaluation ofthe patients' health condition was performed every 4 to 6months.ResultsThe incidence of urinary tract calculosis in patients of bothgenders was almost equal - 13,092 (51.70%) men and12,229 (48.29%) women. The greatest number of patients,about 35%, was between 31 and 40 years old, while theincidence of urinary tract calculosis in patients under 30and between 41 and 50 was almost equal - about 20%(Table 4). As for localization in the urinary tract, 2/3 of thecalculi were in the kidney, one third of which was in the pyelon.One third of the calculi were located in the ureters and only anegligible number of calculi were primarily in the bladder(Table 1 and 2). Over 90% of the patients were treated on anambulatory basis, while the procedure was performed in hospitalconditions only in rare cases (Table 3). The percentage ofsuccessfulness after the first treatment was about 60%, while thetreatment was repeated more than three times only in 9% of thepatients - mainly in cases of calculus consistency (cystine, orsimilar cases), when the calculus diameter was 4 cm or more, orin cases of staghorn calculosis (Table 5).Table 1. Urinary tract calculosis - LocalisationKidney Ureter Ves. urin.N - patients 16.831 8.480 10% 66,47 33,48 0,0039Table 2. Nephrocalculosis - Localisation.KidneypelvicCaluxupperCaluxintermedCaluxlowerN - patients 7.931 3.036 1.854 4.010% 31,32 11,99 7,32 15,83Table 3. Ambulatory and stationarytreatments - rateN - Amb. % N - Stat. %patientspatients23.206 91,647 2.115 8,353Table 4. Urinary tract calculosis – appearance in dependence fromstatureAge strata < 30 31 - 40 41 - 50 51 - 60 > 60N - patients 5.352 8.865 4.931 3.632 2.541% 21,13 35,01 19,47 14,34 10,03Table 5. Effectiveness of the first et other ESWL treatments(stone free rate)N of treatments I II III > IIIN - patients 14.520 4.721 3.774 2.306% 57,34 18,64 14,90 9,10Table 6. Major and Minor complications after ESWLN %Colic or pain 12.240 48,33Skin bruising 633 2,5Transitory hematuria 10.973 43,33Nausea and vomiting 11.454 45,23PSVT, VT, arrhythmia 1.231 4,86Steinstrasse 3.928 17,72Fever 837 3,30High blood pressure 372 1,46Urosepsis 78 0,30Acute Renal Failure 32 0,92Renal/Perirenal hematomas 12 0,04Rupture of the pelvis 0 0Nephrectomy 1 0,0039Unknown 0 0As for complications, they were mostly minor in the formof colic or pain, transitory hematuria, nausea and vomiting.Major complications like paroxysm supraventricular tachycardia,VT, urosepsis or significant renal/perirenal hematomas wereregistered in a non-significant number of cases (Table 6).

83 BANTAO Journal 2007; 5 (2)DiscussionExtracorporeal shock wave lithotripsy has been the subjectof many studies, even the multicentric ones, but only someof them have evaluated more than a few thousand patients.There are different opinions on frequency and significance ofside effects, complications in other organs and systems, and onthe matter if this method should be considered primary intreatment of urinary tract calculosis or whether it should bereplaced by modern endourological procedures. There aremany studies that point out numerous complications afterESWL. According to them, parenchymal lesion, intra- andperirenal hematomas occur even in more than 66% of theundertaken procedures. However, we must not ignore thefact that these are mainly the studies conducted on animalmodels without calculosis and with direct effect ofultrasound or electromagnetic shock waves on the kidneyparenchyma [1,5,16-20]. There are also some dilemmasabout the risk of application of ESWL in elderly patients,determination of the upper limit of the calculus diametersuitable for ESWL, as well as on the issue if this procedureis appropriate for cystic calculi, or if the surgical procedureshould be performed right away [9,14].Many studies abstain from giving any definite conclusionson ESWL until all the dilemmas have been resolved bymulticentric studies [2-4]. Since 1987, many authors havestated that extracorporeal shock wave lithotripsy is aconvenient method with no need for analgesia oranesthesia, and it can be considered safe [7,10-13].With this ten-year study, we wanted to help resolve thesedilemmas and to draw useful conclusions on a reallyrepresentative sample. The results of this study suggest thatthis is, in fact, a truly convenient method that involveshospitalization of patients only in rare cases. Furthermore,indications for this procedure do not depend on sex, age,physical constitution, concomitant diseases, localization andconsistency of calculi and in many cases they do not evendepend on the calculus volume. There is only a question ofcost-efficiency in the last case because of possible multipleESWL treatments. As for complications after ESWL, it isquite clear that they are minor and temporary, and thatmajor complications occur in a negligible percentage. Wehave gathered important experience in application of thismethod and our results have been significantly improvingfor the last few years. The successfulness of the firsttreatment has increased almost to 70%, the percentage ofminor complications has decreased significantly, while thepercentage of major complications is almost annulled.Hopefully, the way we have established such anoutstanding performance will be the subject of a futurecontrolled prospective study.ConclusionThanks to the general technological advancement, ESWLas a semi invasive therapeutic procedure has anindisputably important place among therapeutic modalitiesof urinary tract calculosis. In recent years, it has undergonesome considerable technical and technologicalmodifications - from Dornier lithotripter (bath unit) toelectromagnet shock waves with a whole range of impactheads and shock waves focuses. All these technologicalnovelties have brought a new perspective on extracorporeallithotripsy in terms of its effectiveness, safety andconvenience. Based on many years of experience inapplication of this therapeutic procedure, we can rightfullyconclude that it is a highly effective method with almostnegligible side effects. With the right knowledge of theprocedure, well-trained staff, proper preparation of patientsand adequate clinical support, extracorporeal lithotripsytakes the leading place in treatment of urinary tractcalculosis, replacing invasive surgical techniques.Furthermore, combined with endourological procedures, itoffers a final solution to urinary tract calculosis in almost100% of cases.The diagnostic-therapeutic approach has in many wayschanged, thus changing the number of early detectedcalculosis, including the growing number of children.Therefore, dealing with this problem does not involve onlythe therapeutic procedure but also the comprehensivemetabolic diagnostic procedure, prevention and observationof the patients which will, in the next study, certainly resultin a considerable change of the mentioned correlations tothe mutual benefit.Conflict of interest statement. None declared.References1. Krestin GP, Fischbach M et al. Alternations in renalmorphology and function after ESWL therapy:evaluation with dynamic contrast-enhanced MRI.European Radiology Journal 1993; Vol 3 (3).2. Brümmer F, Bräuner Th, Hüster DF. Biological effectsof shock waves. World Journal of Urology, dec. 1990;Vol 8 (4).3. Lynn RW, Andrew PE, Bret AC et al. Prevention oflithotripsy – Induced Renal injury by PretreatingKidneys with Low – Energy Shock Waves. J Am SocNephrol 2006; 17: 663-73.4. Lynn R Willis, Andrew P Evan, Bret A Connors et al.Relationship between kidney size, Renal injury andRenal Impairment Induced by Shock WaveLithotripsy. J Am Soc Nephrol 1999; 10: 1753-62.5. Bret A Connors, Andrew P Evan, Lynn R Willis et al.The Effects of Discharge Voltage on Renal Injury andImpairment Caused by Lithotripsy in the Pig. J AmSoc Nephrol 2000; 11: 310-8.6. Prevention and Treatment of Kidney Stones. NIHConsensus Development Conference Statement,March 1998; 28-30.7. Zogovic J. Extracorporeal shock wave lithotripsy:prophylaxis, complications and therapy. Srp Arh CelokLek 1997; 125 (11-12): 345-8.8. Biedermann R. ESWL in the Treatment of Stones.Urologik, Fachzeitschrift für Urologie, 2005: 2.9. Velibor S Markovic. Urologija – Hirurgija mokracnihorgana, Beograd, 1997; 417-25.10. Jonathan IR, Peter HA et al. Kidney Changes afterExtracorporeal Shock Wave Lithotripsy: CTEvaluation. J Am Radiology 1987; 162: 21-4.11. Bruce R, Kevin W, Samuel S et al. Kidney Changesafter Extracorporeal Shock Wave Lithotripsy:Apperanse on MR Imaging. J Am Radiology 1987;163: 5331-534.

84 BANTAO Journal 2007; 5 (2)12. Gary S Karlin, David Schulsinger, Morton Urivetskyand Arthur D Smith. Absence of PersistingParenchymal Damage after Extracorporeal ShockWave Lithotripsy as judged by Excretion of renalTubular Enzymes. J Am Urology 1990; 144: 13-4.13. Craber S F, Danuser H et al. A prospectiverandomized trial comparing 2 lithotripters for stonedisintegration and induced renal trauma. J Am Urology2003; 169 (1): 54-7.14. Knapp R, Frauscher F et al. Age – related Changes inResistive Index following ESWL. J Am Urology 1995;154: 955-8.15. Albrecht H, Hans-Göran T, Andrea J. Urinary Stones –Diagnosis, treatment and Prevention of Recurrence.Basel 2002.16. Christian GC, Gerhard JF. Current State and FutureDevelopments of Noninvasive Treatment of HumanUrinary Stones with ESWL. J Am Urology 1989; Part2, Vol. 141, 78-9.17. Delius M, Enders G et al. Biological effects of shockwaves. Lung hemorrhage by shock waves in dogs –pressure dependence. Ultrasound Med Biol 1987; 13:61.18. Newman RC, Hackett RL, Senior DF et al. ESWL –does it damage the kidney?. J Am Urology 1986; part2, 135: 182A.19. Frank P, Russell K et al. Electrohydraulic shock waveinduced renal injury. J Am Urology 1989; 142: 155-9.20. Christian W, Michael EM et al. Injury of Rat RenalVessels following Extracorporeal Shock WaveTreatment. J Am Urology 1992; 147: 476-81.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 85–89Original ArticleBelgrade Hantavirus Infection is Associated With the most Severe ClinicalForm of Hemorrhagic Fever with Renal SyndromeKatarina Obrencevic, Dragan Jovanovic, Zoran Kovacevic and Ljiljana IgnjatovicClinic of Nephrology, Military Medical Academy, Belgrade, SerbiaAbstractBackground. Hemorrhagic fever with renal syndrome(HFRS) is an acute viral disease characterized by fever,hemorrhage and acute renal failure and is caused by closelyrelated zoonotic viruses of genus Hantavirus of the familyBunyaviridae. Hantaviruses produce a spectrum of illnesseswith specific manifestations depending on the particularvirus involved. Hantaan and Belgrade/Dobrava virusescause the most severe disease, Puumala the least severe,and Seoul produces disease of intermediate severity. WhileHantaan, Puumala and Seoul may cause a wide disparity indisease manifestations even with the same serotype,Belgrade virus, which is found in the former Yugoslavia, isassociated only with severe form of illness.Methods. 128 patients with HFRS have been treated in ourunit during the period from 1989 to 2004. We retrospecttivelyanalyzed 108 of them and 20 followed prospectively.Results. The disease is serologically confirmed in all 128patients: Hantaan in 45%, Belgrade in 35% and Puumala in20%. Clinical course of the disease followed up by sixphases: prodromal phase in 45%, febrile in all patients,hypotensive in 30,5%, oliguric phase in 90,6%, diuretic andconvalescent phase in all patients. All patients had acute renalfailure (ARF), which was anuric at 30% of them, andtreatment with dialysis was necessary in 55%. We observedfavorable effect of "an early dialysis" to the course of thedisease and its outcome. More than half of those treated withdialysis were infected with Belgrade virus-62%. Acute respiratorydistress syndrome (ARDS) was presented in 11%. Thecause of the disease in 8 of them was Belgrade, and in 6 Hantaanvirus. 3 patients (2,3%) died, in 2 infected with Belgradethe cause of death was cerebral hemorrhage, and 1 infectedwith Hantaan died of shock. After the convalescent phase wenoted a chronic renal failure in 8 patients (6,25%) who had asevere form of the disease. All of them had hypovolemicshock, severe ARF, ARDS, visceral haemorrhage and disseminatedintravscular coagulation (DIK). The cause of thedisease in 5 patients was Belgrade, and in 3 Hantaan virus.In 4 of them infected with Belgrade we noted a progressionto terminal renal failure. Other chronic sequeale were hypertensionin 3 patients, hypothyreosis in 2, hypocorticism in1, sterility in 2, and acute myocardial infarction in 1.Conclusions. According to clinical characteristic andsyndromes that follow HFRS, most of our patients had severeform of illness. Belgrade virus infection is associated with amore severe disease type and development of chronic renalfailure as a sequela of the disease. The long term follow up ofrenal function in these patients is recomended.Keywords: Acute renal failure, Belgrade/Dobrava virus,hantaviruses, hemorrhagic fever with renal syndromeIntroductionHemorrhagic fever with renal syndrome is an acute viraldisease characterized by fever, hemorrhage and acute renalfailure and is caused by closely related zoonotic viruses ofgenus Hantavirus of the family Bunyaviridae [1].Hantaviruses have single-stranded, negative-sense RNAgenomes that are divided into three segments: small (S),medium (M) and large (L) segment, which encode thenucleocapsid protein, the glycoprotein precursor and theputative RNA polymerase, respectively [2]. Eachhantavirus is maintained in nature by infecting a singlerodent species, which serves as its primary naturalreservoir. Transimission to humans occur predominatelytrough inhalation of aerosols of contaminated rodentexcreta [3]. More than 30 different hantaviruses have beendistinguished so far, at least half are related to disease inhumans. One of the main features of hantaviruses is theclose association between the virus type and the hostspecies. This results in the circulation of distincthantaviruses in the Old and New World and in geographicalclusters of hantavirus genetic variants [4]. These virusescause two types of disease in humans: hemorrhagic feverwith renal syndrome (HFRS) in Asia and Europe andhantavirus pulmonary syndrome (HPS) in North andSouth America. HFRS is caused by Hantaan,Belgrade/Dobrava, Seoul and Puumala viruses, while HPSis caused by Sin Nombre and related viruses (New Worldhantaviruses). Hantaviruses produce a spectrum of illnesseswith specific manifestations depending on the particular virusinvolved. Hantaan and Belgrade/Dobrava virus causes themost severe disease, Puumala the least severe- callednephropathia epidemica, and Seoul produces disease ofintermediate severity [5]. While Hantaan, Puumala and maycause a wide disparity in disease manifestations even withthe same serotype, Belgrade virus, which is found in theformer Yugoslavia and the Balkan Peninsula, is associatedpredominately with severe form of illness [6]. It has beenestimated that hantaviruses cause over 200 000 cases ofclinically manifested disease world-wide, with contributionof China and Korea with more than 100 000 cases. Thelethality of hantavirus infection is known to be 0,1-1% for______________________Correspodence to: Katarina Obrencevic, Bulevar umetnosti 15/25, 11070 Belgrade, Serbia;Tel. +381 11 2136 413; E-mail: katarinao@EUnet.yu

86 BANTAO Journal 2007; 5 (2)Puumala virus associated disease, 5-15% for Hantaan andBelgrade virus associated disease, and 25-50% forhantaviruses causing HPS [7].The aim of this study is to present clinical manifestationsand laboratory findings in patients with HFRS withparticular analysis of those infected with Belgrade virus.Patients and methods128 patients with HFRS have been treated in our unit duringthe period from 1989 to 2004. There were 126 males and 2females, aged from 18 to 62 years. We retrospectivelyanalyzed 108 patients treated in Military Medical Academyduring the period from 1989 to 2000 with all data receivedfrom available medical records. Another 20 patientshospitalized in the period from 2000 to 2004 were followedprospectively, during the acute phase of illness. Diagnosisin both groups was made from the clinical symptoms and signs,laboratory findings, and confirmed by serologic tests to detectspecific anti hantavirus antibodies: enzyme linkedimmunosorbent assays (ELISA) IgM and indirect immunofluorescenceassay IgG (performed in Torlak Institute ofImmunology and Virology). In 24 patients renal biopsy wasdone and tissue samples were analysed by light microscopic,electron microscopic and immunohystochemical methods inInstitute of pathology Military Medical Academy.Tipical clinical symptoms and signs, as well as clinicalsyndromes that follow HFRS and the laboratory findingswere analysed in all patients. We compared results obtainedin our study with results of two other author groups aboutHFRS caused by Hantaan and Seoul viruses in Korea and byPuumala in Sweden with noted differences and similarities.ResultsHantavirus infections occur in two main seasonal outbreaks:in the beginning of the spring (from second half of Marchuntil the end of May) and in the end of summer (August).During the largest epidemic in 1994/95, frequency of thedisease was equal trough the whole year, without seasonalchanging.The patients came to our unit in different phases of thedisease. Only two of them were hospitalized in the febrilephase (1,6%), 26 in hypotensive (20,3%), and most of themwere in oliguric phase - 80 patients (62,5%). In polyuricphase there was 16 patients (12,5%), and 4 (3,1%) inconvalescence phase.The disease was serologically confirmed in all 128 patients:Hantaan in 45%, Belgrade in 35% and Puumala in 20%.Clinical course of the disease followed up by six phases(Table 1). Clinical manifestations and frequency of somesymptoms and signs are shown in Table 2 with comparisonto clinical picture of HFRS in other part of the world. Allour patients had acute renal failure (ARF), which wasanuric at 30% of them.Table 1. Comparison of clinical course of the HFRS in patients treated in Military Medical Academyand those presented by Lee JS (5)PhaseFrequencyKorea% of patinetnsFrequencyMMA *% of patientsAverage durationKorea(days)Average durationMMA*(days)Prodromal 10-20 45 3-10 3-10Febrile 100 100 3-6 3-8Hypotensive 37 30,5 1 few hours-1 dayOliguric 60 90,6 3-5 3Polyuric 95 100 7-14 10Convalescence 100 100 4-8 weeks 3-12 weeks* MMA- Military Medical AcademyTable 2. Comparison of clinical manifestations in HFRS in patients treated in Military MedicalAcademy and those presented by Lee JS (5), and Settergren B et al (18)Korea- HTN † Korea-SEO ‡ Sweden-PUU § Serbia, MontenegroSymptoms(229 pts * ) (40 pts * ) (355 pts * 3 serotypes)and signs% of pts * % of pt * % of pts * (128 pts * )% of pts *Fever 100 100 94 100Headache 96 45 45 100Anorexia 96 95 95 100Myalgia 69 51 37 82Abdominal pain 90 72 48 100Back pain 92 28 66 95Blurred vision 54 9 7 25Subconjuctivalhemorrhage14 8 3 75Melena 16 5 < 1 32Hematemesis 3 5 < 1 30Hypertension 60 36 10 65Shock 24 - - 25Hypotension 34 10 30 30ARDS - - - 11* Pts- patients, † HTN- Hantaan virus, ‡ SEO- Seoul virus, § PUU- Puumala virus

BANTAO Journal 2007; 5 (2) 87Belgrade virus was serologically confirmed as etiologicagent in 45 patients (35%). All of these patients had severeARF which was anuric in more than half (20 patients oftotal number of 38 anuric patients). Dialysis was necessaryfor the treatment of ARF in 43 (95,5%) patients infectedwith Belgrade. Among these patients, 45% hadhypotension, 33% developped shock, in 74% severevisceral hemorrhage were presented (melena, hematemesis,bleeding into central nervous system) and 28% haddisseminated intravscular coagulation (DIK). Eight patientsinfected with Belgrade (17,7%) developed acute respiratorydistress syndrome (ARDS). In another 6 with ARDS,Hantaan virus was the cause of the disease (Table 3).Laboratory findings are similar to those in Korean HFRS(Table 4). All patients had acute renal failure (ARF) withelevation of serum creatinine from 135 to 1700 µmol/l, andserum blood urea nitrogen (BUN) from 11 to 70 mmol/l.Proteinuria was presented in all patients with averagevalues of 7,2g per day and the largest of 22g per day.Table 3. The most important clinical and laboratory characteristicsof patients with HFRS caused by three serotypes treated inMilitary Medical AcademyBGD † HTN ‡ PUU §Symptoms(45 pts * ) (58 pts * ) (25 pts * )and signs% of pts * % of pts * % of pts *Fever 100 100 100Headache 100 100 100Abdominal pain 100 100 100Back pain 100 86 80Hypotension 45 29 4Shock 33 29 -Visceral hemorrhage 74 69 -ARF ║ 100 100 100Anuric ARF ║ 45 31 -Treatment with dialysis 95 46 -DIC 28 19 -ARDS ** 18 10 -CRF †† 11 5 -* Pts- patient, † BGD- Belgrade virus, ‡ HTN- Hantaan virus, §PUU- Puumala virus, ║ ARF- acute renal failure, HBI- hroničnabubrežna insuficijencija,** ARDS- acute respiratory distresssyndrome, †† CRF- chronic renal failureTable 4. Comparison of laboratory findings in HFRS in patients treated in MilitaryMedical Academy and those presented by Lee JS (5), and Settergren B et al (18)KoreaHTN ‡(229 pts † )% of pts † KoreaSEO §(40 pts † )% of pts † SwedenPUU ║(355 pts † )% of pts † MMA *HTN ‡ ,BGD ,PUU ║(128 pts † )% of pts †Leukocytosis 91 75 57 95Thrombocyto-penia 96 80 62 91Elevated BUN 98 90 99 100Elevated creatinine 98 90 99 100DIC 20 3 < 1 19ElevatedAST, ALT 5 22 - 55Hematuria 85 - 73 95Proteinuria 100 100 89 100*MMA- Military Medical Academy, † Pts- patients, ‡ HTN- Hantaan virus, § SEO-Seoul virus, ║ PUU- Puumala virus, BGD- Belgrade virusMajor histopathologic findings on renal biopsy tissuesamples were: interstitial nephritis with hemorrhage intomedullar interstitium, edema and inflammatory cellinfiltrations followed by tubular epithelial and luminalalterations. There were slight glomerular mesangial changesand mild swelling of epithelial cells of Bowman's capsule.The vessels showed endothelial cell damage and reaction(Figure 1).Treatment of HFRS consists of symptomatic and supportivecare and strict management of fluid and electrolytes.Patients who developed ARDS treated with oxygenationand mechanical ventilation. Treatment with dialysis wasnecessary in 70 patients with ARF (55%). Indications forstarting this method of treatment have been moved to lowervalues of serum creatinine of 400-500 μmol/l. Dialysiswere performed once daily, with average 3 to 4 proceduresby patient.Fig. 1. Histopathologic findings in HFRS show interstitialnephritis with hemorrhage into medullary interstitium, edema andinflammatory cell infiltrations followed by tubular epithelial andluminal alterations. There were slight glomerular mesangialchanges. The vessels showed endothelial cell damage and reactionThree patients (2,3%) died, in 2 infected with Belgrade thedeath was caused by cerebral hemorrhage, and 1 infectedwith Hantaan died of shock. After the convalescent phasewe noted chronic renal failure in 8 patients (6,25%) whohad severe form of the disease. All of them hadhypovolemic shock, severe ARF, ARDS, visceralhaemorrhage and disseminated intravscular coagulation(DIK). Cause of the disease in 5 patients was Belgrade, and

88 BANTAO Journal 2007; 5 (2)in 3 Hantaan virus. In 4 patients infected with Belgrade wenoted progression to terminal renal failure, in 2 of themkidney transplantation has been done, another two are onchronic dialysis program.Other chronic sequeale were hypertension in 3 patients(2,34%), hypothyreosis in 2 (1,56%), hypocorticism in 1(0,78%), sterility in 2 (1,56%), and acute myocardialinfarction in 1 (0,78%).DiscussionHFRS is endemic in the Balkan Peninsula and formerYugoslavia, where sporadic cases and outbreaks have beenreported. Hantaviruses associated with disease in humans inBalkans are Belgrade/Dobrava virus carried by the yellowneckedmouse (Apodemus flavicollis), and Puumala carriedby red bank vole (Clethrionomys glareolus). Dobrava wasoriginally isolated in Slovenia where a number of severecases of HFRS had occured [8], and genetic analysesshowed that Dobrava is a unique hantavirus type. Belgradevirus was isolated from blood and urine specimenscollected from Yugoslavian patients (in central and southSerbia) with clinically severe HFRS [9]. Nucleotidesequencing of the G2-encoding region in the mediumsegment of the viral genome, reverse transcribed andamplified by polymerase chain reaction, revealed Belgradevirus to be substantially different from Hantaan and othermajor serotypes, but identical to Dobrava virus [10]. It hasbeen reported that Belgrade/Dobrava virus carried byyellow-necked mouse (Apodemus flavicollis) is associatedwith severe clinical form of HFRS with a fatality rate up to10 % [8,9]. Recently, another host for Belgrade/Dobravavirus was reported- striped field mice (Apodemus agrarius),causing a milder disease than that associated with A.flavicolis in Estonia, Russia, Slovakia and Balkans. [11,12].These findings suggest that striped field mice (Apodemusagrarius), which are known to be natural host for Hantaanin Asia, also carry Dobrava in Central and Eastern Europe[13]. Puumala virus causes nephropathia epidemica, amilder form of HFRS, with a fatality rate less than 1% [14](Table 5). It has been reported that Hantaan virus, which isendemic for Asia, causes HFRS in Balkans and the formerYugoslavia [6].Table 5. Relationship between rodent host, hantaviruses related tohuman disease, and severity of clinical form of the diseaseGenus Rodent host Clinical formHantaan (HTN)Apodemus agrarius Severe(Asia, Europe)Seoul (SEO)Rattus norvegicus Moderate(World wide)ClethrionomysMildPuumala (PUU)glareolus(Scandinavia,Europe,Balkans)Belgrade/Dobrava(BGD/DOB)Apodemus flavicolis(Balkans)Apodemus agrarius(Balkans, Estonia,Russia, Slovakia)SevereMildWe serologically confirmed three serotypes of hantavirusesas etiologic agents of HFRS in our patients: Hantaan in45%, Belgrade in 35% and Puumala in 20%. The diseaseshowed two main seasonal outbreaks: in the beginning ofthe spring and in the end of the summer, like other reportedcases [4]. During the largest epidemic in 1994/95,frequency of the disease was equal trough the whole year,without seasonal changing, because of the war and largemigrations of army forces and population. Patients werehospitalized in later phases of the disease, mostly inoliguric phase with manifested ARF. Clinicalmanifestations and laboratory findings of Hantaan andPuumala associated disease are similar to these in otherparts of the world. There is a wide disparity in diseasemanifestations from asymptomatic, mild, to severe form,even with the same serotype [5]. This is reported forHantaan and Puumala viruses, but Belgrade virus isassociated mostly with more severe disease type [6,15].Clinical course of the HFRS in our patients followed upby six phases, similar to Korean HFRS caused byHantaan virus. We noted higher frequency of prodromaland oliguric phase (Table1), also as a more frequentanuric ARF in 30% of patients, in opposite to 10% inKorean HFRS due to Hantaan [5]. Treatment withdialysis was necessary in 70 patients with ARF (55%).Indications for starting dialysis have been moved tolower values of serum creatinine of 400-500 μmol/l. Weobserved favorable effect of "an early dialysis" to thecourse of the disease and outcome, with normalisation ofBUN and creatinine in average 14 days. Dialysis wasperformed once daily, with average 3 to 4 procedures bypatient. More then half of those treated with dialysiswere infected with Belgrade virus-62%. Most of thesepatients infected with Belgrade developed severe clinicalmanifestation with high frequency of hypotension,shock, visceral hemorrhage (melena, hematemesis,bleeding into central nervous system) and DIK. Eightpatients infected with Belgrade and six infected withHantaan developed acute respiratory distress syndrome(ARDS). It is well known that ARDS is associated withHPS, but it can be part of the severe clinical form ofHFRS.We noted long duration of the convalescent phase, over 3months in half of our patients. After the convalescent phasewe noted chronic renal failure in 8 patients (6,25%) whohad severe form of the disease. All of them hadhypovolemic shock, severe ARF, ARDS, visceralhaemorrhage and disseminated intravscular coagulation(DIK). The cause of the disease in 5 patients wasBelgrade, and in 3 Hantaan virus. In 4 patients infectedwith Belgrade we noted progression to terminal renalfailure, in 2 of them kidney transplantation has beendone, another two are on chronic dialysis program.These results agree with studies that show an associationbetween past hantaviral infection and chronic renaldisease [16,17]. Other chronic sequeale werehypertension in 3 patients (2,34%), hypothyreosis in 2(1,56%), hypocorticism in 1 (0,78%), sterility in 2(1,56%), and acute myocardial infarction in 1 (0,78%).ConclusionAccording to clinical characteristic and syndromes thatfollow HFRS, most of our patients had severe form ofillness. Belgrade virus infection is associated with a moresevere disease type and development of chronic renal

BANTAO Journal 2007; 5 (2) 89failure as a sequela of the disease. The long term follow upof renal function in these patients is recomended.Conflict of interest statement. None declared.References1. Cosgriff TM. Mechanisms of disease in Hantavirusinfection: pathophysiology of hemorrhagic fever withrenal syndrome. Rev Infect Dis 1991; 13: 97-107.2. Mackow ER, Gavrilovskaya IN. Celullar receptors andhantavirus pathogenesis. Curr Top Microbiol Immunol2001; 256: 91-115.3. McCaughey C, Hart CA. Hantaviruses. J MedMicrobiol 2000; 49(7): 587-99.4. Hart CA, Bennet M. Hantavirus infections:epidemiology and pathogenesis. Microb Infect 1999; 1(14): 1229-37.5. Lee JS. Clinical features of hemorrhagic fever withrenal syndrome in Korea. Kidney International 1991;64 Suppl 35: S 86-93.6. Avsic-Zupanc T, Poljak M, Furlan P, Kaps R, XiaoSY, LeDuc JW. Isolation of a strain of a Hantaan virusfrom a fatal case of hemorrhagic fever with renalsyndrome in Slovenia. Am J Trop Med Hyg 1994; 51(4): 393-400.7. Schmaljohn C, Hjelle B. Hantaviruses: a globaldisease problem. Emerg Infect Dis 1997; 3:95.8. Avsic-Zupanc T, Xiao SY, Gligic A, Van der GroenG, LeDuc JW. Characterization of Dobrava virus: ahantavirus from Slovenia. J Med Virol 1992; 38: 132-7.9. Gligić A, Dimković N, Shye-Yuan X, et al. Belgradevirus: A New Hantavirus Causing Severe Hemorrhagicfever with Renal Syndrome in Yugoslavia. J Infect Dis1992; 166: 113-20.10. Taller AM, Xiao SY, Godec MS, et al. Belgrade virus,a cause of hemorrhagic fever with renal syndrome inthe Balkans, is closely related to Dobrava virus of fieldmice. J Infect Dis 1993; 168(3): 750-3.11. Avsic-Zupanc T, Nemirov K, Petrovec M, et al.Genetic analysis of wild-type Dobrava hantavirus inSlovenia: co-existence of two distinct genetic lineageswithin the same natural focus. J Gen Virol 2000; 81(Pt 7): 1747-55.12. Klempa B, Stanko M, Labuda M, Ulrich R, Meisel H,Kruger DH. Central European Dobrava Hantavirusisolate from a striped field mouse (Apodemusagrarius). J Clin Microbiol 2005; 43(6): 2756-63.13. Sibold C, Ulrich R, Labuda M, et al. Dobravahantavirus causes hemorrhagic fever with renalsyndrome in central Europe and is carried by twodifferent Apodemus mice species. J Med Virol 2001;63(2): 158-67.14. Kuzman I. Clinical picture of hemorrhagic fever withrenal syndrome in Croatia. Acta Med Croatica 2003;57 (5): 393-7.15. Cebalo L, Dusek T, Kuzman I, Markotic A. Grading ofseverity of disease in patients with Puumala orDobrava virus infections from 1995 to 2000 in Croatia.Acta Med Croatica 2003; 57(5): 355-9.16. Glass GE, Watson AJ, LeDuc JW, Childs JE.Domestic cases of hemorrhagic fever with renalsyndrome in the United States. Nephron 1994; 68(1):48-51.17. Ledina D, Bradaric N, Ivic I, et al. Is permanent renalfunction damage possible after hemorrhagic fever withrenal syndrome? Acta Med Croatica 2003; 57 (5):365-8.18. Settergren B, Juto P, Trollfors B, Wadell G, NorrbySR. Hemorrhagic complications and other clinicalfindings in nephropathia epidemica in Sweden: a studyof 355 serologically verified cases. The Journal ofInfectius diseases 1988; 157(2): 380-2.

BANTAO Journal 2007; 5 (2) : 90–93BJBANTAO JournalOriginal ArticleTherapeutic Monitoring of Cyclosporine by Determination of C 2 andAUC 0-4 Levels in the First Two Years after the Kidney TransplantationNeven Vavic 1 , Ljiljana Ignjatovic 1 , Biljana Draskovic 2 , Rajko Hrvacevic 1 , Zoran Kovacevic 1 , ZoranPaunic 1 and Dragan Jovanovic 11 Nephrology Clinic, 2 Medical Research Institute, Military Medical Academy, Belgrade, SerbiaAbstractBackground. Therapeutic monitoring (TM) of cyclosporine(CyA), by measuring drug concentrations (conc.) in the bloodtwo hours after the administration (C2), and according to thecalculated value of the area under the concentration – timecurve in the first four hours after the application (AUC0-4),shows a good correlation with the clinical manifestations in thetransplanted patients (pts). The aim of this study was toinvestigate possibilities of reaching target C2 and AUC0-4levels in the early phase after kidney transplantation (Tx), toanalyze the administered doses and conc. of CyA in the firsttwo years after Tx and to determine, as well, which of theindividual concs. in the early phase after the drugadministration shows the best correlation with the AUC0-4.Methods. In 25 pts (living donor kidney recipients treatedby immunosuppressive therapy including Pred, MMF,CyA), the doses of CyA were adjusted after the Txaccording to target levels of C2 and AUC0-4.Results. The average daily doses of CyA in the first 14days ranged from 9,6 to 10,1 mg/kg (the largest dose wasgiven on the sixth day). The target C2/AUC0-4 was reachedon the sixth day in 36,3% of pts, on the 9 th day in 62,5% ofpts. and, on the 14 th day in 76% of pts. In each monitoredtime interval, the target AUC0-4 in relation to C2, wasreached by most of the pts. The maximum CyA concs werethe highest 2 hours after the administration (C2), ascompared with the concs after the first and the third hour(C1 and C3). In comparison with C1 and C3, C2 showedthe best correlation with AUC0-4. 68% of pts displayed thesigns of acute CyA nephrotoxicity in the first year and, in28% of pts the administration of the drug was interrupted inthe first two years. A stable graft function was maintainedin the first two years after the transplantation.Conclusion. The highest CyA concentrations in our pts weredetermined 2 hours after the drug administration, whereas C2showed the best correlation with AUC0-4. A considerablenumber of pts displayed the signs of nephrotoxicity.Keywords: cyclosporine monitoring, C2, C0, immunouppreion,kidney transplantationIntroductionaccepted. The measurement of the drug conc. level in theblood prior to the administration of the next successive dose(C0) and dosing of the drug on the basis of this drug conc.,represent the more common way of CyA TM [1]. Recently,it has been shown that C0 does not correlate well with theepisodes of acute rejection, and undesirable drug effects aswell [2]. The latest studies shown that the absorption, butnot the elimination phase, is primarily significant for theCyA effectiveness [3], and that the area under theconcentration-time curve in the first 4 hours after the drugadministration (AUC0-4) adequately reflects the exposureof the organism to the drug and correlates well with clinicalevents [4]. It was also shown that, out of all drugconcentration levels separately measured at some points oftime during the absorption phase, the drug conc. leveldetermined 2 hours after the administration (C2) correlatesthe best with AUC0-4 [5]. Recommended target levels ofC2 and AUC0-4 [6] mostly refer to the time interval of upto one year after Tx, but there are no generally acceptedrecommendations for desirable conc. levels of thoseparameters to be applied in the future. However, thesignificant inter-individual, racial and other specificitiesimpose the need to investigate the feasibility of performingof this type of TM in one's own pts.Patients and methodsStudy group included 25 pts (living donor kidneyrecipients). The patients who underwent cadaveric kidneytransplantation or kidney retransplantation, patientsreceiving induction therapy with biological antibodies andpatients in whom the titar of cytotoxic antibodies in theserum was found to be 50% higher before Tx wereexcluded. After Tx, the triple immunosuppressive therapywas introduced in all those pts. It included corticosteroids(Methylprednisolon-Lemod Solu, Hemopharm; Pronison,Galenika) administered according to the local departmentregimen, mikofenolat mofetil (CellCept,RocheLaboratories) in the doses of 1,0 gr every 12 h,administered 2 days before Tx, as well as cyclosporin(Neoral, Novartis Pharma). Cyclosporin was administeredperorally and its administration started on the day of Tx, at05:00 h early in the morning with 6 mg/kg dose. Nextmorning, when the creatinine level in the blood was 30%lower in relation to the levels measured before Tx, the dailyAlthough it has already been known that the clinical effectof the CyA depends on the reached conc. levels in theblood, the best way of TM of this drug is not universally______________________Correspodence to: Neven Vavic, Nephrology Clinic, Military Medical Academy, Crnotravska 17, Belgrade, Serbia;Tel.+381113670784; E-mail: nvavic@sbb.co.yu

BANTAO Journal 2007; 5 (2) 91doses of the drug were increased to 10-12 mg/kg andadministered in two daily doses, every 12 h (at 08:00 and20:00 h).Adjustment of CyA doses was done according to thealgorithm presented by Cole et al. [7]. The firstdetermination of CyA conc. was done on the 3rd day afterTx, two hours after administration of the morning drugdose. On the 6th day after Tx, drug conc. was measuredimmediately before the administration of the morning dose(C0) and continued to be measured after the first (C1), thesecond (C2) and the 3rd (C3) hour after the drugadministration. On the basis of the obtained measures, theAUC level was determined for the first three hours after thedrug application (AUC0-3) according to the regressiveformula based on C1, C2 and C3 (AUC0-3=256+C1+0,9xC2+1,4xC3) which was proved to have agood correlation (r=0,99) with AUC0-4 and AUC0-12 aswell 8 . The target C2 level on the 6th day after Tx was 1700ng/ml, while AUC0-4 level was 4400 ng/ml. The bloodsample for C2 was taken 2 hours ± 15 min. after theadministration of the morning drug dose (usually at 10,0h±15 min).CyA concentrations were measured by fluorescentpolarized immunoassay (FPIA, TDx Abbott Labaratories,Chicago, IL, USA) at the Institute of ExperimentalMedicine and Immunology, Military Medical Academy.The laboratory in which the CyA conc. were determined isa member of the international network for controlling thequality of CyA testing (Bioanalitical Services Ltd, London,UK) and the control is carried our once a month. Thementioned method is a commercial method of the AbbotCompany and the detailed instruction may be obtained froma manufacturer.CyA nephrotoxicity was defined as more than 30% increasein serum creatinin that was not attributed to any otheridentifiable cause and that improved with decrease in theCyA dose.Kidney function was measured by serum creatinin levelsand calculated creatinine clearance (Cockroft-Gault).The patients were informed about the aims and the methodsof conducting this research study. Before admitting thosepts to the study, they were required to give the writteninformed consent.Table 1. The average doses of CyA (mg/kg)applied in the study group of pts. in the first 24months after TxCyA dosesmg/kg / SD3 days 9,6 / 0,66 days 10,1 / 0,814 days 9,3 / 1,11 months 6,6 / 2,33 months 7,2 / 2,86 months 4,8 / 1,812 months 3,8 / 1,624 months 3,7 / 1,5The average concentrations of cyclosporine (ng/ml) afterthe first (C1), the second (C2) and the 3rd (C3) hour uponthe administration of the drug and, the levels of AUC0-4measured in the monitored time intervals within 24- monthperiod are presented in the Table 2.Table 2. The average cyclosporine concs. (ng/ml) after the first(C1), the second (C2) and the 3rd (C3) hour upon theadministration of the drug and the levels of AUC0-4 measured inthe monitored time intervals within 24- month periodC1 ± SD C2 ± SD C3 ± SD AUC 0-4 ±SD3 days 1108,0 1017,5 ±344,36 days 1167,1 ±335,91342,7 ±415,11069,7 ±315,24028,0 ±839,69 days 1414,0 ±330,91416,0 ±287,21053,4 ±172,64545,2 ±497,014 days 1518,6 ±414,41548,0 ±316,01174,5 ±316,04798,5 ±881,31 months 1516,4 ±371,41733,3 ±552,61071,7 ±282,15557,0 ±350 43 months 1278,5 ±471,61232,3 ±122,7779,0 ±245,23744,0 ±646,66 months 1128,5 ±343,41075,4 ±16,2723,3 ±179,63281,3 ±579,812 766,8 ± 813,6 ± 504,4 ± 2514,3 ±months24months345,3588,0 ±221,7323,7535,7 ±207,3190,3314, 0 ±89,0657,81546,4 ±248,7ResultsThe study group included 16 male (64%) and 9 female pts(36%) aged 17-48 (32,5 on average). Before Tx, 14 pts(56%) underwent hemodialysis and 3 pts (12%) underwentperitoneal dialysis while pre-dialysis Tx was performed in 8pts (32%). Duration of hemodialysis prior to Tx was 14,1months on average. Apart from the parents, we had abrother and a sister as donors in 2 cases, relatives of thesecond generation in another 2 cases and a wife in case of 1pts. The average age of donors was 54,9 (35-68). Theaverage time of cold ischemia was 27,5 min., of warmischemia was 78,6 sec. and the time of rewarming was 31,7min.The average doses of CyA (mg/kg) applied in the studygroup of patients in the first 24 months after Tx arepresented in the Table 1.Table 3. Correlation (r) of AUC0-4 with C1, C2 and, C3 on the6th and the 9th day after TxAUC 0-4 - C1 AUC 0-4 - C2 AUC 0-4 - C3r P value r P value r P value6.day 0,34 0,011 0,85 0,001 0,58 0,0039. day 0,38 0,52 0,87 0,001 0,57 0,036Correlation (r) of AUC0-4 with C1, C2 and, C3 on the 6thand the 9th day after Tx is presented in the Table 3.One of the target C2/AUC0-4 levels was reached on the 6thday by 36,3% of pts., on the 9th day by 62,5% of pts and,on the 14th day by 76% of pts while, on the 30th day, 84%of patients reached that concentration level. Five pts didn'tmanage to reach the target conc. levels in the first 30 daysafter Tx. By separate analysis of C2 and AUC0-4, it couldbe observed that the target C2 conc. level was reached onthe 6th day by 6 pts (27,2%) and the target AUC0-4 level

92 BANTAO Journal 2007; 5 (2)by 7 pts (31,8%, P=0,95). The target C2 was reached byanother 2 pts (33,3%) on the 9th day and the target AUC0-4level was reached by another 6 pts (54,1%, P=0,35). On the14th day after Tx, 11 pts (44%) reached the target C2 leveland 17 pts. (68%, P=0,23) reached the target AUC0-4 level.The signs of cyclosporine nephrotoxicity were displayed by44% of pts in the first 14 days, and by 68% of pts in thefirst year. Administration of CyA in the first two years waspermanently interrupted in 7 pts (28%) due to the impairedgraft function and the possible impact of the cyclosporinenephrotoxicity. The average creatinine clearance in thestudy group was 65 ml/min after 3 months, 66,2 ml/minafter 6 monthts, 61,5 ml/min after 12 months and 60,8ml/min, after 24 months. There was no loss of graftreported within the monitoring period.DiscussionRecent studies shown that the desirable CyA efficacy maybe achieved if adequate drug concsentration levels in theblood are reached in the initial phase, up to the 7th day afterthe Tx [8].The average CyA doses used in our study were very similarto the doses applied in other studies in which TM wasperformed by C2 monitoring: as presented in acomprehensive, randomized and multicenter study(MO2ART) [9], the average daily dose of the drug on the5th day after Tx was 10,3 mg/kg, and 11 mg/kg in theCanadian study [10]. The drug dose started to be reducedafter Tx and, after one month, it was 35% (6,6+2,3) smallerin relation to the initial dose. The rapid reduction of thedrug dose was also described in the MO2ART study [9],according to which, the average daily dose of CyA after onemonth was 6,7 mg/kg.Opelz et al investigated the relationship between the dailydoses of CyA one year after Tx with the long-term kidneygraft function in the group of cadaveric kidney recipients[11]. The results indicated that the 7-year graft survivalperiod in pts receiving CyA after the first year in the dosesbellow 2 mg/kg was the shortest, whereas, it was thelongest in the group of pts receiving the average daily dosesof about 5 mg/kg. However, the graft survival was also veryshort in pts receiving daily doses of over 6 mg/kg of CyA.The average daily CyA dose in the group of our pts oneyear after Tx reached the medium of the mentioned levels(3,8±1,6) and the administered drug doses were relativelyconstant till the second year (3,7±1,5) We think thatmaintenance of the stable CyA conc levels (even within thefirst two years after Tx) may be very important for the longtermgraft function.In our pts in the first two weeks after Tx (except for the 3rdday), the maximum CyA conc. level was determined 2hours after the drug administration, while C2 shown thebest correlation with AUC0-4, what was confirmed in otherstudies [12,13]. Such findings could justify the choice of C2as the most appropriate separate point for TM of CyA inour patients.Apart from relatively high drug doses given immediatelyafter Tx, only more than one third of our patients managedto reach the target C2 or AUC0-4 conc. levels on the 6thday, what constituted to be a problem observed in otherstudies in which TM was managed by C2. In the Italianstudy [14], the target C2 of 1700 ng/ml was reached by50% of patients on the 7 th day and, according to theCanadian study 15 , the target AUC0-4 conc. level wasreached by 49% of pts on the same day. Taking intoconsideration the fact that the target AUC0-4 levels inrelation with C2 levels in each monitored time intervalswere reached by a larger number of our pts, it may beobserved that, in nearly 25% of our pts, the CyA dosewould be increased in the first 14 days after Tx if the drugTM is managed by C2 level monitoring only.ConclusionIn the group of pts in which TM was performed byC2/AUC0-4 level monitoring, the highest conc.of CyA wasdetermined in C2, which correlated well with AUC0-4.Since the smaller number of pts reached the targetC2/AUC0-4 level in the early monitoring period and that aconsiderable number of pts displayed the signs ofnephrotoxicity, the target C2/AUC levels could be lowerthan that of recommended for our pts. The graft functionwas stable in the study group.Conflict of interest statement. None declared.References1. Belitsky P, Levy GA, Johnston. Neoral absorptionprofiling: an evolution in effectiveness. TranplantProc 2000; 32 Suppl. 3A: 45S-52S.2. Nankivell BJ, Hibbinis M, Chapman JR: Diagnosticutility of whole blood cyclosporine measurments inrenal transplantation using triple therapy.Transplantation 1994; 58: 989-996.3. Johnston A, David OJ, Cooney GF. Phramacocineticvalidation of Neoral absorption profiling. TranplantProc 2000; 32 Suppl. 3A: 53S-56S.4. Mahalati K, Belitsky P, Sketeris I, et al. Neoralmonitoring by simplified sparse sampling area underthe concetration-time curve: its relationship to acuterejection and cyclosporin nephrotoxycity early afterkidney transplantation. Transplantation 1999; 68: 55-62.5. Cantarovich M, Besner J-G, Barkun JS et al. Twohourcyclosporine level determination is theappropriate tool to monitor Neoral therapy. ClinTransplant 1998; 12: 243–249.6. Stefoni S, Midtved K, Cole E, Thervet E, Cockfield S,Buchler M et al. Efficacy and safety outcomes amongde novo renal transplant recipients managed by C2monitoring of cyclosporine a microemulsion: results ofa 12-month, randomized, multicenter study.Transplantation 2005; 79(5): 577-83.7. Cole E, Mitvedt K, Johnson A, et al.Recommendations for implementation of neoral C2monitoring in clinical practice. Transplantation 2002;73(9): S19-S22.8. Mahalati K, Belitsky P, West K, et al. Approachingthe therapeutic window for cyclosporine in kidneytransplantation: a prospective study. J Am Soc Nephrol2001; 12: 828-33.9. Pfefer P, Stefoni S, Carreno C, et al.for the MO2ARTStudy Group. Monitoring of 2-hour Neoral absorption

BANTAO Journal 2007; 5 (2) 93in renal transplantation show low incidence of acuterejection in the early post-graft period: interim resultsof the MO2ART study. American Society ofTransplantation Congress, 26 April-1 May, 2002.Washington DC, USA.10. Margreiter R. Efficacy and safety of tactrolimuscompared with cyclosporin microoemulsion in renaltransplantation: a randomised multicentre study.Lancet 2002; 359: 741.11. Opelz for the Collaborative Transplant Study.Relationship between maintenance dose of cyclosporinand long term kidney graft survival. Transplant Proc1998; 30: 1716-17.12. Morris RG, Russ GR, Cervelli MJ, Juneja R,McDonald SP, Mathew TH Comparison of trough, 2-hour, and limited AUC blood sampling for monitoringcyclosporin (Neoral) at day 7 post-renaltransplantation and incidence of rejection in the firstmonth. Ther Drug Monit 2002; 24: 479–86.13. Levy G, Thervet E, Lake J, Uchida K, on behalf of theCONCERT group. Patient management by Neoral C2monitoring: An international consensus statement.Transplantation 2002; 73(9) Suppl. S12-S18.14. Di Paolo, Teutonico A, Stallone G. Cyclosporinexposure correlates with 1 year graft function andhistological damage in renal transplanted patients.Nephrol Dial Transplant 2004; 19: 2107-211.15. Clase CM, Mahalati K, Kiberd BA et al. Adequateearly cyclosporin exposure is critical to prevent renalallograft rejection: patients monitored by absorptionprofiling. Am J Transplant 2002; 2: 789–95.

BANTAO Journal 2007; 5 (2) : 94–96Original ArticleBJBANTAO JournalComplications in the Kidney Transplanted Patients Previously Treated byPeritoneal Dialysis - 10-Year Experience in a Single CenterVioleta Rabrenovic, Zoran Kovacevic, Dragan Jovanovic and Ljiljana IgnatovicClinic of Nephrology, Military Medical Academy, BelgradeAbstractBackground. The aim of this study was to review thecomplications and renal functions in the kidney transplanted(KTx) patients previously treated by peritoneal dialysis.Method. Retrospective analyses in period from Jan1996-Dec 2006 incuded 35 pts with KTx. The etiology of ESRDwas: glomerulonephritis in 23 (65%), diabetes mellitus in 7(20%), juvenile nephronophthisis in 2 (6%), VUR, kidneyhypoplasia and Sy Good Pasture in 3 separate cases. Wefollowed: graft survival, development of early and chroniccomplications and the renal function.Results. Early surgical complications were: thrombosis ofthe renal artery and the early loss of graft occurred in 6 pts(17,1%), bleeding in 5 pts. (14,2%), hematoma in 4pts.(11,4%), lymphocele in 5 pts.(14,2%).Renal functionwas delayed in 5 pts (14,2%), 9 pts (25,7%) with acuterejection. There wasn’t any case of peritonitis. Chroniccomplications were: 4 (11,4%) chronic rejection with 1(2,8%) loss graft and 3 (8,5%) urethrostenosis. As forinfections, we found 4 (11,4%) bacterial infections and 9(25,7%) reactivation of CMV. The recurrence of the diseaseoccurred in 2 (5,7%) pts. The stable medium level mcreatinine/s was 125, 76+ 12, 3 umol/l in the begining and135, 24+14, 1 umol/l in the final phase of the monitoring.The medium level of glomerular filtration rate was63,80+6,1 ml/min in the early phase and 62,47+7,2 ml/minin its final phase.Conclusion. Surgical (vascular) complications morefrequently occurred in patients with diabetes mellitus. Therewasn’t any case of peritonitis reported most probably becausethe peritoneal catheter was removed during the procedure. Thelargest number of pts managed to maintain the stable graftfunction throughout the whole monitoring period.Key words: complications, graft survival, peritonealdialysis, transplantationIntroductionThere is still a lot of controversy over the approach whichof treatment modalities of the end-stage renal diseaseperitoneal dialysis (PD) and hemodialysis (HD) is morefavorable before kidney transplantation. [1-3]. Peritonealdialysis was introduced into practice as a pre-transplanttreatment modality 20 years ago and hemodialysis morethan forty years. Progress made in the field of surgicaltreatment and in the management of immunosuppressive______________________Correspodence to:therapy allowed a good control over potential complicationssuch as graft thrombosis, delayed graft function, acute andchronic rejection, the occurrence of peritonitis and otherinfections developing in the post-transplantation period.Peritoneal dialysis is a good choice as a first treatmentmodality for the patients with end stage renal disease whohave living donors. These patients have mild form ofanemia, better urine output, lower exposure to the hepatitisviruses and satisfactory rehabilitation. Many authorscouldn’t find differences between PD and HD patientsaccording to the postoperative complications [4-6].Patients and methodsIn the period from January 1996 to December 2006, 213kidney transplantations were performed at the NephrologyClinic, Military Medical Academy in Belgrade. Out of those213 transplantations, 35 (16,4%) were done in PD patients (21(60%) male and 14 (40%) female pts aged 33,37+4,1 onaverage). They were monitored for the 5 to 95- monthperiod (52,2 months on average). The quadruple immunosuppre-ssivetherapy with ATG, MMF, KS, CS vs Tac wasapplied n 19 (54%) of cases, while in the other 16 (45%)pts, the triple therapy with MMF, KS, CS or Tac wasintroduced. The graft and patient’s survival, occurrence ofearly and chronic complications and the renal function weremonitored with serum creatinine and glomerular filtrationrate.ResultsRetrospective analyses were conducted in 35 pts. Theunderlying diseases causing renal insufficiency wereglomerulonephritis reported in 23 (65%) cases, diabetesmellitus in 7 (20%) cases, and juvenile nephronophthisis in2 (6%) cases while VUR, kidney hypoplasia and Sy GoodPasture were identified in 3 separate cases. According tothose underlying diseases, glomerulonephritis and diabetesmellitus were found to occur in the largest percentage whilethe percentage of occurrence of the other reported diseaseswas much smaller. Having in mind the fact that we don'thave the developed deceased donor network, living donorTxs make up the largest percentage of all the performedtransplantations. The percentage of deceased Txs was only14 (5 Txs) and as of the living donor kidney Txs, it was 86(30Txs). A peritoneal catheter was removed during theprocedures in all the cases.The early surgical complications included thrombosis of therenal artery, bleeding and hematoma of the lymphocele outVioleta Rabrenovic, Clinic of Nephrology, Military Medical Academy, Crnotravska 17, Belgrade,Serbia; Tel. + 381 641398436; E-mail: kaca3110@infosky.net

BANTAO Journal 2007; 5 (2) 95of which renal artery thrombosis occurred in the largestpercentage of patients (17,1%) mainly diagnosed withdiabetes mellitus. Due to those renal artery thromboses,kidney explantation was required to be done. Thepercentage of the other complications that developed wassubstantially smaller, among which bleeding occurred in 5patients (14,2%) hematoma at the surgical site in 4 patients(11,4%) and lymphocele in 5 patients (14,2%). Eighteenreinterventions were required to be performed.Early complications associated with the graft function andrejections by the recipients were expected to develop.Delayed graft function occurring in 14, 2% of cases (5 pts.)required placement of CVK and introduction ofhemodialysis. The acute rejection occurred in 25, 7% ofcases (9 pts.). There was not any case of infectiouscomplications such as peritonitis, most probably due to thefact that the peritoneal catheter was removed during thetransplantation procedure.In the course of monitoring period, a slightly smallerpercentage of chronic complications was reported to occursuch as chronic rejection (4 pts - 11, 4%), loss of graft (1pts -2,8%) and urethrostenosis (3 pts - 8,5%).Within that period, 11,4% of bacterial infectious associatedwith the urinary tract developed more frequently in patientswith diabetes mellitus. The germs mostly isolated were E-coli, Klebsiela and Enterococus. CMV infections recurredin 25,7 % of cases out of which 5 were patients receivingquadruple immunosuppressive therapy and were efficientlytreated with antibiotic and antiviral and carefully correctedimmunosuppressive therapy (Table 1, Table 2).Table 1. Early complications - frequency rateComplicationsFrequency Frequencynumber %thrombosis 6/35 17,1%bleeding 5/35 14,2%hematoma 4/35 11,4%lymphocele 5/35 14,2%delayed graft function 5/35 14,2%acute rejection 9/35 25,7%peritonitis 0/35 0 %Table 2. Late complications - frequency rateComplicationsFrequency Frequencynumber %chronic rejection 4/35 11,4%graft loss 1/35 2,8%urethral stenosis 3/35 8,5%bacterial infections 4/35 11,4%reactivation CMV inf 9/35 25,7%Recurrence of the disease was reported in 2 pts (5,7%) andwas associated with membrane-proliferative GN and IgAglomerulonephritis. Three patients underwent retransplantationdue to the loss of graft.During the follow up no one died. On the basis of the meanlevel of serum creatinine as the kidney function parameter,it could be observed that there was no statisticallysignificant differences in the initial (125, 76+12, 3 umol/l)and the final phase (135, 24+14,1 umol/l) of the monitoringperiod. It indicated that the stable graft function wasmaintained throughout the whole monitoring period. It wasalso confirmed by monitoring the blood levels ofglomerular filtration rate (GFR) and no statisticallysignificant differences were found in the initial (63,80+6,1umol/l) and the final phase (62,47+7,2 umol/l) of themonitoring period. (Figure 1).150100500CrsGFRFig. 1. The medium level of cretinine and GFR measured inthe initial and the final phase of the monitoring periodDiscussionThe impact of the pre-transplantation treatment modality ofthe terminal renal insufficiency on the development ofpostoperative complications, function, infections and graftsurvival represents the subject of interest of manynephrologists. For a long time, the opinion wascontroversial, but an approach that the peritoneal dialysis asthe first treatment modality is as good choice of treatmentas hemodialysis has prevailed nowadays [1-8]. Someauthors indicate that the peritoneal dialysis is a goodtreatment modality for the patients with the insufficiency ofthe transplanted kidney [9].Vascular thrombosis was reported as characteristic earlypostoperative complications occurring in that group ofpatients.But studies of many authors indicated that there weren't anysignificant differences in the transplantation outcomeidentified in the groups of PD patients as compared with thegroup of HD patients (3,47% -41% in the PD group and,1,9%-30% in the HD group [5,7,10]. Renal arterythrombosis occurred in 6 patients (17,1%). Most of patientswere insulin dependent diabetics (4/6) with advancedarteriolosclerosis. During the operation surgeons performedendartherectomy of internal iliac artery before they madeanastomosis with renal artery. Immediately aftertransplantation we didn’t found flow through renal arterywith color Doppler sonography and selective angiography,so we had to perform graft nephrectomy.The frequency rate of acute graft rejection occurring in bothPD and HD groups of patients didn't differ to a greaterextent. Based on the published data, 27 - 49, 2 % ofrejection reactions were reported in the PD group ofpatients and 27-43, 6% in the HD group [7,8]. In our PDgroup of transplanted patients, the acute graft rejectionoccurred in 25, 7% of cases. Experiences of our Centerindicated that the graft survival rate in this group of patientsduring the monitoring period was 75% what correlated withthe data obtained by other authors (5-year survival periodamong CAPD patients was reported in 61-67% of caseswhile that percentage ranged from 63-66% among HDpatients [11,12].

96 BANTAO Journal 2007; 5 (2)The delayed graft function was identified in 12-30% of PDpatients and in 16-50,4 % of HD pts. [7,11,13]. Within ourgroup of patients, 14,2 % of them was reported to havedelayed graft function treated by the short-termhemodialysis.Infections always represented the types of complicationsmost often occurring in PD patients but, recently there is agreat number of studies indicating the contrary. So,Vanholder, et al described that no significant differenceswere found in those two Tx groups of patients in relation tosurgical complications and infections and, recommendedPD as a therapy of choice in cases of patients indicated fortransplantation [13].Infections complications occurring in the first days aftertransplantation were described in 67% of PD pts and in 25,9% of HD pts. Those infections were mainly caused bymicroorganisms colonizing the skin and, according to thesite of the infection, they were intra-abdominal and theinfections occurring on the peritoneal catheter site. It, ofcourse, interfered with the recovery in the early posttransplantedperiod, then prolonged the patient'shospitalization and substantially affected the graft survival[14]. Contrary to those infections, frequency rate of theurinary tract infections, infections associated withintravenous and intra-arterial lines and other sites as welldidn't differ in those groups of PD and HD patients [14]. Byintroducing this technique of removing the peritonealcatheter during the surgical procedure, we managed toprevent any episodes of peritonitis in the posttransplantationperiod.ConclusionThis study shown that surgical (vascular) complicationsoccurred more frequently in patients with diabetes mellitus.There wasn't any case of peritonitis reported most probablydue to the removal of peritoneal catheter during the Txprocedure. Careful dosing of immunosuppressive drugsparticularly in diabetes patients could reduce the occurrenceof urinary tract infections and reactivation of CMV. Thelargest number of patients maintained the stable graftfunction throughout the whole monitoring periodConflict of interest statement. None declared.References1. Lameire N, Van Biesen W, Vanholder R: Impact ofPeritoneal Dialysis on Patient and Graft Outcome afterKidney Transplantation. Ronco C, Dell´Aquila R,Rodighiero MP (eds): Peritoneal Dialysis Today.Contrib Nephrol Basel, Karger, 2003; vol 140, pp 226-41.2. Cancarini GC, Sandrini S, Setti G, Bossini PM,Guerini S, Cassamali N et al. Renal transplantationand peritoneal dialysis .Ronco C, Dell´Aquila R,Rodighiero MP (eds): Peritoneal Dialysis Today.Contrib Nephrol Basel, Karger, 2003; vol 140, pp 242-50.3. Joseph JT, Jindal RM. Influence of dialysis on post –transplant events. Clinical Transplant 2002; 16(1): 18.4. Van Biesen W, Vanholder R, Van Loo A, Van DerVennet M, Lameire N. Peritoneal dialysis favorablyinfluences early graft function after renaltransplantation compared to hemodialysis.Transplantation 2000; 69(4): 508-14.5. Perez Fontan M, Rodriguez-Carmona A, GarciaFalcon T, Tresancos C, Bouza P, Valdes F. Peritonealdialysis is not risk factor for primary vascular graftthrombosis after renal transplantation. Perit Dial Int1998; 18 (3): 311-6.6. Chiaramonte S, Dissegna D, Inguaggiato P. Clinicalmanagement of the PD patient after transplantation.Ronco C, Dell´Aquila R, Rodighiero MP (eds):Peritoneal Dialysis Today. Contrib Nephrol Basel,Karger, 2003; vol 140, pp 256-63.7. Snyder JJ, Kasiske BL, Gilbertson DT, Collins AJ. Acomparison of transplant outcomes in peritoneal andhemodialysis patients. Kidney International 2002; 62(4): 1423-30.8. Chalem Y, Ryckelynck JP, Tuppin P, Verger C,Chauve S, Glotz D et al. Access to, and outcome of,renal transplantation according to treatment modalityof edd-stage renal disease in france. KidneyInternational 2005; 67(6): 2448-53.9. De Jonge H, Bammens B, Lemahieu W, Maes DB,Vanrenterghem Y. Comparison of peritoneal dialysisand haemodialysis after renal transplant failure.Nephrol Dial Transplant 2006; 21(6): 1669-74.10. McDonald RA, Smith JM, Stablein D, Hammon WE.Pretransplant peritoneal dialysis and graft thrombosisfollowing pediatric kidney transplantation: ANAPRTCS report. Pediatr Transplantation 2003; 7:204-8.11. Joseph JT, Jindal RM. Influence of dialysis on post –transplant events. Clinical Transplant 2002; 16(1): 18.12. O Donoghue D, Manos J, Pearson R, Scott P, BakranA, Johnson R et al. Continuous ambulatory peritonealdialysis and renal transplantation : a ten-yearexperience in single center. Perit Dial Int 1992; 12(2):242-9.13. Vanholder R, Heering P, Loo AV, Biesen WV,Lambert MC, Hesse U et al. Reduced incidence ofacute renal graft failure in patients treated withperitoneal dialysis compared with hemodialysis. Am JKidney Dis 1999; 33 (5): 934-40.14. Passalacqua JA, Wiland AM, Fink JC, Bartlett ST,Evans DA, Keav S. Increased incidence ofpostoperative infections associated with peritonealdialysis in renal transplant recipients, Transplantation1999; 68 (4): 535-40.

BJBANTAO JournalBANTAO Journal 2007; 5 (2) : 97–98Case reportA Rare Cause of Headache in a Patient with Poststreptococcal AcuteGlomerulonephritisErkan Dervisoglu 1 , Gokhan Erbag 1 , Murat Alemdar 2 and Ahmet Yilmaz 11 Department of Internal Medicine, Division of Nephrology, 2 Department of Neurology, School of Medicine, KocaeliUniversity, Kocaeli, TurkeyAbstractWe report a 34 year-old male patient with poststreptococcalacute glomerulonephritis who developed headachesecondary to spontaneous intracerebral haemorrhage. Hewas treated medically and recovered completely. This caseshows that spontaneous intracerebral haemorrhage canoccur in patients with poststreptococcal acuteglomerulonephritis. Whether this association is due to adecreased coagulation attributable to the post-infectiousdisorder or to an involvement of the brain vessel wall mustbe better clarified with further studies.Keywords: headache, intracerebral haemorrhage,poststreptococcal acute glomerulonephritisIntroductionshowed a specific gravity of 1023, 2+ positive for proteinand microscopic hematuria with numerous red blood cellsand red blood cell casts. Serum biochemistry work-uprevealed a serum creatinine of 1.3 mg/dL [ref. 0.7-1.3],blood urea nitrogen of 30 mg/dL [ref. 7-25] serum C3 levelof 27.1 mg/dL [ref. 79-152], the serum antistreptolysin O(ASO) titer of 226 IU/mL [ref. 0-200]. Cryoglobulins, antinuclearand anti-neutrophil cytoplasmic antibodies were notdetected. Serological tests for hepatitis B, C and HIVviruses were negative. Renal ultrasound showed normalsizedkidneys, non-distended urinary bladder and noevidence of hydronephrosis. The diagnosis of acutenephritic syndrome due to PSAGN was based on theselaboratory and clinical findings. The patient washospitalized. Two-dimensional and Dopplerechocardiography demonstrated normal hearth function.The classic presentation of poststreptococcal acuteglomerulonephritis (PSAGN) is a reversible nephriticsyndrome with oliguric acute renal failure. Hematuria(characterized by red urine), headache, and generalizedsymptoms such as anorexia, nausea, vomiting, and malaiseconstitutes well known clinical feature of poststreptococcalglomerulonephritis [1]. Headache, which naturally occursin the disease process, may therefore constitute a negligiblesymptomatology. We report a patient with PSAGN whowas detected to have intracerebral haemorrhage during theevaluation for intractable headache. A description of hisclinical course provides important information on theclinical features of PSAGN complicated by intracerebralhaemorrhage.Case reportA 34 year-old man was admitted to our hospital with edemaat eyelids, hands and lower legs and oliguria which startedfive days ago. He was treated for 5 days with intravenouscefazolin for pharyngitis, two weeks before presentingsymptoms. At physical examination, his blood pressure was150/80 mmHg and hearth rate was 84 b.p.m., his bodytemperature was 36.5 ºC. Blood work results were asfollows: Hgb 16.5 g/dL, WBC 9.500/mm³, platelet count315.000/mm³, erythrocyte sedimentation rate 4 mm/hr, C-reactive protein (CRP) level 0.375 mg/dL (normal:

98 BANTAO Journal 2007; 5 (2)eyelids, hands and lower legs improved and daily urinaryoutput got normalized but headache did not improved. Onthe 7 th day of admission cranial computed tomography (CT)showed an intraparenchymal hemorrhagic lesion at frontalcerebral region which opened into the ventricular system(Figure 1). Simultaneously examined routine coagulationtests revealed a prothrombin time of 13.8 sec [ref. 11.5-15.5, INR: 1.1] and activated partial thromboplastin time of27.6 sec [ref. 26.5-40.0].The patient received mannitol therapy for the consecutivethree days. The brain magnetic resonance imaging (MRI)did not reveal any vascular or structural pathologyunderlying the intracerebral haemorrhage. Within 14 days,his symptoms including headache improved and he wasdischarged.DiscussionPSAGN is an immune-mediated disease associated withthroat or skin infections with certain nephritogenic strainsof group A streptococci and usually diagnosed on clinicaland serologic grounds without the need for renal biopsy [2].Most patients have milder disease, and subclinical cases arecommon [1]. The long term prognosis is generallyfavorable, but some patients may have life-threateningacute complications due to impairment of renal functions orsecondary to systemic hypertension. Hypertension is foundin most of patients at initial presentation and in some casesmay result with hypertensive encephalopathy [2]. However,intracerebral haemorrhage during the clinical course isunusual.In the pathogenesis of intracerebral haemorrhage, it isknown that acute raised blood pressure can definitelyprecipitate this life threatening state, particularly inpreviously normotensive individuals whose cerebral bloodflow autoregulation is within the normal range [3]. In thepresent case, the patient did not have a history of chronichypertension but his arterial blood pressure was at stage 1hypertension level on admission. Undoubtedly,hypertension is neither a sufficient nor a necessary cause ofintracerebral haemorrhage [3].Co-existent glomerulonephritis and intracerebral haemorrhageshave rarely been reported up to day. In a series bySugiyama et al. in which the rapidly progressive glomerulonephritis(RPGN) cases were studied, two patients withRPGN associated with systemic lupus erythematosus werereported to die secondary to cerebral haemorrhages [4].Intracranial haemorrhage as spontaneous subarachnoidhaemorrhage has been reported in a 6-year-old boy withPSAGN [5]. In that case, the outcome was reported to begood as in our case. Gilboa et al. reported a child withPSAGN who developed spontaneous pulmonaryhaemorrhage. The patient in their case was successfullytreated with methylprednisolone [6].The present case shows that spontaneous intracerebralhaemorrhage can occur in patients with poststreptococcalacute glomerulonephritis. Whether this association is due toa decreased coagulation attributable to the post-infectiousdisorder or to an involvement of the brain vessel wall mustbe better clarified with further studies.Conflict of interest statement. None declared.References1. Hahn RG, Knox LM, Forman TA. Evaluation ofpoststreptococcal illness. Am Fam Physician 2005; 71:1949-1954.2. Sulyok E. Acute proliferative glomerulonephritis. In:Avner E, Harmon WE, Niaudet P, eds. PediatricNephrology. Lippincot Williams & Wilkins, Phiadelphia,USA: 2004; 601-613.3. Warlow CP, Dennis MS, van Gijn J, Hankey GJ,Sandercock PAG, Bamford JM, Wardlaw JM. Stroke aPractical Guide to Management. Blackwell ScienceLtd, London, UK: 2001; 339-375.4. Sugiyama H, Makino H, Wada J, et al. A clinicopathologicalstudy of patients with immune complextype and pauci immune type rapidly progressive glomerulonephritis.Nippon Jinzo Gakkai Shi 1993; 35:777-782.5. DeBeukelaer MM, Young GF. Subarachnoid hemorrhagecomplicating acute poststreptococcal glomerulonephritis.Arch Neurol 1978; 35: 473-474.6. Gilboa N, McIntire S, Hopp L, Ellis D. Acute noncresentricpoststreptococcal glomerulonephritis presentingwith pulmonary hemorrhage. Pediatr Nephrol1993; 7: 147-150.

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AnnouncementsCongress of the ERA-EDTA45th ERA-EDTA Congress in Stockholm (Sweden) from May 10 to May 13, 2008.BJBANTAO JournalERA-EDTA/ISN COMGAN sponsored CME ActivitiesFrom prevention in progression of CKD and related CVD and CKD-MBD problems to kidney transplantationCME Course - April 5th, 2008, Conference Center, Radon Plaza Hotel, Sarajevo, Bosnia and HerzegovinaContacts: Promo Tours (ismet@promotours.ba); www.promotours.ba.The 6th Renal Failure AcademyAn ERA-EDTA and ISN/COMGAN postgraduate course - June 4-7, 2008, Venus resort at the Black Sea, RomaniaContacts: Adrian Covic (acovic@xnet.ro) and Paul Gusbeth (paulgusbeth@yahoo.com); www.rfa.ro.From Clinical Nephrology and CKD Related Problems to Prolonged Kidney Transplant SurvivalCME Course - October 11, 2008 - Sofia, BulgariaBulgarian Congress of Nephrology - October 9-11, 2008 - Sofia, BulgariaContacts: Pencho Simeonov (nephcl@abv.bg) and Evgueniy Vazelov (estevaz@yahoo.com).WORLD KIDNEY DAYMeeting of the Macedonian Nephrologists, Health Authorities and Dialysis Patients AssociationMarch 13th, 2008, Macedonian Academy of Sciences and Arts, Skopje, MacedoniaContact: Acad. Momir Polenakovic (maknefpo@mt.net.mk)5th Croatian Congress of Nephrology, Dialysis and TransplantationApril 18th - 21st, 2008, Hotel Elaphusa, Bol, island Brač, CroatiaContact: Nikola Janković (tajnik@hdndt.org)Danube SymposiumAugust 28, 2008 - Krems, AustriaEuropean Society of Artificial Organs annual meeting3-6 September, 2008, Geneva, SwitzerlandContacts and info: www.esao2008.medecine.unige.ch4th Slovenian Congress of Nephrology22-25 October 2008, Hotel Golf, Bled, SloveniaContacts and info: www.nephro-slovenia.si