Effect of L-carnitine Supplementation on Left Ventricular Functions in ...

<strong>Effect</strong> <strong>of</strong> L-<strong>carnitine</strong> <strong>Supplementation</strong> onLeft Ventricular Functions inHemodialysis PatientsThesisSubmitted to Faculty <strong>of</strong> Medicine, Alexandria Universityin partial fulfillment <strong>of</strong> the requirements for theDegree <strong>of</strong> Master<strong>of</strong>Internal MedicineByRehab Hussien Mohamed MersalMBBCh., Alex. University, 1995Faculty <strong>of</strong> MedicineAlexandria University2005

CONTENTSChapterPageI. Introduction .................................................................................. 1II. Aim <strong>of</strong> the Work .......................................................................... 45III. Subjects ........................................................................................ 46IV. Methods ........................................................................................ 48V. Results .......................................................................................... 54VI. Discussion .................................................................................... 108VII. Summary ...................................................................................... 119VIII. Conclusion ................................................................................... 121IX. References ................................................................................... 122ProtocolArabic Summary

My sincere thanks to my supervisor, Pr<strong>of</strong>essor Dr.Salah Said Naga, Pr<strong>of</strong>essor <strong>of</strong> Internal Medicine andNephrology, Faculty <strong>of</strong> Medicine, University <strong>of</strong>Alexandria, for his generous and continuous help,encouragement, criticism and support.I would like also to acknowledge the distinguishedadvice, help, support and experience given byPr<strong>of</strong>essor Dr. Mohamed Magdy Abd El Kader, Pr<strong>of</strong>essor<strong>of</strong> Internal Medicine and Nephrology, Faculty <strong>of</strong>Medicine, University <strong>of</strong> Alexandria.My gratitude to Pr<strong>of</strong>essor Dr. Tarek Hussien ElZawawey, Pr<strong>of</strong>essor <strong>of</strong> Cardiology and Angiology,Faculty <strong>of</strong> Medicine, University <strong>of</strong> Alexandria for hishelp and supervision.I would like to express my special thanks toAssistant Pr<strong>of</strong>essor Dr. Akram El Deghady, AssistantPr<strong>of</strong>essor <strong>of</strong> Clinical Pathology, Faculty <strong>of</strong> Medicine,University <strong>of</strong> Alexandria for his effort, time & support.I am deeply grateful to patients; without theirconsent this thesis would not have been possible.

Introduction 1.INTRODUCTIONChronic renal failure (CRF) is a progressive disease characterized byprogressive destruction <strong>of</strong> the renal mass with increasing inability <strong>of</strong> thekidney to maintain normal homeostasis <strong>of</strong> protein metabolism (e.g. urea),normal blood pressure and hematocrit, water, and electrolytes. (1)Etiology <strong>of</strong> chronic renal failureThere are many causes <strong>of</strong> chronic renal failure, they can be divided into:1- Primary glomerular diseases:• Membranous nephropathy.• Immunoglobulin A (IgA) nephropathy. (2)• Focal and segmental glomerulosclerosis (FSGS).• Minimal change disease.• Membranoproliferative glomerulonephritis.• Rapidly progressive (crescentric) glomerulonephritis.2- Secondary glomerular diseases:• Diabetic glomerulosclerosis.• Systemic lupus erythrematosis(SLE) ,PAN. (3)• Rheumatoid arthritis.• Mixed connective tissue disease.• Scleroderma.• Goodpasture syndrome.• Wegener granulomatosis.

Introduction 2.• Mixed cryoglobulinemia.• Post infectious glomerulonephritis.• Bacterial endocarditis.• Hepatitis B and C.• Syphilis, HIV infection. (4)• Parasitic infections.• Heroin use.• Gold, pencillamine.• Amyloidosis.• Light chain deposition disease.• Neoplasia.• Thrombotic thrombocytopenic purpura (TTP).• Hemolytic uremic syndrome (HUS).• Henoch-schenolein purpura.• Schistosomiasis-associated glomerulopathy. (4)3- Tubulo-interstitial diseases:• Drugs (e.g; sulfa, allopurinol). (5)• Infection (viral, bacterial as T.B., parasitic).• Sarcoidosis.• Sjogren syndrome.• Multiple myloma (cast nephropathy).

Introduction 3.• Gouty nephropathy.• Nephrocalcinosis.4- Hereditary and genetic diseases:• Polycystic kidney disease.• Alport’s syndrome.• Congenital hypoplasia.5- Vascular diseases:• Renal artery stenosis.• Antineutrophil cytoplasmic antibody (ANCA).♦ Cytoplasmic pattern antineutrophil cytoplasmic antibody(C-ANCA).♦ Positive and perinuclear pattern antineutrophil cytoplasmicantibody (P-ANCA).• Hypertensive nephrosclerosis.• Renal vein thrombosis.6- Urinary tract obstruction:• Urolithiasis.• Benign prostatic hyperplasia. (6)• Tumours.• Retroperitoneal fibrosis.• Urethral stricture.• Neurogenic bladder. (7)

Introduction 4.Pathogenesis <strong>of</strong> chronic renal failure:Approximately 1-1.3 million nephrons are present in each kidney,each contributing to the total GFR regardless <strong>of</strong> the etiology <strong>of</strong> renal injury,with progressive destruction <strong>of</strong> nephrons, the kidney has an innate ability tomaintain GFR by hyperfiltration and compensatory hypertrophy <strong>of</strong> theremaining healthy nephrons. This nephron adaptability allows forcontinued normal clearance <strong>of</strong> plasma solutes such as urea and creatinine,these substances start to show significant increases in their plasma levelsonly after total GFR has decreased to 50%, when the renal reserve has beenexhausted. A rise in plasma creatinine from a baseline value <strong>of</strong> 0.6 mg/dl to1.2 mg/dl in a patient, although still within the reference range, actuallyrepresents a loss <strong>of</strong> 50%<strong>of</strong> the functioning nephron mass. (8)Although, the residual nephrons hyperfiltration and hypertrophy arebeneficial, it may be a major cause <strong>of</strong> progressive renal dysfunction. This isbecause <strong>of</strong> increased glomerular capillary pressure, which damages thecapillaries and leads initially to focal and segmental glomerulosclerosis andeventually to global glomrulosclerosis.Factors other than the underlying disease process and glomerularhypertension that may cause progressive renal injury include the following:• Systemic hypertension. (9)• Acute insults: nephrotoxins or decreased perfusion.• Proteinuria. (10)• Increased renal ammoniagenesis with interstitial injury.• Hyperlipidemia.• Hyperphosphatemia with calcium-phosphate deposition. (11)• Decreased levels <strong>of</strong> nitric oxide.

Introduction 5.Morbidity and mortality:Chronic renal failure is a major cause <strong>of</strong> morbidity and mortality, the5-year survival rate for a patient undergoing chronic dialysis isapproximately 35%. This rate decrease to approximately 20% in patientswith diabetic nephropathy. (12,13)Age:CRF can be found in people <strong>of</strong> any age, from infants to the very old,but the elderly population is the most rapidly growing ESRD population.Aging also results in concomitant progressive physiological decreasein muscle mass such that daily urinary creatinine excretion also decrease;this combination <strong>of</strong> factors results in constant serum creatinine values overtime in a given individual, despite a decrease in CrCl and GFR. (14)Pathophysiology and biochemistry <strong>of</strong> uremia:The uremic syndrome results from functional derangement <strong>of</strong> manyorgan systems, although the prominence <strong>of</strong> specific symptoms variesamong patients. Azotemia refers to the retention <strong>of</strong> nitrogenous wasteproducts as renal insufficiency develops. Uremia; refers to the moreadvanced stages <strong>of</strong> progressive renal insufficiency when the complexmultiorgan system derangements become clinically manifest. The termuremia was originally used because <strong>of</strong> the presumption that all <strong>of</strong> theabnormalities results from retention in the blood <strong>of</strong> end products <strong>of</strong>metabolism normally excreted in the urine. (15)The most likely toxins in uremia are the by-products <strong>of</strong> protein andamino acid metabolism. A number <strong>of</strong> such products have been identified

Introduction 6.(Table 1). The clinical symptoms <strong>of</strong> uremia correlate poorly with the bloodlevels <strong>of</strong> these products. This is because uremia involves more than renalexcretory failure alone. The metabolic and endocrine functions subservedby the kidney are also impaired, resulting in anemia; malnutrition; impairedmetabolism <strong>of</strong> carbohydrate, fats, and proteins, defective utilization <strong>of</strong>energy; and metabolic bone disease. (16)Table (1): Uremic “toxins” (16)By-products <strong>of</strong> protein and amino acid metabolismUrea-80% <strong>of</strong> total excreted nitrogenGuanidino compoundsGuanidineMethylguanidineDimethylguanidineCreatinineCreatineGuanidinosuccinic acidUrates and hippuratesEnd products <strong>of</strong> nucleic acid metabolismEnd products <strong>of</strong> aliphatic amine metabolismEnd products <strong>of</strong> aromatic amino acid metabolismTryptophanTyrosinePhenylalanineOther nitrogenous substancesPolyaminesMyoinositolPhenolsBenzoatesIndolesAdvanced glycation end productsInhibitors <strong>of</strong> ligand-protein bindingGlucuronoconjugates and aglyconesInhibitors <strong>of</strong> somatomedin and insulin action

Introduction 7.The pathophysiology <strong>of</strong> the uremic syndrome can be divided to:1- Abnormalities due to accumulation <strong>of</strong> products <strong>of</strong> protein metabolism.2- Abnormalities due to loss <strong>of</strong> the other renal functions, such as fluid andelectrolytes homeostasis and synthesis <strong>of</strong> certain hormones [e.g.erythropoietin (EPO), 1-25 dihydroxy cholecalciferol ]. (17)One <strong>of</strong> the major causes <strong>of</strong> the uremic toxicity is urea which maycontribute to some <strong>of</strong> the clinical abnormalities including anorexia,malaise, vomiting, and headache. Elevated levels <strong>of</strong> plasmaguanidinosuccinic acid, by interfering with activation <strong>of</strong> platelet factor IIIby ADP, lead to impairement in the platelet function in chronic renaldisease (CRD). Creatinine converts to metabolites such as sarconine andmethylguanidine. (18)Other nitrogenous compounds are also retained in CRD and maycontribute to morbidity and mortality in uremic patients. (19) accumulation <strong>of</strong>cytokines and growth factors in uremic plasma is due to decrease renalmass with subsequent decreased catabolism <strong>of</strong> the circulating plasmaproteins and polypeptides; (20) also there is increase in the plasma levels <strong>of</strong>many polypeptide hormones as parathyroid hormone(PTH), and prolactine.This is due to decrease excretion and increase glandular secretion. (21)PTH has an adverse effect <strong>of</strong> elevating cellular cytosolic Ca 2+ levelsin some tissues and organs, so its excessive level in CRD can be consideredan important “uremic toxin”. (22)

Introduction 8.Clinical and laboratory manifestations <strong>of</strong> chronic renalfailureThe clinical uremic syndrome manifestations usually appear whenthe GFR decline to

Introduction 9.The retained phosphate leads to secondary hyperparathyroidism in CRF,this occurs by decreasing renal production <strong>of</strong> calcitriol and by loweringplasma ionized calcium. The calcitriol exerts negative feed back control onthe parathyroid gland, leading to increase in the plasma calcium (bystimulation <strong>of</strong> intestinal absorption <strong>of</strong> Ca), and inhibiting parathormonesecretion. (26)The patients with CRF have a significantly low plasma calciumconcentration which is due to:• High level <strong>of</strong> phosphate (which form Ca- phosphate deposit in s<strong>of</strong>ttissues leading to declines in serum calcium concentrations).• Decrease intestinal absorption <strong>of</strong> Ca.• Vitamin D deficiency. The hypocalcemia is a potent stimulus to the PTHsecretion leading to hyperplasia <strong>of</strong> the parathyroid gland (secondaryhyperparathyroidism). (22)With progression <strong>of</strong> the chronic renal disease, the elevated PTHlevels adversely affect bone metabolism causing increase in the osteoclasticand osteoblastic activity leading to renal osteodystrophy. (27)Metabolic acidosis:In chronic renal failure, the kidneys are unable to produce enoughammonia in the proximal tubules to excrete the endogenous acid into theurine in the form <strong>of</strong> ammonium. (28) Manifestations <strong>of</strong> acidosis include;nausea, vomiting, anorexia, exercise intolerance, and abnormalities in themental status. (29)

Introduction 10.The metabolic acidosis affects metabolism in several organs; itcauses bone disease by increasing renal osteodystrophy by acceleratingskeletal mineral loss to buffer retained H + . (30)Metabolic acidosis, alsocontributes to glucose intolerance <strong>of</strong> uremia by causing insulin resistance,and induces protein catabolism. (31)Correction <strong>of</strong> metabolic acidosisresolves these effects and improve the nutritional status. (32)2- Cardiovascular manifestations:The patients with CRD have many <strong>of</strong> the cardiovascularabnormalities as hypertension, congestive heart failure, pericarditis,astherosclerosis <strong>of</strong> coronary and peripheral arteries, cardiac tamponade,hemorrhagic pericardial effusion. (33)3- Respiratory manifestations:Pleurisy, pulmonary oedema, pleural effusion, acidotic breathing. (34)4- Gastrointestinal manifestations:Anorexia, hiccough, nausea, and vomiting are the common earlymanifestations <strong>of</strong> uremia. Uremic fetor (uriniferous odor <strong>of</strong> the breath),unpleasent metallic taste sensation, gastritis, and peptic ulcer are commonin uremic patients. (35)5- Hematologic manifestations:A normocytic, normochromic anemia is present in the majority <strong>of</strong>patients with CRD. (36) Also those patients have abnormal hemostasis withtendency to spontaneous bleeding into the GIT.

Introduction 11.6- Neurological manifestations:Disturbances <strong>of</strong> the central nervous system function include inabilityto concentrate, drowsiness, insomnia, mild behavioral changes, loss <strong>of</strong>memory. In advanced CRD, peripheral neuropathy is a commonmanifestation. Neuromuscular manifestations include cramps,fasciculations, and twitching <strong>of</strong> the muscles, asterixis, myoclonus in theterminal uremia. (37)7- Musculoskeletal manifestations:Generalized myopathy, muscle cramps, osteodystrophy, which is acommon bone lesion in CRF. It include osteomalacia, osteoprosis, andosteitis fibrosa cystica, aplastic bone disease. (27)8- Endocrinal manifestations:Hyperparathyroidism, ammenorhea, impotence, infertility.9- Metabolic manifestations:Glucose metabolism is impaired and glucose intolerance is commonin uremic patients. Because the kidney contributes to insulin removal fromthe circulation, so plasma levels <strong>of</strong> insulin are elevated in most uremicpatients, so the insulin requirements decrease in the diabetic uremicpatients, however, insulin resistance may occur in CRD patients. (21)Hyperurecemia and gout are common in CRD. (38)

Introduction 12.10- Dermatologic manifestations:Pruritis, and excoriations, pallor (due to anemia), dryness,ecchymosis (due to defective hemostasis), uremic frost which is seen inadvanced uremia.11- Immunological manifestations:Enhanced susceptibility to infections due to impairment in theleukocytes formations and functions in uremia. Lymphocytopenia andatrophy <strong>of</strong> lymphoid structure occures. The coexisting acidosis,hyperglycemia, protein malnutrition, all lead to defect in the defensivemechanisms <strong>of</strong> the skin, and mucosa. So both humoral and cellularimmunity decrease with uremia. (39)12- Abnormalities in uremic lipoprotein metabolism and itsimpact on cardiovascular diseasePatients with end stage renal disease (ESRD) suffer from asecondary form <strong>of</strong> complex dyslipidemia which appears to be one <strong>of</strong> themajor risk factors. It consists <strong>of</strong> both quantitative and qualitativeabnormalities in serum lipoorotein resulting from alterations in lipoproteinmetabolism and composition. The predominant feature <strong>of</strong> uremicdyslipidemia is an increase in serum triglycerides levels. (40)Triglycerides are increased predominantly in the very low densitylipoprotein (VLDL) fraction, intermediate density lipoprotein (IDL), andlow density lipoprotein (LDL) triglyceride is also increased. High density

Introduction 13.lipoprotein (HDL) cholesterol is decreased whereas LDL and intermediate(IDL) density lipoproteins cholesterol are increased. These changes inlipoprotein composition occur early in the course <strong>of</strong> renal failure,suggesting that they are a consequence <strong>of</strong> renal failure and not aconsequence <strong>of</strong> treatment. (41)The lipid composition <strong>of</strong> each lipoprotein fraction is also abnormal.The triglyceride content <strong>of</strong> HDL and LDL is increased whereas cholesterolconcentration is increased in VLDL and chylomicron remnants. Theprotein content <strong>of</strong> each lipoprotein subfraction increases relative to lipidthus chronic renal failure is associated with an increased plasma level <strong>of</strong>apolipoprotein-rich, lipid-poor lipoproteins. (42)Lipoprotein(a)[LP(a)] has been identified as a prominent andindependent risk factor in atherogenesis in dialysis patients. (43)LP(a)consists <strong>of</strong> a molecule <strong>of</strong> LDL to which one molecule <strong>of</strong> the apolipoproteinapo(a) has been covalently attached to apo B100. The size <strong>of</strong> the apo (a)molecule in LP(a) is genetically determind and distributed in the populationin a non- normal fashion. (44)A majority <strong>of</strong> individuals have the largest apo(a) and the lowestplasma LP(a) concentration. LP(a) levels are increased in patients with avariety <strong>of</strong> renal diseases including CRF. Unlike inherited increases inplasma LP(a) levels, acquired increases in LP(a) are not associated withincreased apo(a)size. (45)

Introduction 14.Apo A-I and apo A-II are apolipopoteins secreted by liver andintestine and are found predominantly in HDL. Apo A-I correlatesinversely with atherosclerotic disease in patients and is necessary for theaction <strong>of</strong> lecithin cholesterol ester transferase (LCAT). ApoE is secreted bya variety <strong>of</strong> tissues and is recognized by both the remnant receptor in liverand the scavenger receptor in macrophages. ApoE is found on alllipoproteins. (46)Plasma apo A-I and apo A–II are decreased, and apoE is decreased inmen with CRF. Decreased apo A-I is in part a consequence <strong>of</strong> reducedsynthesis, since apo A-I is a necessary constituent <strong>of</strong> HDL, its reducedplasma concentration may cause the low HDL levels characteristic <strong>of</strong> CRF.Apo B, an apolipoprotein necessary for triglyceride-rich lipoproteins(VLDL and chylomicrons (CM)), may be elevated.Apo B 48, an is<strong>of</strong>orm only secreted by the intestine in humans, isincreased in the VLDL fraction, suggesting the presence <strong>of</strong> CM remmantparticles within the VLDL fraction. (47)All apo C lipoproteins are increased but the most important change isan increase in apo C-III relative to apo C-II leading to an increased apoC-III /apo C –II ratio. Apo Cs acts to either catalyze ( C-II) or inhibit (C-II)the action <strong>of</strong> liporotein lipase(LPL), the rate limiting enzyme hydrolyzingtriglycerides within CM and VLDL, and also inhibit the uptake <strong>of</strong> remantsby the liver. The changed apo C-III/C-II ratio should inhibit LPL and beimportant in the pathogenesis <strong>of</strong> hypertriglyceridemia in CRF. (48)

Introduction 15.Disordered lipoprotein metabolism in CRFAlthough triglyceride production may be increased in CRF,decreased catabolism predominates. Serum from patients inhibits LPL,suggesting the presence <strong>of</strong> a LPL inhibitor in CRF. (40) Together thesefindings provide a basis for reduced lipolysis <strong>of</strong> triglycerids richlipoproteins in CRF. VLDL is synthesized in the liver and catabolized onthe vascular endothelium (Figure 1). (49)Figure (1): Metabolism <strong>of</strong> VLDL (49)Processed VLDL remnants are released and then may be either takenup directly by the liver by a receptor that recognizes apoE, or furthermetabolized to LDL, and then taken up by the liver via the LDL receptor ,which targets apo B 100. CM are synthesized in the intestine and processedto remnants in much the same way as in VLDL, but are not processed toLDL and can not be a target for the LDL receptor because they carry theapo B 48 is<strong>of</strong>orm , one not recognized by the LDL receptor. Although CMthemselves have no significant risk for atherogensis, CM remnants areatherogenic. (49) Remnant particles accumulate extensively in plasma <strong>of</strong>CRF patients . (40)

Introduction 16.HDL plays a vital role in metabolism <strong>of</strong> both CM and VLDL.Mature HDL 2 is necessary for transport <strong>of</strong> the essential LPL c<strong>of</strong>actor, apoC-II to nascent VLDL and CM (Figure 2). (50) ApoC-II is recycled from CMand VLDL remnants by HDL 2 , without recycling, the action <strong>of</strong> LPL onthese large lipoproleins will be reduced. (50)Figure (2): Metabolism <strong>of</strong> chylomicrons (50)During hydrolysis <strong>of</strong> CM and VLDL, Discoid HDL is released inplasma (Figure 1). Discoid HDL is a liquid bilayer and only becomes aspherical lipoprotein by the action <strong>of</strong> LCAT (which is an enzyme thatesterifies free cholesterol), the cholesterol ester sink into the core <strong>of</strong> thelipid bilayer transforming it into small spherical HDL 3 particles. LCATalso act on HDL transforming it into layer HDL 2 molecules so discoid HDLparticles are structurally altered and hepatic cholesterol clearance islimited. Although all forms <strong>of</strong> HDL are reduced in CRF, HDL2 is the mostform <strong>of</strong> lipoprotein that is reduced in CRF providing another mechanismfor reduced lipolysis. (51)

Introduction 17.The change in HDL composition observed in CRF occur as aconsequence <strong>of</strong> LCAT deficiency and also due to reduced apo A-Isynthesis, both leading to reduction in HDL in CRF. (40) This altherogenicform <strong>of</strong> dyslipidemia is causes <strong>of</strong> cardiovascular diseases in patients withchronic renal failure this may be due to interference with deterioratingaspects <strong>of</strong> the activated acute-phase response. (52)Cardiovascular abnormalities in patients with endstage renal diseaseCardiovascular disease accounts for half the deaths in adults treatedwith maintenance dialysis and mortality from cardiovascular causes is farhigher than that in the general population. (53)Cardiovascular mortality for those treated with dialysis continues t<strong>of</strong>ar exceed that predicted by the combined risks attributable to age, sex,systolic blood pressure, left ventricular hypertrophy, serum total and HDLcholesterol, cigarette smoking and diabetes mellitus. (54) The risk <strong>of</strong>atherosclerotic cardiovascular disease in patients with chronic renal failure,especially patients on renal replacement therapy, has been shown to be10-20 times greater than in the general population. Therefore, patients withchronic renal disease should be considered in the highest risk group forsubsequent cardiovascular events and proper preventive measures shouldbe undertaken. (55) The care <strong>of</strong> chronic renal failure patients can not start inthe period <strong>of</strong> ESRD or after the initiation <strong>of</strong> dialysis but must be set into

Introduction 18.motion when progressive renal disease is diagnosed and renal failure firstbegins. Optimal treatment prevents detrimental influence <strong>of</strong> uremia on themetabolic balance, function, and structure <strong>of</strong> the body. Reduction <strong>of</strong> boththe “traditional” atherosclerosis risk factors as well as specific risk factorsrelated to CRF should be one <strong>of</strong> the main targets <strong>of</strong> early management <strong>of</strong>patients with chronic renal disease. (56)Risk factors <strong>of</strong> atherosclerosis in chronic renal diseaseSeveral risk factors for cardiovascular manifestation in chronic renaldisease patients are similar to the progression <strong>of</strong> atherosclerosis in thegeneral population because <strong>of</strong> the higher incidence <strong>of</strong> ESRD in elderly.Atherosclerosis is a multifactorial disease. The approach to the“traditional” cardiovascular risk factors like hypertension, diabetesmellitus, obesity, hyperlipidemia, oxidative stress, smoking, physicalinactivity should be guided by the principle that chronic renal diseasepatients belong to the highest risk group for subsequent cardiovascularcomplications. During the course <strong>of</strong> the renal disease progression excessrisk may appear that influence significantly the outcome. (57)Patients on HD typically have many risk factors associated with poorcardiac functions, which is caused by the hemodynamic and metabolicfactors like progressive proteinuria, hypoalbuminemia, malnutrition,electrolyte imbalance, hyperuricemia, high levels <strong>of</strong> fibrinogen, increasedextracellular volume, anemia, uremic toxins, hyperphosphatemia, lipidabnormalities, hypertension. (58)

Introduction 19.L-CarnitineCarnitine, is a low molecular weight compound (161.20) that wasfirst characterized in muscle extracts in 1905 and named from the latincarnis (flesh) because L-<strong>carnitine</strong> appeared to act as a vitamin in themealworm (tenebrio molitor), it was called vitamin B T . Vitamin B T turnedout to be a misnomer when scientists discovered that humans and otherhigher organisms synthesize L-<strong>carnitine</strong>. (59) The chemical structure laterwas shown to be 3- hydroxy – 4- (N- trimethyl-ammonio)butanoate, (60) andin 1962 the physiological form <strong>of</strong> L- <strong>carnitine</strong> was identified as theL-isomer, or levo<strong>carnitine</strong>, which is the only physiologically active form <strong>of</strong><strong>carnitine</strong>. (Figure 3) (61)CH 3- + OOCCH2 CHCH 2 N CH 3OH CH 3Figure (3): Structural formula <strong>of</strong> L-<strong>carnitine</strong> (61)L-<strong>carnitine</strong> is normally present in most human tissues, its majorsource (75%) come from the diet mainly, meat, poultry, fish, and dairyproducts being the richest sources <strong>of</strong> L-<strong>carnitine</strong>. Tempeh (fermented soyabeans) wheat, and avocados contain some L-<strong>carnitine</strong>, while fruits,vegetables and grains contain relatively little L-<strong>carnitine</strong>. The remaining(25%) <strong>of</strong> L-<strong>carnitine</strong> come from de novo synthesis, the average adultconsumes 30 to 50 mg <strong>carnitine</strong> per day. (62)The normal rate <strong>of</strong> L-<strong>carnitine</strong> biosynthesis in humans ranges from0.16 to 0.48 mg/ Kg <strong>of</strong> body weight / day. (59)Thus a 70 Kg person would synthesize from 11 to 34 mg/day.Omniverous diets have been found to provide 20 to 200 mg/day <strong>of</strong>

Introduction 20.L-<strong>carnitine</strong> for a 70 Kg person, while strict vegetarian diets may provide aslittle as 1 mg/day for 70 Kg person. This rate <strong>of</strong> synthesis combined withthe reabsorption <strong>of</strong> about 95% <strong>of</strong> the L-<strong>carnitine</strong> filtered by the kidneys isenough to prevent deficiency in generally healthy people, including strictvegetarians. (61)Some <strong>carnitine</strong> rich foods and their <strong>carnitine</strong> content in mg are listedin Table (2). (61)Table (2) (61) Food ServingL-<strong>carnitine</strong>(mg)Beef steak 3 ounces 81Gound beef 3 ounces 80Pork 3ounces 24Canadian bacon 3 ounces 20Milk ( whole) 1cup 8Fish( cod) 3 ounces 5Ice cream ½ cup 3Whole- wheat Bread 2 slices 0.2Avocado 1(medium) 2In mammals, <strong>carnitine</strong> is present as free <strong>carnitine</strong> and acylated<strong>carnitine</strong>; the latter are product <strong>of</strong> reactions that involve the transfer <strong>of</strong> acylgroups from acyl coenzyme A (CoA). These acyl groups vary in lengthfrom short chain (acetyl) to long chain (palmitoyl).Typically in healthy humans, approximately 80% to 85% <strong>of</strong> <strong>carnitine</strong>exist as the free form in plasma at concentrations <strong>of</strong> approximately 40µmol/L to 50 μmol/L in healthy adult men. (63) Plasma <strong>carnitine</strong> is low atbirth, the transplacental transport <strong>of</strong> <strong>carnitine</strong> or its precursors appears to beimportant for the formation <strong>of</strong> <strong>carnitine</strong> depot in the fetal life. After the first

Introduction 21.week, total plasma <strong>carnitine</strong> is progressively increasing till it reaches theadult level after the first year. (64) There is no sex difference in plasma<strong>carnitine</strong> during childhood and puberty up to 17 years <strong>of</strong> age, however inadult plasma total free and acyl <strong>carnitine</strong> are significantly higher in malesthan in females. (65)Carnitine present in the human diet is almost completely absorbed,the peak blood level is reached 2-4½ hours after L-<strong>carnitine</strong>administration. (66)Carnitine biosynthesisCarnitine is biosynthesized from the essential amino acids lysine andmethionine. In mammals, trimethyl lysine (mostly protein bound) acts as aprecursor for <strong>carnitine</strong> and this conversion is relatively rapid process. (67)Thus, the majority <strong>of</strong> body trimethyl lysine is present outside theliver mainly in the skeletal muscles, so 95% <strong>of</strong> <strong>carnitine</strong> is stored in theskeletal muscle and the myocardium, some is concentrated in the liver,kidneys (68) , sperms and the brain (hence its use in Alzheimer disease). (65)The sequence for <strong>carnitine</strong> biosynthesis from extra hepatictrimethllysine involves protein degradation to release free trimethyllysine,then conversion to trimethylammonio-butanoate (Y-butyrobetaine),followed by transport in the plasma with ultimate hydroxylation to<strong>carnitine</strong> in the liver (Figure 4). This later step serves as a regulatory pointin the <strong>carnitine</strong> synthesis pathway because the liver and kidney are themajor sites <strong>of</strong> <strong>carnitine</strong> production. (69) However, the rate <strong>of</strong> proteinturnover, which produces trimethllysine, is the limiting step in thebiosynthesis <strong>of</strong> <strong>carnitine</strong> (Figure 4). (70)

Introduction 22.COO -CHCH 2 CH 2 CH 2 CH 2 NH 2+ NH3 Lysine+3 S-Adenosylmethionine3 S-AdenosylmocysteineCOO -CH 3+CHCH 2 CH 2 CH 2 CH 2 N 3 S-AdenosylmocysteineCH 32-Oxoglutarate + O 2 Fe 2+ , Ascorbic acidSuccinate + CO 2COO -CH 3+CHCH(OH)CH 2 CH 2 CH 2 N NH 3NH 3 CH 3No-Trimethyl-3-hydroxylsinePyridoxal phosphate glysineCH 3+OHCCH 2 CH 2 CH 2 N NH 3CH 34-Trimethylaminobutyraldehyde- OOCCH2 CH 2 CH 2+ NCH 3NADNADH + H +NH 3CH 34-Trimethylaminobutyrate2-Oxoglutarate + O 2Fe 2+ , Ascorbic acidSuccinate + CO 2CH 3- + OOCCH2 CHCH 2 N CH 3OH CH 3CarnitineFigure (4): Synthesis <strong>of</strong> <strong>carnitine</strong> (70)

Introduction 23.Carnitine is turned over rapidly in the kidney, which is the main site<strong>of</strong> regulation <strong>of</strong> plasma <strong>carnitine</strong> concentration. It is excreated in the urineas free and acyl conjugates mainly as H-trimethylamine oxide and as H-butyrobetaine. (71)Free <strong>carnitine</strong> is filtered at the glomerulus and over 90% undergotubular reabsorption. In contrast renal tubular absorption <strong>of</strong> acyl<strong>carnitine</strong> islimited; as a result, the clearance <strong>of</strong> acyl<strong>carnitine</strong> is 4 to 8 times greaterthan that <strong>of</strong> free <strong>carnitine</strong>. This difference in clearance is consistent withthe concept that esterification with <strong>carnitine</strong> is a pathway for detox<strong>of</strong>icationand elimination <strong>of</strong> toxic acyl groups. (72)Functions <strong>of</strong> <strong>carnitine</strong>Carnitine has a very important role in fatty acid oxidation. In mammals,fatty acids are a primary source <strong>of</strong> energy in a number <strong>of</strong> systems, includingskeletal muscle and heart. Dietary fat is digested and transformed intotriglyceride for subsequent storage in adipose tissue, a process stimulated byinsulin. When required, stored triglycerdes are hydrolyzed to free fatty acidsand glycerol, this process <strong>of</strong> lipolysis is regulated by epinephrine andglucagon. Fatty acids are released into the circulation and transported tovarious tissues by attachment to albumin. Within the cell, fatty acids enter themitochondria through the <strong>carnitine</strong> system as acyl<strong>carnitine</strong> and aremetabolized by β- oxidation. In this pathway, energy is released, acetyl CoAis produced, and the fatty acid chain is shortened by two carbons with eachcycle. The released Acetyl-CoA then enters the citric acid cycle, during whichfurther energy is generated. (73)

Introduction 24.L-<strong>carnitine</strong> plays an important role in energy production bychaperoning activated fatty acids (acyl-CoA) into the mitochondrial matrix formetabolism and chaperoning intermediate compounds out <strong>of</strong> themitochondrial matrix to prevent their accumulation, so the main function <strong>of</strong>L-<strong>carnitine</strong> is in the mitochondria. It involves the reversible formation <strong>of</strong>acyl<strong>carnitine</strong>, which unlike acyl CoA is able to cross the mitochondrialmembrane. (74)1- Transport <strong>of</strong> long chain fatty acids into the mitochondrial matrixThe activation <strong>of</strong> long chain fatty acid to form Acyl CoA occurs in themicrosomal fraction <strong>of</strong> the endoplasmic recticulum on the outer surface <strong>of</strong> themitochondrial outer membrane. Acyl CoA then must traverse the outermembrane into the mitochondrial intermembrane space , an important processthat uses the voltage-dependent anion channel (porin). (75,76) Acyl CoA betweenthe outer and inner boundray membranes is converted to acyl<strong>carnitine</strong> by themalonyl-CoA- sensitive <strong>carnitine</strong> palmitoyl transferase I (CPT-I).Acyl<strong>carnitine</strong> next is transported across the mitochondrial inner membraneby a <strong>carnitine</strong>- acyl<strong>carnitine</strong> translocase, an important regulatory site that isresponsive to intramitochondrial <strong>carnitine</strong> content. (77)In the matrix,acyl<strong>carnitine</strong> acts as a substrate for <strong>carnitine</strong> palmitoyltransferase II (CPT-II),with resulting transfer <strong>of</strong> the acylgroup to CoA and the release <strong>of</strong> <strong>carnitine</strong>.AcylcoA then enters the fatty acid β- oxidation pathway. (Figure 5) (77)

Introduction 25.Figure (5): The mitochondrial <strong>carnitine</strong> system (77)2- Buffering <strong>of</strong> the short – chain acyl CoA – CoA ratioCarnitine can directly modulate the short – chain AcylCoA- CoAratio, implying that the system can transfer acyl group (as acyl<strong>carnitine</strong>derivatives) from one compartement to another in a tissue – and substrate –dependent fashion. (78) The main buffering action <strong>of</strong> <strong>carnitine</strong> occurs duringexercise, when acetyl<strong>carnitine</strong> accumulate at workload greater than thelactate threshold, but no change in skeletal muscle <strong>carnitine</strong> occurs. Under

Introduction 26.low – intensity exercise these increases in the acetyl<strong>carnitine</strong> – <strong>carnitine</strong>ratio reflect the increased production <strong>of</strong> acetyl CoA as a result <strong>of</strong> increasedpyruvate generation during high intensity exercise. (79) The accumulatedAcetyl CoA exceeds its utilization in the Krebs cycle, and it is thus toxic tothe cell and must be exported to the outside via <strong>carnitine</strong>. (80) Accumulation<strong>of</strong> propionate or its metabolic product propionyl CoA can disturb normalcellular metabolism by inhibiting short – chain fatty acid oxidation, as wellas other metabolic pathways. Carnitine can partly reverse this inhibition bygenerating propionyl <strong>carnitine</strong>, thereby decreasing propionyl CoAconcentrations and increasing the availability <strong>of</strong> free CoA. (81)3- Trapping and elimination <strong>of</strong> unphysiological acyl groupsThis is examplified by valproic acid (used in the treatment <strong>of</strong> epilepsy),which is converted to valproyl CoA, which in an exchange reaction forms<strong>carnitine</strong> esters. Acyl <strong>carnitine</strong>s unlike the corresponding acyl CoA derivativesdiffuse across the cell membrane. These are excreted in urine and so may leadto <strong>carnitine</strong> losses. (82) Under certain conditions where there is overproduction<strong>of</strong> long chain fatty acids, e.g., during prolonged muscular exercise. Rapidaccumulation <strong>of</strong> long chain acyl <strong>carnitine</strong> occurs. This return back to bloodstream causing a rise in its level in the post-exertional state. (83)Branched-chain amino acid metabolismCarnitine also has a role in the oxidation <strong>of</strong> BCAA, shown by itsability to enhance the oxidation <strong>of</strong> leucine and valine derivatives. (84)

Introduction 27.Extramitochondrial free <strong>carnitine</strong> rapidly interacts with matrix short – chainaliphatic acylCoAs generated from alpha- keto acids <strong>of</strong> branched – chainamino acids and pyruvate in the presence and absence <strong>of</strong> malate. Thiseffect appears to involve a mechanism similar to the buffering effect <strong>of</strong><strong>carnitine</strong> on other metabolic processes. (85)Carnitine transferasesCarnitine transferases represent important regulatory targets in fattyacid metabolism. There are three groups <strong>of</strong> transferases distinguishedprimarily by their substrate specificity, and localization, as shown in (Table 3). (86)Table (3): Carnitine acyltransferases and their subcellular localization (86)Enzyme Group Substrate Location1- Carnitine acetyl- transferase Short- chain acyl groups(C1-C4) with high activity inheart and musclemitochondriaInnermitochondrialmembraneCarnitinepalmitoyltransferase I(CPTI)Carnitine palmitoyltransferaseIICarnitine octanoyltransferase.Long- chain acyl groups(>C12) & inhibited bymalonyl CoA (so it isimportant regulatory step)Long chain acyl groupsMedium- chain acyl groups(C5-C12)OutermitochondrialmembraneInnermitochondrialmembrane.peroxisomes

Introduction 28.Role <strong>of</strong> <strong>carnitine</strong> in long chain fatty acid oxidationusing palmitate as an example1- Transfer <strong>of</strong> palmitoyl CoA through the outer mitochondrialmembrane to intermembrane space.2- Transfer <strong>of</strong> palmitoyl group from CoA <strong>carnitine</strong> using <strong>carnitine</strong>palmitoyl transferase (CPT-I) which is located on the outer surface <strong>of</strong>the inner mitochondrial membrane.3- Translocation <strong>of</strong> palmitoyl <strong>carnitine</strong> through the inner membraneusing the <strong>carnitine</strong> / acyl <strong>carnitine</strong> translocase which is an antiportsystem where palmitoyl <strong>carnitine</strong> is transported in the mitochondrialmatrix in exchange for <strong>carnitine</strong>.4- Trasnsfer <strong>of</strong> palmitoyl group from the palmitoyl <strong>carnitine</strong> to formpalmitoyl CoA using <strong>carnitine</strong> palmitoyl transferase II (CPT-II).5- Palmitoyl CoA enters the β- oxidation pathway at the long chainacyl CoA dehydrogenase point. (87)Other roles for <strong>carnitine</strong>:Carnitine has a protective role by removing long –chain acyl CoAsfrom cell membranes, thereby stabilizing them. Fatty acids oxidationmediated by <strong>carnitine</strong> is believed to be important component <strong>of</strong>gluconeogenesis. (69) Other functions for <strong>carnitine</strong> include energy storage insperm and macrophages and calcium transport. (88)

Introduction 29.Control <strong>of</strong> fatty acid oxidation:Fatty acids oxidation is completely dependent on <strong>carnitine</strong> and<strong>carnitine</strong> palmitoyl transferase I (CPT -I). Malonyl CoA (the product <strong>of</strong>CoA carboxylase and the first intermediate in fatty acid synthesis) inhibitsthe outer CPT- I and hence the fatty acid oxidation. In conditions <strong>of</strong>increased fatty acid oxidation and ketogenesis as in diabetes melitus,hyperthyroidism and fasting states, there is an increase in free fatty acidoxidation and long chain acyl <strong>carnitine</strong>. Malonyl CoA hence is decreasedand there is an increase in the delivery <strong>of</strong> fatty acid to the liver foroxidation. (89)Renal handling <strong>of</strong> <strong>carnitine</strong>Carnitine is an important intermediary in fat metabolism. Themetabolism <strong>of</strong> <strong>carnitine</strong> is disturbed in renal failure; as a result, free<strong>carnitine</strong> deficiency may be a significant problem, especially in patients onmaintenance dialysis.Because <strong>carnitine</strong> is a small water-soluble molecule, it is freelyexcreted in urine as free and variable acyl conjugates. (90)Free <strong>carnitine</strong> is filtered at the glomerulus and over 90% undergoestubular reabsorption. In contrast, renal tubular absorption <strong>of</strong> acyl<strong>carnitine</strong> islimited; as a result, the clearance <strong>of</strong> acyl<strong>carnitine</strong> is 4 to 8 times greaterthan that <strong>of</strong> free <strong>carnitine</strong>. (72)

Introduction 30.Carnitine homeostasis depends significantly on the glomerularfiltration <strong>of</strong> free <strong>carnitine</strong> and its reabsorption by renal tubules.As glomerular function declines with progressive kidney disease,plasma <strong>carnitine</strong> concentration is elevated. Further decrease in kidneyfunction lead to an accumulation <strong>of</strong> acyl<strong>carnitine</strong> in plasma. Also,incomplete fatty acids oxidation leads to accumulation <strong>of</strong> acyl<strong>carnitine</strong>.The combined effect for uremic patients who are not on dialysis therapy isthat increased levels <strong>of</strong> both free <strong>carnitine</strong> (FC) and total <strong>carnitine</strong> (TC) andmarkedly elevated concentrations <strong>of</strong> acyl<strong>carnitine</strong> (AC). The ratio <strong>of</strong>acyl<strong>carnitine</strong> (AC) to free <strong>carnitine</strong> (FC) is abnormally high. (91)Carnitine in hemodialysis patientsUnlike undialysed uremic patients, most hemodialysis (HD) patientsexhibit relative <strong>carnitine</strong> deficiency, which is manifested as subnormalplasma / serum FC concentrations (92) and diminished muscle stores. (93) Aswith uremic patients, hemodialysis (HD) patients have markedly elevatedAC levels, (Figure 6). (94) HD patients demonstrate an abnormally high ratio<strong>of</strong> asyl to free <strong>carnitine</strong>, an AC:FC ratio <strong>of</strong> greater than 0.40 indicates arelative FC deficiency (insufficiency); in normal patients the AC:FC ratiois approximately 0.19, while it is increased to 0.87 in hemodialysispatients. (95) Despite the abnormal <strong>carnitine</strong> fractions, most HD patients havenormal or decreased plasma concentration <strong>of</strong> TC. (96) The possible reasonsfor subnormal FC concentrations are included in Table (4). (95)

Introduction 31.Figure (6): Plasma <strong>carnitine</strong> pr<strong>of</strong>ile in HD patients and normal ranges (94)Table (4): Potential factors contributing to <strong>carnitine</strong> depletion in HDpatients (95)Decreased availabilityLow dietary intake <strong>of</strong> <strong>carnitine</strong>-rich food(meat and dairy products)Increased requirementsAbnormal fatty acid metabolismDecreased endogenous production <strong>of</strong> <strong>carnitine</strong>Nonselective dialytic losses (FC and AC)Dialytic lossesCarnitine is a small water soluble molecule that is well dialyzed;during one HD session, plasma concentrations <strong>of</strong> <strong>carnitine</strong> declined asmuch as 75%. (97) This rapid decrease is quickly corrected by transport <strong>of</strong><strong>carnitine</strong> from tissue stores ,which may lead to a decrease in muscle<strong>carnitine</strong> levels. (98) Muscle <strong>carnitine</strong> content 6 hours after HD remainedlower than predialysis concentrations. (99) Plasma levels <strong>of</strong> TC return topredialysis levels 6 hours after HD. (98) Although the TC lost during dialysisper week is similar to weekly urinary <strong>carnitine</strong> excretion in normal

Introduction 32.individuals, FC clearance by HD is greater than that <strong>of</strong> AC, a pattern thatis the reverse <strong>of</strong> normal urinary <strong>carnitine</strong> excretion, which may contributeto decrease in FC concentration. (100)Dialysis vintageL-<strong>carnitine</strong> deficiency progresses with dialysis vintage (duration <strong>of</strong>dialysis); significant negative correlation has been found between dialysisduration (vintage) and plasma FC concentration, (Figure 7); (101) as well asbetween months on dialysis and muscle <strong>carnitine</strong> content, (Figure 8). (102)Figure (7): Correlation between dialysis vintage and free <strong>carnitine</strong> levels in HD patients (101)Figure (8): Correlation between dialysis vintage and muscle <strong>carnitine</strong> levels in HD patients (102)

Introduction 33.Bazzi et al (99) found that patients undergoing HD for more than 10years had decreased muscle <strong>carnitine</strong>; this was not seen in patients who hadbeen on HD for less than 3 years. (99)Significant reductions in predialysis TC levels with dialysis vintagehave been documented as well. Over a 25-week period, Rodriguz-Segade etal (103) found a gradual decrease in serum TC levels, and Kudoh et al (92)documented a gradual reduction in predialysis plasma TC levels over a 2-years period. Older patients appear to be at greatest risk for <strong>carnitine</strong>deficiency; there is a significant negative correlation between serum FClevels and age. (104)Carnitine deficiencyCarnitine level is regulated by a number <strong>of</strong> processes. Amongst theseare the endogenous biosynthesis from lysine and methionine, intestinalabsorption, renal excretion and catabolism in the body. Carnitine deficiencycould be defined as decrease in intracellular free <strong>carnitine</strong> levels leading toinhibition <strong>of</strong> acyl transport via the inner mitochondrial membrane and theaccumulation <strong>of</strong> acyl CoA. (105) This may lead to the following:1- Intracellular free <strong>carnitine</strong> becomes too low to sustain mitochondrialfatty acid oxidation. Glycogen and glucose becomes the preferredsubstrates for energy production leading to hypoglycemia.2- Intracellular free <strong>carnitine</strong> become too low to enable acetyl CoAexport from the mitochondria to cytosol via <strong>carnitine</strong> transport system.3- Increased acyl CoA ester leads to inhibition <strong>of</strong> ATP production. (106)Carnitine deficiency is divided into:1- Primary <strong>carnitine</strong> deficiency.2- Secondary <strong>carnitine</strong> deficiency.

Introduction 34.Primary <strong>carnitine</strong> deficiencyThe primary <strong>carnitine</strong> deficiency could be defined by the following criteria:• The metabolic disorder is caused directly by inadequate tissueconcentration <strong>of</strong> <strong>carnitine</strong>.• It is accompanied by impaired fatty acid oxidation.• It is corrected when <strong>carnitine</strong> concentration is restored to normal.• It is not secondary to a defect <strong>of</strong> mitochondrial β-oxidation.The possible aetiologies for primary <strong>carnitine</strong> deficiency:1- Defective biosynthesis and dietary intake.2- Defective intestinal absorption.3- Defective transport affecting uptake and / or release <strong>of</strong> <strong>carnitine</strong>from the tissues.4- Renal loss due to decreased tubular reabsorption or increasedexcretion. (40)There are two forms <strong>of</strong> primary <strong>carnitine</strong> Deficiency:1- Myopathic.2- Systemic.Primary myopathic <strong>carnitine</strong> deficiency:It is characterized by progressive muscle weakness & wastinglimited to skeletal and cardiac muscles. The symptoms <strong>of</strong> myopathic<strong>carnitine</strong> deficiency include muscle pain and progressive weakness,symptoms may begin in childhood or adulthood.

Introduction 35.There is accumulation <strong>of</strong> lipids in the muscle fibers and low <strong>carnitine</strong>in the skeletal muscles and serum – L <strong>carnitine</strong> levels are generally normal.It may be due to defect in the <strong>carnitine</strong> importing protein in the plasmamembrane <strong>of</strong> skeletal muscles. This results in failure <strong>of</strong> <strong>carnitine</strong> transportmechanism into the muscle, the primary myopathic <strong>carnitine</strong> deficiency istransmitted as autosomal recessive trait. (107)2- Primary systemic <strong>carnitine</strong> deficiency:It is genetic disorder that is usually detected in infancy or earlychildhood. It is characterized by low serum L–<strong>carnitine</strong> levels and ifuntreated may result in life – threatening damage to the liver, heart, orbrain. It is also known as <strong>carnitine</strong> carrier deficiency, the underlying causeis a mutation in the gene coding for the protein that transports L-<strong>carnitine</strong>into cells. As a result <strong>of</strong> this defect, intestinal absorption <strong>of</strong> dietary L-<strong>carnitine</strong> is poor and reabsorption by the kidney is impaired, resulting inincreased urinary loss <strong>of</strong> L-<strong>carnitine</strong>. (108)Secondary <strong>carnitine</strong> deficiencyIt may be hereditary or acquired, in all cases they are characterizedby decreased availability <strong>of</strong> free L-<strong>carnitine</strong>. In such cases, total L-<strong>carnitine</strong>levels may be normal, but free L-<strong>carnitine</strong> levels are decreased.Hereditary causes:It includes genetic defects in amino acids degradation, so there isincreased excrtion <strong>of</strong> acyl <strong>carnitine</strong> in urine resulting in secondary <strong>carnitine</strong>

Introduction 36.deficiency; the more common is propionic aciduria, methlymalonicaciduria and glutaric aciduria. (109)Increased L-<strong>carnitine</strong> loss:Haemodialysis, fanconi syndrome, and the metabolism <strong>of</strong> somemedications as after therapy with valproate (anticonvulsant) andpivampicillin, pivamecillinam and pivcephaexin) also zidovudine (AZT),didanosine (ddI), Zalcitabine (ddc), stavudine (dut) that are used intreatment <strong>of</strong> HIV infection may result in substantial L-<strong>carnitine</strong> loss,resulting in L- <strong>carnitine</strong> deficiency. (89,110)Insufficient L-<strong>carnitine</strong> synthesis:Due to deficient supply <strong>of</strong> L-<strong>carnitine</strong> and its precursors amino acids(methionine and lysine) in the diet, also malabsorption syndromes mayincrease the risk <strong>of</strong> secondary <strong>carnitine</strong> deficiency. (111)Defective hepatic synthesis:Due to hepatic impairment, since the liver is the main part for<strong>carnitine</strong> synthesis. So any alterations in the hepatic functions will beassociated with change in the plasma <strong>carnitine</strong>. (112)Nutrient interactions:The synthesis <strong>of</strong> L-<strong>carnitine</strong> is catalyzed by the concerted action <strong>of</strong>five different enzymes. This process requires two essential amino acids(lysine and methionine), iron (Fe 2+ ), vitamin C, vitamin B 6 , and niacin inthe form <strong>of</strong> nicotinamide adenine dinucleotide (NAD).

Introduction 37.One <strong>of</strong> the earliest symptoms <strong>of</strong> vitamin C deficiency is fatigue,thought to be related to decreased synthesis <strong>of</strong> L- <strong>carnitine</strong>. (113)Clinical features <strong>of</strong> <strong>carnitine</strong> deficiency:Dialysis patients suffer from many complications which are similarto those observed with <strong>carnitine</strong> deficiency.Skeletal myopathies:Skeletal myopathies associated with abnormal <strong>carnitine</strong> metabolisminclude; muscle fatigue, weakness, cramps/ aches, and abnormal histology.These are common complications in HD patients; intradialytic musclecramps may occur in as many as 86% <strong>of</strong> patients. (114) HD patients withmuscle symptoms exhibit a significantly lower level <strong>of</strong> FC (Figure 9a) (101) ,and a higher AC:FC ratio (Figure 9b) (101) , than those without symptoms. (101)Figure (9): Difference in (A) free <strong>carnitine</strong> levels and (B) AC:FC ratio in HD patients (101)Exercise performance:HD patients have severely limited exercise capacity and a low peakoxygen consumption. These limitations are seen even in those patients withnormal cardiac and pulmonary function and normal hematocrit, suggesting

Introduction 38.that the defect is at the level <strong>of</strong> skeletal muscle. (115) There is a positivecorrelation between endogenous muscle <strong>carnitine</strong> content and maximalexercise capacity in HD patients (Figure 10) (102) ; exercise duration wasreduced by 50% in <strong>carnitine</strong>- deficient patients. (102)Figure (10): Correlation between exercise capacity and muscle stores in HD patients (102)Cardiac dysfunction:Cardiovascular disease is a significant cause <strong>of</strong> mortality andaccounts for as many as 50% <strong>of</strong> deaths in dialysis patients. (116) Inheritedsystemic <strong>carnitine</strong> deficiency (non-ESRD) causes familial cardiomyopathy. (117)It was found that there is subnormal levels <strong>of</strong> FC in ischemic heart diseaseand heart failure. (118)Secondary <strong>carnitine</strong> deficiency is associated with dialysis-resistantcardiomegaly; plasma free <strong>carnitine</strong> levels in patients on chronic HD weremarkedly reduced and inversely correlated with cardiothoracic ratio(Figure 11). (93) There is also a significant association between low FCconcentration and reduced ejection fraction (Figure 12). (91)

Introduction 39.Figure (11): Inverse correlation between plasma free <strong>carnitine</strong> levels andcardiothoracic ratio in HD patients (93)Figure (12): Correlation between ejection fraction and plasma free <strong>carnitine</strong> levels in HD patients (91)Intradialytic complications:One <strong>of</strong> the most common complications during HD is hypotension.Riley et al (104) found significantly lower serum levels <strong>of</strong> TC and FC in welldialyzedHD patients with intradialytic hypotension episodes (a decrease <strong>of</strong>more than 15 mm/ Hg) compared to HD patients without these episodes(Table 5). (104)

Introduction 40.Table (5): Serum <strong>carnitine</strong> levels in patients with (n = 8) and without(n = 23) intradialytic hypotension (104)Without hypotensionWith hypotensionTotal <strong>carnitine</strong> (TC)(µmol/L)Free <strong>carnitine</strong> (FC)(µmol/L)27.0±2.7 18.4±2.2 a18.8±2.0 10.9±1.7 ba p < 0.05b p < 0.01Rehabilitation:Riley et al (104) also found a significant correlation between a reducedKarn<strong>of</strong>sky score (an indicator <strong>of</strong> functional status ) and increased AC: FCratio (Figure 13). (104) The low functional status in patients with reducedserum <strong>carnitine</strong> levels may be linked to poor cardiac function and/or poormuscle function.Figure (13): Relationship between Karn<strong>of</strong>sky Activity Scale score and acyl: free<strong>carnitine</strong> ratio in HD patients (104)

Introduction 41.Anemia:While the most important cause <strong>of</strong> anemia in dialysis patients isdecreased erythropoietin (EPO), evidence is mounting that <strong>carnitine</strong> alsoplays a role. Lower TC and FC levels have been found in HD patients withanemia compared to those without. Kooistra et al (119) found that patientswith lower TC levels required higher EPO doses to maintain a hematocrit<strong>of</strong> 30 or more (Figure 14). (120) A significant inverse correlation has alsobeen reported between FC levels and EPO dosage. (120) These studiessuggest that <strong>carnitine</strong> deficiency contributes to anemia and may be one <strong>of</strong>the causes <strong>of</strong> relative EPO resistance.Figure (14): Relationship between required dose <strong>of</strong> rHuEPO and total <strong>carnitine</strong> levelsin HD patients (120)Carnitine as a therapeutic agentL-<strong>carnitine</strong> therapy has been used as a therapy for treatment andprevention <strong>of</strong> some diseases that involve both primary and secondary<strong>carnitine</strong> deficiency. (121) Treatment with L-<strong>carnitine</strong> can be used as anadjuvant therapy in the following conditions:

Introduction 42.• Myocardial infarction:Myocardial infarction (MI) occurs when atherosclerotic plaque in acoronary artery ruptures. The resultant blood clot can obstruct the bloodsupply to the heart muscle, causing injury or damage to the heart.L-<strong>carnitine</strong> treatment has been found to reduce injury to the heart muscleresulting from ischemia. (122)• Heart failure:Impairment <strong>of</strong> the heart’s ability to pump enough blood for all thebody’s needs is known as heart failure. In coronary artery disease, theaccumulation <strong>of</strong> atherosclerotic plaque in the coronary arteries may preventparts <strong>of</strong> the heart muscle from getting adequate circulation, ultimatelyresulting in damage and impaired pumping ability. Myocardial infarction(MI) may also damage the heart muscle, resulting in the development <strong>of</strong>heart failure. Because physical exercise increases the demand on theweakened heart, measures <strong>of</strong> exercise tolerance are frequently used tomonitor the severity <strong>of</strong> the heart failure. Echocardiogaphy is also used todetermine the left ventricular ejection fraction (LVEF), an objectivemeasure <strong>of</strong> the heart’s pumping ability.An LVEF <strong>of</strong> less than 40% is indicative <strong>of</strong> systolic heart failure. (123)The addition <strong>of</strong> L-<strong>carnitine</strong> to the standard medical therapy for heart failurespecially in patients with higher LVEF values (greater than 30%), exercisetolerance was significantly improved, with significant decrease in leftventricular size. (124)

Introduction 43.• Angina pectoris:The addition <strong>of</strong> L-<strong>carnitine</strong> to the pharmacologic therapy forchronic stable angina has been found to improve exercise tolerance anddecrease the time required for exercise- induced ST segment changes toreturn to baseline. (125)Intermittent claudication in peripheral arterial diseaseIn peripheral arterial disease, atherosclerosis <strong>of</strong> the arteries supplyingthe lower extensities may diminish blood flow to the point that it isinsufficient to supply the metabolic needs <strong>of</strong> exercising muscles, leading toischemic leg or hip pain known as claudication. (126)Administration <strong>of</strong> L-<strong>carnitine</strong> in these patients significantly increasesthe maximal walking distance and the distance walked prior to the onset <strong>of</strong>claudication in patients whose initial maximal walking distance was lessthan 250 meters. (127)• Alzheimer’s disease (dementia):It was found that some patients with early-onset Alzheimer’s disease(65 years and younger) experienced more rapid cognitive decline that wassignificantly slowed by L-canitine treatment. (128)• HIV/AIDS:One <strong>of</strong> the hallmarks <strong>of</strong> infection with the retrovirus, HIV, is aprogressive decline in the numbers <strong>of</strong> CD4T lymphocytes (CD4cells),ultimately leading to the development <strong>of</strong> AIDS. Lymphocytes <strong>of</strong> HIV-

Introduction 44.infected individuals inappropriately undergo programmed cell death(apoptosis).L-<strong>carnitine</strong> supplementation increases CD4 cell counts significantlyand markers <strong>of</strong> lymphocytes apoptosis decreased, although there was nosignificant change in plasma levels <strong>of</strong> HIV virus (viremia). (129)Some antiretroviral agents (nucleoside analogues) used to treat HIVinfectionappear to cause a secondary L-<strong>carnitine</strong> deficiency that may leadto their toxic side effects. (130) It was found that the nerve concentration <strong>of</strong> L-<strong>carnitine</strong> was significantly lower in HIV patients who developed peripheralneuropathy while taking nucleioside analogues. (131)Patients with painful neuropathies show improvement withL-<strong>carnitine</strong> supplementation, so it may be a beneficial adjuvant toantiretroviral therapy in some HIV-infected individuals. (132)• Decreased sperm motility:L-<strong>carnitine</strong> is concentrated in the epididymis, where sperms matureand acquire their motility. (133) It was found that L-<strong>carnitine</strong> supplementationresulted in significant improvement in sperm motility. (134) It was also foundthat L-<strong>carnitine</strong> concentrations in semen were positively correlated with thenumber <strong>of</strong> sperm, the percentage <strong>of</strong> motile sperm, and the percentage <strong>of</strong>normal appearing sperm in the sample, (135) suggesting that measuringL-<strong>carnitine</strong> levels in semen may be useful in the evaluation <strong>of</strong> maleinfertility.

Aim <strong>of</strong> the Work 45.AIM OF THE WORKThe aim <strong>of</strong> this work is to study the effect <strong>of</strong> the L-<strong>carnitine</strong>deficiency on the left ventricular functions as well as evaluation <strong>of</strong> thetherapeutic efficacy <strong>of</strong> L-<strong>carnitine</strong> supplementation on left ventricularfunctions and lipid pr<strong>of</strong>ile in hemodialysis patients.

Subjects 46.SUBJECTSThis study was carried out on 50 patients and 10 healthy control,subjects are classified into three groups as follow:Group I (G I):10 patients with chronic renal insufficiency on conservative medicaltreatment with GFR 20-50 ml / mint. They didn’t receive L-<strong>carnitine</strong>supplementation.Group II (G II):It includes 40 patients with ESRD on regular maintenancehemodialysis for more than 6 months, the dialysis schedule was 4 hours, 3-times/ week. This group was divided into 2 subgroups (a) & (b).G II (a):Include 20 patients with ESRD on regular dialysis and receive oralL-<strong>carnitine</strong> supplementation at a dose one-g/ day for 6 months. This groupsubdivided into GIIaS 1 (patients on HD before receiving L-<strong>carnitine</strong>supplementation) and GIIaS 2 (patients on HD after receiving L-<strong>carnitine</strong>supplementation).G II (b):Include 20 patients with ESRD on regular dialysis who didn’treceive L-<strong>carnitine</strong> supplementation.

Subjects 47.Group III:Include 10 normal persons as a control group.N.B:Patients <strong>of</strong> G II were maintained on regular hemodialysis in thenephrology unit in the Alex University Students Hospital.N.B:Patients suffering from diseases that would affect the myocardialfunctions were excluded from the study as:• Diabetes mellitus.• Ischemic heart diseases.• Extensive myocardial calcifications.• Arrhythmias specially atrial fibrillation.• Hyperlipidemia.• Significant valvular lesions.

Methods 48.METHODSAll patients were subjected to the following:I- Detailed history taking:Stressing on the possible cause <strong>of</strong> renal failure.II- Clinical examination:III- Routine laboratory investigations:• Blood urea (136) , serum creatinine. (137)• Creatinine clearance (A = body surface area (m 2 )u × v 1.73 × ). (138)P A• Serum albumin & total proteins. (139)• Serum uric acid. (140)• Serum sodium and serum potassium. (141)• Serum triglycerids and serum LDL, HDL cholesterol. (142)• Complete blood picture; RBc, WBc, Platelets, Hb level, Hct. (143)IV- Electrocardiogram.V- Echocardiogram: to assess the left ventricular dimensions andfunctions, including:1- Left ventricular- end diastolic dimensions (LVEDd).2- Left ventricular –end systolic dimensions (LVESd).3- Left ventricular systolic functions.• Ejection fraction (EF).

Methods 49.• Fractional shortening (FS).4- Left ventricular diastolic functions.• Peak velocity <strong>of</strong> early filling (E) / peak velocity <strong>of</strong> late filling (A).• E- integral (Ei).• A-integral (Ai).• Ei /Ai ratio.5- Left ventricular mass.VI- Estimation <strong>of</strong> serum L-<strong>carnitine</strong> level:We estimated the serum level <strong>of</strong> L- <strong>carnitine</strong> in all the studiedgroups, in group IIa and group IIb, the sample was taken predialysis. Weused the spectrophotometric–kinetic method, The concentration <strong>of</strong> L-<strong>carnitine</strong> in serum was measured using L-<strong>carnitine</strong> enzymatic U-V test.Roche Diagnostics GmbH Germany. (144,145)The following reagents were used:(1) 3 X 0.7 co-enzyme buffer/mixture:• Lyophlizate.• Consisting <strong>of</strong> tris buffer, pH 7.0 NADH, 5mg, ATP, 6mg;Acetyl-coenzyme A, 4mg; PEP, 3mg; Magnesium acetate andstabilizers.(2) 3 ml enzyme suspension, consisting <strong>of</strong>;• Acetyl-CoA synthetase approx. 2 U.• Myokinase approx. 160 U.• Lactate dehydrogenase approx. 240 U.• Pyruvate kinase approx. 240 U.(3) 0.2 ml enzyme suspension <strong>carnitine</strong> acetyl transferase approx. 60U

Methods 50.(4) L-<strong>carnitine</strong> standard solution approx. 100mg/l.(5) Detergent solution.Principle:L-<strong>carnitine</strong> is acetylated to acetyl <strong>carnitine</strong> by acetyl coenzyme A(acetyl CoA) in the presence <strong>of</strong> the enzyme <strong>carnitine</strong> acetyl transferase(CAT). The resulting Co A is acetylated back to acetyl CoA in the presence<strong>of</strong> adenosine-5 ’ -triphosphate (ATP) and acetate. Catalyzed by the enzymeacetyl CoA synthetase (ACS). This results in the formation <strong>of</strong> adenosine-5 ’ -monophosphate (AMP) and inorganic pyrophosphate (PPi). In the presence<strong>of</strong> ATP, supported by myokinase (MK) AMP forms twice the amount <strong>of</strong>adenosine-5 ’ -diphosphate (ADP). This is converted in the followingreaction with phosphoenol pyruvate (PEP) in the presence <strong>of</strong> pyruvatekinase(PK). The pyruvate formed is reduced to L-lactate by reducednicotinamid adenine dinucleotide (NADH) in the presence <strong>of</strong> lactatedehydrogenase (LDH).The amount <strong>of</strong> NADH consumed during the reaction is equivalent tohalf the amount <strong>of</strong> L- <strong>carnitine</strong>. NADH is the parameter to be measured, Itis determined on the basis <strong>of</strong> its absorption at 334 (Hg)nm., 340 or365(Hg) nm.(1) L- carnirtine + acetyl CoA ⎯ CAT ⎯ →acetyl <strong>carnitine</strong> + CoA(2) CoA + ATP + acetate ⎯ ACS ⎯ →acetyl CoA + AMP +PPi(3) AMP +ATP ⎯ MK ⎯→2ADP(4) 2ADP + 2PEP ⎯ PK ⎯→2ATP + 2 pyruvate(5) 2 pyruvate + 2 NADH + 2 H + ⎯ LDH ⎯⎯ →2 L- lactate + 2 NAD

Methods 51.Reference values:Serum: 6.9mg/L or 43 µM.Preparation <strong>of</strong> serum or plasma samples:The samples was first deproteinized as follows:• 1 ml perchloric acid solution (0.6M) was pipeted into 10 ml centrifugedtubes.• It was mixed properly, and kept in an ice bath for 10 min, thencentrifuged at 3000 x g for 10 min.• 1 ml <strong>of</strong> the supernatant was pipetted into a fresh centrifuge tube.• 200 µl potassium carbonate solution (approx. 1.2M) was added.• It was mixed properly and kept in an ice-bath for 20 min.• Then centrifuged at 3000 x g for 5 min.• The supernatant was pipetted into fresh tube.Protocol:The following steps were done at temperature 20- 25 °C, andmeasured against air, WL 340

Methods 52.(1) The following solutions were pipetted into cuvettes:Reagent Blank Sample StandardCoenzyme buffer/mixture 1ml 1 ml 1mlSerum Sample - 500µl -L-<strong>carnitine</strong> standard solution - - 100µlEnzyme suspension 100µl 100µl 100µlDouble distilled water 1.1 ml 600µl 1ml(2) They were mixed by stirring spatula.(3) The absorbances <strong>of</strong> the solution (A 1 ) were measured after 10 min.(4) The reaction was started by the addition <strong>of</strong> 5 µl <strong>of</strong> <strong>carnitine</strong> acetyltransferase suspension.(5) Then mixed by stirring spatula.(6) 30 min after the enzyme suspension was added, the absorbances <strong>of</strong> thesolutions was measured in quick succession (A 2 ).(7) 10 min later, the absorbances was measured again (A 3 ).Absorbance difference:• Absorbance difference <strong>of</strong> the blank =(A 1 – A 2 ) blank –3 x (A 2 -A 3 ) blank’ =(ΔA blank ).• Absorbance difference <strong>of</strong> the sample =(A 1 -A 2 ) sample –3 x (A 2 -A 3 ) sample =(ΔA sample ).

Methods 53.The absorbance difference <strong>of</strong> the blank was subtracted from theabsorbance difference <strong>of</strong> the sample to obtain? A.Calculation:(1) General calculation:According to the general equation for reactions in which the amount<strong>of</strong> NADH consumed is equivalent to half the amount <strong>of</strong> substrate, theconcentration is calculated by:V × MW × FC = × ΔA (mg / L)ε × d × v × 2V= final volume (ml)v= sample volume (ml)MW= molecular weight <strong>of</strong> the substance to be assayed (g /mol)d= path length (cm)ε= absorbance coefficient <strong>of</strong> NADH at 340 nm= 6.3 (L x mmol -1 x cm -1 )F= dilution factor(2) For serum sample, the L-<strong>carnitine</strong> concentration is:C =2.205×161.2×2.346.3×1×0.5×2× ΔAC =831.7× ΔA6.3C = (mg L-<strong>carnitine</strong> / L sample solution)

Results 54.RESULTSI- Demographic dataAge and sex distributionAge and sex distribution study was carried out on 50 patientsdistributed in 3 groups as follows:• In group I: it included 10 patients they were 7 males and 3 females, theirages ranged from 20-50 years with mean age <strong>of</strong> 34.1±10.35.• In group II: it included 40 patients in 2 subdivided groups:- Group IIa: included 20 patients they were 11 males and 9 females,their ages ranged from 22-55 years with a mean <strong>of</strong> 39.75±10.32.- Group IIb: included 20 patients they were 8 males and 2 females, theirages ranged from 19-49 years with a mean <strong>of</strong> 31.85±9.92.• Group III: It included 10 healthy control they were 4 males and 6females their ages ranged from 18-45 years with a mean <strong>of</strong> 30.7±9.96.There is no significant difference between the studied groups asregards age and sex.

Results 55.Table (6):Age and sex distribution <strong>of</strong> group I, II in comparison with thecontrol (group III)Age“years”RangeMeanS.D.FpSexMaleFemaleX 2pGroup III Group I Group IIb Group IIa18-45 20-50 19-49 22-5530.7 34.1 31.85 39.759.96 10.354 9.928 10.321.850.35, N.S.4 (40.0%) 7 (70.0%) 8 (40.0%) 11 (55.0%)6 (60.0%) 3 (30.0%) 12 (60.0%) 9 (45.0%)3.000.39, N.S.NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementation

Results 56.5039.754030.734.131.85Mean3020100Group III Group I Group IIb Group IIaAgeMaleFemale%807060504030201007060605540404530Group III Group I Group IIb Group IIaSexFig. (15) :Demographic data <strong>of</strong> the different studied groups.

Results 57.II- Laboratory investigations1- Hemoglobin level (g/dl)• In group I, hemoglobin level ranged from 6.5-9.5 g/dl with a mean <strong>of</strong>7.77±1.02g /dl.• In group II b, hemoglobin level ranged from 5.2-10.1 g/dl with a mean <strong>of</strong>7.57±1.312 g/dl.• In group II a S 1 , hemoglobin level ranged from 5.3-11.1 g/dl with a mean<strong>of</strong> 7.79±1.49g /dl.• In group IIaS 2 , hemoglobin level ranged from 9.3-12.1g /dl with a mean<strong>of</strong> 11.023±1.18g /dl.• In group III, hemoglobin level ranged from 12-16g /dl with a mean <strong>of</strong>14.06±2.23g /dl.It was observed that, there is significant differences between thestudied groups as (F = 9.88) (p = 0.003).2- Red blood cells (×10 6 /mm 3 )• In group I, the RBC ’ s ranged from 1.85-3.5 with a mean <strong>of</strong> 2.62±0.49.• In group IIb, the RBC ’ s ranged from 1.85-6.75 with a mean <strong>of</strong>3.90±0.526.• In group IIa S 1 , the RBC’s ranged from 2.1-8.3 with a mean <strong>of</strong> 3.2±1.48.• In group IIaS 2 , the RBC’s ranged from 3.7-5.9 with a mean <strong>of</strong>4.22±0.91.

Results 58.• In group III, the RBC’s ranged from 3.5-5.7 with a mean <strong>of</strong> 4.1±098.It was observed that, there is significant statistical differencebetween the studied groups as (F = 9.82) (p = 0.02).3- White blood cells (×10 6 /mm 3 )• In group I, the WBC’s ranged from 3.6-6.8 with a mean <strong>of</strong> 5.13±1.97.• In group IIb, the WBC’s ranged from 4.0-5.4 with a mean <strong>of</strong> 4.92±1.003.• In group IIaS 1 , the WBC’s ranged from 3.7-5.6 with a mean <strong>of</strong>4.655±1.33.• In group IIaS 2 , the WBC’s ranged from 4.2-6.8with a mean <strong>of</strong>5.46±1.11.• In group III, the WBC’s ranged from 4.1-6.0 with a mean <strong>of</strong> 5.3±0.98.It was observed that, there is no significant statistical differencesbetween the studied groups as regarding the WBC’s count (F = 1.98) (p = 0.43).4- Platelets (×10 6 /mm 3 )• In group I, the platelets ranged from 201-293 with a mean <strong>of</strong>263.10±28.47.• In group IIb, the platelets ranged from 237-380 with a mean <strong>of</strong>189.30±72.848.• In group IIaS 1 , the platelets ranged from 230-381 with a mean <strong>of</strong>197.25±71.32.

Results 59.• In group IIaS 2 , the platelets ranged from 141-350 with a mean <strong>of</strong>228.2±53.80.• In group III, the platelets ranged from 248-440 with a mean <strong>of</strong>304.2±53.56.It was observed that, there is significant statistical differencesbetween the studied groups as (F= 20.32) (p = 0.0001).5- Hematocrit (Hct) %• In group I, the Hct ranged from 18.7-28 with a mean <strong>of</strong> 23.68±3.52.• In group IIb, the Hct ranged from 14.2-31.1 with a mean <strong>of</strong> 22.24±5.148.• In group IIaS 1 , the Hct ranged from 13.5-30.1 with a mean <strong>of</strong>23.505±4.67.• In group IIaS 2 , the Hct ranged from 21.5-32.1 with a mean <strong>of</strong>28.25±3.25.• In group III, the Hct ranged from 25-35 with a mean <strong>of</strong> 29.55±2.93.It was observed that, there is significant statistical differencesbetween the studied groups as regarding Hct as (F = 16.5) (p = 0.002).

Results 60.Table (7): Blood picture <strong>of</strong> the different studied groups.RBCs(x10 6 /mm 3 )RangeMeanS.D.F,pWBCs(x10 3 /mm 3 )RangeMeanS.D.F,pHb (gm/dl)RangeMeanS.D.F,pGroupIII3.5-5.74.1 a0.984.1-6.05.30.9812.0-16.014.06 a2.23GroupI1.85-3.52.62 b0.493.6-6.85.131.976.5-9.57.77 b1.02GroupIIb1.85-6.753.90 b0.5269.82,0.02*4.0-5.44.921.0031.98,0.43 N.S.5.2-10.17.57 b1.3129.880.003*GroupIIas 12.1-8.33.2 ab1.483.7-5.64.6551.335.3-11.17.79 b1.49GroupIIas 23.7-5.94.22 a0.914.2-6.85.461.119.3-12.111.023 c1.18• NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementation

Results 61.Table (7) Cont.: Blood picture <strong>of</strong> the different studied groups.Platelet(x10 3 /mm 3 )FpRangeMeanS.D.Hct (%)FpRangeMeanS.D.GroupIII248-440304.2 a53.5625-3529.55 a2.93GroupI201-293263.10 b28.4718.7-2823.68 b3.52GroupIIb237-380189.30 c72.84820.32,0.0001*14.2-31.122.24 b5.14816.85,0.002*GroupIIas 1230-381197.25 c71.3213.5-30.123.505 b4.67GroupIIas 2141-350228.2 b53.8021.5-32.128.25 a3.25• NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementation

Results 62.5645Mean32Mean432110Group IIIGroup IGroup IIbGroup IIa S1Group IIa S20Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2RBCs (x106/mm3)WBCs (x106/mm3)161412Mean1086420Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Hb %Fig. (16) :Blood picture <strong>of</strong> the different studied groups.

Results 63.350300250Mean200150100500Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Platelet (x10-3/mm3)353025Mean20151050Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Hct (%)Fig. (16) Cont. :Blood picture <strong>of</strong> the different studied group

Results 64.6- Urea ( mg/dl)• In group I, the blood urea level ranged from 36-110 with a mean <strong>of</strong>78.2±25.03.• In group IIb, the blood urea level ranged from 111-225 with a mean <strong>of</strong>166.45±38.031.• In group IIaS 1 , the blood urea ranged from 109-261 with a mean <strong>of</strong>168.85±41.03• In group IIaS 2 , the blood urea ranged from 109-117 with a mean <strong>of</strong>111.10±3.96• In group III, the blood urea level ranged from 22-35 with a mean <strong>of</strong>28.9±6.72.It was observed that there is significant al differences between thestudied groups as (F = 24.3) (p = 0.002).7- Creatinine (mg/dl)• In group I, the serum creatinine level ranged from 0.7-2.4 with a mean <strong>of</strong>1.349±0.53.• In group IIb, the serum creatinine level ranged from 9.5-16.7 with amean <strong>of</strong> 12.28±2.096.• In group IIaS 1 , the serum creatinine level ranged from 9.8-17.1 with amean <strong>of</strong> 12.60±2.49.• In group IIaS 2 , the serum creatinine level ranged from 9.5-15.1 with amean <strong>of</strong> 11.805±2.12.

Results 65.• In group III, the serum creatinine level ranged from 0.31-0.9 with a mean<strong>of</strong> 0.573±0.19.It was observed that, there is significant statistical differencesbetween the studied groups as (F = 78.98) (p = 0.0001).8- Uric acid (mg/dl)• In group I, the serum uric acid level ranged from 3.5-8.1 with a mean <strong>of</strong>6.23±1.52.• In group IIb, the serum uric acid level ranged from 4.12-9.6 with a mean<strong>of</strong> 6.32±1.444.• In group IIaS 1 , the serum uric acid level ranged from 4.3-8.3 with amean <strong>of</strong> 6.37±1.15.• In group IIaS 2 , the serum uric acid level ranged from 4.1-7.9 with amean <strong>of</strong> 5.76±1.06.• In group III, the serum uric acid level ranged from 3.4-7.4 with a mean<strong>of</strong> 5.62±1.44.It was observed that there is no significant statistical differencesbetween the studied groups as regarding the uric acid level.

Results 66.Table (8): Blood urea, serum creatinine and uric acid in the differentUrea(mg/dl)RangeMeanS.D.FpCreatinine(mg/dl)RangeMeanS.D.FpUric acid(mg/dl)RangeMeanS.D.F, pLSDstudied groups.GroupIII22-3528.9 a6.720.31-0.90.573 a0.193.4-7.45.621.44GroupI36-11078.2 b25.030.7-2.41.349 b0.533.5-8.16.231.52GroupIIb111-225166.45 c38.03124.3,0.002*9.5-16.712.28 c2.09678.98,0.0001*4.12-9.66.321.4443.21, 0.89N.S.GroupIIas 1109-261168.85 c41.039.8-17.112.60 c2.494.3-8.36.371.15GroupIIas 2109-117111.10 d3.969.5-15.111.805 c2.124.1-7.95.761.06• NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementation

Results 67.200150Mean100500Group IIIGroup IGroup IIbUrea (mg/dl)Group IIa S1Group IIa S2141210Mean864270Group IIIGroup IGroup IIbCreatinine mg/dlGroup IIabs1Group IIas265Mean43210Group IIIGroup IGroup IIbGroup IIa S1Uric acid (mg/dl)Group IIa S2Fig. (17) : Boold urea, serum creatinine and uric acid in the different stugroups.

Results 68.9- Total protein (mg/dl)• In group I, the total protein level ranged from 5.6-8.5 with a mean <strong>of</strong>3.97 ± 0.416.• In group II b, the total protein level ranged from 4.5-7.5with a mean <strong>of</strong>6.13 ± 0.955.• In group II a S 1 , the total protein level ranged from 4.1-8.1with a mean<strong>of</strong> 6.32 ± 0.89.• In group II a S 2 , the total protein level ranged from 6.0-8.3 with a mean<strong>of</strong> 7.1 ± 0.56.• In group III, the total protein level ranged from 7.0-8.5 with a mean <strong>of</strong>7.83 ± 0.69.It was observed that there is no significant statistical differencesbetween the studied groups as ( F= 2.11) ( P= 0.27).10- Serum albumin (mg / dl):• In group I, the serum albumin level ranged from 3.5-4.7 with a mean <strong>of</strong>3.97 ± 0.416.• In group II b, the serum albumin ranged from 2.3-4.7 with a mean <strong>of</strong>3.53 ±0.696.• In group II a S 1 , the serum albumin level ranged from 2.1-4.9 with amean <strong>of</strong> 4.605 ± 0.75.• In group II aS 2 , the serum albumin level ranged from 3.1-5.5 with amean <strong>of</strong> 4.605 ± 0.75.• In group III, the serum albumin ranged from 4.4-6.5 with a mean <strong>of</strong>5.14 ± 0.40.It was observed that there is statistical differences between thestudied groups as ( F= 5.16) ( P= 0.03).

Results 69.Table (9): Total plasma protein and serum albumin in the differentTotalprotein(g/dl)RangeMeanS.D.FpSerumalbumin(g/dl)RangeMeanS.D.F,pstudied groups.GroupIII7.0-8.57.830.694.4-6.55.14 a0.40GroupI5.6-8.56.740.8263.5-4.73.97 b0.416GroupIIb4.5-7.56.130.9552.110.27 N.S.2.3-4.73.53 b0.6965.16,0.03*GroupIIas 14.1-8.16.320.892.1-4.93.646 b0.76GroupIIas 26.0-8.37.10.563.1-5.54.605 ab0.75• NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong>supplementation

Results 70.108Mean6420Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Total plasma protein (g/dl)654Mean3210Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Serum albumin (g/dl)Fig. (18) :Total protein and serum albumin in thedifferent studied groups.

Results 71.11- Sodium ( mEq /l):• In group I, the sodium level ranged from 136-141 with a mean <strong>of</strong> 138.7±1.636.• In group II b, the sodium ranged from 132-145 with a mean <strong>of</strong>138.55±4.347.• In group II a S 1 , the sodium ranged from 132-149 with a mean <strong>of</strong>13865±3.92.• In group II a S 2 , the sodium ranged from 132-142 with a mean <strong>of</strong>138.15±2.37.• In group III, the sodium level ranged from 132-144 with a mean <strong>of</strong>139.3± 6.24.It was observed that there is no significant differences between thestudied groups as (F=1.52) ( P= 0.58).12- Potassium ( mEq /l):• In group I, the potassium level ranged from 3.6-5.0 with a mean <strong>of</strong>4.25±0.510.• In group II b, the potassium level ranged from 3.4-6.0 with a mean <strong>of</strong>5.11±0.695.• In group II a S 1 , the potassium level ranged from 4.1-6.0 with a mean <strong>of</strong>4.905±0.63.• In group II a S 2 , the potassium ranged from 3.9-5.8 with a mean <strong>of</strong>4.625±0.50.• In group III, the potassium level ranged from 3.1-4.1 with a mean <strong>of</strong>3.85±0.48.It was observed that, there is no significant differences between thestudied groups as ( F+ 2.52) (P= 0.28).

Results 72.Table (10): Serum sodium and potassium in the different studiedgroups.GroupIIIGroupIGroupIIbGroupIIas 1GroupIIas 2Sodium(mEq/l)RangeMeanS.D.132-144139.36.24136-141138.71.636132-145138.554.347132-149138.653.92132-142138.152.37Fp1.52,0.58 N.S.Potassium(mEq/l)RangeMeanS.D.3.1-4.13.850.483.6-54.250.5103.4-65.110.6954.1-64.9050.633.9-5.84.6250.50Fp2.520.28, N.S.• NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementation

Results 73.160140120100Mean806040200Group IIIGroup IGroup IIbGroup IIa S1Sodium (meq/L)Group IIa S2654Mean3210Group IIIGroup IGroup IIbPotassium meq/LGroup IIas1Group IIas2Fig. (19) : blood sodium, and potassium in the differentstudied groups.

Results 74.13- HDL cholesterol (mg /dl):• In group I, HDL level ranged from 41-89 with a mean <strong>of</strong> 59.1±17.451.• In group II b, HDL level ranged from 29-60 with a mean <strong>of</strong> 39.80±9.480.• In group II a S 1 , HDL level ranged from 25-55 with a mean <strong>of</strong>36.9±8.21.• In group II a S 2 , HDL level ranged from 31-73 with a mean <strong>of</strong>49.55±12.56.• In group III, HDL level ranged from 43-90 with a mean <strong>of</strong> 76.2 ± 13.05.It was observed that there is significant statistical differencesbetween the studied groups as ( F= 24.5) ( P= 0.003).14 – LDL cholesterol ( mg /dl):• In group I, LDL level ranged from 75-150 with a mean <strong>of</strong> 109.5±27.024.• In group II b, LDL level ranged from 142-310 with a mean <strong>of</strong>223.70±54.314.• In group II a S 1 , LDL level ranged from 160-320 with a mean <strong>of</strong>226.3±50.81.• In group II a S 2 , LDL level ranged from 101-210 with a mean <strong>of</strong>166.05±29.84.• In group III, LDL level ranged from 67-130 with a mean <strong>of</strong> 94.9±19.16.It was observed that there is significant differences between thestudied groups as ( F = 19.85) ( P =0.002).

Results 75.15 – Triglcyeride ( mg /dl):• In group I, TG level ranged from 136-225 with a mean <strong>of</strong> 180.5±33.952.• In group II b, TG level ranged from 187-350 with a mean <strong>of</strong>210.30±41.449.• In group II a S 1 , TG level ranged from 136-321 with a mean <strong>of</strong>200.55±41.26.• In group II a S 2 , TG level ranged from 75-195 with a mean <strong>of</strong>117.9±40.75.• In group III, TG level ranged from 40-105 with a mean <strong>of</strong> 75.9±21.34.It was observed that there is significant statistical differencesbetween the studied groups as ( F= 19.65) ( P= 0.001).

Results 76.Table (11): Blood lipid pr<strong>of</strong>ile in the different studied groups.HDL(mg/dl)RangeMeanS.D.F,pLDL(mg/dl)RangeMeanS.D.FpTriglcyeride(mg/dl)RangeMeanS.D.FpGroupIII43-9076.2 a13.0567-13094.9 a19.1640-10575.9 a21.34GroupI41-8959.1 b17.45175-150109.5 a27.024136-225180.5 b33.952GroupIIb29-6039.80 c9.48024.50.003*142-310223.70 b54.31419.85,0.002*187-350210.30 b41.44919.650.001*GroupIIas 125-5536.9 c8.21160-320226.3 b50.81136-321200.55 b41.26GroupIIas 231-7349.55 b12.56101-210166.05 c29.8475-195117.9 c40.75• NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementation

Results 77.250200Mean150100500Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Triglcyeride mg/dl10080Mean6040200Group IIIGroup IGroup IIbHDL mg/dlGroup IIas1Group IIas2250200Mean150100500Group IIIGroup IGroup IIbGroup IIa S1LDL (mg/dl)Group IIa S2Fig. (20) : seurm lipid pr<strong>of</strong>ile in the different studiedgroups.

Results 78.16- L – Carnitine (mg /dl):• In group I, serum L-<strong>carnitine</strong> level ranged from 3.8-7.5 with a mean <strong>of</strong>5.997± 0.969.• In group II b, L-<strong>carnitine</strong> level ranged from 1.92-3.5 with a mean <strong>of</strong>2.62± 0.724.• In group II a S 1 , L-<strong>carnitine</strong> level ranged from 1.3-3.51 with a mean <strong>of</strong>2.571±0.66.• In group II a S 2 , L-<strong>carnitine</strong> level ranged from 4.84-16-76 with a mean <strong>of</strong>7.158±2.40.• In group III, L-<strong>carnitine</strong> level ranged from 6.58-12.67 with a mean <strong>of</strong>9.171±2.18.It was observed that there is significant statistical differencesbetween the studied groups as ( F= 29.65) ( P= 0.0001)

Results 79.Table (12): Serum L-<strong>carnitine</strong> in the different studied groups.GroupIIIGroupIGroupIIbGroupIIas 1L-<strong>carnitine</strong>(mg/L)Range 6.58- 3.8- 1.92- 1.3-12.67 7.5 3.5 3.51Mean 9.171 a 5.997 b 2.62 c 2.571 cS.D. 2.18 0.969 0.724 0.66F29.65p0.0001*GroupIIas 24.84-16.767.158 a2.40• NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementation

Results 80.108Mean6420Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Fig. (21) : serum L-<strong>carnitine</strong> (mg/L) in the differentstudied groups.

Results 81.III- Echocardiograhy:1- Left ventricular- end diastolic dimensions (LVEDd) (mm):• In group I, LVEDd ranged from 45-60 with a mean <strong>of</strong> 54.3 ±4.92.• In group II b, LVEDd ranged from 57-83 with a mean <strong>of</strong> 68.00 ±8.903.• In group II a S 1 , LVEDd ranged from 59-79 with a mean <strong>of</strong> 68.45±6.134.• In group II a S 2 , LVEDd ranged from 39-57 with a mean <strong>of</strong> 50.50±5.808.• In group III, LVEDd ranged from 35-57 with a mean <strong>of</strong> 46.6 ±8.25.It was observe that there is significant statistical deference betweenthe studied groups as ( F= 19.65) ( P= 0.0001).2- Left ventricular- end systolic dimensions (LVESd) (mm):• In group I, LVESd ranged from 35-43 with a mean <strong>of</strong> 39.5± 2.55.• In group II b, LVESd ranged from 35-51 with a mean <strong>of</strong> 47.95 ±4.283.• In group II a S 1 , LVESd ranged from 43-60 with a mean <strong>of</strong> 49.80±4.786.• In group II a S 2 , LVESd ranged from 23-42 with a mean <strong>of</strong> 34.80±6.371.• In group III, LVESd ranged from 22-40 with a mean <strong>of</strong> 31.3±6.33.It was observed that here is significant differences between thestudied groups as ( F= 8.69) ( P= 0.023).3- Ejection fraction ( EF) %:• In group I, EF ranged from 54-77 with a mean <strong>of</strong> 66 ±7.07.• In group II b, EF ranged from 20-31 with a mean <strong>of</strong> 25.33 ±3.25.• In group II a S 1 , EF ranged from 25-31 with a mean <strong>of</strong> 25.12 ±7.185.• In group II a S 2 , EF ranged from 49-60 with a mean <strong>of</strong> 52.81 ± 5.109.• In group III, EF ranged from 50-77 with a mean <strong>of</strong> 64.6 ± 8.80.

Results 82.It was observed that there is significant differences between thestudied groups as ( F= 11.98) ( P= 0.021).4- Fractional shortening (FS) %:• In group I, FS ranged from 20-41 with a mean <strong>of</strong> 32.9 ± 3.66.• In group II b, FS ranged from 19-30 with a mean <strong>of</strong> 23.95 ± 3.323.• In group II a S 1 , FS ranged from 15-25 with a mean <strong>of</strong> 21.10 ± 3.672.• In group II a S 2 , Fs ranged from 25-41 with a mean <strong>of</strong> 31.85 ± 4.782.• In group III, FS ranged from 27-46 with a mean <strong>of</strong> 37.0 ± 7.60.It was observe that there is significant differences between thestudied groups as ( F= 9.85) ( P= 0.035).5- E – integral(Ei):• In group I, E ranged from 0.5-0.9 with a mean <strong>of</strong> 0.72 ± 0.13.• In group II b, E ranged from 0.32-0.53 with a mean <strong>of</strong> 0.42 ± 0.081.• In group II a S 1 , E ranged from 0.35-0.55 with a mean <strong>of</strong> 0.41 ± 0.016.• In group II a S 2 , E ranged from 0.45-0.80 with a mean <strong>of</strong> 0.62 ± 0.044.• In group III, E ranged from 0.5-1.0 with a mean <strong>of</strong> 0.8 ± 0.17.It was observed that there is significant differences between thestudied groups as ( F= 8.18) ( P= 0.034).6- A –integral(Ai):• In group I, A ranged from 0.3-0.53 wit a mean <strong>of</strong> 0.41 ± 0.09.• In group II b, A ranged from 0.14-0.22 with a mean <strong>of</strong> 0.19 ± 0.016.• In group II a S 1 , A ranged from 0.16-0.26 with a mean <strong>of</strong> 0.19 ± 0.019.• In group II a S 2 , A ranged from 0.3-0.61 with a mean <strong>of</strong> 0.51 ± 0.060.

Results 83.• In group III, A ranged from 0.3-0.6 with a mean <strong>of</strong> 0.46 ± 0.11.It was observed that there is significant differences between thestudied groups as ( F = 5.93) ( P= 0.023).7- Ei / Ai:• In group I, E /A ranged from 1.4-2.0 with a mean <strong>of</strong> 1.71 ± 0.11.• In group II b, E /A ranged from 0.91-1.76 with a mean <strong>of</strong> 1.41 ± 0.324.• In group II a S 1 , E /A ranged from 0.87-1.66 with a mean <strong>of</strong> 1.13±0.130.• In group II a S 2 , E /A ranged from 1.05-2.1 with a mean <strong>of</strong> 1.32 ± 0.293.• In group III, E /A ranged from 1.4-2.33 with a mean <strong>of</strong> 1.72 ± 0.27.It was observed that there is no significant differences between thestudied groups as ( F= 2.53) (P= 0.12).8- Peak velocity <strong>of</strong> early filling (E)/Peak velocity <strong>of</strong> late filling (A)• In group I, E /A ranged from 1.4-1.9 with a mean <strong>of</strong> 1.62 ± 0.9.• In group II b, E /A ranged from 0.82-1.75 with a mean <strong>of</strong> 1.41 ± 0.32.• In group II a S 1 , E /A ranged from 0.9-1.5 with a mean <strong>of</strong> 1.2±0.130.• In group II a S 2 , E /A ranged from 1.1-1.9 with a mean <strong>of</strong> 1.3 ± 0.29.• In group III, E /A ranged from 1.3-2.0 with a mean <strong>of</strong> 1.13 ± 0.1.It was observed that there is no significant differences between thestudied groups as ( F= 2.5) (P= 0.12).9- Left ventricular mass ( m 2 ):• In group I, LV mass range from 131-135 with a mean <strong>of</strong> 130.067 ± 1.54.• In group II b, LV mass ranged from 130-149 with a mean <strong>of</strong>134.60±3.267.

Results 84.• In group II a S 1 . LV mass ranged from 137-152 with a mean <strong>of</strong>146.45±3.52.• In group II a S 2 , LV mass ranged from 118-139 with a mean <strong>of</strong>129.22±6.35.• In group III, LV mass ranged from 125-130 with a mean <strong>of</strong> 129.25±3.60.It was observed that there is significant differences between thestudied groups as ( F = 9.85) ( P= 0.03).

Results 85.Table (13): Echocardiographic parameters in the different studiedLVEDd(mm)RangeMeanS.D.FpLVESd(mm)RangeMeanS.D.FpEF (%)RangeMeanS.D.Fpgroups.GroupIII35-5746.6 a8.2522-4031.3 a6.3350-7764.6 a8.80GroupI45-6054.3 a4.9235-4339.5 a2.5554-7766 a7.07Group IIb Group IIas 1 Group57-8368.00 b8.90319.650.0001*35-5147.95 b4.2838.690.023*20-3125.33 b3.2511.98,0.021*59-7968.45 b6.13443-6049.80 b4.78625-3125.12 b7.185IIas 239-5750.50 a5.80823-4234.80 a6.37149-6052.81 a5.109• NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementationLVEDd : Left ventricular end diastolic dimensionLVESd : Left ventricular end systolic dimensionEF: Ejection fraction

Results 86.Table (13) Cont.: Echocardiographic parameters in the differentstudied groups.FS (%)RangeMeanS.D.FpEi (meter)RangeMeanS.D.FpAiRangeMeanS.D.FpGroupIII27-4637.0 a7.600.5-1.00.8 a0.170.3-0.60.46 a0.11GroupI20-4132.9 a3.660.5-0.90.72 a0.130.3-0.530.41 a0.09GroupIIb19-3023.95 b3.3239.850.035*0.32-0.530.42 b0.0818.180.034*0.14-0.220.19 b0.0165.93,0.023*GroupIIas 115-2521.10 b3.6720.35-0.550.41 b0.0160.16-0.260.19 b0.019GroupIIas 225-4131.85 a4.7820.45-0.800.62 ab0.0440.3-0.610.51 a0.060• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementationFS : Fractional shorteningEi : E-integralAi : A-integral

Results 87.Table (13) Cont.: Echocardiographic parameters in the differentstudied groups.GroupIIIGroupIGroupIIbGroupIIas 1GroupIIas 2Ei/AiRangeMeanS.D.FpE/ARangeMeanS.D.FpLV mass(m 2 )RangeMeanS.D.FP1.4-2.331.720.271.3-2.01.130.1125-130129.25 a3.601.4-2.001.710.111.4-1.91.620.9131-135130.067 a1.540.91-1.761.410.3242.530.12 N.S.0.82-1.751.40.322.50.12 N.S.130-149134.60 a3.2679.850.03*0.87-1.661.130.1300.9-1.51.20.130137-152146.45 b3.521.05-2.11.320.2931.1-1.91.30.29118-139129.22 a6.35• NS : No significant difference.• The groups having the same superscript letter indicate no statisticalsignificant difference, meanwhile the groups with different superscriptletter have a statistical significant difference.Group III: Control group.Group I : end- stage renal disease patients not on HD.Group II b: Patients on HD didn’t receive L. <strong>carnitine</strong> supplementationGroup II aS 1 : Patients on HD before L. <strong>carnitine</strong> supplementationGroup II aS 2 : Patients on HD after L. <strong>carnitine</strong> supplementationEi/Ai : E-integeral/A-inttegralLV mass : Left ventricular massE/A : Peak velocity <strong>of</strong> early filling (E)/ Peak velocity <strong>of</strong> late filling (A)

Results 88.807060Mean50403020100Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Left ventricular end diastolic dimension (mm)605040Mean3020100Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Left ventricular end systolic dimensions (mm)Fig. (22) : Echocordiographic parameteres <strong>of</strong> left ventricularfunctions (LVEDd and LVESd) inthe different studied groups.

Results 89.706050Mean403020100Group IIIGroup IGroup IIbGroup IIa S1Ejection fraction(%)Group IIa S24030Mean20100Group IIIGroup IGroup IIbGroup IIa S1Group IIa S2Fractional shortening (%)Fig. (22) Cont. : Echocordiographic parameteres <strong>of</strong> left ventriculfunctions (EF and FS) in thedifferent studied groups.

Results 90.10.8Mean0.60.40.20Group IIIGroup IGroup IIbGroup IIas1Group IIas2E-integral (Ei) (meter)0.60.50.4Mean0.30.20.10Group IIIGroup IGroup IIbGroup IIa S1A-integral (Ai) (meter)Group IIa S2Fig. (22) Cont. :Echocordiographic parameteres <strong>of</strong> leftventricular functions (E and A) inthe different studied groups.

Results 91.Correlation between L-<strong>carnitine</strong> and high-density lipoprotein(HDL)In this study we found that there is significant positive correlationbetween serum L-<strong>carnitine</strong> level and serum level <strong>of</strong> HDL. High level <strong>of</strong>serum L-<strong>carnitine</strong> was associated with increase serum HDL level Fig. (23).140120Serum HDL (mg/dl)10080604020 00 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (23): Correlation between L-<strong>carnitine</strong> and HDL

Results 92.Correlation between serum L-<strong>carnitine</strong> and low-densitylipoproteinThere is a significant negative correlation between serum L-<strong>carnitine</strong>level and serum level <strong>of</strong> LDL High level <strong>of</strong> serum L-<strong>carnitine</strong> wasassociated with low level <strong>of</strong> serum LDL Fig. (24).350Serum LDL (mg/dl)30025020015010050 0-500 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (24): Correlation between L-<strong>carnitine</strong> and LDL

Results 93.Correlation between serum L-<strong>carnitine</strong> and TriglycerideA present study we found that there is significant negativecorrelation between serum L-<strong>carnitine</strong> level & serum T.G high serum level<strong>of</strong> L-<strong>carnitine</strong> associated with low level <strong>of</strong> serum.T.G Fig. (25).400Serum tri-glyceride (mg/dl)300200100 0-1000 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (25): Correlation between L-<strong>carnitine</strong> and T.G

Results 94.Correlation between serum L-<strong>carnitine</strong> level and left ventend- diastolic dimensionsFrom present study we found that there is significant negativecorrelation between serum L-<strong>carnitine</strong> level & LVEDd, high level <strong>of</strong> serumL-<strong>carnitine</strong> associated with increase in LVEDd Fig. (26).100Left ventricular end diastolic dimensions80604020 00 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (26): Correlation between L-<strong>carnitine</strong> and Left ventricularend diastolic dimensions

Results 95.Correlation between serum L-<strong>carnitine</strong> level and level and leftvent end- Systolic dimensionsThere was a significant negative correlation between serum L-<strong>carnitine</strong> level and LVESd low level <strong>of</strong> serum L-<strong>carnitine</strong> associated withincrease in LVESd Fig. (27).70Left ventricular end systolic dimensions6050403020 1000 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (27): Correlation between L-<strong>carnitine</strong> and Left ventricularend systolic dimensions

Results 96.Correlation between serum L-<strong>carnitine</strong> level and EjectionFractionThere was a significant positive correlation between serum L-<strong>carnitine</strong>level and EF high level <strong>of</strong> serum L-<strong>carnitine</strong> associated with increase EF Fig.(28).Ejection fraction (%)806040 2000 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (28): Correlation between L-<strong>carnitine</strong> and Ejection fraction

Results 97.Correlation between serum L-<strong>carnitine</strong> and FractionalshorteningThere was a significant positive correlation between serum L-<strong>carnitine</strong>level and FS high level <strong>of</strong> serum L-<strong>carnitine</strong> associated with increase FS Fig.(29).50Fractional shortening403020 1000 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (29): Correlation between L-<strong>carnitine</strong> and Fractionalshortening

Results 98.Correlation between serum L-<strong>carnitine</strong> and E-integral (Ei)There was a significant positive correlation between serum L-<strong>carnitine</strong>level and Ei high level <strong>of</strong> serum L-<strong>carnitine</strong> associated with increase Ei Fig.(30).1.2E-integral (meter)10.80.60.4 0.200 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (30): Correlation between L-<strong>carnitine</strong> and Ei-integral

Results 99.Correlation between serum L-<strong>carnitine</strong> and A-integral (Ai)There was a significant negative correlation between serum L-<strong>carnitine</strong>level and Ai. High level <strong>of</strong> serum L-<strong>carnitine</strong> associated with decrease Ai Fig.(31).1.2A-integral (meter)10.80.60.40.2 00 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (31): Correlation between L-<strong>carnitine</strong> and Ai-integral

Results 100.Correlation between serum L-<strong>carnitine</strong> and Ei/AiThere was a significant positive correlation between serum L-<strong>carnitine</strong> level and Ei/Ai. High serum L-<strong>carnitine</strong> level associated withincrease Ei/Ai ratio Fig. (32).2.5E-integeral/A-integral21.510.5 00 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (32): Correlation between L-<strong>carnitine</strong> andEi-integeral/Ai-integral

Results 101.Correlation between serum L-<strong>carnitine</strong> & peak velocity <strong>of</strong>early filling(E)/ peak velocity <strong>of</strong> late filling (A)There was a significant positive correlation between serum L-<strong>carnitine</strong>level & E/A. High level <strong>of</strong> serum L.<strong>carnitine</strong> associated with increase E/Aratio Fig. (33).2.5E-integeral/A-integral21.510.5 00 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (33): Correlation between L-<strong>carnitine</strong> and E/A

Results 102.Correlation between serum L-<strong>carnitine</strong> and left ventricularmassThere was a significant negative correlation between serum L-<strong>carnitine</strong> level and LV mass. High serum L-<strong>carnitine</strong> level associated withdecrease L.V mass Fig. (34)LV mass16014012010080 60402000 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (34): Correlation between L-<strong>carnitine</strong> and LV mass (g/m 2 )

Results 103.Correlation between serum L-<strong>carnitine</strong> and HemoglobinlevelThere was a significant positive correlation between serum L-<strong>carnitine</strong> level and Hemoglobin level. High serum L-<strong>carnitine</strong> levelassociated with increase Hemoglobin level Fig. (35)Hemoglobin (%)14121086 4200 5 10 15 20Serum L-<strong>carnitine</strong> (mg/L)Fig. (35): Correlation between L-<strong>carnitine</strong> and hemoglobin level

105.formulae:STATISTICAL ANALYSISStatistical <strong>of</strong> the results were carried out according to the following1- Arithmetic mean ( X )Was calculated as follows:X∑ x=nWhere ; X = arithmetic mean∑ X = Sum <strong>of</strong> observationsn= number <strong>of</strong> observations2- Standard deviation (S.D.):Was calculated as follows:SD =( x)2 ∑∑ x −nn −12Where ; X = sum <strong>of</strong> squared observations( ∑ X ) 2 = square <strong>of</strong> the sum <strong>of</strong> observationsn3- “t” test:t =S2PX1− X 22 1 1SP( +n n21S1( n1−1)+ S2( n 2=n + n − 21= number <strong>of</strong> observations2)22−1)2Where: S P = Pooled variance

106.2S 1 = Variance <strong>of</strong> sample (1)2S 2 = Variance <strong>of</strong> sample (2)n 1 = Size <strong>of</strong> sample (1)n 2 = Size <strong>of</strong> sample (2)X 1 = Mean <strong>of</strong> sample (1)X 2 = Mean <strong>of</strong> sample (2)S 1 = Standard deviation <strong>of</strong> sample (1)S 2 = Standard deviation <strong>of</strong> sample (2)4- Student t-test:F =2AS / S2 WWhereS 2 A = Mean square among groups.S 2 W = Mean square within groups.5- Z test:Significance tests used to compare differences between proportions.Z =Mean −S.Dσ xSpecificity: The ability <strong>of</strong> a test to indicate non-disease when no diseaseis present.Specificity: The ability <strong>of</strong> a test to detect a disease when it is present.

107.6- Chi-square (X 2 ):For comparison between distribution <strong>of</strong> patients according todifferent items <strong>of</strong> study and use this formula for calculation:X 2 ( O − E)= ∑E2O = Observed resultsE = Expected results(O-E) 2 = difference squaredWhere E =Total row × total columnGrand total

Discussion 108.DISCUSSIONCardiovascular diseases are the most frequent cause <strong>of</strong> death amongdialysis patients, and mortality from cardiovascular causes is far higherthan that in the general population. (146)There is a high prevalence <strong>of</strong> left ventricular dysfunctions, leftventricular hypertrophy, and ventricular arrhythmias among the chronichemodialysis patients, and they constitute a common morbidity comparedwith the control population. (147)Many risk factors are involved in the pathogenesis <strong>of</strong> cardiovascularcomplications in CRF including hypertension, diabetes mellitus, uremicdyslipidemia and smoking. (148)Patients on chronic hemodialysis treatment are at elevatedatherogenic risk due to uremic dyslipidemia, which is a secondary form <strong>of</strong>complex dyslipidemia consisting <strong>of</strong> quantitative and qualitativeabnormalities in serum lipoproteins resulting from alteration in lipoproteinmetabolism and composition particularly the predictive value <strong>of</strong> lipoprotein aand the apolipoprotein ratios, as well as, the ratio <strong>of</strong> apolipoprotin AI toapolipoprotein CIII and to lipoprotein B. (149)Among the various metabolic abnormalities documented in dialysispatients, are abnormalities related to the metabolism <strong>of</strong> fatty acids.Abnormal fatty acid metabolism has been associated with the promotion <strong>of</strong>free- radical production, insulin resistance, and cellular apoptosis. These

Discussion 109.processes have been identified as important contributors to morbidityexperienced by dialysis patients. (150)Patients receiving hemodialysis have been shown to be <strong>carnitine</strong>deficient,as manifested by reduced levels <strong>of</strong> plasma free <strong>carnitine</strong> and anincrease in the acyl: free <strong>carnitine</strong> ratio. The skeletal muscles and thecardiac muscle metabolism is largely oxidative and dependant on free aciddelivery and mitochondrial transport, more over, the myocyte has one <strong>of</strong>the highest intracellular <strong>carnitine</strong> concentrations in the body. Sorecognition <strong>of</strong> the deleterious effect <strong>of</strong> fatty acids and the effect <strong>of</strong> <strong>carnitine</strong>deficiency on myocardial cells is important in the aim to prevent andmanage the cardiovascular complications in chronic hemodialysispatients. (151)Our study estimates the level <strong>of</strong> L- <strong>carnitine</strong>, the lipid pr<strong>of</strong>ile, as wellas, the left ventricular functions in the different types <strong>of</strong> patients withchronic renal failure aiming to evaluate the theraputic efficacy <strong>of</strong> L-<strong>carnitine</strong> on the left ventricular functions and lipid pr<strong>of</strong>ile in thehemodialysis patients.In the present study, we estimated the level <strong>of</strong> serum L- <strong>carnitine</strong> in60 persons divided into three groups:- Group I: included 10 patients with chronic renal insufficiency onconservative medical treatment with GFR <strong>of</strong> 20-50 ml / min, they didn ’ treceive L- <strong>carnitine</strong> supplementation.

Discussion 110.- Group II: involved 40 patients with end- stage renal disease onmaintenance hemodialysis for more than 6 months, the dialysis schedulewas 4 hours, 3 times / week. This group was subdivided into twosubgroups.- Group II a: included 20 patients with end- stage renal disease onhemodialysis and received oral L-<strong>carnitine</strong> supplement at a dose 1 gm /day for 6 months- Group II b: included 20 patients with end- stage renal disease onmaintenance hemodialysis and didn’t receive L-<strong>carnitine</strong>supplementation.- Group III: presented with 10 healthy persons as a control group.In our study, the control group (III) showed normal parameters <strong>of</strong>echocardiography especially in wall thickness, and ejection fraction, whileGI showed No statistical significant difference as regarding theseparameters.Meanwhile group II b, and group II a S 1 showed abnormalitiesincluding left ventricular hypertrophy and reduced ejection fraction ( lessthan 40%), reduced serum level <strong>of</strong> L- <strong>carnitine</strong>, and abnormalities in thelipid pr<strong>of</strong>iles including increased TG level, decreased HDL, and increase inthe LDL level.In the present study, the control group ( group III) showed statisticalsignificant difference compared with patients in group I ( ESRD) asregarding lipid pr<strong>of</strong>ile and L-<strong>carnitine</strong> level.

Discussion 111.These results were comparable to that <strong>of</strong> Ahmed’s et al in 2001. Wh<strong>of</strong>ound that L- <strong>carnitine</strong> concentration decreased by 75 % after ahemodialysis session in the hemodialysis patients compared to normalcontrol subjects. (91)Rodriguez-Segade et al (103) found a gradual decrease in serum total<strong>carnitine</strong> (Tc) levels, and Kudoh et al. (92) documented a gradual reduction inpredialysis plasma Tc levels in the hemodialyzed patients.Evans et al in 2004 (152) examined the time course <strong>of</strong> <strong>carnitine</strong>depletion in patients undergoing dialysis, he found that within the firstweek <strong>of</strong> dialysis, <strong>carnitine</strong> levels had significantly decreased. After 12months <strong>of</strong> dialysis, the mean level <strong>of</strong> plasma free <strong>carnitine</strong> had fallen by40% and patients receiving dialysis for more than 12 months had a furtherreduction to a mean <strong>of</strong> 22.0 ± 5.4 μmol / L ( healthy adult normal level43.3± 8.6 μmol /L). During the first 12 months <strong>of</strong> dialysis, total muscle<strong>carnitine</strong> level had decreased by 20 %.The explanation <strong>of</strong> development <strong>of</strong> <strong>carnitine</strong> deficiency in dialysisdependentpatients, include poor dietary intake <strong>of</strong> meat and dairy productsthat are significant source <strong>of</strong> <strong>carnitine</strong>, loss <strong>of</strong> the ability <strong>of</strong> the kidney tosynthesize <strong>carnitine</strong>, and the loss <strong>of</strong> <strong>carnitine</strong> during the dialysis procedure.Whereas decreased intake and synthesis contribute to the deficiency, themost significant cause <strong>of</strong> <strong>carnitine</strong> deficiency is substantial reduction in<strong>carnitine</strong> with each dialysis session. (153)

Discussion 112.The L-<strong>carnitine</strong> level decreased by approximately 70 % with eachdialysis session, and the inability <strong>of</strong> the dialysis membrane to reabsorbfiltered <strong>carnitine</strong> as opposed to a healthy kidney. The absolute loss <strong>of</strong><strong>carnitine</strong> during dialysis exceeds normal urinary loss in most patients,whereas, patients with normal kidney function will reabsorb most <strong>carnitine</strong>once the serum <strong>carnitine</strong> level is decreased, while the dialysis patientscontinue to lose <strong>carnitine</strong> because <strong>of</strong> the passive nature <strong>of</strong> the dialysismembrane. (153)In the present study, the control group (group III), showed normalparameters <strong>of</strong> echocardiography especially in, ejection fraction and showedno statistical significant difference with group I as regarding theechocardiographic parameters. Meanwhile group II b and group II a S 1showed abnormalities expressed as left ventricular hypertrophy andreduced ejection fraction (less than 40%). Group II a S 2 (after L-<strong>carnitine</strong>supplementation) showed statistical significant differences with G IIa S 1(before L-<strong>carnitine</strong> supplementation) expressed as increased ejectionfraction with improvement <strong>of</strong> the other echocardiographic parameters.These results were matched with that <strong>of</strong> Romagnoli et al in 2002 (154)who studied the effect <strong>of</strong> L-<strong>carnitine</strong> treatment on LVEF in HD patients,and he found a significant impairment <strong>of</strong> systolic dysfunction, after 8months <strong>of</strong> levo<strong>carnitine</strong> therapy. There was a marked improvement inLVEF.

Discussion 113.Trovato et al in 1998. (155) documented the effect <strong>of</strong> long termlevo<strong>carnitine</strong> therapy in HD patients with impairment <strong>of</strong> LVEF, he found asignificant rise in LVEF and significant decrease in LVED dimensions.Also Khoss et al in 1989 (156) studied the effect <strong>of</strong> L-<strong>carnitine</strong> therapy onsystolic function in a different hemodialysis population with low serum<strong>carnitine</strong>, the patients had echocardiographic measurement <strong>of</strong> reduced FS andafter 18 months <strong>of</strong> oral L- <strong>carnitine</strong> therapy, the FS rose from 32 % to 45%.Van Es et al in 1992 (157) studied the effect <strong>of</strong> L- <strong>carnitine</strong> therapy inchronic hemodialysis patients with reduced mean LVEF and who were<strong>carnitine</strong> deficient; the L- <strong>carnitine</strong> therapy was associated with asignificant increase in LVEF.Matsumoto et al in 2000 (158) studied the effect <strong>of</strong> oral L-<strong>carnitine</strong>administration for 6 months in chronic hemodialysis patients, he found thatLVEF increased significantly from 44.9 ± 1.2 to 53.8 ±13.8, L- <strong>carnitine</strong>treatment was also associated with a significant reduction in left ventricularmass, and improvement <strong>of</strong> the cardiac symptoms such as dyspnea onexertion, palpitations and chest pain.Kurien et al. (159) showed that ventricular arrythmias can be induced inexperimental animals by the elevation <strong>of</strong> plasma free fatty acids (FFAs)and that reduction in FFA levels reduced the ventricular ectopy.Suzuki et al. (160) documented ventricular or supraventriculararrythmias in HD patients with low serum level <strong>of</strong> L- <strong>carnitine</strong>, and high

Discussion 114.level <strong>of</strong> plasma FFA, and with administration <strong>of</strong> L- <strong>carnitine</strong> there was asignificant reduction in both dialysis- induced rise in FFA levels andfrequency <strong>of</strong> ventricular premature beats and their severity.The possible explanation for the improvement <strong>of</strong> LVEF seen with L-<strong>carnitine</strong> treatment include a reduction in cardiomyocyte apoptosis or animprovement in cardiac energy metabolism. L- <strong>carnitine</strong> also has beenshown to prevent both myocardial dysfunction and ceramide- inducedcardiomyocyte apoptosis in rats exposed to adriamycin, a potent inducer <strong>of</strong>apoptosis in cardiac cells, (161,162) and increase ATP production in ischemicperfusedrat hearts. (163)Many disorders <strong>of</strong> metabolism described in dialysis patients, one <strong>of</strong>them is the disposition <strong>of</strong> fatty acids, which consist <strong>of</strong> 3 elements:- Evidence <strong>of</strong> elevated plasma fatty acid levels in patients with chronicrenal failure treated with hemodialysis.- Decreased tissue metabolism <strong>of</strong> fatty acids in these patients.- Alteration <strong>of</strong> individual fatty-acid moieties and the acyl: free <strong>carnitine</strong>ratio in the HD patients.Gadegbeku et al in 2004. (164) documented an elevated plasmanonesterified fatty acid level in patients on HD.Bartel et al. (165) demonstrated an increase in circulating plasma fattyacids in HD patients.

Discussion 115.De Gomez Dumm et al in 2001. (166) reported an increase in palmiticand monounsaturated fatty acids in the plasma <strong>of</strong> dialysis patients with acorresponding decrease in polyunsaturated fatty acids.Maeda et al. (167) documented a significant reduction in intradialyticfree fatty acid concentration in the plasma <strong>of</strong> HD patients after 12 weeks <strong>of</strong>the administration <strong>of</strong> oral L-<strong>carnitine</strong>.In the present study, the control group (G III) showed statisticalsignificant difference compared to GIIa S 1 , GIIa S 2 , GIIb regarding serumlipids, meanwhile GIIb, GIIa S 1 (before L-<strong>carnitine</strong> supplementation)showed no statistical significant difference regarding their lipid pr<strong>of</strong>ileincluding high TG level, increased level <strong>of</strong> LDL and a low level <strong>of</strong> HDLcholesterol. There was statistical significant difference between GIIa S 1 andGIIa S 2 regarding the lipid pr<strong>of</strong>ile, in GIIa S 2 (after L- <strong>carnitine</strong>supplementation) the level <strong>of</strong> TG deceased with reduction also <strong>of</strong> LDLlevel and improvement <strong>of</strong> HDL level occurred.These results were matched with the result <strong>of</strong> Vesela et al in2001. (168) who found a significant improvement in the lipid parameters afterL- <strong>carnitine</strong> administration for 6 months.Also the study <strong>of</strong> Guarnieri et al. (169) and Lacour et al. (170) reported asignificant decrease in serum triglyceride levels after L-<strong>carnitine</strong>supplementation for 14 weeks.

Discussion 116.Bertoli et al in 1981. (171) documented an increase in serum highdensity lipoprotein ( HDL) cholesterol in hemodialysis patients treated withL-<strong>carnitine</strong>.Also the study <strong>of</strong> Vacha et al in 1983. (172) on hypertriglyceridemichemodialyzed patients who were treated with L-<strong>carnitine</strong> for 3 months,documented a significant reduction in the level <strong>of</strong> TG.Many <strong>of</strong> the patients maintained on HD are unable to achieve ahemoglobin level <strong>of</strong> 10 g /dl, despite the use <strong>of</strong> extremely high doses <strong>of</strong>rHuEPO. (173)Approximately 40 % <strong>of</strong> dialysis patients fail to achieve their goalhemoglobin <strong>of</strong> > 11 g/dl, despite the fact that 25 % <strong>of</strong> dialysis patients areprescribed rHuEPO doses equal to or > 270 units / kg per week. (174)The inability to attain adequate Hct been shown to be associated notonly with a poorer patient's quality <strong>of</strong> life but with reduced patientssurvival as well, iron deficiency, aluminum toxicity, and osteitis fibrosacystica have traditionally been cited as causes <strong>of</strong> an inadequate response toeryhropoietin therapy, but rHuEPO resistance has shown to be related todialysis patients morbidity and mortality. (175)Galucci et al in 1999. (176) studied the rHuEPO requirements inhemodialysis patients, there were 2 factors that distinguished the patientswith a higher rHuEPO• Increased serum lactate dehydrogenase.• Increased Red cell membrane MDA level, an indicator <strong>of</strong> lipidperoxidation resulting from free radicals.

Discussion 117.The mechanism by which the free radicals affect anemia, is throughan effect on the RBC membrane and consequent eythrocyte deformabilitywith reduction in the red cell survival.Ly et al in 2004. (177) demonstrated a marked reduction in red cellsurvival in hemodialysis patients, in addition there was a significant higherosmotic fragility <strong>of</strong> the RBCs from patients on HD. (178)A similar study by Ibrahim et al in 2002. (179) documented an increasein the RBCs osmotic fragility in RBCs from dialysis patients with a lowvalues <strong>of</strong> erythrocyte deformability.In the present study, it was observed that group I, group II b, andgroup II a S 1 had a low hemoglobin level and reduced Hct value with nosignificant differences between them, meanwhile group II a S 2 ( patients onHD and receiving L-<strong>carnitine</strong> therapy) and group III ( control group) had ahigher Hb level and Hct % with a statistical significant difference betweenthem and the other groups.Similar studies found that administration <strong>of</strong> L-<strong>carnitine</strong> inhemodialysis patients has been shown to reduce RBC membrane MDAlevel, improve RBC deformability and osmotic fragility.Vlassopouos et al in 2002. (180) reported that administration <strong>of</strong> L-<strong>carnitine</strong> for 1 year to hemodialysis patients with low RBC osmotic resistance(RBCOR), lead to improvement in the RBCOR and with no further reduction.Also, Sotirakopoulos et al in 2000 (181) studied the effect <strong>of</strong> L-<strong>carnitine</strong> supplementation for 3 months on the Hct and RBC deformabilityin HD patients, he found an increase in the Hct level.

Discussion 118.Trovato. (182) found that treatment <strong>of</strong> hemodialysis patients with L-<strong>carnitine</strong> for 1 year was associated with a significant increase in thehemoglobin and hematocrit levels.Caruso et al in 1998. (183) found that hemodialysis patients receivingL-<strong>carnitine</strong> for 6 months had a decreased rHuEPO / Hct ratio (an indication<strong>of</strong> EPO sensitivity), and after discontinuation <strong>of</strong> L-<strong>carnitine</strong> this ratio wasincreased again. During L-<strong>carnitine</strong> treatment period, there was asignificant correlation between the level <strong>of</strong> L-<strong>carnitine</strong> and the reduction inthe EPO / Hct ratio.A recent study was done by Vesela et al in 2001. (184) revealed thathemodialysis patients treated with L-<strong>carnitine</strong> for 6 months had asignificant rise in the hematocrit level and the corresponding rHuEPOrequirement in the L-<strong>carnitine</strong> treated patients was reduced byapproximately 40 %, meanwhile after 3 months <strong>of</strong> discontinuation <strong>of</strong>L-<strong>carnitine</strong> therapy the Hct level had fallen again with a corresponding risein the rHuEPO requirement.Also, the study <strong>of</strong> Matsumoto et al in 2001. (185) reported thatadministration <strong>of</strong> 500 mg / day <strong>of</strong> L-<strong>carnitine</strong>, resulted in an increase <strong>of</strong> >2%in the Hct in 36 % <strong>of</strong> patients refractory to high dose rHuEPO therapy.Hurot et al in 2002. (186) concluded that there was a significantreduction in the erythropoietin resistance index (ERI), which indicated abeneficial effect <strong>of</strong> L-<strong>carnitine</strong> supplementation on anemia treatment inhemodialysis patients.( the ERI = EPO weekly dose / g <strong>of</strong> Hb achieved).

Summary 119.SUMMARYCardiovascular diseases are the most important cause <strong>of</strong> death amongpatients with chronic renal failure treated with maintenance hemodialysis.The aim <strong>of</strong> the study is to detect the role <strong>of</strong> L-<strong>carnitine</strong> therapy inhemodialysis patients and its relation to cardiovascular complications.In this study, 60 persons were studied by taking detailed medicalhistory, full clinical examination, full laboratory investigations includingestimating the serum level <strong>of</strong> L- <strong>carnitine</strong>, lipid pr<strong>of</strong>ile andechocardiography to estimate the left ventricular functions.The subjects were divided into three groups:♦Group I: 10 patients with chronic renal insufficiency onconservative medical treatment with GFR <strong>of</strong> 20-50 ml /mint.♦Group II with 40 patients with end stage renal disease on maintenanceHD for more than 6 months and this group subdivided into- Group II a: included 20 patients on HD and receiving oral L- <strong>carnitine</strong>supplementation as 1g daily dose for 6 months.- Group II b: included 20 patients on HD and didn’t receive L-<strong>carnitine</strong>supplementation.♦Group III: 10 normal healthy persons as a control group.Patients with diabetes mellitus, ischemic heart diseases and extensivemyocardial calcifications were excluded from the study.

Summary 120.In the present study, group II b and group II a S 1 (patients on HDbefore receiving L-<strong>carnitine</strong> supplementation) showed low serum level <strong>of</strong>L-<strong>carnitine</strong> and abnormalities <strong>of</strong> their echocardiographic parameters whichsuggest that hemodialysis reduce the serum level <strong>of</strong> L-<strong>carnitine</strong> and suggestalso that the risk <strong>of</strong> cardiovascular morbidity and mortality in hemodialysispatients are partially related to the reduced levels <strong>of</strong> L-<strong>carnitine</strong>.The control group (group III) had no statistical significantdifferences with group II a S 2 (patients on HD after receivingL-<strong>carnitine</strong> therapy) as regarding serum level <strong>of</strong> L- <strong>carnitine</strong> and theechocardiographic parameters.Also in the present study, the serum lipid levels showed that therewas no statistical difference between group II b and group II a S 1 (patient onHD before receiving L-<strong>carnitine</strong> therapy) as both groups showed highlipids parameters (TG, LDL), meanwhile group II a S 2 (patient on HD afterreceiving L-<strong>carnitine</strong> supplementation) and group III were significantlydifferent from both groups. This could indicate the relation between thereduced L-<strong>carnitine</strong> level and hypercholesteremia and hypertriglyceridemia.In the present study, the hemoglobin concentration and hematocritlevels showed no statistical differences between group I, group II b, groupII a S 1 (patients on HD before receiving L-<strong>carnitine</strong> supplementation)which is explained by the effect <strong>of</strong> chronic renal failure and HD on thehematological status. Meanwhile group II a S 2 (patients on HD afterreceiving L-<strong>carnitine</strong> supplementation) and group III were significantlydifferent from them , which may suggest the relation between low serum L-<strong>carnitine</strong> level and anemia in patients on hemodialysis.

Conclusion 121.CONCLUSION• Uremic patients on maintenance hemodialysis are liable to L-<strong>carnitine</strong>deficiency.• Hyperlipidemia, mainly hypertriglyceridemia, anemia, leftventricular dysfunction (expressed as increased left ventriculardimensions, decreased ejection fraction, and increased leftventricular mass) were found in uremic patients on maintenance HDand were frequently associated with L-<strong>carnitine</strong> deficiency.• Anemia, hypertriglyceridemia and left ventricular dysfunction werefound to improve significantly after L-<strong>carnitine</strong> supplementation inuremic patients on maintenance HD.

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-الملخص العربىتعتبر أمراض القلب من أهم أسباب الوفاة لدى مرضى الفشل الكلوى المزمن والمعاشينعلى الاستصفاء الدموى.‏هدف هذا البحث دراسة دور ل آارنتين فى مرضى الفشل الكلوى المزمن المعاشين علىالاستصفاء الدموى وعلاقته بمضاعفات القلب والأوعية الدموية لدى هؤلاء المرضى.‏وقد اشتمل هذا البحث على 60 شخص آالآتى:‏المجموعة الأولى:‏ اشتملت علىبالعلاج التحفظى,‏1040مرضى يعانون من قصور فى وظائف الكلى ويعالجونالمجموعة الثانية:‏ اشتملت على مريض يعانون من فشل آلوى مزمن ويعالجون بالاستصفاءالدموى لمدة أآثر من6 شهور.‏وانقسمت هذه المجموعة إلى مجموعتين فرعيتين:‏–اشتملت هذه المجموعة على 20 مريض يعانون من فشل آلوى مزمن ومعاشين علىالاستصفاء الدموى وتم علاجهم بأقراص ل آارنتين 1 جم فى اليوم ولمدة6 شهور.‏•–•اشتملت هذه المجموعة على 20 مريض يعانون من فشل آلوى مزمن ومعاشين علىالاستفصاء الدموى ولم يتم علاجهم با ل آارنتين.‏المجموعة الثالثة:‏ اشتملت على–10أشخاص أصحاء وهى المجموعة الضابطة.‏تم أخذ التاريخ المرضى للمرضى وعمل فحص شامل وعمل تحليلات روتينية آاملة لكلمن شملتهم الدراسة مع قياس مستوى ل آارنتين بالدم ومستوى الدهون بالدم وآذلك عمل موجاتفوق صوتية على القلب.‏

أسفرت النتائج فى الدراسة عن الآتي:‏أظهرت الدراسة أن آلاً‏ من المجموعتين الثانية ‏[مرضى الفشل الكلوى المعاشين على‏[مرضى الفشل الكلوىالاستصفاء الدموى والذين لم يعالجوا با ل آارنتين]‏المعاشين على الاستصفاء الدموى قبل علاجهم با ل آارنتين]‏ بها اختلافات عن المقاييس الطبيعيةفى فحص القلب بالموجات وآذلك انخفاض بمستوى ل آارنتين بالدم وذلك قد يفسر أنالاستصفاء الدموى المتكرر يقلل من مستوى ل آارنتين بالدم وهو ما قد يفسر العلاقة بين ارتفاعمعدلات الإصابة والوفاة بأمراض القلب والأوعية الدموية وانخفاض مستوى ل آارنتين بالدم فىمرضى الفشل الكلوى المزمن المعاشين على الاستصفاء الدموى.‏–bوالثانية II as1–––––آما أظهرت الدراسة أن المجموعة الضابطة ‏(الثالثة)‏ لا توجد بها فروق ذات دلالةإحصائية مع المجموعة الثانية II as2 ‏[مرضى الفشل الكلوى المعاشين على الاستصفاء الدموىبعد علاجهك با ل آارنتين]‏ من حيث مستوى ل-‏ آارنتين فى الدم وآذلك من ناحية فحص القلببالموجات الصوتية.‏آذلك أظهرت هذه الدراسة أنه لا يوجد اختلاف معنوى فى مستوى الدهون فى الدم بين‏[مرضى الفشل الكلوى المعاشين على الاستصفاء الدموى والذين لم يعالجوا با لآارنتين]‏ ‏[مرضى الفشل الكلوى المعاشين على الاستصفاء الدموى قبل علاجهم با لآارنتين]‏ حيث أن آلتا المجموعتين من المرضى يعانون من ارتفاع مستوى الدهون بالدم بينما‏[مرضى الفشل الكلوى المعاشينيوجد اختلاف معنوى بين هاتين المجموعتينعلى الاستصفاء الدموى بعد علاجهم با ل – آارنتين]‏ والمجموعة الضابطة حيث آان مستوىالدهون بالدم أقل فى المجموعتين الأخيرتين مما يشير إلى احتمال وجود علاقة بين انخفاض مستوىآارنتين بالدم وارتفاع مستوى الدهون.‏والمجموعة IIas2Iالمجموعتين II b– و II as1–ل –وأظهرت الدراسةأيضاً‏ عدم وجود فروق معنوية فى مستوى الهيموجلوبين أو نسبة‏[مرضى القصور الكلوى المعالجون بالعلاج التحفظى]‏هيماتوآريت بين آل من المجموعة ‏[مرضى الفشل الكلوى المعاشين على الاستصفاء الدموى والذين لم يعالجوا با‏[مرضى الفشل الكلوى المعاشين على الاستصفاء الدموى قبلآارنتين]‏ل آارنتين]‏ وذلك يشير إلى تأثير مرض الفشل الكلوى والاستصفاء الدموى المتكررعلاجهم با ل على مستوى الهيموجلوبين بينما فى نفس الوقت هناك فرق معنوى بين هذه المجموعاتوالمجموعة الضابطة فى مستوى الهيموجلوبين بالدم مما قد يشير إلى العلاقةبين انخفاض مستوى ل – آارنتين بالدم والأنيميا فى مرضى الفشل الكلوى المعاشين علىالاستصفاء الدموى المتكرروالمجموعة IIb– والمجموعة IIas1–والمجموعة IIas2ويستخلص من الدراسة أهمية الحفاظ على مستوى ل ‏–آارنتين بالدم فى المعدلات الطبيعيةلتجنب المضاعفات الناتجة عن انخفاض مستوى ل – آارنتين فى مرضى الفشل الكلوى المزمنالمعاشين على الاستصفاء الدموى المتكرر.‏