Medical Treatment of Hepatorenal Syndrome - AASLD

Thomas D. Boyer, MDHepatorenal SyndromeNo relationships to disclose.Content of the presentation does not include discussion of off-label /investigative use of medicine(s), medical devices, or procedure(s).

Hepatorenal syndromeThomas D Boyer, MDUniversity of Arizona

Conflicts of interest• Member advisory board for Orphantherapeutics-makers of terlipressin• Off label drugs• Terlipressin• Octreotide• Midodrine

Cirrhosis Evolves Clinically FromCompensated to DecompensatedStage• Compensated cirrhosis• Cirrhosis without complications• Median survival >12 years• Decompensated cirrhosis• Cirrhosis with complications: ascites(± HRS), variceal hemorrhage, jaundice, orencephalopathy• Annual rate of decompensation of 4-5%• Median survival ~1.5 yearsD'Amico G, et al. J Hepatol. 2006;44:217–231.

Pathogenesis of Ascites in CirrhosisCirrhosisIntrahepatic resistancePortal (sinusoidal) hypertensionSplanchnic vasodilatationEffective arterial blood volumeActivation of neurohumoral systemsAscitesSodiumretention

Common Pathogenesis in RefractoryAscites, Hyponatremia, and HRSCirrhosisIntrahepatic resistancePortal (sinusoidal) hypertensionSplanchnic/systemic vasodilatationEffective arterial blood volumeActivation of neurohumoral systemsSodiumretentionWaterretentionRenalvasoconstrictionAscitesRefractoryascitesHyponatremiaHRS

7060504030252015105Neurohumoral Systems AreMaximally Activated in HRSPlasma renin activity(ng/mL-h)80070060050040030025020015010050Plasma aldosterone activity(ng/dL)0HealthyCirrhosis Cirrhosis with asciteswithout without withascites renal renalfailure failure0Healthy CirrhosiswithoutascitesCirrhosis with asciteswithout withrenal renalfailure failureGines A, et al. Gastroenterology. 1993;105:229–236.

Causes of Renal Dysfunctionin Cirrhosis•Acute•Hypovolemia• Diuretics• Gastrointestinal bleed• Diarrhea (lactuloseinduced)•Nephrotoxic drugs• Aminoglycosides• Nonsteroidal antiinflammatorydrugs• Contrast agents•Sepsis•Acute kidney injury•Hepatorenal syndrome•Chronic•Glomerulonephritis• Hepatitis B• Hepatitis C•IgA nephropathy(alcoholic)•Diabetic nephropathy

Type and Frequency of Injury inAcute Renal Failure in CirrhosisTypeATN (ischemic)HypovolemiaHepatorenal syndromeNephrotoxic DrugsObstructionFrequencyCommonVery commonRelativelycommonCommonVery uncommon

Typical Urinalysis in RenalCausePrerenalHypovolemiaHRSIntrinsicATNAINAGDysfunction in CirrhosisOsmolality(mOsm/kg)>500>500

Workup of Renal Dysfunction in Patients withCirrhosisAcute renal failure (SCr >1.5)No AscitesWith ascitesNot HRSEvidence of organicrenal failureGet urinalysis, urine electrolytes,renal ultrasoundRule out sepsis/SBPANDStop diuretics/nephrotoxic drugsVolume expansionDecrease in SCrNo responseNot HRSHRSSBP = Spontaneous bacterial peritonitisScr = Serum Creatinine

Hepatorenal syndrome1. Hepatic insufficiency and portalhypertension2. Low GFR (< 40 ml/min) or creatinine> 1.5 mg/dl3. No shock, bacterial infection, fluid lossand current or recent treatment withnephrotoxic drugs4. No sustained improvement afterwithdrawal of diuretics and infusion of1.5 liters of saline5. Proteinuria of < 500 mg/dl andnegative renal ultrasound

Hepatorenal syndromeAdditional Criteria• Urine volume < 500 ml/d• Urine sodium < 10 meq/L• Urine osmolality > plasma• Urine RBCs < 50/hpf• Serum sodium < 130 meq/L

Hepatorenal syndrome• Type 1-Doubling of serum creatinineto > 2.5 mg/dl in less than 2 weeks.• Type 2-Moderate but steady decreasein renal function to creatinine > 2.5mg/dl.

Type 1 HRS Is Associated WithVery Poor Survival1.0.8Median SurvivalType 1 = 1.7 weeksType 2 = 6 monthsSurvivalprobability.6.4.20Type 2P = .001Type 10 3 4 6 8 10 12Time (months)Gines P, et al. Lancet. 2003;362:1819–1827

Cumulative Probability of Patients WithAscites and Cirrhosis Developing HRSProbability ofdeveloping HRS.6.5.4.3.2.1Probability of HRS1 year: 19%5 years: 39%00 1 2 3 4 5YearsGines A, et al. Gastroenterology. 1993;105:229–236.

Who Develops HRS?•Cirrhotic patients with ascites• May be preceded by precipitating factor• Spontaneous bacterial peritonitis (SBP)• Sepsis• Total paracentesis• Upper GI hemorrhage•Patients with acute alcoholic hepatitis•Patients with acute liver failure

Risk of Developing RenalDysfunction in Patients with50Cirrhosis403027%33%20107%0After GIbleedingAlcoholichepatitisCardenas A, et al. Hepatology. 2001;34:671–676Akriviadis E, et al. Gastroenterology. 2000;119:1637–1648Sort P, et al. N Engl J Med. 1999;341:403–409.Spontaneousbacterialperitonitis

Prevention of HRS

Use of Albumin in SBPPlasma reninactivity (PRA)(ng/mL/hr)25201510Cefotaxime plus albuminCefotaxime without albumin* P < .001** P < .005* * **500 3 6 9DaySort P, et al. N Engl J Med. 1999;341:403–409

Antibiotic Prophylaxis in VaricealBleeding504540*ControlAntibiotic prophylaxisFrequency ofinfections(%)3530252015** P < .05*1050All infectionsSpontaneous bacterialperitonitis (SBP)DeathBernard B, et al. Hepatology. 1999;29:1655–1661.

Vasoconstrictors andVasodilators in HRS• Vasodilators• PG• Nitric oxide• Kallikrein-Kinin system• Glucagon• Vasoconstrictors• Endothelins• AVP• NE• Renin

Prostaglandin Inhibition andEffects on Renal Function160Creatinineclearance(mL/min)1208040BaselineImmediately afterindomethacin24 hours after lastindomethacin dose0Ascites No ascitesChange in creatinine clearance after indomethacinBoyer TD, et al. Gastroenterology. 1979;77:215–222.

•Aggressive treatment of hypotension dueto bleeding•Early treatment of sepsis and spontaneousbacterial peritonitis (SBP)•Use of albumin• SBP• Large-volume paracentesis•Avoidance of nephrotoxic drugs such asaminoglycoside antibiotics and NSAIDs•Caution of use with contrast dyePrevention of Renal Dysfunctionin Cirrhosis

Treatment of HRS General• Stop all diureticsMeasures• Look for nephrotoxic drugs• Examine urine for white cells andcasts• Perform renal ultrasound• Give 1.5 liters saline/albumin• Treat infection

Treatment HRS• Dialysis• TIPS• Liver Transplantation• Vasoactive compounds

Site of Action of CurrentTherapies for HRSCirrhosisLiver transplantationTIPSPortal (sinusoidal)hypertensionSplanchnic/systemic vasodilatationEffective arterial blood volumeActivation of neurohumoral systemsVasoconstrictors+AlbuminRenalvasoconstrictionHRSTIPS, transjugular intrahepatic portosystemic shunt.

Renal ReplacementTherapy for HRS•No controlled studies of hemodialysis inHRS 1•Hemodialysis does not confer long-termsurvival without transplantation 2•Hemodialysis may be of benefit asbridge to transplantation for patientswith HRS 3 1. Gines P, et al. Nephrology. 1999;10:1833–1839.2. Witzke O, et al. J Gastroenterol Hepatol. 2004;19:1369–1373.3. Capling RK, et al. Ren Fail. 2004;26:563–568.

TIPS and HRSGut 47:166; 2000

TIPS for HRS:AASLD Practice Guidelines• Small uncontrolled trials• No comparative survival benefit shown• Common complications• TIPS thrombosis (10–15%)• TIPS occlusions/stenosis (18–78%)• Hepatic encephalopathy (20–31%)‣Not recommended for treatment of HRS,especially type 1,•pending the publication of controlled trialsAASLD, American Association for the Study of Liver Diseases.Boyer TD, et al. Hepatology. 2005;41:386–400.

Treatment of HRS:Pharmacologic Therapy

Vasoconstrictors PlusAlbumin for HRSCirrhosisPortal (sinusoidal)hypertensionSplanchnic/systemic vasodilatationEffective arterial blood volumeVasoconstrictors+AlbuminActivation of neurohumoral systemsRenalvasoconstrictionHRS

Background (II)• Synthetic 12-aminoacid peptideH• Pro-drug, with pharmacologic activityof its ownGlyGlyGlyGlyGlyCysCysTyrTyrPhePhe• Constrictive activity via V1-receptors• vascular & extravascular smooth musclecellsGlyGlyProLysLysCysCysAsnAsnGlnGln• Splanchnic vasoconstriction↓ portal flow↓ portal pressureH 2 NTerlipressin• Systemic vasoconstriction↑ effective blood volume↓ renin and angiotensin renal vasodilatation improvement in serum creatinine

SummaryEndpoint Terlipressin Placebo P-valueAll patients N = 56 (%) N = 56 (%)Treatment success day 14 14 (25) 7 (12.5) 0.093HRS reversal 19 (33.9) 7 (12.5) 0.008Received > 3 days Rx N = 36 N = 39Treatment success day 14 14 (38.9) 7 (17.9) 0.046HRS reversal 19 (52.8) 7 (17.9) 0.002

Reversal of HRS40HRS Reversal (%)30201001 3 5 7 9 11 13 15DayTerlipressinPlacebo

Terlipressin produced a significantimprovement in serum creatinine0.80.60.4Mean Change FromBaseline +/- SE0.20.0-0.2-0.4-0.6-0.81 2 3 4 5 6 7 8 9 10 11 12 13 14Day= Terlipressin = PlaceboChange from Baseline to End of Treatment in Serum Creatinine(ITT Population with Last Observation Carried Forward)

Survival DistributionFunction1.00.90.80.70.60.50.40.30.20.10.0P-value:Impact of Reversal of HRS onTransplant-Free Survival0 14(0.001)30(0.004)60(0.003)Survival (Days)90(0.001)= Censored = HRS Reversal = No HRS Reversal

Survival DistributionFunction1.00.90.80.70.60.50.40.30.20.10.0P-value:Transplant-Free Survival 90 Days0 14(0.875)30(0.477)60(0.991)Survival (Days)= Censored = Terlipressin = Placebo90(0.784)

Adverse EventsTerlipressinN=56PlaceboN=55Adverse Events 93 % 89 %Related 32 % 22 %Serious AEs 66 % 66 %Related 9 % 2 %Deaths 48 % 49 %Related 0 % 0 %Withdrawals due to AE 5 % 4 %Related 5 % 0 %

Midodrine plus Octreotideplus albumin in HRS type 1Test 0 10 20daysCreat. 5.0 4.6 3.3RPF 61 82 181Aldo. 1349 636 379PRA 17 8 5Hepatology 29:1690;1999

Impact of OLTx on RenalGlomerular filtration rate (mL/min)1009080706050403020100FunctionHRSNo HRSPretransplant 30 days 90 days 1 yearGonwa TA, et al. Transplantation. 1991;51:428–430.

HRS conclusions• HRS is a common complication of cirrhosis• Patients with HRS have a poor prognosis• Aggressive treatment of infections and useof albumin may reduce the risk ofdeveloping HRS• Do not use nephrotoxic drugs in patientswith cirrhosis

HRS conclusions continued• Exclusion of other causes of renal failureimportant in management decisions• Type 1 HRS• Refer OLTx center• May wish to try vasopressors plus albumin• Type 2 HRS• Consider use of TIPS• Refer OLTx center

Thank you