Hepatorenal syndrome

Hepatorenal syndrome

Speaker: Dr.S.Ragavendra Preceptors: Dr. Ashutosh Biswas

Dr. Anoop SarayaDr. Sandeep

Mahajan

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Overview• Historical Perspective

• Definition of Hepatorenal syndrome(HRS)

• Types of HRS

• Natural History

• Pathogenesis

• Prevention

• Management

• Conclusion

Historical Perspective… Association between kidney dysfunction and liver diseases-

Frerichs (1877). Observed oliguria with ascites

Absence of urinary protein and low urinary sodium excretion- Hecker and Sherlock (1956)

Functional nature- Koppel et al (1960). Done kidney Tx from HRS patients

Recovered renal dysfunction after liver Tx- Iwasuki et al (1970)

Later, Schroeder et al - renal vasoconstriction in HRS

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Hepatorenal syndrome (HRS)

International ascites club defined HRS as a syndrome that occurs in patients with cirrhosis, portal hypertension and advanced liver failure, characterized by impaired renal function with marked abnormalities in the arterial circulation and activity of endogenous vasoactive systems

Is a functional disorder

Kidneys - histologically normal

Arroyo V et al, Hepatology 1996;23:164e76

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International ascites club (IAC) diagnostic criteria

Major Criteria:o Chronic or acute liver disease with advanced hepatic failure and

portal hypertensiono Low GFR ~ S.cr >1.5mg/dl or 24 hr creatinine clearance <40ml/mino Absence of shock, ongoing bacterial infections, and current or

recent Rx with nephrotoxic drugso Absence of GI fluid losseso Absence of renal fluid losses in response to diuretic therapyo No sustained improvement in renal function after diuretic

withdrawal and expansion of plasma volume with 1.5 liters of isotonic saline

o Proteinuria <500mg/day, and no USG e/o obstructive uropathy or parenchymal renal disease

Arroyo et al, Hepatol, 1996

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International ascites club (IAC) diagnostic criteria

Minor criteriao Urine volume <500ml/dayo Urine sodium <10mmol/Lo Urine osmolality > Plasma osmolalityo Serum Na <130mmol/Lo Urine RBC <50/hpf

Arroyo et al, Hepatol, 1996

New IAC diagnostic criteria 2007

Salerno et al, Gut 2007

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Rationale for the proposed diagnostic criteria for HRS

Serum creatinine (> 1.5 mg%) to establish reduced GFR – consensus

Volume expansion to exclude pre-renal causes

Volume replacement: saline vs albumin

Shock preceding renal failure – a pointer towards “ATN”

Transient AKI due to sepsis – should resolve with antibiotics

Nephrotoxic drugs – commonly used

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Stage Migration

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Rationale for the proposed diagnostic criteria for HRS

Intrinsic renal disease and obstructive uropathy to be ruled out

Urine volume, Urine Na, urine : plasma osmolality

–

o Parameters traditionally used to differentiate

functional renal failure from ATN

o Removed from the revised diagnostic criteria

o Reason: parameters not exclusive for either of

the entities

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Causes of pseudo hepatorenal syndrome

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Types of HRS Type-1 HRS:

Rapidly progressive reduction of renal function as defined by

doubling of the initial S.cr to a level >2.5 mg/dL in < 2 wk

o Clinical pattern: acute renal failure

Type-2 HRS:

Moderate renal failure (S.cr ranging from 1.5 to 2.5 mg/dL)

with a steady or slowly progressive course

o Clinical pattern: refractory ascites

Salerno et al, Gut 2007

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Type 1 vs Type 2 HRS

Probability of survival: Type 1 vs Type 2

Alessandria et al, Hepatol 2005

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Type 3 HRS Recently defined type 85% of end-stage cirrhotics - intrinsic renal

disease on Kidney Bx Allessandria C. Hepatology 2005

Cirrhotics + pre existing renal dysfunction can develop superimposed HRS

Renal histology may be required to accurately diagnose cause of renal failure

May require liver-kid transplant. Never studied in therapeutic trials.

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Type 4 HRS

> 50 % of ALF develop HRS.

Rarely refractory ascites and PHT

Very poor prognosis esp. if ALF acetaminophen-

related.

Pathophysiology ? similar. Lack of studies.

Moore K; Eur J Gastroentrol Hepatol.1999

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S.creatinine: prognostic value

MELD o Score based on creatinine, bilirubin, INRo Predicts mortality in patients undergoing TIPSo Organ allocation based on the scoreo Gives an idea about the requirement of RRT post LTo Predicts short term and long term survival in ESLDo Predicts mortality in variceal bleeding, sepsis and

alcoholic hepatitiso Predicts mortality in HCC resection, cardiac and

abdominal surgerieso Refinements - ∆MELD, MELD-Na

Pathophysiology

Pathogenesis

Gines and Schrier, N Engl J Med, 2009

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Pathogenesis

Endogenous vasoactive factors

Arch intern med 1993

Peripheral vasodilation hypothesis

Arroyo V et al, J Hepatol 2008

Changes in cardiac output

Ruiz-del-Arbol et al, Hepatol 2005

N = 66 nonazotemic cirrhotic patients

40% developed HRS during the study follow up of 1 year

Modified peripheral vasodilation hypothesis


Regional hemodynamics

Guevara et al, Hepatol 1998

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Adrenal dysfunction

Tsai et al, Hepatol 2006

Multiorgan failure & HRS


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Cirrhosis to HRS: Natural progression

Ramon Planas et al, Clin Gastroenterol Hepatol 2006

DH RA

Type 1 Type 2

Ascites to HRS: Natural progression

Gines et al, Gastroenterol 1993

18%

39%

Prevention

Prevention of HRS SBP: IV albumin administration

Severe acute alcoholic hepatitis: Oral pentoxyphylline

Low protein ascites: Norfloxacin as 1o SBP prophylaxis

Large volume paracentesis: IV albumin to prevent paracentesis induced circulatory dysfunction (PICD)

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Arroyo V, et al N Engl J Med 1999;341:407

Prevention of HRS SBP: IV albumin administration

Arroyo V, et al N Engl J Med 1999;341:407

Severe acute alcoholic hepatitis: Oral pentoxyphylline

Akriviadis E et alGastroenterology 2000

Low protein ascites: Norfloxacin as 1o SBP prophylaxis

Large volume paracentesis: IV albumin to prevent PICD

Management

Management of HRS Liver transplantation is the only definitive

treatment option

Renal failure at time of transplant has poorer outcomes

Bridge to Liver Transplantation needed

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Initial Management checklist

Admission to monitored care setting with Vitals montiroing

Central line placement for CVP helpful, not mandatory

Routine blood and urine investigations Abdominal USG Diagnostic paracentesis Discontinue diuretics Plasma expansion with albumin Evaluation for Orthoptic liver transplantation

Pharmacologic therapy

Randomized trials on type 1 or type 2 HRS Treatments compared:

1. Terlipressin (+ albumin) vs no intervention, albumin or NA + albumin

2. Octreotide + albumin vs albumin

3. Terlipressin + albumin given as continuous or bolus infusion

N=376

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Other drugs Noradrenaline + albumin

o Results similar to terlipressino Cheapero 0.1 mcg/kg/min infusion (max 0.7)

Alessandria et al, J hepatology 2007

Midodrine and octreotideo Oral α adrenergic agonist + long acting s/c somatostatin

analogueo Direct vasoconstrictor + inhibits endogenous vasodilatorso 5 mg tds + 100mcg tds s/co Given along with albumino OPD use. Not studied for Type 2

Angeli p;Hepatology.1999

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Other drugs Misoprostol

o Synthetic-PGE1o Patients have low urinary levels of vasodilatory

prostaglandinso Evidence poor

Gines;J Hepatol.1993

Renal vasoconstrictor antagonistso Saralasin - Angitensin II receptor antagonist -worsening hypotension, abandoned

o Endothelin antagonists- non specific tezosentan Endothelin A receptor antagonist(BQ123)

Soper CP;Lancet.1996

TIPS(Transjugular intrahepatic portosystemic

shunting) Few studies available (case series)

Decreases portal pressure and consequently reduces renal sympathetic activity

Improvement in renal function and survival noted compared to no treatment (but may take several weeks)

Careful patient selection needed to optimize safety and efficacy

Guevara et al,hepatology 1998;28:416-22

Renal replacement therapy

Paucity of datao Optimal method not knowno Impact on prognosis not knowno No studies in comparison with medical Rx

To be used in patients with an urgent indication of HD and for patients with no response to vasoconstrictor therapy

Available studies:o Keller et al, Ren Fail, 1995 – retrospective analysis, n = 26, better

survivalo Witzke et al, J Gastroenterol Hepatol, 2004 – prospective

observational study, n = 30, RRT not predictive of improved survival

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Artificial hepatic support

Detoxification treatment ~ form of artificial extracorporeal liver support.

Considered to be a bridge to liver transplantation Liver dialysis devices –

o Molecular Adsorbents Recirculation System

(MARS)

o Single Pass Albumin Dialysis (SPAD)

o Prometheus system

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Molecular adsorbent recirculating system (MARS)

Most frequently used albumin dialysis system

Dialysate recirculated and perfused online through charcoal and anion exchanger columns

Improve systemic hemodynamics and renal perfusion.

Better than HD for sodium,creatinine, bilirubin and PT

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MARS

Liver transplantation

Treats the causative organ dysfunction

1 yr survival rate: not on HD – 78.8% , on HD – 73.7%

survival with s.cr at similar MELD scores (at 15-17 and 24-40)

Similar 2 yr and 5 yr survival among non HRS and HRS LT

Beneficial outcomes with renal protective immunosuppression

Schmitt et al, Transpl Int 2009

Sharma et al, Liver Transpl 2009

Jeyarajah et al, Transplantation 1997

Lopez Lago et al, Transplant Proc 2007

Liver-Kidney transplantation

Usual norms:o Preoperative HRS/ ATN usually don’t need KTPo Many times 1o renal disease can be managed

medically

Factors contributing to renal failure:o Improved medical management leading to

better survivalo Long waiting time for transplanto Post-LT calcineurin inhibitors


Issues to be addressed pre-LT:o Will the ARF reverse?o Is there a way to predict who will recover?o What is the acceptable degree of recovery?

Patients of HRS who required prolonged HD (> 4 - 8 wks) may require KLT and better outcomes have been reported

Ruiz et al, Arch Surg 2006


Tanriover et al, Transplantation 2008

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Summary

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Conclusion

Prevention is utmost important

Low threshold to diagnose and investigate renal failure in presence of liver dysfunction.

Early diagnosis and timely therapeutics can increase life expectancy for HRS patients while these are waiting for liver transplantation as a definitive treatment.

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THANK YOU

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Ques to be answered Definitions.. Fluid therapy Cvp based? Do pts develop structural changes? Therapy lacunae?

SummaryDecompensated cirrhosis with renal failure

Rule out pre-renal causes: stop diuretics, volume expansion (NS or albumin), CVP measurement

Rule out intrinsic and obstructive renal disease: urine analysis, USG KUB, check out nephrotoxic drugs

Surveillance for sepsis, low threshold for antibiotics usage

Medical mx to increase urine output and improvizing KFT, optimization of diuretics and management of refractory ascites,

dialyze as per clinical indication

TIPS/List for LT

Triple therapy vs Terlipressin

Type I (n=23) Type II (n=14)

HRS (n=37)

Terlipressin (n=12)Triple (n=11) Triple (n=10) Terlipressin (n=4)

Terlipressin in Type I HRS

Variable Pre-treatment Post-treatment p-value

Urine output 275.5±184.4 1169.4±790.7 0.02

S Creatinine 2.9±1.0 2.6±1.9 0.3

Blood urea 118.7±38.8 118.8±88.1 0.9

Urine sodium 21.7±12.9 72.3±36.7 0.02

Albumin 2.7±0.6 2.8±0.5 0.4

Triple therapy in Type I HRS


Urine output 335.0±247.3 1061.0±645.8 0.02

S Creatinine 3.7±1.7 3.2±3.1 0.4

Blood urea 137.9±45.8 138.4±71.8 0.1

Urine sodium 26.9±22.3 53.8±23.1 0.01

Albumin 2.3±0.6 2.7±0.7 0.06

Terlipressin in Type II HRS


Urine output 495.0±313.1 (200-1000)

1310.0±636.7 (200-2500)

0.01

S Creatinine 2.0±0.3 (1.5-2.5) 1.3±0.7 (0.7-2.7) 0.02

Urine sodium 10.4±9.2 (1-30) 51.3±34.7 (8-126) 0.008

Triple therapy in Type II HRS


Urine output 512.5±295.5 (150-800)

1675.0±670.2 (700-2200)

0.06

S Creatinine 2.0±0.4 (1.6-2.4) 1.4±0.7 (0.8-2.4) 0.1

Urine sodium 11.7±12.1 (1-29) 103.5±36.1 (78-129) 0.1

HRS-I: terlipressin vs triple therapy

Variable p-value

Increase in urine output 0.5

Decrease in S. creatinine 0.3

Increase in 24 hour urine sodium

0.3

Variable p-value

Increase in urine output 0.4

Decrease in S. creatinine 0.8

Increase in 24 hour urine sodium

0.1

HRS-II: terlipressin vs triple therapy

Education

Hepatorenal syndrome