Hepatorenal syndrome a defined entity with a standard treatment? Falk Symposium 162 Dresden - October 14, 2007 Alexander L. Gerbes Klinikum of the University of Munich Grosshadern Department of Medicine II Munich, GERMANY
Hepatorenal syndrome has a very poor prognosis - treatment and prophylaxis are urgent! Ruiz-Del-Arbol et al., Hepatology 2005;42:439-447
HRS Type I: rapidly progressing renal failure (< 2 weeks) > 2-fold increase of serum creatinine to > 2.5 mg/100 ml or 50% decrease of creatinine clearance to < 20 ml/min HRS Type II: not rapidly progressing renal failure Serum creatinine > 1.5 mg/100 ml or Creatinine clearance < 40 ml/min Arroyo V, Gines P, Gerbes AL et al., Hepatology 1996;23:164-176
New diagnostic critera of HRS Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Gut 2007;56:1310-8 Type 1: Serum creatinine > 2.5 mg/dl or GFR < 20 ml/min Type 2: Serum creatinine > 1.5 mg/dl or GFR < 40 ml/min No improvement of serum creatinine after volume expansion with 1500 ml NaCl 0,9% Albumin (1g/kg/d) and diuretic withdrawal Absence of shock, ongoing bacterial infection, nephrotoxic drugs or prerenal failure
Albumin in addition to antibiotics reduces renal impairment and improves survival in SBP Renal impairment Death - in hospital - at 3 months Cefotaxim (n = 63) 21 (33%) 18 (29%) 26 (41%) Cefotaxim plus Albumin (n = 63) 6 (10%) ** 6 (10%) ** 14 (22%) * Sort P et al.,nejm 1999;341:403-409
Therapeutic approaches for HRS Paracentesis Dopamine Liver transplantation TIPS Vasoconstrictors + Albumin
Renal function determines short- and long-term outcome in patients after liver transplantation Nair S et al. Hepatology 2002;35:1179-1185
Renal ischemia with HRS : a functional disorder - normal angiogram post mortem
Pathomechanisms of ascites and HRS in cirrhosis the basis for novel therapeutic strategies Hemodynamic changes portal hypertension, peripheral vasodilatation reduced effective blood volume Neurohumoral activation Effects on renal function Hepatorenal Syndrome
TIPS for controlled reduction of portal hypertension
TIPS increases central blood volume Wong F et al.;gastroenterology 1997;112:899-907
Survival following TIPS for HRS HRS Type I 9/23: very poor liver function no TIPS 1.0 Survival probability 0.8 0.6 0.4 0.2 0.0 p=0.025 HRS Type II (n=17) HRS Type I (n=14) 0 13 26 39 52 65 78 91 104 Weeks Brensing KA et al., Gut 2000;47:288-295
Pathomechanisms of ascites and HRS in cirrhosis - the basis for novel therapeutic strategies Hemodynamic changes portal hypertension, peripheral vasodilatation reduced effective blood volume Neurohumoral activation Effects on renal function Hepatorenal Syndrome
Vasopressin receptors as therapeutic targets Terlipressin Vasopressin Desmopressin Smooth muscle V 1 V 2 kidney IP 3 PKA Ca 2+ exozytosis of aquaporine vasoconstriction antidiuresis
V1 Receptor Agonist Terlipressin modifies blood volume and hemodynamics in cirrhosis Thoracic blood volume + 6 % Liver blood volume + 12 % Syst. vascular resistance + 34 % Mean art. pressure + 21 % Kiszka-Kanowitz, Henriksen JH et al., Scand J Gastroenterol 2004;39:486-492
Ornipressin and Albumin for HRS Type I Urinary Sodium Excretion 80 Ornipressin 60 100 80 Creatinine Clearance Ornipressin [mmol/24 h] 40 [ml/min] 60 40 20 20 0-5 0 5 10 15 20 25 30 35 day 0-5 0 5 10 15 20 25 30 35 day Gülberg V et al., Hepatology 1999; 30: 870-875
Vasoconstrictor Terlipressin in HRS Type 1 Author Ganne-C. 1996 Le Moine 1998 Danalioglu 2003 Duhamel 2000 Colle 2002 Halimi 2002 Moreau 2002 Uriz 2000 Mulkay 2001 Angeli 2006 Ortega 2002 Hadengue 1998 Solanki 2003 Type of study C C R R R R R PU PU PU PC RCT RCT Success of treatment 1/1 1/1 3/7 6/12 11/18 12/16 53/99 4/6 12/12 12/19 T+A: 8/9 T-A: 1/7 6/9 T:5/12 P:0/12 135/228 Dose (M±SEM) mg/day 2 6 2-4 2-6 2.8±0.1 1.5-12 3.2±1.2 3-6 1-6 2-12 2 2 2 Duration (days) 67 30 3-14 3-10 9±1 2-16 11±12 5-15 8-14 15 4-14 2 14 Survival at 4 weeks yes yes 3/7 nd 9/18 1/16 37/99 4/6 3/12 13/19 T+A:8/9 T-A: 1/7 nd nd 81/195 Adverse events yes no no 4/12 0/18 4/16 23/99 1/6 4/12 nd 1/16 0/9 5/12 43/209 C = case; R = retrospective; PU = prospective uncontrolled; PC = prospective controlled; RCT = randomized controlled trial
Terlipressin for HRS type 1 prospective randomized trials Placebo Terlipessin Crea < 1.5 mg/dl 13% (9%) 34% (39%) * Crea mg/dl 0-0.7 * SAE 1% 9% Sanyal A, AASLD 2006 (Martin-Llahi M, EASL 2007)
Terlipressin for HRS type 1 - responders show improved survival Moreau R et al., Gastroenterology 2002;122:923-930
Take home messages Hepatorenal Syndrome HRS Type 1 is rapidly progressive with poor prognosis Infections, particularly SBP have a high risk for HRS. Therefore, prophylaxis with albumin is recommended for pts. with SBP Patients with HRS waiting for liver transplantation should be offered TIPS (at bilirubin < 3-5 mg/dl) or vasoconstrictors (Terlipressin) plus Albumin These novel therapeutic strategies seem to improve short-term survival
Noradrenalin vs terlipressin for HRS ( 9 HRS type 1, 13 HRS type 2 ) noradrenalin and albumin terlipressin and albumin Alessandria C. et al., J Hepatol 2007;47:499-505
Albumindialyse bei Hepatorenalem Syndrom Endpunkt: 30 Tage Überleben MARS + HDF HDF Patientenzahl 8 5 CP score 12.5 ± 1.2 12.2 ± 0.8 Ergebnisse Kreatinin (mg/dl) 3.8 2.3* 4.4 3.8 Bilirubin (mg/dl) 27 17* 24 22 Mortalität Tag 7 5 5 Tag 30 6 5 Mitzner S et al, Liver Transpl 2000;6:277-286
Albumindialyse bei äthyltoxischer Zirrhose und akuter Verschlechterung durch Infektion oder AH Bilirubin > 6 mg/dl und (HRS oder HE II), Fallzahl-Planung: 20; 40% Senkung des Bilirubins nach 7 Tagen MARS + SMT SMT Patientenzahl 9 9 Alkohol. Hepatitis 5 3 HRS Typ 1/2 3/2 2/3 CP score 13 (11-14) 12 (10-13) Ergebnisse Bilirubin (mg/dl) 23 11* 14 16 Kreatinin (mg/dl) 1 1 1.3 0.8 Enzephalopathie (Grad) 2.5 1* 2 2 Mortalität Krankenhaus 5 5 HRS 3 3 Kein Effekt auf Blutdruck, Zytokine, ROS, Ammoniak Sen S et al, Liver Transpl 2004;10:1109-1119
Our results certainly suggest that the liberal unrestricted use of MARS outside of a research setting should be discouraged until such data is available. Sen S,et al., Jalan R, Liver Transpl 2004;10:1109-1119
TIPS increases urinary sodium excretion in patients with refractory ascites 120 100 p = 0.05 UNaV UNaV mmol/24 h 80 60 40 20 0 before TIPS 7 days after TIPS Gerbes AL et al., Hepatology 1998; 28: 683-688
Vasopressin receptors as therapeutic targets Terlipressin Vasopressin Desmopressin Smooth muscle V 1 V 2 kidney IP 3 PKA Ca 2+ exozytosis of aquaporine vasoconstriction antidiuresis
Pathomechanisms of ascites and HRS in cirrhosis - the basis for novel therapeutic strategies Hemodynamic changes Portal hypertension, peripheral vasodilatation Reduced effective blood volume Neurohumoral activation Effects on renal function Ascites, Hepatorenal Syndrome