Hepatorenal syndrome a defined entity with a standard treatment?

Transcription

1 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

2 Hepatorenal syndrome has a very poor prognosis - treatment and prophylaxis are urgent! Ruiz-Del-Arbol et al., Hepatology 2005;42:

3 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:

4 New diagnostic critera of HRS Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Gut 2007;56: 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

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6 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:

7 Therapeutic approaches for HRS Paracentesis Dopamine Liver transplantation TIPS Vasoconstrictors + Albumin

8 Renal function determines short- and long-term outcome in patients after liver transplantation Nair S et al. Hepatology 2002;35:

9 Renal ischemia with HRS : a functional disorder - normal angiogram post mortem

10 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

11 TIPS for controlled reduction of portal hypertension

12 TIPS increases central blood volume Wong F et al.;gastroenterology 1997;112:

13 Survival following TIPS for HRS HRS Type I 9/23: very poor liver function no TIPS 1.0 Survival probability p=0.025 HRS Type II (n=17) HRS Type I (n=14) Weeks Brensing KA et al., Gut 2000;47:

14 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

15 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

16 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:

17 Ornipressin and Albumin for HRS Type I Urinary Sodium Excretion 80 Ornipressin Creatinine Clearance Ornipressin [mmol/24 h] 40 [ml/min] day day Gülberg V et al., Hepatology 1999; 30:

18 Vasoconstrictor Terlipressin in HRS Type 1 Author Ganne-C 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 ± ± Duration (days) ± ± 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

19 Terlipressin for HRS type 1 prospective randomized trials Placebo Terlipessin Crea < 1.5 mg/dl 13% (9%) 34% (39%) * Crea mg/dl * SAE 1% 9% Sanyal A, AASLD 2006 (Martin-Llahi M, EASL 2007)

20 Terlipressin for HRS type 1 - responders show improved survival Moreau R et al., Gastroenterology 2002;122:

21 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

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23 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:

24 Albumindialyse bei Hepatorenalem Syndrom Endpunkt: 30 Tage Überleben MARS + HDF HDF Patientenzahl 8 5 CP score 12.5 ± ± 0.8 Ergebnisse Kreatinin (mg/dl) * Bilirubin (mg/dl) 27 17* Mortalität Tag Tag Mitzner S et al, Liver Transpl 2000;6:

25 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* Kreatinin (mg/dl) 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:

26 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:

27 TIPS increases urinary sodium excretion in patients with refractory ascites p = 0.05 UNaV UNaV mmol/24 h before TIPS 7 days after TIPS Gerbes AL et al., Hepatology 1998; 28:

28 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

29 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