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Hepatorenal syndrome

Hepatorenal syndrome. P. Angeli D ept. of Clinical and Experimental Medicine Universit y of Pad ova (Italy). TReviso 8 Giugno 2009. Hepatorenal syndrome (HRS). Definition of HRS.

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Hepatorenal syndrome

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  1. Hepatorenal syndrome P. Angeli Dept.ofClinical and Experimental Medicine Universityof Padova (Italy) TReviso 8 Giugno 2009

  2. Hepatorenal syndrome (HRS) Definition of HRS HRS is a functional renal failure caused by intrarenal vasoconstriction which occurs in patients with end stage liver disease as well as in patients with acute liver failure or alcoholic hepatitis. HRS is characterized by impaired renal function, marked alterations in cardiovascular function, and overactivity in the endogenous vasoactive systems. F. Salerno, et al. Gut 2007 ; 56 : 1310-1318.

  3. Hepatorenal syndrome (HRS) FUNCTIONAL RENAL ABNORMALITIES IN CIRRHOSIS Abnormality Clinical consequence • Sodium retention • Water retention • Renal vasoconstriction • Ascites and edema • Dilutional hyponatremia • Hepatorenal syndrome

  4. Hepatorenal syndrome (HRS) Peripheral arterial vasodilation “hypothesis” Portal hypertension/liver failure Increased release of NO, CO and other vasodilators Splanchnic arterial vasodilation Reduction of effective circulating volume Activation of endogenous vasocontrictor systems Renal functional abnormalities RW. Schrier, et al. Hepatology 1988 ; 8 : 1151-1157.

  5. Hepatorenal syndrome (HRS) Acute renal failure in patients with cirrhosis and ascites • Acute tubular necrosis (41.7%) • Prerenal failure (38%) • Hepatorenal syndrome (20%) • Postrenal failure (0.3%) R. Moreau, et al. Hepatology 2003 ; 37 : 233-243.

  6. Hepatorenal syndrome (HRS) New Diagnostic Criteria • Cirrhosis with ascites; • Serum creatinine > 133 µmol/l (1.5 mg/dl); • No sustained improvement of serum creatinine (decrease to a level of 133 µmol/l or less) after at least two days of diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day to a maximum of 100 g/day; • Absence of shock • No current or recent treatment with nephrotoxic drugs; • Absence of parenchimal disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells per high power field) and/or abnormal renal ultrasonography. F. Salerno, et al. Gut 2007 ; 56 : 1310-1318.

  7. Hepatorenal syndrome (HRS) Clinical types Type 1 HRS : rapidly progressive reduction of renal function as defined by a doubling of the initial serum creatinine to a level > 226 µmol/l or 2.5 mg/dl in less than two weeks. It may occurs spontaneously, but it can also follow a precipitating event. Clinical pattern: acute renal failure Type 2: is characterized by moderate renal failure (serum creatinine from 133 to 226 µmol/l or 1.5 to 2.5 mg/dl) with a steady or slowly progressive course. Clinical pattern: refractory ascites F. Salerno, et al. Gut 2007 ; 56 : 1310-1318.

  8. Hepatorenal syndrome (HRS) Probability of survival in patients with HRS % P < 0.001 Type 2 HRS Type 1 HRS 2 4 6 8 10 12 months P. Gines, et al. Lancet 2003 ; 362 : 1819-1827.

  9. Hepatorenal syndrome (HRS) Clinical types Type 1 HRS : rapidly progressive reduction of renal function as defined by a doubling of the initial serum creatinine to a level > 226 µmol/l or 2.5 mg/dl in less than two weeks. It may occurs spontaneously, but it can also follow a precipitating event. Clinical pattern: acute renal failure Type 2: is characterized by moderate renal failure (serum creatinine from 133 to 226 µmol/l or 1.5 to 2.5 mg/dl) with a steady or slowly progressive course. Clinical pattern: refractory ascites F. Salerno, et al. Gut 2007 ; 56 : 1310-1318.

  10. Hepatorenal syndrome (HRS) Precipitating events • Spontaneous bacterial peritonitis • Paracentesis without plasma expansion • Gastrointestinal hemorrhage • Alcoholic hepatitis • Unknown

  11. Hepatorenal syndrome (HRS) Prevalence and types of renal failure (RF) precipitated by spontaneous bacterial peritonitis (SBP) Cirrhotic patients with ascites and SBP (n° 116) • Renal failure 29 25.0 • Onset of renal failure 10 8.6 • Impairment of pre-existing renal failure 20 17.2 • Type 1 HRS 19 16.4 n ° % P. Angeli, et al. Aliment. Pharmacol. Ther. 2006 ; 23 : 75-84.

  12. Hepatorenal syndrome (HRS) Prevalence of renal failure in the different types of bacterial infections in patients with cirrhosis and ascites (%) P < 0.0001 P < 0.0001 Subdiaphramatic Infections S. Fasolato, et al. Hepatology 2007 ; 45 : 223-229.

  13. Hepatorenal syndrome (HRS) Predictive factors of the deveopment of renal failure in cirrhotic patients with ascites • High MELD score • High peak count of neutrophyl leukocyte in blood • Lack of resolution of infection S. Fasolato, et al. Hepatology 2007 ; 45 : 223-229.

  14. Hepatorenal syndrome (HRS) Plasma levels of endotoxin in patients with cirrhosis with and without SBP * = P < 0.01 vs cirrhosis without SBP pg/ml * M. Navasa, et al. Hepatology 1998 ; 27 : 1227-1232.

  15. Hepatorenal syndrome (HRS) Correlation between serum level of nitrite and nitrate (NOx) and plasma level of endotoxin in patients with cirrhosis r = 0.65, P < 0.001 ° ° ° ° NOx (nmol/ml) ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° 50 100 150 200 250 Endotoxin (pg/ml) C. Guarner et al. Hepatology 1993 ; 18 : 1139-1148.

  16. Hepatorenal syndrome (HRS) CO-Hb (%) Carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis (SBP) * = P < 0.01 vs the other groups * D. De Las Heras, et al. Hepatology 2003 ; 38 : 452-459.

  17. Further increased release of NO, CO and other vasodilators Bacterial infections Further splanchnic arterial vasodilation Further reduction of effective circulating volume Maximal activation of endogenous vasocontrictor systems Chronic liver failure (CLF) Peripheral arterial vasodilation “hypothesis” Portal hypertension/liver failure Severe renal arterial vasoconstriction RW. Schrier, et al. Hepatology 1988 ; 8 : 1151-1157.

  18. Hepatorenal syndrome (HRS) Plasma renin activity (ng/ml/hr) Characteristics of patients with cirrhosis and SBP-precipitated HRS P < 0.05 M. Navasa, et al. Hepatology 1998 ; 27 : 1227-1232.

  19. Hepatorenal syndrome (HRS) Systemic heamodynamics before and after the onset of HRS after the resolution of SBP 5 L. Ruiz-del-Arbol, et. al. Hepatology 2003 ; 38 : 1210-1218.

  20. Hepatorenal syndrome (HRS) Systemic heamodynamics before and after the onset of type 1 HRS in patients with cirrhosis and ascites without a precipitating factor 5 L. Ruiz-del-Arbol, et. al. Hepatology 2005 ; 62 : 439-447.

  21. Hepatorenal syndrome (HRS) EFFECTIVE CIRCULATING VOLUME Circulatory dysfunction in HRS Cardiac output Changes Splanchnic arterial vasodilation Cirrhosis Ascites Type 1 HRS Time V. Arroyo, et. al. J. Hepatol. 2007 ; 46 : 935-946.

  22. Hepatorenal syndrome (HRS) Portal pressure (mm Hg) Pathophysiology of HRS precipitated by SBP * = P < 0.025 vs value at diagnosis * HRS HRS No HRS No HRS L. Ruiz-del-Arbol. et. al. 2003 ; 38 : 1210-1218.

  23. Hepatorenal syndrome (HRS) Portal pressure (mm Hg) Pathophysiology of HRS non precipitated by SBP * = P < 0.05 vs value before HRS * L. Ruiz-del-Arbol, et. al. Hepatology 2005 ; 62 : 439-447.

  24. Hepatorenal syndrome (HRS) Hepatic blood flow (ml/nin) Pathophysiology of HRS non precipitated by SBP * = P < 0.005 vs value before HRS * L. Ruiz-del-Arbol, et. al. Hepatology 2005 ; 62 : 439-447.

  25. Hepatorenal syndrome (HRS) Effects of albumin infusion on morbility and mortality due to SBP P. Sort, et al. N. Engl. J. Med. 1999 ; 341 : 403-409.

  26. Hepatorenal syndrome (HRS) Plasma renin activity (ng/ml/h) # = P < 0.005 * = P < 0.001 # * * P. Sort, et al. N. Engl. J. Med. 1999 ; 341 : 403-409.

  27. Hepatorenal syndrome (HRS) Cardiac index (l/ml/m2) * = P < 0.025 vs other group * J. Fernandez, et al. J. Hepatol. 2004 ; 41 : 384-390.

  28. Hepatorenal syndrome (HRS) Mean plasma levels of nitric oxide and S-nitrosothiols in humans J. S. Stamler, et al. Proc. Natl. Acad. Sci 1992 ; 89 : 7674-7677.

  29. Hepatorenal syndrome (HRS) Effects of albumin vs hydroxyethyl starch on serum levels of nitrates and nitrites in cirrhotic patients with spontaneous bacterial peritonitis * = P < 0.05 vs value at diagnosis of SBP * dynsec•cm-5 J. Fernandez, et al. Hepatology. 2005 ; 42 : 627-634.

  30. Albumin reduces NO overproduction in heart Albumin reduces NO overproduction in lung ALBUMIN IN SEPSIS Effects of albumin on expression of inducible NOS (iNOS) in heart of septic mice Albumin reduces iNos expression in heart F. Meziani, et al. Am. J. Pathol. 2007 ; 171 : 1753-1761.

  31. ALBUMIN IN SEPSIS Albumin β-adgrenergic signaling in cardiac tissue

  32. Hepatorenal syndrome (HRS) Dose-responses to isoproterenol in isolated left ventricular papillary muscles from bile duct ligated- (BLD) rats and sham-operated rats. Sham BLD + L-Name (Contractility % of basal) BLD 10 - 8 10 - 7 10 - 6 10 - 5 Isoproterenol (M) H. Liu, et al. Gastroenterology 2000 ; 118 : 937-944.

  33. ALBUMIN AND OXIDATIVE STRESS Effects of albumin on cardiac contractility in cirrhotic rats 25 Control 20 Cirrhotic + albumin * 15 * Cirrhotic LVDP (mm Hg) 10 5 * = P < 0.01  0 -10.0 -9.5 -9.0 -8.5 -8.0 Log . Isoproterenol P. Angeli et al. AALSD 2007

  34. Hepatorenal syndrome (HRS) Albumin β-adgrenergic signaling in cardiac tissue

  35. Hepatorenal syndrome (HRS) β-adgrenergic signaling in cardiac tissue AC (+) 2- AR Gαs Gαs 1- AR (-) Gαi (-) RGS2 (+) (-) PDE2a cAMP (+) (+) PLN PKA L-type C a2+ Troponin I Ca2+ SR Ca 2+ (+) Myofibril G. Ceolotto, et al. Hepatology 2008 (in press).

  36. Hepatorenal syndrome (HRS) Rats with cirrhosis plus albumin * P. Angeli et al. AALSD 2007 Effects of albumin on β-adgrenergic signaling in cardiac tissue * =p < 0.01 vs controll P < 0.01 vs control * Control rats Rats with cirrhosis * * Gene Expression (∆∆Ct) * RGS2 PDE2A Gαi2 Adcy3 G. Ceolotto, et al. Hepatology 2008 (in press).

  37. Hepatorenal syndrome (HRS) Effects of albumin vs hydroxyethyl starch on cardiac function in cirrhotic patients with spontaneous bacterial peritonitis * = P < 0.01 vs value at diagnosis of SBP * g  m/m2 J. Fernandez, et al. Hepatology. 2005 ; 42 : 627-634.

  38. Hepatorenal syndrome (HRS) The therapeutic approaches to HRS • TIPS • Vasoconstrictors plus albumin • Extracorporeal liver/renal support

  39. Hepatorenal syndrome (HRS) Effects of midodrine plus octreotide and albumin in cirrhotic patients with ascites and HRS Plasma renin activity (ng/ml/hr) * = P < 0.01, ** = P < 0.005 vs basal * ** ** P. Angeli , et al. Hepatology 1999 ; 29 : 1690-1697.

  40. Hepatorenal syndrome (HRS) Pharmacologic therapy for HRS (1) • Albumin (20-40 g/day intravenously) • Terlipressin (0.5-2 mg/4hr or 2-12 mg/24hr intravenously) J. Uriz, et al. J. Hepatol. 2000 ; 33 : 43-48. P. Angeli, et al. Aliment. Pharmacol. Ther. 2006 ; 23 : 75-84.

  41. Hepatorenal syndrome (HRS) Pharmacologic therapy for HRS (2) • Albumin (20-40 g/day, intravenously) • Midodrine (7.5-12.5 mg t.i.d, orally) • Octreotide (100-200 µg t.i.d, subcutaneously) P. Angeli, et al. Hepatology 1999 ; 29 : 1690-1697. F. Wong, et al. Hepatology 2004 ; 40 : 55-64. • Albumin (20-40 g/day, intravenously) • Noradrenalin (0.5-3 mg/hr, intravenously) C. Duvoux, et al. Hepatology 2002 ; 36 : 374-380. C. Alessandria, et al. J. Hepatol. 2007 ; 47 : 499-505.

  42. Hepatorenal syndrome (HRS) Probability of survival in cirrhotic patients with ascites and type 1 HRS tretaed with terlipressin and albumin vs albumin Terlipressin plus albumin P < 0.0001 Albumin 0-15 days 15-30 days 30-60 days 60-90 days 90-180 days S. Neri, et al. Dig. Sis. Sci. 2008 ; 53 : 830-835.

  43. Hepatorenal syndrome (HRS) Terlipressin and albumin vs albumin in cirrhotic patients with ascites and type 1 HRS in two controlled clinical trials Spain Trial (n° = 45)1 USA Trial (n° = 112)2 * = p <0.025 ; # = p < 0.01 1) M. Martin-Llhai, et al. Gastroenterology 2008 ; 134 : 1352-1359 2) A. Sanyal, et al. Gastroenterology 2008 ; 134 : 1360-1368.

  44. Hepatorenal syndrome (HRS) Predictive value of Child-Pugh score (CPT) on survival in patients treated with terlipressin and albumin for Type 1 hepatorenal syndrome % CPT < 11 P < 0.025 CPT  11 30 60 90 days R. Ortega, et al. Hepatology 2002 ; 36 : 941-948.

  45. Hepatorenal syndrome (HRS) Recovery of renal function according to the use of albumin % Terlipressin plus albumin P < 0.05 Terlipressin 2 4 6 8 10 12 days R. Ortega, et al. Hepatology 2002 ; 36 : 941-948.

  46. Hepatorenal syndrome (HRS) Terlipressin and albumin vs albumin in cirrhotic patients with ascites and type 1 HRS in two controlled clinical trials Spain Trial (n° = 45)1 USA Trial (n° = 112)2 * = p <0.025 ; # = p < 0.01 1) M. Martin-Llhai, et al. Gastroenterology 2008 ; 134 : 1352-1359 2) A. Sanyal, et al. Gastroenterology 2008 ; 134 : 1360-1368.

  47. Hepatorenal syndrome (HRS) Effects of terlipressin on systemic haemodynamics and regional blood flow in cirrhosis M. Kiszka-Kanowitz, et al. Scand. J. Gastroenterol. 2004 ; 5 : 486-492.

  48. Hepatorenal syndrome (HRS) Cardiac output in cirrhotic patients according to the Child-Pugh-Turcotte class (ml/min) * = P < 0.025 * * = P < 0.01 * * * * K. Brinch, et al. J. Hepatol. 2003 ; 39 : 24-31.

  49. Hepatorenal syndrome (HRS) Effects of terlipressin on systemic haemodynamics and regional blood flow in cirrhosis M. Kiszka-Kanowitz, et al. Scand. J. Gastroenterol. 2004 ; 5 : 486-492.

  50. Hepatorenal syndrome (HRS) Effects of inhibition of inducibile nitric oxide synthesis by L-NIL on the contractile responses to phenylephrine (PHE) in isolated aortas in LPS-treated cirrhotic rats * Contraction (g) * * * = P < 0.05 (log M PHE) L-NIL placebo R. Moreau et al. Hepatology 2002 ; 36 : 1070-1078.

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