KEY WORDS: hepatorenal syndrome, liver cirrhosis, albumin, terlipressin

2009; 15: 227 233 1 1 1 1 1 1 1 1 1 1 1 2004 2009 929 1.5 mg/dl 142 International Ascites Club 1 106 27 1 1 Child-Pugh score 12.4 15.1 mg/dl 3.22 mg/dl 16 5 6 21 terlipressin 11 11 1 1 Terlipressin 16 15 12 1 25 KEY WORDS: hepatorenal syndrome, liver cirrhosis, albumin, terlipressin Narahara Y 1, Kanazawa H 1, Fukuda T 1, Harimoto H 1, Matsushita Y 1, Kidokoro H 1, Katakura T 1, Atsukawa M 1, Nakatsuka K 1, Sakamoto C 1 : Incidence, clinical characteristics, treatment and prognosis of type 1 hepatorenal syndrome: A single institution experience. JJPH 2009; 15: 227 233 I. 1 2 1, 2 1 spontaneous bacterial peritonitis: SBP 3, 4 1 transjugular intrahepatic portosystemic shunt: TIPS 3, 4 19 5 5, 6 1 1 International Ascites 1 113-8603 1-1-5 1 Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603 Japan 2009 6 12 2009 8 3 Club IAC 3, 7 1 IAC 1 IAC 1 retrospective II. 2004 1 2009 3 929 creatinine: Cre 1.5 mg/dl 142 8 10 Cre 50 1.5 mg/dl Cre 1.5 mg/dl Cre 50 9 2009; 15: 227 233 227

1 1.5 L 1 12.5 g 1 L plasma volume expansion Cre creatinine clearance: Ccr Cre Ccr 1 1996 IAC 7 Major criteria 5 2 Cre 2.5 mg/dl Ccr 50 20 ml/min 1 2 2005 2 2006 9 IAC 1 5 terlipressin pilot study 11 2007 5 1 terlipressin 1 6 6 terlipressin 11 1 142 IAC 1 mean S.D., Wilcoxon p 0.05 Kaplan-Meier III. 1 1 142 21 1 14 36 106 84 22 22 18 3 1 84 44 40 23 12 8 1 27 1 13 2 1 3 25 1 2 1 27 12 27 20 1 1 β Ca 8 1 1 6 1International Ascites Club Major criteria 1 2 Creatinine 1.5 mg/dl creatinine clearance 40 ml/min 3 4 1.5 L plasma volume expansion 5 500 mg/day Additional criteria 1 500 ml/day 4 RBC 50/HPF 2 Na 10 meq/l 5 Na 130 meq/l 3 228 2009; 15: 227 233

1 2 (n = 27) median (range) (n =16) median (range) Age (year) 66.5 10.6 68 (45 82) 70.3 9.7 73 (51 82) Sex (male/female) 18/9 10/6 Etiology (HCV/HBV/ALC/Others) 11/3/10/3 6/2/6/2 Ascites (moderate/severe) 11/16 9/7 Hepatic encephalopathy (yes/no) 7/20 6/10 Hepatocellular carcinoma (yes/no) 8/19 6/10 Child grade (B/C) 1/26 0/16 Child-Pugh score 12.4 1.1 13 (9 13) 12.4 1.0 13 (10 13) MELD score 33.7 6.2 35.7 (20.8 40.0) 33.4 6.3 35.7 (20.8 40.0) Serum total bilirubin (mg/dl) 15.1 10.6 13.5 (1.4 41.2) 17.1 10.9 17.9 (1.4 41.2) Serum albumin (g/dl) 2.3 0.5 2.3 (1.4 3.3) 2.4 0.5 2.5 (1.5 3.3) Prothrombin time ( ) 40.3 18.0 38.6 (18.0 94.5) 42.6 15.2 42.7 (19.2 72.9) Serum creatinine (mg/dl) 3.22 0.94 2.74 (2.03 5.76) 3.09 0.90 2.65 (2.03 4.72) Creatinine clearance (ml/min) 11.3 5.6 12.0 (0.9 23.6) 12.1 6.2 12.6 (0.9 23.6) Mean arterial pressure (mmhg) 77 10 76 (57 97) 76 8 76 (57 91) Heart rate (beats/min) 88 10 90 (60 104) 85 11 84 (60 104) Urine volume (ml/day) 450 358 425 (0 1726) 355 253 330 (0 763) Urinary sodium excretion (meq/day) 13.3 11.8 11.8 (0.9 44.9) 14.8 11.5 12.4 (0.9 44.9) Serum sodium (meq/l) 128 7 126 (117 147) 128 8 127 (118 147) Plasma renin activity (ng/ml/hr) 20.7 19.2 15.4 (2.2 73.9) Aldosterone (pg/ml) 630 604 301 (36 2011) Norepinephrine (pg/ml) 1601 748 1576 (563 3410) Antidiuretic hormone (pg/ml) 3.2 1.3 3.0 (1.3 5.5) Atrial natriuretic peptide (pg/ml) 37.5 26.0 30.0 (15.6 102.7) HCV: hepatitis C virus, HBV: hepatitis B virus, ALC: alcoholic, MELD: model for end stage liver disease 1 16 5 3 1 2 16 SBP 7 2 2 1 4 5 1 2 3 1 3 4 L 2009; 15: 227 233 229

3 1 27 Child-Pugh score 12.4 1.1 15.1 10.6 mg/dl 2.3 0.5 g/dl 40.3 18.0 Cre 3.22 0.94 mg/dl Ccr 11.3 5.6 ml/min Na 3 16 2 10 4.8 4.2 10 8.7 6.7 1 14 hemodiafiltration: HDF 1 11 3 16 Cre 2 Cre 3.09 0.90 mg/dl 4.42 2.15 mg/dl p = 0.048 Cre 1.5 mg/dl Cre 1.5 mg/dl 20 16 2 12.5 2 12.5 Cre 20 16 12 75 3 16 15 3 16 12.0 11.2 7 14 31.3 11.6 30 9.4 8.2 60 0 2 1 20 g/ 4 3 12 56 Cre 2.74 mg/dl 1.22 mg/dl 46 1 3 13 HDF 11 12.5 g/ 9 3 6 μg/kg/ 25 71 Cre 4.72 mg/dl 1.39 mg/dl 11 HDF 25 2 1 3 7 20 g/ 5 24 Cre 4.01 mg/dl 3.05 mg/dl 15 1 3 16 0.1 0.6 μg/kg/ 12.5g/ 14 25 Cre 3 Cre mg/dl 1 DOA 3 μg/kg/ 11 2.69 6.33 (135) 11 2 Alb 12.5 g 7 + DOA 3 μg/kg/ 13 2.62 5.84 (123) 15 3 2.51 8.78 (250) 14 4 3.96 3.96 (0) 2 5 Alb 12.5 g 1 + DOA 3 μg/kg/ 3 2.24 2.91 (30) 3 6 4.59 7.29 (59) 6 7 Alb 20g 5 4.01 3.05 (-24) 15 8 Alb 12.5 g 3 + DOA 3 μg/kg/ 3 4.39 4.39 (0) 3 9 Alb 12.5 g 3 + DOA 3 μg/kg/ 5 2.61 4.08 (56) 6 10 DOA 3 μg/kg/ 7 2.65 4.78 (80) 7 11 Alb 12.5 g 1 + DOA 3 μg/kg/ 10 2.55 6.33 (148) 10 12 Alb 20 g 4 2.74 1.22 (-56) 46 13 HDF 11 +Alb 12.5 g 9 + DOA 3 6 μg/kg/ 25 4.72 1.39 (-71) 25 HDF 14 Alb 12.5 g 1 + DOA 3 μg/kg/ 3 2.52 3.98 (58) 3 15 DOA 3 μg/kg/ 7 2.64 4.89 (85) 7 16 NE 0.1 0.6 μg/kg/ 14 + Alb 12.5 g 14 2.03 1.53 (-24) 19 Cre: creatinine, DOA: dopamine, NE: norepinephrine, Alb: albumin, HDF: hemodiafiltration 230 2009; 15: 227 233

Creatinine (mg/dl) P=0.048 10 8 6 4 2 0 2 1 n = 16 1.0 0.8 Probability of survival 0.6 0.4 0.2 0 0 10 20 30 40 50 Days 3 1 n = 16 2.03 mg/dl 1.53 mg/dl 19 12 15 1 11 1 IV. IAC 1 IAC 1 3 25 12 IAC 1 1, 2 2009; 15: 227 233 231

5, 12 Cre 1.5 mg/dl 8 10 30 ml/min 13 IAC 3, 7 1 25 17 5 TIPS 1 SBP 106 66 62 1 2 4, 14 16 vasopressin ornipressin terlipressin α 1 terlipressin terlipressin 1 60 75 2 4, 14 16, 1 5 terlipressin pilot study 11 5 3 60 25 1 14 2 1 HDF 1 1 8, 17, 18 10 40 8, 17, 18 terlipressin 1 terlipressin 2 4 terlipressin 19, 20 21, 22 TIPS 1 22 24 TIPS 25 TIPS 2 4, 14, 15 16 7 15 1 terlipressin 21 26 1 V. 1 3 25 SBP 12 1 Gines A, Escorsell A, Gines P, et al: Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 1993; 105: 229 236 2 Gines P, Guevara M, Arroyo V, et al: Hepatorenal syndrome. Lancet 2003; 362: 1819 1827 3 Salerno F, Gerbes A, Gines P, et al: Diagnosis, prevention and treatment of hepatorenal syndrome. Gut 2007; 56: 1310 1318 4 Arroyo V, Terra C, Gines P, et al: Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome. J Hepatol 2007; 46: 935 946 5 Garcia-Tsao G, Parikh CR, Viola A: Acute kidney injury in cirrhosis. Hepatology 2008; 48: 2064 2077 6 Moreau R, Lebrec D: Acute kidney injury: new concepts. Hepatorenal syndrome: the role of vasopressors. Nephron Physiol 2008; 109: 73 79 7 Arroyo V, Gines P, Gerbes AL, et al: Definition and 232 2009; 15: 227 233

diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996; 23: 164 173 8 Peron JM, Bureau C, Gonzalez L, et al: Treatment of hepatorenal syndrome as defined by the international ascites club by albumin and furosemide infusion according to the central venous pressure: a prospective pilot study. Am J Gastroenterol 2005; 100: 2702 2707 9 Moreau R, Lebrec D: Diagnosis and treatment of acute renal failure in patients with cirrhosis. Best Pract Res Clin Gastroenterol 2007; 21: 111 123 10 Fang JT, Tsai MH, Tian YC, et al: Outcome predictors and new score of critically ill cirrhotic patients with acute renal failure. Nephrol Dial Transplant 2008; 23: 1961 1969 11 : terlipressin 2006; 12: 285 290 12 Moreau R, Lebrec D: Acute renal failure in patients with cirrhosis: perspectives in the age of MELD. Hepatology 2003; 37: 233 243 13 Bataller R, Gines P, Guevara M, et al: Hepatorenal syndrome. Semin Liver Dis 1997; 17: 233 247 14 Arroyo V, Bataller R, Guevara M: Treatment of hepatorenal syndrome in cirrhosis. in Ascites and renal dysfunction in liver disease: pathogenesis, diagnosis, and treatment, ed by Arroyo V, Gines P, Rodes J, Schrier RW, 1st Ed, Blackwell Science, Malden, 1999: 492 510 15 Arroyo V, Terra C, Gines P: New treatments of hepatorenal syndrome. Semin Liver Dis 2006; 26: 254 264 16 Moreau R, Lebrec D: The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond. Hepatology 2006; 43: 385 394 17 Martin-Llahi M, Pepin M, Guevara M, et al: Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008; 134: 1352 1359 18 Sanyal AJ, Boyer T, Garcia-Tsao G, et al: A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008; 134: 1360 1368 19 Alessandria C, Ottobrelli A, Debernardi-Venon W, et al: Noradrenaline vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol 2007; 47: 499 505 20 Sharma P, Kumar A, Shrama BC, et al: An open label, pilot randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response. Am J Gastroenterol 2008; 103: 1689 1697 21 Angeli P, Volpin R, Gerunda G, et al: Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999; 29: 1690 1697 22 Wong F, Pantea L, Sniderman K: Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 2004; 40: 55 64 23 Brensing KA, Textor J, Perz J, et al: Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut 2000; 47: 288 295 24 Guevara M, Gines P, Bandi JC, et al: Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems. Hepatology 1998; 28: 416 422 25 : TIPS 50 2009; 106: 356 369 26 Moreau R, Durand F, Poynard T, et al: Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 2008; 134: 1352 1359 Incidence, clinical characteristics, treatment and prognosis of type 1 hepatorenal syndrome: A single institution experience Yoshiyuki Narahara 1, Hidenori Kanazawa 1, Takeshi Fukuda 1, Hirotomo Harimoto 1, Yoko Matsushita 1, Hideko Kidokoro 1, Tamaki Katakura 1, Masanori Atsukawa 1, Katsuhisa Nakatsuka 1, Choitsu Sakamoto 1 1 Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School A total of 929 patients with liver cirrhosis were admitted to our department between 2004 and 2009. Of these, 142 patients were complicated by kidney injury, with creatinine of 1.5 mg/dl or higher at or after admission. One hundred six out of 142 patients developed acute kidney injury, and including 27 with type 1 hepatorenal syndrome. We retrospectively investigated the background, treatment and prognosis of type 1 hepatorenal syndrome in 27 patients. The 27 patients were selected according to the diagnostic criteria for hepatorenal syndrome proposed by International Ascites Club. Average Child-Pugh score was 12.4, total bilirubin 15.1 mg/dl, and creatinine 3.22 mg/dl in the 27 patients. Precipitating factors were infection (n=16), paracentesis (n=5) and other causes (n=6). These 27 patients were treated with albumin (n=21), terlipressin (n=11), dopamine (n=11), noradrenaline (n=1), hemodiafiltration (n=1). Of 16 patients treated with conventional therapies other than terlipressin, 15 died. Their mean survival time was 12 days. Type 1 hepatorenal syndrome occurred in 25 of the cirrhotic patients with acute kidney injury. This syndrome developed as a consequence of severe hepatic failure and the prognosis following conventional therapy was quite poor. 2009; 15: 227 233 233