Pathogenesis and Treatment of Hepatorenal
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These findings contrast sharply with those of seven studies in patients with type-1 HRS not receiving specific treatment or treated with plasma volume expansion alone or associated with vasodilators (dopamine) or octreotride or with
peritoneovenous shunting. 23,24,56,66,73,76,77 Reversal of HRS was observed in only 4 out of the 137 patients (2.9%) included in these studies. Survival data were recorded in 13 studies (8 using vasoconstrictors and 5 using other treatments). Forty (41.6%) and 29 (30%) of the 96 patients with type-1 HRS treated with vasoconstrictors were alive 1 and 3 months after treatment, respectively. The corresponding figures in 65 patients receiving other treatments were 2 (3%) and 0 (0%), respectively. Thirty-four patients treated with vasoconstrictors reached liver transplantation. A retrospective survey in 99 patients with type-1 HRS admitted to 22 hospitals in France and treated with terlipressin (all cases) and albumin (70% of cases) showed a rate of improvement in renal function of 58%. 78 The probability of survival was 40% at 1 month and 22% at 3 months. Improvement of survival was related to reversal of HRS. Thirteen patients received a liver transplant. This study, which reflects what occurs in regular clinical practice, confirms the results previously described in several pilot studies including short series of patients. Two randomized controlled studies finished re- cently comparing albumin versus albumin plus terlipres- sin in patients with type-1 HRS (Sanyal et al and Guevara et al, unpublished results), and they confirm the results obtained in the pilot studies. Reversal of HRS was significantly more frequent in patients treated with terlipressin and albumin. On the other hand, survival of patients responding to treatment was significantly longer than that of patients not responding to treatment or treated with albumin alone. These studies clearly indicate that vasoconstrictors associated with I.V. albumin should be recommended Figure 5 HRS as a part of a multiorgan failure. A-II, angiotensin-II; NE, norepinephrine; ADH, antidiuretic hormone; HRS, hepatorenal syndrome. 90 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1 2008 for the management of patients with type-1 HRS since they normalize serum creatinine in a high proportion of patients and may improve survival. Terlipressin has been the most widely used vasoconstrictor agent in type-1 HRS. It is very effective and is associated with a low incidence of side effects. The efficacy of the association of oral midodrine and I.V. or subcutaneous octreotide is probably due exclusively to the vasoconstrictor effect of midodrine. Noradrenaline has also been shown to be effective and safe and there is a randomized controlled trial in a small number of patients with type-1 and type-2 HRS (mainly type-2) indicating that it is as effective as terlipressin. 75 However, whereas there is much experi- ence with terlipressin, noradrenaline and midodrine have been used only in few studies. Based on these consid- erations, terlipressin should be the drug of choice for the treatment of type-1 HRS. Reversal of type-1 HRS in two pilot studies in which terlipressin was given alone (7 out of 28 patients, 25%) 69,71 was lower than that observed in the studies in which vasoconstrictors were associated with I.V. albumin, suggesting that albumin is an important component in the pharmacological treatment of type-1 HRS. Two recent studies 16,79 suggest that the beneficial effect of albumin on circulatory and renal function in patients with type-1 HRS is related not only to the expansion of the plasma volume but also to a direct vaso- constrictor effect on the peripheral arterial circulation. Terlipressin dosage should be progressive, start- ing with 0.5 to 1 mg/4 to 6 h. If serum creatinine does not decrease by more than 30% in 3 days, the dose should be doubled. The maximal dose of terlipressin has not been defined, although there was consensus that patients not responding to 12 mg/day will not respond to higher doses. Albumin should be given starting with a priming dose of 1 g/kg of body weight followed by 20 to 40 g/day. It is advisable to monitor central venous pressure. In patients responding to therapy, treatment should be continued until normalization of serum creatinine (< 1.5 mg/dL). Transjugular Intrahepatic Portosystemic Shunt Three pilot studies have evaluated TIPS in type-1 HRS. 74,80,81
In the first study, 80 14 patients with type- 1 HRS (12 with alcoholic cirrhosis, 9 with active alcoholism) and 17 with refractory ascites (some of them with type-2 HRS) not suitable for liver trans- plantation were treated with TIPS. Patients with bilir- ubin > 15 mg/dL, Child-Pugh score > 12 points, or hepatic encephalopathy were excluded. Eleven out of the 31 patients developed de novo hepatic encephalopathy or deterioration of previous hepatic encephalopathy. The 3-, 6-, and 12-month survival rates in patients with type- 1 HRS were 64%, 50%, and 20%, respectively. The second study 81 was performed in 7 patients (4 alcoholics) with type-1 HRS and a Child-Pugh score < 12 points. Marked decrease in serum creatinine was observed in 6 patients and reversal of HRS in 4. Five patients developed episodes of hepatic encephalopathy after TIPS but they responded satisfactorily to medical treat- ment. Five patients were alive after 1 month of TIPS but only 2 after 3 months. The third study 74 was performed in 14 patients (13 with alcoholic cirrhosis) with type-1 HRS treated initially with vasoconstrictors (midodrine and octreotide) plus albumin. Reversal of HRS was obtained in 10 patients. TIPS devices were subsequently inserted in 5 of these 10 patients who had bilirubin
5 mg/dL, international normalized ratio < 2, and Child-Pugh score < 12 points. Normalization of GFR was obtained in all cases and patients were alive between 6 to 30 months after TIPS. TIPS, therefore, is effective in normalizing serum creatinine in a significant propor- tion of patients with cirrhosis and severe azotemia and is an alternative treatment to vasoconstrictors in type-1 HRS. Extracorporeal Albumin Dialysis Three pilot studies including 29 patients (26 with type-1 HRS and 21 with alcoholic cirrhosis and/or severe acute alcoholic hepatitis) aimed at assessing molecular adsorbents recirculating system (MARS) in patients with type-1 HRS have been reported. 82–84
Since MARS incorporates a standard dialysis machine or a continuous veno-venous hemofiltration monitor and GFR was not measured, it is not possible to know the effect of this treatment on renal function. The decrease in serum creatinine observed in most patients could be related to the dialysis process. However, clear beneficial effects on systemic hemodynamics and on hepatic ence- phalopathy were observed. The survival rate 1 and 3 months after treatment was 41% (12 patients) and 34% (10 patients), respectively. A recent randomized controlled trial in a large series of cirrhotic patients with hepatic encephalopathy, 85 many of them with HRS, has demonstrated a clear beneficial effect of MARS on the rate and time of recovery of encephalopathy. Since the end point of this trial was encephalopathy, no conclusion can be obtained in relation to survival. TREATMENTS FOR TYPE-2 HRS In patients with type-2 HRS, most of whom may reach a liver transplant, the main clinical problem is refractory ascites. Therefore, treatment of type-2 HRS should consider not only survival but also the control of ascites. Transjugular Intrahepatic Portosystemic Shunt Five trials comparing TIPS versus paracentesis in pa- tients with refractory and/or recidivant ascites have so far been published. 52,86–89
In total, 172 patients were PATHOGENESIS AND TREATMENT OF HEPATORENAL SYNDROME/ARROYO ET AL 91
treated by TIPS. Unfortunately, very few of these patients had HRS. Patients with serum creatinine > 3 mg/dL were excluded from three studies. Only two studies gave the number of patients with HRS included (6 out of 53). Finally, mean serum creatinine was below 1.5 mg/dL in the groups treated by TIPS in these five studies. Therefore, data from these five trials are not valid for the assessment of TIPS in the manage- ment of patients with type-2 HRS. There are only two pilot studies specifically assessing TIPS in type-2 HRS. 80,90 In one study, 90 a significant reduction of serum creatinine (from 2.1 Æ 0.3 to 1.4 Æ 0.3 mg/dL 1 month after TIPS) was observed in eight out of nine patients. This was associated with a significant improvement in the control of ascites. Four of these patients died, two within the first month and two 12 and 14 months after the procedure. The remaining five patients had longer survival. No data were given on the type and rate of complications associated with TIPS. A second study included 14 patients with type-1 HRS and 17 with type-2 HRS treated by TIPS. 80 Mean baseline serum creatinine concentration in patients with type-2 HRS was only 1.44 Æ 0.3 mg/dL, but mean creatinine clearance was 28 Æ 14 mL/min. A sig- nificant improvement in serum creatinine and creatinine clearance was observed in the whole group of 31 patients as was as an improvement in the control of ascites in 24 cases. Six patients developed TIPS dysfunction and 11 developed hepatic encephalopathy during follow-up. The 1-year probability of survival in the 17 patients with type-2 HRS treated by TIPS was 70%. TIPS is therefore effective in reversing type-2 HRS, although more data on complication rate and survival are needed before advocating a widespread use of this procedure. The introduction of covered stents should be a stimulus to re-evaluate the role of TIPS in the management of refractory ascites and type-2 HRS. Vasoconstrictors and Albumin Three pilot studies provided data on the effect of terlipressin plus albumin in 39 patients with type-2 HRS.
67,71,90 Reversal of HRS was obtained in most cases (21 cases, 80%). In one of these studies 90 the course of renal function after stopping treatment was assessed in 11 patients and HRS recurred in all cases. There were no data on survival. This high prevalence of HRS recur- rence has been confirmed recently in a second study by Alessandria et al. 75 In a randomized comparative study of terlipressin versus noradrenaline in 22 patients with type-1 and type-2 HRS, reversal of HRS was obtained in 17 patients. HRS recurrence was observed in 8 patients, 5 with type-2 HRS. The current state of knowledge on vasoconstrictor therapy in type-2 HRS is therefore very poor. It appears to be not as effective as in type-1 HRS due to the high rate of HRS recurrence. PREVENTION OF HRS Three randomized controlled studies in large series of patients have shown that HRS can be prevented in specific clinical settings. In the first study, 56 the admin- istration of albumin (1.5 g/kg I.V. at infection diagnosis and 1 g/kg I.V. 48 hours later) to patients with cirrhosis and SBP markedly reduced the incidence of circulatory dysfunction and type 1 HRS (10% incidence of type-1 HRS in patients receiving albumin versus 33% in the control group). Hospital mortality rate (10% versus 29%) and the 3-month mortality rate (22% versus 41%) were lower in patients receiving albumin. The second study was performed in cirrhotic patients at a high risk of developing SBP and type-1 HRS. 91
oral norfloxacin was given to 35 patients with low protein ascites (< 15 g/L) and advanced liver failure (Child-Pugh score ! 9 points with serum bilirubin ! 3 mg/dL) or impaired renal function (serum creatinine level ! 1.2 mg/dL; blood urea nitrogen level ! 25 mg/ dL, or serum sodium level 130 mEq/L). Thirty-three patients received placebo. Norfloxacin administration was associated with a significant decrease in 1-year probability of development of SBP (7% versus 61%) and type-1 HRS (28% versus 41%) and with a significant increase in the 3-month and 1-year probability of sur- vival (94% versus 62% and 60% versus 48%, respectively). In this study, patients developing SBP received I.V. albumin (1.5 g/kg I.V. at infection diagnosis and 1 g/kg I.V. 48 hours later) and only 1 patient developed HRS associated with SBP. Type-1 HRS, however, was the principal cause of death in this study. Therefore, oral norfloxacin prevented type-1 HRS in these patients by a mechanism different from the prevention of SBP. Several studies have shown that in patients with cirrhosis in addition to bacterial translocation there is transloca- tion of products of bacterial origin (endotoxin, bacterial DNA) that induce a systemic inflammatory reaction, activation of nitric oxide, and impairment in circulatory function. 92–94
The administration of oral norfloxacin in these patients prevents this translocation of bacterial products and improves circulatory function with a sig- nificant increase in arterial pressure and systemic vascular resistance and suppression of plasma renin activity and plasma norepinephrine concentration. 92,94 An improve- ment in circulatory function, which makes patients less susceptible to type-1 HRS, is, therefore, the most likely mechanism of the beneficial effect of oral norfloxacin found in this study. In the third study, 95 the administration of the tumor necrosis factor inhibitor pentoxyfilline (400 mg three times a day) to patients with severe acute alcoholic hepatitis reduced the occurrence of HRS (8% in the pentoxyfilline group versus 35% in the placebo group) and the hospital mortality (24% versus 46%, respec- tively). Because bacterial infections and acute alcoholic 92 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1 2008 hepatitis are important precipitating factors of type 1 HRS, these prophylactic measures may decrease the incidence of this complication. ABBREVIATIONS GRF glomerular filtration rate HRS hepatorenal syndrome MARS molecular adsorbents recirculating system SBP spontaneous bacterial peritonitis TIPS transjugular intrahepatic portosystemic shunt REFERENCES 1. Gine`s P, Rode´s J. Clinical disorders of renal function in cirrhosis with ascites. In: Arroyo V, Gine`s P, Rode´s J, Schrier RW, eds. Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. Malden: Blackwell Science; 1999:36–62 2. Hecker R, Sherlock S. Electrolyte and circulatory changes in terminal liver failure. Lancet 1956;271:1121–1125 3. Gine`s A, Escorsell A, Gine`s P, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 1993;105:229–236 4. Koppel MH, Coburn JW, Mims MM, et al. Transplantation of cadaveric kidneys from patients with hepatorenal syn- drome: evidence for functional nature of renal failure in advanced liver disease. N Engl J Med 1969;280:1367– 1373
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