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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. References

The Consensus Conference on Hepatorenal Syndrome (HRS) organized by the International Ascites Club in 1994 redefined HRS, introduced new diagnostic criteria that are now widely accepted, and proposed the distinction between two types of HRS: type 1 and type 2. Before the introduction of the new therapeutic options, the median survival of patients with type 1 HRS was only 1.7 weeks, and 6–12 months in patients with type 2 HRS. Liver transplantation (LT) was the first therapeutic option to change the prognosis of cirrhotic patients with HRS and 5-year survival after LT in patients with HRS is only slightly less than that of transplanted patients without HRS and markedly increased when compared to survival in nontransplanted patients with HRS. Nevertheless, a large proportion of patients die before LT is possible because of the poor prognosis of HRS and the prolonged waiting times in most transplant centres. Other therapeutic approaches were therefore developed to increase survival in patients with HRS. Vasoconstrictors and transjugular intrahepatic portosystemic shunt (TIPS) are the most promising. The administration of vasoconstrictors together with albumin has been shown to reverse type 1 HRS and even to completely normalize renal function in 60–70% of treated patients. To date, four studies assessing TIPS in the management of type 1 HRS have been reported and TIPS insertion was technically successful in all of them. Given the shortage of donors for LT, vasoconstrictor therapy and TIPS strategies may be considered as a bridge to LT in patients with type 1 HRS.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. References

It is well known that hepatorenal syndrome (HRS) represents the most serious complication in patients with cirrhosis and ascites. In clinical practice, the impact of HRS on prognosis is well explained by an old definition of this syndrome, that is ‘terminal functional renal failure’. Up to the end of the 1990s, the development of HRS was considered an irreversible and terminal event in patients with cirrhosis and ascites.

The Consensus Conference on Hepatorenal Syndrome, organized by the International Ascites Club in 1994, redefined HRS and introduced new diagnostic criteria that are now widely accepted. Also proposed was the distinction of two types of HRS: type 1 and type 2. Type 1 HRS is a rapidly progressive renal failure with a very poor prognosis, while type 2 HRS is a moderate, steady renal impairment with a better prognosis. In type 1 HRS a precipitating event, mainly a severe bacterial infection, is frequently identified whereas type 2 HRS arises spontaneously and represents the main cause of refractory ascites. It should be recognized that the distinction between type 1 and type 2 HRS is limited to clinical and laboratory findings and to their different impact on survival.1 Elucidation of the pathological differences is still awaited.

The distinction between type 1 and type 2 HRS makes it difficult to consider the data on the prognosis of HRS published before 1994. Although it can be accepted that probably type 1 HRS represents what was previously defined as ‘terminal functional renal failure’, ‘acute HRS’, or ‘severe HRS’, while type 2 HRS probably parallels what was previously described merely as refractory ascites.

Until the introduction of the new therapeutic options, the median survival of patients with type 1 HRS was only 1.7 weeks2 whereas it was 6–12 months in patients with type 2 HRS.3, 4

Liver transplantation (LT) was the first therapeutic option to change the prognosis of cirrhotic patients with HRS. Five-year survival after LT in patients with HRS is only slightly reduced compared to that of transplanted patients without HRS (60% vs. 68%, P < 0.05)5 and markedly increased compared to survival in nontransplanted patients with HRS (0–20%).5 Nevertheless the presence of HRS at the time of LT is associated with an increased morbidity, and a longer stay in both intensive care unit and hospital. Immediately after LT, a further impairment in renal function occurs in patients with HRS who then required longer hospitalization and more frequent dialysis treatment (35% vs. 5%, P < 0.001). Nevertheless, only 5% of these patients progress to end-stage renal disease.5 However the main problem regarding LT for patients with type 1 HRS is that because of the poor prognosis of HRS and the prolonged waiting times in most transplant centres, a great proportion of patients die before LT is possible. As a consequence, other therapeutic approaches were developed to increase survival in patients with HRS. The administration of vasoconstrictors and transjugular intrahepatic portosystemic shunt (TIPS) are the most promising approaches.

The administration of vasoconstrictors together with albumin has been shown to reverse type 1 HRS and even to completely normalize renal function in 60–70% of treated patients.6–10 However, despite the proven beneficial effect of this pharmacological approach on renal function, its impact on survival is still under debate. In retrospective studies the median transplant-free survival in patients with type 1 HRS was 21–24 days indicating that, despite treatment, the prognosis of type 1 HRS is still very poor.11, 12 The probability of transplant-free survival was higher in patients without a precipitating factor of HRS, in patients who showed an improvement in renal function, and in those who received a dose of terlipressin (Glypressin®) higher than 3 mg/day.10–12 In prospective studies the median transplant-free survival was 5.7–11.9 weeks10–12 as compared to 1.0 weeks in patients treated with albumin and low-dose dopamine. The transplant-free survival was higher in patients with a baseline Child–Pugh score < 11, in patients who were treated with both terlipressin and albumin, and in those who showed a complete renal response to the treatment.6–10 In addition, it has recently been shown that the use of vasoconstrictors and albumin before LT improves the outcome of LT in patients with type 1 HRS making it similar to that observed in patients transplanted with normal renal function.13

Few data exist on the effect of the administration of vasoconstrictors together with albumin in cirrhotic patients with type 2 HRS. The response rate to treatment in these patients was similar to that of patients with type 1 HRS. Moreover, after treatment the transplant-free survival rate among patients with type 2 HRS was higher as compared to patients with type 1 HRS (100% at 3 months). However, these results should be viewed with caution because the survival of untreated patients with type 2 HRS is longer than that of untreated patients with type 1 HRS.9 There have been four randomized controlled trials comparing TIPS with paracentesis in the treatment of refractory ascites.14–17 In all studies TIPS was clearly superior to paracentesis in the control of ascites. In two studies the risk of severe hepatic encephalopathy was higher in the TIPS group. In no study was the transplant-free survival statistically different between the two treatments and in only one of them was the treatment with TIPS an independent predictive factor of survival.15 The mean survival was 12.4 months in the paracentesis group and 19.8 months in the TIPS group (P = N.S.).17 Two-year survival was 30–32% in the paracentesis group and 30–58% in the TIPS group.15, 16

To date, studies assessing TIPS in the management of type 1 HRS have been reported. In total 30 patients were treated and TIPS insertion was technically successful in all of them. After 1–4 weeks, renal function improved markedly and stabilized thereafter. Median survival after TIPS was 14.6 weeks in patients with type 1 HRS, which was significantly higher than that observed in the nonshunted control group (1.9 weeks). However, it should be noted that almost one-third of patients with type 1 HRS cannot be treated by TIPS because of contraindications. As a consequence control patients had more hepatic failure than patients in the TIPS group.18, 19 Severe hepatic failure is a limiting factor for the efficacy of treatment with vasoconstrictors and for the applicability of TIPS in cirrhotic patients with type-1 HRS. In this context, it should be noted that in a controlled clinical trial the efficacy of an extracorporeal albumin dialysis molecular adsorbent recirculating system (MARS) was assessed in patients with type 1 HRS. Although performed in very few patients, in this study MARS improved renal function, as well as hepatic function and mean arterial pressure. As a consequence, survival was slightly but significantly improved in the MARS group compared to patients with type 1 HRS who received no specific treatment.20

In conclusion, both vasoconstrictor therapy and TIPS not only improve renal function in patients with type 1 HRS but also seem to prolong transplant-free survival. Given the shortage of donors for LT, both strategies may be considered a bridge to LT in patients with type 1 HRS. These preliminary results should be proven by randomized controlled trials. In type 2 HRS TIPS should be used as an effective treatment for refractory ascites in patients undergoing paracentesis more than three times per month or in patients that cannot tolerate paracentesis or in whom paracentesis is ineffective. The decision to insert a TIPS should be based on patient issues and on informed consent regarding the risks of severe encephalopathy.21

References

  1. Top of page
  2. Summary
  3. Introduction
  4. References