Hepatorenal Syndrome Treatment & Management
- Author: Deepika Devuni, MBBS; Chief Editor: BS Anand, MD more...
Every attempt should be made to establish a precipitating cause of hepatorenal syndrome (HRS). This is particularly true for type 1 HRS, which rarely occurs spontaneously and may be associated with spontaneous bacterial peritonitis (SBP) in 25% of cases. If renal function does not improve after institution of third-generation cephalosporins for SBP, a follow-up diagnostic paracentesis is recommended 48 hours later.
Patients with HRS should be evaluated for liver transplantation, at a liver transplant center if possible. This may be more applicable for patients with type 2 HRS, who have a longer survival time, as opposed to patients with type 1 HRS, whose survival is extremely short and who may require alternative therapeutic methods (eg, TIPS, vasoconstrictors) as a bridge to transplantation.
Reasons for transferring patients to a liver transplant center include the following:
Assessment of candidacy for liver transplantation
Lack of facilities for performing dialysis at local/referring hospital
Entrance into study/treatment protocol for HRS at referral center
If patients are not candidates for liver transplantation, they have a poor prognosis and outpatient care will only be palliative in nature.
Guidelines from the British Society of Gastroenterology, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend cefotaxime as the antibiotic of choice for SBP and large-volume paracentesis for the management of ascites greater than 5 L in volume. For HRS, cautious diuresis, volume expansion with albumin and the use of vasoactive drugs are recommended.
The ideal treatment of HRS is liver transplantation; however, because of the long waiting lists in the majority of transplant centers, most patients die before transplantation. An urgent need exists for effective alternative therapies to increase survival chances for patients with HRS until transplantation can be performed. This is reinforced by a study that reported that patients successfully treated medically for HRS before liver transplantation had posttransplantation outcome and survival comparable to that of patients who underwent transplantation without being treated for HRS. Interventions that have shown some promise are drugs with vasoconstrictor effects in the splanchnic circulation and the use of the transjugular intrahepatic portosystemic shunt (TIPS).
Numerous medications have been used to treat HRS with little, if any, effect. The pharmacologic approach has shifted, however, with greater attention now focused on the role of vasoconstrictors as opposed to the initial predominant use of vasodilators. The rationale for this change is that the initial event in HRS is vasodilatation of the splanchnic circulation and use of a vasoconstrictor may thus prevent homeostatic activation of endogenous vasoconstrictors. Promising results have been reported in small studies and case reports with agonists of vasopressin V1 receptors, such as ornipressin and terlipressin, which predominantly act on the splanchnic circulation.[21, 22, 23, 24, 25]
Although only a few controlled trials have been conducted in this arena, the results so far are encouraging and suggest an increasing role for medical therapy, given the current shortage of the donor pool in the face of an ever-increasing demand for organs.
Low-dose dopamine (2-5 mcg/kg/min) is frequently prescribed to patients with renal failure in the hope that its vasodilatory properties may improve renal blood flow. Little evidence exists to support this practice; a placebo-controlled randomized trial by Bellomo and colleagues did not demonstrate any role for low-dose dopamine in early renal dysfunction. Five studies have evaluated the role of dopamine in HRS, and none have reported significant changes in RPF, GFR, or urine output.
These studies are limited by small sample size and lack of a control arm. Nonetheless, they demonstrate that dopamine administration in patients with cirrhosis, with or without HRS, does not improve renal function.
Misoprostol is a synthetic analogue of PG E1, whose use in HRS was based on the observation that these patients had low urinary levels of vasodilatory PGs.
Five studies have assessed the role of either parenteral or oral misoprostol in HRS. None of these studies demonstrated an improvement in the GFR, sodium excretion, or renal function in patients with HRS. Although Fevery et al demonstrated reversal of HRS in 4 patients, these patients also received large doses of colloids. The likely scenario is that the massive administration of fluids played a predominant role here because Gines et al were unable to reproduce these findings with misoprostol alone.
Renal vasoconstrictor antagonists
Saralasin, an antagonist of angiotensin II receptors, was used first in 1979 in an attempt to reverse renal vasoconstriction. Because this drug inhibited the homeostatic response to hypotension commonly observed in patients with cirrhosis, it led to worsening hypotension and deterioration in renal function. Poor results were also observed with phentolamine, an alpha-adrenergic antagonist, highlighting the importance of the SNS in maintaining renal hemodynamics in patients with HRS.
A case series by Soper et al reported an improvement in the GFR in 3 patients with cirrhosis, ascites, and HRS who received an antagonist of endothelin A receptor (BQ123). All 3 patients showed a dose-response improvement in inulin and para-aminohippurate excretion, RPF, and the GFR in the absence of changes in systemic hemodynamics. These 3 patients were not candidates for liver transplantation and subsequently died. More work is needed to explore this therapeutic approach as a possible bridge to transplantation for patients with HRS.
These medications have shown promise for the treatment of HRS; they include vasopressin analogues (ornipressin, terlipressin), somatostatin analogues (octreotide), and alpha-adrenergic agonists (midodrine).
In 1956, Hecker and Sherlock used norepinephrine to treat patients with cirrhosis who had HRS; they were the first to describe an improvement in arterial pressure and urine output. However, no improvement was observed in the biochemical parameters of renal function, and all patients subsequently died.
Octapressin, a synthetic vasopressin analogue, was first used in 1970 to treat type 1 HRS. RPF and the GFR improved in all patients, all of whom subsequently died from sepsis, gastrointestinal bleeding, and liver failure. Because of these discouraging results, the use of alternate vasopressin analogues, particularly ornipressin, attracted attention. Three important studies by Lenz and colleagues demonstrated that short-term use of ornipressin resulted in an improvement in circulatory function and a significant increase in RPF and the GFR.[31, 32, 33]
The combination of ornipressin and albumin was subsequently tried by Guevera in patients with HRS.[34, 35] This was based on data suggesting that the combination of plasma volume expansion and vasoconstrictors normalized renal sodium and water handling in patients who have cirrhosis with ascites. In this important paper, 8 patients were originally to be treated for 15 days with ornipressin and albumin. Treatment had to be discontinued in 4 patients after fewer than 9 days because of complications from ornipressin use that included ischemic colitis, tongue ischemia, and glossitis. Although a marked improvement in the serum creatinine level was observed during treatment, renal function deteriorated upon treatment withdrawal. In the remaining 4 patients, the improvement in RPF and the GFR was significant and was associated with a reduction in serum creatinine levels. These patients subsequently died, but no recurrence of HRS was observed.
Due to the high incidence of severe adverse effects with ornipressin, the same investigators used another vasopressin analogue with fewer adverse effects, namely terlipressin. In this study, 9 patients were treated with terlipressin and albumin for 5-15 days. This was associated with a marked reduction in serum creatinine levels and improvement in mean arterial pressure. Reversal of HRS was noted in 7 of 9 patients, and HRS did not recur when treatment was discontinued. No adverse ischemic effects were reported, and, according to this study, terlipressin with albumin is a safe and effective treatment of HRS.
Since this early study, terlipressin has become the most studied vasopressin analogue in HRS. When used in conjunction with albumin, improvement in GFR and reduction in serum creatinine levels to below 1.5 mg/dL occur in 60-75% of patients with type 1 HRS. This may take several days, and although recurrent HRS after treatment discontinuation is uncommon (< 15%), a repeat course of terlipressin with albumin is usually effective. Ischemic complications are also rare (< 5%), but one limitation of terlipressin is its unavailability in many countries, including the United States. Under these circumstances, such agents as octreotide, albumin, and alpha-adrenergic agonists may be considered.
Gluud et al reviewed 10 randomized studies to determine whether vasoconstrictor drugs reduce mortality in patients with type 1 or type 2 HRS. The trials, on a total of 376 patients, investigated outcomes of HRS treatments using terlipressin alone or with albumin, using octreotide plus albumin, or using noradrenalin plus albumin. In their analysis, Gluud and colleagues found that administration of terlipressin plus albumin may lead to short-term mortality reduction in patients with type 1 HRS, but the authors saw no such reduction in patients with the type 2 form of the disease. Trials using octreotide and noradrenaline therapies were small and indicated neither harmful nor beneficial effects from these treatments. The authors advised that the response duration from terlipressin therapy be taken into account when treatment and the timing of liver transplantation are considered for patients with type 1 HRS.
In a randomized controlled trial that compared the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in 27 patients, Cavallin and colleagues found a significantly higher rate of improvement in renal function with telipressin plus albumin compared to midodrine/octreotide plus albumin.
Angeli et al showed that long-term administration of midodrine (an alpha-adrenergic agonist) and octreotide improved renal function in 8 patients with type 1 HRS. All patients also received albumin, and this approach was compared to dopamine at nonpressor doses. Not surprisingly, none of the patients treated with dopamine showed any improvement in renal function, but all 8 patients treated with midodrine, octreotide, and volume expansion had improvement in renal function. No adverse effects were reported in these patients. A study of 14 patients by Wong et al reported improvement in renal function in 10 patients. Three of these patients subsequently underwent liver transplantation.
These studies demonstrate several important points. First, vasoconstrictors play an important role in the treatment of HRS, but further work is needed to identify the ideal agent and to determine if the addition of albumin is necessary. Another important conclusion of these studies is that patients may maintain relatively preserved renal function once therapy is discontinued. This suggests that if the precipitating factor, such as spontaneous bacterial peritonitis (SBP), is not readily identified, an irreversible decline in renal function ensues.
N-acetylcysteine (NAC): In 1999, the Royal Free group reported their experience with NAC for the treatment of HRS. This was based on experimental models of acute cholestasis, in which administration of NAC resulted in an improvement in renal function. Twelve patients with HRS were treated with intravenous NAC, without any adverse effects, and the survival rates were 67% and 58% at 1 month and 3 months, respectively (this included 2 patients who received liver transplantation after improvement in renal function). The mechanism of action remains unknown, but this interesting study encourages further optimism for medical treatment of a condition that once carried a hopeless prognosis in the absence of liver transplantation. Controlled studies with longer follow-up may help answer these pressing questions.
Institute a low-salt (2 g) diet. Do not restrict protein intake unless patient has severe encephalopathy.
Peritoneovenous shunting (PVS) seems attractive in theory because it leads to plasma volume expansion and improvement of circulatory function. However, very few studies evaluating the role of PVS in this area have been performed because PVS has been used predominantly for treating refractory ascites.
This may be important for patients with type 2 hepatorenal syndrome (HRS), who often develop refractory ascites, are not candidates for orthotopic liver transplantation, and do not tolerate frequent LVPs.
PVS has no role in type 1 HRS.
No description on the treatment of HRS is complete without a brief review of the role of portacaval shunts, particularly with the introduction of TIPS.
Despite the theoretical benefit of improving portal hypertension and thus HRS with a portosystemic shunt, only a few scattered case reports have shown some benefit.
Currently, no indication exists for portacaval shunts in this setting.
In a matched-pair study by Goldaracena et al, living (LDLT) and deceased donor liver transplantation (DDLT) led to comparable long-term outcomes in patients with HRS. The investigators evaluated outcomes between 30 patients with HRS who received LDLT and 90 patients with HRS who received a full-graft DDLT. They did not identify any differences in graft survival and patient survival at 1, 3, and 5 years, and the incidence of postsurgical chronic kidney disease was similar between the two groups.
Patients with HRS have a higher risk of postoperative morbidity, early mortality, and longer hospitalization. Gonwa et al reported that at least one third of patients require hemodialysis postoperatively, with a smaller percentage (5%) requiring long-term hemodialysis.
Because renal dysfunction is common in the first few days following transplantation, avoiding nephrotoxic immunosuppressants generally is recommended until recovery of renal function. However, the GFR gradually improves and reaches an average of 40-50 mL/min by the sixth postoperative week. The systemic and neurohumoral abnormalities associated with HRS also resolve in the first postoperative month.
Long-term survival rates are excellent, with the survival rate at 3 years approaching approximately 60%. This is only slightly lower than the 70-80% survival rate of transplant recipients without HRS and is markedly better than the survival rate of patients with HRS not receiving transplants, which is virtually 0% at 3 years.
The importance of a nephrologist in the multidisciplinary management of patients with hepatorenal syndrome (HRS) cannot be overemphasized. Nephrologists play a critical role in assisting hepatologists and liver transplant surgeons in the management of these critically ill patients.
No controlled studies evaluating the role of dialysis in this setting have been performed, but most centers dialyze patients with HRS who are on a waiting list.
Continuous arteriovenous or venovenous hemofiltration has also been used, but the efficacy of these 2 measures has yet to be determined.
Variations of hemodialysis include the molecular adsorbent recirculating system. This is a modified dialysis method that uses an albumin-containing dialysate that is recirculated and perfused online through charcoal- and anion-exchanger columns. A prospective, randomized, controlled trial showed improvement of type 1 HRS with this method, although long-term survival remained very poor, with survival of more than 1 month in only 1 of 8 patients in the treatment arm.
If transplantation is not available, hemodialysis probably will continue to be performed for patients on the waiting list.
The use of TIPS in the treatment of HRS has yet to be established. Due to its ability to reduce portal hypertension in patients with variceal bleeding and refractory ascites, its role in HRS initially seemed logical, particularly in view of isolated reports of renal function improvement following surgical shunts in the 1970s. However, TIPS quickly fell out of favor because of high morbidity and mortality rates.
Small, uncontrolled studies indicate that TIPS may improve RPF and the GFR and reduce the activity of the RAAS and SNS in patients who have cirrhosis with types 1 and 2 HRS. Improvement in renal function is usually slow and occurs in approximately 60% of patients. However, the effects on renal function can be variable, and some patients fare worse. As a result, the role of TIPS in the treatment of HRS remains investigational because of the lack of prospective studies and the known risks of the procedure.
The main precipitating factor of type 1 HRS is spontaneous bacterial peritonitis (SBP). When this develops in patients with type 2 HRS, the probability of developing type 1 HRS is very high. This may be prevented by antibiotic prophylaxis with Bactrim or fluoroquinolones in patients with a prior history of SBP. Alternatively, patients with type 2 HRS who are on the waiting list may benefit from prophylactic antibiotics, irrespective of whether they have a prior history of SBP.
A randomized controlled trial has shown that the incidence of SBP-related renal failure is reduced if these patients are treated with antibiotics and undergo plasma volume expansion with albumin (1.5 g/kg upon diagnosis and 1 g/kg 48 h later). The incidence of HRS in patients with SBP who received albumin together with antibiotic therapy was 10% compared with an incidence of 33% in patients who did not receive albumin; in addition, hospital mortality rates were also lower in patients who received albumin expansion.
LVP is considered another risk factor for the development of HRS, which may be prevented by the administration of albumin.
Patients who have cirrhosis with ascites have a 10% chance of developing HRS at 1 year and a 40% chance at 5 years. One alternative to treatment aimed at preventing HRS is performing liver transplantation in these patients before HRS develops, particularly because risk factors for the development of HRS have been identified. With the current donor shortage, this does not seem to be a realistic possibility.
In patients with acute alcoholic hepatitis, one study reported that the administration of pentoxifylline (400 mg tid for 28 d) reduced the incidence of HRS and mortality rates (8% and 24%, respectively) compared with a placebo group (35% and 46%, respectively). However, no long-term data exist on renal function or mortality rates in these patients.
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