Hepatorenal Syndrome Treatment & Management

Updated: Sep 22, 2022
  • Author: Deepika Devuni, MD; Chief Editor: BS Anand, MD  more...
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Approach Considerations

Every attempt should be made to establish a precipitating cause of hepatorenal syndrome (HRS). This is particularly true for HRS-acute kidney injury (AKI), which rarely occurs spontaneously and may be associated with spontaneous bacterial peritonitis (SBP) in 25% of cases. If renal function does not improve after administrattion 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 HRS-AKI, whose survival is extremely short and who may require alternative therapeutic methods (eg, transjugular intrahepatic portosystemic shunt [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 the 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 (BSG), 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. [21] For HRS, cautious diuresis, volume expansion with albumin, and the use of vasoactive drugs are recommended.


Medical Care

The ideal treatment of hepatorenal syndrome (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 the survival chances for patients with HRS until transplantation can be performed. This is reinforced by a study that reported patients successfully treated medically for HRS before liver transplantation had posttransplantation outcome and survival comparable to those 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, therapies aimed at volume expansion, and the use of the transjugular intrahepatic portosystemic shunt (TIPS).

Treatment overview based on acute kidney injury (AKI) stage

Stage 1 AKI

Close monitoring

Removal and minimizing risk factors:

  • Withdraw diuretics
  • Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and nephrotoxic drugs
  • Treat infection, if present
  • Consider volume expansion with albumin

Stage 2 or 3 AKI

Withdrawal of diuretics

Volume expansion with albumin

If no response to the above therapies, then proceed to vasoconstrictors and albumin


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 the 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 terlipressin, which predominantly act on the splanchnic circulation. [25, 26, 27, 28, 29]

In a systematic review and network meta-analysis of vasoactive treatments for HRS from 26 RCTs comprising 1,736 patients, investigators found that terlipressin increased HRS reversal compared with placebo, and it may reduce mortality. [30] In addition, owing to the inaccessibility of terlipressin in many countries, initial norepinephrine administration may be more appropriate than an initial trial with midodrine+octreotide. [30]

In September 2022, the FDA approved terlipressin to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.

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. [31] Five studies have evaluated the role of dopamine in HRS, and none have reported significant changes in renal plasma flow (RPF), the glomerular filtration rate (GFR), or urine output. These studies are limited by small sample size and the 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 four patients with HRS. Although Fevery et al demonstrated reversal of HRS in four patients, these patients also received large doses of colloids. [32] 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. [33]

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 three patients with cirrhosis, ascites, and HRS who received an antagonist of endothelin A receptor (BQ123). [34] All three patients showed a dose-response improvement in insulin and para-aminohippurate excretion, RPF, and the GFR in the absence of changes in systemic hemodynamics. These three 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.

Systemic vasoconstrictors

These medications have shown promise for the treatment of HRS; they include vasopressin analogues (terlipressin), somatostatin analogues (octreotide), and alpha-adrenergic agonists (midodrine). [35]


Terlipressin is a synthetic vasopressin with twice the selectivity for V1 receptors compared to V2 receptors. V1 vasopressin receptors are abundantly expressed in the mesenteric arteries as compared with other vascular areas, whereas V2 receptors are expressed in the renal tubules. The primary actions of V1 and V2, respectively, stimulate vasoconstriction and water resorption, and thereby result in decreased portal blood inflow and reduced portal hypertension.

Approval by the FDA in September 2022 was established by the CONFIRM trial, a phase 3, randomized controlled trial that included patients with type-1 hepatorenal syndrome (HRS-1) and rapidly worsening renal function. [36] This trial accessed the percentage of patients with improved renal function via verified HRS reversal, without the need for renal replacement therapy for 10 days after treatment. Verified HRS reversal was observed in 32% of those treated with terlipressin compared with 17% in the placebo group (P = 0.0006). However, deaths due to respiratory disorders were higher in the terlipressin group compared with placebo after 90 days (11% vs 2%). Use of terlipressin is not recommended in patients with hypoxia (SpO2 < 90%), and oxygenation levels should be monitored during treatment. [36]

Early vasopressin analogue trials

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 (not approved in the United States), a synthetic vasopressin analogue, was first used in 1970 to treat HRS-AKI. 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 (not approved in the United States), attracted attention. Three important studies by Lenz and colleagues demonstrated that short-term use of ornipressin resulted in an improvement in the circulatory function and a significant increase in RPF and the GFR. [37, 38, 39]

The combination of ornipressin and albumin was subsequently tried by Guevera in patients with HRS, [40, 41]  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 the 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 HRS-AKI. This process 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%). The overall reversal rate been described to be 40%-80%. [42] One limitation of terlipressin is it is not available in many countries. Under these circumstances, such agents as octreotide, albumin, and alpha-adrenergic agonists may be considered. [43]

Gluud et al reviewed 10 randomized studies to determine whether vasoconstrictor drugs reduce mortality in patients with HRS-AKI or type 2 HRS. [44] 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 HRS-AKI, 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 HRS-AKI.

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. [45]

Wong et al studied the impact of reduction in AKI stage on overall survival in patients with cirrhosis and HRS-AKI. Subjects were grouped by AKI stage and received either terlipressin with albumin (n=91) vs placebo with albumin (n=93). Reduction in AKI stage was determined by serum creatinine levels. Patients with a reduction in AKI stage had improved survival despite not having HRS-AKI reversal. [46]

Angeli et al showed that long-term administration of midodrine (an alpha-adrenergic agonist) and octreotide improved renal function in eight patients with HRS-AKI. [47] 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 eight 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. [48]

Current practice is to use terlipressin first line, if and when available, with an initial dose of 0.5-1 mg intravenous (IV) bolus every 4-6 hours. If there is less than a 25% reduction in serum creatinine (sCr) in 3 days, the dose can be increased to 2 mg IV every 4-6 hours. It should be discontinued within 14 days of there is no improvement in renal function. In countries where terlipressin is not available, octreotide (somatostatin analogue) at 100-200 micrograms subcutaneously every 8 hours with midodrine (alpha-adrenergic agonist) 7.5 -12.5 mg orally three times daily may be used. For HRS-AKI, continuous noradrenaline infusion at 0.5-3 mg/h with a titration goal of increasing mean arterial blood pressure by 10 mmHg may be used. Albumin is recommended to be used in combination with vasoconstrictor drug regimens with 2 days of IV 1 g/kg/day, followed by 20-40 g IV daily. [49]

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 two 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.

Dietary considerations

Institute a low-salt (2 g) diet. Do not restrict protein intake unless the patient has severe encephalopathy.


Surgical Care

Peritoneovenous shunting

Peritoneovenous shunting (PVS) seems attractive in theory because it leads to plasma volume expansion and improvement of the 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 arge-volume paracenteses.

PVS has no role in HRS-AKI.

Surgical shunts

No description on the treatment of HRS is complete without a brief review of the role of portacaval shunts, particularly with the introduction of  transjugular intrahepatic portosystemic shunt (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.

Liver transplantation

Liver transplantation is the ideal treatment of HRS, with partial to complete recovery in 75% of the patients, but it is limited by the availability of donors. [13, 50]

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. [51] 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. [51] 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. [52]

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 glomerular filtration rate (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.

Simultaneous liver-kidney transplantation is the preferred treatment in patients whose renal function is not expected to recover despite liver transplantation. Due to a lack of reliable predictive biomarkers of renal recovery post liver transplantation, there has been a dramatic increase in simultaneous liver-kidney transplantation in relatively recent years. [49] In August 2017, new guidelines for simultaneous liver-kidney transplant was published by the Organ Procurement and Transplantation Network (UNOS). [53] The patient must meet at least one of three diagnosis categories, as follows:

  • A diagnosis of chronic kidney disease with a GFR of less than 60 mL/min for more than 90 consecutive days and have begun dialysis, or have a GFR of less than 30 mL/min on the day of registration on the organ waiting list;
  • Has sustained acute kidney injury (AKI) with dialysis at least once every 7 days or a GFR less than 25 mL/min at least once every 7 days;
  • Has metabolic disease with hyperoxaluria, or atypical hemolytic uremic syndrome from mutations in factor H or I, or familial non-neuropathic systemic amyloidosis, or methylmalonic aciduria

In a retrospective study (2009-2019) that evaluated predictors of renal recovery in recipients of liver transplant alone who met 2017 simultaneous liver-kidney transplant criteria, investigators found that an estimated glomerular filtration rate (eGFR) level above 30 mL/min within 90 days pre-liver transplantation was associated with achieving sustained relative renal recovery (RRR)—and was protective of adverse outcomes—whereas a predictor of failure to have sustained RRR was prolonged severe renal impairment pre-liver transplantation. [54]  The investigators concluded that "candidates who meet 2017 UNOS criteria for [simultaneous liver-kidney transplantation] yet undergo [liver transplant alone] can still have post-[liver transplant] renal recovery, exceeding 80% with short-term follow-up and 40% with long- term follow-up." [54]




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.

Hemodialysis (HD) has been used by most major centers on patients who are on the transplant list. Studies have generally used continuous veno-venous hemofiltration (CVVH) and intermittent HD, the modality dependent on the hemodynamic stability of the patient.

A retrospective cohort study of 472 patients with HRS or tubular necrosis who underwent intermittent HD or CVVH, with 6-month survival as the primary outcome, found 15% of nonlisted subjects were alive 6 months after initiating renal replacement therapy (RRT), of which 78% of the patients had recovered renal function and were off dialysis. [55] Of the listed patients who did not receive transplantation, 38% were alive and off dialysis by the end of 6 months. Overall, 24% of patients were alive by the end of 6 months. The study suggested a potential benefit of using of RRT as a bridging therapy to organ transplantation. [55]

An earlier study on the clinical course of four patients with HRS who underwent HD in an attempt to bridge to liver transplantation found only one of the patients received the transplant. [56] Mean survival was 236 days (range: 31 to 460 days), with 33% of the days spent hospitalized. Overall, the study reflected the high cost and burden of morbidity as well as inpatient hospitalization in such patients and cautioned for evaluation of patients on an individual basis. [56]

A study of 30 patients with HRS treated with either CVVH or HD found that 30-day survival was 27% (8 patients); none of the patients on mechanical ventilation survived. This suggested that dialysis may be a viable therapeutic option in those patients who have not decompensated to the point of mechanical ventilation. [57] An older 1995 retrospective study of 107 patients found that of the 46% of patients placed on dialysis, predictors of future hemodialysis did not include diagnosis of HRS itself but were related to thrombocytopenia, encephalopathy, and malignoma. [58]

Continuous arteriovenous or venovenous hemofiltration has also been used, but the efficacy of these two measures has yet to be determined. Variations of hemodialysis include the molecular adsorbent recirculating system. [9] 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 HRS-AKI 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.

Overall, the decision to initiate hemodialysis should be individualized to the patient. If transplantation is not available, hemodialysis probably will continue to be performed for patients on the waiting list.

Interventional radiologist

Due to its ability to reduce portal hypertension in patients with variceal bleeding and refractory ascites, the role of transjugular intrahepatic portosystemic shunt (TIPS) in HRS initially seemed logical, particularly in view of isolated reports of renal function improvement following surgical shunts in the 1970s. Small, uncontrolled studies have indicated that TIPS may improve renal plasma flow (RPF) and the glomerular filtration rate (GFR) as well as reduce the activity of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) in patients who have cirrhosis with both types HRS. Improvement in renal function is usually slow and occurs in approximately 60% of patients.

In relatively more recent years, there have been a few publications that investigated the role of TIPS in HRS. A meta-analysis of nine studies with a total of 128 patients observed post-TIPS survival to be between 47% and 64%. Overall, renal function improved in 83% of the patients. In patients with maintain stable hepatic function but experience renal decompensation, TIPS may effectively improve renal function. [59]

An observational retrospective cohort study (2005-2014) with 79,354 patients found lower inpatient mortality when comparing patients with HRS-AKI without variceal bleeding who underwent TIPS versus receiving dialysis as treatment. [60] A similar retrospective study demonstrated reduced inpatient mortality to be true in men but not women, although the drivers of this sex-disparity is unclear. [61] However, it is fairly well known that TIPS carries the risk of an increasing incidence of hepatic encephalopathy. In addition, there are many limitations of TIPS. HRS patients typically have chronic and decompensated liver failure, and they may be precluded from the procedure due to elevated bilirubin levels or cardiac dysfunction. Moreover, the contrast burden associated with TIPS has the potential of worsening renal function. [62] Although more studies now exist that evaluate the role of TIPS in the treatment of HRS, its use remains investigational because of the lack of prospective studies and the known risks of the procedure, as well as the preference of medical management as a first-line treatment.



The main precipitating factor of hepatorenal syndrome-acute kidney injury (HRS-AKI) (formerly type 1 HRS) is spontaneous bacterial peritonitis (SBP). When this condition develops in patients with type 2 HRS, the probability of developing HRS-AKI is very high. This may be prevented by antibiotic prophylaxis with sulfamethoxazole and trimethoprim (Bactrim) or fluoroquinolones in patients with a prior history of SBP. Alternatively, patients with type 2 HRS who are on the liver transplant waiting list may benefit from prophylactic antibiotics, irrespective of whether they have a prior history of SBP.

A randomized controlled trial showed 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 hours later). [63] The incidence of HRS in patients with SBP who received albumin together with antibiotic therapy was 10% compared to 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.

Large-volume paracentesis 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. Unfortunately, with the current donor shortage, this does not seem to be a realistic possibility.

Regarding patients with acute alcoholic hepatitis, a study reported that the administration of pentoxifylline (400 mg three times daily for 28 days) reduced the incidence of HRS and mortality (8% and 25%, respectively) compared with a placebo group (35% and 46%, respectively). [64] However, no long-term data exist on the renal function or mortality in these patients.