Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a severe form of kidney failure that characteristically occurs in people with advanced cirrhosis and ascites. Its hallmark is intense narrowing of the kidney's arteries without substantial damage visible in kidney tissue: the failure is driven mainly by the circulatory changes of a failing liver. Newer research adds systemic inflammation, oxidative stress and bile-salt injury to the tubules as contributors, so HRS is no longer described as purely "functional". Liver transplantation is described as the only curative treatment.

Table of Contents

  1. What is Hepatorenal Syndrome?
  2. Pathophysiology: The Circulatory Collapse Behind HRS
  3. HRS-AKI vs HRS-CKD: The 2015 ICA Classification
  4. Triggers and Precipitants
  5. Diagnosis: The Updated ICA 2015 Criteria
  6. Terlipressin: The Key Vasoconstrictor Treatment
  7. Albumin Infusion and the Role of Volume Expansion
  8. Norepinephrine and Octreotide/Midodrine Alternatives
  9. Liver Transplantation: The Only Cure
  10. Renal Replacement Therapy and Prognosis
  11. Key Research Papers
  12. Connections
  13. Featured Videos

What is Hepatorenal Syndrome?

Hepatorenal syndrome (HRS) is a form of kidney function impairment that characteristically occurs in cirrhosis. A 2018 review in Nature Reviews Disease Primers (Ginès and colleagues) describes the acute form as a severe impairment of kidney function caused by constriction of the renal arteries "in the absence of substantial abnormalities in kidney histology". In the 2022 review by Bera and Wong, HRS is the subset of acute kidney injury (AKI) in cirrhosis that does not respond to volume replacement alone; the same review gives the overall incidence of acute tubular necrosis (15–60%) and prerenal azotemia (15–45%) in cirrhosis as higher than that of HRS (10–40%).

The older view of HRS as a purely "functional" failure rests on observations such as a 1969 New England Journal of Medicine report on transplanting kidneys taken from patients who had HRS, which its authors presented as evidence for the functional nature of the renal failure. A 2019 position paper (Angeli and colleagues, Journal of Hepatology) states that systemic inflammation, oxidative stress and bile salt-related tubular damage may contribute significantly, giving HRS an additional structural component that would make traditional diagnostic criteria less reliable and would help explain why some patients do not respond to vasoconstrictors plus albumin.

HRS has two broad patterns. HRS-AKI (formerly type 1 HRS) is a rapid deterioration of kidney function that often follows a precipitating event. HRS-CKD (formerly type 2 HRS) is a moderate, stable or slowly progressive kidney dysfunction that often has no obvious precipitant and is mainly characterised clinically by refractory ascites. In a 2005 series of 105 consecutive patients (Alessandria and colleagues), median survival was 1 month with type 1 HRS; with type 2 HRS it was 3 months when the MELD score was 20 or higher and 11 months when it was below 20. The 2018 review gives a median survival of 3 months or less for AKI-HRS.

In a 1993 follow-up study of 234 patients with cirrhosis and ascites who did not have azotemia at entry (Ginès and colleagues), the probability of developing HRS was 18% at 1 year and 39% at 5 years. Low serum sodium, high plasma renin activity and absence of an enlarged liver were the independent predictors; the cause of cirrhosis and the Child-Pugh score were not.

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Pathophysiology: The Circulatory Collapse Behind HRS

The classic explanation is the peripheral arterial vasodilation hypothesis. A 2015 review (Bernardi and colleagues) calls it "undisputed" that splanchnic arterial vasodilation (widening of the arteries supplying the gut) contributes to portal hypertension and is the basis of ascites and hepatorenal syndrome.

The 2022 review by Bera and Wong summarises the sequence. Overproduction of vasodilating substances, including nitric oxide, carbon monoxide and endocannabinoids, widens the splanchnic and systemic arteries. Increased gut permeability linked to portal hypertension lets bacteria and bacterial products pass from the gut into the splanchnic circulation, and some of these products are themselves vasodilators. The result is systemic hypotension. The body responds by raising cardiac output and activating vasoconstrictor systems: the renin-angiotensin-aldosterone system, the sympathetic nervous system, and a non-osmotic increase in vasopressin release. The kidney's circulation is very sensitive to these vasoconstrictors, and the end result is renal vasoconstriction. Sodium and water are retained at the same time, and water retention in excess of sodium retention leads to low blood sodium.

A 1986 review (Arroyo and colleagues) describes increased production of prostaglandins in the kidneys of people with cirrhosis and ascites as a homeostatic response that counteracts the vascular effects of these vasoconstrictors and the tubular action of antidiuretic hormone.

Systemic inflammation is a second driver. Bera and Wong report that at least one-third of patients with HRS-AKI show evidence of inflammation without any documented infection. Inflammation may be sterile (alcoholic hepatitis, drug-induced liver injury) or infectious. The 2015 review by Bernardi and colleagues proposes that multiorgan dysfunction in advanced cirrhosis likely begins with the spread of bacterial products through the body, which activates the innate immune response, widens arteries and damages organs through pro-inflammatory cytokines and reactive oxygen and nitrogen species.

This is why vasoconstrictor drugs, used together with albumin, are the medical treatment described for HRS: they counteract the splanchnic arterial vasodilation (Ginès 2018).

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HRS-AKI vs HRS-CKD: The 2015 ICA Classification

The 1996 International Ascites Club criteria (Arroyo and colleagues) defined type 1 HRS, as summarised by Bera and Wong, as a rapid rise in serum creatinine, doubling from baseline within 2 weeks to at least 2.5 mg/dL, without evidence of structural kidney disease. In 2015 the International Club of Ascites (ICA) revised the nomenclature and diagnostic criteria, renaming type 1 HRS HRS-AKI (Angeli 2015; described in Angeli 2019). According to a 2018 review (Solé and colleagues), the new criteria are based on small changes in serum creatinine relative to earlier values within a short period, with no need to reach a fixed creatinine threshold, so that vasoconstrictors and albumin are started at lower creatinine values.

AKI Definition and Staging in Cirrhosis

As tabulated in the 2022 review by Bera and Wong (adapted from the ICA 2015 recommendations):

The same review notes that urine output has not been generally accepted by hepatologists as a criterion for AKI in cirrhosis, because people with cirrhosis and ascites usually pass little urine as a result of avid sodium and water retention.

HRS-CKD (Formerly Type 2 HRS)

Under the new nomenclature, the slowly progressive form previously called type 2 HRS is classed as a form of chronic kidney disease (Bera and Wong 2022). It is mainly characterised clinically by refractory ascites (Angeli 2019). The vasoconstrictor trials described below enrolled patients with type 1 HRS (HRS-AKI).

When HRS-AKI develops on top of chronic kidney disease, the 2022 review reports that the episode tends to have a much more aggressive course.

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Triggers and Precipitants

The 2022 review by Bera and Wong reports that most HRS-AKI episodes are precipitated by an acute event, and that infection was the most common precipitating factor of AKI in cirrhosis. Its list of precipitating factors includes infections, sepsis, excessive diuretic use, nephrotoxic drugs or radiologic contrast, gastrointestinal blood loss, diarrhoea from lactulose, and alcoholic hepatitis.

Spontaneous Bacterial Peritonitis (SBP)

The 2018 review by Ginès and colleagues names bacterial infections, particularly spontaneous bacterial peritonitis, as the main triggering factors of AKI-HRS. In the Sort trial (NEJM 1999), 126 patients with cirrhosis and SBP were randomised to the antibiotic cefotaxime alone or cefotaxime plus intravenous albumin (1.5 g/kg at diagnosis and 1 g/kg on day 3). Renal impairment developed in 33% of the antibiotic-only group and 10% of the albumin group; in-hospital mortality was 29% vs 10%, and 3-month mortality 41% vs 22%.

Large-Volume Paracentesis

Removing a large volume of ascites can cause post-paracentesis circulatory dysfunction. A 2012 meta-analysis of 17 randomised trials with 1,225 patients (Bernardi and colleagues) found that, compared with alternative treatments, albumin reduced post-paracentesis circulatory dysfunction (odds ratio 0.39), low blood sodium (odds ratio 0.58) and mortality (odds ratio 0.64). Bera and Wong list albumin with paracentesis of more than 5 litres among the prevention strategies recommended by liver societies.

Gastrointestinal Bleeding

Gastrointestinal blood loss is among the precipitating factors listed by Bera and Wong, and the prevention strategies recommended by liver societies include prophylaxis against bacterial infection during an episode of gastrointestinal bleeding.

Infection Beyond SBP

The 2022 review describes bacterial infection as precipitating AKI through excessive production of inflammatory cytokines, and reports that a complete septic workup and empiric antibiotics are recommended in all patients with HRS-AKI.

Nephrotoxic Medications

Because kidney prostaglandins help offset the vasoconstrictor systems in cirrhosis with ascites, the 1986 review by Arroyo and colleagues concluded that nonsteroidal anti-inflammatory drugs (NSAIDs) need caution in these patients because they may induce acute renal failure and water retention. The prevention strategies summarised by Bera and Wong include avoidance of nephrotoxic drugs and of NSAIDs, and the ICA criteria for HRS-AKI require no current or recent treatment with nephrotoxic drugs.

Over-Diuresis

Excessive diuretic use is a listed precipitating factor. The prevention strategies recommended by liver societies, as summarised by Bera and Wong, include regular monitoring of kidney function when diuretics are started and avoidance of excessive diuretic use.

Antibiotic Prophylaxis Research

In a 2007 randomised trial (Fernández and colleagues), 68 patients with cirrhosis, low ascitic fluid protein (below 15 g/L) and either advanced liver failure (Child-Pugh score of 9 or more with bilirubin of 3 mg/dL or more) or impaired kidney function (creatinine 1.2 mg/dL or more, blood urea nitrogen 25 mg/dL or more, or sodium 130 mEq/L or less) received the antibiotic norfloxacin or placebo. Norfloxacin reduced the 1-year probability of SBP (7% vs 61%) and of HRS (28% vs 41%), and improved 3-month survival (94% vs 62%). The 2022 review also reports a more recent prospective study in which primary SBP prophylaxis was associated with more AKI (48% vs 30%) and higher 90-day mortality (35% vs 22%) than secondary prophylaxis, and notes the suggestion that antibiotic prophylaxis be individualised by weighing risks and benefits.

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Diagnosis: The Updated ICA 2015 Criteria

HRS-AKI is a diagnosis of exclusion, made after prerenal azotemia and structural causes of AKI such as acute tubular necrosis have been ruled out (Bera and Wong 2022). The 2018 review by Ginès and colleagues notes the lack of specific diagnostic tools, with acute tubular necrosis the main alternative diagnosis.

Diagnostic Criteria for HRS-AKI

As tabulated by Bera and Wong (adapted from the ICA 2015 recommendations):

  1. Cirrhosis with ascites.
  2. AKI of stage 2 or higher.
  3. No full or partial response after at least 2 days of diuretic withdrawal and volume expansion with albumin, at a dose of 1 g/kg body weight per day, to a maximum of 100 g/day.
  4. Absence of shock.
  5. No current or recent treatment with nephrotoxic drugs.
  6. No signs of kidney parenchymal disease, as indicated by proteinuria above 500 mg/day, microhaematuria (more than 50 red blood cells per high-power field), urinary injury biomarkers (if available) and/or abnormal kidney ultrasound.

Laboratory Clues and Biomarkers

The 2022 review describes examining the urine for proteinuria, haematuria and casts to rule out structural causes of AKI. Serum creatinine is currently the only parameter used to define and stage AKI in cirrhosis. Urinary biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 and kidney injury molecule-1 have been studied for separating HRS-AKI from other causes; the review reports that NGAL identified acute tubular necrosis in 86% of cases at a cut-off of 220–244 µg/g creatinine, but that clinical usefulness remains unclear because of limited availability and no widely accepted cut-off. A 2018 review (Solé and colleagues) reports consistent data that urine biomarkers, particularly NGAL, may be useful for this differential diagnosis.

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Terlipressin: The Key Vasoconstrictor Treatment

Terlipressin is a synthetic vasopressin analogue. Its US prescribing information describes twice the selectivity for vasopressin V1 receptors over V2 receptors, and says it acts both as a prodrug for lysine-vasopressin and with activity of its own. The label states that terlipressin is thought to increase kidney blood flow in HRS by reducing portal hypertension and blood flow in the portal vessels and by increasing effective arterial volume and mean arterial pressure. The CONFIRM trial report notes that terlipressin is used for type 1 HRS in many parts of the world and is part of European clinical practice guidelines; in 2015 it was not available in the United States (Cavallin and colleagues). The US Food and Drug Administration approved terlipressin on September 14, 2022 (NDA 022231 approval letter) "to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function".

Mechanism of Action

Bera and Wong describe terlipressin as producing vasoconstriction through V1 receptors on vascular smooth muscle. It lowers portal pressure by reducing portal inflow and intrahepatic resistance; the resulting shift of blood volume into the systemic circulation raises mean arterial pressure and improves the kidney's circulation. The review also cites evidence that terlipressin reduces systemic inflammation by reducing bacterial translocation in decompensated cirrhosis.

Dosing in the Label and in Trials

The US label gives 0.85 mg of terlipressin every 6 hours by slow intravenous injection on days 1 to 3. On day 4, if serum creatinine has fallen by at least 30% from baseline the same dose continues; if it has fallen by less than 30%, the dose may be increased to 1.7 mg every 6 hours; if creatinine is at or above baseline, terlipressin is discontinued. Treatment continues until 24 hours after two consecutive creatinine values of 1.5 mg/dL or less at least 2 hours apart, or for a maximum of 14 days. In CONFIRM, patients received 1 mg of terlipressin acetate (equivalent to 0.85 mg in the label) every 6 hours. European trials used other schedules: 1–2 mg every 4 hours intravenously (Martín-Llahí 2008), or a continuous infusion starting at 3 mg/24 hours and rising to 12 mg/24 hours (Cavallin 2015). In the trials summarised here, terlipressin was given together with albumin.

Evidence: The CONFIRM Trial

The phase 3 CONFIRM trial (Wong and colleagues, NEJM 2021; PubMed PMID: 33657294) randomised 300 adults with type 1 HRS in a 2:1 ratio to terlipressin (199) or placebo (101) for up to 14 days, with albumin strongly recommended in both groups. Verified HRS reversal (two consecutive serum creatinine values of 1.5 mg/dL or less at least 2 hours apart, and survival without renal replacement therapy for at least 10 days after treatment) occurred in 32% with terlipressin vs 17% with placebo (P = 0.006). The efficacy table in the US label reports 29.1% vs 15.8% (P = 0.012). By day 90, 23% vs 29% had received a liver transplant and 51% vs 45% had died. More adverse events, including abdominal pain, nausea, diarrhoea and respiratory failure, occurred with terlipressin; death within 90 days from respiratory disorders occurred in 11% vs 2%. The authors concluded that terlipressin was more effective than placebo in improving kidney function but was associated with serious adverse events, including respiratory failure. The 2022 review by Bera and Wong reports no difference in overall or transplant-free survival up to 90 days.

Earlier, in a 2008 randomised trial of 46 patients (Martín-Llahí and colleagues), kidney function improved in 43.5% with terlipressin plus albumin vs 8.7% with albumin alone; 3-month survival did not differ significantly (27% vs 19%). A 2022 network meta-analysis of 26 randomised trials with 1,736 patients (Pitre and colleagues) found with high certainty that terlipressin increases HRS reversal compared with placebo, found with low certainty that it may reduce mortality, and found with moderate certainty that it probably increases serious adverse events.

Boxed Warning, Contraindications and Cautions in the Label

The US label carries a boxed warning for serious or fatal respiratory failure; patients with volume overload or with acute-on-chronic liver failure (ACLF) grade 3 are at increased risk. In CONFIRM, serious or fatal respiratory failure occurred in 14% of patients on terlipressin and 5% on placebo. The label states that terlipressin is not to be started in patients with hypoxia (for example, SpO2 below 90%) until oxygenation improves, calls for continuous pulse oximetry, and lists contraindications in patients experiencing hypoxia or worsening respiratory symptoms and in those with ongoing coronary, peripheral or mesenteric ischaemia. Other warnings cover ischaemic events (cardiac, cerebrovascular, peripheral or mesenteric), possible fetal harm, and adverse reactions that may make a patient ineligible for liver transplantation; for patients with high transplant priority (for example, MELD 35 or above) the label says the benefits may not outweigh the risks. Patients with a serum creatinine above 5 mg/dL are unlikely to benefit. The most common adverse reactions (10% or more) were abdominal pain, nausea, respiratory failure, diarrhoea and dyspnoea; postmarketing reports include headache, low blood sodium, skin necrosis and gangrene.

Bera and Wong cite a 2021 conference report of CONFIRM data in which respiratory failure occurred in 16 of 200 terlipressin-treated patients (8%) vs 3 of 100 on placebo (3%), with 12 of the 16 terlipressin cases in patients with ACLF grade 3. In studies of terlipressin, responders had significantly better 90-day survival than non-responders, and even a partial response with a 20% fall in creatinine was associated with improved survival.

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Albumin Infusion and the Role of Volume Expansion

Albumin has two roles in HRS: it is part of the diagnostic step (volume expansion to separate volume-responsive AKI from HRS-AKI) and it is given together with vasoconstrictors. A 2014 review (Arroyo and colleagues) lists prevention of post-paracentesis circulatory dysfunction, prevention of type 1 HRS associated with bacterial infections, and treatment of type 1 HRS as the main indications for albumin in decompensated cirrhosis, each associated with improved survival.

Mechanisms

The 2014 review describes albumin's capacity to bind lipopolysaccharide and other bacterial products, reactive oxygen species, nitric oxide and prostaglandins, through which it modulates inflammation. Its benefits have traditionally been attributed to plasma volume expansion but could also relate to these anti-inflammatory effects. The 2022 review by Bera and Wong describes the antioxidant and scavenging role of the free cysteine at position 34 (Cys-34), and reports that in cirrhosis circulating albumin is structurally modified and functionally impaired: increased oxidative stress converts it to an oxidised form that is less able to bind free radicals.

Doses Reported in Guidelines and Trials

For the diagnostic step, the ICA dose is 1 g/kg body weight per day to a maximum of 100 g/day. With vasoconstrictors, the ICA recommends 20–40 g/day, although Bera and Wong note that no dose-response study underlies this regimen. The Martín-Llahí and Cavallin trials used 1 g/kg on day 1 followed by 20–40 g/day. In SBP, the Sort trial used 1.5 g/kg at diagnosis and 1 g/kg on day 3, which reduced renal impairment from 33% to 10%.

In the 2012 paracentesis meta-analysis (Bernardi and colleagues), albumin reduced post-paracentesis circulatory dysfunction compared with each of the other volume expanders tested, including dextran, gelatin, hydroxyethyl starch and hypertonic saline.

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Norepinephrine and Octreotide/Midodrine Alternatives

Before terlipressin was available in the United States, midodrine and octreotide with albumin were used there as an alternative (Cavallin 2015). Norepinephrine is the other main alternative.

Norepinephrine

Bera and Wong describe norepinephrine as an alpha-1 adrenergic agonist and systemic vasoconstrictor that raises mean arterial pressure and so kidney perfusion pressure. The review gives a dose range of 0.5–3 mg/hour, adjusted to maintain mean arterial pressure. It is less expensive than terlipressin, but the need for a central venous catheter and cardiac monitoring in an intensive care unit may offset that saving. No trial has compared norepinephrine with placebo. Small randomised trials (96 patients on norepinephrine, 99 on terlipressin in total) reported HRS reversal with norepinephrine of 39% to 70%, equivalent to terlipressin, but all were at high risk of bias; in one trial in ACLF, terlipressin was superior to norepinephrine.

A 2017 Cochrane review (Israelsen and colleagues; 10 trials, 474 participants, mostly terlipressin vs norepinephrine) found insufficient evidence to support or refute benefits or harms of terlipressin versus other vasoactive drugs, all evidence being of very low quality; terlipressin seemed to increase diarrhoea or abdominal pain. The 2022 network meta-analysis (Pitre and colleagues) found that norepinephrine may increase HRS reversal compared with placebo (low certainty), and concluded that until access to terlipressin improves, initial norepinephrine may be more appropriate than an initial trial of midodrine plus octreotide.

Octreotide and Midodrine

Bera and Wong describe midodrine as an oral alpha-adrenergic agonist that raises mean arterial pressure, and octreotide as a nonspecific antagonist of splanchnic vasodilating substances, especially glucagon. Octreotide alone has been shown to be ineffective in type 1 HRS, and the response to the combination is slow and can take weeks.

The Cavallin randomised trial (Hepatology 2015; PubMed PMID: 25644760) compared terlipressin plus albumin (27 patients) with midodrine (7.5 mg three times daily, up to 12.5 mg) plus subcutaneous octreotide (100 µg three times daily, up to 200 µg) plus albumin (22 patients). Kidney function recovered in 70.4% (19/27) with terlipressin vs 28.6% (6/21) with midodrine-octreotide (P = 0.01). The Cochrane review notes that this comparison rests on one small trial.

TIPS (Transjugular Intrahepatic Portosystemic Shunt)

In a 1998 study of 7 patients with type 1 HRS (Guevara and colleagues), TIPS lowered the portal pressure gradient from 20 to 10 mmHg, kidney function improved in 6, and serum creatinine fell from about 5 to 1.8 mg/dL at 30 days; mean survival was 4.7 months, and the authors called for controlled studies. In a 2002 randomised trial of 70 patients with refractory ascites (Ginès and colleagues), TIPS lowered ascites recurrence and the development of HRS compared with repeated paracentesis plus albumin, but did not improve survival and was associated with more severe hepatic encephalopathy and higher costs.

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Liver Transplantation: The Only Cure

The 2018 review by Ginès and colleagues calls liver transplantation the ideal treatment for AKI-HRS in patients without contraindications, and the 2022 review by Bera and Wong calls it the only curative treatment, because it corrects the underlying portal hypertension and liver dysfunction.

MELD Score and Transplant Priority

Bera and Wong report that patients with HRS-AKI on the transplant waiting list are prioritised because of the rise in serum creatinine and the associated rise in MELD score. Some have debated whether vasoconstrictor treatment is worthwhile, because a response lowers the MELD score and so the priority; the review reports, however, that response before transplant is associated with better survival after transplant and that vasoconstrictor treatment reduces the likelihood of needing renal replacement therapy before and after transplant. In the 2005 Alessandria series, HRS type and MELD score were the only independent predictors of survival.

Simultaneous Liver-Kidney Transplantation

Bera and Wong describe simultaneous liver-kidney transplantation (SLKT) for HRS-AKI as controversial, because it takes a kidney from patients on the kidney waiting list and its survival benefit is questioned, particularly in patients not on dialysis. Under the US Organ Procurement and Transplantation Network criteria they tabulate, eligibility includes: sustained AKI for at least 6 consecutive weeks with eGFR or creatinine clearance of 25 mL/min or less and/or dialysis; chronic kidney disease with eGFR of 60 mL/min or less for more than 90 days together with end-stage kidney disease on dialysis or eGFR of 35 mL/min or less at or after kidney-list registration; or certain inherited metabolic disorders. A "safety net" gives increased kidney priority to liver-alone recipients registered on the kidney list between 60 and 365 days after transplant who are on chronic dialysis or have an eGFR of 20 mL/min or less.

Bridging Therapy and Outcomes

In a 2004 case-control study (Restuccia and colleagues), 9 patients whose HRS was treated with vasopressin analogues before transplant had post-transplant outcomes similar to 27 matched patients transplanted without HRS (3-year survival 100% vs 83%, not significantly different), with no significant differences in post-transplant kidney impairment, severe infections, rejection, intensive care or hospital days. The authors' background statement notes that patients with HRS otherwise have a poor outcome after transplant compared with those without HRS. Bera and Wong report that the most important predictor of kidney recovery after transplant in patients on renal replacement therapy is the duration of that therapy before transplant, with a reported cut-off of 14 days, and describes palliative care for patients who are not transplant candidates.

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Renal Replacement Therapy and Prognosis

Renal replacement therapy (RRT), meaning dialysis or continuous renal replacement therapy (CRRT), does not correct the circulatory abnormality behind HRS. The 2022 review by Bera and Wong describes its use in HRS as controversial and typically dependent on the patient's transplant status.

Indications and Modality

According to the same review, RRT is indicated in HRS-AKI unresponsive to drug treatment when there is volume overload, electrolyte derangement or uremia. Continuous RRT is preferred over intermittent RRT in these patients because the rapid fluid and solute shifts of intermittent RRT are complicated by low blood pressure during dialysis and by cerebral oedema. Risks include low blood pressure and haemodynamic instability, cardiac events, venous access problems, bleeding and infection. The review states that RRT does not offer a survival benefit on its own, that the decision is individualised by the goal of care, and that RRT is regarded as a bridge in liver transplant candidates; in selected patients it may prolong life by several weeks to months. Recent data suggest that in HRS-AKI as part of ACLF, improving kidney function with RRT may lower 28-day mortality.

Prognosis

Bera and Wong describe the prognosis of untreated type 1 HRS as very poor, with median survival measured in days to weeks. In the 2005 Alessandria series, median survival was 1 month for type 1 HRS, and for type 2 HRS 3 months with a MELD score of 20 or more and 11 months below 20. Terlipressin treatment has not improved overall or transplant-free survival in trials, but responders consistently have better 90-day transplant-free survival than non-responders. In CONFIRM, 51% of terlipressin-treated and 45% of placebo-treated patients had died by day 90.

Predictors of Response to Vasoconstrictors

Other Approaches Under Study

Bera and Wong report that therapeutic plasma exchange improved survival in non-transplanted patients with acute liver failure in an open randomised study and improved haemodynamics and encephalopathy in ACLF, but no study has assessed kidney function in HRS-AKI specifically. Kidney biomarkers such as NGAL are being studied for diagnosis. None of these approaches is described as replacing liver transplantation.

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Key Research Papers

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  3. Angeli P, Gines P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol. 2015;62(4):968–974. — PubMed PMID: 25638527
  4. Cavallin M, Kamath PS, Merli M, et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial. Hepatology. 2015;62(2):567–574. — PubMed PMID: 25644760
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