Shopping Cart

Introduction

Hepatorenal syndrome (HRS) is a type of progressive renal failure that occurs primarily in patients with cirrhosis without any accompanying structural kidney damage.¹ This condition is responsible for 11% to 20% of all acute kidney injury (AKI) cases and is linked to high mortality among hospitalized patients with cirrhosis.² Results of a prospective cohort study suggest that approximately 45.8% of hospitalized patients with cirrhosis and renal failure may have HRS. ³ In this study, the 3-month mortality rates were 76% for patients with type 1 HRS and 60% for patients with type 2 HRS.

The pathophysiology of HRS involves an interplay of the renin-angiotensin-aldosterone (RAAS), sympathetic nervous, and cardiac systems.⁴ Progressive liver cirrhosis increases vascular resistance within the liver leading to portal hypertension.^2,4 Increased portal hypertension and stress on portal blood vessels cause the endothelium to produce vasodilators, such as prostanoids, nitric oxide, and endogenous cannabinoids. These vasodilators interact with the splanchnic vasculature leading to vasodilation. Cardiac output is unable to compensate for the reduced systemic vascular resistance and signals a decreased circulating volume. The decreased mean arterial blood pressure activates the RAAS, visceral sympathetic nervous system, and the release of vasopressin and local endothelin resulting in increased cardiac output and heart rate, reduced intraglomerular blood flow, and retention of water and sodium.

Several risk factors or triggering events may precipitate HRS, specifically type 1 HRS, a more severe type of HRS, while type 2 HRS occurs spontaneously in most cases.^5,6 Spontaneous bacterial peritonitis remains the most common trigger for type 1 HRS.⁵ Patients presenting with acute-on-chronic liver failure (ACLF), marked by acute hepatic or extrahepatic organ failure, is another risk factor for developing AKI and HRS. Other triggering events for HRS include a history of progressive jaundice, gastrointestinal bleeding, and large volume paracentesis. Providers should monitor for type 1 HRS in patients with a recent spontaneous bacterial peritonitis and/or ACLF.

Diagnosis of HRS

The International Club of Ascites (ICA) provides guidelines on the diagnosis of HRS.⁶ The diagnosis encompasses the presence of cirrhosis, ascites, and an elevated serum creatinine (SCr) (>1.5 mg/dL or 133 µmol/L) for at least 48 hours despite diuretic withdrawal and treatment with albumin. Per the guideline, albumin should be administered at 1 g/kg of body weight up to a maximum of 100 g of albumin per day. Patients must be free from any parenchymal kidney disease (defined as proteinuria >500 mg/day, microhematuria, and/or abnormal results from renal ultrasound scanning), shock, and current or recent use of nephrotoxic drugs. Hepatorenal syndrome is classified into 2 types: type 1 and type 2 (Table 1). Patients with type 1 HRS experience rapid worsening of renal failure over less than 2 weeks, while patients with type 2 HRS have moderate renal failure (defined as SCr >1.5 mg/dL or 133 µmol/L) over a more extended time period.

Proposed changes to the current diagnostic criteria

Recently, practitioners recognized that the ICA diagnostic criteria for types 1 and 2 HRS may delay administration of effective treatments. ^7,8 For example, the ICA criteria encourage clinicians to wait until a SCr >2.5 mg/dL to diagnose, and subsequently initiate appropriate treatment, in patients with type 1 HRS. However, patients with lower SCr levels respond faster and have better outcomes to some agents used for HRS treatment.

In 2015, the ICA published revised consensus recommendations to the HRS definition.⁸ This document advises removal of the current cutoff for SCr values, especially for type 1 HRS, since SCr levels may not reliably represent renal impairment in patients with cirrhosis, which may change dynamically over time.² Assay interference with bilirubin, reduced hepatic creatine synthesis, decreased muscle mass, and malnutrition may affect SCr levels in patients with cirrhosis as well. ^2,9

In 2019, another document, authored by the same leading author as the 2015 revised consensus recommendations, proposed changes to the HRS classification.⁷ The document advises to classify HRS by types of renal dysfunction instead of by types 1 and 2 HRS. The proposed subtypes of HRS consist of HRS-AKI (HRS due to AKI), HRS-AKD (HRS due to acute kidney disease (AKD)), and HRS-CKD (HRS due to chronic kidney disease (CKD)). Table 2 lists the accepted definitions for AKI, AKD, and CKD, while Table 3 shows the proposed re-classification and corresponding definitions of HRS subtypes. Due to these changes, the definition for HRS-AKI incorporates urine output (obtained only via a urinary catheter) and updated SCr thresholds.⁷ The definitions for HRS-AKD and HRS-CKD change historic SCr thresholds to glomerular filtration rate (GFR) thresholds as GFR thresholds are more commonly utilized in CKD or AKD settings. To date, most of the literature still uses historic nomenclature of types 1 and 2 HRS, and the ICA website links to the initial definitions of types 1 and 2 HRS.⁶

Predicting prognosis

Several factors assist in predicting prognosis in patients with HRS including disease classification, cardiac function, biomarkers, and infection.² A diagnosis of type 1 HRS is linked to worse morbidity and mortality compared with type 2 HRS.¹¹ Using historic definitions of HRS types, patients with type 1 HRS typically present with more severe liver and renal failure and impaired circulatory function compared to patients with type 2 HRS. The estimated median survival is 1 month for type 1 HRS and 6.7 months for type 2 HRS.

Patients with a low cardiac output in the presence of systemic vasodilation, as with cirrhosis and refractory ascites, are at risk for HRS and have a worse prognosis.² Close to 45% of patients with cirrhosis, ascites, and reduced cardiac output may develop type 1 HRS. ¹² Low cardiac output is the consequence of cirrhotic cardiomyopathy, which is an abnormal cardiac response affecting patients with cirrhosis. Administering beta-blockers such as propranolol to patients with cirrhosis and spontaneous bacterial peritonitis may increase the diagnostic rate of HRS, prolong hospitalization time, and decrease survival.^13-15

Serum creatinine and cystatin C may serve as biomarkers to predict prognosis in patients with HRS.² Increasing SCr correlates with the severity of AKI. However, renal function is not the only factor contributing to SCr levels. Dietary protein intake, muscle mass, and nonrenal clearance can also affect SCr. Lately, serum cystatin C has been used as an alternative to SCr to predict outcomes in patients with HRS. All nucleated cells in the body secrete cystatin C, which only kidneys can remove. An observational study showed that increased serum cystatin C is an independent predictor of mortality and development of type 1 HRS in patients with cirrhosis and ascites. ¹⁶

The presence of infection in patients with type 1 HRS signals worse outcomes. The survival of patients with type 1 HRS due to infection is estimated to be around 75% after 3 months.¹⁷ Lack of infection resolution is a key mortality predictor as it prevents HRS reversal. Patients with persistent type 1 HRS and infection that develop septic shock experience 100% mortality after 3 months. Therefore, immediate treatment of infection in patients with type 1 HRS is crucial.

Treatment approach to HRS

The management of HRS involves pharmacologic and non-pharmacologic interventions. Once providers establish an HRS diagnosis, the first step is to discontinue diuretics, beta-blockers, vasodilators, and medications that decrease blood volume.^1,7 Providers should also halt nephrotoxic medications such as nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, and certain antibiotics. ²

Promptly initiating appropriate pharmacologic therapy may lead to improved renal function and better survival, especially in patients with type 1 HRS. ⁷ To counteract splanchnic vasodilation, vasoconstrictors in combination with albumin are the first-line pharmacologic treatments for HRS.² Albumin expands intravascular volume, and thus, increases mean arterial pressure in patients with hemodynamic dysfunction, while vasoconstrictors attenuate splanchnic arterial vasodilation. ^1,2,18 As a result, the combination of a vasoconstrictor with albumin leads to better kidney perfusion and improves renal function. ¹⁸ Vasoconstrictors used concomitantly with albumin are terlipressin, norepinephrine, octreotide, and midodrine.² Terlipressin is the first-line vasoconstrictor in Europe and has been extensively studied for this indication ; however, it is unavailable in the United States and Canada. ^9,19 Terlipressin remains non-Food and Drug Administration (FDA)-approved as the results of a study performed in the United States and Canada showed similar survival and HRS reversal outcomes with terlipressin and albumin versus albumin alone.^2,20 Moreover, patients receiving terlipressin experienced more ischemic events. Other vasoconstrictors – norepinephrine, octreotide, and midodrine – are available in the United States.²¹

The combination of a vasoconstrictor and albumin is typically administered for up to 14 days and then discontinued if patients do not respond to treatment.⁷ Depending on the therapies used, up to 50% of patients with type 1 HRS may respond to the combination therapy, but close to 20% of patients may experience recurrence after therapy discontinuation. ^7,22 Recurrence is especially high in patients with type 2 HRS who received terlipressin with albumin. Patients experiencing recurrence may benefit from retreatment with pharmacologic therapies, but may require long-term treatment and prolonged hospitalization.²² Outpatient pharmacologic treatment is an option for these patients, but further studies are necessary to identify the appropriate agents for this setting.

Nonpharmacologic interventions for HRS consist of paracentesis, transjugular intrahepatic portosystemic shunting (TIPS), and liver transplantation.² Paracentesis drains ascites, provides symptom relief for increased intra-abdominal pressure, and may improve renal function in patients with type 1 HRS. Patients with tense and symptomatic ascites are candidates for paracentesis.

Patients who do not respond to pharmacologic therapy or have several relapses may benefit from TIPS, which improves renal blood flow. ² The main limitation of TIPS is an increased incidence of hepatic encephalopathy and the potential worsening of arterial vasodilation for up to 12 months .^2,18 Because TIPS may potentially worsen renal function in patients with renal dysfunction, new research on outcomes with TIPS in HRS had not been published for over a decade.¹⁸ The available evidence suggests that TIPS improves renal function mainly in patients with type 2 HRS.²² The procedure is also contraindicated in patients with severe liver failure, which limits its use in patients with HRS. Renal replacement therapy (RRT), such as intermittent hemodialysis or continuous RRT, is an option for patients with HRS not responding to vasoconstrictor therapy.¹⁸ Renal replacement therapy is not a definitive treatment, but instead a bridge to liver transplantation. A study showed that RRT in addition to combination therapy with vasoconstrictors and albumin does not improve survival and actually prolongs hospital stay in patients with type 1 HRS.²³

Liver transplantation is the definitive treatment for HRS because curing liver disease reverses HRS.² Patients not responding to vasoconstrictors are candidates for liver transplantation.¹⁸ Predicting renal recovery remains challenging, and the following factors may influence renal outcomes: pre-existing comorbidities, intrinsic renal disease, perioperative events, and post-transplant immunosuppression.⁷ For example, patients receiving dialysis for a shorter time period are more likely to experience HRS reversal after liver transplantation.¹⁸ A simultaneous liver and kidney transplant may benefit patients with HRS at high risk for renal nonrecovery. Providers must assess the duration of AKI, dialysis needs, and presence of underlying CKD to identify the best candidates for simultaneous liver and kidney transplantation.⁷

Evidence behind pharmacologic options

Adding albumin to vasoconstrictor therapies (terlipressin, norepinephrine, and the combination of midodrine and octreotide) improves clinical outcomes because albumin maintains or increases cardiac output even in the advanced stages of liver disease. ⁷ Results from a prospective nonrandomized study of 21 patients with HRS (16 with type 1 HRS and 5 with type 2 HRS) revealed that adding albumin to terlipressin improved rates for completely reversing HRS compared with terlipressin alone (77% versus 25%, respectively; p=0.03).²⁴ Moreover, combination therapy decreased SCr levels, increased arterial pressure, and suppressed RAAS, outcomes that terlipressin alone failed to achieve.

As noted prior, terlipressin, a vasopressin analog, has been extensively studied and is the first-line therapy for HRS in Europe. ² Terlipressin creates vasoconstrictor effects primarily in the splanchnic bed due to greater affinity for vasopressin 1 receptors in this area compared with vasopressin 2 receptors in the kidneys. Terlipressin is a prodrug, which slowly releases lysine vasopressin.²⁵ The half-life of terlipressin is 6 hours, while the half-life of vasopressin is 24 minutes. Terlipressin’s half-life allows for administering it as an intermittent bolus. Patients with ischemic heart disease, peripheral vascular disease, or recent stroke should not receive terlipressin because it may cause ischemia.²

In the United States, some institutions may use vasopressin instead of terlipressin, but the literature supporting use of this agent is limited. ² The recently published literature does not discuss vasopressin as an option for HRS; the article supporting its use is an observational study published in 2005.²⁶ That study included 43 patients with HRS and revealed that vasopressin alone or in combination with octreotide improved the recovery rate for SCr compared with octreotide monotherapy (42% versus 38% versus 0%, p=0.01 for each comparison to octreotide monotherapy).

Norepinephrine is a catecholamine with a-adrenergic agonist properties, which causes vasoconstriction in the vasculature and minimal effects on the myocardium.²⁷ In many countries, norepinephrine is cheaper than terlipressin and is the preferred agent.⁷ But because norepinephrine is administered through a central venous line and requires continuous monitoring, only intensive care units provide an adequate environment for administering this agent.

For managing HRS, midodrine and octreotide are combined to improve outcomes and are used only if terlipressin or norepinephrine is unavailable or contraindicated.²⁷ Midodrine possesses α-adrenergic agonist properties, while octreotide is a somatostatin analog.

Vasoconstrictors alone may improve mortality in patients with HRS. A meta-analysis of 10 randomized controlled trials involving 376 patients with type 1 or type 2 HRS revealed that vasoconstrictor monotherapy or in combination with albumin reduced mortality compared with albumin alone or no intervention (relative risk [RR], 0.82; 95% confidence interval [CI], 0.70 to 0.96).²⁸ A subgroup analysis showed improved mortality mainly with the combination of terlipressin and albumin compared with albumin alone (RR, 0.81; 95% CI, 0.68 to 0.97). In another meta-analysis of 8 studies that included 377 patients, terlipressin decreased all-cause mortality by 15% (risk difference, -0.15%; 95% CI,-0.26 to -0.03) and HRS-related mortality by 9% (risk difference,-0.09%; 95% CI, -0.18 to 0.00).²⁹ However, not all meta-analyses reveal mortality benefits with vasoconstrictor therapy. A meta-analysis of 12 randomized controlled trials involving 700 patients with type 1 HRS had unclear mortality benefits when comparing the combination of terlipressin and albumin with albumin alone or placebo.³⁰ The results showed that the combination of terlipressin and albumin reversed HRS more frequently (RR, 2.54; 95% CI, 1.51 to 4.26), but patients in the terlipressin group experienced a trend towards higher rate of adverse events (RR, 4.32; 95% CI, 0.75 to 24.86), especially ischemic events (RR, 3.56; 95% CI, 1.64 to 7.72).

The comparative evidence supports similar clinical outcomes between terlipressin and norepinephrine. A Cochrane review of 25 trials that included 1,263 patients with decompensated cirrhosis and HRS showed similar mortality among the most common interventions such as terlipressin with albumin versus norepinephrine with albumin, and terlipressin with albumin versus albumin alone.³¹ Another Cochrane review of 10 trials with 474 patients showed that terlipressin had similar effects on mortality as other vasoactive medications (RR, 0.96; 95% CI, 0.88 to 1.06).³² A meta-analysis of 4 studies with 154 patients diagnosed with HRS showed similar 30-day mortality outcomes between treatments with terlipressin versus norepinephrine (RR, 1.04; 95% CI, 0.84 to 1.30).³³ A meta-analysis of 12 randomized controlled trials revealed that the combination of terlipressin with albumin and norepinephrine with albumin had similar effects on the reversal of type 1 HRS.³⁰ However, a recent open-label randomized controlled trial of 120 patients with ACLF and AKI-HRS indicated significantly better outcomes with terlipressin and albumin compared with norepinephrine and albumin for the following measures: reversal of HRS (40% versus 16.7%; p=0.004), reduction in the need for RRT (56.6% versus 80%; p=0.006), and improvement in 28-day survival (48.3% versus 20%; p=0.001).³⁴

The comparative evidence suggests that treatment with midodrine and octreotide yields inferior clinical outcomes compared with other therapies such as terlipressin with albumin or norepinephrine with albumin. Two Cochrane reviews revealed that terlipressin with albumin reversed HRS more effectively compared with midodrine plus octreotide plus albumin or octreotide plus albumin.^31,32 A network meta-analysis of 13 randomized studies that included 739 patients with type 1 HRS revealed that terlipressin plus albumin (odds ratio (OR) 26.25; 95% CI 3.07 to 224.21) and norepinephrine plus albumin (OR, 10.00; 95% CI, 1.49 to 50.00) are superior to midodrine plus octreotide plus albumin for reversing HRS. ³⁵ Another network meta-analysis of 16 randomized controlled trials found higher rates for completely reversing HRS with terlipressin plus albumin (OR, 6.7; 95% CI, 2.1 to 21.3) and norepinephrine plus albumin (OR, 6.8; 95% CI, 1.9 to 24.8) compared with albumin alone, but complete HRS reversal was similar between midodrine plus octreotide plus albumin versus albumin alone (OR 0.3; 95% CI, 0.02 to 3.1).³⁶

Although available pharmacologic therapies may reduce mortality and reverse HRS, pharmacologic therapy developments for managing HRS have stagnated over the past 2 decades. A meta-analysis of 14 randomized controlled trials carried out between 2002 and 2018, enrolling a total of 778 patients with type 1 HRS, revealed that more recent studies showed similar survival rates (OR, 1.02; 95% CI, 0.94 to 1.11; p=0.66) and HRS reversal rates (OR, 1.03; 95% CI, 0.96 to 1.11; p=0.41) as studies performed in the early 2000s. ³⁷ Thus, a need exists for continued research on optimizing available pharmacologic treatments as well as developing new agents to treat HRS.

Dosing and monitoring of pharmacologic options

The appropriate dosing and monitoring of pharmacologic therapies are essential for positive outcomes in patients with HRS (Table 4). The recommended dosing of intravenous (IV) albumin consists of 1 g/kg (up to 100 g) on the first day, followed by 20 to 40 g per day on the following days .²⁷ In the United States, albumin is available as a solution at concentrations of 5% and 25%; albumin 25% is indicated in patients with cirrhosis.^21,38,39Providers should measure central venous pressure or use other measures for assessing blood volume to titrate the dose of albumin and avoid fluid overload.²² Other laboratory monitoring includes blood pressure, pulse, urinary output, electrolytes, and hemoglobin/hematocrit.³⁸ Providers should monitor for signs of allergic or anaphylactic reactions. Typically, the combination of a vasoconstrictor and albumin is administered until SCr is within 0.3 mg/dL of the patient’s baseline SCr.⁷ The treatment is discontinued after 14 days in patients without an appropriate response.

A meta-analysis of 19 studies (N=574 patients) determined that a dose-response relationship exists between a cumulative dose of albumin and survival of patients with type 1 HRS.⁴⁰ Survival improved as the cumulative albumin dose increased in increments of 100 g. The survival rates at 30 days were 43.2% with 200 g of cumulative albumin dose, 51.4% with 400 g, and 59.0% with 600 g. Thus, some providers recommend administering albumin at 40 g per day, the higher end of the recommended range, to patients with type 1 HRS if tolerated. ²⁷

Terlipressin may be administered as a continuous IV infusion or intermittent IV boluses.² Providers should double the dose of terlipressin in a stepwise manner up to a maximum of 12 mg/day if SCr does not increase by >25% after 2 to 3 days of treatment.^7,22,27 Treatment with terlipressin lasts about 14 days unless HRS completely reverses within a shorter period of time.²⁷ New evidence suggests that administering terlipressin as a continuous intravenous infusion improves the adverse effect profile compared with intermittent IV boluses. A randomized controlled trial of 78 patients with type 1 HRS showed a similar response rate, for both partial and complete response, between continuous infusion and intermittent boluses of terlipressin, but patients receiving a continuous infusion experienced less total adverse events (35.29% versus 62.16%; p<0.025), although individual adverse events did not significantly differ between the groups.⁴¹ Patients in the continuous infusion group also received lower daily doses of terlipressin (2.23±0.65 mg/day versus 3.51±1.77 mg/day; p<0.05). Of note, the intermittent bolus group trended towards a higher 90-day survival compared with the continuous infusion group, even though the results did not reach statistical significance (69% versus 53%, p=0.255). Several case reports describe administering terlipressin continuous infusion on an outpatient basis as a bridge to liver transplantation. ^42,43 Terlipressin continuous infusion was administered for a median of 21 to 22 days, and doses ranged from 1.7 mg to 3.4 mg over 24 hours. Thus, terlipressin continuous administration may not only improve the safety profile, but also serve as an outpatient bridge to liver transplantation in some patients.

When initiating terlipressin, providers should monitor for several adverse effects. The common adverse effects, especially with intermittent IV bolus therapy, consist of diarrhea, abdominal pain, circulatory overload, and cardiovascular ischemic complications, including myocardial infarction. ^22,44 Due to cardiac effects, patients should receive an electrocardiogram (ECG) prior to the initiation of terlipressin.

Although the evidence for vasopressin in HRS remains limited, some institutions may use it as a substitute for terlipressin. Providers may initiate vasopressin at 0.01 units/min and titrate based on mean arterial pressure.⁴⁵ In the 2005 observational study, the mean vasopressin dose was 0.23 ± 0.19 units/min in patients who responded to treatment.²⁶ Vasopressin is an option only for critically ill patients in the intensive care unit.⁴⁵ Patients receiving vasopressin may develop severe skin necrosis, thrombosis, hyponatremia, anaphylaxis, bronchospasm, urticaria, and ischemia of the gastrointestinal tract.²⁵ Patients should receive periodic ECGs due to an increased risk for myocardial infarction, especially in patients with prior vascular disease.⁴⁶

Administering IV norepinephrine at doses of 0.5 to 3 mg/h in combination with albumin should increase mean arterial pressure by 10 mmHg.^7,22,27 Patients receive norepinephrine via a central venous line, and thus, must be admitted to an intensive care unit.²² Providers should monitor for skin necrosis and extravasation.⁴⁷ At infusion initiation, blood pressure should be measured every 2 minutes until target blood pressure is achieved, and then, blood pressure should be measured every 5 minutes.

In patients with HRS, midodrine is typically administered orally at doses of 7.5 to 12.5 mg three times a day and octreotide subcutaneously at doses of 100 to 200 µg three times a day.²⁷ Some institutions use a continuous infusion of octreotide at 50 mg/h, which can be administered on an internal medicine unit.⁴⁵ But the evidence for the continuous infusion is limited and dates back to a 2003 study revealing similar effects on renal function between octreotide and placebo.⁴⁸ The doses of midodrine and octreotide are typically titrated to achieve an increase of 15 mmHg in mean arterial pressure.⁹ The combination of midodrine plus octreotide plus albumin is only administered when terlipressin or norepinephrine are contraindicated or unavailable. ²⁷ Providers should monitor blood pressure and heart rate because midodrine may cause hypertension and decrease heart rate.⁴⁹ Octreotide may contribute to biliary tract abnormalities, cardiac conduction abnormalities, hyperglycemia or hypoglycemia, and hypothyroidism. ⁵⁰ Providers may monitor glucose levels and ECG readings; following total and/or free T4 levels is recommended mainly for chronic therapy with octreotide.

Pharmacist role in managing patients with HRS

Pharmacists play an important role in the care of patients with HRS and ensure the appropriate use of drug therapy. For example, the literature extensively documents pharmacists’ impact on recognizing appropriate indications and dosing of albumin. A retrospective cohort study revealed that a pharmacist-driven albumin protocol improved the appropriate use of albumin for indications such as large volume paracentesis, spontaneous bacterial peritonitis, and type 1 HRS.⁵¹ Implementing the protocol decreased the inappropriate use of albumin by 51.3% over 5.7 months, which saved about $137,000 per year. Another study found that introducing an evidence-based protocol in conjunction with a pharmacist-led audit and feedback decreased the overall inappropriate use of albumin by 79.3%, which summed up to an annual savings of $211,600.⁵² The services with noteworthy reduction in inappropriate use of albumin were: pulmonology (reduced by 93%), surgery (reduced by 92%), nephrology (reduced by 86%), and critical care (reduced by 78.5%). In another project, pharmacists’ daily monitoring of albumin use reduced inappropriate prescribing by 54%.⁵³ Pharmacists’ involvement impacted the utilization of albumin in the following units: critical care, solid organ transplant, adult step-down, and cardiology.

Pharmacists may identify risk factors, including nephrotoxic medications, for AKI and HRS. A cross-sectional survey-based study of 117 physicians and 135 pharmacists determined that a higher proportion of physicians identified risk factors for AKI compared with pharmacists, while pharmacists were more likely to identify AKI-causing medications compared with physicians.⁵⁴ Only half of the respondents who encountered AKI cases in their practice performed an AKI risk assessment. Thus, pharmacists may fill the gap by identifying risk factors for AKI and HRS, notifying physicians of AKI-causing medications that should be temporarily or permanently discontinued, and assessing the prognostic risk factors for outcomes in patients with HRS.

Pharmacists may select the appropriate agents for managing HRS, monitor for response to therapy, and assess any potential safety concerns. Pharmacists familiar with current evidence on HRS treatments can effectively select and advise prescribers on the most appropriate agents and corresponding durations of therapy for individual patients. During therapy, pharmacists can monitor for a response, any safety concerns, and necessary laboratory values for selected treatments. For patients experiencing recurrence, pharmacists can assist providers with medication selection and prolonged treatment, especially when patients transition from inpatient to outpatient settings.

Summary

Hepatorenal syndrome remains a high mortality condition, especially among patients with cirrhosis, and causes up to 11% to 20% of all AKI cases. The ICA provides definitions for HRS and divides HRS into type 1 and type 2. Type 1 HRS is a more severe type, marked by worse morbidity and mortality outcomes. The 2015 and 2019 proposals to redefine HRS recommend reevaluating current cutoffs for SCr values and reclassifying type 1 and type 2 HRS as HRS-AKI, HRS-AKD, and HRS-CKD. Factors such as disease classification, cardiac function, biomarkers, and infection may aid in predicting the prognosis for patients with HRS.

The management of HRS involves pharmacologic and non-pharmacologic interventions. Non-pharmacologic options consist of paracentesis, TIPS, and liver transplantation, while pharmacologic options involve agents such as albumin, terlipressin, norepinephrine, midodrine, and octreotide. Liver transplantation remains the definitive treatment for HRS, because curing liver disease reverses HRS. The evidence supports combining albumin with terlipressin or norepinephrine as the first-line therapy for managing HRS. These combinations may improve survival and reverse HRS. Midodrine plus octreotide plus albumin should be reserved for situations when terlipressin or norepinephrine are contraindicated or unavailable, because this combination has worse outcomes for reversing HRS. A continued need exists for further research on optimizing available pharmacological treatments and developing new therapies for HRS. Pharmacists play a crucial role in taking care of patients with HRS through ensuring the appropriate use and dosing of pharmacologic therapies, especially albumin, identifying AKI-causing medications, and recognizing risk factors for causing HRS and prognostic factors for predicting outcomes with HRS. Pharmacists also monitor for response to therapy, assess any potential safety concerns, and assist with the transition to an outpatient setting.

Resources

Guideline from the European Association for the Study of the Liver (EASL): management of decompensated cirrhosis: https://easl.eu/publication/management-of-decompensated-cirrhosis-guideline/

Case Studies

Case study 1: BK, a 56-year old woman with acute liver failure due to autoimmune hepatitis, is awaiting liver transplantation. She developed jaundice and delirium warranting her admission to an internal medicine unit in a hospital. Her notable labs are: temperature 37.1˚C, blood pressure 110/55 mmHg, HR 60 beats per minute, albumin 2.4 mg/dL, total bilirubin 15.4 mg/dL, ALT 1040 IU/L, AST 738 IU/L, SCr 3.6 mg/dL. According to clinic records from 9 days ago, her labs were: total bilirubin 7.9 mg/dL, ALT 1844 IU/L, AST 1451 IU/L, SCr 0.57 mg/dL. She currently takes only prednisone. Her providers believe that she developed AKI and HRS. What initial pharmacologic therapy for HRS should be administered on an internal medicine floor?

Answer: Adding albumin to a vasoconstrictor improves the rate of HRS reversal, decreases SCr levels, increases arterial pressure, and suppresses RAAS. A vasoconstrictor, depending on the agent, may reverse HRS and improve mortality. Available vasoconstrictor choices consist of terlipressin, norepinephrine, or the combination of midodrine and octreotide. Terlipressin has been extensively studied, but is not available in the United States. Norepinephrine is administered through a central venous line and requires continuous monitoring, and thus, must be used only in an intensive care unit. Because the patient is admitted to an internal medicine floor, the combination of midodrine plus octreotide remains the only vasoconstrictor option. Providers administer this combination only if terlipressin or norepinephrine is contraindicated or unavailable. The combination of midodrine plus octreotide yields inferior clinical outcomes compared with other vasoconstrictor therapies. Thus, due to the patient’s location, BK should receive albumin plus midodrine plus octreotide. Providers may admit BK to an intensive care unit to administer norepinephrine and albumin to improve HRS outcomes.

Case study 2: DS, a 54-year old man, was admitted to an intensive care unit with symptoms of worsening jaundice and abdominal pain, rapid cognitive decline, and epigastric pain. His diagnoses consist of acute liver failure due to chronic alcoholic liver disease and brain abscess. DS underwent abdominal paracentesis, which eventually caused spontaneous bacterial peritonitis. The medical team initiated appropriate empiric broad-spectrum antibiotics. His SCr increased from 2.4 mg/dL to 8.5 mg/dL over 3 days, and his current blood pressure is 86/50 mmHg. The medical team diagnosed type 1 HRS and plans to initiate pharmacologic treatment. Provide a recommendation on an agent(s) to initiate, dosing, and monitoring parameters.

Answer: Adding albumin 25% to a vasoconstrictor improves the rate of HRS reversal, decreases SCr levels, increases arterial pressure, and suppresses RAAS. The recommended dosing of albumin 25% consists of 1 g/kg IV (up to 100 g) on the first day, followed by 20 to 40 g per day on the following days. Because a recent meta-analysis showed a dose-response relationship between a cumulative dose of albumin and survival of patients with type 1 HRS, providers should administer albumin at the higher end of the recommended range – 40 g per day if DS tolerates higher fluid intake. Providers may measure central venous pressure or use other measures for assessing blood volume to titrate the dose of albumin and avoid fluid overload. DS should also receive a vasoconstrictor. Because terlipressin is not available in the United States and DS is admitted to the intensive care unit, norepinephrine is the best choice. The evidence reveals similar positive outcomes for survival and HRS reversal between terlipressin and norepinephrine. The recommended dose for norepinephrine is 0.5 to 3 mg/h as a continuous IV infusion, administered via a central venous line. The combination of norepinephrine and albumin should increase mean arterial pressure by 10 mmHg. The combination should be administered until SCr is within 0.3 mg/dL of the baseline SCr, and treatment should be discontinued after 14 days if no response.

References

1. Sease JM, Wilder AG. Portal hypertension and cirrhosis. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach. 11th ed. New York, NY: McGraw-Hill. http://accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectionid=219317120. Accessed February 10, 2020.

2. Amin AA, Alabsawy EI, Jalan R, Davenport A. Epidemiology, pathophysiology, and management of hepatorenal syndrome. Semin Nephrol. 2019;39(1):17-30.

3. Salerno F, Cazzaniga M, Merli M, et al. Diagnosis, treatment and survival of patients with hepatorenal syndrome: a survey on daily medical practice. J Hepatol. 2011;55(6):1241-1248.

4. Facciorusso A. Hepatorenal syndrome type 1: current challenges and future prospects. Ther Clin Risk Manag. 2019;15:1383-1391.

5. Velez JCQ, Therapondos G, Juncos LA. Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis. Nat Rev Nephrol. 2019. doi: 10.1038/s41581-019-0218-4.

6. Guidelines for hepatorenal syndrome. International Club of Ascites website. http://www.icascites.org/about/guidelines/. Accessed February 10, 2020.

7. Angeli P, Garcia-Tsao G, Nadim MK, Parikh CR. News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond the International Club of Ascites (ICA) consensus document. J Hepatol. 2019;71(4):811-822.

8. 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.

9. Mindikoglu AL, Pappas SC. New developments in hepatorenal syndrome. Clin Gastroenterol Hepatol. 2018;16(2):162-177.

10. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-184.

11. Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology. 2005;41(6):1282-1289.

12. Krag A, Bendtsen F, Henriksen JH, Moller S. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut. 2010;59(1):105-110.

13. Serste T, Melot C, Francoz C, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology. 2010;52(3):1017-1022.

14. Mandorfer M, Bota S, Schwabl P, et al. Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):1680-1690.

15. Ruiz-del-Arbol L, Urman J, Fernandez J, et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology. 2003;38(5):1210-1218.

16. Seo YS, Park SY, Kim MY, et al. Serum cystatin C level: an excellent predictor of mortality in patients with cirrhotic ascites. J Gastroenterol Hepatol. 2018;33(4):910-917.

17. Barreto R, Fagundes C, Guevara M, et al. Type-1 hepatorenal syndrome associated with infections in cirrhosis: natural history, outcome of kidney function, and survival. Hepatology. 2014;59(4):1505-1513.

18. Adebayo D, Neong SF, Wong F. Ascites and hepatorenal syndrome. Clin Liver Dis. 2019;23(4):659-682.

19. Moreau R, Durand F, Poynard T, et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology. 2002;122(4):923-930.

20. Boyer TD, Sanyal AJ, Wong F, et al. Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology. 2016;150(7):1579-1589.e1572.

21. Clinical Pharmacology [database online]. New York, NY: 2020. https://www.clinicalkey.com/pharmacology/?kbmRecipientKyCd=K52318174&keyCode=16n14255. Accessed February 10, 2020.

22. EASL clinical practice guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-460.

23. Zhang Z, Maddukuri G, Jaipaul N, Cai CX. Role of renal replacement therapy in patients with type 1 hepatorenal syndrome receiving combination treatment of vasoconstrictor plus albumin. J Crit Care. 2015;30(5):969-974.

24. Ortega R, Gines P, Uriz J, et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology. 2002;36(4 Pt 1):941-948.

25. Kam PC, Williams S, Yoong FF. Vasopressin and terlipressin: pharmacology and its clinical relevance. Anaesthesia. 2004;59(10):993-1001.

26. Kiser TH, Fish DN, Obritsch MD, Jung R, MacLaren R, Parikh CR. Vasopressin, not octreotide, may be beneficial in the treatment of hepatorenal syndrome: a retrospective study. Nephrol Dial Transplant. 2005;20(9):1813-1820.

27. Mattos AZ, Schacher FC, Mattos AA. Vasoconstrictors in hepatorenal syndrome - a critical review. Ann Hepatol. 2019;18(2):287-290.

28. Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology. 2010;51(2):576-584.

29. Hiremath SB, Srinivas LD. Survival benefits of terlipressin and non-responder state in hepatorenal syndrome: a meta-analysis. Indian J Pharmacol. 2013;45(1):54-60.

30. Gifford FJ, Morling JR, Fallowfield JA. Systematic review with meta-analysis: vasoactive drugs for the treatment of hepatorenal syndrome type 1. Aliment Pharmacol Ther. 2017;45(5):593-603.

31. Best LM, Freeman SC, Sutton AJ, et al. Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev. 2019;9:CD013103. doi: 013110.011002/14651858.CD14013103.pub14651852.

32. Israelsen M, Krag A, Allegretti AS, et al. Terlipressin versus other vasoactive drugs for hepatorenal syndrome. Cochrane Database Syst Rev. 2017;9:CD011532. doi: 011510.011002/14651858.CD14011532.pub14651852.

33. Mattos AZ, Mattos AA, Ribeiro RA. Terlipressin versus noradrenaline in the treatment of hepatorenal syndrome: systematic review with meta-analysis and full economic evaluation. Eur J Gastroenterol Hepatol. 2016;28(3):345-351.

34. Arora V, Maiwall R, Rajan V, et al. Terlipressin is superior to noradrenaline in the management of acute kidney injury in acute on chronic liver failure. Hepatology. 2018. doi: 10.1002/hep.30208.

35. Facciorusso A, Chandar AK, Murad MH, et al. Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2017;2(2):94-102.

36. Sridharan K, Sivaramakrishnan G. Vasoactive agents for hepatorenal syndrome: a mixed treatment comparison network meta-analysis and trial sequential analysis of randomized clinical trials. J Gen Intern Med. 2018;33(1):97-102.

37. Thomson MJ, Taylor A, Sharma P, Lok AS, Tapper EB. Limited progress in hepatorenal syndrome (HRS) reversal and survival 2002-2018: a systematic review and meta-analysis. Dig Dis Sci. 2019. doi: 10.1007/s10620-019-05858-2.

38. Albumin 25% [package insert]. Los Angeles, CA: GRIFOLS; 2018.

39. Albutein 5% [package insert]. Los Angeles, CA: GRIFOLS; 2018.

40. Salerno F, Navickis RJ, Wilkes MM. Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis. BMC Gastroenterol. 2015;15:167. doi: 110.1186/s12876-12015-10389-12879.

41. 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.

42. Vasudevan A, Ardalan Z, Gow P, Angus P, Testro A. Efficacy of outpatient continuous terlipressin infusions for hepatorenal syndrome. Hepatology. 2016;64(1):316-318.

43. Robertson M, Majumdar A, Garrett K, Rumler G, Gow P, Testro A. Continuous outpatient terlipressin infusion for hepatorenal syndrome as a bridge to successful liver transplantation. Hepatology. 2014;60(6):2125-2126.

44. Francoz C, Durand F, Kahn JA, Genyk YS, Nadim MK. Hepatorenal syndrome. Clin J Am Soc Nephrol. 2019;14(5):774-781.

45. Runyon BA. Hepatorenal syndrome. In: Sterns RH, Forman JP, eds. UpToDate. Waltham, MA: UpToDate; https://www.uptodate.com/contents/hepatorenal-syndrome?search=hepatorenal%20syndrome&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed February 10, 2020.

46. Vasopressin [package insert]. Chestnut Ridge, NY: Par Pharmaceuticals; 2016.

47. Norepinephrine [package insert]. Deerfield, IL: Baxter; 2018.

48. Pomier-Layrargues G, Paquin SC, Hassoun Z, Lafortune M, Tran A. Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study. Hepatology. 2003;38(1):238-243.

49. Midodrine [package insert]. Princeton, NJ: Sandoz; 2017.

50. Octreotide [package insert]. Lake Zurich, IL: Fresenius Kabi; 2018.

51. Kobayashi K, Raines A, Wilkinson J, Dick TB, Harmston G. Outcomes of a pharmacist-driven protocol for albumin use in patients with liver cirrhosis. Pharmacotherapy. 2010;30(10):437e.

52. Dastan F, Jamaati H, Emami H, et al. Reducing inappropriate utilization of albumin: the value of pharmacist-led intervention model. Iran J Pharm Res. 2018;17(3):1125-1129.

53. Borges Filho WM, Almeida SM, Ferracini FT, Fernandes Junior CJ. Pharmacy contribution to the prescription and rational use of human albumin at a large hospital. Einstein (Sao Paulo). 2010;8(2):215-220.

54. Alabdan N, Elfadol AH, Bustami R, Al-Rajhi YA, Al-Sayyari AA. Awareness of acute kidney injury risk factors and perspectives on its practice guidelines. Hosp Pract (1995). 2018;46(3):137-143.