Acute-on-chronic liver failure (ACLF) is a complex syndrome defined by the existence of different organ failures (OFs) in patients with chronic liver disease, mainly cirrhosis. Several definitions have been proposed to define the syndrome, varying in the grade of the subjacent liver disease, the type of precipitants and the organs considered in the definition. Liver, coagulation, brain, kidney, circulatory and pulmonary are the six types of OFs proposed in the different classifications, with different prevalence worldwide. Irrespective of the definition used, patients who develop ACLF present a hyperactive immune system, profound haemodynamic disturbances and several metabolic alterations that finally lead to organ dysfunction. These disturbances are triggered by different factors such as bacterial infections, alcoholic hepatitis, gastrointestinal bleeding or hepatitis B virus flare, among others. Because patients with ACLF present high short-term mortality, a prompt recognition is needed to start treatment of the trigger event and specific organ support. Liver transplantation is also feasible in carefully selected patients and should be evaluated.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) occurs in the setting of advanced chronic liver disease, portal hypertension, and ascites. HRS-AKI is found in ∼20% of patients presenting to the hospital with AKI, but it may coexist with other causes of AKI and/or with preexisting chronic kidney disease, thereby making the diagnosis challenging. Novel biomarkers such as urinary neutrophil gelatinase-associated lipocalin may be useful. While HRS-AKI is a functional form of AKI related to circulatory and neurohormonal dysfunction, there is increasing recognition of the importance of systemic inflammation and the renal microenvironment. Early diagnosis and initiation of HRS-AKI-specific treatment can improve outcomes. The mainstay of therapy is a vasoconstrictor (terlipressin or norepinephrine) combined with albumin, which achieves resolution of HRS in 40-50% of cases. Liver transplantation is the only option for patients failing to respond to medical therapies.

Acute kidney injury (AKI) in patients with acute-on-chronic liver failure (ACLF) is driven by the severity of systemic inflammation, acute portal hypertension driving circulatory dysfunction, hyperbilirubinemia, and toxicity of bile acids. The spectrum is mostly structural, associated with reduced response to vasoconstrictors. The progression is rapid, and need of renal replacement therapy and extracorporeal therapies may be required for the management. The development of renal failure is usually considered when defining the syndrome of ACLF.

In the current review we discuss the pathophysiological basis, natural course, and response to the current therapeutic modalities and challenges in assessing and managing AKI in patients with ACLF. We conducted a comprehensive search of electronic databases such as PubMed, Web of Science, and Scopus using keywords like lactate, NGAL, and PHTN, as well as CRRT, PLEX, ACLF, and AKI phases for our review. Peer-reviewed English papers that addressed our issue were considered.

The difficulties and specific management strategies for AKI in ACLF patients are discussed emphasizing the importance of customized protocols, risk assessment guided by biomarkers, and investigation of extracorporeal therapies that target bile acids.

Acute kidney injury (AKI) frequently complicates the course of hospitalized patients with cirrhosis and negatively affects their prognosis. How AKI response influences the timing of liver transplantation (LT) remains unclear. We sought to assess the impact of AKI response to treatment on survival and LT rates in patients with cirrhosis awaiting LT. This was a retrospective multicenter study of cirrhosis patients waitlisted for LT and hospitalized with AKI in 2019. The exposure was AKI response versus no response during hospitalization. Outcomes were 90-day overall and transplant-free survival, and rates of LT with time to transplant. We adjusted for age, sex, race, cirrhosis etiology, site, and Model for End-Stage Liver Disease-Sodium (MELD-Na) score. Among the 317 patients in this study, 170 had an AKI response (53.6%), and 147 had no response (46.4%). Compared to nonresponders, responders had better 90-day overall survival (89.4% vs. 76.2%, adjusted subhazard ratio for mortality 0.34, p =0.001), and transplant-free survival (63.5% vs. 25.2%, aHR for probability of death or transplant 0.35, p <0.001). The LT rate was lower in responders (45.9% vs. 61.2%, adjusted subhazard ratio 0.55, p =0.005); 79% of transplants in responders occurred after discharge, at a median of 103 days, while 62% of transplants in nonresponders occurred during hospitalization, with the remainder occurring postdischarge at a median of 58 days. In patients with cirrhosis waitlisted for LT who are hospitalized with AKI, AKI response to therapy is associated with improved 90-day survival, despite a reduced LT rate and longer time to LT.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p <0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p =0.12; D90: 78% vs. 68%, p =0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p <0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

The development of acute kidney injury (AKI) in the setting of alcohol-associated hepatitis (AH) portends a poor prognosis. Whether the presence of AH itself drives worse outcomes in patients with cirrhosis and AKI is unknown.

Retrospective cohort study of 11 hospital networks of consecutive adult patients admitted in 2019 with cirrhosis and AKI. AKI phenotypes, clinical course, and outcomes were compared between AH and non-AH groups.

A total of 2062 patients were included, of which 303 (15%) had AH, as defined by National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria. Patients with AH, compared to those without, were younger and had higher Model for End-stage Liver Disease-Sodium (MELD-Na) scores on admission. AKI phenotypes significantly differed between groups (p < 0.001) with acute tubular necrosis occurring more frequently in patients with AH. Patients with AH reached more severe peak AKI stage, required more renal replacement therapy, and had higher 90-day cumulative incidence of death (45% [95% CI: 39%-51%] vs. 38% [95% CI: 35%-40%], p = 0.026). Using no AH as reference, the unadjusted sHR for 90-day mortality was higher for AH (sHR: 1.24 [95% CI: 1.03-1.50], p = 0.024), but was not significant when adjusting for MELD-Na, age and sex. However, in patients with hepatorenal syndrome, AH was an independent predictor of 90-day mortality (sHR: 1.82 [95% CI: 1.16-2.86], p = 0.009).

Hospitalised patients with cirrhosis and AKI presenting with AH had higher 90-day mortality than those without AH, but this may have been driven by higher MELD-Na rather than AH itself. However, in patients with hepatorenal syndrome, AH was an independent predictor of mortality.

Acute kidney injury (AKI) is a common complication among patients with decompensated cirrhosis and its development is associated with worse prognosis in terms of survival. Patients with decompensated cirrhosis may develop a unique type of AKI, known as hepatorenal syndrome (HRS-AKI), characterized by marked impairment of kidney function due to haemodynamic changes that occur in late stages of liver cirrhosis. Besides, patients with cirrhosis also may develop chronic alterations of kidney function (chronic kidney disease, CKD), the incidence of which is increasing markedly and may be associated with clinical complications. The aim of this review is to provide the reader with an update of the most relevant aspects of alterations of kidney function in patients with cirrhossi that may be useful for theri clinical practice.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a severe complication of cirrhosis that carries a poor prognosis. The recent Food and Drug Administration approval of terlipressin has substantial implications for managing HRS-AKI and liver allocation in the United States. Terlipressin has been available in Europe for over a decade, and several countries have adapted policy changes such as Model for End-Stage Liver Disease (MELD) score "lock" for HRS-AKI. In this article, we outline the European experience with terlipressin use and explore the question of whether terlipressin treatment for HRS-AKI should qualify for the MELD score "lock" in the United States in those who respond to therapy. Arguments for the MELD lock include protecting waitlist priority for terlipressin responders or partial responders who may miss offers due to MELD reduction in the terlipressin treatment window. Arguments against MELD lock include the fact that terlipressin may produce a durable response and improve overall survival and that equitable access to terlipressin is not guaranteed due to cost and availability. We subsequently discuss the proposed next steps for studying terlipressin implementation in the United States. A successful approach will require the involvement of all major stakeholders and the mobilization of our transplant community to spearhead research in this area.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.

The definition and diagnostic criteria of hepatorenal syndrome-acute kidney injury (HRS-AKI) has undergone recent changes. A major vasoconstrictor, terlipressin, has recently been approved as pharmacotherapy for HRS-AKI in the United States. The purpose of this review is to familiarize the readers with these new diagnostic criteria of HRS-AKI, and how best to use terlipressin.

Terlipressin is effective either as bolus dosing or continuous infusion and can achieve reversal of HRS-AKI in approximately 40% of patients. Continuous infusion allows lower daily dose with equal efficacy and less side effects but not an approved mode of administration in the United States. Response to terlipressin in the randomized controlled trials was defined as repeat reduction of serum creatinine to less than 1.5 mg/dl. Newer studies will likely require response to treatment to be defined as a repeat serum creatinine to be less than 0.3 mg/dl from baseline. Terlipressin use is associated with ischemic side effects and potential for respiratory failure development.

Careful patient selection and close monitoring are necessary for its use. Response to terlipressin with HRS-AKI reversal is associated with improved outcomes with better survival and less requirement for renal replacement therapy.

Treatment of hepatorenal syndrome-acute kidney injury (HRS-AKI), with terlipressin and albumin, provides survival benefits, but may be associated with cardiopulmonary complications. We analyzed the predictors of terlipressin response and mortality using point-of-care echocardiography (POC-Echo) and cardiac and renal biomarkers.

Between December 2021 and January 2023, patients with HRS-AKI were assessed with POC-Echo and lung ultrasound within 6 hours of admission, at the time of starting terlipressin (48 h), and at 72 hours. Volume expansion was done with 20% albumin, followed by terlipressin infusion. Clinical data, POC-Echo data, and serum biomarkers were prospectively collected. Cirrhotic cardiomyopathy (CCM) was defined per 2020 criteria.

One hundred and forty patients were enrolled (84% men, 59% alcohol-associated disease, mean MELD-Na 25±SD 5.6). A median daily dose of infused terlipressin was 4.3 (interquartile range: 3.9-4.6) mg/day; mean duration 6.4 ± SD 1.9 days; the complete response was in 62% and partial response in 11%. Overall mortality was 14% and 16% at 30 and 90 days, respectively. Cutoffs for prediction of terlipressin nonresponse were cardiac variables [ratio of early mitral inflow velocity and mitral annular early diastolic tissue doppler velocity > 12.5 (indicating increased left filling pressures, C-statistic: 0.774), tissue doppler mitral velocity < 7 cm/s (indicating impaired relaxation; C-statistic: 0.791), > 20.5% reduction in cardiac index at 72 hours (C-statistic: 0.885); p < 0.001] and pretreatment biomarkers (CysC > 2.2 mg/l, C-statistic: 0.640 and N-terminal proBNP > 350 pg/mL, C-statistic: 0.655; p <0.050). About 6% of all patients with HRS-AKI and 26% of patients with CCM had pulmonary edema. The presence of CCM (adjusted HR 1.9; CI: 1.8-4.5, p = 0.009) and terlipressin nonresponse (adjusted HR 5.2; CI: 2.2-12.2, p <0.001) were predictors of mortality independent of age, sex, obesity, DM-2, etiology, and baseline creatinine.

CCM and reduction in cardiac index, reliably predict terlipressin nonresponse. CCM is independently associated with poor survival in HRS-AKI.

Hepatorenal syndrome (HRS) is a form of kidney dysfunction that characteristically occurs in liver cirrhosis. It is characterized by a marked impairment of kidney function in response to circulatory and hemodynamic alterations that occur in advanced stages of liver cirrhosis, aggravated by systemic inflammation and bacterial translocation. The classical definitions of the types of HRS have been recently revisited and 2 forms of HRS have been redefined: the acute form, referred to as acute kidney injury (HRS-AKI), and the chronic form, referred to as chronic kidney disease. HRS-AKI is one of the most severe forms of AKI in patients with cirrhosis and it consists of an abrupt impairment of kidney function, frequently triggered by an infection, appearing in the setting of advanced decompensated cirrhosis. Differential diagnosis with other causes of AKI is crucial because HRS-AKI requires a specific treatment. Differential diagnosis with AKI-acute tubular necrosis may be challenging and kidney biomarkers may be useful in this setting. Treatment of HRS-AKI is based on the administration of vasoconstrictor drugs in combination with volume expansion with albumin. Prognosis of HRS-AKI is poor, and the ideal definitive treatment consists of liver transplantation or simultaneous liver-kidney transplantation. HRS-AKI has a big impact on patients' quality of life. Management of HRS-AKI remains challenging in specific situations such as alcohol-associated hepatitis or metabolic-associated steatotic liver disease cirrhosis. Developing preventive measures for HRS-AKI, improving its early identification, discovering new biomarkers for differential diagnosis, and improving the response to therapy are some of the unmet needs in the field of HRS-AKI.

Hepatorenal syndrome-acute kidney injury (HRS-AKI), a serious complication of decompensated cirrhosis, has limited therapeutic options and significant morbidity and mortality. Terlipressin improves renal function in some patients with HRS-1, while liver transplantation (LT) is a curative treatment for advanced chronic liver disease. Renal failure post-LT requiring renal replacement therapy (RRT) is a major risk factor for graft and patient survival. A post hoc analysis with a 12-month follow-up of LT recipients from a placebo-controlled trial of terlipressin (CONFIRM; NCT02770716) was conducted to evaluate the need for RRT and overall survival. Patients with HRS-1 were treated with terlipressin plus albumin or placebo plus albumin for up to 14 days. RRT was defined as any type of procedure that replaced kidney function. Outcomes compared between groups included the incidence of HRS-1 reversal, the need for RRT (pretransplant and posttransplant), and overall survival. Of the 300 patients in CONFIRM (terlipressin n = 199; placebo, n = 101), 70 (23%) underwent LT alone (terlipressin, n = 43; placebo, n = 27) and 5 had simultaneous liver-kidney transplant (terlipressin, n = 3, placebo, n = 2). The rate of HRS reversal was significantly higher in the terlipressin group compared with the placebo group (37%, n = 16 vs. 15%, n = 4; p = 0.033). The pretransplant need for RRT was significantly lower among those who received terlipressin ( p = 0.007). The posttransplant need for RRT, at 12 months, was significantly lower among those patients who received terlipressin and were alive at Day 365, compared to placebo ( p = 0.009). Pretransplant treatment with terlipressin plus albumin in patients with HRS-1 decreased the need for RRT pretransplant and posttransplant.

Hepatorenal syndrome (HRS) is a rare and highly morbid form of kidney injury unique to patients with decompensated cirrhosis. HRS is a physiologic consequence of portal hypertension, leading to a functional kidney injury that can be reversed by restoring effective circulating volume and renal perfusion. While liver transplantation is the only definitive "cure" for HRS, medical management with vasoconstrictors and i.v. albumin is a cornerstone of supportive care. Terlipressin, a V1a receptor agonist that acts on the splanchnic circulation, has been used for many years outside the United States for the treatment of HRS. However, its recent Food and Drug Administration approval has generated new interest in this population, as a new base of prescribers now work to incorporate the drug into clinical practice. In this article, we review HRS pathophysiology and diagnostic criteria, the clinical use of terlipressin and alternative therapies, and identify areas of future research in the space of HRS and kidney injury in cirrhosis.

Improved surgical techniques and revolutionary immunosuppressive agents have enhanced the long-term outcomes for liver transplantation, with more patients seeking the benefits of liver transplantation, and demand is high. In this review, we hope to delineate where the current data supporting favorable outcomes in using live donation to expand the donor pool compared with the outcomes seen in deceased donor liver transplants. Advances in surgery, transplant and center comfort has made live donor transplantation an asset with favorable patient outcomes in comparison to decease donor data.

International club of ascites (ICA) has introduced revised criteria for hepatorenal syndrome-acute kidney injury (HRS-AKI) with an aim to improve the response rate to treatment. We lack prospective trials to assess its positive impact on the response rate and factors influencing response rate. Thus, we conducted this study with the primary aim of identifying independent factors that predict treatment response to terlipressin.

We prospectively included patients of HRS-AKI as per the revised ICA criteria. All were treated with terlipressin and albumin according to the defined protocol and were followed for 90 days, death or liver transplantation. Baseline parameters, as well as delta serum creatinine (sCr) at day 4 (DCD4), were investigated as predictive factors influencing response to terlipressin (primary endpoint). Secondary endpoints were the overall response rate to terlipressin, response in various subgroups of acute-on-chronic liver failure (ACLF) patients, need for readmission, and 90 days survival.

The study included 114 patients with a median age of 52 years (83% males). 70 (61%) patients responded to terlipressin. Response rate among ACLF1, ACLF2, and ACLF3 were 62%, 48%, and 35%, respectively. On multivariate analysis, baseline creatinine (odds ratio [OR] 7.889, 95% confidence interval [CI] 3.335, 18.664), Child Turcotte Pugh (CTP) score (OR 1.470, 95% CI 1.026, 2.106), and the DCD4 (OR 0.048, 95% CI 0.015, 0.158) were independently predicting response. We also created a Delhi Model (DM) with an excellent predictive ability for response prediction at day 4 with an AUROC of 0.940 (95% CI 0.897, 0.982). Among responder group, 50% of patients required readmission within three months. The 90-days survival among responder and non-responder groups were 68.5% and 9% (P value < 0.01), respectively.

Baseline creatinine, CTP score, and DCD4 independently predict response to terlipressin in HRS-AKI. The DM may guide terlipressin treatment in HRS-AKI but need further validation.

The management of a patient in the peri-transplantation period is highly challenging, and it is even more difficult while the patient is on the transplantation waitlist. Keeping the patient alive during this period involves managing the complications of liver disease and preventing the disease's progression. Based on the pre-transplantation etiology and type of liver failure, there is a difference in the management protocol. The current review is divided into different sections, which include: the management of underlying cirrhosis and complications of portal hypertension, treatment and identification of infections, portal vein thrombosis management, and particular emphasis on the management of patients of hepatocellular carcinoma and acute liver failure in the transplantation waitlist. The review highlights special concerns in the management of patients in the Asian subcontinent also. The review also addresses the issue of delisting from the transplant waitlist to see that futility does not overtake the utility of organs. The treatment modalities are primarily expressed in tabular format for quick reference. The following review integrates the vast issues in this period concisely so that the management during this crucial period is taken care of in the best possible way.

Hepatorenal syndrome (HRS) is a disorder associated with cirrhosis and renal impairment, with portal hypertension as its major underlying cause. Moreover, HRS is the third most common cause of acute kidney injury, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of HRS. We discuss pathogenesis associated with HRS. Mechanisms such as dysfunction of the circulatory system, bacterial infection, inflammation, impaired renal autoregulation, circulatory, and others, which have been identified as critical pathways for development of HRS, have become easier to diagnose in recent years. Additionally, relatively recently, renal dysfunction biomarkers have been found indicating renal injury, which are involved in the pathophysiology of HRS. This review also summarizes the available information on the management of HRS, focusing on vasoconstrictive drugs, renal replacement therapy, and liver transplant together with currently being investigated novel therapies. Analyzing new discoveries for the underlying causes of this condition assists the general research to improve understanding of the mechanism of pathophysiology and thus prevention of HRS.

Hepatorenal syndrome (HRS)-acute kidney injury (HRS-AKI) is a specific type of kidney injury seen in patients with cirrhosis and ascites and is associated with high mortality and morbidity. It is characterized by rapid deterioration of renal function due to reduced renal blood flow secondary to portal hypertensive splanchnic and systemic vasodilation. Early diagnosis and treatment of HRS-AKI are associated with greater likelihood of improvement in renal function, lower need for dialysis, and better post-transplant outcomes.

This review discusses the diagnostic criteria for HRS-AKI, which has undergone several key changes over the last decade, with an aim to secure an early diagnosis and aid swift treatment initiation. Additionally, this review outlines the current treatment paradigms for HRS-AKI.

In the last 20 years, there have been several advances in understanding the pathophysiology and natural course of HRS-AKI. These have led to critical changes in its definition and diagnostic algorithm. However, prognosis of HRS-AKI remains dismal with no significant improvement in HRS-AKI reversal or HRS-related mortality over this time. We discuss several gaps in the current understanding and management of HRS-AKI that will benefit from further research.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) carries significant morbidity and mortality among those with end-stage liver disease. Bolus terlipressin for treatment of HRS-AKI received FDA approval in September 2022. US implementation of terlipressin, however, is hindered by the paucity of local data on the optimal patient population and administration mode, as well as the effect on transplant priority. The INFUSE study is designed to evaluate the use of continuous terlipressin infusion among transplant candidates with advanced liver disease and HRS-AKI.

Fifty prospective patients with HRS-AKI will receive a single bolus of terlipressin 0.5 mg followed by continuous infusions of terlipressin from 2 to 8 mg/day for up to 14 days. The cohort will be enriched with those listed, in evaluation, or eligible for liver transplantation, while those with ACLF grade 3, MELD ≥35, and serum creatinine >5.0 mg/dL will be excluded. Fifty patients who received midodrine plus octreotide or norepinephrine for HRS-AKI will serve as a retrospective comparator cohort.

The INFUSE study aims to assess the safety and efficacy of continuous terlipressin infusion among largely transplant-eligible patients with HRS-AKI, and to provide US-based data on transplant outcomes. This novel study design simultaneously mitigates terlipressin adverse events while providing renal benefits to patients, thus addressing the unmet medical need of those with HRS-AKI who have limited treatment options and are awaiting liver transplantation in the US.

Hepatorenal syndrome stands as one of several potential triggers of acute kidney injury in individuals grappling with either acute or persistent liver ailments. The nature of the decline in kidney function has led to the identification of two variants of hepatorenal syndrome. In cases where terlipressin therapy is accessible, the initial approach involves administering terlipressin alongside albumin. Terlipressin, a synthetic analog of vasopressin, boasts double the preference for vasopressin V1 receptors compared to V2 receptors. The FDA granted approval to terlipressin in September 2022, demonstrating its intrinsic activity, although a significant portion of its function arises from its transformation into lysine vasopressin. This article provides a comprehensive examination of terlipressin's various pharmacodynamic and pharmacokinetic facets, as well as its clinical utility, aiming to keep the scientific community well informed about its safe and efficient utilization.

Improvement in immunosuppression has led to a remarkable improvement in short-term and long-term outcomes post-liver transplant (LT). However, with improvements in long-term survival, complications related to immunosuppressive drugs, either directly or indirectly, have also increased. The adverse events could be drug-specific, class-specific, or generic. Calcineurin inhibitors (cyclosporine and tacrolimus) are the backbone of the immunosuppression after LT and the main culprit associated with most of the complications, including renal failure, post-transplant diabetes mellitus (PTDM), and metabolic syndrome. Steroids are also implicated in the development of diabetes, osteoporosis, and metabolic syndrome post-LT. The development of infections and de novo malignancies (DNMs) is a generic effect linked to the overall cumulative immunosuppression. The development of these complications significantly hampers the quality of life and leads to increased morbidity and mortality post-LT. Thus, it is important to minimize the cumulative immunosuppression dose while simultaneously preventing allograft rejection. This review provides up-to-date, comprehensive knowledge of the complications of long-term immunosuppression post-LT along with associated risk factors and strategies to minimize the risk of complications.

Hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, remains a major complication in patients with advanced cirrhosis, often leading to death before liver transplantation (LT). Recent updates in the pathophysiology, definition, and classification of HRS have led to a complete revision of the nomenclature and diagnostic criteria for HRS type 1, which was renamed HRS-acute kidney injury (AKI). HRS is characterized by severe impairment of kidney function due to increased splanchnic blood flow, activation of several vasoconstriction factors, severe vasoconstriction of the renal arteries in the absence of kidney histologic abnormalities, nitric oxide dysfunction, and systemic inflammation. Diagnosis of HRS remains a challenge because of the lack of specific diagnostic biomarkers that accurately distinguishes structural from functional AKI, and mainly involves the differential diagnosis from other forms of AKI, particularly acute tubular necrosis. The optimal treatment of HRS is LT. While awaiting LT, treatment options include vasoconstrictor drugs to counteract splanchnic arterial vasodilation and plasma volume expansion by intravenous albumin infusion. In patients with HRS unresponsive to pharmacological treatment and with conventional indications for kidney replacement therapy (KRT), such as volume overload, uremia, or electrolyte imbalances, KRT may be applied as a bridging therapy to transplantation. Other interventions, such as transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Although recently developed novel therapies have potential to improve outcomes of patients with HRS, further studies are warranted to validate the efficacy of these novel agents.

Bacterial infections are frequent in patients with cirrhosis and increase the risk of death and drop-out from liver transplant (LT) waiting list. In patients with bacterial infections, LT is frequently delayed because of the fear of poor outcomes. We evaluated the impact of pre-LT infections on post-LT complications and survival.

From 2012 to 2018, consecutive patients transplanted at the Hospital of Padua were identified and classified in two groups: patients surviving an episode of bacterial infection within 3 months before LT (study group) and patients without infections before LT (control group). Post-LT outcomes (complications, new infections, survival) were collected.

A total of 466 LT recipients were identified (study group n = 108; control group n = 358). After LT, the study group had a higher incidence of new bacterial (57% vs. 20%, p <0.001) and fungal infections (14% vs. 5%, p = 0.001) and of septic shock (8% vs. 2%, p = 0.004) than the control group. Along with the model for end-stage liver disease (MELD) score and alcohol-related cirrhosis, bacterial infection pre-LT was an independent predictor of post-LT infections (odds ratio = 3.92; p <0.001). Nevertheless, no significant difference was found in 1-year (88% vs. 89%, p = 0.579) and 5-year survival rates (76% vs. 75%, p = 0.829) between the study group and control group. Within the study group, no association was found between the time elapsed from infection improvement/resolution to LT and post-LT outcomes.

Patients with pre-LT infections have a higher risk of new bacterial and fungal infections and of septic shock after LT. However, post-LT survival is excellent. Therefore, as soon as the bacterial infection is improving/resolving, transplant should not be delayed, but patients with pre-transplant bacterial infections require active surveillance for infections after LT.

Bacterial infections increase mortality and delay transplant in patients with cirrhosis awaiting liver transplantation (LT). Little is known about the impact of adequately treated infections before LT on post-transplant complications and outcomes. The study highlights that pre-LT infections increase the risk of post-LT infections, but post-LT survival rates are excellent despite the risk. These findings suggest that physicians should not delay LT because of concerns about pre-LT infections, but instead should actively monitor these patients for infections after surgery.

Clinical data for older patients with advanced liver disease are limited. This post hoc analysis evaluated the efficacy and safety of terlipressin in patients aged ≥65 years with hepatorenal syndrome using data from 3 Phase III, randomized, placebo-controlled studies (OT-0401, REVERSE, CONFIRM).

The pooled population of patients aged ≥65 years (terlipressin, n = 54; placebo, n = 36) was evaluated for hepatorenal syndrome reversal-defined as a serum creatinine level ≤1.5 mg/dL (≤132.6 μmol/L) while receiving terlipressin or placebo, without renal replacement therapy, liver transplantation, or death-and the incidence of renal replacement therapy (RRT). Safety analyses included an assessment of adverse events.

Hepatorenal syndrome reversal was almost 2-times higher in terlipressin-treated patients compared with patients who received placebo (31.5% vs 16.7%; P = 0.143). Among surviving patients, the need for RRT was significantly reduced in the terlipressin group, with an almost 3-times lower incidence of RRT versus the placebo group (Day 90: 25.0% vs 70.6%; P = 0.005). Among 23 liver-transplant-listed patients, significantly fewer patients in the terlipressin versus placebo group needed RRT by Days 30 and 60 (P = 0.027 each). Fewer patients in the terlipressin group needed RRT post-transplant (P = 0.011). More terlipressin-treated patients who were listed for and received a liver transplant were alive and RRT-free by Day 90. No new safety signals were revealed in the older subpopulation compared with previously published data.

Terlipressin therapy may lead to clinical improvements in highly vulnerable patients aged ≥65 years with hepatorenal syndrome.

OT-0401, NCT00089570; REVERSE, NCT01143246; CONFIRM, NCT02770716.

Hepatorenal syndrome (HRS) is a serious complication of cirrhosis. HRS nomenclature has recently changed to HRS-AKI (acute kidney injury). HRS is a complex response to chronic vasodilatory changes brought about by portal hypertension and exacerbated by inflammatory responses that portends poor prognosis to patients with cirrhosis. This syndrome is commonly seen in the setting of infections, particularly spontaneous bacterial peritonitis. Because of the frequency of renal injury in the patient with cirrhosis, HRS-AKI has to be considered high in the differential diagnosis of AKI. Discontinuation of potential triggering agents and elimination of pre-renal AKI, intrinsic renal disease, and structural uropathy as causes of injury are imperative on presentation. Volume expansion with albumin and vasoconstrictive drugs to counteract the underlying splanchnic vasodilation constitutes the most effective medical modality to manage this process. Although the most effective therapy is generally considered to be liver transplantation (LT), the logistic barriers of offering this life-saving therapy on time to all needing it is a major limitation. Terlipressin has been shown to reverse HRS-AKI in a significant proportion of those treated and consequently can lead to increased LT patient survival and freedom from renal replacement therapy. We will review the impact of HRS on the management of patients awaiting LT, present strategies to prevent this significant complication, and discuss major implications of recent therapeutic advances in the setting of LT.

Liver transplantation (LT) is the definitive therapy for patients with end-stage liver disease, acute liver failure, acute-on-chronic liver failure, hepatocellular carcinoma, and metabolic liver diseases. The acceptance of LT in Asia has been gradually increasing and so is the expertise to perform LT. Preparing a patient with cirrhosis for LT is the most important aspect of a successful LT. The preparation for LT begins with the first index decompensation for a patient with cirrhosis. Patients planned for LT should undergo a thorough screening for infections, and a complete cardiac, pulmonology, and psychosocial evaluation pre-LT. In this review, we discuss the indications and contraindications of LT and the evaluation and assessment of patients with liver disease planned for LT.

The efficacy of terlipressin in improving pre-liver transplant renal function in hepatorenal syndrome (HRS) has been well documented, however, its impact on post-transplant renal function remains poorly described. This study aims to describe the impact of HRS and terlipressin on post-liver transplant renal function and survival.

A single-centre, retrospective, observational study was conducted to identify post-transplant outcomes of patients diagnosed with HRS undergoing liver transplant (HRS cohort) and those undergoing transplant for non-HRS, non-hepatocellular carcinoma cirrhotic indications (comparator cohort) between January 1997 and March 2020. The primary outcome was serum creatinine at 180 days post-liver transplant. Other renal outcomes and overall survival were secondary outcomes.

109 patients with HRS and 502 comparator patients underwent liver transplant. The comparator cohort was younger than the HRS cohort (53 vs. 57 years, P < 0.001). The median creatinine at day 180 post-transplant was higher in the HRS transplant group (119 µmol/L vs. 103 µmol/L, P < 0.001), however, this association lost significance following multivariate analysis. Seven patients (7%) in the HRS cohort received a combined liver-kidney transplant. There was no significant difference in the 12-month post-transplant survival between the two groups (94% vs. 94%, P = 0.5).

Patients with HRS treated with terlipressin who subsequently undergo liver transplantation have post-transplant renal and survival outcomes comparable to patients transplanted for cirrhosis without HRS. This study supports the practice of liver-only transplant in this cohort and the reservation of renal allografts for those who have primary renal disease.

Kidney is the most common extra-hepatic organ involved in patients with advanced liver cirrhosis and acute-on-chronic liver failure. Hepatorenal syndrome-acute kidney injury (HRS-AKI) accounts for most hospitalizations, and liver transplantation (LT) remains the ultimate and long-term treatment in such patients. However, HRS-AKI, being a functional renal failure, has a fair chance of reversal, and as such, patients who achieve reversal of HRS-AKI have better outcomes post-LT.

In this review, we discuss the pharmacokinetics, pharmacodynamics and evidence to support the use of terlipressin in HRS-AKI while we also address predictors of response and the associated adverse events. Further, we discuss the role of terlipressin in the context of LT.

The recommended treatment for HRS-AKI reversal includes a vasoconstrictor in addition to volume expansion with albumin. The three vasoconstrictor regimens generally used to treat HRS-AKI include octreotide plus midodrine, noradrenaline, and terlipressin. Of these, terlipressin is a widely used drug and has been recently approved by US Food and Drug Administration (USFDA) for HRS-AKI. Terlipressin is the most effective drug for HRS-AKI reversal and is associated with a decreased need for renal replacement therapy pre- and post-transplant. Furthermore, terlipressin responders have improved transplant-free and post-transplant survival.

Ascites is the most common complication of cirrhosis, with 5-year mortality reaching 30%. Complications of ascites (ie, spontaneous bacterial peritonitis, hepatorenal syndrome, recurrent/refractory ascites, and hepatic hydrothorax) further worsen survival. The development of ascites is driven by portal hypertension, systemic inflammation, and splanchnic arterial vasodilation. Etiologic treatment and nonselective beta-blockers can prevent ascites in compensated cirrhosis. The treatment of ascites is currently based on the management of fluid overload (eg, diuretics, sodium restriction, and/or paracenteses). In selected patients, long-term albumin use, norfloxacin prophylaxis, and transjugular intrahepatic portosystemic shunt reduce the risk of further decompensation and improve survival.

Type 1 hepatorenal syndrome (HRS) is a rapid deterioration in kidney function in patients with cirrhosis. Data on efficacy of vasoconstrictors for type 1 HRS have shown mixed results.

Literature searched for randomized controlled trials comparing pharmacological therapy for HRS vs placebo or another drug for HRS. Primary outcome was HRS reversal (serum creatinine <1.5mg/dL on 2 readings), and secondary outcomes were liver transplant (LT) free survival and serious adverse events (SAE).

Sixteen studies on 1244 patients (mean age 50.3 yrs., 67.5% males, serum creatinine of 3.07 mg/dL, serum sodium 127.2 mEq/liter, and Model for End-stage Liver Disease (MELD) score of 30.9, and Child-Pugh score 11) with type 1 HRS treated with vasoconstrictors vs placebo or another drug were analyzed. All the patients received intravenous albumin infusion. (A) terlipressin vs placebo: Odds of HRS reversal were 3.3 folds with terlipressin without difference on LT-free patient survival. Terlipressin was associated with higher odds of SAE. (B) Nor-epinephrine (NE) vs terlipressin: No difference on HRS reversal, LT-free survival, and SAE. (C) Terlipressin or NE vs midodrine and octreotide: 91% lower odds of HRS reversal with midodrine and octreotide. There were no differences on SAE (10 of 64 vs 10 of 58, P = .812). Non-responders vs responders had higher mean MELD score (29 vs 27.8), P = .014 and serum creatinine (3.5 vs 3.1), P = .027.

Terlipressin and NE are similar and superior to midodrine octreotide combination for HRS reversal. No therapy improves LT-free patient survival. Response to treatment is better with lower baseline serum creatinine and MELD score. The risk of adverse effects is similar with terlipressin and NE. Studies are needed as basis to identify candidates with best response to treatment with excellent safety profile.

Hepatorenal syndrome type 1 (HRS-1) is a serious complication of advanced cirrhosis and a potentially reversible form of acute kidney injury that is associated with rapidly deteriorating kidney function. Liver transplantation remains the only curative treatment for decompensated cirrhosis. However, terlipressin, a vasopressin analog, successfully reverses HRS-1, and may improve patient survival while awaiting liver transplantation. Patients with higher baseline serum creatinine have a reduced response to treatment with terlipressin. These post hoc analyses examined pooled data from 352 patients with HRS-1 treated with terlipressin in 3 North American-centric, Phase III, placebo-controlled clinical studies (i.e. OT-0401, REVERSE, and CONFIRM)-across 3 serum creatinine subgroups (i.e. <3, ≥3-<5, and ≥5 mg/dL)-to further delineate their correlation with HRS reversal, renal replacement therapy-free survival, and overall survival. Serum creatinine was significantly associated with HRS reversal in univariate and multivariate logistic regression analyses (P<0.001). The incidence of HRS reversal inversely correlated with serum creatinine subgroup (<3 mg/dL, 49.2%; ≥3-<5 mg/dL, 28.0%; ≥5 mg/dL, 9.1%). At Day 30 follow-up, renal replacement therapy-free survival was significantly higher for patients with HRS-1 in the lower serum creatinine subgroups than in the higher subgroup (<5 vs. >5 mg/dL; p=0.01). Terlipressin-treated patients with HRS-1, with a lower baseline serum creatinine level, had a higher overall survival (p<0.001) and higher transplant-free survival at Day 90 (p=0.04). Patients with HRS-1 and lower serum creatinine levels who were treated with terlipressin had higher HRS reversal and survival outcomes, highlighting the significant need to identify and treat patients with HRS-1 early when they often have lower serum creatinine levels, and likely a greater response to terlipressin.

The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available published evidence and expert advice regarding the clinical management of patients with suspected acute kidney injury in patients with cirrhosis.

This article provides practical advice for the management of patients with cirrhosis and acute kidney injury based on the best available published evidence. This best practice document is not based on a formal systematic review. This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through the standard procedures of Clinical Gastroenterology & Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: Acute kidney injury (AKI) should be diagnosed when the serum creatinine increases by ≥0.3 mg/dL within 48 hours or is ≥50% from baseline or when the urine output is reduced below 0.5 mL/kg/h for >6 hours. BEST PRACTICE ADVICE 2: Preventive measures against the development of AKI in cirrhosis include (1) avoidance of potentially nephrotoxic medications like nonsteroidal anti-inflammatory drugs (NSAIDs), (2) avoidance of excessive or unmonitored diuretics or nonselective beta-blockade, (3) avoidance of large-volume paracentesis without albumin replacement, and (4) counseling patients to avoid alcohol use. BEST PRACTICE ADVICE 3: (A) Investigation is directed to determining the cause of AKI, which can be due to hypovolemic causes (volume responsive, and the most common cause of AKI in patients with cirrhosis); acute tubular necrosis; hepatorenal syndrome with AKI (HRS-AKI) (a functional renal failure that persists despite volume repletion); HRS with acute kidney disease, a type of functional renal failure of <3 months- duration in which criteria for HRS-AKI are not met; or postrenal, which occurs only rarely. (B) The specific type of AKI should be identified through a careful history, physical examination, blood biochemistry, urine microscopic examination, urine chemistry (Na+ and urea) and selected urinary biomarkers, and renal ultrasound. BEST PRACTICE ADVICE 4: A rigorous search for infection is required in all patients with AKI. A diagnostic paracentesis should be carried out to evaluate for spontaneous bacterial peritonitis; blood and urine cultures and chest radiograph are also required. There is no role for routine prophylactic antibiotics in patients with AKI, but broad-spectrum antibiotics should be started whenever infection is strongly suspected. BEST PRACTICE ADVICE 5: When AKI is diagnosed, diuretics and nonselective beta-blockers should be held, NSAIDs discontinued, the precipitating cause of AKI treated, and fluid losses replaced, administering albumin 1 g/kg/d for 2 days if the serum creatinine shows doubling from baseline. Urine output, vital signs, and when indicated, echocardiography or CVP (if there is a pre-existing central line) should be used to monitor fluid status. BEST PRACTICE ADVICE 6: When the serum creatinine remains higher than twice the baseline value despite these measures, treatment of HRS-AKI should be initiated with albumin at a dose of 1 g/kg intravenously on day 1 followed by 20-40 g daily along with vasoactive agents (terlipressin; if terlipressin is not available, either a combination of octreotide and midodrine; or norepinephrine, depending on institutional preferences) and continued either until 24 hours following the return of the serum creatinine level to within ≤0.3 mg/dL of baseline for 2 consecutive days or for a total of 14 days of therapy. BEST PRACTICE ADVICE 7: Terlipressin should be initiated as a bolus dose of 1 mg every 4-6 hours (total 4-6 mg/d). The dose should be increased to a maximum of 2 mg every 4-6 hours (total 8-12 mg/d) if there is no reduction in serum creatinine at day 3 of therapy by at least 25% compared to the baseline value. Alternatively, clinicians can administer terlipressin by continuous intravenous infusion at a lower starting dose of 2 mg/d, which may reduce ischemic side effects and increase the dose gradually every 24-48 hours up to a maximum dose of 12 mg/d, or reversal of HRS. As per Food and Drug Administration restrictions, terlipressin should not be used in patients with a serum creatinine ≥5 mg/dL, or oxygen saturation of <90%. BEST PRACTICE ADVICE 8: Oral midodrine when used should be initiated at doses of 7.5 mg and titrated upward to 12.5 mg 3 times daily with octreotide (starting with 100 μg and titrating upward to 200 μg subcutaneously 3 times daily). BEST PRACTICE ADVICE 9: Norepinephrine should be used as a continuous intravenous infusion at a starting dose of 0.5 mg/h and the dose increased every 4 hours by 0.5 mg/h to a maximum of 3 mg/h with the goal of increasing the mean arterial pressure by ≥10 mm Hg and/or the urine output to >50 mL/h for at least 4 hours. BEST PRACTICE ADVICE 10: The risks of ischemic side effects of terlipressin and norepinephrine include angina and ischemia of fingers, skin, and intestine. These side effects may be lowered by starting at the lowest dose and gradually titrating upward. BEST PRACTICE ADVICE 11: Fluid status should be closely monitored because of the risk of pulmonary edema with excessive use of albumin. BEST PRACTICE ADVICE 12: Renal replacement therapy (RRT) may be used in the management of (A) AKI secondary to acute tubular necrosis; (B) HRS-AKI in potential candidates for liver transplantation (that is, RRT should not be used in patients with HRS-AKI who are not candidates for liver transplantation); and (C) AKI of uncertain etiology in which the need for RRT may be considered on an individual basis. BEST PRACTICE ADVICE 13: Transjugular intrahepatic portosystemic shunts should not be used as a specific treatment of HRS-AKI. BEST PRACTICE ADVICE 14: Liver transplantation is the most effective treatment for HRS-AKI. Pharmacotherapy for HRS-AKI before proceeding with liver transplantation may be associated with better post-liver transplantation outcomes. Selected patients with HRS-AKI may require simultaneous liver kidney transplantation based on updated Organ Procurement and Transplantation Network listing criteria.