Liver transplantation (LT) is a life-saving procedure for patients with end-stage liver disease; however, with the growing shortage of organ donors, the need to identify futile transplants has become increasingly urgent. Futility in liver transplantation refers to situations where the expected post-transplant survival or quality of life is poor, making the procedure unlikely to yield a meaningful benefit. Various definitions of futility are used across different countries and transplant centers, with criteria often based on clinical factors such as age, comorbidities, MELD score, and functional status. For hepatologists and transplant surgeons, clearer guidelines are essential to make informed decisions and avoid unnecessary transplants that may place patients at risk without improving their prognosis. While some studies have proposed futility scores, there is currently no universal consensus on a standardized definition or set of criteria. This highlights the need for further prospective trials to evaluate the predictors of futility in liver transplantation, aiming to refine decision-making processes, optimize organ allocation, and improve patient outcomes. Future research should focus on the development of universally accepted futility criteria and explore interventions to mitigate the factors contributing to transplant futility.

Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the "APASL ACLF Research Consortium (AARC)" was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia-Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the 'Golden Therapeutic Window', the 'transplant window', and plasmapheresis as a treatment modality. Also, the data has been key to identifying pediatric ACLF. The European Association for the Study of Liver-Chronic Liver Failure (EASL CLIF) and the North American Association for the Study of the End Stage Liver Disease (NACSELD) from the West added the concepts of organ failure and infection as precipitants for the development of ACLF and CLIF-Sequential Organ Failure Assessment (SOFA) and NACSELD scores for prognostication. The Chinese Group on the Study of Severe Hepatitis B (COSSH) added COSSH-ACLF criteria to manage hepatitis b virus-ACLF with and without cirrhosis. The literature supports these definitions to be equally effective in their respective cohorts in identifying patients with high mortality. To overcome the differences and to develop a global consensus, APASL took the initiative and invited the global stakeholders, including opinion leaders from Asia, EASL and AASLD, and other researchers in the field of ACLF to identify the key issues and develop an evidence-based consensus document. The consensus document was presented in a hybrid format at the APASL annual meeting in Kyoto in March 2024. The 'Kyoto APASL Consensus' presented below carries the final recommendations along with the relevant background information and areas requiring future studies.

Acute-on-chronic liver failure (ACLF) patients with hepatorenal syndrome (HRS-AKI) have limited response to vasoconstrictors and worse outcomes, requiring biomarkers for early detection.

In a prospective cohort of ACLF patients (n = 240), urine NGAL was performed in patients with the clinical diagnosis of HRS-AKI, while in a subset of patients (n = 30), a complete panel of 17 urinary biomarkers was assessed for identifying terlipressin non-response (T-NR).

ACLF patients with HRS-AKI, aged 45.84 ± 10.6 years, 91.2% males, 74.2% with alcohol etiology, mean urine NGAL of 1541.66 ± 1684.69 ng/ml, AARC score 10.19 ± 1.86, 155 (64.5%) had T-NR at day 4. T-NR was maximal for AARC grade 3 and was associated with a higher need of dialysis (50.3% vs 5.9%; OR 16.21, 6.23-42.19) and 28-day mortality (49.0% vs. 17.9%; HR 3.42, 1.96-5.95). AARC grade 3 (OR 38.21, 2.93-497.74), (HR 5.10, 1.19-21.84) and urine NGAL (OR 11.53, 5.66-23.49; AUROC 0.97, NGAL > 900 ng/ml) (HR 1.23, 1.02-1.49) were independent predictors of T-NR and 28-day mortality, respectively. It was interesting to observe a significant elevation in renal injury and a decrease in the repair markers in T-NR (p < 0.05).

Almost 60% of patients with ACLF and HRS-AKI experience non-response to terlipressin which predicts higher mortality and need for dialysis. High NGAL above 900 ng/ml predicts T-NR with 100% specificity for T-NR. ACLF patients with HRS, with AARC grade 3 and high NGAL have a high likelihood of T-NR and should be considered for alternative therapeutic modalities.

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-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.

Terlipressin infusion is effective in hepatorenal syndrome (HRS-AKI). However, its efficacy for HRS-AKI resolution in acute-on-chronic liver failure (ACLF) patients has been suboptimal. Progression of AKI is rapid in ACLF. We investigated whether early initiation of terlipressin(eTerli) can improve response rates.

Consecutive ACLF patients with stage II/III AKI despite albumin resuscitation (40 g) were randomized to receive terlipressin at 2 mg/24 h plus albumin at 12 h (ET, n = 35) or at 48 h as standard therapy (ST, n = 35). (June 22, 2020 to June 10, 2022). The primary end-point was AKI reversal by day7.

Baseline parameters including AKI stage and ACLF-AARC scores in two arms were comparable. Full AKI response at day 7 was higher in ET [24/35 (68.6%)] than ST arm [11/35 (31.4%; P 0.03]. Day3 AKI response was also higher in ET arm [11/35 (31.4%) vs. 4/35 (11.4%), P 0.04]. Using ST compared to ET [HR 4.3; P 0.026] and day 3 serum creatinine > 1.6 mg/dl [HR 9.1; AUROC-0.866; P < 0.001] predicted HRS-AKI non-response at day 7. ET patients showed greater improvement in ACLF grade, mean arterial pressure, and urine output at day 3, and required lower albumin within 7 days than ET arm (149.1 ± 41.8 g vs. 177.5 ± 40.3 g, P 0.006) and had lower 28-day mortality: 40% vs. 65.7%, P 0.031]. Early use of terlipressin than ST [HR 2.079; P 0.038], baseline HE [HR 2.929; P 0.018], and AKI persistence at day 3 [HR 1.369; P 0.011] predicted 28-day mortality. Fifteen (21.4%) patients had treatment related adverse effects, none was life threatening.

In ACLF patients, early initiation of terlipressin for AKI persisting after 12 h of volume expansion with albumin helps in reduced short-term mortality and early AKI reversal with regression of ACLF stage. These results indicate need for change in current practice for terlipressin usage in HRS-AKI.

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.

Acute-on-chronic-liver failure (ACLF) refers to a phenomenon in which patients with chronic liver disease develop multiple organ failure due to acute exacerbation of underlying liver disease. More than 10 definitions of ACLF are extant around the world, and there is lack of consensus on whether extrahepatic organ failure is a main component or a consequence of ACLF. Asian and European consortiums have their own definitions of ACLF. The Asian Pacific Association for the Study of the Liver ACLF Research Consortium does not consider kidney failure as a diagnostic criterion for ACLF. Meanwhile, the European Association for the Study of the Liver Chronic Liver Failure and the North American Consortium for the Study of End-stage Liver Disease do consider kidney failure as an important factor in diagnosing and assessing the severity of ACLF. When kidney failure occurs in ACLF patients, treatment varies depending on the presence and stage of acute kidney injury (AKI). In general, the diagnosis of AKI in cirrhotic patients is based on the International Club of Ascites criteria: an increase of 0.3 mg/dL or more within 48 hours or a serum creatinine increase of 50% or more within one week. This study underscores the importance of kidney failure or AKI in patients with ACLF by reviewing its pathophysiology, prevention methods, and treatment approaches.

There is limited data on natural course and interventions in stage-3 acute kidney injury (AKI-3) in patients with acute-on-chronic liver failure (ACLF). We studied the factors of AKI-3 reversal and outcomes of dialysis in ACLF patients.

Consecutive patients with ACLF were prospectively enrolled (n = 1022) and variables determining AKI and its outcomes were analysed.

At 1 month, 337 (33%) patients had AKI-3, of which, 131 had AKI-3 at enrolment and 206 developed AKI-3 during hospital stay. Of patients with AKI-3 at enrolment, 18% showed terlipressin response, 21% had AKI resolution and 59% required dialysis. High MELD (≥35) (model 1), serum bilirubin (≥23 mg/dL) (model 2) and AARC score (≥11) (model 3) were independent risk factors for dialysis. Dialysis was associated with worse survival in all AKI patients but improved outcomes in patients with AKI-3 (p = .022, HR 0.69 [0.50-0.95]). Post-mortem kidney biopsies (n = 61) revealed cholemic nephropathy (CN) in 54%, acute tubular necrosis (ATN) in 31%, and a combination (CN and ATN) in 15%. Serum bilirubin was significantly higher in patients with CN, CN and ATN compared with ATN respectively ([30.8 ± 12.2] vs. [26.7 ± 12.0] vs. [18.5 ± 9.8]; p = .002).

AKI-3 rapidly increases from 13% to 33% within 30 days in ACLF patients. Histopathological data suggested cholemic nephropathy as the predominant cause which correlated with high bilirubin levels. AKI-3 resolves in only one in five patients. Patients with AARC grade 3 and MELD >35 demand need for early dialysis in AKI-3 for improved outcomes.

Terlipressin with albumin, the recommended treatment for hepatorenal syndrome-acute kidney injury (HRS-AKI), is associated with adverse events. Furthermore, the course of AKI in patients with acute-on-chronic liver failure (ACLF) is unknown. We aimed to analyze the safety and efficacy of terlipressin infusion and AKI course in patients with ACLF. We prospectively enrolled consecutive adult patients with ACLF with HRS-AKI (satisfying EASL criteria) treated with terlipressin infusion between 14 October 2019 and 24 July 2020. The objectives were to assess the incidence of adverse events, response to terlipressin, course of HRS-AKI and predictors of mortality. A total of 116 patients were included. Twenty-one percent of patients developed adverse effects. Only 1/3rd of patients who developed adverse events were alive at day 90. Sixty-five percent of the patients responded to terlipressin. Nearly 22% developed recurrence of HRS, and 5.2% progressed to HRS-chronic kidney disease. TFS was 70.4% at day 30 and 57.8% at day 90. On multivariate stepwise Cox regression analysis terlipressin non-response (hazard ratio [HR], 3.49 [1.85-6.57]; P < 0.001) and MELD NA score (HR,1.12 [1.06-1.18]; P < 0.001) predicted mortality at day-90. Patients with ACLF who develop terlipressin related adverse events have dismal prognoses. Terlipressin non-response predicts mortality in patients with ACLF and HRS-AKI.

Hepatorenal syndrome (HRS) is a life-threatening condition among patients with advanced liver disease. Data trends specific to hospital mortality and hospital admission resource utilization for HRS remain limited.

To assess the temporal trend in mortality and identify the predictors for mortality among hospital admissions for HRS in the United States.

We used the National Inpatient Sample database to identify an unweighted sample of 4938 hospital admissions for HRS from 2005 to 2014 (weighted sample of 23973 admissions). The primary outcomes were temporal trends in mortality as well as predictors for hospital mortality. We estimated odds ratios from multi-level mixed effect logistic regression to identify patient characteristics and treatments associated with hospital mortality.

Overall hospital mortality was 32%. Hospital mortality decreased from 44% in 2005 to 24% in 2014 (P < 0.001), while there was an increase in the rate of liver transplantation (P = 0.02), renal replacement therapy (P < 0.001), length of hospital stay (P < 0.001), and hospitalization cost (P < 0.001). On multivariable analysis, older age, alcohol use, coagulopathy, neurological disorder, and need for mechanical ventilation predicted higher hospital mortality, whereas liver transplantation, transjugular intrahepatic portosystemic shunt, and abdominal paracentesis were associated with lower hospital mortality.

Although there was an increase in resource utilizations, hospital mortality among patients admitted for HRS significantly improved. Several predictors for hospital mortality were identified.

Acute-on-chronic liver failure (ACLF) is acute decompensation of liver function in the setting of chronic liver disease, and characterized by high short-term mortality. In this study, we sought to investigate the clinical course of patients at specific time points, and to propose dynamic prognostic criteria.

We assessed the clinical course of 453 patients with ACLF during a 12-week follow-up period in this retrospective multicenter study. The clinical course of patients was defined as disease recovery, improvement, worsening or steady patterns based on the variation tendency in prothrombin activity (PTA) and total bilirubin (TB) at different time points.

Resolution of PTA was observed in 231 patients (51%) at 12 weeks after the diagnosis of ACLF. Among the remaining patients, 66 (14.6%) showed improvement and 156 (34.4%) showed a steady or worsening course. In patients with resolved PTA, the clinical course of TB exhibited resolved pattern in 95.2%, improved in 3.9%, and steady or worse in 0.8%. Correspondingly, in patients with improved PTA, these values for TB were 28.8%, 27.3%, and 43.9%, respectively. In patients with steady or worsening PTA, these values for TB were 5.7%, 32.3%, and 65.6%, respectively. Dynamic prognostic criteria were developed by combining the clinical course of PTA/TB and the clinical outcomes at 4 and 12 weeks after diagnosis in ACLF patients.

We propose the following dynamic prognostic criteria: rapid progression, slow progression, rapid recovery, slow recovery, and slow persistence, which lay the foundation for precise prediction of prognosis and the improvement of ACLF therapy.

Acute kidney injury (AKI) is common in advanced cirrhosis. Prerenal azotemia, hepatorenal syndrome, and acute tubular necrosis are the main causes of AKI in patients with cirrhosis. Evaluation of renal function and differentiation between functional and structural kidney injury are important issues in the management of cirrhosis. However, AKI in cirrhosis exists as a complex clinical spectrum rather than concrete clinical entity. Based on current evidence, changes in serum creatinine (Cr) levels remain the most appropriate standard for defining AKI in cirrhosis. However, serum Cr has a limited role in assessing renal function in this population. This review examines previous studies that investigated the ability of recent biomarkers for AKI in cirrhosis from the perspective of earlier and accurate diagnosis, classification of AKI phenotype, and prediction of clinical outcomes. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin have been extensively studied in cirrhosis, and have facilitated improved diagnosis and prognosis prediction in patients with AKI. In addition, urine N-acetyl-β-D-glucosaminidase, interleukin 18, and kidney injury molecule 1 are other promising biomarkers for advanced cirrhosis. However, the clinical significance of these markers remains unclear because there are no cut-off values defining the normal range and differentiating phenotypes of AKI. In addition, AKI has been defined in terms of serum Cr, and renal biopsy-the gold standard-has not been carried out in most studies. Further discovery of innovate biomarkers and incorporation of various markers could improve the diagnosis and prognosis prediction of AKI, and will translate into meaningful improvements in patient outcomes.

Acute kidney injury (AKI) in patients with acute-on-chronic liver failure (ACLF) is a distinct syndrome to that in patients with cirrhosis, yet is less characterized. The aim of this meta-analysis was to investigate the impact of AKI on outcome of ACLF. We searched PubMed, Web of Science and Cochrane Library for original articles that evaluated the impact of AKI on outcome of ACLF from 2011 to 2019. Odds ratio (OR) with 95% confidence interval (CI) for 1-month and 3-month mortality was calculated. The response rate of vasoconstrictor for hepatorenal syndrome (HRS)-AKI was assessed. Eight relevant articles with 3610 patients were included. The prevalence of AKI in ACLF patients was 41% (95% CI 32%-50%). The presence of AKI was significantly associated with 1-month mortality of ACLF (OR 3.98, 95% CI 3.09-5.12; P < .001) and 3-month mortality (OR 4.98, 95% CI 3.59-6.92; P < .001). Additionally, patients with AKI stage ≥2 showed a higher 3-month mortality than stage 1 (OR 3.89, 95% CI 2.60-5.82; P < .001), and those of stage 3 had a higher mortality than stage ≤2 (OR 3.77, 95% CI 2.10-6.77; P < .001). The pooled response rate of vasoconstrictors was 32% (95% CI 26%-37%). This meta-analysis indicated that about 40% of ACLF patients complicated with AKI and the presence of AKI substantially increased the short-term mortality, together with a poor response rate of vasoconstrictors for HRS-AKI.

Acute kidney injury (AKI) is a common complication of acute liver failure (ALF). Pyroptosis is a necrosis type related to inflammation. This study aimed to investigate the role of TNF-α/HMGB1 pathway in pyroptosis during ALF and AKI.

An ALF and AKI mouse model was generated using LPS/D-Gal, and a TNF-α inhibitor, CC-5013, was used to treat the mice. THP-1 cells were induced to differentiate into M1 macrophages, then challenged with either CC-5013 or an HMGB1 inhibitor, glycyrrhizin. pLVX-mCMVZsGreen-PGK-Puros plasmids containing TNF-α wild-type (WT), mutation A94T of TNF-α and mutation P84L of TNF-α were transfected into M1 macrophages.

Treatment with CC-5013 decreased the activation of TNF-α/HMGB1 pathway and pyroptosis in the treated mice and cells compared with the control mice and cells. CC-5013 also ameliorated liver and kidney pathological changes and improved liver and renal functions in treated mice, and the number of M1 macrophages in the liver and kidney tissues also decreased. The activation of TNF-α/HMGB1 pathway and pyroptosis increased in the M1 macrophage group compared with the normal group. Similarly, the activation of TNF-α/HMGB1 pathway and pyroptosis in the LPS + WT group also increased. By contrast, the activation of the TNF-α/HMGB1 pathway and pyroptosis decreased in the LPS + A94T and LPS + P84L groups. Moreover, glycyrrhizin inhibited pyroptosis.

The TNF-α/HMGB1 inflammation signalling pathway plays an important role in pyroptosis during ALF and AKI.

Non-alcoholic fatty liver disease (NAFLD) is currently the most common etiology of chronic liver disease (CLD) caused by an accumulation of fat in the liver and globally is the leading indication of liver transplantation. Emerging data has recognized an increased association of NAFLD with risk of other metabolic liver diseases like type 2 diabetes mellitus, chronic kidney disease (CKD) and cardiovascular diseases. Pathophysiologically, NAFLD patients have a state of low-grade systemic inflammation, insulin resistance and atherogenic dyslipidemia which causes renal dysfunction. Patients with NAFLD cirrhosis awaiting liver transplant (LT) face unique challenges and have a significantly higher requirement of simultaneous-liver-kidney transplant as compared to other etiologies. Further, NAFLD not only recurs but also occurs as a de novo manifestation post-LT. There is also a significantly higher risk of waiting list stagnation and dropouts due to burdensome cardiometabolic disorders in NAFLD patients. The current review aims to understand the prevalence and pathogenetic basis of renal dysfunction in NAFLD. Additionally, the review describes the choice of immunosuppression protocols and use of intraoperative renal replacement therapy in context of intra and post-operative renal dysfunction in NAFLD patients. Prospective controlled trials focusing on NAFLD and development of CKD are needed to assess the existence of a causal and/or a bidirectional relationship between NAFLD and CKD.

Transition to chronic kidney disease (CKD) after an episode of acute kidney injury (AKI) is known in patients without cirrhosis. We studied the incidence and risk factors for development of CKD in patients with cirrhosis. Competing risk analysis was performed to identify risk factors for CKD development. Of 818 patients with cirrhosis (age, 50.4 ± 11.8 years; 84% males; Model for End-Stage Liver Disease [MELD], 19.9 ± 9.9), 36% had AKI at enrollment, 27% had previous AKI, and 61% developed new episodes of AKI during the follow-up period. CKD developed in 269 (33%) patients. Serum cystatin C (CysC; subdistribution hazard ratio [SHR], 1.58; 1.07-2.33), episodes of previous AKI (SHR, 1.26; 1.02-1.56), and AKI stage at enrollment (no AKI [SHR, 1] vs. stage 1 [SHR, 3.28; 1.30-8.25] vs. stage 2 [SHR, 4.33; 1.76-10.66] vs. stage 3 [SHR, 4.5; 1.59-12.73]) were identified as baseline risk factors for CKD development. On time-varying competing risk analysis, MELD (SHR, 1.01; 1.00-1.03), number of AKI episodes (SHR, 1.25; 1.15-1.37), and CysC (SHR, 1.38; 1.01-1.89) predicted CKD development. Development of CKD was associated with higher risk of death. Reduction in glomerular filtration rate (GFR) not meeting CKD criteria was observed in 66% of patients with cirrhosis, more so in those with previous AKI episodes and a high CysC level and MELD score. Renal histology, available in 55 patients, showed tubulointerstitial injury in 86%, cholemic nephrosis in 29%, and glomerular changes in 38%. Conclusion: Almost two-thirds of patients with cirrhosis develop episodes of AKI and reduction in GFR; one-third progress to CKD, resulting in adverse outcomes. Higher MELD and CysC levels and number of AKI episodes predict development of CKD in patients with cirrhosis.

Hepatorenal syndrome (HRS) carries a high short-term mortality in patients with cirrhosis and acute on chronic liver failure (ACLF). Terlipressin and noradrenaline are routinely used in cirrhosis with HRS and have been found to be equally effective. There are no data comparing the efficacy of terlipressin with noradrenaline in ACLF patients with HRS. In an open-label, randomized controlled trial (RCT), consecutive patients with ACLF diagnosed with HRS acute kidney injury (AKI) were randomized to albumin with infusion of terlipressin (2-12 mg/day; n = 60) or noradrenaline (0.5-3.0 mg/h; n = 60). Response to treatment, course of AKI, and outcome were studied. Baseline characteristics, including AKI stage and sepsis-related HRS-AKI, were comparable between groups. Compared to noradrenaline, terlipressin achieved greater day 4 (26.1% vs. 11.7%; P = 0.03) and day 7 (41.7% vs. 20%; P = 0.01) response. Reversal of HRS was also better with terlipressin (40% vs. 16.7%; P = 0.004), with a significant reduction in the requirement of renal replacement therapy (RRT; 56.6% vs. 80%; P = 0.006) and improved 28-day survival (48.3% vs. 20%; P = 0.001). Adverse events limiting use of drugs were higher with terlipressin than noradrenaline (23.3% vs. 8.3%; P = 0.02), but were reversible. On multivariate analysis, high Model for End-Stage Liver Disease (MELD; odds ratio [OR], 1.10; confidence interval [CI] = 1.009-1.20; P = 0.03) and noradrenaline compared to terlipressin (OR, 3.05; CI = 1.27-7.33; P = 0.01) predicted nonresponse to therapy. Use of noradrenaline compared to terlipressin was also predictive of higher mortality (hazard ratio [HR], 2.08; CI = 1.32-3.30; P = 0.002). Conclusion: AKI in ACLF carries a high mortality. Infusion of terlipressin gives earlier and higher response than noradrenaline, with improved survival in ACLF patients with HRS-AKI.

In patients with end-stage liver disease, the ability to predict recovery of renal function following liver transplantation (LT) remains elusive. However, several important clinical decisions depend on whether renal dysfunction is recoverable after LT. We used a cohort of patients undergoing LT to independently validate a published pre-LT model predictive of post-transplant renal recovery (Renal Recovery Assessment at Liver Transplant [REVERSE]: high osteopontin [OPN] and tissue inhibitor of metalloproteinases-1 [TIMP-1] levels, age < 57, no diabetes). Serum samples pre-LT and 4-12 weeks post-LT (n = 117) were analyzed for kidney injury proteins from three groups of recipients: (1) estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m² prior to and after LT (irreversible acute kidney injury [AKI]), (2) eGFR < 30 mL/minute/1.73 m² prior to LT and >50 mL/minute/1.73 m² after LT (reversible AKI [rAKI]) (3) eGFR > 50 mL/minute/1.73 m² prior to and after LT (no AKI). In patients with elevated pre-LT serum levels of OPN and TIMP-1, recovery of renal function correlated with decreases in the level of both proteins. At 4 weeks post-LT (n = 77 subset), the largest decline in OPN and TIMP-1 was seen in the rAKI group. Validation of the REVERSE model in this independent data set had high area under the curve (0.78) in predicting full post-LT renal recovery (sensitivity 0.86, specificity 0.6, positive predictive value 0.81, negative predictive value 0.69). Our eGFR findings were confirmed using measured GFR. Conclusion: The REVERSE model, derived from an initial training set combining plasma biomarkers and clinical characteristics, demonstrated excellent external validation performance characteristics in an independent patient cohort using serum samples. Among patients with kidney injury pre-LT, the predictive ability of this model may prove beneficial in clinical decision-making both prior to and following transplantation.

Acute kidney injury is a frequent and ominous complication in cirrhosis. An episode of AKI damages the functional nephron mass, compromising the renal functional reserve. We aimed to study the incidence of AKI, probability of subsequent episodes, whether AKI itself predisposes to future AKI and the reliability of serum cystatin C(sCyC) as a biomarker in a prospective cohort of cirrhotics.

Five hundred and thirty-one cirrhotics without ongoing AKI were followed for development/resolution of AKI. Predictive models for AKI and mortality were developed and validated (Gr. A, Derivative cohort [n = 273], Gr. B, Validation Cohort [n = 258]).

365 episodes of AKI occurred in 233 patients; yielding a mean of 1.56 episodes of AKI per patient. In Gr. A and B, 97 (35.5%) and 78 (30%) patients had prior AKI episodes and were predisposed to further attacks (Gr. A, HR 3.9, 95% CI 2.7-5.6, Gr. B, HR 3.6, 95% CI 2.5-5.4). AKI was thus an independent predictor of the development of new AKI(P < .05) and this risk increased significantly with increase in the number of AKI episodes (P < .001). S.CysC but not s.Cr was an independent predictor of new AKI on multivariate analysis. "AKI-Score" incorporating CysC; and the addition of Cyst into components of MELD, that is the "MELD-Cystatin" score predicted the development of AKI and mortality, respectively, and performed significantly better than the MELD and CTP scores.

An episode of AKI itself predisposes to subsequent attacks of AKI in cirrhotics. Scores incorporating CysC can accurately predict the development of AKI and mortality in these patients.

Total glucosides of paeony (TGP) have been confirmed to be hepatoprotective. However, the underlying mechanism is largely unclear. In this study, we investigated the metabolic profiles of urine and serum in rats with carbon tetrachloride- (CCl₄-) induced experimental liver injury and TGP administration by using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The vehicle or a single dose of TGP was intragastrically administered to Wistar rats once a day for 14 consecutive days. To induce ALI, 50% CCl₄ was injected intraperitoneally into these rats 2 hours after the last time administration of saline of TGP at the 14th day. The results indicated that TGP administration could protect rats from CCl₄-induced ALI and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, as well as hepatocyte apoptosis and inflammation. Furthermore, metabolomics analysis showed that TGP treatment significantly attenuated CCl₄-triggered deregulation of multiple metabolites in both urine and serum, including glycine, alanine, proline, and glutamine. Metabolite set enrichment and pathway analyses demonstrated that amino acid cycling and glutathione metabolism were two main pathways involved in CCl₄-induced experimental liver injury and TGP administration. Taken together, these findings revealed that regulation of metabolites potentially plays a pivotal role in the protective effect of TGP on ALI.

Management of acute kidney injury (AKI) in cirrhotics has undergone a paradigm change. We evaluated the impact of AKI persistence at 48 h on outcome in patients with acute on chronic liver failure (ACLF).

Consecutive patients with ACLF (n = 373) were prospectively followed. AKI was defined as increase in serum creatinine of 0.3 mg/dl or 1.5- to 2-fold from baseline. Persistent AKI was defined as nonresponsive AKI at 48 h with respect to admission serum creatinine.

AKI at admission was present in 177 (47.5 %) patients. At 48 h, 73 % patients had persistent AKI and 27 % had responsive AKI. High Model for End-Stage Liver Disease (MELD) (≥26) [p, odds ratio (OR), 95 % confidence interval (CI)] [<0.001, 3.65 (2.1-3.67)], systemic inflammatory response syndrome (SIRS) [0.03, 1.6 (1.02-21.6)], and age (≥42 years) [0.03, 1.84 (1.19-2.85)] were significant predictors of AKI persistence. Persistent AKI was associated with significantly higher in-hospital mortality [p < 0.001, hazard ratio (HR) 1.7, 95 % CI 1.32-2.27]. We further found a lower cutoff for serum creatinine of 1.14 mg/dl at 48 h with better sensitivity of 61 %, specificity of 61 %, and likelihood ratio (LR+) of 1.6, correctly classifying 61 %, as against the conventional cutoff of 1.5 mg/dl with sensitivity of 37 %, specificity of 57 %, and LR+ of 3.3, correctly classifying 56 %. This new cutoff also predicted mortality with higher odds (OR 2.4, 95 % CI 1.3-4.8) as compared with the conventional cutoff (OR 2.1, 95 % CI 1.1-4.1).

AKI persistence at 48 h predicts mortality better than serum creatinine of 1.5 mg/dl in patients with ACLF. Serum creatinine value of 1.14 mg/dl and smaller increases in its value should be considered for risk stratification of patients with ACLF for interventional strategies.

There is limited data on predictors of acute kidney injury in acute on chronic liver failure. We developed a PIRO model (Predisposition, Injury, Response, Organ failure) for predicting acute kidney injury in a multicentric cohort of acute on chronic liver failure patients.

Data of 2360 patients from APASL-ACLF Research Consortium (AARC) was analysed. Multivariate logistic regression model (PIRO score) was developed from a derivation cohort (n=1363) which was validated in another prospective multicentric cohort of acute on chronic liver failure patients (n=997).

Factors significant for P component were serum creatinine[(≥2 mg/dL)OR 4.52, 95% CI (3.67-5.30)], bilirubin [(<12 mg/dL,OR 1) vs (12-30 mg/dL,OR 1.45, 95% 1.1-2.63) vs (≥30 mg/dL,OR 2.6, 95% CI 1.3-5.2)], serum potassium [(<3 mmol/LOR-1) vs (3-4.9 mmol/L,OR 2.7, 95% CI 1.05-1.97) vs (≥5 mmol/L,OR 4.34, 95% CI 1.67-11.3)] and blood urea (OR 3.73, 95% CI 2.5-5.5); for I component nephrotoxic medications (OR-9.86, 95% CI 3.2-30.8); for R component,Systemic Inflammatory Response Syndrome,(OR-2.14, 95% CI 1.4-3.3); for O component, Circulatory failure (OR-3.5, 95% CI 2.2-5.5). The PIRO score predicted acute kidney injury with C-index of 0.95 and 0.96 in the derivation and validation cohort. The increasing PIRO score was also associated with mortality (P<.001) in both the derivation and validation cohorts.

The PIRO model identifies and stratifies acute on chronic liver failure patients at risk of developing acute kidney injury. It reliably predicts mortality in these patients, underscoring the prognostic significance of acute kidney injury in patients with acute on chronic liver failure.