Allegretti, Andrew S.

Ascites development in cirrhosis reduces 5-year survival from 80% to 30%, yet substantial heterogeneity exists among patients with comparable ascites severity. This multicenter retrospective cohort study included adult liver transplant candidates with ascites at 4 United States centers (2015–2024). Latent class analysis was performed using 7 clinical variables: ascites grade, bilirubin, albumin, platelet count, estimated glomerular filtration rate, systolic blood pressure, and portal vein thrombosis. The derivation cohort (n=625) from the University of California San Francisco and Columbia University was randomly split 80/20 for model development and internal validation. External validation was performed at the University of Southern California (n=59) and Mayo Clinic (n=93). Primary outcomes were acute kidney injury (AKI) and waitlist mortality over 365 days. Three phenotypes emerged: “CKD-Metabolic” (30.4%, lowest eGFR 76.5 mL/min/1.73 m 2 ), “Vasodilatory-Synthetic Dysfunction” (38.9%, highest bilirubin 7.03 mg/dL, lowest blood pressure 117.5 mmHg), and “PVT-Intermediate” (30.7%, severe thrombocytopenia 68.1×10 3 /μL, 24.0% PVT). In validation cohorts (n=305), phenotypes demonstrated robust classification (mean posterior probability 0.823–0.855). Vasodilatory-Synthetic Dysfunction showed increased AKI risk versus CKD-Metabolic in derivation (MELD 3.0-adjusted HR 2.95, 95% CI 2.07–4.22, p <0.001) and validation cohorts (HR 3.39, 95% CI 1.93–5.94, p <0.001). Competing risk analysis revealed no mortality differences, but Vasodilatory-Synthetic Dysfunction was associated with higher transplantation rates (validation: HR 1.63, 95% CI 1.19–2.22, p =0.002). Three reproducible clinical phenotypes of ascites were identified with distinct risk profiles. The Vasodilatory-Synthetic Dysfunction phenotype was associated with a 3-fold increase in the risk of AKI that persisted after adjustment for MELD 3.0. No differences in waitlist mortality were observed, likely reflecting effective MELD-based transplant allocation that preferentially removes the highest-acuity patients from the waitlist.

INTRODUCTION: Evidence on the comparative real-world effectiveness of terlipressin vs midodrine plus octreotide (MO) for hepatorenal syndrome-acute kidney injury (HRS-AKI) in the United Kingdom and the United States is limited. METHODS: Using individual-level chart review data for patients across the United Kingdom (2013–2017) and the United States (2016–2019), an indirect treatment comparison was conducted comparing the efficacy of terlipressin (UK cohort) with MO (US cohort). Covariate balancing propensity scoring matched the cohorts on baseline serum creatinine (SCr), presence of encephalopathy and/or ascites, albumin use and duration, age, and sex. The primary endpoint was HRS reversal, defined as achieving SCr ≤1.5 mg/dL by the last day of treatment. RESULTS: At treatment initiation, 90.2% of UK patients received terlipressin (194/215), while 89.2% of US patients received MO (140/157). Concomitant albumin was administered in 67.9% of UK and 98.7% of US patients. In a covariate balancing propensity score-adjusted cohort, HRS reversal was achieved in 53.2% of terlipressin-treated patients (the United Kingdom, weighted effective sample size of 75) compared with 16.9% of MO-treated patients (the United States, n = 89) (adjusted mean difference (95% CI) 36.3% (22.4, 50.2), P < 0.0001). In adjusted analysis, individuals treated with terlipressin experienced an overall reduction in SCr at completion of treatment (SCr decrease 1.00 mg/dL vs increase of 0.08 mg/dL for MO-treated patients, P < 0.0001). DISCUSSION: HRS-AKI treatment and outcomes differ between the United Kingdom and the United States, attributed to the historical standard of care MO in the United States. In adjusted analyses, real-world use of terlipressin was more effective than MO at improving kidney function and achieving HRS-AKI reversal.

ImportanceThere are no useful treatments to prevent the development of severe complications of liver cirrhosis. Simvastatin and rifaximin have shown beneficial effects in liver cirrhosis.ObjectiveTo assess whether simvastatin combined with rifaximin improves outcomes in patients with decompensated cirrhosis.Design, Setting, and ParticipantsDouble-blind, placebo-controlled, phase 3 trial conducted among patients with decompensated cirrhosis in 14 European hospitals between January 2019 and December 2022. The last date of follow-up was December 2022.InterventionsPatients were randomly assigned to receive simvastatin, 20 mg/d, plus rifaximin, 1200 mg/d (n = 117), or identical-appearing placebo (n = 120) for 12 months in addition to standard therapy, stratified according to Child-Pugh class B or C.Main Outcomes and MeasuresThe primary end point was incidence of severe complications of liver cirrhosis associated with organ failure meeting criteria for acute-on-chronic liver failure. Secondary outcomes included transplant or death and a composite end point of complications of cirrhosis (ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury, and infection).ResultsAmong the 237 participants randomized (Child-Pugh class B: n = 194; Child-Pugh class C: n = 43), 72% were male and the mean age was 57 years. There were no differences between the 2 groups in terms of development of acute-on-chronic liver failure (21 [17.9%] vs 17 [14.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 1.23; 95% CI, 0.65-2.34; P = .52); transplant or death (22 [18.8%] vs 29 [24.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.75; 95% CI, 0.43-1.32; P = .32); or development of complications of cirrhosis (50 [42.7%] vs 55 [45.8%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.93; 95% CI, 0.63-1.36; P = .70). Incidence of adverse events was similar in both groups (426 vs 419; P = .59), but 3 patients in the treatment group (2.6%) developed rhabdomyolysis.Conclusions and RelevanceThe addition of simvastatin plus rifaximin to standard therapy does not improve outcomes in patients with decompensated liver cirrhosis.Trial RegistrationClinicalTrials.gov Identifier: NCT03780673

Key Points In patients with cirrhosis and AKI requiring renal replacement therapy (RRT), hepatorenal syndrome-AKI was not associated with an increased 90-day mortality when compared with other AKI etiologies. Etiology of AKI may not be a critical factor regarding decisions to trial RRT in acutely ill patients with cirrhosis and AKI. Although elevated, mortality rates in this study are comparable with those reported in general hospitalized patients with AKI requiring RRT. Background While AKI requiring renal replacement therapy (AKI-RRT) is associated with increased mortality in heterogeneous inpatient populations, the epidemiology of AKI-RRT in hospitalized patients with cirrhosis is not fully known. Herein, we evaluated the association of etiology of AKI with mortality in hospitalized patients with cirrhosis and AKI-RRT in a multicentric contemporary cohort. Methods This is a multicenter retrospective cohort study using data from the HRS-HARMONY consortium, which included 11 US hospital network systems. Consecutive adult patients admitted in 2019 with cirrhosis and AKI-RRT were included. The primary outcome was 90-day mortality, and the main independent variable was AKI etiology, classified as hepatorenal syndrome (HRS-AKI) versus other (non–HRS-AKI). AKI etiology was determined by at least two independent adjudicators. We performed Fine and Gray subdistribution hazard analyses adjusting for relevant clinical variables. Results Of 2063 hospitalized patients with cirrhosis and AKI, 374 (18.1%) had AKI-RRT. Among them, 65 (17.4%) had HRS-AKI and 309 (82.6%) had non–HRS-AKI, which included acute tubular necrosis in most cases (62.6%). Continuous renal replacement therapy was used as the initial modality in 264 (71%) of patients, while intermittent hemodialysis was used in 108 (29%). The HRS-AKI (versus non–HRS-AKI) group received more vasoconstrictors for HRS management (81.5% versus 67.9%), whereas the non–HRS-AKI group received more mechanical ventilation (64.3% versus 50.8%) and more continuous renal replacement therapy (versus intermittent hemodialysis) as the initial RRT modality (73.9% versus 56.9%). In the adjusted model, HRS-AKI (versus non–HRS-AKI) was not independently associated with increased 90-day mortality (subdistribution hazard ratio, 1.36; 95% confidence interval, 0.95 to 1.94). Conclusions In this multicenter contemporary cohort of hospitalized adult patients with cirrhosis and AKI-RRT, HRS-AKI was not independently associated with an increased risk of 90-day mortality when compared with other AKI etiologies. The etiology of AKI appears less relevant than previously considered when evaluating the prognosis of hospitalized adult patients with cirrhosis and AKI requiring RRT.

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.

Summary Background & Aims 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. Methods 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. Results 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). Conclusions 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.

INTRODUCTION: Urinary neutrophil gelatinase-associated lipocalin (NGAL) has shown promise in differentiating acute tubular necrosis (ATN) from other types of acute kidney injuries (AKIs) in cirrhosis, particularly hepatorenal syndrome (HRS). However, NGAL is not currently available in clinical practice in North America. METHODS: Urinary NGAL was measured in a prospective cohort of 213 US hospitalized patients with decompensated cirrhosis (161 with AKI and 52 reference patients without AKI). NGAL was assessed for its ability to discriminate ATN from non-ATN AKI and to predict 90-day outcomes. RESULTS: Among patients with AKI, 57 (35%) had prerenal AKI, 55 (34%) had HRS, and 49 (30%) had ATN, with a median serum creatinine of 2.0 (interquartile range 1.5, 3.0) mg/dL at enrollment. At an optimal cutpoint of 244 μg/g creatinine, NGAL distinguished ATN (344 [132, 1,429] μg/g creatinine) from prerenal AKI (45 [0, 154] μg/g) or HRS (110 [50, 393] μg/g; P < 0.001), with a C statistic of 0.762 (95% confidence interval 0.682, 0.842). By 90 days, 71 of 213 patients (33%) died. Higher median NGAL was associated with death (159 [50, 865] vs 58 [0, 191] μg/g; P < 0.001). In adjusted and unadjusted analysis, NGAL significantly predicted 90-day transplant-free survival ( P < 0.05 for all Cox models) and outperformed Model for End-Stage Liver Disease score by C statistic (0.697 vs 0.686; P = 0.04), net reclassification index (37%; P = 0.008), and integrated discrimination increment (2.7%; P = 0.02). DISCUSSION: NGAL differentiates the type of AKI in cirrhosis and may improve prediction of mortality; therefore, it holds potential to affect management of AKI in cirrhosis.