Vargas, Hugo E

INTRODUCTION: Hospitalized patients with cirrhosis can develop respiratory failure (RF), which is associated with a poor prognosis, but predisposing factors are unclear. METHODS: We prospectively enrolled a multicenter North American cirrhosis inpatient cohort and collected admission and in-hospital data (grading per European Association for the Study of Liver-Chronic Liver Failure scoring system, acute kidney injury [AKI], infections [admission/nosocomial], and albumin use) in an era when terlipressin was not available in North America. Multivariable regression to predict RF was performed using only admission day and in-hospital events occurring before RF. RESULTS: A total of 511 patients from 14 sites (median age 57 years, admission model for end-stage liver disease [MELD]-Na 23) were enrolled: RF developed in 15%; AKI occurred in 24%; and 11% developed nosocomial infections (NI). At admission, patients who developed RF had higher MELD-Na, gastrointestinal (GI) bleeding/AKI-related admission, and prior infections/ascites. During hospitalization, RF developers had higher NI (especially respiratory), albumin use, and other organ failures. RF was higher in patients receiving albumin (83% vs 59%, P < 0.0001) with increasing doses (269.5 ± 210.5 vs 208.6 ± 186.1 g, P = 0.01) regardless of indication. Admission for AKI, GI bleeding, and high MELD-Na predicted RF. Using all variables, NI (odds ratio [OR] = 4.02, P = 0.0004), GI bleeding (OR = 3.1, P = 0.002), albumin use (OR = 2.93, P = 0.01), AKI (OR = 3.26, P = 0.008), and circulatory failure (OR = 3.73, P = 0.002) were associated with RF risk. DISCUSSION: In a multicenter inpatient cirrhosis study of patients not exposed to terlipressin, 15% of patients developed RF. RF risk was highest in those admitted with AKI, those who had GI bleeding on admission, and those who developed NI and other organ failures or received albumin during their hospital course. Careful volume monitoring and preventing nosocomial respiratory infections and renal or circulatory failures could reduce this risk.

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.

Key Points Hepatorenal syndrome type 1 (HRS-1) is an often fatal, but potentially reversible, kidney failure in patients with decompensated cirrhosis. Treatment with terlipressin in patients with HRS-1 is associated with a reduction in the need for RRT. Background Hepatorenal syndrome type 1 (HRS-1)—also known as hepatorenal syndrome-AKI (HRS-AKI)—is a rapidly progressing and usually fatal, but potentially reversible, kidney failure occurring in patients with decompensated cirrhosis. A large proportion of patients with HRS-1 require renal replacement therapy (RRT). Terlipressin demonstrated efficacy in reversing HRS and improving renal function in patients with HRS-1 in three phase III, randomized, clinical trials (RCTs; i.e. , OT-0401, REVERSE, and CONFIRM). However, these RCTs were not designed to evaluate the effect of terlipressin on the requirement of RRT. In this study, the effect of terlipressin on RRT requirements in the pooled phase III patient population was assessed. Methods For this retrospective analysis, data from patients who participated in the OT-0401, REVERSE, and CONFIRM studies were integrated in the largest-to-date randomized database ( N =608). Results The need for RRT was significantly decreased in patients in the terlipressin group versus the placebo group by day 30 (28.1% versus 35.9%, respectively; P = 0.040) and day 60 (30.1% versus 37.9%, respectively; P = 0.045) in the pooled population and also postliver transplantation (LT) at day 60 (20.5% versus 40.3%, respectively; P = 0.008) and day 90 (25.3% versus 43.1%, respectively; P = 0.018). More patients were alive and RRT-free by day 90 in the overall population (36.9% versus 28.5%; P = 0.030) and among patients who received an LT (60.0% versus 39.7%; P = 0.010). Random assignment to receive terlipressin was an independent positive predictor of avoidance of RRT ( P = 0.042); while higher baseline serum creatinine (sCr) level and Child-Pugh scores were negatively associated with RRT avoidance ( P < 0.001 and P = 0.040, respectively). Conclusions Terlipressin decreased the requirement of RRT compared with placebo among patients with HRS-1, including those receiving LT. A lower sCr level at the beginning of therapy was associated with avoidance of RRT.

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.

Summary Background Previous studies suggested increased mortality in patients with hepatorenal syndrome type 1 (HRS1) and advanced acute‐on‐chronic liver failure (ACLF). Aim To assess mortality and respiratory failure (RF) in patients with HRS1 and ACLF treated with terlipressin. Methods In the CONFIRM study, we randomised 299 patients with HRS1 2:1 to terlipressin or placebo, both with albumin. At enrolment, all patients were assessed for organ failure (OF) using a validated ACLF grading system. Post hoc analyses assessed the effects of terlipressin vs. placebo on the incidence of RF and 90‐day mortality. Results The incidence of RF with terlipressin ( n = 200) was 9.4% in patients with grades 1–2 ACLF, and 30% with grade 3 ACLF ( p = 0.0002); no such difference was observed in placebo‐treated patients ( n = 99) (6.2% grades 1–2 vs. 0% grade 3 ACLF, p > 0.05). RF incidence between terlipressin and placebo in patients with grade 3 ACLF was significant ( p = 0.01). Baseline predictors of RF with terlipressin were INR ( p = 0.011), mean arterial pressure ( p = 0.037), and SpO 2 ( p = 0.014). Prior albumin as a continuous variable was not a predictor of RF. 90‐day survival between terlipressin and placebo arms was similar for grades 1–2 ACLF (55.5% and 56.6%, respectively), but lower for grade 3 ACLF (27.55% vs. 50.0%) ( p = 0.122), mainly related to RF. Conclusion Terlipressin should be used with caution in patients with HRS1 and grade 3 ACLF. Patients with hypoxaemia are at increased risk of RF and mortality.

Abstract Cirrhosis is complicated by a high rate of nosocomial infections (NIs), which result in poor outcomes and are challenging to predict using clinical variables alone. Our aim was to determine predictors of NI using admission serum metabolomics and gut microbiota in inpatients with cirrhosis. In this multicenter inpatient cirrhosis study, serum was collected on admission for liquid chromatography–mass spectrometry metabolomics, and a subset provided stool for 16SrRNA analysis. Hospital course, including NI development and death, were analyzed. Metabolomic analysis using analysis of covariance (ANCOVA) (demographics, Model for End‐Stage Liver Disease [MELD] admission score, white blood count [WBC], rifaximin, and infection status adjusted) and random forest analyses for NI development were performed. Additional values of serum metabolites over clinical variables toward NI were evaluated using logistic regression. Stool microbiota and metabolomic correlations were compared in patients with and without NI development. A total of 602 patients (231 infection admissions) were included; 101 (17%) developed NIs, which resulted in worse inpatient outcomes, including intensive care unit transfer, organ failure, and death. A total of 127 patients also gave stool samples, and 20 of these patients developed NIs. The most common NIs were spontaneous bacterial peritonitis followed by urinary tract infection, Clostridioides difficile, and pneumonia. A total of 247 metabolites were significantly altered on ANCOVA. Higher MELD scores (odds ratio, 1.05; p < 0.0001), admission infection (odds ratio, 3.54; p < 0.0001), and admission WBC (odds ratio, 1.05; p = 0.04) predicted NI (area under the curve, 0.74), which increased to 0.77 (p = 0.05) with lower 1‐linolenoyl‐glycerolphosphocholine (GPC) and 1‐stearoyl‐GPC and higher N‐acetyltryptophan and N‐acetyl isoputreanine. Commensal microbiota were lower and pathobionts were higher in those who developed NIs. Microbial–metabolite correlation networks were complex and dense in patients with NIs, especially sub‐networks centered on Ruminococcaceae and Pseudomonadaceae. NIs are common and associated with poor outcomes in cirrhosis. Admission gut microbiota in patients with NIs showed higher pathobionts and lower commensal microbiota. Microbial–metabolomic correlations were more complex, dense, and homogeneous among those who developed NIs, indicating greater linkage strength. Serum metabolites and gut microbiota on admission are associated with NI development in cirrhosis.

Background. The risk of donor-derived severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in solid organ (heart, lung, liver, kidney, pancreas, and intestine) transplant recipients is poorly understood. Since hematogenous transmission of SARS-CoV-2 has not been documented to date, nonlung solid organs might be suitable for transplantation since they likely portend a low risk of viral transmission. Methods. Abdominal solid organs from SARS-CoV-2–infected donors were transplanted into uninfected recipients. Results. Between April 18, 2021, and October 30, 2021, we performed transplants of 2 livers, 1 simultaneous liver and kidney, 1 kidney, and 1 simultaneous kidney and pancreas from SARS-CoV-2–infected donors into 5 uninfected recipients. None of the recipients developed SARS-CoV-2 infection or coronavirus disease 2019, and when tested, allograft biopsies showed no evidence of SARS-CoV-2 RNA. Conclusions. Transplanting nonlung organs from SARS-CoV-2–infected donors into uninfected recipients demonstrated no evidence of virus transmission.

AbstractBackgroundThe prognosis of acute kidney disease (AKD), defined as a glomerular filtration rate of <60 ml/min/1.73 m2 or a rise in serum creatinine (sCr) of <50% for <3 months, is not clearly known.AimTo study the prevalence, predictive factors and clinical outcomes in hospitalized cirrhotic patients with AKD.MethodsThe North American Consortium for the Study of End‐Stage Liver Disease prospectively enrolled hospitalized decompensated cirrhotic patients. Patients were separated into those with normal renal function (controls or C), AKD or stage 1 AKI as their worst renal dysfunction per International Club of Ascites definition and compared. Parameters assessed included demographics, laboratory data, haemodynamics, renal and patient outcomes.Results1244 patients with cirrhosis and ascites (C: 704 or 57%; AKD: 176 or 14%; stage 1 AKI: 364 or 29%) with similar demographics were enrolled. AKD patients had similar baseline sCr but higher hospital admission in the previous 6 months, and higher peak sCr, compared to controls, with their peak sCr being lower than that in stage 1 AKI patients (all P < .0001). The in‐hospital and 30‐day survival for AKD patients were intermediary between that for controls and stage 1 AKI patients (96% vs 91% vs 86%, P < .0001). The strongest predictors for AKD development while in hospital were the presence of a second infection (OR: 2.44) and diabetes (OR: 1.53).ConclusionsPatients with AKD had intermediate outcomes between stage 1 AKI and controls. AKD patients, especially those with diabetes and a second infection, need careful monitoring and prompt treatment for AKD to prevent negative outcomes.

Background and Aims Acute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort. Approach and Results Inpatients with cirrhosis from 11 North American Consortium of End‐stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis‐free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor–adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3‐dihydroxy‐5‐methylthio‐4‐pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8‐methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor–adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched‐chain amino‐acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes. Conclusions Specific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures.