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Background and Aim: 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. Methods: Consecutive patients with ACLF were prospectively enrolled (n = 1022) and variables determining AKI and its outcomes were analysed. Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background and Aim: Plasma‐exchange (PE) has improved survival in acute liver failure by ameliorating systemic inflammatory response syndrome (SIRS). We evaluated PE and compared it to Fractional Plasma Separation and Adsorption (FPSA) and standard medical treatment (SMT) in a large multinational cohort of ACLF patients. Methods: Data were prospectively collected from the AARC database and analysed. Matching by propensity risk score (PRS) was performed. Competing risk survival analysis was done to identify deaths because of multiorgan failure (MOF). In a subset of 10 patients, we also evaluated the mechanistic basis of response to PE. Results: ACLF patients (n = 1866, mean age 44.3 ± 12.3 yrs, 93% males, 65% alcoholics) received either artificial liver support (ALS) (n = 162); [PE (n = 131), FPSA (n = 31)] or were continued on standard medical therapy (SMT) (n = 1704). In the PRS‐matched cohort (n = 208, [ALS‐119; PE‐94, FPSA‐25)], SMT‐89). ALS therapies were associated with a significantly higher resolution of SIRS (Odd's ratio 9.23,3.42‐24.8), lower and delayed development of MOF (Hazard ratio 7.1, 4.5‐11.1), and lower liver‐failure‐related deaths as compared to FPSA and SMT (P <.05). PE cleared inflammatory cytokines, damage‐associated molecular patterns, and endotoxin in all patients. Responders improved monocyte phagocytic function and mitochondrial respiration and increased the anti‐inflammatory cytokine interleukin‐1 receptor antagonist (IL‐1RA) compared to non‐responders. PE was associated with lesser adverse effects as compared to FPSA. Conclusions: PE improves systemic inflammation and lowers the development of MOF in patients with ACLF. Plasma‐exchange provides significant survival benefit over FPSA and could be a preferred modality of liver support for ACLF patients. [ABSTRACT FROM AUTHOR]

Background: Patients with acute‐on‐chronic liver failure (ACLF) have coagulation failure in the setting of systemic inflammatory syndrome (SIRS), sepsis and extra‐hepatic organ failures. Methods: Consecutive ACLF patients without sepsis at baseline were assessed at days 0, 3 and 7 with thromboelastography (TEG) and specific assays (Factor VIII, von Willebrand factor [vWF], protein C and antithrombin III [ATIII]) and followed for development of sepsis, bleeding and outcome. Results: Of 243 patients, 114 (63% ethanol related; mean age 44.3 ± 11.7 years; 90% male) were recruited. SIRS was noted in 39 (34.2%), 45 (39.5%) and 46 (40%) patients at days 0, 3 and 7 and sepsis in 28 (24%) and 52 (56.1%) patients at days 3 and 7 respectively. The 28‐ and 90‐day survivals were 62% and 51% respectively. A hypocoagulable TEG at baseline was a predictor of bleeding (hazard ratio [HR] 2.1; CI 1.6‐4.9; P = 0.050) and mortality (HR 1.9; CI 1.3‐7.9; P = 0.043). ACLF patients had increased Factor VIII, vWF, tissue factor levels and tissue plasminogen activator (tPA) activity with reduced protein C and ATIII. Coagulation parameters like Coagulation Index (HR 2.1; CI 1.1‐4.5; P = 0.044),clot lysis (HR 3.2; CI 1.9‐3.4; P = 0.033), low protein C < 30% (HR 2.1; CI 1.5‐2.8; P = 0.017), ATIII (HR 1.4; CI 1.7‐3.1; P = 0.052) and tPA (HR 1.5; CI 1.1‐2.4; P = 0.052) were predictors of mortality at day 28. Protein C activity <30% (HR 1.3; CI 1.0‐2.9; P = 0.042) and tPA >20 ng/mL (HR 1.2; CI 1.1‐2.1; P = 0.040) predicted mortality when adjusted for age, gender and baseline MELD. Conclusions: Dynamic coagulation derangements, measured by TEG, determine the likelihood of bleeding and mortality in ACLF. [ABSTRACT FROM AUTHOR]

Background and Aim 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. Patients and Methods 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). Results 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. Conclusions 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. [ABSTRACT FROM AUTHOR]