Kamath, Patrick S.

Background and Aims Among patients with cirrhosis awaiting liver transplantation, prediction of wait‐list (WL) mortality is adjudicated by the Model for End Stage Liver Disease–Sodium (MELD‐Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD‐Na score may improve prediction of WL mortality, especially for women and highest disease severity. Approach and Results We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90‐day WL mortality between MELD‐GRAIL‐Na (re‐estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD‐Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344‐0.424) and the re‐estimated model MELD‐GRAIL‐Na (HR 1.212, 95% CI 1.199‐1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD‐GRAIL‐Na was a better predictor of observed mortality at highest deciles of disease severity (≥ 27‐40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD‐GRAIL‐Na) and 0.51 (MELD‐Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD‐GRAIL‐Na) and 0.55 (MELD‐Na). In 2015, use of MELD‐GRAIL‐Na as compared with MELD‐Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. Conclusion Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD‐GRAIL‐Na instead of MELD‐Na may affect outcomes for 12%‐17% awaiting transplant and affect organ allocation.

OBJECTIVES: Alcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery. METHODS: MR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively. RESULTS: At baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-α, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-γ, and tumor necrosis factor α). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%). DISCUSSION: We showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities.

OBJECTIVES: Nosocomial infections (NIs) can be a major cause of morbidity and mortality in cirrhosis. This study aims to define the determinants of NI development and its impact on 30-day outcomes among hospitalized patients with cirrhosis. METHODS: North American Consortium for the Study of End-Stage Liver Disease enrolled patients with cirrhosis who were admitted nonelectively. Admission variables and 30-day outcomes were compared between patients with and without NI. These were also compared based on whether there was an isolated admission infection, NI, or both. Models were created for NI development using admission variables and for 30-day mortality. RESULTS: The study included 2,864 patients; of which, 15% (n = 436) developed NI. When comparing NI vs no NI, 1,866 patients were found to be infection free, whereas 562 had admission infections only, 228 had only NI, and 208 had both infections. At admission, patients with NI were more likely to be infected and have advanced cirrhosis. NIs were associated with higher rates of acute-on-chronic liver failure, death, and transplant regardless of admission infections. Patients with NI had higher respiratory infection, urinary tract infection, Clostridium difficile infection, fungal infections, and infection with vancomycin-resistant enterococci compared with patients without NI. Risk factors for NIs were admission infections, model for end-stage liver disease (MELD) > 20, systemic inflammatory response syndrome criteria, proton pump inhibitor, rifaximin, and lactulose use, but the regression model (sensitivity, 0.67; specificity, 0.63) was not robust. Age, alcohol etiology, admission MELD score, lactulose use, acute-on-chronic liver failure, acute kidney injury, intensive care unit, and NI increased the risk of death, whereas rifaximin decreased the risk of death. DISCUSSION: NIs are prevalent in hospitalized patients with cirrhosis and are associated with poor outcomes. Although higher MELD scores and systemic inflammatory response syndrome are associated with NI, all hospitalized patients with cirrhosis require vigilance and preventive strategies.

Objectives Pancreatic lesions in autosomal dominant polycystic kidney disease (ADPKD) are primarily cysts. They are increasingly recognized, with isolated reports of intraductal papillary mucinous neoplasia (IPMN). Methods Retrospective study to determine prevalence, number, size, and location of pancreatic abnormalities using abdominal magnetic resonance imaging (MRI) of genotyped ADPKD patients (seen February 1998 to October 2013) and compared with age- and sex-matched non-ADPKD controls. We evaluated presentation, investigation, and management of all IPMNs among individuals with ADPKD (January 1997 to December 2016). Results Abdominal MRIs were examined for 271 genotyped ADPKD patients. A pancreatic cyst lesion (PCL) was detected in 52 patients (19%; 95% confidence interval, 15%–23%). Thirty-seven (71%) had a solitary PCL; 15 (28%) had multiple. Pancreatic cyst lesion prevalence did not differ by genotype. Intraductal papillary mucinous neoplasia was detected in 1% of ADPKD cases. Among 12 IPMN patients (7 branch duct; 5 main duct or mixed type) monitored for about 140 months, 2 with main duct IPMNs required Whipple resection, and 1 patient died of complications from small-bowel obstruction after declining surgical intervention. Conclusions With MRI, PCLs were detected in 19% and IPMNs in 1% of 271 ADPKD patients with proven mutations, without difference across genotypes. Pancreatic cyst lesions were asymptomatic and remained stable in size.

We hypothesize that the prevalence of chronic kidney disease (CKD) among patients with cirrhosis has increased due to the increased prevalence of CKD‐associated comorbidities, such as diabetes. We aimed to assess the characteristics of hospitalized patients with cirrhosis with CKD and its impact on renal and patient outcomes. The North American Consortium for the Study of End‐Stage Liver Disease (NACSELD) prospectively enrolled nonelectively admitted patients with cirrhosis and collected data on demographics, laboratory results, in‐hospital clinical course, and postdischarge 3‐month outcomes. CKD positive (CKD+) patients, defined as having an estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease–4 variable formula) of ≤60 mL/minute for >3 months, were compared with chronic kidney disease negative (CKD–) patients for development of organ failures, hospital course, and survival. There were 1099 CKD+ patients (46.8% of 2346 enrolled patients) who had significantly higher serum creatinine (2.21 ± 1.33 versus 0.83 ± 0.21 mg/dL in the CKD– group) on admission, higher prevalence of nonalcoholic steatohepatitis cirrhosis etiology, diabetes, refractory ascites, and hospital admissions in the previous 6 months compared with the CKD– group (all P < 0.001). Propensity matching (n = 922 in each group) by Child‐Pugh scores (9.78 ± 2.05 versus 9.74 ± 2.04, P = 0.70) showed that CKD+ patients had significantly higher rates of superimposed acute kidney injury (AKI; 68% versus 21%; P < 0.001) and eventual need for dialysis (11% versus 2%; P < 0.001) than CKD– patients. CKD+ patients also had more cases of acute‐on‐chronic liver failure as defined by the NACSELD group, which was associated with reduced 30‐ and 90‐day overall survival ( P < 0.001 for both). A 10 mL/minute drop in eGFR was associated with a 13.1% increase in the risk of 30‐day mortality. In conclusion, patients with CKD should be treated as a high‐risk group among hospitalized patients with cirrhosis due to their poor survival, and they should be monitored carefully for the development of superimposed AKI.

Acute‐on‐chronic liver failure (ACLF) is characterized by multiple organ failure (OF) with high short‐term mortality. There is lack of population‐based data on trends on etiology specific ACLF related burden. National Inpatient Sample (2006‐2014) was queried using ICD‐09 codes for admissions with cirrhosis and ACLF (≥2 extrahepatic OF). Of 1,928,764 admissions for cirrhosis between 2006 and 2014, 112,174 (5.9%) had ACLF (4.5%, 1.2%, and 0.2% with ACLF 1, 2, and 3, respectively). The brain was the most common OF in 11.9%, followed by respiratory failure in 7.7%, cardiac failure in 6.3%, and renal failure in 5.6%. ACLF increased by 24% between 2006 and 2014 with a 63% increase in 179,104 patients with nonalcoholic steatohepatitis (NASH) cirrhosis (3.5% to 5.7%); a 28% increase in patients with 429,306 alcoholic cirrhosis (5.6% to 7.2%); a 25% increase in patients with 1,091,053 with other etiologies (5.2% to 6.5%); and no significant change in 229,301 patients with viral hepatitis (VH) (4.0% to 4.1%). In‐hospital mortality was higher among ACLF patients compared with patients without ACLF (44% versus 4.7%; P < 0.0001). Each NASH‐related ACLF patient compared with other etiologies had a longer mean length of stay (14 versus 12 days), was associated with higher median total charges (US $151,196 versus US $134,597), and had more frequent use of dialysis (45% versus 36%) and longterm care (32% versus 26%; P < 0.0001 for all). Results remained similar in a subgroup analysis after including half of admissions with cryptogenic cirrhosis as NASH. In conclusion, NASH cirrhosis is the most rapidly growing indication for ACLF‐related hospitalization and use of hospital resources. In the setting of improved treatment options for chronic hepatitis, the health care burden of chronic viral‐related liver disease remains stable. Population‐based strategies are needed to reduce the health care burden of cirrhosis, particularly related to NASH.

Acute‐on‐chronic liver failure (ACLF) characterized with ≥2 extrahepatic organ failures in cirrhosis carries a high mortality. Outcomes of patients listed for liver transplantation (LT) after ACLF and after LT are largely unknown. The North American Consortium for the Study of End‐Stage Liver Disease prospectively enrolled 2793 nonelectively hospitalized patients with cirrhosis; 768 were listed for LT. Within 3 months, 265 (35%) received a LT, 395 remained alive without LT, and 108 died/delisted. Compared with nonlisted patients, those listed were younger and more often had ACLF, acute kidney injury, and a higher admission Model for End‐Stage Liver Disease (MELD) score. ACLF was most common in patients who died/delisted, followed by those alive with and without LT respectively, (30%, 22%, and 7%, respectively; P < 0.001). At LT, median MELD was 27.9% and 70% were inpatients; median time from hospitalization to LT was 26 days. Post‐LT survival at 6 months was unchanged between those with and without ACLF (93% each at 6 months). There was no difference in 3‐ and 6‐month mean post‐LT creatinine in those with and without ACLF, despite those with ACLF having a higher mean pre‐LT creatinine and a higher rate of perioperative dialysis (61%). In conclusion, patients with and without ACLF had similar survival after transplant with excellent renal recovery in both groups.