Annette C. and Harold C. Simmons Transplant Institute

Shankar, N., A. Ramani, C. Griffin, U. Agbim, D. Kim, A. Ahmed and S. K. Asrani (2021). “Extrahepatic causes of death in cirrhosis compared to other chronic conditions in the United States, 1999-2017.” Ann Hepatol: 100565.

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INTRODUCTION AND OBJECTIVES: Cirrhosis- related mortality is underestimated and is increasing; extrahepatic factors may contribute. We examined trends in cirrhosis mortality from 1999-2017 in the United States attributed to liver-related (varices, peritonitis, hepatorenal syndrome, hepatic encephalopathy, hepatocellular carcinoma sepsis) or extrahepatic (cardiovascular disease, influenza and pneumonia, diabetes, malignancy) causes, and compared mortality trends with congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) populations. MATERIALS AND METHODS: A national mortality database was used. Changes in age-standardized mortality over time were determined by joinpoint analysis. Average annual percentage change (AAPC) was estimated. RESULTS: Cirrhosis cohort: From 1999-2017, both liver-related (AAPC 1.3%; 95% confidence interval [CI] 0.7-1.9) and extrahepatic mortality (AAPC 1.0%; 95% CI 0.7-1.2) increased. Cirrhosis vs other chronic disease cohorts: changes in all-cause mortality were higher in cirrhosis (AAPC 1.0%; 95% CI 0.7-1.4) than CHF (AAPC 0.1%; 95% CI -0.5- 0.8) or COPD (AAPC -0.4%; 95% CI -0.6- -0.2). Sepsis mortality was highest in cirrhosis (AAPC 3.6%, 95% 3.2- 4.1) compared to CHF (AAPC 0.6%, 95% CI -0.5- 1.7) or COPD (AAPC 0.8%, 95% CI 0.5- 1.2). Cardiovascular mortality increased in cirrhosis (AAPC 1.3%, 95% CI 1.1- 1.5), declined in CHF (AAPC -2.0%, 95% CI -5.3- 1.3) and remained unchanged in COPD (AAPC 0.1%, 95% CI -0.2- 0.4). Extrahepatic mortality was higher among women, rural populations, and individuals >65 years with cirrhosis. CONCLUSIONS: Extrahepatic causes of death are important drivers of mortality and differentially impact cirrhosis compared to other chronic diseases.

Griffin, C., U. Agbim, A. Ramani, N. Shankar, F. Kanwal and S. K. Asrani (2021). “Underestimation of cirrhosis related mortality in the Medicare eligible population, 1999-2018.” Clin Gastroenterol Hepatol Oct 30;S1542-3565(21)01149-6. [Epub ahead of print].

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The burden of cirrhosis may be increasing, especially among the elderly. A recent updated definition of cirrhosis has a >90% positive predictive value (PPV) for identifying cirrhosis and cirrhosis related complications. We hypothesized that cirrhosis-related mortality is underestimated, and that the elderly are disproportionally impacted. In this study, we aimed to 1) examine trends in liver related mortality using this updated definition among the elderly and 2) identify changes by relevant subsets of gender, race and rurality. [No abstract; excerpt from article].

Asrani, S. K., N. Shankar, B. da Graca, M. K. Nadim and A. Cardenas (2021). “Role of novel kidney biomarkers in patients with cirrhosis and after liver transplantation.” Liver Transpl Oct 29. [Epub ahead of print].

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Acute kidney injury (AKI) and chronic kidney disease (CKD) are important drivers of morbidity and mortality in patients with cirrhosis before and after liver transplantation (LT). In this review, we examine the role of novel kidney biomarkers for early recognition of kidney injury. Studies are limited by lack of reference standards, heterogeneous definitions of outcomes and biomarker cutoffs, and inconsistent diagnostic performance. Overall, a change in biomarker is more relevant than an absolute cutoff. CIRRHOSIS: Cystatin C and urinary neutrophil gelatinase-associated lipocalin (NGAL) are the most studied candidate biomarkers and identify AKI or progression of AKI earlier than serum creatinine (sCr). Kidney injury molecule 1 and liver-type fatty acid binding protein (L-FABP) also show potential. NGAL and IL-18 may play a role in differentiating acute tubular necrosis from other forms of AKI. Combining novel biomarkers with the Model for End-Stage Liver Disease (MELD) score may assist prognosis. Persistent elevations in select markers (e.g., NGAL) can portend irreversible injury. TRANSPLANT: Several pretransplant markers (including sCr) predict posttransplant kidney dysfunction. Pretransplant assessment of clinical factors (e.g., age, diabetes) and novel markers (osteopontin and TIMP1) may predict renal kidney recovery after LT. Intraoperative changes in biomarkers predict early post-LT AKI. Prediction of CKD remains difficult, although a combination of biomarkers (e.g., beta 2 microglobulin, CD40) are promising. Novel biomarkers have yet to replace sCr in guideline-based evaluation and management of kidney dysfunction in patients with cirrhosis. We propose a theoretical framework for practical incorporation of these biomarkers that considers patient characteristics (risk for irreversible injury), markers of functional and structural change, and assessment of the AKI-CKD continuum to identify patients at highest risk for progressive kidney disease before and after LT.

Kim, W. R., A. Mannalithara, J. K. Heimbach, P. S. Kamath, S. K. Asrani, S. W. Biggins, N. L. Wood, S. E. Gentry and A. J. Kwong (2021). “MELD 3.0: The Model for End-stage Liver Disease Updated for the Modern Era.” Gastroenterology Sep 2;S0016-5085(21)03469-7. [Epub ahead of print].

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BACKGROUND: The model for end-stage liver disease (MELD) has been established as a reliable indicator of short-term survival in patients with end-stage liver disease. The current version (MELDNa), consisting of INR and serum bilirubin, creatinine, and sodium, has been used to determine organ allocation priorities for liver transplantation in the United States (US). The objective was to optimize MELD further by taking into account additional variables and updating coefficients with contemporary data. METHODS: All candidates registered on the liver transplant waitlist in the US national registry from Jan 2016 – Dec 2018 were included. Uni- and multivariable Cox models were developed to predict survival up to 90 days after waitlist registration. Model fit was tested using the concordance statistic and reclassification, and the liver simulated allocation model (LSAM) was used to estimate the impact of replacing MELDNa with the new model. RESULTS: The final multivariable model was characterized by (1) additional variables of female sex and serum albumin, (2) interactions between bilirubin and sodium and between albumin and creatinine, and (3) an upper bound for creatinine at 3.0mg/dL. The final model (MELD 3.0, henceforth), had better discrimination than MELDNa (concordance statistic 0.869 versus 0.862, p<0.01). Importantly, MELD 3.0 correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplant, particularly in women. In the LSAM analysis, MELD 3.0 resulted in fewer waitlist deaths compared to MELDNa (7,788 versus 7,850, p=0.02). CONCLUSION: MELD 3.0 affords more accurate mortality prediction in general than MELDNa and addresses determinants of waitlist outcomes including the sex disparity.

Karnam, R. S., S. Chen, W. Xu, C. Chen, P. Elangainesan, A. Ghanekar, I. McGilvray, T. Reichman, B. Sayed, M. Selzner, G. Sapisochin, Z. Galvin, G. Hirschfield, S. K. Asrani, N. Selzner, M. Cattral, L. Lilly and M. Bhat (2021). “Sex Disparity in Liver Transplant and Access to Living Donation.” JAMA Surg Aug 18;e213586. [Epub ahead of print].

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IMPORTANCE: The Model for End-stage Liver Disease (MELD)-based organ allocation system has significantly decreased mortality on the transplant waiting list for patients with end-stage liver disease. However, women have remained at a disadvantage with respect to access to deceased donor liver transplant (DDLT) even after introduction of the MELD score for organ allocation. OBJECTIVE: To determine whether availability of living donation in a transplant program can offset inequity in liver transplant (LT) allocation for women. DESIGN, SETTING, AND PARTICIPANTS: This cohort study retrospectively analyzed adult patients listed for LT at the University Health Network in Toronto, Ontario, Canada. Patients included had a potential living donor (pLD) at the moment of listing. This study was performed from November 13, 2012, to May 31, 2019. A total of 1289 listed patients (830 men; 459 women) were analyzed during the study period. MAIN OUTCOMES AND MEASURES: This study performed survival analysis and competing-risk analysis to delineate how access to livers from living donors was associated with events in women vs men on the transplant waiting list (LT, death, or dropout). RESULTS: Of 1289 included patients, 459 (35.6%) were women, and the mean (SD) age was 56.1 (10.0) years at assessment and listing. A total of 783 of 1289 listed patients underwent LT. Among those with no pLD at assessment, there was a higher median (range) Model for End-stage Liver Disease incorporating sodium levels (MELD-Na) score at listing (22 [6-50] vs 19 [6-50]; P < .001) and at LT (27 [6-49] vs 20 [6-52]; P < .001) in women receiving DDLT. Women were at a significant disadvantage without a pLD (hazard ratio [HR], 1.29; 95% CI, 1.04-1.60; P = .01); there was no difference in access to LT with availability of a pLD (HR, 0.93; 95% CI, 0.76,-1.14; P = .44). The instantaneous rate of receiving a transplant in men with a pLD was 1.39 times higher than men who did not have a pLD (HR, 1.39; 95% CI; P < .001) and the instantaneous rate of receiving a transplant in women with a pLD was 1.92 times higher than in women who did not (HR, 1.92; 95% CI, 1.51-2.44; P < .001). The HR was 1.38 times higher in women compared with men across the MELD-Na score strata (HR, 1.38; 95% CI, 1.03-1.84; P = .03) and 2.04 times higher when the MELD-Na score was less than 20 (HR, 2.04; 95% CI, 1.31-3.14; P = .001). CONCLUSIONS AND RELEVANCE: These study findings suggest that women can overcome the complex problem of allocation inequity with access to livers from living donors. Women with access only to DDLT were much more unwell than men independent of liver disease at the time of listing, dropout, or LT. Therefore, the wider availability of living donation liver transplant would be helpful in addressing the sex disparity in access to LT in the current MELD-Na era.