Sumeet K. Asrani M.D.

Levitsky, J., S. K. Asrani, G. Klintmalm, T. Schiano, A. Moss, K. Chavin, C. Miller, K. Guo, L. Zhao, L. W. Jennings, M. Brown, B. Armstrong and M. Abecassis (2019). “Discovery and Validation of a Biomarker Model (Preserve) Predictive of Renal Outcomes after Liver Transplantation.” Hepatology Sep 11. [Epub ahead of print].

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A high proportion of patients develop chronic kidney disease after liver transplantation. We aimed to develop clinical/protein models to predict future GFR deterioration in this population. In independent multicenter discovery (CTOT14) and single center validation (BUMC) cohorts, we analyzed kidney injury proteins in serum/plasma samples at month 3 after liver transplant in recipients with preserved GFR who demonstrated subsequent GFR deterioration vs. preservation by year 1, and year 5 in the BUMC cohort. In CTOT14, we also examined correlations between serial protein levels and GFR over the first year. A month 3 predictive model was constructed from clinical and protein level variables using the CTOT14 cohort (n=60). Levels of beta2-microglobulin and CD40 antigen and presence of HCV infection predicted early (year 1) GFR deterioration (AUC 0.814). We observed excellent validation of this model (AUC 0.801) in the BUMC cohort (n=50) who had both early and late (year 5) GFR deterioration. At an optimal threshold, the model had the following performance characteristics in CTOT14 and BUMC, respectively: accuracy (0.75, 0.8), sensitivity (0.71, 0.67), specificity (0.78, 0.88), positive predictive value (0.74, 0.75) and negative predictive value (0.76, 0.82). In the serial CTOT14 analysis, several proteins, including beta2-microglobulin and CD40, correlated with GFR changes over the first year. Conclusion: We have validated a clinical/protein model (PRESERVE) that early after liver transplantation can predict future renal deterioration vs. preservation with high accuracy. This model may help select recipients at higher risk for subsequent chronic kidney disease for early, proactive renal sparing strategies.

Asrani, S. K., L. W. Jennings, W. R. Kim, P. Kamath, J. Levitsky, M. K. Nadim, G. Testa, M. Leise, J. F. Trotter and G. Klintmalm (2019). “Meld-Grail-Na: Glomerular Filtration Rate and Mortality on Liver-Transplant Waiting List.” Hepatology Sep 16. [Epub ahead of print].

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BACKGROUND & AIMS: Among patients with cirrhosis awaiting liver transplantation, prediction of waitlist (WL) mortality is adjudicated by 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. METHODS: 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 GfR Assessment In Liver disease (GRAIL) developed amongst patients with cirrhosis (Asrani SK Hepatology.2018; www.bswh.md/grail). Multivariate Cox proportional hazards analysis models were utilized to compare predicted 90-day WL mortality between MELD-GRAIL-Na (re-estimated bilirubin, INR, sodium and GRAIL) vs. MELD-Na. RESULTS: 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 (HR 0.382, 95% 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 score >/=32 (observed mortality 0.68), predicted mortality was 0.67 (MELD-GRAIL-Na) and 0.51 (MELD-Na). For women score >/=32 (observed mortality 0.67), predicted mortality was 0.69 (MELD-GRAIL-Na) and 0.55 (MELD-Na). In 2015, use of MELD-GRAIL-Na as compared to 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 impact outcomes for 12-17% awaiting transplant and affect organ allocation.

Agbim, U. and S. K. Asrani (2019). “The Path Chosen Matters for Patients with Cirrhosis and the Acute Kidney Injury to Chronic Kidney Disease Continuum.” Clin Gastroenterol Hepatol 17(11): 2182-2184.

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Renal dysfunction is the penultimate expression of end-stage liver disease; cirrhotic patients with renal failure have a 7-fold increase in mortality compared with patients without renal failure. Surrogates of renal dysfunction, serum sodium and serum creatinine, albeit imperfect, are featured prominently in prognostic models (model for end-stage liver disease [MELD] and MELD-sodium [MELD-Na]) and decisions regarding organ allocation. However, the risk attributed to renal dysfunction is currently not differentiated as being due to acute kidney injury (AKI), chronic kidney disease (CKD), or even related to decompensated liver disease. Increasingly, cirrhotic patients awaiting liver transplantation in the current era have or are at risk for CKD: they are sicker, older, and have more comorbidities such as obesity and diabetes. In addition, cirrhotic patients with nonalcoholic fatty liver disease, a patient population enriched with these comorbidities, continues to increase. Furthermore, little is known about the interplay between AKI and CKD in cirrhotic patients; it increasingly is recognized that the 2 entities should not be considered in isolation and are more interconnected on the spectrum of renal impairment. Among patients listed for liver transplantation, Cullaro et al. examined the impact of AKI, CKD, and AKI on CKD on waitlist mortality. By using data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network database from 2007 to 2014, they identified adult registrants (excluding those with exception points) listed for more than 3 months and categorized them into 4 groups according to renal function: AKI (defined as ≥0.3 mg/dL or ≥50% from previous value or <72 days of renal replacement therapy), CKD (defined as estimated glomerular filtration rate [GFR] <60 mL/min/1.73 m 2 for ≥90 days and a current estimated GFR of ≤30 mL/min/1.73 m 2 or ≥72 days of renal replacement therapy), AKI on CKD (meeting both AKI and CKD), or normal (meeting neither of the aforementioned definitions). Of 22,680 included waitlist registrants, 13% had episodes of AKI and 31% had CKD; approximately 29% died or were removed from the waitlist for being too sick. Cirrhotic patients with CKD had an increased cumulative incidence of death (subdistribution hazard risk, 1.56) while on the waitlist compared with registrants with normal renal function. However, the cumulative incidence of death on the waitlist was much more pronounced for any form of AKI, with those with AKI on CKD having the highest cumulative incidence of waitlist mortality (subdistribution hazard risk, 2.86) compared with those with normal renal function. The impact of renal dysfunction, especially AKI on CKD, increased for higher levels of MELD-Na. In a model predicting 6-month waitlist mortality, adding the pattern of renal injury to MELD-Na increased the area under the receiver operating curve from 0.71 to 0.80. The study notably raised several important issues. (Excerpt from text, p. 2182; no abstract available.)

Gupta, A. and S. K. Asrani (2019). “Role of Living Donor Liver Transplantation in Acute Liver Failure.” Liver Transpl 25(9): 1308-1309.

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The etiology of acute liver failure (ALF) varies widely, with drug toxicity being the leading cause in Western countries, whereas viral hepatitis predominates in Asia.1, 2 The varying etiologies may lead to a different phenotype and clinical course of ALF by location. Without liver transplantation (LT), ALF is frequently fatal due to cerebral edema and multisystem organ failure. In the West, where LT with deceased donors is well established, most eligible ALF patients receive whole liver allografts, often with the highest priority on the waiting list. As a result, living donor liver transplantation (LDLT) is rarely undertaken for ALF patients. In contrast, many countries around the world do not have access to adequate deceased donors and, thus, rely on LDLT for almost all patients, including those with ALF. Pamecha et al. describe a large center in India evaluating outcomes of patients (adult and pediatric) that underwent LDLT for ALF as compared with others that underwent elective LDLT.3 Approximately 15% of their LDLT recipients between 2011 and 2018 underwent transplantation for ALF. All patients transplanted for ALF met King’s College criteria. At the time of transplant, median Model for End‐Stage Liver Disease score was 37; 66% of patients had grade 3 or 4 encephalopathy; and a majority of them were intubated. A total of 51% met the systemic inflammatory response syndrome (SIRS) criteria. A positive culture was detected in almost half of the patients. Though computed tomography scans were not uniformly done during the initial years, among those with imaging, 51% had moderate or severe cerebral edema. Continuous renal replacement therapy was used in a minority of patients (1.6%). The 5‐year actuarial survival was 65.6%, which is lower than the 80% survival seen with elective LDLT but substantially higher than the 22% survival of patients meeting King’s College criteria who did not undergo transplantation. Most of the deaths (76%) were within the first 30 days. Sepsis and cerebral edema were the most common causes of early mortality. On adjusted analysis, cerebral edema, SIRS, and sepsis were drivers of mortality. Median time to donor evaluation was 18 hours. The donor operation was safe, and donor morbidity was 13%. No donor mortality was reported. Overall, the authors demonstrate that LDLT is feasible and safe for ALF in a highly selected group of patients with an experienced team. (Excerpt from text of authors’ commentary on the article, Pamecha V, Vagadiya A, Sinha PK, Sandhyav R, Parthasarathy K, Sasturkar S, et al. Living donor liver transplantation for acute liver failure: donor safety and recipient outcome. Liver Transpl 2019; 25: 1408– 1421.)

Gupta, A. and S. K. Asrani (2019). “Role of living donor liver transplantation in acute liver failure.” Liver Transpl Jul 25. [Epub ahead of print].

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The etiology of acute liver failure (ALF) varies widely, with drug toxicity being the leading cause in Western countries while viral hepatitis predominates in Asia.(1, 2)Th varying etiology may lead to a different phenotype and clinical course of ALF by location. Without liver transplantation (LT), ALF is frequently fatal with due to cerebral edema and multi-system organ failure. In the West, where LT with deceased donors is well established, most eligible ALF patients receive whole liver allografts, often with the highest priority on the waitlist. As a result, live donor liver transplant (LDLT) is rarely undertaken for ALF patients. In contrast, many countries in the Far East do not have access to adequate deceased donors, and thus rely on LDLT for almost all patients, including those with ALF. (Excerpt from text, p. 1308; no abstract available.)