Sumeet K. Asrani M.D.

Panchal, S., M. Serper, T. Bittermann, S. K. Asrani, D. S. Goldberg and N. Mahmud (2021). “The impact of race-adjusted GFR estimation on eligibility for simultaneous liver-kidney transplantation.” Liver Transpl. [Epub ahead of print].

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BACKGROUND: Estimated glomerular filtration rate (eGFR) is adjusted for Black race in commonly used formulas. This has potential implications for access to simultaneous liver-kidney transplant (SLKT), as qualifying criteria rely on eGFR. METHODS: We performed a retrospective study of United Network for Organ Sharing (UNOS) national transplant registry data between 2/28/2002 and 3/31/2019 to evaluate the proportion of Black patients who would be reclassified as meeting SLKT criteria (as defined per current policies) if race adjustment were removed from two prominent eGFR equations (MDRD-4 and CKD-EPI). RESULTS: Of the 7,937 Black patients listed for transplant during the study period, we found that 3.6% would have been reclassified as qualifying for chronic kidney disease (CKD)-related SLKT with removal of race adjustment for MDRD-4, and 3.0% for CKD-EPI; this represented 23.7% and 18.7% increases in SLKT candidacy, respectively. Reclassification impacted women more than men (e.g. 4.5% vs. 3.0% by MDRD-4, p<0.05). In an exploratory analysis, patients meeting SLKT criteria by race unadjusted eGFR equations were significantly more likely to receive liver transplantation alone (LTA) as compared to SLKT. Approximately 2% of reclassified patients required kidney transplantation within one year of LTA, versus 0.3% of non-reclassified patients. DISCUSSION: In conclusion, race adjustment in eGFR equations may impact SLKT candidacy for 3-4% of Black patients listed for LTA overall. Approximately 2% of patients reclassified as meeting SLKT criteria require short-term post-LTA kidney transplantation. These data argue for developing novel algorithms for GFR estimation free of race to promote equity.

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.

Lago-Hernandez, C., Nguyen, N.H., Khera, R., Loomba, R., Asrani, S.K. and Singh, S. (2021). “Cost-Related Nonadherence to Medications Among US Adults With Chronic Liver Diseases.” Mayo Clin Proc Jun 10;S0025-6196(21)00255-X. [Epub ahead of print].

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OBJECTIVE: To estimate the prevalence, risk factors, and consequences of cost-related medication nonadherence (CRN) in individuals with chronic liver diseases (CLDs) in the United States. PATIENTS AND METHODS: Using the National Health Interview Survey from January 1, 2014, to December 31, 2018, we identified individuals with CLDs. Using complex weighted survey analysis, we obtained national estimates and risk factors for CRN and its association with cost-reducing behaviors and measures of financial toxicity. We evaluated the association of CRN with unplanned health care use, adjusting for age, sex, race/ethnicity, insurance, income, education, and comorbid conditions. RESULTS: Of 3237 respondents (representing 4.6 million) US adults with CLDs, 813 (representing 1.2 million adults, or 25%; 95% CI, 23% to 27%) reported CRN, of whom 68% (n=554/813) reported maladaptive cost-reducing behaviors. Younger age, female sex, low income, and multimorbidity were associated with a higher prevalence of CRN. Compared with patients without CRN, patients experiencing CRN had 5.1 times higher odds of financial hardship from medical bills (adjusted odds ratio [aOR], 5.05; 95% CI, 3.73 to 6.83) and 2.9 times higher odds of food insecurity (aOR, 2.85; 95% CI, 2.02 to 4.01). The CRN was also associated with 1.5 times higher odds of emergency department visits (aOR, 1.46; 95% CI, 1.11 to 1.94). CONCLUSION: We observed a high prevalence of CRN and associated consequences such as high financial distress, financial hardship from medical bills, food insecurity, engagement in maladaptive cost-reducing strategies, increased health care use, and work absenteeism among patients with CLD. These financial determinants of health have important implications in the context of value-based care.

Singapura, P., Ma, T.W., Sarmast, N., Gonzalez, S., Durand, F., Maiwall, R., Nadim, M.K., Fullinwider, J., Saracino, G., Francoz, C., Sartin, R., Trotter, J. and Asrani, S.K. (2021). “Estimating glomerular filtration rate in cirrhosis using creatinine- and cystatin C- based equations: systematic review and meta-analysis.” Liver Transpl Jun 18. [Epub ahead of print].

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BACKGROUND AND AIMS: Accurate estimation of kidney function in cirrhosis is crucial for prognosis and decisions regarding dual organ transplantation. Several estimating glomerular filtration rate (GFR) equations are used, however, most overestimate kidney function. APPROACH AND RESULTS: We performed a systematic review/meta-analysis to assess the performance of creatinine and cystatin C-based GFR estimating (eGFR) equations as compared to measured GFR (mGFR) in patients with cirrhosis. Standardized mean difference (SMD) of each eGFR equation was compared to mGFR. Twenty-five studies (n= 4,565, 52.0years, 37.0% female) comprising 18 equations met the inclusion criteria. All GFR: Creatinine-based equations overestimated GFR (SMD 0.51, 95% CI0.31-0.71) and cystatin C-based equations underestimated GFR (SMD -0.3, 95% CI-0.6- -0.02). Equations based on both creatinine and cystatin C were the least biased (SMD -0.14, 95% CI -0.46-0.18). CKD-Epi-sCr-CysC was the least biased but had low precision and underestimated GFR by -3.6 ml/min/1.73m(2) (95% CI -17.4-10.3). GFR<60ml/min/1.73m(2) : All equations significantly overestimated GFR (+21.7 ml/min/1.73m(2) , 95% CI17.7-25.7); of these, CKD-Epi-CysC (10.3 ml/min/1.73m(2) , 95% CI2.1-18.4) and GFR Assessment in Liver disease (GRAIL) (12.6 ml/min/1.73m(2) , 95%CI 7.2-18.0) were the least biased followed by Royal Free Hospital (RFH) (15 ml/min/1.73m(2) , 95%CI 5.5-24.6) and MDRD-6 (15.7 ml/min/1.73m(2) , 95%CI 10.6-20.8).; however there was overlap in the precision of estimates and studies were limited. Ascites: Overestimation of GFR was common (+8.3 ml/min/1.73m(2) , 95%CI -3.1-19.7). CONCLUSION: CKD-Epi-sCr-CysC may be acceptable across the spectrum of GFR. However, overestimation of GFR by 10-20 ml/min/1.73m(2) is common in patients with cirrhosis with most equations, especially in conjunction with ascites and/or kidney dysfunction. There is wide overlap in confidence intervals/precision. A tailored approach is required based on clinical scenario, especially for decisions regarding dual organ transplantation.