Linda Jennings Ph.D.

O’Leary, J.G., Philippe, A., Freeman, R., Heidecke, H., Jennings, L.W., Catar, R., Klintmalm, G.B. and Dragun, D. (2021). “Non-HLA Autoantibodies at 1 Year Negatively Affect 5-Year Native Renal Function in Liver Transplant Recipients.” Transplant Proc Feb 9;S0041-1345(21)00017-8. [Epub ahead of print].

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BACKGROUND: Angiotensin II type-1 receptor (AT(1)R) and endothelin-1 type A receptor (ET(A)R) autoantibodies, in addition to allograft injury, can bind native endothelial cells and cause vascular vasoconstriction and fibrosis progression in nontransplanted organs. Therefore, we investigated long-term native renal function in liver transplant (LT) recipients with and without anti-AT(1)R-Abs and/or anti-ET(A)R-Abs present in serum. METHODS: Primary LT recipients at our single center from January 2000 to April 2009 had their prospectively collected pre-LT (1269 patients) and year 1 post-LT (795 patients) serum tested retrospectively for anti-AT(1)R-Abs and/or anti-ET(A)R-Abs. Anti-AT(1)R-Abs and anti-ET(A)R-Abs testing was accomplished with a standardized solid phase assay in which >10 U was considered positive. RESULTS: Pretransplant anti-AT(1)R-Abs and/or anti-ET(A)R-Abs did not change the median delta creatinine from pretransplant to 1 year post-transplant. In multivariable analysis controlling for diabetes (DM) and calcineurin inhibitor (CNI) use, anti-AT(1)R-Abs and/or anti-ET(A)R-Abs at 1-year remained statistically significantly associated with a decline in GFR (measured by Modification of Diet in Renal Disease-6) from years 1-5 post-LT (P = .04). In diabetic patients the association with a decline in renal function was more pronounced with (-9.29 mL/min) vs without (-2.28 mL/min) anti-AT(1)R-Abs and/or anti-ET(A)R-Abs at year 1, respectively (P = .004). CONCLUSION: At 1-year post-LT, the autoantibodies anti-AT(1)R-Abs and/or anti-ET(A)R-Abs are associated in multivariable analysis with an increased risk of native renal function decline especially in diabetic patients.

Asrani, S. K., L. W. Jennings, W. R. Kim, P. S. Kamath, J. Levitsky, M. K. Nadim, G. Testa, M. D. Leise, J. F. Trotter and G. Klintmalm (2020). “MELD-GRAIL-Na: Glomerular Filtration Rate and Mortality on Liver-Transplant Waiting List.” Hepatology 71(5): 1766-1774.

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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.

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.

Levitsky, J., S. K. Asrani, M. Abecassis, R. Ruiz, L. W. Jennings and G. Klintmalm (2019). “External Validation of a Pre-Transplant Biomarker Model (REVERSE) Predictive of Renal Recovery after Liver Transplantation.” Hepatology Apr 19. [Epub ahead of print].

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In patients with end stage liver disease, the ability to predict recovery of renal function following liver transplantation alone (LTA) remains elusive. However, several important clinical decisions depend on whether renal dysfunction is recoverable after LTA. We used a cohort of patients undergoing LT to independently validate a pre-LT model predictive of post-LTA renal recovery (REVERSE: high osteopontin (OPN) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels, age <57, no diabetes). Serum samples pre-LT and 4-12 weeks post-LTA (n=117) were analyzed for kidney injury proteins from 3 groups of recipients: (1) estimated GFR (eGFR)<30ml/min/1.73m(2) prior to LTA and <30 ml/min/1.73m(2) after LTA (irreversible acute kidney injury = iAKI), (2) eGFR<30ml/min/1.73m(2) prior to LTA and >50 ml/min/1.73m(2) after LTA (reversible AKI = rAKI) (3) eGFR>50 ml/min/1.73m(2) prior to LTA and >50 ml/min/1.73m(2) after LTA (no AKI = nAKI). In patients with elevated pre-LTA serum levels of OPN and TIMP-1, recovery of renal function correlated with decreases in the level of both proteins. At four weeks post-LT (n=77 subset), the largest decline in OPN and TIMP-1 was seen in the rAKI group. Validation of the REVERSE model in this independent dataset had high area under the curve (AUC) (0.78) in predicting full post-LT renal recovery (sensitivity 0.86, specificity 0.6, PPV 0.81, NPV 0.69). Our eGFR findings were confirmed using measured GFR (mGFR). CONCLUSION: The REVERSE model, derived from an initial training set combining novel plasma biomarkers and clinical characteristics, demonstrated excellent external validation performance characteristics in an independent patient cohort using serum samples. Among patients with kidney injury pre-LTA, the predictive ability of this simple tool may prove beneficial in clinical decision-making both prior to and following transplantation.

Asrani, S. K., L. W. Jennings, J. F. Trotter, J. Levitsky, M. K. Nadim, W. R. Kim, S. A. Gonzalez, B. Fischbach, R. Bahirwani, M. Emmett and G. Klintmalm (2019). “A Model for Glomerular Filtration Rate Assessment in Liver Disease (GRAIL) in the Presence of Renal Dysfunction.” Hepatology 69(3): 1219-1230.

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Estimation of glomerular filtration rate (eGFR) in patients with liver disease is suboptimal in the presence of renal dysfunction. We developed a model for GFR assessment in liver disease (GRAIL) before and after liver transplantation (LT). GRAIL was derived using objective variables (creatinine, blood urea nitrogen, age, gender, race, and albumin) to estimate GFR based on timing of measurement relative to LT and degree of renal dysfunction (www.bswh.md/grail). The measured GFR (mGFR) by iothalamate clearance (n = 12,122, 1985-2015) at protocol time points before/after LT was used as reference. GRAIL was compared with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD-4, MDRD-6) equations for mGFR < 30 mL/min/1.73 m(2) . Prediction of development of chronic kidney disease (mGFR < 20 mL/min/1.73 m(2) , initiation of chronic dialysis) and listing or receipt of kidney transplantation within 5 years was examined in internal cohort (n = 785) and external validation (n = 68,217, 2001-2015). GRAIL had less bias and was more accurate and precise as compared with CKD-EPI, MDRD-4, and MDRD-6 at time points before/after LT for low GFR. For mGFR < 30 mL/min/1.73 m(2) , the median difference (eGFR-mGFR) was GRAIL: 5.24 (9.65) mL/min/1.73 m(2) as compared with CKD-EPI: 8.70 (18.24) mL/min/1.73 m(2) , MDRD-4: 8.82 (17.38) mL/min/1.73 m(2) , and MDRD-6: 6.53 (14.42) mL/min/1.73 m(2) . Before LT, GRAIL correctly classified 75% as having mGFR < 30 mL/min/1.73 m(2) versus 36.1% (CKD-EPI), 36.1% (MDRD-4), and 52.8% (MDRD-6) (P < 0.01). An eGFR < 30 mL/min/1.73 m(2) by GRAIL predicted development of CKD (26.9% versus 4.6% CKD-EPI, 5.9% MDRD-4, and 10.5% MDRD-6) in center data and needing kidney after LT (48.3% versus 22.0% CKD-EPI versus 23.1% MDRD-4 versus 48.3% MDRD-6, P < 0.01) in national data within 5 years after LT. Conclusion: GRAIL may serve as an alternative model to estimate GFR among patients with liver disease before and after LT at low GFR.