Stevan A. Gonzalez M.D.

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.

Asrani, S. K., J. Trotter, J. Lake, A. Ahmed, A. Bonagura, A. Cameron, A. DiMartini, S. Gonzalez, G. Im, P. Martin, P. Mathurin, J. Mellinger, J. P. Rice, V. H. Shah, N. Terrault, A. Wall, S. Winder and G. Klintmalm (2020). “Meeting Report: The Dallas Consensus Conference on Liver Transplantation for Alcohol Associated Hepatitis.” Liver Transpl 26(1): 127-140.

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Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short-term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol-use disorders should be incorporated into pre- and post-LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.

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.

Asrani, S. K., G. Saracino, J. G. O’Leary, S. Gonzales, P. T. Kim, G. J. McKenna, G. Klintmalm and J. Trotter (2018). “Recipient characteristics and morbidity and mortality after liver transplantation.” J Hepatol 69(1): 43-50.

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BACKGROUND AND AIMS: Over the last decade, liver transplantation of sicker, older non-hepatitis C cirrhotics with multiple co-morbidities has increased in the United States. We sought to identify an easily applicable set of recipient factors among HCV negative adult transplant recipients associated with significant morbidity and mortality within five years after liver transplantation. METHODS: We collected national (n=31,829, 2002-2015) and center-specific data. Coefficients of relevant recipient factors were converted to weighted points and scaled from 0-5. Recipient factors associated with graft failure included: ventilator support (five patients; hazard ratio [HR] 1.59; 95% CI 1.48-1.72); recipient age >60years (three patients; HR 1.29; 95% CI 1.23-1.36); hemodialysis (three patients; HR 1.26; 95% CI 1.16-1.37); diabetes (two patients; HR 1.20; 95% CI 1.14-1.27); or serum creatinine >/=1.5mg/dl without hemodialysis (two patients; HR 1.15; 95% CI 1.09-1.22). RESULTS: Graft survival within five years based on points (any combination) was 77.2% (0-4), 69.1% (5-8) and 57.9% (>8). In recipients with >8points, graft survival was 42% (model for end-stage liver disease [MELD] score <25) and 50% (MELD score 25-35) in recipients receiving grafts from donors with a donor risk index >1.7. In center-specific data within the first year, subjects with >/=5points (vs. 0-4) had longer hospitalization (11 vs. 8days, p<0.01), higher admissions for rehabilitation (12.3% vs. 2.7%, p<0.01), and higher incidence of cardiac disease (14.2% vs. 5.3%, p<0.01) and stage 3 chronic kidney disease (78.6% vs. 39.5%, p=0.03) within five years. CONCLUSION: The impact of co-morbidities in an MELD-based organ allocation system need to be reassessed. The proposed clinical tool may be helpful for center-specific assessment of risk of graft failure in non-HCV patients and for discussion regarding relevant morbidity in selected subsets. LAY SUMMARY: Over the last decade, liver transplantation of sicker, older patient with multiple co-morbidities has increased. In this study, we show that a set of recipient factors (recipient age >60years, ventilator status, diabetes, hemodialysis and creatinine >1.5mg/dl) can help identify patients that may not do well after transplant. Transplanting sicker organs in patients with certain combinations of these characteristics leads to lower survival.

Gonzalez, S. A. and J. F. Trotter (2018). “The rise of the opioid epidemic and hepatitis C-positive organs: A new era in liver transplantation.” Hepatology 67(4): 1600-1608.

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The use of hepatitis C virus (HCV)-positive organs in liver transplantation (LT) has increased in the era of direct-acting antiviral therapy. A rising demand for organs, the increased ability to effectively treat HCV infection in the transplant setting, and an unprecedented increase in HCV-positive donors have all contributed to this trend. A recent abrupt rise in opioid use in the United States has resulted in a surge of injection drug use, transmission of HCV, and opioid-related overdose deaths. Geographical areas most affected by the opioid epidemic have experienced a rapid increase in recovery and utilization of HCV-positive donor organs, in which the proportion of deceased donor LTs in the United States from donors who are HCV positive has increased nearly 2-fold within the last 3 years. The prospect of expanding the organ donor pool with HCV-positive donors and achieving acceptable posttransplant outcomes has generated much interest in the areas of liver, kidney, and thoracic transplantation, including the potential for transplanting organs from HCV positive donors into HCV-negative recipients. Developing strategies to ensure appropriate selection of potential recipients of HCV-positive organs, initiating timely antiviral therapy, and defining associated risks will be critical in achieving optimal posttransplant outcomes in this setting.