Beta Cell Death by Cell-Free DNA and Outcome after Clinical Islet Transplantation

AbstractBackgroundOptimizing engraftment and early survival after clinical islet transplantation is critical to long-term function, but there are no reliable, quantifiable measures to assess beta cell death. Circulating cell free DNA (cfDNA) derived from beta cells has been identified as a novel biomarker to detect cell loss, and was recently validated in new-onset type 1 diabetes and in islet transplant patients.MethodsHerein we report beta cell cfDNA measurements after allotransplantation in 37 subjects and the correlation with clinical outcomes.ResultsA distinctive peak of cfDNA was observed 1hr after transplantation in 31/37 (83.8%) of subjects. The presence and magnitude of this signal did not correlate with transplant outcome. The 1hr signal represents dead beta cells carried over into the recipient after islet isolation and culture, combined with acute cell death post infusion. Beta cell cfDNA was also detected 24hrs posttransplant (8/37 subjects, 21.6%). This signal was associated with higher 1-month insulin requirements (p=0.04), lower 1-month stimulated C-peptide levels (p=0.01) and overall worse 3-month engraftment, by insulin independence (ROC:AUC=0.70, p=0.03) and Beta 2 score (ROC:AUC=0.77, p=0.006).ConclusionscfDNA-based estimation of beta cell death 24hrs after islet allotransplantation correlates with clinical outcome and could predict early engraftment. Background Optimizing engraftment and early survival after clinical islet transplantation is critical to long-term function, but there are no reliable, quantifiable measures to assess beta cell death. Circulating cell free DNA (cfDNA) derived from beta cells has been identified as a novel biomarker to detect cell loss, and was recently validated in new-onset type 1 diabetes and in islet transplant patients. Methods Herein we report beta cell cfDNA measurements after allotransplantation in 37 subjects and the correlation with clinical outcomes. Results A distinctive peak of cfDNA was observed 1hr after transplantation in 31/37 (83.8%) of subjects. The presence and magnitude of this signal did not correlate with transplant outcome. The 1hr signal represents dead beta cells carried over into the recipient after islet isolation and culture, combined with acute cell death post infusion. Beta cell cfDNA was also detected 24hrs posttransplant (8/37 subjects, 21.6%). This signal was associated with higher 1-month insulin requirements (p=0.04), lower 1-month stimulated C-peptide levels (p=0.01) and overall worse 3-month engraftment, by insulin independence (ROC:AUC=0.70, p=0.03) and Beta 2 score (ROC:AUC=0.77, p=0.006). Conclusions cfDNA-based estimation of beta cell death 24hrs after islet allotransplantation correlates with clinical outcome and could predict early engraftment. aThese authors contributed equally to this study. bJoint senior authors. Corresponding author contact information: A.M. James Shapiro, MD, PhD, Canada Research Chair in Transplantation Surgery and Regenerative Medicine, Professor, Director of Clinical Islet and Living Donor Liver Transplant Programs, Clinical Islet Transplant Program, University of Alberta. 2000 College Plaza, 8215-112th St, Edmonton T6G 2C8, Canada. amjs@islet.ca, Telephone: +1-780-4077330, Fax: +1-780-4078259 Authorship: B.L.G-L., B.G., R.S., Y.D. and A.M.J.S. designed research studies; B.L.G-L, T.K., P.S., D.O., A.J.M. and A.M.J.S. performed transplant procedures; D.N. and S.P processed plasma and analyzed cfDNA; B.L.G-L., T.K, A.R.P., P.C., B.G., R.S., Y.D. and A.M.J.S. acquired and analyzed data; and B.L.G-L., B.G., R.S., Y.D. and A.M.J.S. wrote the paper. Disclosure: The authors declare no conflicts of interest. Funding: B.G-L. is supported through the Alberta Innovates: Health Solutions (AIHS) Clinician Fellowship and through the CNTRP. A.P. is supported through AIHS Postgraduate Fellowship and CNTRP. A.M.J.S. is supported through AIHS, and holds a Canada Research Chair in Transplantation Surgery and Regenerative Medicine funded through the Government of Canada. AMJS is also funded by AIHS Collaborative Research and Innovation Opportunity Team Award and the Diabetes Research Institute Foundation of Canada (DRIFCan). Supported by grants from the Juvenile Diabetes Research Foundation (JDRF) (3-SRA-2014-38-Q-R, to Y.D and A.M.J.S), National Institute of Health (NIH) (HIRN grant UC4 DK104216, to Y.D), DON foundation (Stichting Diabetes Onderzoek Nederland) (to Y.D), the European Union (ELASTISLET project, to Y.D.) and the Kahn foundation (to Y.D, R.S and B.G). Supported in part by a grant from The United States Agency for International Development (USAID) American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University sequencing core facility. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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