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Beta Cell Death by Cell-free DNA and Outcome After Clinical Islet Transplantation

Gala-Lopez, Boris, L., MD, MSc, PhD1,5; Neiman, Daniel2; Kin, Tatsuya, MD, PhD1; O’Gorman, Doug1; Pepper, Andrew, R., PhD1; Malcolm, Andrew, J., PhD2; Pianzin, Sheina2; Senior, Peter, A., MD, PhD3; Campbell, Patricia, MD3; Glaser, Benjamin, MD4; Dor, Yuval, PhD2; Shemer, Ruth, PhD2; Shapiro, A.M., James, MD, PhD1,3,5

doi: 10.1097/TP.0000000000002083
Original Clinical Science—General

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 1 hour after transplantation in 31 (83.8%) of 37 subjects. The presence and magnitude of this signal did not correlate with transplant outcome. The 1-hour 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 24 hours 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 (receiver operating characteristic-area under the curve = 0.70, P = 0.03) and beta 2 score (receiver operating characteristic-area under the curve = 0.77, P = 0.006).

Conclusions cfDNA-based estimation of beta cell death 24 hours after islet allotransplantation correlates with clinical outcome and could predict early engraftment.

Death and injury can lead to release of cell-free DNA in transplantation. The level of cell-free DNA released at 1 hour after islet transplantation reflects beta cell death from the processing, culture, and implantation of islets and does not correlate with outcomes, but the level at 24 hours after transplantation does.

1 Department of Surgery and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada.

2Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

3 Department of Medicine and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada.

4 Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

5 Canadian National Transplant Research Program (CNTRP).

Received 5 August 2017. Revision received 13 November 2017.

Accepted 27 November 2017.

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. A.M.J.S. 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.

The authors declare no conflicts of interest.

B.L.G.-L., and D.N. contributed equally to this study.

B.G., Y.D., R.S., A.M.J.S. are joint senior authors.

B.L.G-L., B.G., R.S., Y.D. and A.M.J.S. designed the research studies; B.L.G-L, T.K., P.S., D.O., A.J.M. and A.M.J.S. performed the 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 article.

Correspondence: A.M. James Shapiro, MD, PhD, Clinical Islet and Living Donor Liver Transplant Programs, University of Alberta, 2000, College Plaza, 8215-112th St, Edmonton, AB, Canada T6G 2C8. (amjs@islet.ca).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

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