Analysis of biomarkers within the initial 2 years posttransplant and 5-year kidney transplant outcomes: results from Clinical Trials in Organ Transplantation-17

ABSTRACT Background An early posttransplant biomarker/surrogate marker for kidney allograft loss has the potential to guide targeted interventions. Previously published findings, including results from the Clinical Trials in Organ Transplantation (CTOT)-01 study, showed that elevated urinary chemokine CXCL9 levels and elevated frequencies of donor-reactive interferon gamma-(IFNγ)-producing T cells by enzyme linked immunosorbent spot (ELISPOT) assay associated with acute cellular rejection within the first year and with lower 1-year posttransplant estimated glomerular filtration rate (eGFR). How well these biomarkers correlate with late outcomes, including graft loss, is unclear. Methods In CTOT-17, we obtained 5-year outcomes in the CTOT-01 cohort and correlated them with a) biomarker results and b) changes in eGFR (Chronic Kidney Disease Epidemiology Collaboration formula) over the initial 2 years posttransplant using univariable analysis and multivariable logistic regression. Results Graft loss occurred in 14/184 subjects (7.6%) 2 to 5 years posttransplant. Neither IFNγ ELISPOTs nor urinary CXCL9 were informative. In contrast, a ≥40% decline in eGFR from 6 months to 2 years posttransplant independently correlated with thirteen-fold odds of 5-year graft loss [adjusted odds ratio (aOR) 13.1; 95% CI 3.0-56.6], a result that was validated in the independent Genomics of Chronic Allograft Rejection cohort (n=165, aOR: 11.2). Conclusions We conclude that while pre and early posttransplant ELISPOT and chemokine measurements associate with outcomes within 2-years posttransplant, changes in eGFR between 3 months or 6 months and 24 months are better surrogates for 5-year outcomes, including graft loss. Corresponding author: Peter S Heeger, MD, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, USA, Email: peter.heeger@mssm.edu, Phone: 212 241 6324, Fax: 212 987 0389 Authorship Geovani Faddoul, M.D. Participated in data analysis and writing/editing of the manuscript Girish N Nadkarni, M.D. Participated in data analysis and writing/editing of the manuscript Nancy D. Bridges, M.D. Participated in study design and writing/editing of the manuscript Jens Goebel, M.D. Participated in writing/editing of the manuscript Donald E. Hricik, M.D. Participated in study design, data analysis and writing/editing of the manuscript Richard Formica, M.D. Participated in study design and writing/editing of the manuscript Madhav C Menon, M.D. Participated in study design, data analysis and writing/editing of the manuscript Yvonne Morrison, Participated in study design and writing/editing of the manuscript Barbara Murphy, M.D. Participated in study design and writing/editing of the manuscript Kenneth Newell, M.D. Participated in study design and writing/editing of the manuscript Peter Nickerson, M.D. Participated in study design and writing/editing of the manuscript Emilio D. Poggio, M.D. Participated in study design and writing/editing of the manuscript David Rush, M.D. Participated in study design and writing/editing of the manuscript Peter S. Heeger, M.D. Participated in study design, data analysis and writing/editing of the manuscript Disclosure The authors of this manuscript have no conflicts of interest to disclose. Funding The study was supported by National Institutes of Health U01 grant AI63594 awarded to P Heeger and K23DK107908 to G Nadkarni Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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