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Analysis of Biomarkers Within the Initial 2 Years Posttransplant and 5-Year Kidney Transplant Outcomes: Results From Clinical Trials in Organ Transplantation-17

Faddoul, Geovani, MD1; Nadkarni, Girish, N., MD1; Bridges, Nancy, D., MD2; Goebel, Jens, MD3; Hricik, Donald, E., MD4; Formica, Richard, MD5; Menon, Madhav, C., MD1; Morrison, Yvonne, MS2; Murphy, Barbara, MD1; Newell, Kenneth, MD6; Nickerson, Peter, MD7; Poggio, Emilio, D., MD8; Rush, David, MD7; Heeger, Peter, S., MD1for the CTOT-17 consortium

doi: 10.1097/TP.0000000000002026
Original Clinical Science—General

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 (7.6%) of 184 subjects 2 to 5 years posttransplant. Neither IFNγ ELISPOTs nor urinary CXCL9 were informative. In contrast, a 40% or greater decline in eGFR from 6 months to 2 years posttransplant independently correlated with 13-fold odds of 5-year graft loss (adjusted odds ratio, 13.1; 95% confidence interval, 3.0-56.6), a result that was validated in the independent Genomics of Chronic Allograft Rejection cohort (n = 165; adjusted odds ratio, 11.2).

Conclusions We conclude that although pretransplant and early posttransplant ELISPOT and chemokine measurements associate with outcomes within 2 years posttransplant, changes in eGFR between 3 or 6 months and 24 months are better surrogates for 5-year outcomes, including graft loss.

This retrospective analysis data from the Clinical Trials in Organ Transplantation study suggests that changes in eGFR within the first 2 years after transplantation, but not urinary chemokine CXCL9 and donor-reactive interferon gamma-(IFNg)-producing T cells, are associated with graft loss at 5 years.

1 Department of Medicine, Translational Transplant Research Center, Recanati Miller Transplant Institute, Immunology Institute Icahn School of Medicine at Mount Sinai, New York, NY.

2 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

3 Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.

4 Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH.

5 Department of Medicine, Yale University School of Medicine, New Haven, CT.

6 Department of Surgery, Emory University Medical Center, Atlanta, GA.

7 Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

8 Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, OH.

Received 30 August 2017. Revision received 12 October 2017.

Accepted 21 October 2017.

G.F. and G.N.N. contributed equally.

The study was supported by National Institutes of Health U01 grant AI63594 awarded to P Heeger and K23DK107908 to G Nadkarni.

The authors declare no conflicts of interest.

G. F. and M.D. participated in data analysis and writing/editing of the article. G. N. N. and M.D. participated in data analysis and writing/editing of the article. N.D.B. and M.D. participated in study design and writing/editing of the article. J.G. and M.D. participated in writing/editing of the article. D.E.H. and M.D. participated in study design, data analysis and writing/editing of the article. R.F. and M.D. participated in study design and writing/editing of the article. M.C.M. and M.D. participated in study design, data analysis, and writing/editing of the article. Y.M. participated in study design and writing/editing of the article. B.M. and M.D. participated in study design and writing/editing of the article. K.N. and M.D. participated in study design and writing/editing of the article. P.N. and M.D. participated in study design and writing/editing of the manuscript. E.D.P. and M.D. participated in study design and writing/editing of the article. D.R. and M.D. participated in study design and writing/editing of the article. P.S.H. and M.D. participated in study design, data analysis and writing/editing of the article.

Correspondence: Peter S Heeger, MD, Translational Transplant Research Center Icahn School of Medicine at Mount Sinai, New York, NY. (peter.heeger@mssm.edu).

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