Analysis of Biomarkers Within the Initial 2 Years Posttransplant and 5-Year Kidney Transplant Outcomes

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.

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

“…However, a subsequent study with a longer follow-up (CTOT-17) showed that changes in eGFR between 3 or 6 months and 24 months better predicted 5-year graft loss than CXCL-9 measurement [ 64 ].…”

Understanding and using AlloSure donor derived cell-free DNA

“…The authors also concluded that 30% decline in eGFR between years 1 and 3 after kidney transplant is common and strongly associated with risks of subsequent death and death-censored graft failure, which mirrors findings in CKD (Clayton et al 2016 ). Faddoul et al reported results from clinical trials in organ transplantation (CTOT) 17 also identifying a 40% decrease in post-kidney transplant eGFR from 6 months post 2 years post-transplant as a surrogate for 5-year outcomes (Faddoul et al 2018 ).…”

Impact of preformed T-cell alloreactivity by means of donor-specific and panel of reactive T cells (PRT) ELISPOT in kidney transplantation

“…Recent works have shown a strong association between positive pre-transplant d-sp ELISPOT and increased risk of BPAR after transplantation, particularly TCMR, and especially, in patients not receiving T-cell depleting induction therapies [ 8 , 14 , 18 ]. Faddoul G and colleagues [ 33 ] reported a close association between d-sp alloreactivity evaluated with d-sp ELISPOT and an increased risk of BPAR and worse graft function at 2 years in positive patients. Our current findings confirm and expand previous evidence in a larger cohort of patients, where the relationship between pre-transplant d-sp ELISPOT and a higher risk of BPAR was mainly driven by patients not induced with Thymoglobulin.…”