Elevations in Donor-Derived Cell-Free DNA and Allograft Outcomes in Kidney Transplantation.
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Klein Jeffrey A, Taber David, Wojciechowski David, Mandelbrot Didier A, Glehn-Ponsirenas Renata, Olaitan Oyedolamu, Jain Pranjal, Lu James, McGrath Martina M, Narayanan Mohanram, Patel Anup M, Merzkani Massini, Permpalung Nitipong, Choudhury Rashikh A, Josephson Michelle A, Anand Sanjiv, Vaitla Pradeep, Langewisch Eric, Ajaimy Maria, Kumar Dhiren, Burke George W, Pesavento Todd E, Langone Anthony J, Huang Yihung, Leeser David, Fischbach Bernard, Costa Nadiesda, Sureshkumar Kalathil, Qannus Abd A, Fan Chun-Po Steve, Zaky Ziad, Shihab Fuad, Kulkarni Sanjay, Maw Thin Thin, Tanriover Bekir, Akalin Enver, Cooper Matthew, Tawhari Ibrahim, Weir Matthew R, Alhamad Tarek, Brennan Daniel C, Leca Nicolae, Bunnapradist Suphamai, Shen Ling, Woodward Robert N, Chuang Peale, Anand Prince, Poggio Emilio D, Guerra Giselle, Wiseman Alexander, Paramesh Anil, Cibrik Diane, Bromberg Jonathan, KOAR Study Investigators
Аннотация
BACKGROUND: Although donor-derived cell-free DNA (dd-cfDNA) correlates with histologic rejection and injury severity, its association with long-term graft outcomes has yet to be well established in kidney transplant recipients. We hypothesize that among patients monitored with dd-cfDNA, an initial elevation may be associated with subsequent allograft dysfunction and loss.
METHODS: The Kidney Allograft Outcomes AlloSure Registry is a prospective, multicenter cohort of 1743 adult kidney transplant recipients from 56 US centers; this analysis included 1258 patients who initiated dd-cfDNA surveillance 15-60 days post-transplant with up to 3-year follow-up. A multistate model was applied to characterize transitions from a low dd-cfDNA state (no elevations) to intermediate (0.5%-1.0% with ≥61% relative change value) or high (≥1.0%) dd-cfDNA states, and their unadjusted and covariate-adjusted associations with allograft loss or all-cause death were quantified using hazard regression models.
RESULTS: Within 3 years, 36% of patients transitioned to an elevated dd-cfDNA state (intermediate n =216; high n =233). Allograft dysfunction by 36 months occurred significantly more often in patients with dd-cfDNA elevations despite preserved allograft function at the time of elevation (eGFR ≥60 ml/min per 1.73 m 2 in 42% of intermediate and 33% of high), consistent with subclinical injury. Transitions from low to elevated dd-cfDNA states were strongly associated with subsequent allograft loss (adjusted hazard ratios, 3.70 [95% confidence interval [CI], 1.38 to 9.90] for intermediate; 6.36 [95% CI, 2.80 to 14.42] for high), while mortality did not differ by dd-cfDNA state.
CONCLUSIONS: Initial dd-cfDNA elevations exceeding established thresholds were independently associated with higher risks of allograft dysfunction and loss across both elevation categories, whereas patients who remained in the low dd-cfDNA state experienced favorable outcomes.