It’s about time: A target trial emulation of preemptive vs. non-preemptive kidney transplantation

Importance: Preemptive kidney transplantation (before dialysis) is promoted as optimal therapy for kidney failure, yet evidence of a true survival advantage remains uncertain due to confounding, selection, and lead-time biases.
Objective: To estimate causal effect of preemptive versus non-preemptive kidney transplantation on mortality and graft outcomes using a target trial emulation among transplanted recipients.
Design: Retrospective cohort study using the Scientific Registry of Transplant Recipients data from January 1, 2005, to November 30, 2023. Analyses incorporated inverse probability of treatment weighting (IPTW) for baseline confounding and left-truncated Cox proportional hazards models with a common time-zero to address selection and lead-time biases, respectively.
Setting: Nationwide registry of all U.S. kidney transplant centers.
Participants: 32,770 adult first kidney-alone transplant recipients with recorded wait-time start at estimated glomerular filtration rate (eGFR) ≤20 mL/min/1.73 m². Groups were balanced using stabilized inverse-probability-of-treatment-weighting to emulate randomization across demographic, clinical, and socioeconomic factors identified by a causal diagram.
Exposures: Preemptive versus non-preemptive kidney transplantation, defined by dialysis before transplant.
Main outcomes and measures: Primary outcome: all-cause mortality. Secondary outcomes: all-cause graft failure, death-censored graft failure, and delayed graft function. Weighted Kaplan-Meier curves estimated survival differences; hazard ratios (HRs) and odds ratios (ORs) were derived from weighted left-truncated cox proportional hazards and logistic regression models, respectively.
Results: Among 15,894 preemptive and 16,876 non-preemptive transplant recipients (over 302 829 person-years follow-up), 8,494 deaths occurred (25.6% preemptive vs 26.3% non-preemptive). Preemptive transplantation showed no mortality benefit (HR 1.01; 95% CI, 0.96, 1.07). Weighted survival differences were ~2% annually. Preemptive transplantation was associated with lower odds of delayed graft function (OR 0.68; 95% CI, 0.64, 0.72) and reduced risk of death-censored graft failure (HR 0.81; 95% CI, 0.74, 0.88) - an effect largely attenuated after adjustment for delayed graft function - and all-cause graft failure (HR 0.94; 95% CI, 0.90, 0.98).
Conclusions and relevance: Preemptive transplantation did not improve survival despite lower rates of delayed graft function and death-censored graft failure. Findings challenge the presumed survival advantage and suggest preemptive strategies should focus on preventing early graft dysfunction and optimizing use of high-risk kidneys rather than expected mortality benefit.