Machine perfusion modulates cold-preservation injury in kidney transplantation: IDEAL stage 4 United States population cohort study.

Hypothermic machine perfusion (HMP) has surged in popularity for donor kidney preservation. Continuous HMP (cHMP) has shown clear benefits over static cold storage (SCS), whereas randomized trials on short-duration end-ischemic-HMP (eiHMP) have not. We assessed whether HMP modulates injury from increasing cold-preservation time (CPT) and analyzed the impact of HMP on short- and long-term outcomes, using Organ Procurement and Transplantation Network data (OPTN; 2010-2024) on single-kidney-transplant recipients (n = 137 835). Multivariable nonlinear (restricted cubic spline) regression with interaction terms was used. Median CPT was long (17.3 hours; interquartile range, 12.0-22.9), especially in the eiHMP cohort (median, 23.0 hours; interquartile range, 17.3-30.5). HMP was associated with significant reductions in delayed graft function (cHMP: adjusted odds ratio [aOR], 0.484; 95% confidence interval [CI], 0.467-0.501; eiHMP: aOR, 0.459; 95% CI, 0.435-0.485; and transport-only-HMP: aOR, 0.535; 95% CI, 0.512-0.558) and length of stay. Interaction analyses revealed that HMP mitigated the negative effect of increasing CPT compared with SCS. cHMP showed benefit across all CPTs, whereas eiHMP was beneficial only at longer CPTs. HMP was also associated with improved 5-year graft and patient survival. In conclusion, HMP reduces the negative impact of each additional hour of CPT. Therefore, the treatment effect is not fixed and increases as CPT increases, likely explaining the lack of benefit in trials of short-duration eiHMP. The association with improved 5-year graft survival and mortality provides IDEAL (idea, development, exploration, assessment, and long-term follow-up) stage 4 evidence. This study addressed questions beyond the reach of randomized trials but of clear clinical relevance.