Cytomegalovirus Infection Determines Microvascular Inflammation Risk beyond Alloimmunity in Kidney Transplantation

Microvascular inflammation (MVI) is a major determinant of kidney allograft failure, yet its upstream drivers remain incompletely defined. Natural killer (NK) cells contribute to donor-specific antibody (DSA)-positive and DSA-negative MVI via antibody-dependent cytotoxicity and missing-self recognition. Cytomegalovirus (CMV) infection durably remodels the NK cell compartment, inducing memory-like populations with heightened effector function. In a contemporary multicenter cohort of 4,411 kidney transplants with 10,214 post-transplant biopsies in the CMV prophylaxis era, CMV seropositivity, indicative of prior infection, was independently associated with a twofold higher hazard of MVI and increased graft failure. This association extended across antibody-mediated and DSA-negative, C4d-negative MVI and acted synergistically with HLA-DSA and missing self. Post-transplant CMV replication and disease were associated with subsequent MVI only in seronegative recipients, consistent with an effect of primary CMV infection. Together, these findings identify CMV infection as a clinically relevant and previously underrecognized determinant of MVI, beyond alloimmune factors.