Functional Natural Killer-cell Genetics and Microvascular Inflammation After Kidney Transplantation: An Observational Cohort Study.

BACKGROUND: Recent evidence highlights the pivotal role of natural killer (NK) cells in allograft rejection. METHODS: We explored associations of missing self and gene polymorphisms determining the phenotype and/or functionality of NK cells with microvascular inflammation (MVI) in a single-center cohort of 507 consecutive kidney transplant recipients. Patients were genotyped for killer cell Ig-like receptors and polymorphisms in 4 selected genes ( FCGR3AV/F158 [rs396991], KLRC2wt/del , KLRK1HNK/LNK [rs1049174], and rs9916629-C/T). RESULTS: MVI was detected in 69 patients (13.6%). In a proportional odds model, the KLRC2del/del variant reduced MVI risk (odds ratio [OR] 0.26; 95% confidence interval [CI], 0.05-0.93; P †=†0.037) independent of donor-specific antibodies, HLA class II eplet mismatch, and number of biopsies. Conversely, missing self (OR 1.40; 95% CI, 1.08-1.80; P †=†0.011) and the rs9916629 T/T gene variant increased the risk (OR 1.70; 95% CI, 1.08-2.68; P †=†0.021). Graft loss tended to be more frequent among patients with missing self ≥2 (hazard ratio 1.97; 95% CI, 0.89-4.37; P †=†0.097), without influence on estimated glomerular filtration trajectories. FCGR3A variants were associated with MVI only in patients with preformed and/or de novo donor-specific antibodies (OR 4.14; 95% CI, 0.99-17.47; P †=†0.052). CONCLUSIONS: Missing self and NK-cell genetics may contribute to MVI, underscoring the important role of NK cells in transplant rejection.