Missing Self–Induced Microvascular Rejection of Kidney Allografts: A Population-Based Study

Significance Statement Microvascular inflammation (MVI) of the kidney transplant is an important determinant of allograft outcome. Although MVI is considered a cardinal manifestation of antibody-mediated rejection, it is often encountered in the absence of circulating donor-specific antibodies, which raises uncertainty about the underlying cause. The authors used genotyping of killer cell Ig-like receptors of recipients and high-resolution HLA genotyping to assess the presence of missing self, a nonhumoral natural killer cell stimulus, in a large cohort of kidney transplantations. They found that missing self specifically increases the risk of MVI after transplantation, and could explain one fifth of patients without detectable antibodies. This study suggests systematic evaluation of missing self improves our understanding of MVI, and might be relevant for improved diagnostic classification and patient risk stratification. Background Circulating anti-HLA donor-specific antibodies (HLA-DSA) are often absent in kidney transplant recipients with microvascular inflammation (MVI). Missing self, the inability of donor endothelial cells to provide HLA I–mediated signals to inhibitory killer cell Ig-like receptors (KIRs) on recipient natural killer cells, can cause endothelial damage in vitro , and has been associated with HLA-DSA–negative MVI. However, missing self’s clinical importance as a nonhumoral trigger of allograft rejection remains unclear. Methods In a population-based study of 924 consecutive kidney transplantations between March 2004 and February 2013, we performed high-resolution donor and recipient HLA typing and recipient KIR genotyping. Missing self was defined as the absence of A3/A11, Bw4, C1, or C2 donor genotype, with the presence of the corresponding educated recipient inhibitory KIR gene. Results We identified missing self in 399 of 924 transplantations. Co-occurrence of missing self types had an additive effect in increasing MVI risk, with a threshold at two concurrent types (hazard ratio HR, 1.78; 95% confidence interval 95% CI, 1.26 to 2.53), independent of HLA-DSA (HR, 5.65; 95% CI, 4.01 to 7.96). Missing self and lesions of cellular rejection were not associated. No HLA-DSAs were detectable in 146 of 222 recipients with MVI; 28 of the 146 had at least two missing self types. Missing self associated with transplant glomerulopathy after MVI (HR, 2.51; 95% CI, 1.12 to 5.62), although allograft survival was better than with HLA-DSA–associated MVI. Conclusion Missing self specifically and cumulatively increases MVI risk after kidney transplantation, independent of HLA-DSA. Systematic evaluation of missing self improves understanding of HLA-DSA–negative MVI and might be relevant for improved diagnostic classification and patient risk stratification.