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

Abstract

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.

Keywords: antibody-mediated rejection; kidney transplantation; microvascular inflammation; missing self; natural killer cells.

Graphical abstract

Figure 1.

Missing self types cumulatively associate with risk of MVI. (A) Definition of missing self types. (B) Histogram of the possible combinations of missing self types within the study population (n=924). C1 and C2 missing self are mutually exclusive by definition. C1/2DL3 and C1/2DL2 indicate C1 missing self in presence of the KIR2DL2 and KIR2DL3 gene, respectively. (C) Prevalence of specific missing self types in transplantations with and without MVI during histologic follow-up after the baseline biopsy (n=890 transplantations, with 3476 posttransplant biopsies). (D) Number of missing self types in transplantations with and without MVI, chi-squared test for comparison. (E) Kaplan–Meier survival curves for incidence of MVI, censored for recipient death and allograft failure, with groups stratified according to the number of missing self types present within a donor-recipient pair. MS, missing self type. *P<0.05; **P<0.01.

Figure 2.

Missing self independently associates with risk of MVI (n=890 transplantations with 3476 post-transplant biopsies). (A) Prevalence of pretransplant HLA-DSA in transplantations with and without MVI during histologic follow-up, chi-squared test for comparison. (B) Pretransplant donor/recipient CMV IgG status in transplantations with and without MVI during follow-up, chi-squared test for comparison. (C) Kaplan–Meier survival curves for incidence of MVI, censored for recipient death and allograft failure, stratified according to high versus low missing self (2–3 versus 0–1 types) and pretransplant HLA-DSA. (D) Survival curves for incidence of MVI, stratified according to high missing self and post-transplant risk for CMV disease (high risk: donor and/or recipient CMV seropositive; low risk: donor and recipient CMV seronegative). (E) Venn diagram depicting the independence of high missing self, pretransplant HLA-DSA and CMV disease risk as pretransplant predictors for MVI (occurring in n=222 transplantations), and the proportion of MVI incidence associated with each predictor. (F) Venn diagram depicting the prevalence of high missing self, prior symptomatic CMV disease and HLA-DSA, either current or previous, at the first moment of diagnosis in the 222 transplantations with MVI. MS, high missing self; ⁺/⁻, CMV IgG positive/negative. **P<0.01; ****P<0.0001.

Figure 3.

Missing self specifically associates with vascular lesions (n=890 transplantations with 3476 post-transplant biopsies). (A) Association of high missing self (2–3 types) and other NK cell stimuli with kidney allograft rejection phenotypes. The estimates and 95% CIs are on the basis of a logistic mixed-effect regression model with random intercepts and a linear fixed effect of post-transplant time, corrected for HLA class I and class II mismatch number, donor age, recipient sex, and repeat transplantation. HLA-DSA positivity was defined as presence at transplantation or de novo occurrence after transplantation. The hazard ratio for cold ischemia time is given per 1-hour increase. (B) Association of high missing self with presence of individual Banff lesions, on the basis of the logistic mixed-effect regression model described in (A), with additional correction for HLA-DSA and CMV disease. OR with 95% CI are plotted. Red color indicates statistical significance. (C) Association between number of missing self types and severity of MVI in early post-transplant biopsies (n=748 biopsies). Estimates and confidence bounds are on the basis of an ordinal logistic regression model, correcting for the covariates described in (B), in addition to tacrolimus exposure and induction therapy. (D) Kaplan–Meier survival curves for incidence of transplant glomerulopathy after the first MVI biopsy, for patients without cg at diagnosis and with available histologic follow-up (n=190). Patients were stratified according to high missing self and HLA-DSA status. ABMRh, biopsies fulfilling the first 2 Banff 2019 criteria for ABMR; v, intimal arteritis; g, glomerulitis; ptc, peritubular capillaritis; i, interstitial inflammation; c4d, c4d deposition in peritubular capillaries; cg, transplant glomerulopathy; cv, arterial fibro-intimal thickening; t, tubulitis; ct, tubular atrophy; ah, arteriolar hyalinosis; ci, interstitial fibrosis.