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

J Am Soc Nephrol. 2021 Aug;32(8):2070-2082. doi: 10.1681/ASN.2020111558. Epub 2021 Jul 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies / blood
  • Female
  • Genotype
  • Graft Rejection / immunology*
  • Graft Survival
  • HLA Antigens / genetics*
  • HLA Antigens / immunology*
  • HLA-A11 Antigen / genetics
  • HLA-A11 Antigen / immunology
  • HLA-A3 Antigen / genetics
  • HLA-A3 Antigen / immunology
  • HLA-B Antigens / genetics
  • HLA-B Antigens / immunology
  • HLA-C Antigens / genetics
  • HLA-C Antigens / immunology
  • Histocompatibility Testing
  • Humans
  • Kidney Transplantation
  • Killer Cells, Natural / immunology*
  • Male
  • Microvessels
  • Middle Aged
  • Receptors, KIR / genetics*
  • Receptors, KIR2DL2 / genetics
  • Receptors, KIR2DL3 / genetics
  • Tissue Donors
  • Transplant Recipients
  • Vasculitis / complications
  • Vasculitis / genetics*

Substances

  • Antibodies
  • HLA Antigens
  • HLA-A11 Antigen
  • HLA-A3 Antigen
  • HLA-B Antigens
  • HLA-Bw4 antigen
  • HLA-C Antigens
  • KIR2DL2 protein, human
  • KIR2DL3 protein, human
  • Receptors, KIR
  • Receptors, KIR2DL2
  • Receptors, KIR2DL3