KIR and their HLA Class I ligands: Two more pieces towards completing the puzzle of chronic rejection and graft loss in kidney transplantation

Abstract

Background: Kidney transplantation is a life-saving treatment for patients with end-stage renal disease. However, despite progress in surgical techniques and patient management, immunological rejection continues to have a negative impact on graft function and overall survival. Incompatibility between donors and recipients for human leukocyte antigens (HLA) of the major histocompatibility complex (MHC) generates a series of complex cellular and humoral immune response mechanisms that are largely responsible for rejection and loss of graft function. Within this context, a growing amount of evidence shows that alloreactive natural killer (NK) cells play a critical role in the immune response mechanisms elicited by the allograft. Killer immunoglobulin-like receptors (KIRs) are prominent mediators of NK cell alloreactivity.

Methods and findings: A cohort of 174 first cadaveric kidney allograft recipients and their donors were selected from a total cohort of 657 transplanted patients for retrospective immunogenetic analyses. Patients with HLA Class II mismatches were excluded. HLA Class I allele frequencies were compared among patients with chronic rejection, patients with stable graft function and a group of 2388 healthy controls. Activating and inhibitory KIR gene frequencies, KIR haplotypes, KIR-HLA ligand matches/mismatches and combinations of recipient KIRs and donor HLA Class I ligands were compared among patients with and without chronic rejection and a group of 221 healthy controls. Patients transplanted from donors homozygous for HLA-C1 antigens had a significantly higher risk for chronic rejection than patients transplanted from donors homozygous or heterozygous for HLA-C2 antigens or with epitopes belonging to the HLA-Bw4 ligand group. The Kaplan-Meier curves obtained by dividing the patients into 3 groups according to the presence or absence of one or both of the combinations of recipient KIRs and donor HLA ligands (rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4) showed a significantly higher cumulative incidence of chronic rejection in the group of patients completely lacking these functional units. These patients showed a progressively stronger decline in modification of diet in renal disease-estimated glomerular filtration rate.

Conclusions: KIR genotyping should be performed at the time of enrolment of patients on the waiting list for organ transplantation. In our study, a significantly higher risk of chronic rejection after kidney transplantation was observed when recipient (r) and donor (d) pairs completely lacked the two functional rKIR-dHLA ligand combinations rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4. This immunogenetic profile corresponds to low levels of NK cell inhibition. Therefore, patients with this high risk profile could benefit from immunosuppressive therapy aimed at reducing NK-cell cytotoxicity.

Fig 1. Kaplan-Meier cumulative incidence of chronic rejection in the three groups of patients stratified according to the presence or absence of one or both of the following combinations of recipient (r) KIRs and donor (d) HLA ligands: rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4.

Patients with both combinations = high NK cell inhibition; patients with one combination = partial NK cell inhibition; patients lacking both combinations = low NK cell inhibition.

Fig 2. Glomerular filtration rate measured at 1, 6, 12, 24, 36, 48, 60 and 72 months after transplantation normalized to baseline levels measured at 1 month after transplantation.

The error bar at each point represents the 95% Confidence Interval. The group of patients with low NK cell inhibition (completely lacking the two functional units rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4) showed a statistically significant difference in comparison to the groups of patients with either partial or high NK cell inhibition; P = 3.5·10⁻¹⁴ obtained by calculating the area under the curve.

Fig 3. Risk of chronic rejection according to the presence or absence of specific recipient (r) KIR and donor (d) HLA ligand combinations.