MICA and NKG2D gene polymorphisms influence graft survival, and response to therapy in kidney transplantation

Abstract

Background: Antibody-mediated rejection is a significant cause of kidney transplant failure. Recent studies have shown that the MHC class I MICA gene influences the transplantation outcome. However, the role of the primary MICA receptor, NKG2D, has yet to be explored.

Aim: We aimed to investigate the correlation between recipient/donor MICA allele matching and NKG2D genotype with the risk of antibody-mediated rejection and their potential clinical effects and implications for organ maintenance therapy.

Methods: Of the 524 patients who underwent transplantation, 387 were eligible for the study. Complete MICA allele and two functional polymorphisms of NKG2D (rs1049174C>G and rs2255336G>A) were analyzed in 148 transplanted patients and 146 controls.

Results: Increased recipient/donor MICA allele mismatches correlate with an elevated risk of antibody-mediated rejection (X² = 6.95; Log-rank=0.031). Notably, the rs1049174[GG] genotype contributes to a significantly increased risk of antibody-mediated rejection (X² = 13.44; Log-rank=0.001 and X ² = 0.34; Log-rank=0.84). The combined effect of two MICA allele mismatches and rs1049174[GG] genotype shows the highest risk (X² = 23.21; Log-rank<0.001). Most importantly, patients with rs1049174[GG] and rs2255336[AA] genotypes may respond less to mTOR inhibitor immunosuppressive therapy than Calcineurin inhibitors (rs1049174[GG]; P=0.035; and rs2255336[AA]; P=0.002).

Conclusion: Recipient/donor MICA allele mismatches and specific NKG2D variants, as well as their combinations, influence kidney transplant outcomes, providing insights for personalized treatment and enhancing graft survival.

Keywords: DSA; MICA; NKG2D; antibody-mediated rejection; kidney transplant.

Figure 1

Selection process and characteristics of kidney transplant recipients in the study. Out of 524 patients who underwent kidney transplants over ten years, 387 were enrolled for analysis based on specific criteria, including renal biopsies at 1 and 3 years after transplantation (as required for post-transplant follow-up by the Cagliari transplant center), absence of second transplant and pre-transplant donor-specific HLA antibodies. Among these, 68 patients (21.3%) experienced a progressive decline in graft function attributed to antibody-mediated rejection (ABMR), with histological confirmation through renal biopsies. Some of these patients showed a mixed histological picture of ABMR and TCMR. The 68 patients with ABMR presented with a histological picture of MVI+ (g+, ptc ≥ 2). They were divided into three subgroups based on the presence or absence of C4d and the presence or absence of DSA (MVI+, C4d+, DSA+;MVI+, C4d+, DSA-; MVI+, C4d-, DSA-). The remaining 319 patients never exhibited clinical, histological, or laboratory signs of organ damage. Eighty patients (MVI-, C4d-, DSA-), randomly selected, were used as a control group (SGF). (ABMR, antibody-mediated rejection; DSA, donor-specific HLA antibodies; MVI, microvascular inflammation; TCMR, T-cell-mediated rejection).

Figure 2

(A) Cumulative incidence for antibody-mediated rejection according to recipient-donor (R/D) MICA allele mismatches. The cumulative incidence of rejection events is graphically presented for a cohort of 148 patients observed over 120 months. Patients were categorized based on three groups of patients stratified according to donor-recipient MICA allele mismatches [0MM (black), 1MM (green), 2 MM (red)]. P-values were calculated using the two-sided Log-rank test without correction. χ2: Chi-square. MM: Mismatches. (B) Cumulative incidence for antibody-mediated rejection according to recipient-donor (R/D) MICA-129 allele mismatches. The cumulative incidence of rejection events is graphically presented for a cohort of 148 patients observed over 120 months. Patients were categorized on four groups of patients stratified according to recipient-donor MICA allele mismatches based on substitution of valine (V) with methionine (M) at position 129 (MICA-129) of the MICA protein: [R/D VV/MM (Red), R/D MM/VV (blue), R/D MM/MV (green) and R/D VV/MV (black)]. P-values were calculated using the two-sided Log-rank test without correction. χ2, Chi-square.

Figure 3

Cumulative incidence for antibody-mediated rejection according to NKG2D rs1049174 (G>C) genotype. The cumulative incidence of rejection events is graphically presented for a cohort of 148 patients observed over 120 months. Patients were categorized into three groups based on their NKG2D genotype for rs1049174 (G>C) [GG (red), GC (green), CC (black)]. This allele is linked to the haplotype blocks NKG2D hb-1, which produces NKG2D_R with low (rs1049174 [CC]; LNK) or high (rs1049174 [GG]; HNK) natural cytotoxic activity phenotypes. P-values were calculated using the two-sided Log-rank test without correction. χ2, Chi-square.

Figure 4

Cumulative incidence for antibody-mediated rejection according to NKG2D rs2255336 (A>G) genotype. The cumulative incidence of rejection events is graphically presented for a cohort of 148 patients observed over 120 months. Patients were categorized into three groups based on their NKG2D genotype for rs2255336 (A>G) [AA (light blue), AG (green), GG (red)]. This allele is linked to the haplotype blocks NKG2D hb-2, which produces _R NKG2D with low (rs2255336 [GG]; LNK) or high (rs2255336 [AA]; HNK) natural cytotoxic activity phenotypes. P-values were calculated using the two-sided Log-rank test without correction. χ2, Chi-square.

Figure 5

Cumulative incidence for antibody-mediated rejection according to NKG2D rs1049174 [GG] genotype and MICA allele mismatches. The cumulative incidence of rejection events is graphically presented for a cohort of 148 patients observed over 120 months. Patients were categorized based on their NKG2D genotype GG for and rs1049174 in combination with the donor-recipient MICA allele mismatches. The rs1049174 [GG], which produces _RNKG2D with high natural cytotoxic activity phenotypes, has been correlated with donor-recipient MICA allele mismatches. Six groups were formed based on the number of MICA allele mismatches and the presence or absence of the GG (rs1049174) genotype: 1. Two MICA R/D allele mismatches and rs1049174 _RNKG2D[GG] (purple) 2. One MICA R/D allele mismatches and rs1049174 _RNKG2D[GG] (green) 3. One MICA R/D allele mismatches and rs1049174 _RNKG2D[GG] (red) 4. Two MICA R/D allele mismatch and rs1049174 _RNKG2D[CG] and [CC] (light blue) 5. MICA R/D alleles match and rs1049174 _RNKG2D[GG] (orange) 6. MICA R/D alleles match and rs1049174 _RNKG2D[CG] and [CC] (black). P-values were calculated using the two-sided Log-rank test without correction. χ2, Chi-square. MM, mismatches.

Figure 6

Cumulative incidence for antibody-mediated rejection in patient’s HLA-DRB1 and HLA-DQB1 match R/D according to NKG2D genotype and MICA allele mismatches. The cumulative incidence of rejection events is graphically presented for a cohort of 33 patients with HLA-DRB1 and HLA-DQB1 match R/D observed over 120 months. Patients were categorized into three groups based on the following criteria: 1. R/D MICA alleles match independently of the NKG2D rs1049174 genotype (black). 2. R/D MICA alleles 1-2 mismatches with NKG2D rs1049174 CG or CC genotype (marked as GG-) (green). 3. R/D MICA alleles 1-2 mismatch with NKG2D rs1049174 GG genotype (red). P-values were calculated using the two-sided Log-rank test without correction. χ2, Chi-square. MM, mismatches; R/D, recipient-donor.

Figure 7

Cumulative incidence for antibody-mediated rejection in patient’s HLA-B match R/D according to NKG2D genotype and MICA allele mismatches. The cumulative incidence of rejection events is graphically presented for a cohort of 12 patients with HLA-B match R/D observed over 120 months. Patients were categorized into two groups based on the following criteria: 1. R/D MICA alleles match independently of the NKG2D rs1049174 genotype (black). 2. R/D MICA alleles 1-2 mismatch independently of the NKG2D rs1049174 genotype (red). P-values were calculated using the two-sided Log-rank test without correction. χ2, Chi-square. MM, mismatches; R/D, recipient-donor.