MICA AND NKG2D GENE POLYMORPHISMS INFLUENCE CHRONIC REJECTION, GRAFT FUNCTION, AND RESPONSE TO THERAPY IN KIDNEY TRANSPLANTATION

Introduction:

Chronic antibody-mediated rejection is a significant cause of kidney transplant failure. Traditionally, compatibility between the HLA system of the donor and recipient has been considered the most important genetic factor in reducing the risk of rejection. Recent studies have shown that other factors, such as the major histocompatibility complex (MHC) class I MICA gene can also influences the transplantation outcome. However, the role of the primary MICA receptor, NKG2D, has yet to be explored.We aimed to investigate the correlation between recipient/donor MICA allele matching and NKG2D genotype with the risk of chronic antibody-mediated rejection and their potential clinical effects and implications for organ maintenance therapy.

Methods:

524 patients who underwent kidney transplantation at the Organ Transplantation Center of the G. Brotzu Hospital in Cagliari, Italy were evaluate. We excluded 1) cases lacking patient/donor biological material or incomplete clinical data. 2) patients who experienced acute graft rejection, underwent a second transplant or had pre-transplant donor-specific HLA antibodies (pre-Tx DSA). The remaining 148 patients were compared with a healthy cohort of 146 Sardinian individuals and underwent systematic evaluations of clinical and immunological parameters that significantly impact transplantation outcomes. These parameters included HLA class I mismatches, HLA class II mismatches, recipient NKG2D (KLRK1) polymorphisms rs1049174 and rs2255336, MICA mismatches 

Results:

As previous demonstrated, recipient/donor MICA allele mismatches correlate with an elevated risk of chronic antibody-mediated rejection (X2=6.95; Log-rank=0.031). At 120 months after transplantation, the incidence of chronic rejection was only 16.7% (4/24) in patients matched for MICA alleles, compared to 53.8% (28/52) and 50.0% (36/72) in patients with 1 and 2 mismatches (1 MM and 2 MM), respectively. Notably, the rs1049174 [GG] NKG2D genotype contributes to a significantly increased risk of chronic rejection (X2=13.44; Log-rank=0.001). At 120 months after transplantation, the incidence of chronic rejection was 58.8% (20/34) in these patients, while in patients with rs1049174 [CG] and rs1049174 [CC] genotypes, it was 37.0% (20/54) and 46.6% (28/60), respectively. Moreover, the combined effect of two MICA allele mismatches and presence of rs1049174 [GG] genotype shows the highest risk (X2=23.21; Log-rank<0.001). (Figure 1). In patients carrying rs1049179 [GG] and rs2255336 [AA] immunosuppressive therapy based on mTOR inhibitors appears to be less effective in preventing CR compared to maintenance therapies based on CNIs inhibitors (rs1049179 [GG]; P=0.035; and rs2255336 [AA];P=0.002).(Table1).  

Conclusions:

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

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.