A Valine Mismatch at Position 129 of MICA Is an Independent Predictor of Cytomegalovirus Infection and Acute Kidney Rejection in Simultaneous Pancreas⁻Kidney Transplantation Recipients.

Rafael Michita,Falko Heinemann,Sabine Schramm,José Chies,Vera Rebmann,Richard Viebahn,Peter Horn,Peter Schenker,Andreas Wunsch

doi:10.3390/ijms19092618

Abstract

The polymorphic major histocompatibility complex class I chain-related molecule A (MICA) and its soluble form (sMICA) interact with activating receptor natural-killer group 2 member D (NKG2D) on natural-killer (NK) and T cells, thereby modifying immune responses to transplantation and infectious agents (e.g., cytomegalovirus). Two single-nucleotide polymorphisms (SNPs), rs2596538GA in the MICA promoter and rs1051792AG in the coding region (MICA-129Val/Met), influence MICA expression or binding to NKG2D, with MICA-129Met molecules showing higher receptor affinity. To investigate the impact of these SNPs on the occurrence of cytomegalovirus infection or acute rejection (AR) in individuals who underwent simultaneous pancreas–kidney transplantation (SPKT), 50 recipient-donor pairs were genotyped, and sMICA levels were measured during the first year post-transplantation. Recipients with a Val-mismatch (recipient Met/Met and donor Val/Met or Val/Val) showed shorter cytomegalovirus infection-free and shorter kidney AR-free survival. Additionally, Val mismatch was an independent predictor of cytomegalovirus infection and kidney AR in the first year post-transplantation. Interestingly, sMICA levels were lower in rs2596538AA and MICA129Met/Met-homozygous recipients. These results provide further evidence that genetic variants of MICA influence sMICA levels, and that Val mismatch at position 129 increases cytomegalovirus infection and kidney AR risk during the first year post-SPKT.

Highlights

Simultaneous pancreas and kidney transplantation (SPKT) is the most effective treatment for diabetes mellitus type 1 patients with end-stage renal disease
Kaplan–Meier curves indicated that MICA-129 mismatch status conferred shorter cytomegalovirus-infection-free survival
We report that the direction and type of MICA mismatches, rather than their number, influence SPKT outcomes

Summary

Introduction

Simultaneous pancreas and kidney transplantation (SPKT) is the most effective treatment for diabetes mellitus type 1 patients with end-stage renal disease. Despite the overall improvement in SPKT, acute rejection (AR) remains the major challenge in solid-organ transplantation, as it has a negative effect on the allograft function and may trigger chronic rejection. The occurrence of AR in SPKT is partially attributed to donor type, as the majority of pancreas and kidney donors are deceased (cardiac-dead and brain-dead donors). Allografts from such donors are more strongly affected by ischemia-reperfusion injury capable of causing delayed graft function and/or ultimate rejection. Another complication influencing graft survival is human cytomegalovirus infection, which frequently occurs after transplantation and leads to severe complications. Cytomegalovirus infection increases the risk of opportunistic infections, allograft dysfunction, and the overall cost of transplantation

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Results

Conclusion