Allogenomics: a new concept evaluating Donor/Recipient mismatches in living-related kidney transplants?

In living related kidney transplant recipients, current strategies to improve graft outcome consider information at the HLA locus. Given that more than 50 % of fully HLA matched kidneys fail at 10 years post-transplant, we investigated whether information outside of the HLA locus can also impact long-term graft function (LTGF).

We used a new method using DNA exome sequencing from kidney graft recipients (R) and their living donors (D) to determine R/D mismatches at the amino acid level over entire exomes. We estimated the number of amino acid mismatches in transmembrane proteins, more likely to be recognized as foreign by the recipient's immune system, and designated this tally as the allogenomics mismatch score (AMS). The AMS can be measured prior to transplantation for potential donor and recipient pairs and could be used in graft attribution algorithms. We examined the degree of relationship between the AMS and post-transplantation kidney allograft function using mixed models, considering transplants from three independent cohorts (total 106 exomes, 53 pairs, 239 observations of estimated glomerular filtration rate (eGFR) which reflect kidney graft function. We found that the AMS has a significant and consistent effect on the eGFR across the entire range of the score: -19.4 [-37.7, -1.1], P=0.0042, χ2= 8.1919, d.f.=1). This effect is independent of HLA mismatches, donor age, and time post-transplantation. These results show that the AMS is a strong and robust predictor of LTGF in kidney transplant recipients, independently of the HLA locus. Our data indicate that graft function can also be influenced by R/D mismatches in sets of genes whose identity varies for each R/D pair and that the set of mismatches for any given pair of transplants could be predicted.