Role of standard HLA mismatch in modifying associations between non-pharmacologic risk factors and solid organ malignancy after kidney transplantation.

BACKGROUND: Human leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). METHODS: In a secondary analysis from a previous study, 166,256 adult KTRs in 2000-2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1-3, and 4-6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. RESULTS: Compared with 0 HLA-mm, 1-3 HLA-mm was not associated, and 4-6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94-1.17 and HR = 1.11, 95% CI = 1.00-1.34, respectively]. Both 1-3 HLA-mm and 4-6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08-1.18) and (HR = 1.16, 95% CI = 1.09-1.22), respectively]. KTR's history of pre-transplant cancer, age 50-64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1-3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1-3 and 4-6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. CONCLUSION: Direct association between SOM and the degree of HLA mismatching is equivocal and limited to the 4-6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.