The relative importance of cytokine gene polymorphisms in the development of early and late acute rejection and six-month renal allograft pathology

Background. Acute rejection episodes and 6-month protocol biopsy acute pathology are highly correlated with long-term outcomes in renal transplant recipients. Recurrent, vascular, and late rejections are particularly deleterious. Methods. We determined the relative contribution of human leukocyte antigen matching, cytokine genotypes, delayed graft function (DGF), and baseline immunosuppression to the development of acute rejection and allograft pathology in 118 renal transplant recipients. Results. Multivariate logistic regression modeling demonstrated that the adjusted odds ratio and 95% confidence interval for recurrent (>= 2) early rejections (0-3 rnonths) increased linearly for high (H) > intermediate (1) > low (L) interferon-gamma (1.8; 1.1-3.2) and tumor necrosis factor (TNF)alpha (3.0; 1.3- 6.9) genotype, whereas every 1 mu g/L increase in the cyclosporine A level was protective (0.991; 0.984-0.999). The odds ratio for recurrent late rejections (4-6 months) increased for H > I > L TNF alpha (5.1; 1.8-14.7) genotype and DGF (7.1; 1.6-30.2), whereas H > I/L transforming growth factor-beta(1), genotype decreased the relative risk (0.09: 0.02-0.49). Vascular rejection was only predicted by H > I > L TNF alpha phenotype (3.0; 1.2-7.9). The odds ratio for the 6-month BanffAcute Score (6A >= 4) increased for H > I > L TNFa (2.7; 1.1-6.7) and interleukin-10 (3.4; 1.2-6.2) genotype, and DGF (3.4; 1.1-11.5). Treatment of early subclinical rejection decreased the relative risk (0.20; 0.07-0.62). Conclusions. High transforming growth factor-beta(1) producer phenotype seems to be protective against acute inflammation, whereas H and I interferon-gamma, TNF alpha, and interleukin-10 producer genotypes correlate with adverse outcomes. Cytokine genotyping identifies individuals who may benefit from more intensive surveillance and treatment posttransplant.