Association Between Cytokines and Their Receptor Antagonist Gene Polymorphisms and Clinical Risk Factors and Acute Rejection Following Renal Transplantation

Abstract

BackgroundAcute rejection (AR) after renal transplantation affects both patient and graft survival. There is growing evidence of the genetic association between cytokine or its receptor antagonist and AR in solid organ transplantation. The objectives of this study were to investigate the role of recipient TNF β, IL-10, IL-1β, and IL-1 receptor antagonist (ra) gene polymorphism, as well as traditional clinical variables such as panel-reactive antibody (PRA) levels, donor type, and HLA mismatches in AR following renal transplantation.Material/MethodsTNF β (+252A/G), IL-10 (−592A/C), IL-1β (−511C/T) and IL-1ra (86 bp VNTR) gene polymorphisms were determined in 195 renal allograft recipients with and without AR, using PCR. Both these genotypic variants and clinical risk factors were investigated for correlation with AR within the first year after renal transplantation.ResultsPatients with increased pre-transplant PRA levels (P<0.001) and donor type (P=0.012) were prone to the development of AR. After adjusting for all variables of P<0.2, a PRA level >10% (OR=4.515, 95% confidence intervals=1.738–11.727, P=0.002) and the receipt of a graft from a donation after cardiac death (DCD) donor (OR=2.437, 95% confidence intervals=1.047–5.673, P=0.039) remained significantly associated with AR in a multivariate logistic regression analysis. No correlation could be found between recipients with an episode and absence of acute rejection and the gene polymorphisms of these cytokines investigated in the present study.ConclusionsThis study shows that the presence of increased pre-transplant levels of PRA and the receipt of a graft from DCD donor other than cytokine gene polymorphisms are significant risk factors for AR in renal transplantation. To reduce the occurrence of AR, clinicians should take necessary measures to lower the PRA levels and pay more attention to patients who received a graft from a DCD donor.

No Major Effect of Innate Immune Genetics on Acute Kidney Rejection in the First 2 Weeks Post-Transplantation

“…In terms of the impact of IL2 -330T > G, IL10 -1082G > A, and TNF -308G > A on BPAR incidence, our results are in accordance with previous meta-analyses (Hu et al, 2011;Hu et al, 2015;Xiong et al, 2015;Hu et al, 2016) indicating these SNPs are not significant determinants of BPAR incidence in Caucasian kidney transplant recipients receiving TAC or ciclosporin. Our study also supports cross-sectional studies in which IL1B -511C > T did not affect BPAR incidence in kidney transplant recipients receiving TAC or ciclosporin (Marshall et al, 2000;Marshall et al, 2001;Manchanda and Mittal, 2008;Seyhun et al, 2012;Ding et al, 2016). Some studies reported that IL1B 3954C > T and TLR4 896A > G and 1196C > T affected BPAR incidence but without multiple comparison adjustment (Ducloux et al, 2005;Palmer et al, 2006;Manchanda and Mittal, 2008).…”

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“…However, Ding and associates, in their investigation on whether clinical variables significantly effected acute rejection, found that panel reactive antibody levels > 10% were significantly associated with acute rejection. 15 In our study, area under the curve values showed that urinary TNF-α levels were better than serum TNF-α levels and serum creatinine for the determination of rejection. Budak and associates 14 used receiver operating characteristic analysis to estimate acute rejection and found that serum TNF-α receptor levels determined on day 7 and month 1 have the highest sensitivity and specificity.…”

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

“…72,74 While TNF inhibition has demonstrated success in treating autoimmune diseases such as rheumatoid arthritis or psoriasis, patients undergoing anti-TNF therapy for these indications are at risk for developing demyelinating CNS lesions, indicating a disease-specific effect. 40,75 Supporting the clinical findings, GWAS studies in MS identified TNF lowering alleles for both cytokines TNF-a and TNF-b that were associated with higher risk for MS. 23,76 We provide additional genetic evidence in line with observational, clinical, and GWAS findings for a potentially protective role of TNF-b in MS.…”