PREDICTIVE FACTORS FOR ACUTE REJECTION IN A POPULATION OF KIDNEY TRANSPLANTED PATIENTS

Aims: The purpose of the present study is the identification of genotypes at higher relative risk of Acute Rejection (AR) by the analysis of gene polymorphisms implicated in apoptosis and inflammation processes. AR still represents an important complication leading to organ dysfunction, especially if it occurs late. Many studies have emphasized a key role of inflammatory molecules and apoptosis mediators in the pathogenesis of AR. Some cytokines, such as IL-4, IL-6 and IL-10, carry gene polymorphisms (Single Nucleotide Polymorphisms, SNPs) responsible for the individual production levels of the molecule. These polymorphisms, generally located in the promoter region of the gene, determine the presence in the general population of genotypes defined as “low, intermediate and high producers”, that have been associated with the risk of AR. Moreover, a correlation between the increased expression of genes encoding for apoptosis molecules and the incidence and severity of AR appears to be likely. Methods: Genotype analysis has been carried out for polymorphisms of Granzyme B (GzmB), Perforin (PRF1) and Serine Proteinase Inhibitor member 9 (PI9) amongst apoptosis genes and three SNPs located in the promoter region of IL-10 gene amongst inflammatory molecules. For each polymorphism, a case-control study was conducted within a panel of 70 patients who had received cadaveric kidney transplants between 1998 and 2002 at the Institute of Nephrology of the St. Orsola University Hospital of Bologna by comparing the allele frequencies between AR group (n 29) and non-AR group (n 41). Cases and controls were matched for age and number of HLA-DR mismatches. Genotype analysis was performed by RFLP (Restriction Fragment Lenght Polymorphism) and Primer Extension/ denaturing High-Performance Liquid Chromatography assay. Results: By variance analysis (ANOVA e Student’s t-test), it has been established which variables (clinical parameters, unmodifiable factors and distribution of genotypes) showed significative differences in case and control groups. In this study, the polymorphisms of apoptosis genes do not seem to influence acute kidney rejection episodes. In contrast, the heterozygous genotype for IL-10/G–1082A polymorphism showed a higher frequency in the non-AR group. When considering the sinergistic effect of the three SNPs of IL-10 gene on the cytokine production, the high/intermediate producer genotypes highlighted an inversely positive association with creatinine plasma levels. Conclusions: These results seem to indicate a protective effect towards AR of the heterozygous genotype for IL-10/G–1082A polymorphism and a possible relationship between renal function and IL-10 high/intermediate production in kidney transplant recipients.