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.