الفهرس 
Introduction and Aim of the workOnly 14 pages are availabe for public view
 |  | from | 214 |  |  |
| | | from | 214 | | |
Abstract
Kidney transplantation is the treatment of choice for end stage renal disease. There are different immune mechanisms involved in the pathogenesis of acute rejection and graft loss. Many genes contribute to the outcome of the transplantation. The major genetic contributors to immunological acceptance of the graft are human leukocyte antigen (HLA) genes. Also other non-HLA gene polymorphisms may predict the future risk of complications. The present work was done in order to assess the role of the polymorphism of some non-HLA genes; TLR 2 & 4, CD14 & MIC-A on the outcome of kidney transplantation in Egyptian patients. This study was performed on 96 couples (recipient & donor) of kidney transplantation cases, selected from outpatient clinics and Hemodialysis unit of Urology & Nephrology Center, Mansoura University, the cases underwent transplantation from well-matched suitable living donors with repeated negative cross-matching in the period between 1994-2003. All subjects were subjected to full history, clinical examination, complete routine laboratory and radiological investigation. In our study, genotyping of DNA samples was performed with Taqman, Applied Biosystems assays to detect TLR2 SNPs at positions /-16934 A→T, /+596 C→T and / +1349 T→C, and TLR4 SNPs at positions /-6143A→G, / -5724 T→C and / +4434 A→G, / +7263 G→C and/ +8469 T→C. The genotyping of CD14 SNP at positions -159 C→T was performed by PCR-RFLP and MICA polymorphism-129met→val was performed by Nested PCR-RFLP. The following results were obtained: There was statistically significant difference between the degree of relation and the incidence of graft loss. There was no statistical significant difference in genotyping of TLR2 SNPs at positions /-16934 A→T, /+596 C→T and / +1349 T→C, in recipients or donors regarding acute rejection or graft loss. There was no statistical significant difference in genotyping of TLR4 SNPs at positions /-6143A→G, / -5724 T→C and / +4434 A→G, and/ +8469 T→C, in recipients or donors regarding acute rejection or graft loss. There was statistical significant difference between recipients without acute rejection and with acute rejection as regard TLR4 SNPs at position +7263. There was statistical significant difference between donors without incidence of acute rejection and with acute rejection as regard TLR4 SNPs at position +7263. There was statistical significant difference between recipients without graft loss and with graft loss as regard TLR4 SNPs at position +7263. There was significant correlation with TLR4/ +7263G→C; in recipients: there was significant negative correlation between the occurrence of C allele and graft loss, while in donors: the occurrence of C allele was negatively correlated to clinical rejection. There was no statistical significant difference in genotyping of CD14 SNP at positions-159 C→T, in recipients or donors regarding acute rejection or graft loss. The statistical analysis of MICA-129met→val genotyping of recipients and donors revealed nonstatistical significant relationship with acute rejection or graft loss, while there was statistically significant difference on analyzing the relationship between acute rejection and MICA matching, also the relationship between graft loss and MICA matching at position 129 showed statistically significant difference. There was statistically significant correlation between MICA matching with acute rejection and graft loss. Conclusion: The degree of relation between the recipient and the donor has an impact on the long term outcome of renal transplantation. TLR4/ +7263G→C polymorphism showed that the C allele is protective against the incidence of acute rejection and graft loss in kidney transplantation, but what is not yet known and clearly requires further study is whether immunosuppressive regimens can be tailored to TLR genotypes. CD14 SNP -159 C→T has no role in the outcome of renal transplantation. MICA-129met→val matching between recipient and donor in kidney transplantation is important to avoid acute rejection and graft loss in HLA matched couple. This research demonstrates the lack of robust polymorphisms among studied SNPs in investigated genes that could be included in routine analysis in a clinical laboratory. Even though weak associations were found, their predictive value was insufficient for use in clinical decision-making. However, as future technology advances are likely to make large-scale genetic tests affordable, data on several hundreds of genetic markers may be combined and used in personalized patient treatment. Recommendations: More investigations are recommended to clear the role of TLR in the pathogenesis of acute rejection and graft loss in kidney transplantation, especially specifying the ligand of TLRs and on what immunological mechanism they work in transplantation. MICA matching between recipient and donor is important, and we recommend adding it to the routine pretransplantation evaluation. More attention should be paid toward MICA in cases of renal transplantation, and further study is needed to evaluate the role of MICA- 129met→val polymorphism mismatch in initiation of antibody production. Meta-analyses are recommended to collect the results of genetic studies in the field of renal transplantation to overcome the shortage in the number of cases in each study to reach a final conclusion about the role of the candidates gene in the pathogenesis of rejection.