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Tacrolimus is an immunosuppressive drug widely used in kidney transplantation. Cytochrome P450 3A5 (CYP3A5) protein is involved in tacrolimus metabolism. Single nucleotide polymorphism in the CYP3A5 gene (6986A>G) results in alteration in metabolic activity of CYP3A5 protein which eventually affects the tacrolimus concentration. Patients with CYP3A5 expresser genotypes (A/A *1/*1 and A/G *1/*3) metabolize tacrolimus more rapidly than CYP3A5 nonexpressers (G/G *3/*3). We performed meta-analysis to estimate the effect of CYP3A5 polymorphism on the trough concentration-dose ratio (Co/D) and risk of renal allograft rejection with similar post-transplant periods and Asian vs. European populations. Our results showed that the tacrolimus Co/D ratio is significantly lower in CYP3A5 expresser group as compared with nonexpresser in Asian as well as in European populations at any post-transplant period (p < 0.00001). No significant association was found with renal allograft rejection episodes between expressers and nonexpressers in European populations (OR: 1.12; p = 0.47). Interestingly, Asian population (with expresser genotypes) and patients after 3 years post-transplantation (with expresser genotypes) have a higher risk of rejection (OR: 1.62; p < 0.05), (OR: 1.68; p < 0.05), respectively. This could be due to high prevalence of expresser genotypes in Asian population. Few tacrolimus-based studies are identified with long-term graft survival. There is a need to have more studies looking for long-term graft survival in expresser as well as no-expresser groups especially in Asian populations who have high frequency of CYP3A5 functional genotype.

Background: Interferon-gamma inducible protein-10 (IP-10/CXCL10) is a chemokine involved in the alloimmune response against kidney allograft. We aimed to investigate the association of urinary CXCL10 protein levels with rejection in renal transplant patients., Methods: A total of 273 urine samples from (biopsy-proven) rejection and non-rejection patients and controls were included in this study. CXCL10 levels were analyzed for association with rejection., Results: The data showed statistically significant differences in the CXCL10 levels between rejection vs. non-rejection (p < 0.001). Among the rejection groups, statistically significant differences for CXCL10 levels were found between ACR vs. NAD (p < 0.001), ACR vs. BLR (p = 0.019) and AVR vs. NAD (p = 0.009). Receiver Operating Characteristic (ROC) curve analysis of CXCL10 showed an area under the curve (AUC) of 0.74 with 72% sensitivity and 71% specificity at 27.5 pg/ml between rejection and non-rejection group. Kaplan-Meier curve analysis among different levels of CXCL10 showed a better rejection-free graft survival in patients with <100 pg/ml when compared to >200 pg/ml (38 ± 6 vs. 12 ± 1.0 weeks; log-rank p < 0.001) and 100-200 pg/ml (38 ± 6 vs. 22 ± 9 weeks; log-rank p = 0.442) concentration., Conclusion: The results indicate significantly increased levels of CXCL10 protein in the urine at the time of allograft rejection. This association of urinary CXCL10 protein levels with rejection could provide an additional tool for the non-invasive monitoring of allograft rejection.

Background: CCL2 is a chemoattractant for monocytes/macrophages, T cells, and natural killer cells. It is shown to be involved in the immunological responses against renal allograft. This study was conducted to access the role of urinary CCL2 expression in predicting the rejection episodes in renal transplant patients., Method: A total of 409 urine samples included in this study. The samples were consisted of (a) biopsy-proven graft rejection (n = 165); (b) non-rejection (n = 93); (c) non-biopsy stable-graft (n = 42), and (d) healthy renal donors (n = 109). The samples were quantified for the CCL2 using the MCP-1/CCL2 ELISA kit. The data were analyzed using the Statistical Package for Social Sciences (SPSS ® ) and MedCalc ® statistical software., Results: Results showed that the CCL2 levels were significantly increased in rejection group when compared with the non-rejection, stable-graft, and control, P < 0.05. The receiver operating curve's characteristics illustrated that the urinary CCL2 level is a good predictor for graft rejection, with an area under the curve of 0.81 ± 0.03 with optimum sensitivity and specificity of 87% and 62%, respectively, at a cut-off value of 198 pg/mL. Kaplan-Meier curve also showed better cumulative rejection-free graft survival time in group with less than 198 pg/mL of CCL2 as compared to those with expression levels of more than 198 pg/mL (30 weeks vs. 3 weeks; log-rank test, P < 0.001)., Conclusion: In our study, noninvasive investigation of CCL2 levels in urine has showed potential to predict rejection episodes. It is suggested that the CCL2, with others markers, may help in early detection and monitoring of graft rejection episodes.

Abstract: Background: Gene polymorphisms of the chemokine receptors CCR2 and CCR5 (CCR2V64I, CCR5-59029G>A and CCR5Δ32) have been shown to be associated with renal allograft rejection. The aim of this study was to investigate the association of these polymorphisms with allograft rejection among Pakistani transplant patients. Method: A total of 606 renal transplant patients and an equal number of their donors were included in this study. DNA samples were used to amplify polymorphic regions of CCR2V64I, CCR5-59029G>A and CCR5Δ32 by polymerase chain reaction using sequence specific primers. The amplified products of CCRV64I and CCR5-59029G>A were digested with restriction enzymes (BsaB1 and Bsp12861) respectively. The CCR5Δ32 genotypes were determined by sizing the PCR amplicons. The association of these polymorphisms with the biopsy proven rejection and other clinical parameters was evaluated using the statistical software SPSS v.17. Results: In this study, the G/G genotype of CCR2V64I was associated with a high frequency of allograft rejection (p=0.009; OR=2.14; 95% CI=1.2–3.7). Rejection episode(s) in the GA+AA genotypes were found to be significantly lower as compared to the GG genotype (p=0.009; OR=0.4; 95% CI=0.2–0.8). The Kaplan–Meier curve also indicated a reduced overall allograft survival for patients with the G/G genotype of CCR2V64I (59.2±1.4weeks, log p=0.008). There was a significant association with rejection by female donors possessing the CCR2 GG genotype (p=0.02; OR=2.6; CI=1.1–6.3) and male donors with the CCR5-59029 GG genotype (p=0.004; OR=1.7; CI=1.03–3.01). Conclusion: This study shows an association of the CCR2V64I (G/G) genotype with renal allograft rejection. However, no such association was found for the CCR5 gene polymorphisms. Therapeutic interventions such as blocking the CCR2 receptor (especially G polymorphism) may yield better survival of renal allograft in this patient group. Further, chemokine receptors may be added to the spectrum of the immunogenetic factors that are known to be associated with renal allograft rejection. [Copyright &y& Elsevier]