BK virus associated nephropathy (BKVN) can cause clinically significant viral infections in renal transplant recipients, leading to allograft dysfunction and loss. The usual management of BKVN involves reduction of immunosuppression and the addition of leflunomide, quinolones, and cidofovir, but the rate of graft loss remains high. The aim of this study was to assess the impact of treatment with intravenous immunoglobulin (IVIG) on the outcome of BKVN in renal transplant recipients. Upon diagnosis of BKVN, patients remained on anti-polyomavirus treatment consisting of reduction of immunosuppression and the use of leflunomide therapy. Treatment with IVIG was given only to patients who did not respond to 8 weeks of the adjustment of immunosuppression and leflunomide. All 30 patients had persistent BK viremia and BKVN with their mean BK viral loads higher than the baseline (range 15,000 - 2 millions copies/mL). Mean peak BK load was 205,314 copies/mL compared to 697 copies/mL after one year follow-up. Twenty-seven patients (90%) had positive responses in clearing viremia. The actuarial patient and graft survival rates after 12 months were 100% and 96.7%, respectively. IVIG administration appeared to be safe and effective in treating BK viremia and BKVN and in preventing graft loss in patients who had inadequate response to immunosuppression reduction and leflunomide therapy.

Background: Cytomegalovirus (CMV) is one of the most common cause of viral infection, causing morbidity and mortality among kidney transplant recipients (RTRs). The dimeric NF-kB transcription factors play critical roles in diverse cellular processes including adaptive and innate immunity, cell differentiation, proliferation and apoptosis. It regulates the expression of numerous genes that play a key role in the inflammatory and immune responses. Inhibitors of NF-kB, known as inhibitor kappa B-alpha (IkB-α), block NF-kB transcriptional activity by forming stable IkB-α:NF-kB complexes. The aim was to investigate the association of gene polymorphisms in the NF-kB and IkB pathway with CMV infection in RTRs. Methods: IkB-α promoter polymorphisms at position -881 (A/G), -826 (C/T), and 297 (C/T) were studied in 247 RTRs (52 RTRs with CMV infection and 195 without CMV infection), using DNA-based polymerase chain reaction with sequence-specific primers and restriction. In the case of NF-kB genotypes, the following single nucleotide polymorphisms (SNPs) were included: NF-kB1 (rs3774959, rs3774932, rs3774937, rs230526, rs230519), NF-kB2 (rs1056890, rs7897947, rs12769316) and NF-kB inducing kinase (NIK) (rs9908330, rs7222094). Results: Median time to CMV infection was 6 months with a mean peak CMV viral load of 7925 copies per ml. Patients with donor-positive/recipient-negative [D+/R-] serostatus were found to be associated with a high risk of CMV infection (p=0.001). A statistically significant correlation was found between IkB-α -297T allele polymorphism and the risk of CMV. Three common haplotypes were found, of which haplotype 2 (GTT) was significantly associated with an increased risk for CMV infected group as compared to non-CMV group (p=0.01). The association was independently significant in multiple logistic regression (p=0.02) along with serologic status D+/R-, acute rejection and thymoglobulin induction. The allelic as well as genotypic frequencies of NF-kB SNPs did not significantly differ between CMV infection and non-CMV group. Conclusion: These results indicated that the NF-kB activation pathway might be associated with the CMV infection.

Background: Tacrolimus is a substrate of metabolic enzyme cytochrome P450 3A, and a cell membrane transporter, ABCB1 gene product, P-glycoprotein (P-gp). This study aims to investigate the effect of the new functional CYP3A4*22, CYP3A5 and ABCB1 polymorphisms on Tac trough concentrations in renal transplant recipients (RTRs). Methods: We investigated the impact of the CYP3A4*22 (intron 6 C>T), CYP3A5*3 6986 G>A, ABCB1 C1236>T and ABCB1 C3435>T polymorphisms on Tac pharmacokinetics in 229 Hispanic RTRs at months 1, 3, and 6 post transplantation. Trough blood levels ([Tac](0) in ng/ml), dose-adjusted [Tac](0) (ng/ml per mg/kg bodyweight) as well as doses (mg/kg bodyweight) required to achieve target concentrations were compared among patients according to allelic status for CYP3A4*22, CYP3A5 and ABCB1. Results: Frequencies of variant alleles among the RTRs were CYP3A5*3, 82.3%; ABCB1 1236T, 54% and ABCB1 3435T, 56.2%. The CYP3A4*22 variant allele was observed in only 17 (6.6%) patients. The overall mean daily-dose requirement to reach the same predose Tac blood concentration was 29% lower for carriers of the CYP3A4*22 T variant allele than for CC patients (95%CI, -43% to 18%; p=0.02). When CYP3A4/CYP3A5 genotypes were combined, the difference was even more striking as the so-defined CYP3A poor metabolizer group presented dose-adjusted concentration 1.4- and 3.9-fold higher for Tac than the intermediate metabolizer and extensive metabolizer groups, respectively. Renal function, assessed by calculation of SCr (mg/dL) was not statistically significant between CYP3A4*22 T allele carriers at 1,3,6 months of follow-up compared with wild-type patients. Higher Tac trough blood concentrations were observed in the homozygous CYP3A5*3 allele and homozygous ABCB1 C1236>T TT genotype. Conclusions: The CYP3A4*22 (intron 6 C>T) polymorphism is associated with a significant alter Tac metabolism. Analysis of CYP3A4*22 intron 6 C>T along with CYP3A5*3 and ABCB1 just before transplantation may help to identifying patients at risk of Tac overexposure.

BACKGROUND:Cytomegalovirus (CMV) is the most common cause of viral infection, causing morbidity and mortality among renal transplant recipients (RTRs). Cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and interferon-gamma (IFN-γ) have been shown to possess antiviral properties, and their polymorphisms are associated with disease outcome. The aim was to investigate the association of gene polymorphisms in IL-10, IFN-γ, and TNF-α with CMV infection in RTRs.METHODS:IL-10 -1082 A>G, -592 A>C; TNF-α -308 A>G; and IFN-γ +874 A>T gene polymorphisms were studied in 247 Hispanic RTRs (52 RTRs with CMV infection and 195 without CMV infection), using DNA-based polymerase chain reaction with sequence-specific primers and restriction.RESULTS:Median time to CMV infection was 8 months, with a mean peak CMV viral load of 25,314 copies/mL. Patients with donor-positive/recipient-negative (D+/R-) serostatus were found to be associated with a high risk of CMV infection (P = 0.001). A statistically significant correlation was found between IFN-γ +874 A>T polymorphism and the risk of CMV infection. The IFN-γ +874 AA genotype was associated with a 3.4-fold increased risk for the CMV-infected group compared to the non-CMV group (odds ratio = 3.4, 95% confidence interval = 1.24-9.34, P = 0.01). The association was independently significant in multiple logistic regression (P = 0.01), along with serologic status D+/R-, acute rejection, and anti-thymocyte globulin induction. The allelic as well as genotypic frequencies of TNF-α and IL-10 did not significantly differ between the CMV-infection group and the control group. Individuals with IFN-γ +874 AT and AA genotypes exhibited higher risk of allograft loss.CONCLUSION:This study suggested that RTRs with variant homozygous IFN-γ AA genotype were at risk of CMV infection, whereas the high producer IFN-γ +874 TT genotype appears to be associated with lower risk of CMV infection.

P315 Body: Diabetes Mellitus (DM) is the most common cause of end-stage renal disease (ESRD). The mortality and morbidity of DM patients on dialysis is high, with survival rate 61% at 2 yrs. and 26% at 5 yrs. For diabetic patients with ESRD, several recent studies have shown transplantation is better than dialysis. Aim of Study: 1). To compare the renal transplant outcome between diabetic vs. non-diabetic patients, and 2) to compare mortality rate of diabetic patients remaining on dialysis vs. those transplanted. Methods: Retrospectively we analysed 336 diabetic patients waiting for transplant vs. 453 diabetic patients who received a kidney transplant. Graft and patient survival of diabetic transplanted patients (n=453) compared to non-diabetic patients (n=1150) transplanted between 1996 to 2002. Anova T-test and Kaplan Meier were used for data analyses. Results:FigureFigureConclusion: Despite additional risk factors associated with transplantation for diabetic patients, the mortality rate of diabetic patients remaining on dialysis is significantly greater than those transplanted at 20% vs. 8% (P=0.001). However, the post-transplant patient and graft survival of diabetic vs. non-diabetic patients is equivalent. In conclusion, transplantation is the best option for diabetic patients with ESRD.