Don Vu

Efficacy of Intravenous Immunoglobulin in the Treatment of Persistent BK Viremia and BK Virus Nephropathy in Renal Transplant Recipients

BK virus-associated nephropathy (BKVN) can cause clinically significant viral infection in renal transplant recipients, leading to allograft dysfunction and loss. The usual management of BKVN involves the 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 human immunoglobulin (IVIG) on the outcome of BKVN in renal transplant recipients. Upon diagnosis of BKVN, patients remained on anti-polyomavirus treatment, consisting of the 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 BKV viremia and BKVN with their mean BK viral loads higher than the baseline (range, 15,000-2 million copies/mL). Mean peak BK load was 205,314 copies/mL compared with 697 copies/mL after 1 year of follow-up. Twenty-seven patients (90%) had a positive response 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 BKV viremia and BKVN and preventing graft loss in patients who had inadequate response to immunosuppression reduction and leflunomide therapy.

Influence of Cyclooxygenase-2 (COX-2) gene promoter-1195 and allograft inflammatory factor-1 (AIF-1) polymorphisms on allograft outcome in Hispanic kidney transplant recipients

Cyclooxygenase-2 (COX-2) alleles have been associated with allograft outcomes in kidney transplant recipients; however, these alleles may be in linkage with other genes. Human allograft inflammatory factor-1 (AIF-1) is a cytoplasmic protein and is produced by macrophages. Its synthesis is regulated by several cytokines, including interferon gamma. We investigated whether polymorphisms of gene encoding COX-2 and AIF-1 were associated with allograft outcomes among Hispanic renal transplant recipients (RTRs). A total of 527 de novo RTRs of Hispanic ethnicity were included in this study transplanted at St. Vincent Medical Center (SVMC) during 2000-2009. Patients were genotyped for the following: COX-2 (-1195C>T rs689466, intron 6 rs2066826) and AlF1 (rs2269475). Analysis of the results showed that COX-2-1195 CC genotype (OR=1.92, CI%=1.00-3.67, p=0.04) were more frequent, but COX-2-1195 CT genotype was less frequent in kidney allograft acute rejection in comparison with control group (OR=0.59, CI%=0.38-0.91, p=0.017). The genetic variant TT/CT of the AIF-1 gene was associated with a lower risk of rejection (OR=0.63, CI%=0.41-0.98, p=0.038). No association of COX-2 (rs2066826) was observed with allograft rejection. We are unable to find statistically significant association between COX-2 and AIF-1 gene polymorphisms and allograft survival. The -1195C>T in the COX-2 promoter and AIF-1 gene polymorphisms could be a potential predictor of allograft rejection in our Hispanic kidney transplant recipients.

Impact of NF-κB gene polymorphism on allograft outcome in Hispanic renal transplant recipients

BACKGROUND The dimeric NF-κB 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 response during kidney allograft rejection. This study aims to determine the association of NF-κB gene polymorphisms with allograft outcomes in the Hispanic renal transplant recipients. METHODS A total of 607 Hispanic renal transplant recipients at St. Vincent Medical Center between 2001 and 2010 were included in this study. The NF-κB genotypes were studied along with clinical data. In the case of NF-κB genotypes, the following single nucleotide polymorphisms (SNPs) were included: NF-κB1 (rs3774959, rs3774932, rs3774937, rs230526, rs230519), NF-κB2 (rs1056890, rs7897947, rs12769316) and NF-κB inducing kinase (NIK) (rs9908330, rs7222094). The association of each genotype with renal allograft survival and acute rejection was evaluated. RESULTS NF-κB1 (rs3774937) CC genotype showed protective association with allograft rejection (OR=0.66, 95% CI=0.44-0.99, p=0.04). There was a significant increase in allograft survival time associated with the NF-κB1 (rs3774959) A allele (OR=0.76, 95% CI=0.60-0.98, p=0.03) while GG genotype was associated with a higher risk of graft failure (OR=1.51, 95% CI=1.02-2.21, p=0.03). There were no associations between polymorphic markers in NF-κB2 and NIK genes with allograft survival or acute rejection. Among non-genetic factors, we found that the use of tacrolimus, a deceased donor, delayed graft function and acute rejection were associated with allograft failure. CONCLUSION The result of present study suggests that NF-κB1 gene polymorphisms may determine the incidence of acute rejection or graft survival among Hispanic allograft recipients.

Association of interferon gamma gene polymorphisms with BK virus infection among Hispanic renal allograft recipients.

Background BK virus nephropathy is one of the most common viral infections that affect up to 10% of renal transplant recipients (RTRs), causing allograft dysfunction and graft loss. Interferon-gamma (IFN-&ggr;) gene polymorphisms have been associated with parvovirus B19, hepatitis C virus, HIV-1/AIDS infection, cytomegalovirus viremia, and disease. IFN-&ggr; is known to have potent inhibitory effects on BK virus gene expression, both at the level of transcription and translation. Methods It was investigated whether IFN-&ggr; polymorphisms are associated with BKV infection. Genotyping of four single-nucleotide polymorphisms located in the IFN-&ggr; gene were performed on DNA collected from a total of 251 RTRs (71 RTRs with BKV infection and 180 without BKV infection). Results Analysis of the results showed that IFN-&ggr; (rs12369470) CC genotype was significantly associated with susceptibility to BKV infection (OR: 2.9, 95% CI: 1.29–6.44, P=0.007) while the IFN-&ggr; +874 (rs2435061) TT and (rs2406918) CC genotypes appear to be markers for protection against BKV infection (OR: 0.29, 95% CI: 0.1–0.83, P=0.01 for rs245061; OR: 0.61, 95% CI: 0.4–0.94, P=0.02 for rs24069718). A haplotype analysis using the combination of rs2435061-rs2406918-rs2870953 showed that the A-G-T haplotype was associated with a significantly reduced risk for BKV infection (OR: 0.43, 95% CI: 0.25–0.73, P=0.001). Conclusion Polymorphisms in the IFN-&ggr; gene may confer certain protection or predisposition for BKV infection.

Genetic polymorphisms of UGT1A8, UGT1A9 and HNF-1α and gastrointestinal symptoms in renal transplant recipients taking mycophenolic acid.

Mycophenolic acid (MPA), a widely used immunosuppressant, has a complex metabolism that involves a number of enzymes. Some of its metabolites are thought to be the cause of gastrointestinal (GI) side effects. In this study, we investigated whether polymorphisms of UDP-glucuronosyltransferases (UGT1) A8, 1A9, and hepatocyte nuclear factor (HNF1α) genes or pharmacokinetic parameters of mycophenolic acid (MPA) were associated with the severity of GI symptoms in patients receiving MPA therapy. A total of 109 kidney transplant patients taking mycophenolic acid (MPA) derivatives were genotyped for UGT1A8, 1A9 and HNF1α genes. Among these, a total of 15 patients were participants in the pharmacokinetic study. Severity of GI symptoms was assessed using a validated Gastrointestinal Symptom Rating Scale (GSRS). The overall and subscale GSRS scores were measured at 1 week (baseline), 2 weeks, 3 months and 6 months post-transplantation. In the case of the pharmacokinetic study, EC-MPS was administered and a total of nine blood samples were obtained at -1, 0, 0.5, 1, 2, 4, 6, 8, and 12h. Genotypes of UGT1A8 were significantly associated with the overall GSRS scores at week 1 (p=0.02) and week 2 (p=0.036). Subscales were only statistically significant for constipation at week 1 (p=0.002) and indigestion at week 2 (p=0.02), while UGT1A9 was only significant for the constipation at week 1 (p=0.04). HNF1α genotypes were significantly different at week 1 in the overall GSRS (p=0.004), and for abdominal pain (p=0.04), acid reflux (p=0.036) and constipation subscales (p=0.04). In addition, abdominal pain was statistically significantly different at 3 months and 6 months after transplantation (p=0.03 and 0.02, respectively). In the case of the pharmacokinetic study, we have found some correlations between MPAC0 and constipation (p=0.02) where MPAAUC was correlated with acid reflux (p=0.02) and constipation (p=0.012), MPAGCL/F was correlated to acid reflux, indigestion, constipation and the sum of the GSRS scores (p=0.037, p=0.032, p=0.033 and p=0.04, respectively). Multinomial regression analysis for MPAGCL/F showed a statistical significance for the subscale indigestion and the sum of the GSRS (p=0.033 and p=0.037, respectively). Our data suggests that among patients receiving MPA the UGT1A9 alleles might play a role in determining the severity of early GI side effects, while the HNF1α allele appears to be associated with a later effect as well as early side effects. Our data also showed that some kinetic parameters might predict MPA side effects.

Association between granzyme B and perforin I polymorphisms and allograft outcomes in Hispanic kidney transplant recipients

Granzyme B (GZMB) and perforin 1 gene (PRF1) are key effector molecules of cytotoxic T lymphocytes, in causing acute and chronic solid organ transplant rejection. In this study, we analyzed the impact of GZMB and PRF1 polymorphism on kidney allograft outcomes. In all, 527 de novo kidney Hispanic allograft recipients were genotyped for PRF1 (rs10999426, rs35947132) and GZMB (rs8192917, rs7144366). PRF1 (rs10999426, rs35947132) G alleles and GG genotypes were negatively associated with allograft rejection, demonstrating protection against allograft rejection (OR = 0.61, p = 0.005 for rs1099946; OR = 0.4, p = 0.01 for rs 35947132). On the other hand, the GA heterozygosity of PRF1 was found marginally associated with the rejection group (OR = 1.53, p = 0.05 for rs10999426; OR = 2.24, p = 0.07 for rs35947132). There was a significant increase in allograft survival in time period studied for the PRF1 (rs10999426) GG genotype, while the GA heterozygosity was associated with graft failure. We found no association for polymorphic markers in GZMB gene with allograft rejection. Survival was significantly improved for patients who were homozygous TT for the GZMB (rs8192917) (TT vs. CC/TT, p = 0.041). The result suggests that PRF1 and GZMB gene polymorphisms may determine the incidence of acute rejection or graft survival among Hispanic allograft recipients.

Effects of mycophenolic acid on highly sensitized patients awaiting kidney transplant

BACKGROUND 10-30% of dialysis population awaiting renal transplantation is sensitized. Mycophenolic acid (MPA) has been shown to reduce panel reactive antibody (PRA) formation in kidney transplant recipients. Our aim was to investigate whether MPA could effectively reduce anti-HLA antibody levels and allow successful transplantation. METHODS A total of 40 highly sensitized patients were treated orally with MPA. All patients had T-cell PRA values greater than 30% (73% of patients were ≥ 75%). The PRAs, T-cell/B-cell flow cytometry crossmatch (FCXM) mean channel shift (MCS), patient/graft survival, acute rejection, and serum creatinine (SCr) were recorded. RESULTS All 40 patients showed a decrease in PRA levels. Eighteen of the 40 patients (40%) received a transplant. All four living donor recipients converted to a negative crossmatch. There was a significant decrease in FCXM MCS in all 18 transplanted patients. The mean SCr at 24 months was 1.00 ± 0.25mg/dL. Five patients (28%) experienced acute rejection. The overall one year actuarial patient and graft survival were 94% and 88%, respectively. CONCLUSIONS These findings suggest that MPA therapy is effective in reducing PRAs and increases the likelihood of successful transplantation in sensitized recipients in a potentially simpler and more cost effective manner than the current regimens employed.

Association of Interferon-γ and Tumor Necrosis Factor-α Cytokine Gene Polymorphisms with Symptomatic BK Virus Infection: 2475

Introduction: BK virus (BKV)-associated nephropathy (BKVAN) is currently the most challenging infectious cause of renal graft dysfunction in kidney transplant patients, leading to graft loss in up to 10%. Several single nucleotide polymorphisms (SNPs) in the promoter of cytokines have been associated with parvovirus B19, hepatitis C virus, HIV-1/AIDS infection. Deregulated production of pro-or anti-inflammatory cytokines plays an important role in the disease susceptibility and progression. In the present study, we aimed at genotyping the SNPs of the promoter regions of tumor necrosis factor alpha (TNF-α) and the interferon gamma (IFN-γ) in a group of renal allograft recipients affected by BK virus infection, taking into account the role that these cytokines might play in the immune response against BK virus. Methods: The TNF-α −308G/A (rs1800629) and IFN-γ [(rs2069718, G/A) (intron3), (rs12369470, C/T) and (rs2870953, T/A) (3‘ untranslated region)] genotypes were determined in 70 kidney allograft recipients with BKVN and 182 without BKVN (control group). Distributions of genotypes were compared to the Hardy-Weinberg theoretical distribution using the chi-square test. A logistic regression model was used to evaluate the effect of the genetic polymorphisms on BKVN. Nongenetic and genetic characteristics were included in the multivariate risk model. A p value less than 0.05 was considered statistically significant. Results: BKVN developed at an average of 1.6 years post-transplantation (range from 38 days to 8 years). Analysis of the results showed that IFN-γ (rs12369470) C allele (p=0.002, OR=1.93) was more frequent, but IFN-γ (rs2069718) G allele (p=0.024, OR=0.61) was less frequent in BKVN group in comparison with control group. Using multiple logistic regression along with race, donor type, and recipient age showed that the GG genotype of the IFN-γ (rs2069718) may have a protective effect with regard to BKVN (p=0.034). The allelic as well as genotypic frequencies of -308G >A TNF-α gene polymorphism did not significantly differ between the BKVN and control groups (p>0.05). Of the nongenetic factors, the use of tacrolimus and mycophenolate mofetil was associated with increased risk for BKVN. Conclusion: The results suggest that IFN-γ (rs12369470 and rs2069718) gene polymorphisms has predictive values for the development of BKVN in renal allograft recipients. MONDAY MORNING MINI ORAL ABSTRACTS