Genetic variations in a Sestrin2/Sestrin3/mTOR Axis and development of new-onset diabetes after kidney transplantation.

BACKGROUND: Genetic variations in Sestrin2/Sestrin3/ mTOR axis may cause obesity-associated metabolic syndrome, including lipid accumulation and insulin resistance thereby increasing individual's risk of diabetes. In this study, we explored the association between single nucleotide polymorphisms (SNPs) of these genes and new onset diabetes after transplantation in Hispanic renal transplant recipients (RTRs). METHODS: Nine potential functional polymorphisms in Sestrin2, Sestrin3 and mTOR genes were genotyped using the Taqman qPCR method in this study. We compared 160 Hispanic RTRs with no evidence of pre-existing diabetes, who developed new onset diabetes after transplantation (NODAT) with 152 controls with no history of diabetes. The logistic proportional hazard model was used to examine risks for NODAT. Nongenetic and genetic characteristics were included in the multivariate risk model. RESULTS: Significant associations were observed between NODAT and mTOR TT (rs2295080 OR = 1.79, 95% CI =1.14-2.82, p = 0.01), Sestrin2 AA (rs580800, OR = 0.42, 95% CI =0.27-0.67, p = 0.002), and Sestrin3 AA (rs684856, OR = 0.45, 95% CI = 0.27-0.75, p = 0.001). Sestrin2 AA (rs580800), Sestrin3 AA (rs684856) and mTOR TT (rs2295080) remained significantly associated with NODAT after adjusting for acute rejection and sirolimus use. No interactions observed between the mTOR rs2295080 and Sestrin3 rs684856 and risk of NODAT (mTOR rs2295080 and Sestrin3 rs684856, p = 0.123 and mTOR rs2295080 and Sestrin2 rs580800, p = 0.167). Of the nongenetic factors, use of sirolimus and older age were associated with an increased risk for NODAT. CONCLUSION: Polymorphisms in the Sestrin2/Sestrin3/ mTOR gene may confer certain protection/predisposition for NODAT.

Effects of intravenous immunoglobulin therapy and Fc gamma receptor polymorphisms on BK virus nephropathy in kidney transplant recipients.

BACKGROUND: BK virus nephropathy (BKVN) is a major complication in kidney transplant patients. This study aimed to investigate the efficacy of intravenous immunoglobulin (IVIG) therapy against persistent BKVN and to evaluate the association between persistent BKVN and Fc gamma receptor (FcγR) single nucleotide polymorphisms (SNPs). METHODS: A total of 86 patients out of 279 kidney recipients with BKVN were investigated in a single-center retrospective study. The majority of 86 patients were Hispanic and Asian (69.8% and 17.4%). Patients were treated with adjunctive IVIG or standard therapy (controls). Subgroup analysis was performed between IVIG responders and non-responders. BK virus copy number and serum creatinine (SCr) were measured to evaluate the impact of IVIG. We analyzed the association between the response to IVIG and genotype at FcγR3A (rs396991) and FcγR2A (rs1801274) SNPs. RESULTS: Viral load in IVIG non-responders was significantly higher than in responders at the time of diagnosis (219 271.8 vs 29 816.3 copies/mL, P = .015) and after 6 months of IVIG use (12 789.5 vs 1369.5 copies/mL, P < .001). However, analyses SNP of FcγR2A (OR = 0.807, CI = 0.435-1.496 P = .495) and FcγR3A (OR = 0.997, CI = 0.505-1.970, P = .993) SNPs showed no significant differences between the 2 groups. CONCLUSION: IVIG appears to lower BK DNA viral load significantly in patients with persistent BKVN. However, no associations were identified between BKVN and FcγR2A or FcγR3A SNPs.

Analysis of genetic and clinical risk factors of post-transplant thrombocytopenia in kidney allograft recipients.

BACKGROUND: Hematological abnormalities after transplantation are complications that may arise after renal transplantation, of which thrombocytopenia is associated with increased risk of bleeding and other complications. The development of thrombocytopenia is affected by various clinical conditions, and the stromal-derived factor 1 (SDF1) and platelet factor 4 (PF4) genes are known to be involved in the production or destruction of platelets. The purpose of this study was to investigate the prevalence of posttransplant thrombocytopenia and its association with other clinical conditions and genetic polymorphisms of SDF1 and PF4 genes a long time after transplantation. METHODS: This is a retrospective study that includes a total of 305 kidney transplant (KT) recipients between 2008 and 2012 at St. Vincent Medical Center, Los Angeles, CA. In this study, posttransplant thrombocytopenia was defined as a 30% reduction in platelet count from the baseline in the first week or a decrease of <100 (×103/µL) within 1 year after KT. The subjects were divided into posttransplant thrombocytopenia and control groups. The chi-square test, t-test, and logistic regression were used for the analyses. RESULTS: In the first week, 65 patients had a 30% reduction in platelet count (21.3%). Gender, simultaneous kidney-pancreas transplantation, induction therapy (IT), and only alleles of rs2297630 of SDF1, among the SDF1 and PF4 genes, showed statistically significant differences. The rs2297630 alleles were consistently significant risk factors (non G vs. G: odds ratio = 0.445; 95% confidence interval, 0.224-0.884; p = .021) in the multiple logistic regression. In the 1-year study, 61 patients (20.0%) had platelet counts of <100 × 103/µL and had statistically significant differences in patients who had delayed graft function and induction therapy. CONCLUSIONS: In this study, non-G group of rs2297630 in SDF1 significantly increased the risk of post-transplant thrombocytopenia in the first week of kidney transplantation.

Association of genetic polymorphisms of macrophage inhibitory factor (MIF) and B-cell activating factor (BAFF) with the detection of donor specific antibodies in kidney allograft recipients.

The posttransplant development of donor specific antibodies (DSA) initiates the antibody mediated rejection (AMR), which is associated with the increased rate of graft loss. One of the characteristics of AMR is the infiltration of innate immune system including macrophages, monocytes, neutrophils or NK cells. Macrophage inhibitory factor (MIF) and B-cell activating factor (BAFF) are well known cytokines that are associated with the activation of the innate immune system which can damage kidney allograft. In this article, the association of the genetic polymorphisms of MIF and BAFF with the development of DSA including Class I and II in kidney transplant patients is investigated. A total of 231 renal transplant patients between 2008 and 2012 at St. Vincent Medical Center, CA were studied in a retrospective study design. DSA were determined by Luminex technology, and single nucleotide polymorphisms (SNP) of MIF and BAFF were determined by the real time PCR based on 5' nuclease allelic discrimination assay. The genetic polymorphisms of MIF rs1007888 (C/T) was associated with increased risk of positive DSA detection (p=0.04) after transplantation, and consistently significant after 1year (p=0.016). Furthermore, the presence of C allele were associated with the increased risk of Class I DSA detection (OR 1.816, CI 1.141-2.889, p=0.011). Also, genetic polymorphisms of BAFF rs12583006 were associated with the increased risk of Class II DSA detection (p=0.033). In conclusion, the genetic polymorphisms of MIF and BAFF may increase the risk of posttransplant development of DSA. This result suggests the association between the development of posttransplant DSA and the activation of innate immune system.

Renal Transplant Patients Biopsied for Cause and Tested for C4d, DSA, and IgG Subclasses and C1q: Which Humoral Markers Improve Diagnosis and Outcomes?

The association between donor specific antibodies (DSA) and renal transplant rejection has been generally established, but there are cases when a DSA is present without rejection. We examined 73 renal transplant recipients biopsied for transplant dysfunction with DSA test results available: 23 patients diffusely positive for C4d (C4d+), 25 patients focally positive for C4d, and 25 patients negative for C4d (C4d-). We performed C1q and IgG subclass testing in our DSA+ and C4d+ patient group. Graft outcomes were determined for the C4d+ group. All 23 C4d+ patients had IgG DSA with an average of 12,500 MFI (cumulative DSA MFI). The C4d- patients had average DSA less than 500 MFI. Among the patients with C4d+ biopsies, 100% had IgG DSA, 70% had C1q+ DSA, and 83% had complement fixing IgG subclass antibodies. Interestingly, IgG4 was seen in 10 of the 23 recipients' sera, but always along with complement fixing IgG1, and we have previously seen excellent function in patients when IgG4 DSA exists alone. Cumulative DSA above 10,000 MFI were associated with C4d deposition and complement fixation. There was no significant correlation between graft loss and C1q positivity, and IgG subclass analysis seemed to be a better correlate for complement fixing antibodies in the C4d+ patient group.

Association of genetic polymorphisms of angiopoietin-like 4 with severity of posttransplant proteinuria in kidney allograft recipients.

BACKGROUND: Proteinuria is a hallmark of glomerular injury, and persistent proteinuria is associated with graft failure in kidney transplant patients. Recently, it is known that the level of circulating angiopoietin-like 4 (ANGPTL4) is elevated in the patients with human nephrotic syndrome, in which ANGPTL4 is responsible for relieving proteinuria. PURPOSE: The purpose of this study is to determine effects of clinical factors and genetic polymorphism of ANGPTL4 on proteinuria after kidney transplantation. METHODS: A total of 282 patients out of 400 renal transplant patients between 2008 and 2012 at St. Vincent Medical Center, CA were studied in a retrospective study design. The level of proteinuria was measured by random urine protein to creatinine ratio, and divided into two groups (Group 1: UPC<500mg/day, Group 2: ≥500mg/day). Single nucleotide polymorphisms of ANGPTL4 genes (rs1044250, rs2278236, rs116843064, rs11672433, rs4076317) were determined by real time PCR with sequence specific primers. RESULTS: Among various clinical factors, only delayed graft function, mTOR inhibitor use and fish oil use were significantly associated with posttransplant proteinuria. Statistical differences were found in genetic polymorphisms of ANGPTL4 (rs1044250, rs2278236) in regards to proteinuria among tested patients. rs1044250 (C/T, T228M, missense mutation) alleles showed multiple significant differences (Group 1 vs. Group 2: C vs. T: OR=1.893, CI=1.322-2.710, p<0.001). Similar trends were found in rs2278236 (A/G) alleles with statistical significances (Group 1 vs. Group 2: A vs. G: OR=0.620, CI=0.443-0.867, p=0.005). With multiple logistic regression, rs1044250 was still a significant risk factor of moderate/severe proteinuria (p=0.021). CONCLUSIONS: This study suggests that the presence of C allele of rs1044250 and G allele of rs2278236 in ANGPTL4 gene is associated with higher risk of moderate/severe proteinuria in renal transplant patients.

Clinical risk factors associated with the post-transplant anemia in kidney transplant patients.

BACKGROUND: Anemia is a very common occurrence in post-renal transplant patients. Post-transplantation anemia (PTA) is associated with significant graft loss or cardiovascular morbidity. The objective of this study is to identify clinical risk factors associated with anemia after kidney transplantation. METHODS: Our retrospective cohort study included a total of 570 renal transplant recipients. For the definition of anemia, we adopted "the lower limit of normal for Hgb concentration of blood" proposed by Beutler E and Waalen J [14], which has adjustments for age, gender and ethnicity. Post-transplant anemia (PTA) was defined as anemia that arose between 30 and 180days after transplantation. Based on this definition, of the 570 renal transplant recipients, 344 patients (62.1%) experienced PTA. The patients were divided into anemic and non-anemic groups, and a total of 20 clinical factors were compared between the two groups. RESULTS: In the univariate analysis, age, race, multiple transplants, delayed graft function (DGF), and use of tacrolimus, sirolimus, thymoglobulin, ganciclovir, ACE inhibitors, and ARBs were associated with PTA. In the multivariate analysis, age (>60years old, OR=2.62, p=0.001), race (OR=2.54, p=0.001), and use of sirolimus (OR=2.01, p=0.019), antiviral agents (OR=1.96, p=0.015), thymoglobulin (OR=1.86, p=0.011), and DGF (OR=2.78, p=0.001) remained significant. CONCLUSION: The current results show that undergoing a transplant at age 60 or older, use of sirolimus, antiviral agents, and thymoglobulin are independent clinical risk factors associated with PTA. In terms of ethnicity, AA, MEA, or PI is higher risk for PTA and Hispanic is significantly lower risk for PTA compared to Caucasians.

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.

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.

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.

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 vitamin D binding protein polymorphism with long-term kidney allograft survival in Hispanic kidney transplant recipients.

Polymorphism of genes encoding components of the vitamin D pathway including vitamin D receptor (VDR) and vitamin D binding protein (VDBP), have been widely explored due to the complex role played by vitamin D in renal transplant outcomes. In this study, we investigated whether polymorphisms of genes encoding VDR and VDBP were associated with allograft survival or acute rejection (AR) among a Hispanic kidney transplant population. A total of 502 Hispanic renal allograft recipients at the St. Vincent Medical Center between 2001 and 2010 were genotyped for four different single nucleotide polymorphisms of VDR: FokI C>T (rs2228570), BsmI G>A (rs1544410), ApaI T>G (rs7975232), and TaqI T>C (rs731236). We also performed genotyping for one common polymorphism in the VDBP gene (rs4588). Survival was significantly improved for patients who were homozygous GG for the rs4588 G>T allele in the VDBP gene (GG vs. GT + TT, OR = 0.63, p = 0.02) while GT genotype was associated with a higher risk of graft loss (GT vs. GG + TT, OR = 1.67, p = 0.01). We found no association for polymorphic markers in VDR with allograft survival and AR. The frequency of the haplotype GTCG (in the order of VDR FokI C>T, BsmI G>A, ApaI T>G, and TaqI T>C), was significantly different in the patients with graft rejection compared to the control (p = 0.007) while ACCA haplotype was found to be associated with graft loss (p = 0.02). Hence, the VDBP G>T polymorphism (rs4588) and two haplotypes (GTCG and ACCA) of VDR appear to be associated with renal allograft outcomes among Hispanic allograft recipients.

Impact of a faculty orientation and development committee.

This paper describes the faculty enrichment activities and outcomes of a faculty orientation and development committee at a college of pharmacy. The committee used a continuous quality improvement (CQI) framework that included needs assessment, planning and implementation of programs and workshops, assessment of activities, and evaluation of feedback to improve future programming. Some of the programs established by the committee include a 3-month orientation process for new hires and development workshops on a broad range of topics including scholarship (eg, research methods), teaching (eg, test-item writing), and general development (mentorship). Evidence of the committee's success is reflected by high levels of faculty attendance at workshops, positive feedback on workshop evaluations, and overall high levels of satisfaction with activities. The committee has served as a role model for improving faculty orientation and retention.

Genetic and clinical risk factors of new-onset diabetes after transplantation in Hispanic kidney transplant recipients.

BACKGROUND: New-onset diabetes after transplantation (NODAT) is one of the major complications after transplantation and is associated with reduced overall patient and graft survival. The objective of this study was to determine the genetic and clinical risk factors for NODAT in Hispanic kidney transplant recipients. METHODS: Hispanic kidney allograft recipients without evidence of preexisting diabetes who developed NODAT (n=133) were studied using Hispanic kidney transplant recipients with no evidence of diabetes as a control group (n=170). NODAT was defined as fasting glucose levels ≥126 mg/dL on two or more occasions or patients taking any insulin or oral hypoglycemic agents 1 month or later after kidney transplantation. Fourteen alleles in nine genes were genotyped and other patients' clinical data with genotype data were analyzed by logistic regression. RESULTS: Among 14 alleles, hepatocyte nuclear factor 4 alpha (HNF4A) AA (rs2144908, odds ratio [OR]=1.96, confidence interval [CI]=1.08-3.50, P=0.010), HNF4A TT (rs1884614, OR=2.44, CI=1.42-4.48, P=0.002), and insulin receptor substrate 1 AA+AG (rs1801278, OR=2.71, CI=1.16-6.89, P=0.021) remained significant after logistic regression. Among the clinical factors, average age (OR=1.01, CI=1.00-1.08, P=0.048), sirolimus (OR=5.36, CI=3.02-10.4, P=0.001), deceased donor (OR=1.96, CI=1.16-2.94, P=0.015), and acute rejection (OR=2.92, CI=1.31-5.77, P=0.009) remained significant after logistic regression. CONCLUSION: This study indicates that polymorphism of two alleles of HNF-4A gene (rs2144908 and rs1884614) and insulin receptor substrate 1 (rs1801278) are significantly associated with NODAT in kidney transplant patients with Hispanic ethnicity. In the case of clinical factors, older age (>50 year), deceased donor type, acute rejection, and sirolimus use are associated with NODAT in Hispanic kidney transplant recipients.

The pharmacokinetics of enteric-coated mycophenolate sodium and its gastrointestinal side effects in de novo renal transplant recipients of Hispanic ethnicity.

OBJECTIVE: The aim of the study is to characterize the pharmacokinetics and the gastrointestinal side effect profiles of enteric-coated mycophenolate sodium (EC-MPS) in de novo kidney transplant patients of Hispanic ethnicity. MATERIALS AND METHODS: The pharmacokinetic study of EC-MPS was conducted in 11 de novo kidney transplant patients of Hispanic ethnicity. Eight blood samples were obtained after EC-MPS was given at the steady state. Blood concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were measured. RESULTS: The mean age (± standard deviation) was 39.4 (± 12.3) years. The mean daily dose of EC-MPS at the time of the pharmacokinetic study was 1408 ± 108 mg. For MPA and MPAG, the time to peak concentration was 2.5 ± 1.3 hours and 4.6 ± 3.1 hours, respectively; the peak concentration (Cmax) was 19.3 ± 17.2 mg/L and 109.4 ± 49.2 mg/L; and the area under the curve from 6 to 12 hours (AUC6-12) was 32.2 ± 19.3 mg·hr/L and 373.7 ± 235.8 mg·hr/L, respectively, which represents 41.3% and 43.0% of AUC0-12. The AUC0-12 for MPA measured 77.8 ± 53.1 mg·hr/L and for MPAG 869.2 ± 388.8 mg·hr/L. Seven patients (64%) exhibited a second peak at approximately 8.3 hours after the dose at a mean concentration (± standard deviation) of 10.3 ± 7.6 mg/L. The Cmax or AUC of MPA does not correlate with overall Gastrointestinal Symptom Rating Scale scores or subscale scores, but the Cmax of MPAG correlates with indigestion subscale (P = 0.022), diarrhea (P = 0.032), and overall scores (P = 0.028). The AUC of MPAG also correlates with acid reflux (P = 0.024) and indigestion (P = 0.032). DISCUSSION AND CONCLUSION: The pharmacokinetics of EC-MPS has a high variability in de novo kidney transplant patients of the Hispanic ethnicity, which was similar to other ethnic groups. The MPA exposure expressed by the AUC appears to be higher in Hispanic patients than those reported in other ethnic groups, which may be the result of various factors such as difference of the uridine diphosphate glucuronosyltransferase enzyme genotypes, but gastrointestinal side effects were acceptable and the Cmax or AUC of MPAG showed correlations with gastrointestinal symptoms.

Gene polymorphism of vascular endothelial growth factor -1154 G>A is associated with hypertensive nephropathy in a Hispanic population.

The aim of this study was to determine the association between hypertensive nephropathy and gene polymorphisms of vascular endothelial growth factor (VEGF) in a self-reported Hispanic patient group. A total of 155 Hispanic living kidney donors as controls and a total of 86 Hispanic kidney transplant patients, whose renal failure was attributed to hypertensive nephropathy after ruling out diabetes mellitus or other causes, were genotyped for four different single nucleotide polymorphisms of VEGF: -2578 C>A (rs699947), -1154 G>A (rs1570360), -460 C>T (rs833061), and +936 C>T (rs3025039). The homozygous mutant type (AA) of VEGF -1154 G>A (rs1570360) was found with significantly higher frequency in the hypertensive nephropathy patients than in controls. On the other hand, homozygous wild type (GG) was found less frequently in the hypertensive nephropathy patient group than in the control group. Linkage disequilibrium (LD) analyses revealed a high degree of LD among VEGF -2578 C>A (rs699947), VEGF -1154 G>A (rs1570360), and VEGF -460 C>T (rs833061). The haplotype analysis revealed that two haplotypes, CGTC and CATC (in the order of VEGF -2578 C>A (rs699947), -1154 G>A (1570360), -460 C>T (rs833061), and +936 C>T (3025039)), were significantly associated with hypertensive nephropathy in Hispanic patients. Hence, the -1154 G>A polymorphism (rs1570360) and two haplotypes (CGTC and CATC) of VEGF appear to be associated with hypertensive nephropathy in Hispanic patients who developed end-stage renal disease requiring kidney transplant.

Genetic polymorphisms of MRP2 and UGT2B7 and gastrointestinal symptoms in renal transplant recipients taking mycophenolic acid.

The aim of this study was to determine the relationship between single nucleotide polymorphisms in multidrug resistance protein 2 (MRP2) and uridine diphosphate glucuronosyltransferase (UGT) 2B7 and the severity of gastrointestinal (GI) symptoms in patients receiving mycophenolic acid (MPA). A total of 67 renal transplant recipients taking MPA derivatives were included in the study. Genotypes for MRP2 C-24 T and UGT2B7 C802 T were determined. The incidence and severity of GI symptoms were assessed using the validated Gastrointestinal Symptom Rating Scale (GSRS) at baseline, 2 weeks, 3 months, and 6 months after transplantation. The mean overall GSRS score and the score on the subscale for diarrhea were compared using the Kruskal-Wallis test. The overall GSRS scores (23.5 +/- 4.5 vs. 26.7 +/- 9.9, P = 0.68) or diarrhea subscores (3.5 +/- 0.9 vs. 5.1 +/- 3.3, P = 0.08) were not significantly different among patients with the heterozygous variant MRP2 C-24 T and those with the homozygous wild type. For UGT2B7, the overall mean GSRS scores were significantly different between the homozygous wild type and the variant type (CC vs. CT + TT, 29.2 +/- 9.3 vs. 24.0 +/- 8.2, P = 0.009), although diarrhea subscale scores did not reach statistical significance (CC vs. CT + TT, 5.7 +/- 4.1 vs. 4.1 +/- 1.9, P = 0.13). When the genotypes for MRP2 and UGT2B7 were considered together, patients with the variant forms of MRP2 and UGT2B7 had significantly lower overall GSRS scores (CC-CC vs. CT-CT/TT, 22.5 +/- 4.3 vs. 30.1 +/- 10.1, P = 0.04) and diarrhea subscale scores compared to wild type (CC-CC vs. CT-CT/TT, 3.4 +/- 0.7 vs. 6.2 +/- 4.4, P = 0.03). However, there were no differences in GSRS scores between patients receiving either mycophenolic mofetil (MMF) or enteric-coated mycophenolic acid (EC-MPA) regardless of whether the patients were receiving different calcineurin inhibitors. In conclusion, this study suggests that among patients receiving MPA, those with UGT2B7 variant genotypes are protected from the GI side effects of MPA regardless of the formulation used or concurrent calcineurin inhibitors administered. MRP2 genotypes did not show significant differences in GI side effects among patients taking MPA therapy.

CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects.

To determine the relationship between CYP3A5 polymorphism and cyclosporine pharmacokinetic parameters among healthy volunteers, an oral cyclosporine (CsA) pharmacokinetic study was performed in 16 healthy subjects. Blood CsA concentrations were measured by high-performance liquid chromatography. Concentration-versus-time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the CYP3A5 using the polymerase chain reaction and pyrosequencing. CsA pharmacokinetic parameters were dichotomized and compared using the 1-way ANOVA test according to the CYP3A5*3C genotype. There were 6 homozygous A/A (wild type), 6 homozygous G/G (variant), and 4 heterozygous A/G genotypes for CYP3A5*3 C in these 16 healthy volunteers. All whites were G/G group, and all African Americans except 1 were either A/A or A/G group. The mean AUC (ng x h/mL) of CsA for the 3 genotype groups were 4962 +/- 1074 (A/A), 6677 +/- 1153 (G/G), and 5416 +/- 1817 (A/G), (A/A versus G/G, P = 0.03), and the mean CL/F (mL/min/kg) were 15.6 +/- 3.1 (A/A), 12.0 +/- 2.3 (G/G), and 14.7 +/- 5.9 (A/G), (A/A versus G/G, P = 0.04). None of the other parameters were significantly different among the 3 genotypes. In conclusion, the CYP3A5*3C polymorphism appears to affect AUC and CL/F of oral CsA significantly in healthy subjects, which may partly explain some of the differences of pharmacokinetics in CsA between African Americans and whites.

Association of the CYP3A4*1B 5'-flanking region polymorphism with cyclosporine pharmacokinetics in healthy subjects.

To determine the relationship between CYP3A4*1B polymorphism and cyclosporine pharmacokinetic parameters among healthy volunteers, the oral cyclosporine pharmacokinetic study was performed in 14 healthy subjects. Blood cyclosporine concentrations were measured by a high performance liquid chromatography. Concentration-time data were analyzed by a non-compartmental method using WinNonLin, and the blood samples were genotyped for the CYP3A4*1B 5'-promotor region using the polymerase chain reaction and a restriction digest. Each cyclosporine pharmacokinetic parameter was compared using the one-way ANOVA test according to his or her CYP3A4*1B genotype. There were four (4) homozygous A/A (wild-type), four (4) homozygous G/G (variant) and six (6) heterozygous A/G genotypes for CYP3A4*1B in these 14 healthy volunteers. The mean AUC/D (ng.hr/mL/mg) of CsA were 21.5 +/- 6.0 (A/A), 11.7 +/- 3.2 (G/G) and 19.2 +/- 2.3 (A/G), P = 0.0103 and the mean CL/F (L/hr) were 49.4 +/- 13.9 (A/A), 83.5 +/- 16.0 (G/G), and 52.5 +/- 5.6 (A/G), P = 0.0024. All other parameters were not significantly different among the three genotypes.