Tariq Shah

Impact of Epstein–Barr virus donor and recipient serostatus on the incidence of post-transplant lymphoproliferative disorder in kidney transplant recipients

BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of transplantation. METHODS Using the OPTN/UNOS database, primary kidney recipients (2000-2009) were stratified according to transplant type (deceased donor, DD or living donor, LD), donor (D) and recipient (R) Epstein-Barr virus (EBV) serostatus (R+; D+/R- and D-/R-) and recipient age. Incidence and adjusted risk of PTLD and death were compared. RESULTS Of the 137 939 primary kidney recipients transplanted between 2000 and 2009, 913 subsequently developed PTLD. In 90 208 recipients with known EBV serostatus, we found a trend toward a decrease in PTLD incidence in years 2007-2009 when compared to 2000-2003. This was due to a significant decrease in PTLD incidence in EBV- recipients. Of those, 61 273 had a known donor serostatus and were further examined. In adults, PTLD incidence (in 1000 person-years) in DD and LD was 7.0 and 7.0 in D+/R-; 3.0 and 2.5 in D-/R- and 1.2 and 1.0 in R+, respectively. The hazard ratio (HR) for PTLD (R+ as reference) in D+/R- (6.2 in DD and 7.2 in LD) was double to thrice than for D-/R- transplants (2.4 in both DD and LD). In pediatric recipients, PTLD incidence in DD and LD was 15.9 and 17.3 in D+/R-; 12 and 18 in D-/R- and 1.2 and 2.2 in R+, respectively. The HR for PTLD was 17.4 and 6.9 in D+/R- and 15.9 and 7.6 in D-/R- in DD and LD, respectively. CONCLUSION A D+/R-, compared with a D-/R- transplant, may contribute to an increase in PTLD incidence of 35 and 42% in adult DD and LD transplants, respectively.

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.

Role of sodium and volume in the pathogenesis of hypertension in hemodialysis.

Hypertension is a common finding in chronic hemodialysis (HD) patients. Cardiovascular (CV) disease is the leading cause of death in this population, and hypertension is a significant risk factor for CV events. Understanding the etiology of hypertension in chronic HD patients is critical in order to optimize treatment and reduce the morbidity and mortality associated with hypertension. Although the pathogenesis of hypertension in HD patients is multifactorial, two of the major risk factors are increased extracellular volume and sodium intake. Control of extracellular volume has been shown to normalize blood pressure (BP), but this normalization lags behind the extracellular volume contraction (“lag phenomenon”). A sodium load leads to an increase in BP by causing an increase in extracellular volume, resulting in a transient increase in cardiac output and an increase in total peripheral resistance. Sodium may be implicated in the hypertension of end‐stage renal disease (ESRD) patients through hypervolemia‐independent mechanisms. Aggressive control of extracellular volume and dietary sodium intake can normalize BP in chronic HD patients and reduce the morbidity associated with hypertension‐related CV disease.

HYPERTENSION IN HEMODIALYSIS PATIENTS: Role of Sodium and Volume in the Pathogenesis of Hypertension in Hemodialysis

Hypertension is a common finding in chronic hemodialysis (HD) patients. Cardiovascular (CV) disease is the leading cause of death in this population, and hypertension is a significant risk factor for CV events. Understanding the etiology of hypertension in chronic HD patients is critical in order to optimize treatment and reduce the morbidity and mortality associated with hypertension. Although the pathogenesis of hypertension in HD patients is multifactorial, two of the major risk factors are increased extracellular volume and sodium intake. Control of extracellular volume has been shown to normalize blood pressure (BP), but this normalization lags behind the extracellular volume contraction (“lag phenomenon”). A sodium load leads to an increase in BP by causing an increase in extracellular volume, resulting in a transient increase in cardiac output and an increase in total peripheral resistance. Sodium may be implicated in the hypertension of end‐stage renal disease (ESRD) patients through hypervolemia‐independent mechanisms. Aggressive control of extracellular volume and dietary sodium intake can normalize BP in chronic HD patients and reduce the morbidity associated with hypertension‐related CV disease.

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.

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.

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 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.