Kelly A. Birdwell

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing

Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose‐adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).

Decreased Antibody Response to Influenza Vaccination in Kidney Transplant Recipients: A Prospective Cohort Study

BACKGROUND Antibody response to the inactivated influenza vaccine is not well described in kidney transplant recipients administered newer, but commonly used, immunosuppression medications. We hypothesized that kidney transplant recipient participants administered tacrolimus-based regimens would have decreased antibody response compared with healthy controls. STUDY DESIGN Prospective cohort study of 53 kidney transplant recipients and 106 healthy control participants during the 2006-2007 influenza season. All participants received standard inactivated influenza vaccine. SETTING & PARTICIPANTS Kidney transplant recipients administered tacrolimus-based regimens at a single academic medical center and healthy controls. PREDICTOR Presence of kidney transplant. OUTCOMES Proportion of participants achieving seroresponse (4-fold increase in antibody titer) and seroprotection (antibody titer > or = 1:32) 1 month after vaccination. MEASUREMENTS Antibody titers before and 1 month after vaccination by means of hemagglutinin inhibition assays for influenza types A/H1N1, A/H3N2, and B. RESULTS A smaller proportion of the transplantation group compared with the healthy control group developed the primary outcomes of seroresponse or seroprotection for all 3 influenza types at 1 month after vaccination. The response to influenza type A/H3N2 was statistically different; the transplantation group had 69% decreased odds of developing seroresponse (95% confidence interval, 0.16 to 0.62; P = 0.001) and 78% decreased odds of developing seroprotection (95% confidence interval, 0.09 to 0.53; P = 0.001) compared with healthy controls. When participants less than 6 months from the time of transplantation were considered, this group had a significantly decreased response to the vaccine compared with healthy controls. LIMITATIONS Decreased sample size, potential for confounders, outcome measure used is the standard but does not give information about vaccine efficacy. CONCLUSIONS Kidney transplant recipients, especially within 6 months of transplantation, had diminished antibody response to the 2006-2007 inactivated influenza vaccine.

Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies

BackgroundIn addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation.MethodsWe describe here the design and implementation of a customized genome-wide genotyping array, the ‘TxArray’, comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios.ResultsWe show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms.ConclusionsWe have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies.

Clinical and Genetic Factors Associated with Cutaneous Squamous Cell Carcinoma in Kidney and Heart Transplant Recipients.

Background Cutaneous squamous cell carcinoma (cSCC) occurs with higher frequency and recurrence rates, increased morbidity and mortality, and more aggressive metastasis in kidney and heart transplant recipients compared to the general population but all transplant recipients do not develop cSCC. In addition, the phenotypic expression of cSCC among transplant recipients can vary between mild disease and extensive recurrent metastatic disease. These clinically observed differences in occurrence and severity of cSCC among transplant recipients suggest the possibility that an underlying genetic component might modify risk. Methods We identified 88 white posttransplant cSCC cases (71 kidney and 17 heart) and 300 white posttransplant controls (265 kidney and 35 heart) using a DNA biobank linked with deidentified electronic medical records. Logistic regression was used to determine adjusted odds ratios (OR) for clinical characteristics and single nucleotide polymorphisms (SNP) associated with cSCC in both a candidate SNP and genomewide analysis. Results Age (OR, 1.08; 95% confidence interval [95% CI], 1.05-1.11; P < 0.001) and azathioprine exposure (OR, 8.64; 95% CI, 3.92-19.03; P < 0.001) were significantly associated, whereas sex, smoking tobacco use, dialysis duration, and immunosuppression duration were not. Ten candidate SNPs previously associated with nonmelanoma skin cancer in the general population were significantly associated with cSCC in transplant recipients. Genomewide association analysis implicated SNPs in genes previously associated with malignancy, CSMD1 (OR, 3.14; 95% CI, 1.90-5.20) and CACNA1D (OR, 2.67; 95% CI, 1.73-4.10]). Conclusions This study shows an association of increasing age and azathioprine exposure with cSCC and confirms a genetic contribution for cSCC development in kidney and heart transplant recipients.

Utilization of an EMR-biorepository to identify the genetic predictors of calcineurin-inhibitor toxicity in heart transplant recipients.

Calcineurin-inhibitors CI are immunosuppressive agents prescribed to patients after solid organ transplant to prevent rejection. Although these drugs have been transformative for allograft survival, long-term use is complicated by side effects including nephrotoxicity. Given the narrow therapeutic index of CI, therapeutic drug monitoring is used to prevent acute rejection from underdosing and acute toxicity from overdosing, but drug monitoring does not alleviate long-term side effects. Patients on calcineurin-inhibitors for long periods almost universally experience declines in renal function, and a subpopulation of transplant recipients ultimately develop chronic kidney disease that may progress to end stage renal disease attributable to calcineurin inhibitor toxicity (CNIT). Pharmacogenomics has the potential to identify patients who are at high risk for developing advanced chronic kidney disease caused by CNIT and providing them with existing alternate immunosuppressive therapy. In this study we utilized BioVU, Vanderbilt University Medical Centers DNA biorepository linked to de-identified electronic medical records to identify a cohort of 115 heart transplant recipients prescribed calcineurin-inhibitors to identify genetic risk factors for CNIT We identified 37 cases of nephrotoxicity in our cohort, defining nephrotoxicity as a monthly median estimated glomerular filtration rate (eGFR)<30 mL/min/1.73 m2 at least six months post-transplant for at least three consecutive months. All heart transplant patients were genotyped on the Illumina ADME Core Panel, a pharmacogenomic genotyping platform that assays 184 variants across 34 genes. In Cox regression analysis adjusting for age at transplant, pre-transplant chronic kidney disease, pre-transplant diabetes, and the three most significant principal components (PCAs), we did not identify any markers that met our multiple-testing threshold. As a secondary analysis we also modeled post-transplant eGFR directly with linear mixed models adjusted for age at transplant, cyclosporine use, median BMI, and the three most significant principal components. While no SNPs met our threshold for significance, a SNP previously identified in genetic studies of the dosing of tacrolimus CYP34A rs776746, replicated in an adjusted analysis at an uncorrected p-value of 0.02 (coeff(S.E.)=14.60(6.41)). While larger independent studies will be required to further validate this finding, this study underscores the EMRs usefulness as a resource for longitudinal pharmacogenetic study designs.

Role of pharmacogenomics in dialysis and transplantation.

Purpose of reviewPharmacogenomics is the study of differences in drug response on the basis of individual genetic background. With rapidly advancing genomic technologies and decreased costs of genotyping, the field of pharmacogenomics continues to develop. Application to patients with kidney disease provides growing opportunities for improving drug therapy. Recent findingsPharmacogenomics studies are lacking in patients with chronic kidney disease and dialysis, but are abundant in the kidney transplant field. A potentially clinically actionable genetic variant exists in the CYP3A5 gene, with the initial tacrolimus dose selection being optimized based on CYP3A5 genotype. Although many pharmacogenomics studies have focused on transplant immunosuppression pharmacokinetics, an expanding literature on pharmacodynamic outcomes, such as calcineurin inhibitor toxicity and new onset diabetes, is providing new information on patients at risk. SummaryAppropriately powered pharmacogenomics studies with well-defined phenotypes are needed to validate existing studies and unearth new findings in patients with kidney disease, especially the chronic kidney disease and dialysis population.

High prevalence of non-steroidal anti-inflammatory drug use among acute kidney injury survivors in the southern community cohort study

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are widely used and have been linked to acute kidney injury (AKI), chronic kidney disease (CKD) and cardiovascular disease (CVD). Patients who survive an AKI episode are at risk for future adverse kidney and cardiovascular outcomes. The objective of our study was to examine the prevalence and predictors of NSAID use among AKI survivors.MethodsThe Southern Community Cohort Study is a prospective study of low-income adults aged 40–79 in the southeastern US. Through linkage with Centers for Medicare and Medicaid Services, 826 participants with an AKI diagnosis (ICD-9 584.5-584.9) at any age prior to cohort enrollment were identified. At baseline, data were collected on regular use of prescription and over-the-counter NSAIDs, as well as demographic, medical and other characteristics. Additional comorbidities were ascertained via linkage with CMS or the US Renal Data System.ResultsOne hundred fifty-four AKI survivors (19%) reported regular NSAID use at cohort enrollment (52 prescription, 81 OTC, 21 both) and the percentage of NSAID users did not vary by time since AKI event. Over 58% of users were taking NSAIDS regularly both before and after their AKI event. Hypertension (83%), arthritis (71%), heart failure (44%), CKD (36%) and diabetes (35%) were prevalent among NSAID users. In a multivariable model, history of arthritis (OR: 3.00; 95% CI: 1.92, 4.68) and acetaminophen use (OR: 2.43; 95% CI: 1.50, 3.93) were significantly associated with NSAID use, while prevalent CKD (OR: 0.63; 95% CI: 0.41, 0.98) and diabetes (OR: 0.44; 95% CI: 0.29, 0.69) were significantly inversely associated.ConclusionsNSAID use among AKI survivors is common and highlights the need to understand physician and patient decision-making around NSAIDs and to develop effective strategies to reduce NSAID use in this vulnerable population.

Seasonal maintenance of influenza vaccine-induced antibody response in kidney transplant recipients.

Background/Aims: Although annual influenza vaccination is recommended for kidney transplant recipients, efficacy as reflected by serum antibody titers has not been well studied beyond 1 month in kidney transplant recipients. Methods: We performed a single-center prospective cohort study of 51 kidney transplant recipients and 102 healthy controls receiving the 2006–2007 influenza vaccine. Anti-hemagglutinin antibody titers to A/H1N1, A/H3N2, and B were measured before and 1 month after vaccination, and again at the end of influenza season. The primary outcome was the proportion of participants maintaining seroprotection (antibody titer ≥1:32) for the duration of the influenza season after influenza vaccination. Results: Median follow-up time was 175 and 155 days in the transplant and control groups, respectively. For types A/H1N1 and B, a similar high proportion of the transplant and control groups (88.5 and 81.6% vs. 83.7 and 74.2% for A/H1N1 and B, respectively) maintained seroprotection. For type A/H3N2, significantly less of the transplant group (66.7%) versus the control group (90%) maintained a protective influenza vaccine response (odds ratio 0.21, 95% confidence interval 0.07–0.64). This difference disappeared in adjusted analyses. Actual geometric mean titers decreased significantly within both groups (p < 0.001) but this did not differ between groups. Conclusions: Once they have developed protective vaccine-induced antibody responses to influenza vaccine, kidney transplant recipients are able to maintain adequate protective levels of antibody compared with healthy controls.

Longitudinal Assessment of Cardiac Morphology and Function Following Kidney Transplantation

Abnormal cardiac morphology is a risk factor for cardiovascular complications in kidney transplant patients. A supraphysiologic level of fibroblast growth factor 23 (FGF‐23) has been associated with myocardial hypertrophy in this patient population. Our aim was to evaluate the change in cardiac morphology and function following kidney transplantation and to evaluate the association between the change in FGF‐23 concentrations and cardiac morphology.

Evidence for extensive pleiotropy among pharmacogenes.

AIM We sought to identify potential pleiotropy involving pharmacogenes. METHODS We tested 184 functional variants in 34 pharmacogenes for associations using a custom grouping of International Classification and Disease, Ninth Revision billing codes extracted from deidentified electronic health records of 6892 patients. RESULTS We replicated several associations including ABCG2 (rs2231142) and gout (p = 1.73 × 10(-7); odds ratio [OR]: 1.73; 95% CI: 1.40-2.12); and SLCO1B1 (rs4149056) and jaundice (p = 2.50 × 10(-4); OR: 1.67; 95% CI: 1.27-2.20). CONCLUSION In this systematic screen for phenotypic associations with functional variants, several novel genotype-phenotype combinations also achieved phenome-wide significance, including SLC15A2 rs1143672 and renal osteodystrophy (p = 2.67 × 10(-) (6); OR: 0.61; 95% CI: 0.49-0.75).