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Renal function and genetic polymorphisms in pediatric heart transplant recipients.

ABSTRACT: Common genetic variations influence rejection, infection, drug metabolism, and side effect profiles after pediatric heart transplantation. Reports in adults suggest that genetic background may influence post-transplant renal function. In this multicenter study, we investigated the association of genetic polymorphisms (GPs) in a panel of candidate genes on renal function in 453 pediatric heart transplant recipients.We performed genotyping for functional GPs in 19 candidate genes. Renal function was determined annually after transplantation by calculation of the estimated glomerular filtration rate (eGFR). Mixed-effects and Cox proportional hazard models were used to assess recipient characteristics and the effect of GPs on longitudinal eGFR and time to eGFR < 60 mL/min/1.73m(2).Mean age at transplantation was 6.2 ± 6.1 years. Mean follow-up was 5.1 ± 2.5 years. Older age at transplant and black race were independently associated with post-transplant renal dysfunction. Univariate analyses showed FASL (C-843T) T allele (p = 0.014) and HO-1 (A326G) G allele (p = 0.0017) were associated with decreased renal function. After adjusting for age and race, these associations were attenuated (FASL, p = 0.075; HO-1, p = 0.053). We found no associations of other GPs with post-transplant renal function, including GPs in TGF?1, CYP3A5, ABCB1, and ACE.In this multicenter, large, sample of pediatric heart transplant recipients, we found no strong associations between GPs in 19 candidate genes and post-transplant renal function. Our findings contradict reported associations of CYP3A5 and TGF?1 with renal function and suggest that genotyping for these GPs will not facilitate individualized immunosuppression for the purpose of protecting renal function after pediatric heart transplantation.

SUBMITTER: Feingold B

PROVIDER: S-EPMC3428223 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Renal function and genetic polymorphisms in pediatric heart transplant recipients.

Feingold Brian B Brooks Maria M MM Zeevi Adriana A Ohmann Erin L EL Burckart Gilbert J GJ Ferrell Robert E RE Chinnock Richard R Canter Charles C Addonizio Linda L Bernstein Daniel D Kirklin James K JK Naftel David C DC Webber Steven A SA

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20120711 9

<h4>Background</h4>Common genetic variations influence rejection, infection, drug metabolism, and side effect profiles after pediatric heart transplantation. Reports in adults suggest that genetic background may influence post-transplant renal function. In this multicenter study, we investigated the association of genetic polymorphisms (GPs) in a panel of candidate genes on renal function in 453 pediatric heart transplant recipients.<h4>Methods</h4>We performed genotyping for functional GPs in 1 ...[more]

PMID: 22789135

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Project description:PurposeCYP3A5 genotype is a significant contributor to inter-individual tacrolimus exposure and may impact the time required to achieve therapeutic concentrations and number of tacrolimus dose adjustments in transplant patients. Increased modifications to tacrolimus therapy may indicate a higher burden on healthcare resources. The purpose of this study was to evaluate whether CYP3A5 genotype was predictive of healthcare resource utilization in pediatric renal and heart transplant recipients.Patients and methodsPatients <18 years of age with a renal or heart transplant between 6/1/2014-12/31/2018 and tacrolimus-based immunosuppression were included. Secondary use samples were obtained for CYP3A5 genotyping. Clinical data was retrospectively collected from the electronic medical record. Healthcare resource utilization measures included the number of dose changes, number of tacrolimus concentrations, length of stay, number of clinical encounters, and total charges within the first year post-transplant. Rejection and donor-specific antibody (DSA) formation within the first year were also collected. The impact of CYP3A5 genotype was evaluated via univariate analysis for the first year and multivariable analysis at 30, 90, 180, 270, and 365 days post-transplant.ResultsEighty-five subjects were included, 48 renal transplant recipients and 37 heart transplant recipients. CYP3A5 genotype was not associated with any outcomes in renal transplant, however, a CYP3A5 expresser phenotype was a predictor of more dose changes, more tacrolimus concentrations, longer length of stay, and higher total charges in heart transplant recipients. CYP3A5 genotype was not associated with rejection or DSA formation. Age and induction therapy were associated with higher total charges.ConclusionCYP3A5 genotype may predict healthcare resource utilization in the first year post-transplant, although this may be mitigated by differences in tacrolimus management. Future studies should evaluate the impact of genotype-guided dosing strategies for tacrolimus on healthcare utilization resources.

Project description:Background: Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on CYP3A5, MRP2 and UGT1A9 genes in Chilean pediatric kidney recipients using TAC and MPA. Patients and Methods: A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years [Q1-Q3 4.5-11.6 years] and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The CYP3A5 polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while MRP2 -24G > A, UGT1A9 -275T > A, and UGT1A9 -2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C0), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C0/D), and area under the curve in 12 h normalized by dose requirements (AUC0-12h/D). Results: The frequencies of the variant alleles CYP3A5*3, MRP2-24A, UGT1A9-275A, and UGT1A9-2152T were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC0-12h/TAC-D were 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1 carriers (CYP3A5*1/*3 and CYP3A5*1/*1). When analyzing patients with steroid withdrawal, CYP3A5*3/*3 patients had 1.7-fold higher AUC0-12h/TAC-D than the other genotypes. Patients carrying the CYP3A5*3/*3 genotype had higher TAC-C0, lower TAC-D and higher TAC-C0/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between MRP2 and UGT1A9 genotypes were observed in MPA-C0, MPA-D or MPA-C0/D. However, patients carrying the UGT1A9-275A allele had lower AUC0-12h/MPA-D than those carrying the UGT1A9-275T ancestral allele. Conclusions: These results support that CYP3A5 and UGT1A9 genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.

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Renal function and genetic polymorphisms in pediatric heart transplant recipients.

Publications

Renal function and genetic polymorphisms in pediatric heart transplant recipients.

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