RESUMEN
OBJECTIVE: It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. METHODS: In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. RESULTS: The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (nâ =â 86) and control (nâ =â 168) patients [geometric means ratios (GMR)â =â 0.99, 95% confidence interval (CI)â =â 0.92-1.06 and GMRâ =â 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR)â =â 0.94, 0.49-1.84 and RRâ =â 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed nâ =â 23, control nâ =â 45), if cotreated with cyclosporine (nâ =â 17 vs. nâ =â 26) or with tacrolimus (nâ =â 8 vs. nâ =â 17). CONCLUSIONS: In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.
Asunto(s)
Tasa de Filtración Glomerular , Trasplante de Riñón , Transportador 1 de Anión Orgánico Específico del Hígado , Ácido Micofenólico , Humanos , Trasplante de Riñón/efectos adversos , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/farmacocinética , Masculino , Femenino , Persona de Mediana Edad , Tasa de Filtración Glomerular/efectos de los fármacos , Adulto , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Alelos , Inmunosupresores/efectos adversos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Polimorfismo de Nucleótido Simple , Anciano , Estudios de Cohortes , Rechazo de Injerto/genética , Rechazo de Injerto/prevención & controlRESUMEN
Variant allele at the inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C has been associated with increased enzyme activity and reduced susceptibility to mycophenolic acid (MPA) in vitro. It has been suggested associated with an increased risk of acute rejection in renal transplant recipients on MPA-based immunosuppression, but not unambiguously. We assessed one-year evolution of the estimated glomerular filtration rate (eGFR) in transplanted variant allele carriers and wild-type subjects, while controlling for a number of demographic, pharmacogenetic, (co)morbidity, and treatment baseline and time-varying covariates. The eGFR slopes to day 28 (GMR = 1.01, 95% CI 0.93-1.09), and between days 28 and 365 (GMR = 1.01, 95% CI 0.99-1.02) were practically identical in 52 variant carriers and 202 wild-type controls. The estimates (95%CIs) remained within the limits of ±20% difference even after adjustment for a strong hypothetical effect of unmeasured confounders. Polymorphism IMPDH2 3757T>C does not affect the renal graft function over the 1st year after transplantation.
Asunto(s)
Tasa de Filtración Glomerular , Rechazo de Injerto , IMP Deshidrogenasa , Inmunosupresores , Trasplante de Riñón , Ácido Micofenólico , Polimorfismo de Nucleótido Simple , Humanos , Trasplante de Riñón/efectos adversos , IMP Deshidrogenasa/genética , Ácido Micofenólico/uso terapéutico , Ácido Micofenólico/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Tasa de Filtración Glomerular/efectos de los fármacos , Adulto , Rechazo de Injerto/genética , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología , Polimorfismo de Nucleótido Simple/genética , Anciano , Terapia de Inmunosupresión/métodos , Terapia de Inmunosupresión/efectos adversosRESUMEN
A recently discovered haplotype-CYP2C:TG-determines the ultrarapid metabolism of several CYP2C19 substrates. The platelet inhibitor clopidogrel requires CYP2C19-mediated activation: the risk of ischemic events is increased in patients with a poor (PM) or intermediate (IM) CYP2C19 metabolizer phenotype (vs. normal, NM; rapid, RM; or ultrarapid, UM). We investigated whether the CYP2C:TG haplotype affected efficacy/bleeding risk in clopidogrel-treated patients. Adults (n = 283) treated with clopidogrel over 3-6 months were classified by CYP2C19 phenotype based on the CYP2C19*2*17 genotype, and based on the CYP2C19/CYP2C cluster genotype, and regarding carriage of the CYP2:TG haplotype, and were balanced on a number of covariates across the levels of phenotypes/haplotype carriage. Overall, 45 (15.9%) patients experienced ischemic events, and 49 (17.3%) experienced bleedings. By either classification, the incidence of ischemic events was similarly numerically higher in PM/IM patients (21.6%, 21.8%, respectively) than in mutually similar NM, RM, and UM patients (13.2-14.8%), whereas the incidence of bleeding events was numerically lower (13.1% vs. 16.6-20.5%). The incidence of ischemic events was similar in CYP2C:TG carries and non-carries (14.1% vs. 16.1%), whereas the incidence of bleedings appeared mildly lower in the former (14.9% vs. 20.1%). We observed no signal to suggest a major effect of the CYP2C19/CYP2C cluster genotype or CYP2C:TG haplotype on the clinical efficacy/safety of clopidogrel.