The aim of this study was to develop a population pharmacokinetic model of tacrolimus in pediatric kidney transplant patients, identify factors that explain variability, and determine dosage regimens. Pharmacokinetic samples were collected from 50 de novo pediatric kidney transplant patients (age 2-18 years) who were on tacrolimus treatment. Population pharmacokinetic analysis of tacrolimus was performed using NONMEM, and the impact of variables (demographic and clinical factors, and CYP3A4-A5, ABCB1, and ABCC2 polymorphisms) was tested. The pharmacokinetic data were described by a two-compartment model that incorporated first-order absorption and lag time. The apparent oral clearance (CL/F) was significantly related to body weight (allometric scaling); in addition, it was higher in patients with low hematocrit levels and lower in patients with CYP3A5*3/*3. The population pharmacokinetic-pharmacogenetic model developed in de novo pediatric kidney transplant patients demonstrated that, in children, tacrolimus dosage should be based on weight, hematocrit levels, and CYP3A5 polymorphism. Individualization of therapy will enable the optimization of tacrolimus exposure, with resultant beneficial effects on kidney function in the initial post-transplantation period.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• MMF has been proposed as a treatment of steroid-dependent nephrotic syndrome and in the recent years, several studies have suggested its positive effect in preventing relapses. WHAT THIS PAPER ADDS• The population pharmacokinetics of MPA was first evaluated in children with idiopathic nephrotic syndrome and data fitted well with a two-compartment model with first-order absorption and lag time.• Body weight and serum albumin had a significant impact on oral clearance. • A three-point (T0, T1 and T4h) Bayesian estimator of AUC0-12 was developed. AIMSTo develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration-time curve over 12 h (AUC0-12). METHODSThe pharmacokinetic model of MMF was described from 23 patients aged 7.4 Ϯ 3.9 years (range 2.9-14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag-time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method. RESULTSThe population pharmacokinetic parameters were apparent oral clearance 9.7 l h , lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC0-12 was obtained using the combination of three MPA concentrations measured just before (T0), 1 and 4 h (T1 and T4) after drug intake with a small error of 0.298 mg h -1 ml -1 between estimated and reference AUC0-12. CONCLUSIONSThe population pharmacokinetic model of MPA was developed in children with INS. A three-point (T0, T1 and T4h) Bayesian estimator of AUC0-12 was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing.

Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort. We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular -expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts. Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3' untranslated region of (=9.3×10). Conditional analysis identified two additional independent risk alleles upstream of (rs28366266,=3.7×10) and in the 3' untranslated region of (rs9348883,=9.4×10) within introns of and These three risk alleles were independent of the risk haplotype identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1. Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.

Idiopathic nephrotic syndrome (INS) has been studied for decades in attempt to understand the physiopathological mechanisms explaining the disease. It is recognized as a multifactorial disease, with immunological components targeting kidney functions. Many hypotheses have been discussed or tested, including the role of a circulating factor, polymorphisms of genes implicated in lymphocyte maturation and differentiation, and DNA epigenetic modifications. In the present review, the data supporting these different (and probably combinatorial) hypotheses have been reviewed in order to identify and discuss the possible pathways implicated in the physiopathology of INS.