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Aims: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. Methods: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed‐effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. Results: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non‐GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug‐specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non‐GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50‐5.69) (gentamicin), 7.77 L/h (95% CI 7.26‐8.19) (amikacin) and 4.70 L/h (95% CI 4.61‐4.80) (vancomycin). Conclusions: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention. [ABSTRACT FROM AUTHOR]

Aims: Azathioprine (AZA) and 6‐mercaptopurine are prescribed in acute lymphoblastic leukaemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6‐thioguanine (6TGN) and 6‐methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation. Methods: The first paediatric TDM samples received during year 2021 were analysed, whatever indication and thiopurine drug. Target concentration ranges were 200–500, <6000 pmol/8 × 108 RBC for 6TGN and 6MMPN. Results: Children (n = 492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (P <.0001). ALL received 6‐mercaptopurine (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti‐inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [interquartile range: 142.5; 309.6] and 1144.6 [419.4; 3574.3] pmol/8 × 108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine aminotransaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant. Conclusion: TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow‐up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome. [ABSTRACT FROM AUTHOR]

Background Idiopathic nephrotic syndrome (INS) is likely a primary immune disorder, but viruses might also be involved in the mechanisms of the disease. Here, we investigate the link between herpesvirus infection and the first manifestation of INS in children. Methods A prospective, multicentre, and population-based case-control study called NEPHROVIR included 164 patients, aged 6 months to 15 years old, newly diagnosed with INS, and 233 controls matched for gender, age, and period of sample. The analysis was done on 124 patients and 196 controls. Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), and human herpesvirus-7 (HHV-7) DNA prev alence at diagnosis were assessed from whole peripheral blood samples, as well as EBV and CMV viral load and seroprevalence. Results EBV DNA was significantly more prevalent in cases than in controls (50.8 vs 29.1 %; OR=2.6; p=0.0002), with no difference in viral load. A significant difference was also found for CMV (11.3 vs 3.6 %; p=0.02) and HHV-7 (83 vs 72 %; p=0.02) DNA prevalence between cases and controls. There were significantly more EBV and CMV recent infections or reactivations based on VCA-IgM and CMV IgM in cases than controls, while there were no differences in IgG seroprevalence. Conclusion The prevalence of positive EBV DNA detection and recent infection or reactivation is higher in children at onset of INS compared to a population matched for age, gender, and time of sampling. Keywords Epstein-barr virus * Cytomegalovirus * Steroid-sensitive nephroticsyndrome * Proteinuria Nephrovir, Introduction Steroid-sensitive idiopathic nephrotic syndrome (INS) is likely a primary immune disorder since proteinuria is fully sensitive to prednisone, and numerous immunosuppressive drugs have the ability to control the occurrence [...]

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates and infants, is limited by a paucity of good‐quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts by complementary information about targeted and nontargeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis‐generating, allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a subdivision into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as are the type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, noninvasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (eg liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, such as artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to the identification complex phenotypes and subpopulations of patients to improve the development of medicines for children with potential economic advantages. [ABSTRACT FROM AUTHOR]

Thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) are used extensively in pediatric and adult patients with inflammatory and neoplastic diseases. They are metabolized to 6-thioguanine nucleotides (6-TGN) or to 6-methyl-mercaptopurine nucleotides (6-MMPN). The balance between 6-TGN and 6-MMPN is highly variable and monitoring is recommended, but its benefit in outcome gives rise to conflicting results, potentially increased by differences in quantifying 6-MP metabolism. Our aim was to report (1) the HPLC-UV procedure used in our laboratory to quantify red blood cells (RBCs) with 6-TGN and 6-MMPN (as its derivate: 6-MMP(d)) in patients treated with thiopurines and (2) additional tests, sometimes confirmatory, to improve method standardization. The comparison of two methods to count RBCs shows that metabolite concentrations were slightly lower in the washed and resuspended RBCs than in whole blood. Perchloric acid (0.7 M), dithiothreitol (DTT, final 0.013 M sample concentration) and 60 min hydrolysis were selected for acid hydrolysis. (3) Monitoring data from 83 patients receiving AZA or 6-MP showed that at steady state, only 53/183 (29%) had 6-TGN and 6-MMPN in the recommended therapeutic range. Our method is discussed in light of the technical conditions and sample stability data from 17 publications identified since the first analytical report in 1987. Monitoring data demonstrate, if required, that inter-patient variability in 6-TGN and 6-MMPN concentrations is high in samples from treated patients. [ABSTRACT FROM AUTHOR]

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. Keywords Epigenetics * Glucocorticoids. Kidney disease * Nephrotic syndrome * Proteinuria * Pediatric * Idiopathic nephrotic syndrome * INS, Introduction Idiopathic nephrotic syndrome (INS) is the most prevalent kidney disease in children. Described as a rare and complex disease, INS is clinically defined by the triad of massive proteinuria [...]

Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea and/or calcium channel blocker (CCB) co-administration. We report a renal transplant recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough concentration in both conditions, diarrhoea and CCB co-administration, and with genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our knowledge, this is the first case to be investigated for such polymorphisms. Clinicians should be reminded of the possibility of highly increased levels of tacrolimus in situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and their influence in high-risk situations when enzyme activity is already affected by enterocyte damage due to diarrhoea and CCB competition. Keywords Calcium channel blocker * Cytochrome P450 * Diarrhoea * P-glycoprotein * Polymorphisms * Renal transplant * Tacrolimus, Introduction Tacrolimus is a calcineurin inhibitor increasingly used for immunosuppression in renal transplantation [1]. Following oral administration, tacrolimus is preferentially absorbed in the duodenum and jejunum with highly variable pharmacokinetics [...]