Search

Abstract Background Autosomal dominant pseudohypoaldosteronism type 1 (PHA1) is a rare inherited condition that is characterized by renal resistance to aldosterone as well as salt wasting, hyperkalemia, and metabolic acidosis. Renal PHA1 is caused by mutations of the human mineralcorticoid receptor gene (MR), but it is a matter of debate whether MR mutations cause mineralcorticoid resistance via haploinsufficiency or dominant negative mechanism. It was previously reported that in a case with nonsense mutation the mutant mRNA was absent in lymphocytes because of nonsense mediated mRNA decay (NMD) and therefore postulated that haploinsufficiency alone can give rise to the PHA1 phenotype in patients with truncated mutations. Methods and Results We conducted genomic DNA analysis and mRNA analysis for familial PHA1 patients extracted from lymphocytes and urinary sediments and could detect one novel splice site mutation which leads to exon skipping and frame shift result in premature termination at the transcript level. The mRNA analysis showed evidence of wild type and exon-skipped RT-PCR products. Conclusion mRNA analysis have been rarely conducted for PHA1 because kidney tissues are unavailable for this disease. However, we conducted RT-PCR analysis using mRNA extracted from urinary sediments. We could demonstrate that NMD does not fully function in kidney cells and that haploinsufficiency due to NMD with premature termination is not sufficient to give rise to the PHA1 phenotype at least in this mutation of our patient. Additional studies including mRNA analysis will be needed to identify the exact mechanism of the phenotype of PHA.

Background: Isotonic fluids are becoming the standard for hydration and maintenance fluid therapy, but there is no consensus on the optional choice among the different types of isotonic solution., Methods: This study is a single-center, non-randomized controlled trial at Kobe University Hospital, Japan, between April 2021 and March 2023. The study included pediatric patients aged 1-19 years who underwent kidney biopsies. From April 2021 to March 2022, 0.9% sodium chloride (saline) was administered, and from April 2022 to March 2023, balanced crystalloids were used. The primary outcome was the occurrence of hyponatremia (< 137 mEq/L) after a kidney biopsy. Secondary outcomes included other electrolyte balances, blood gas parameters, creatinine-based estimated glomerular filtration rate (Cr-eGFR), and arginine vasopressin concentrations (UMIN Clinical Trial Registry: UMIN 000044330)., Results: Of 61 patients enrolled, 2 were excluded, leaving 34 in the saline group and 25 in the balanced crystalloid group. No hyponatremia occurred, and serum sodium concentrations were similar between both groups (138.7 vs. 138.9 mEq/L, P = 0.08). The saline group showed a greater increase in serum chloride (+ 1.7 vs. + 0.2, P < 0.01) and a greater decrease in HCO 3 - concentrations (- 0.6 vs. + 0.9, P < 0.01). There were minimal changes in pH (- 0.01 vs. - 0.01, P = 0.99) and Cr-eGFR (- 1.5 vs. + 1.1 mL/min/1.73 m 2 , P = 0.96) in both groups., Conclusions: During pediatric kidney biopsy, both saline and balanced crystalloids were effective in preventing hyponatremia. Although saline infusion results in higher serum chloride concentrations and lower blood HCO 3 - concentrations than balanced crystalloids infusion, the clinical significance was minimal., Competing Interests: Declarations. Ethics approval: This study involving human participants was conducted in accordance with the Declaration of Helsinki. Ethics approval was obtained from the Kobe University Graduate School of Medicine Ethics Review Committee (IRB number: B200377). Consent to participate/consent for publication: Written consent for kidney biopsy was obtained from all patients. However, as this study involves routine clinical management, consent to participate and consent for publication were not required. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: This study aims to develop a population pharmacokinetic (PK) model of mycophenolic acid (MPA) in pediatric patients with different diseases., Methods: To develop the PK model, electronic medical records (EMR) of pediatric patients with different diseases who received mycophenolic acid mofetil (MMF) at the National Center for Child Health and Development from February 2013 to May 2022 and the results of the MMF pharmacokinetic study of pediatric complicated frequently relapsing steroid-dependent nephrotic syndrome under the Advanced Medical Care B protocol (JSKDC09 study) from October 2015 to June 2019 were integrated and analyzed. Non-linear mixed-effects modeling was used to 1) develop a cross-disease population PK model and 2) estimate PK parameters (apparent clearance CL/F and Q/F; apparent volume of distribution Vc/F and Vp/F; absorption rate constant Ka) by post-hoc Bayesian methods. Patient backgrounds, concomitant medications, and laboratory data were included in the covariate analysis. Visual predictive checks with bootstrap and predictive correction were performed to evaluate the final model., Results: A total of 249 patients with 1495 measurements were used in the analysis, including 68 with post-liver transplant, 65 with nephrotic syndrome, 28 with post-renal transplant, 31 with autoimmune diseases (17 with lupus nephritis and 14 with other collagen diseases), 13 with hematopoietic stem cell transplantation, and 5 with others from EMR and 39 with nephrotic syndrome from the JSKDC09 study. A two-compartment model with a first-order rate absorption process best explained the PK of MPA. A nonlinear relationship between dose and MPA exposure was observed and described by the power function of the model. The final population mean PK parameter estimates (95% confidence interval) for non-renal transplant patients and average albumin levels were CL/F 15.2 (13.3, 18.0) L/h/70 kg, Vc/F 15.4 (14.4, 17.2) L, Vp/F 246.8 (159.1, 332.1) L, Q/F 7.0 (5.0, 9.0) L/h, and Ka (without proton pump inhibitor [PPI]) 4.4 (2.4, 4.9) h -1 . Weight, disease (post-renal transplant), and serum albumin level were significant covariates for CL/F, and serum albumin level for Vc/F. The use of PPIs also affected Ka., Conclusions: An integrated population PK model of MPA was developed in children with the following conditions: post-solid organ transplantation, post-HSCTx, autoimmune disease, and nephrotic syndrome. Estimated parameters and parameter covariates were similar to those previously reported. This model is expected to provide useful information for using MPA in various diseases in the Japanese population., Competing Interests: Declarations of competing interest KI reports a research grant for clinical trials and clinical research from Zenyaku Kogyo Co., Ltd. to his institution; consulting fees from Kyowa Kirin Co., Ltd., and Chugai Pharmaceutical Co., Ltd.; honoraria for manuscript writing from Zenyaku Kogyo Co., Ltd.; payment for expert testimony to his institution from Zenyaku Kogyo Co., Ltd.; and serves as a member of the advisory board of Kyowa Kirin Co., Ltd. and Chugai Pharmaceutical Co., Ltd.. KN is a member of advisory groups for Kyowa Kirin Co., Ltd., Toa Eiyo Co., Ltd., Zenyaku Kogyo Co., Ltd., and Taisho Pharmaceutical Co., Ltd.; Lecture fee from Ono Pharmaceutical Co., Ltd., Astellas Pharma Inc., Novo Nordisk Pharma Ltd., Alexion Pharmaceuticals Inc., Sumitomo Pharma Co., Ltd., Sanofi K.K., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., and Miyarisan Pharmaceutical Co., Ltd.; Speaker's bureaus from Sumitomo Pharma Co., Ltd., Chugai Pharmaceutical Co. Ltd., JCR Pharmaceuticals Co., Ltd., Sanofi K.K., Zenyaku Kogyo Co. Ltd., and Kyowa Kirin Co. Ltd.. HN reports grants for regulatory science on facilitating pediatric drug development from Japan Agency for Medical Research and Development; Consulting fees from Tohoku University, Daiichi Sankyo Company, Limited, and Pfizer R&D Japan G.K.; Honoraria for lectures from Japan Pharmaceutical Manufacturers Association, Pfizer Global Supply Japan Inc., Bristol Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., and Northern Science Consulting Inc.; and serves as a member of advisory board of Taisho Pharmaceutical Holdings Co., Ltd. for drug development for diabetes, a member of advisory board of Sato Pharmaceutical Co., Ltd. for drug development for dermatology, Chairman of the Committee on Pharmaceutical Affairs of Japan Pediatric Society, and Chairman of the Steering Committee of Japan Society on Developmental Pharmacology and Therapeutics., (Copyright © 2024. Published by Elsevier B.V.)

Objective: This study aimed to measure and compare cerebrospinal fluid neuronal injury biomarkers in the acute phase of complex febrile seizure (CFS) and infection-triggered acute encephalopathy (AE). Furthermore, we determined the pathogenesis of AE with biphasic seizures and late reduced diffusion (AESD)., Methods: Pediatric patients with febrile status epilepticus who visited Hyogo Prefectural Kobe Children's Hospital from November 1, 2016, to December 31, 2022, and whose cerebrospinal fluid samples were collected within 24 h of neurological symptom onset were included. Patients were classified as having CFS or infection-triggered AE according to their definitions. Patients with AE were further categorized into AESD or unclassified AE. Cerebrospinal fluid biomarkers (neuron-specific enolase, growth differentiation factor 15 [GDF-15], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein, and tau protein were measured and compared among the groups., Results: Total of 63 patients (45 with CFS and 18 with AE) were included. Among the AE patients, nine were classified as having AESD and nine as having unclassified AE. S100B levels were significantly higher in patients with AESD than in patients with CFS (485 pg/ml vs. 175.3 pg/ml) and were even higher in patients with AESD and neurological sequelae (702.4 pg/ml). GDF-15 levels were significantly elevated in patients with AE compared to patients with CFS (85.8 pg/ml vs. 23.6 pg/ml)., Conclusions: The elevation of S100B suggests that activated astrocytes may be closely associated with the early pathology of AESD. Elevated GDF-15 levels in infection-triggered AE suggest the activation of defense mechanisms caused by stronger neurological injury., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Buccal midazolam (buc MDL) is the first buccal mucosal delivery formulation applied for status epilepticus in Japan. Herein, we aimed to investigate the effectiveness and adverse events of buc MDL as a pre-hospital treatment for epileptic seizures in real-world clinical practice., Methods: This study involved a retrospective review based on medical records. We included children who received buc MDL as pre-hospital treatment for epileptic seizures and were subsequently transported to the emergency department between April 2021 and November 2023., Results: This study included 26 patients (136 episodes). The overall efficacy rate, which was defined as seizure cessation within 10 min after buc MDL administration with no recurrence within 30 min, was 43 %. Moreover, 70 % of the episodes did not require additional medications. None of the episodes required bag-mask ventilation or intubation following seizure cessation with buc MDL alone. The efficacy was decreased when buc MDL was administered longer than 15 min from seizure onset. Furthermore, the efficacy did not decrease as long as it was within 0.2-0.5 mg/kg, even if the dose was smaller than the appropriate dose for the specific age., Conclusions: The response rate was significantly higher in episodes where buc MDL was administered within 15 min. Additionally, there was no concern regarding respiratory depression with buc MDL alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)