金井 孝裕

Glucocorticoid-induced osteoporosis (GIOP) is a significant complication of prolonged glucocorticoid treatment in paediatric nephrotic syndrome, but the optimal treatment strategy remains unclear. We report the case of a 17-year-old boy with steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis who developed progressive bone fragility during high-dose glucocorticoid treatment. Four months after initiation of glucocorticoids, his lumbar bone mineral density (BMD) decreased 9.2%, serum alkaline phosphatase (S-ALP) decreased 22% and serum tartrate-resistant acid phosphatase-5b (S-TRACP-5b) increased 47% compared with baseline, indicating compromised bone strength. Oral alendronate (35 mg/week) was initiated to prevent progression of GIOP. One month after antiresorptive treatment, S-TRACP-5b decreased 87% from the level measured at 4 months. BMD and S-ALP initially continued to decline slightly until 7 months but subsequently demonstrated sustained recovery. S-TRACP-5b levels were lower than baseline levels to a greater extent than the S-ALP levels between 5 and 28M, corresponding to progressive improvement in the BMD. No fragility fractures or adverse events occurred, and remission of nephrotic syndrome was maintained. This case suggests that alendronate rapidly suppresses bone resorption, promotes a bone formation-dominant state in conjunction with glucocorticoid tapering and may prevent bone fragility in paediatric GIOP. A ≥ 34% increase in S-TRACP-5b accompanied by a ≥ 22% decrease in S-ALP from baseline may indicate the appropriate timing for initiating antiresorptive treatment. Further investigations are warranted to establish evidence-based management strategies for paediatric GIOP.

AIM: The pathophysiology of idiopathic steroid-sensitive nephrotic syndrome (ISSNS) remains unclear. This study aimed to explore the pathophysiology by examining E-cadherin injury, observed in atopic dermatitis, and VE-cadherin injury, associated with systemic edema formation. METHODS: Twenty-one paediatric patients with ISSNS were enrolled. Serum E- and VE-cadherin levels were measured using ELISA and compared between the nephrotic and remission phases. Correlations between each serum E- and VE-cadherin level and urinary protein/creatinine (UP/UCr) ratios and serum albumin (Alb) levels were analysed. Additionally, a correlation between changes in serum VE-cadherin levels and in body weight between phases was analysed. RESULTS: Both serum E- and VE-cadherin levels were elevated in the nephrotic phase compared to the remission phase (p < 0.01 for both). Remission-phase E-cadherin levels remained higher than those in healthy children, while remission-phase VE-cadherin levels were similar to those in healthy children. Serum E-cadherin levels showed a significant correlation with UP/UCr ratios (p = 0.04), but not with serum Alb levels. Serum VE-cadherin levels did not correlate with either UP/UCr ratios or serum Alb levels. However, changes in VE-cadherin levels between the phases were significantly correlated with changes in body weight (p = 0.04). CONCLUSION: Elevated E- and VE-cadherin levels during the nephrotic phase suggest that injury to these adhesion molecules may be correlated with the disease status and could serve as biomarkers for paediatric ISSNS. Injury to E-cadherin may contribute to proteinuria while injury to VE-cadherin may lead to systemic edema. These findings provide new insights into paediatric ISSNS pathophysiology.

BACKGROUND: Fabry disease is a hereditary disorder caused by a deficiency of α-galactosidase A, leading to the accumulation of globotriaosylceramide (GL-3) in multiple cell types throughout the body. Terminally differentiated non-dividing cells, such as podocytes, are particularly susceptible to such accumulation and therefore require effective therapeutic intervention. Gene therapy is an ideal therapeutic intervention for replacing the deficient enzyme; however, one of the major challenges is maintaining long-term expression of episomal transgenes during cell division. In this regard, podocytes, as non-dividing cells, represent an ideal target for gene therapy in Fabry disease. Nevertheless, it has not been confirmed yet whether gene therapy vectors can transduce podocytes and reduce GL-3 accumulation especially in podocytes. METHODS: Male Fabry disease model mice (TgG3S/GLA knockout mice) received an intravenous injection of 2 × 1012 vector genomes of AAV9 encoding human GLA at 6 weeks of age. Kidney tissues were analyzed 8 weeks after administration by electron microscopy (EM) and immunogold EM. RESULTS: In AAV9/hGLA-treated mice, GL-3 accumulation was markedly reduced in most podocytes, endothelial cells, and tubular epithelial cells, whereas it was evident in untreated mice. Virus-like particles were detected only in treated mice. Furthermore, immunogold EM confirmed the presence of AAV9 particles in the podocytes of treated mice. CONCLUSIONS: AAV9/hGLA gene therapy may reduce podocyte GL-3 accumulation in a Fabry disease mouse model, potentially through AAV9 transduction of podocytes; however, given the technical limitations of our approach, the precise cellular mechanisms remain to be determined.

Background/Objectives: Therapeutic drug monitoring (TDM) of immunosuppressants is essential in treating pediatric kidney diseases; however, repeated venipuncture is burdensome in children. We evaluated whether minimally invasive fingerstick capillary sampling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides results analytically comparable to those of conventional venous sampling. Methods: Capillary whole blood (2.8 µL) was collected via fingersticks from pediatric patients receiving mycophenolate mofetil, with or without tacrolimus (TAC) or cyclosporine A (CsA). Drug concentrations were quantified using a previously validated simultaneous LC-MS/MS method and compared with conventional venous sampling using linear regression and Bland-Altman analyses. Results: Seventy-four paired samples from 21 patients were analyzed. Strong correlations were observed between capillary and venous samples for mycophenolic acid (MPA), TAC, and CsA (R2 > 0.90). Hematocrit correction improved agreement for MPA. Bland-Altman analyses demonstrated acceptable bias across analytes. Conclusions: Fingerstick-based microvolume sampling combined with LC-MS/MS provides analytically reliable immunosuppressant quantification in pediatric patients. Although larger clinical validation is required, this minimally invasive approach may reduce procedural burden and may support future outpatient or home-based TDM strategies.

Idiopathic steroid-sensitive nephrotic syndrome (ISSNS) is the most common glomerular disease in children, yet its molecular mechanisms and lipid-mediated pathophysiology remain poorly understood. In this study, we performed comprehensive non-targeted metabolomic analysis of serum samples obtained from children with ISSNS during both the nephrotic and remission phases to identify metabolic alterations associated with disease status. Using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS), we profiled low-molecular-weight metabolites and identified significant alterations in several lipid classes, including sphingolipids, glycerophospholipids, and lysophospholipids. Several sphingomyelin and phosphatidylcholine species showed strong correlations with total cholesterol levels, reflecting lipid alterations consistent with the hyperlipidemic state that characterizes ISSNS. In contrast, oxidized phosphatidylcholines may more specifically reflect oxidative membrane injury and glomerular permeability changes associated with disease status. These findings highlight membrane lipid remodeling as a key feature of active disease and suggest potential lipid-based biomarkers for disease monitoring and therapeutic evaluation in pediatric ISSNS. This study provides a metabolomic framework for understanding lipid-driven mechanisms of ISSNS pathophysiology.