Idiopathic nephrotic syndrome is one of the most common glomerular diseases in children and adolescents. Monogenic nephrotic syndrome is associated with lower rates of remission following treatment with standard immunosuppressive therapies and a higher risk of progression to end-stage kidney disease. Advances in genetic testing technologies have identified more than 100 single-gene causes of nephrotic syndrome and made genetic testing more accessible in clinical practice. The vast majority of genes implicated in the etiology of nephrotic syndrome are associated with the glomerular filtration barrier and primarily with the podocyte. A molecular diagnosis of nephrotic syndrome has implications for medication choice, prognostication, indications for further testing, and transplant planning. Like all clinical tools, however, it must be utilized in the appropriate clinical context, though no standardized guidelines exist for indications for genetic testing in nephrotic syndrome. Standard treatment of nephrotic syndrome consists of immunosuppressive therapies. However, patients with monogenic nephrotic syndrome are less likely to achieve remission with immunosuppression, and alternative treatment options are under investigation.

Epstein-Barr virus (EBV), a member of the herpesvirus family, establishes lifelong latency following primary infection and may be reactivated under conditions of immunosuppression. EBV reactivation is classically associated with infectious mononucleosis and Burkitt lymphoma and rarely associated with cold agglutinin syndrome. Here, we describe a case of minimal change nephrotic syndrome complicated by cold agglutinin syndrome secondary to EBV reactivation in the setting of human immunodeficiency virus (HIV) infection and corticosteroid-induced immunosuppression. A 63-year-old man with well-controlled HIV infection owing to antiretroviral therapy was admitted for nephrotic syndrome. He was treated with prednisolone (80 mg/day), and renal biopsy performed on day 9 confirmed minimal change nephrotic syndrome. Complete remission was achieved by day 18; however, the patient subsequently developed hyperbilirubinemia, elevated transaminase and lactate dehydrogenase levels, progressive anemia, and thrombocytopenia, accompanied by pharyngitis, malaise, and fever. Laboratory investigations revealed a positive cold agglutinin test, positive direct Coombs test, reduced haptoglobin level, and positive urine urobilinogen, consistent with cold agglutinin syndrome. CMV reactivation was also suggested by transient CMV antigenemia positivity, although no organ-invasive CMV disease was evident. Although EBV serology indicated a past infection, the EBV DNA load was elevated, which suggested viral reactivation. The patient responded to supportive measures, along with early tapering of the corticosteroid dose to reduce immunosuppression. This case highlights that HIV infection in combination with corticosteroid therapy may create an immunosuppressive milieu, predisposing patients to EBV reactivation and subsequent development of cold agglutinin syndrome. Clinicians should be vigilant for EBV-related complications in patients with minimal change nephrotic syndrome requiring corticosteroid therapy, particularly in those with underlying HIV infection.

Objective The main objective of this study is to assess bone mineral density (BMD) and ocular complications in children with steroid-sensitive nephrotic syndrome (SSNS) receiving prolonged corticosteroid therapy and to identify factors associated with these complications. Methods This cross-sectional observational study was conducted at a tertiary care center over 18 months. Children aged 1-18 years with SSNS who had received corticosteroids for more than six months were enrolled. Clinical details, including cumulative steroid dose and duration of therapy, were recorded. All participants underwent ophthalmologic evaluation, biochemical assessment, and lumbar spine dual-energy X-ray absorptiometry (DEXA) to determine BMD Z-scores. Associations between steroid exposure and bone and ocular outcomes were analyzed. Results Fifty children were included, 66% were boys, and the mean age was 6.08 ± 2.84 years. Osteopenia was found in 25 children (50%), and osteoporosis in nine (6%). Longer steroid duration was significantly associated with lower BMD (p = 0.025). Children with osteoporosis had significantly higher parathormone (PTH) and alkaline phosphatase (ALP) levels and lower vitamin D levels (p < 0.001). Ocular complications were identified in nine children (18%), most commonly refractive errors (16%). Refractive errors were significantly associated with longer steroid duration (p = 0.013) and higher cumulative steroid dose (p = 0.012). Posterior subcapsular cataract and raised intraocular pressure were observed in one child each. Conclusion Prolonged corticosteroid therapy in children with SSNS is associated with reduced BMD and ocular complications. Regular monitoring of bone health, vitamin D status, and ophthalmologic evaluation should be part of long-term care.

Membranous nephropathy (MN) is uncommon in children overall, but secondary MN is relatively common in younger children. Inflammatory bowel disease (IBD) can be complicated by kidney disease, but IBD complicated by MN is rarely reported. A 3-year-old boy diagnosed with very early onset IBD (VEO-IBD) a year earlier was incidentally found to have proteinuria via urine screening system. Laboratory tests revealed nephrotic syndrome with microscopic hematuria and signs of ongoing inflammation associated with IBD activity. Kidney biopsy showed mesangial cell proliferation and dense subepithelial immune complex deposits, along with negative PLA2R staining, which supported a diagnosis of secondary MN. Oral steroid therapy was initiated for its potential benefit for both nephrotic syndrome and the underlying VEO-IBD. As a result, four months later, proteinuria and hematuria had resolved, and kidney function remained stable. This is the youngest reported patient with MN associated with IBD. Routine urinalysis is suggested by this case to be useful for detecting kidney complications of IBD, including MN. Moreover, steroid therapy is likely to be useful for MN secondary to IBD. Our report suggests that potential kidney complications should also be considered in patients with VEO-IBD.

Focal segmental glomerulosclerosis (FSGS) is a major cause of nephrotic syndrome and end-stage kidney disease (ESKD). Many cases are attributable to pathogenic variants in podocyte-related genes, such as inverted formin 2 (INF2). However, no specific treatment exists for hereditary FSGS, and experimental platforms that faithfully model podocyte injury remain limited. Therefore, in this study, we developed an injury model by generating induced pluripotent stem cells (iPSCs) from a patient with INF2-associated FSGS and differentiating them into kidney organoids. Podocytes were validated by immunofluorescence staining for podocyte-specific markers. We induced podocyte injury in this model using puromycin aminonucleoside (PAN) in a dose-dependent manner. Injury severity was quantified by measuring podocalyxin fluorescence intensity. Cyclosporine A (CsA) or voclosporin (VCS) was administered as a 1-h pretreatment before PAN exposure to evaluate their podocyte-protective effects. The kidney organoids exhibited well-defined podocyte marker expression, confirming successful differentiation. PAN exposure caused a significant and concentration-dependent reduction in podocalyxin fluorescence, indicating robust induction of podocyte injury in organoids harboring the INF2 variant. Pretreatment with CsA or VCS significantly attenuated PAN-induced podocyte injury and preserved podocyte marker expression. CsA and VCS reduced podocyte injury to similar extents. In conclusion, we established a patient-specific kidney organoid model of INF2-associated FSGS that reliably recapitulated podocyte vulnerability to toxic injury. This platform demonstrated that calcineurin inhibitors, including the novel agent VCS, exert direct podocyte-protective effects in a genetic FSGS background and provide a practical system for mechanistic studies and therapeutic screening.

We report a case of normolipidemic lipoprotein glomerulopathy (LPG) associated with the APOE Kyoto variant. A 54-year-old Chinese man was referred for evaluation of persistent low-level proteinuria detected on routine screening, with preserved renal function and no clinical features of nephrotic syndrome. Laboratory evaluation showed proteinuria without overt dyslipidemia. Extensive evaluation excluded secondary causes. Renal biopsy revealed markedly dilated capillary loops filled with characteristic lipoprotein thrombi, consistent with LPG. Subsequent genetic testing identified a heterozygous APOE c.127C>T (p.Arg43Cys) mutation, consistent with the APOE Kyoto variant. Because fasting lipid levels remained within reference ranges, lipid-lowering therapy was not initiated. Angiotensin receptor blockade was associated with a reduction in urine protein-to-creatinine ratio from 0.38 to 0.28 g/g over 2 months. This case broadens the phenotypic spectrum of APOE Kyoto-associated LPG by demonstrating biopsy-proven disease in the setting of largely normal systemic lipid levels.