RARE DISEASE
Genetic steroid-resistant nephrotic syndrome
Genetic steroid-resistant nephrotic syndrome
Genetic steroid-resistant nephrotic syndrome
Synonyms: Familial idiopathic steroid-resistant nephrotic syndrome, Genetic SRNS, Hereditary steroid-resistant nephrotic syndrome
Synonyms: Familial idiopathic steroid-resistant nephrotic syndrome, Genetic SRNS, Hereditary steroid-resistant nephrotic syndrome
Synonyms: Familial idiopathic steroid-resistant nephrotic syndrome, Genetic SRNS, Hereditary steroid-resistant nephrotic syndrome
Drug discovery
6
drugs
With orphan designations
Overview
Genetic steroid-resistant nephrotic syndrome (SRNS) is an inherited form of nephrotic syndrome caused by mutations in podocyte-related genes such as NPHS1, NPHS2, and WT1, leading to proteinuria, hypoalbuminemia, edema, and hyperlipidemia unresponsive to corticosteroids [1][6][13]. It accounts for 10–20% of childhood nephrotic syndrome cases, with genetic etiology identified in ~30% of pediatric and 66% of congenital cases [1][13][16]. Progression to end-stage kidney disease (ESKD) occurs in 50% within 5–10 years, driven by podocyte dysfunction [1][2][10]. Management focuses on renin-angiotensin system inhibitors and supportive care, as immunosuppressants are typically ineffective in monogenic forms [8][9][10].
Therapies
ACE inhibitors/ARBs and diuretics for symptom control [1][8].
Calcineurin inhibitors (e.g., tacrolimus) are first-line for non-genetic SRNS (70% response) [8][10].
Gene therapy targeting podocin mutations shows preclinical promise [3][9].
Kidney transplantation is curative but reserved for ESKD, with low recurrence risk in genetic cases [1][13].
Categories: rare genetic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
511 drug discovery papers about Genetic steroid-resistant nephrotic syndrome, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
511 drug discovery papers about Genetic steroid-resistant nephrotic syndrome, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-05-29 | Biallelic pathogenic variants in FLNB are associated with paediatric steroid-resistant nephrotic syndrome via podocyte cytoskeletal dysfunction.
Steroid-resistant nephrotic syndrome (SRNS) is a severe paediatric kidney disease and a leading cause of end-stage kidney disease in children, with a high genetic contribution. While over 80 monogenic causes of SRNS have been identified, a significant proportion of affected patients still lack a clear genetic diagnosis, indicating that additional causative genes remain to be discovered. Through whole-exome sequencing of a paediatric SRNS cohort, we identified three probands carrying biallelic FLNB pathogenic variants. Sanger sequencing was performed for familial cosegregation verification and ACMG classification. Expression of Filamin B, Nephrin and Synaptopodin in renal tissues was assessed by immunohistochemistry/immunofluorescence. Wild-type and patient-derived variant FLNB plasmids were constructed and transfected into HEK293T cells and immortalised human podocytes (HPCs). The effects of these variants on protein expression, localisation and cytoskeletal organisation were assessed by western blotting and immunofluorescence. FLNB expression in HPCs was silenced using shRNA to evaluate the impact on podocyte marker proteins, cytoskeletal integrity and migratory capacity. A zebrafish flnb knockdown model was employed to validate its effects on renal development. All three probands presented with isolated SRNS without skeletal developmental abnormalities, and renal tissues showed significantly reduced Filamin B protein expression. In vitro, p.L117P and p.M1803L variants led to markedly reduced protein expression, while p.R470L and p.K2586R induced perinuclear aggregation of Filamin B accompanied by F-actin rearrangement. FLNB silencing led to downregulation of Nephrin and Synaptopodin, cytoskeletal disorganisation and impaired cell migration. Zebrafish flnb knockdown exhibited pericardial oedema, defective nephron development and abnormal podocyte foot processes. We report for the first time that biallelic FLNB pathogenic variants are associated with paediatric SRNS by disrupting Filamin B expression, cytoskeletal integrity and podocyte function, providing evidence that FLNB is a novel monogenic cause of SRNS.
2025-12-12 | Immune mechanisms and immunomodulatory therapies in steroid-resistant nephrotic syndrome.
Steroid-resistant nephrotic syndrome (SRNS) is a complex and refractory kidney disease generally causing chronic kidney dysfunction, characterized by persistent proteinuria despite prolonged corticosteroid therapy. This review comprehensively explores the mechanisms of immunity driving SRNS, mainly focusing on the complex function network within immune cells, pro-inflammatory cytokines, and podocyte injury. Current immunosuppressive therapies show limited efficacy, prompting exploration of precision immunomodulatory strategies. Emerging approaches include IL-17 or low-dose IL-12 modulation, proteasome or CD38 blockade, C5/factor B inhibition, and Rho kinase or caspase inhibition. Additionally, personalized strategies leveraging genetic profiling and biomarker-guided therapies are advancing tailored interventions. These targeted therapies address SRNS heterogeneity while minimizing systemic immunosuppression, offering new promise for halting disease progression. Future directions emphasize combinatorial regimens and mechanistic stratification to optimize therapeutic outcomes.
2025-09-25 | Genetic evidence for repurposing GLP-1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti-inflammatory pathways beyond glycaemic control.
Despite observational links between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and kidney benefits, causal mechanisms remain unclear. This study aims to dissect genetic causality and mediation pathways underlying the effects of GLP-1RAs on chronic kidney disease (CKD) and related renal outcomes. Using large-scale Genome - Wide Association Study (GWAS) data, we applied two-sample Mendelian randomisation (MR) to estimate the causal effects of GLP-1RAs on CKD, estimated glomerular filtration rate (eGFR) and subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome and chronic glomerulonephritis), with sensitivity analyses. The glycaemic markers (glycated haemoglobin [HbA1c] and blood glucose), type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) served as positive controls. Mediation MR assessed body mass index (BMI), lipids, glycaemic markers and inflammatory proteins. Data were sourced from MRC Integrative Epidemiology Unit Open Genome - Wide Association Studies OpenGWAS, FinnGen, GWAS Catalogue and cohort-specific studies. Positive control analyses revealed that genetically predicted GLP-1R activation was associated with reduced levels of HbA1c (p = 4.93E-15) and blood glucose (p = 9.73E-5), as well as a decreased risk of T2DM (p = 2.45E-4) and DN (p = 6.35E-4), fully validating the reliability of the genetic instruments. Genetic proxies for GLP-1R activation lowered risks of CKD (odds ratio [OR] = 0.83, p = 9.22E-9), immunoglobulin A nephropathy (IgAN) (OR = 0.70, p = 2.11E-3) and kidney function preservation (β = 0.01, p = 9.11E-3), but showed null effects on other CKD subtypes. Mediation analyses indicated that fibroblast growth factor 23 (FGF23) suppression mediated 26.57% of the effect on eGFR and 13.50% of CKD protection, whereas metabolic traits (BMI: 2.08% for CKD, 5.51% for eGFR; high-density lipoprotein: 0.79% for CKD, 2.34% for eGFR; HbA1c: 8.25% for eGFR) partially explained the benefits on CKD and eGFR. Only BMI exhibited a mediation effect on IgAN. Sensitivity analyses confirmed minimal pleiotropy. This study provides robust genetic evidence for repurposing GLP-1RAs in CKD and IgAN through anti-inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.
2025-04-15 | Glucagon-like peptide-1 receptor agonists, inflammation, and kidney diseases: evidence from Mendelian randomization.
It has been proved that glucagon-like peptide-1 receptor (GLP1R) agonists have positive effects on renal outcomes in diabetic patients. However, it remains unknown whether GLP1R agonists could provide similar protection against other kidney diseases. We performed two-sample Mendelian randomization (MR) analyses to determine the causal effects of GLP1R agonists on multiple kidney diseases. Exposure to GLP1R agonist was proxied by the available cis-eQTLs for GLP1R. Primary outcomes included the risk assessment for diabetic nephropathy, IgA nephropathy, membranous nephropathy, nephrotic syndrome, chronic kidney disease, acute glomerulonephritis, chronic glomerulonephritis and calculus of kidney/ureter. Type 2 diabetes and body mass index were used as positive control. Two-stage network MR analyses were conducted to assess the mediation effect of inflammatory proteins on the relationships between GLP1R agonists and kidney diseases. After meta-analyses of both discovery and validation cohorts, genetically proxied GLP1R agonist was found to significantly associated with a decreased risk of diabetic nephropathy (OR = 0.72, 95%CI = 0.54-0.97, p = 0.031) and IgA nephropathy (OR = 0.58, 95%CI = 0.36-0.94, p = 0.027). Two-stage network MR revealed that there was an indirect effect of GLP1R agonist on IgA nephropathy through signaling lymphocytic activation molecule family member 1 (SLAMF1), with a mediated proportion of 34.27% (95% CI, 1.47-67.03%, p = 0.041) of the total effect. The findings of current study presented genetic proof for the potential protective effects of GLP1R agonists in the development of diabetic nephropathy and IgA nephropathy, offering a novel sight for future mechanistic and clinical applications.
2024-06-19 | The Protective Role of KANK1 in Podocyte Injury.
Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.
small molecules
2026-08-03 | NEPHROTIC SYNDROME IN SAUDI CHILDREN: A SYSTEMATIC REVIEW OF CLINICAL CHARACTERISTICS, MANAGEMENT AND OUTCOMES
Background: Paediatric Nephrotic Syndrome (NS) is a major chronic disorder characterized by heavy proteinuria, hypoalbuminemia, hyperlipidaemia, and peripheral edema. While minimal change disease (MCD) is the predominant histopathology globally, paediatric populations in Saudi Arabia demonstrate distinct generic patterns, higher rates of consanguinity, and a varying prevalence of steroid-resistant nephrotic syndrome. (SRNS). Methods: A systematic literature search was conducted across Medline/PubMed, EMBASE, and reginal databases following PRISMA guidelines. Observational cohort studies, retrospective reviews, and clinicopathological studies focusing on paediatric primary nephrotic syndrome in Saudi Arabia evaluated. Results: Synthesis of included studies indicates a median age of presentation between 3 and 5.5 years, with a male-to-female ratio ranging from 1.5:1 to 2.3:1. Initial responsiveness to corticosteroid therapy ranges between 70% and 85%. However, among biopsy-proven steroid-resistant cases, Focal Segmental Glomerulosclerosis (FSGS) is the single most common histopathological pattern (39-54%), followed by IgM nephropathy, Mesangioproliferative Glomerulonephritis (MesPGN), and MCD variants. Familial clustering is noted in up to 6-12% of cases, strongly correlated with high rates of consanguinity. Calcineurin inhibitors (tacrolimus, cyclosporine) and mycophenolate mofetil remain the primary second-line immunosuppressive protocols are key to optimizing long-term renal outcomes. Conclusion: Saudi children with nephrotic syndrome demonstrate a high burden of focal segmental glomerulosclerosis, elevated risk of steroid dependency or resistance, and significant risk of infectious complications (predominantly peritonitis and urinary tract infections). Early genetic screening for podocyte gene mutations and aggressive second -line immunosuppressive protocols are key to optimizing long-term renal outcomes. Keywords: Paediatric Nephrotic Syndrome, Saudi Arabia, Minimal Change Disease, Focal segmental Glomerulosclerosis, Steroid-Resistant Nephrotic Syndrome, Immunosuppression.
2026-07-28 | A multi-national study examined the response sustainability to calcineurin inhibitors and long-term kidney survivals in children with genetic podocytopathies.
While calcineurin inhibitors (CNI) reduce proteinuria in a subgroup of children with genetic podocytopathies, previous reports suggest that the response is short-lived and of no benefit to long-term outcomes. Here, we assess CNI response sustainability and the association between different patterns of response preservation and kidney survival. We performed a retrospective cohort study of patients aged 0-18 years with genetic podocytopathies treated with CNI for at least three months from 34 pediatric nephrology centers worldwide. Response status was defined in accordance with International Pediatric Nephrology Association Clinical Practice Recommendations. We analyzed 136 patients with genetic podocytopathies over a median follow-up period of 42.1 months (between CNI initiation and last follow-up or commencement of kidney replacement therapy, whichever occurred first). At least partial response was attained in 28% and 22% of patients at six months post-CNI initiation and last follow-up, respectively. Compared to non-response group, patients with at least partial response at six months had significantly lower urine protein-to-creatinine ratios across various time points post-CNI. 71%, 11% and 18% exhibited no response, non-sustained and sustained response, respectively, throughout the observation period. Both sustained and non-sustained responses were significantly associated with superior kidney survival compared to no response. Importantly, no patients with sustained response developed kidney failure over a follow-up period of 42 (interquartile range 19-62) months. Patients with non-sustained response had a 92% lower risk of kidney failure compared to non-responders. A subset of children with genetic podocytopathies experienced a sustained response to CNI, and none developed kidney failure. Children with non-sustained response still demonstrated superior kidney survival compared to non-responders. Our findings may support a trial of CNI in genetic podocytopathies, and continuing therapy among those showing clinical response.
2026-07-12 | Kidney outcomes of coenzyme Q10 supplementation in patients with genetically confirmed CoQ10 nephropathy in Japan.
Coenzyme Q10 (CoQ10) nephropathy is a rare mitochondrial kidney disease caused by defects in CoQ10 biosynthesis and represents a unique form of steroid-resistant nephrotic syndrome with a disease-specific therapy. However, data on treatment outcomes of this disease in Japanese patients remain limited. We conducted a retrospective observational study of Japanese patients. Patients with a genetically confirmed diagnosis of CoQ10 nephropathy who received CoQ10 supplementation and had available longitudinal clinical data were included. Changes in the urinary protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate before and after treatment were evaluated, and adverse events were assessed. Twelve patients were included in the analysis. The median age at treatment initiation was 9.0 years, and COQ8B was the predominant causative gene (n = 11). One patient harbored a COQ6 variant. CoQ10 supplementation was initiated at a median dose of 10.0 mg/kg/day. The median UPCR decreased from 1.66 g/gCr at baseline to 0.19 g/gCr at 12 months, and 6/7 (86%) patients with available 12-month data achieved a ≥ 50% reduction in proteinuria. Kidney function remained stable, and no patients progressed to end-stage kidney disease during a median follow-up of 28.8 months. Adverse events were mild and did not lead to treatment discontinuation. In Japanese patients with CoQ10 nephropathy, CoQ10 supplementation was associated with a substantial reduction in proteinuria and stabilization of kidney function. These findings indicate the importance of early genetic diagnosis and prompt initiation of targeted therapy for this treatable hereditary kidney disease.
2026-06-06 | Update on APOL1 and chronic kidney diseases in children.
Chronic kidney disease (CKD) is a major global health burden that disproportionately impacts people of recent African ancestry. The discovery of risk variants in the apolipoprotein L1 (APOL1) gene has transformed the understanding of racial disparities in CKD. In particular, APOL1 variants have been associated with increased risk of focal segmental glomerulosclerosis, virus-associated nephropathy, and other glomerular diseases in Black adults. While approximately 10-15% of Black Americans have a high-risk APOL1 genotype, disease penetrance is variable and is likely mediated by additional genetic and environmental "second hits." Variants in APOL1 have also been implicated in kidney transplant outcomes and pregnancy complications, underscoring its broad clinical relevance. Advances in therapeutic strategies, including small molecule inhibitors of APOL1 pore function, APOL1 antisense oligonucleotides, and JAK-STAT pathway modulation, offer promise for targeted interventions in adult populations. Emerging data in children highlight similar genotype-phenotype associations, with evidence of high-risk APOL1 genotype impacting steroid-resistant nephrotic syndrome and CKD progression. However, pediatric studies remain limited and underpowered, leaving critical gaps in the understanding of disease epidemiology, mechanisms, and long-term outcomes. This review will explore current knowledge of APOL1 kidney disease (AMKD) with a particular focus on pediatric populations and highlight the need for inclusion of children in future studies.
2026-03-05 | Epigenetic mechanisms and steroid-resistant nephrotic syndrome: The future potential for SRNS diagnosis.
Nephrotic syndrome (NS) is commonly managed with glucocorticoid (GC) therapy, yet about 10%-30% of children do not achieve remission after an adequate initial steroid course and are classified as steroid-resistant nephrotic syndrome (SRNS); in adults, proportions are generally higher and heterogeneous across histologies. Currently, genetic testing can identify causative mutations in 30% of SRNS cases, highlighting the need for complementary pre-treatment stratification approaches. This review synthesizes human evidence linking epigenetic dysregulation to GC responsiveness, highlighting differential DNA methylation patterns in genes such as NLRP3 and SOCS3. Simultaneously, the expression levels of microRNAs (miRNAs) such as miR-142 and miR-30 have been shown to be associated with the efficacy of GC treatment. We propose a multi-biomarker integrative analysis strategy that combines methylation profiles with miRNA expression and emerging histone modification signals for pre-treatment risk stratification and prediction of therapeutic response, thereby reducing ineffective steroid exposure and enabling mechanism-informed management pending prospective validation.
gene therapies
2026-03-28 | Advances in SRNS Gene Research: From Precision Classification to Precision Diagnosis and Treatment.
To clarify the genetic classification, diagnostic strategies, and precision treatment pathways of steroid-resistant nephrotic syndrome (SRNS), this review systematically reviews the genetic stratification system of SRNS by integrating recent advances in genetic testing technologies and pathogenesis research. It contains the pathogenic mechanisms, diagnostic protocols, and therapeutic correlations of different genetic subtypes, while summarizing current progress and clinical challenges in gene therapy. Results indicate SRNS can be categorized into genetic (38-58%) and non-genetic/immune-mediated (40-60%). A stepwise diagnostic system comprising core proteinuria gene panel testing, whole-genome sequencing (WGS), whole-exome sequencing (WES), and supplementary multi-omics/long-range sequencing is proposed, suited for populations with "typical phenotypes and moderate genetic risk", "atypical phenotypes and high genetic suspicion", and "complex structural/non-coding region variants" respectively. Pathogenic mechanisms directly determine therapeutic strategies: COQ2/PDSS2 mutations respond to coenzyme Q10 suplementation, while NPHS1 mutations necessitate early renal transplantation. Adeno-associated virus (AAV)-mediated gene therapy and CRISPR-Cas editing show preclinical promise but face challenges including incomplete detection coverage and clinical translation difficulties. Genetic technologies are driving SRNS management transformation from "empirical treatment" to "mechanism-oriented precision diagnosis and therapy". Future efforts should focus on overcoming genetic testing limitations and gene therapy translation bottlenecks to enhance diagnostic and therapeutic efficacy.
2026-03-06 | Molecular mechanisms in podocytopathies: finding suitable targets for a new era of glomerular gene therapy.
Podocytopathies encompass a spectrum of glomerular disorders driven by structural and functional impairments in podocytes: specialized cells critical for maintaining the glomerular filtration barrier. Dysregulation of key podocyte components-such as slit-diaphragm proteins (nephrin, podocin), cytoskeletal regulators (ACTN4, TRPC6), and adhesion complexes (integrins, dystroglycan)-leads to proteinuria and progressive glomerulosclerosis. Current therapies often fail to address underlying genetic or molecular defects, particularly in hereditary or refractory cases. Gene therapy has emerged as a transformative approach, leveraging adeno-associated viral (AAV) vectors, CRISPR-based editing, and RNA modulation to correct pathogenic mutations or restore disrupted pathways. Recent advances in capsid engineering, tissue-specific promoters, and delivery strategies have enhanced podocyte targeting while minimizing off-target effects. Preclinical successes, including AAV-mediated rescue of NPHS2-associated nephrotic syndrome and complement modulation in IgA nephropathy, highlight the therapeutic potential. However, challenges such as immune responses, vector biodistribution, and disease heterogeneity remain. This review synthesizes the molecular mechanisms underlying podocytopathies, evaluates current gene-therapy strategies, and discusses translational hurdles and future directions, including patient-derived organoid models and combinatorial therapies. By bridging mechanistic insights with innovative gene-based interventions, this work underscores the promise of precision medicine in revolutionizing the treatment of podocytopathies.
2026-02-17 | Treatment outcomes and ongoing pediatric trials in steroid-resistant nephrotic syndrome.
Despite an increasing number of therapeutic options for pediatric patients with steroid-resistant nephrotic syndrome (SRNS), treatment resistance and risk of progression to kidney failure are still high. Children with monogenic forms of SRNS and resistance to non-steroidal immunosuppressants are at the highest risk. Advances in the understanding of SRNS pathogenesis have enabled the development of novel therapies that target genetic, immunologic, and metabolic mechanisms of disease development and progression. In this review, we summarize select contemporary cohort study findings, novel therapeutic agents and their mechanistic targets, and eight recent and ongoing clinical trials for pediatric patients with SRNS.
2025-11-12 | A CPEB2/ANGPTL3 feedback loop promotes the progression of podocyte injury in nephrotic syndrome.
Podocyte injury is the primary pathology responsible for 70-90% of nephrotic syndrome (NS) in children, a condition closely associated with the aberrant expression of Angiopoietin-like-3 (ANGPTL3). The regulatory mechanism by which ANGPTL3 is upregulated during NS progression remains elusive. In this study, we found that ANGPTL3 can be regulated by Cytoplasmic polyadenylation element binding protein 2 (CPEB2) through translational control, and conversely, CPEB2 can be transcriptionally regulated in response to ANGPTL3 signaling as a feedback loop. Exposure to puromycin aminonucleoside (PAN) or adriamycin (ADR) dose-dependently increased the expression of both CPEB2 and ANGPTL3 in MPC-5 cells. Ectopic overexpression of CPEB2 in MPC-5 cells significantly promoted cell apoptosis and migration, which could be abrogated by knockdown of ANGPTL3. Mechanistically, the regulation of ANGPTL3 by CPEB2 was attributed to translational promotion. CPEB2 could directly bind the 3' untranslated coding region (UTR) of ANGPTL3 mRNA, thereby promoting the recruitment of ANGPTL3 transcripts to the translation initiation complexes. Consequently, polysomal profiling suggested that the abundance of ANGPTL3 transcripts in actively high-translating polysomes was dramatically increased upon CPEB2 overexpression. On the other hand, ANGPTL3 signaling could increase the mRNA stability of CPEB2, thereby promoting the mRNA expression of CPEB2. Furthermore, the role of CPEB2/ANGPTL3 in podocyte injury was validated in vivo. Depletion of CPEB2 with adeno-associated virus (AAV9)-shCPEB2 significantly decreased the expression of ANGPTL3, and consequently mitigated albuminuria and histopathological injury in ADR-induced NS mice. In conclusion, this study highlighted the CPEB2/ANGPTL3 feedback loop as a novel mechanism contributing to the progression of podocyte injury.
2025-10-01 | Utility of Genetic Testing in CKD with Nephrotic-Range Proteinuria
Introduction: Recent advancements in genetics are transforming clinical practice in all medical fields, including nephrology. Case Description: We present a 55-year-old female with a past medical history of obesity, hypertension, and a BRCA-1 variant of uncertain significance (which she underwent hysterectomy and salpingo-oophorectomy for), referred for chronic kidney disease (CKD) with nephrotic proteinuria. Kidney biopsy was inconclusive and complicated by post-procedural bleeding requiring hospitalization. Genetic testing revealed a pathogenic variant in COL4A4. While she had no overt signs of Alport’s syndrome, including family history, ophthalmic or otologic complications, additional testing revealed mild sensorineural hearing loss. Discussion: This case exemplifies the emerging potential of genetic testing for the evaluation of CKD with nephrotic proteinuria. Generally, kidney biopsies are the “gold standard” workup when the etiology of a nephrotic proteinuria is unclear on initial evaluation. However, due to advancements in less invasive secondary work-up, such as serologic testing, clinicians can often solidify a diagnosis and treatment plan for select patients with glomerular diseases without a biopsy. Genetic testing ought to become a more common, minimally invasive tool to avoid unnecessary or risky biopsies. In fact, current KDIGO guidelines for glomerular diseases dictate that conditions such as Alport’s, Fabry, and familial FSGS can be treated without a confirmatory biopsy; notably, these diseases are all detectable on a genetic panel. Moreover, genetic testing is a more sensitive and accurate diagnostic tool than using a combination of clinical features, family history, and biopsy results in some conditions: Alport’s syndrome is an example of this phenomenon. Due to its elusive clinical nature, guidelines suggest testing for COL4A3–COL4A5 genes in patients with persistent proteinuria >0.5 g/d, steroid-resistant nephrotic syndrome, or FSGS. Furthermore, ongoing genetic research in conditions that cause nephrotic range proteinuria, such as FSGS and steroid-resistant nephrotic syndrome, suggests an optimistic future where genetic testing may complement or eliminate the need for a biopsy. Currently, kidney biopsy remains an invaluable and relatively safe procedure to evaluate nephrotic-range proteinuria. However, our case highlights the value of genetic testing as a less invasive and risky tool.
antibodies
2026-09-03 | Outcome of children treated with rituximab for steroid-resistant nephrotic syndrome: Renal histopathology as a response marker.
Steroid-resistant nephrotic syndrome (SRNS) in children remains a major therapeutic challenge. Although calcineurin inhibitors (CNIs) are commonly used as first-line therapy, a substantial proportion of patients fail to achieve remission, and prolonged use may result in nephrotoxicity. Rituximab has emerged as a potential therapeutic option for refractory SRNS; however, treatment responses appear variable, and the influence of underlying renal histopathology remains incompletely understood. The objective of the study was to evaluate the association between renal histopathological findings and clinical response to rituximab in children with CNI-resistant SRNS. Study design and setting: This prospective observational study was conducted between 2011 and 2020 at a university-affiliated tertiary pediatric nephrology center. The study aimed to evaluate the efficacy of rituximab in children with CNI-resistant SRNS and to examine the association between renal histopathological findings and treatment response. Twenty-four children aged 2-12 years were enrolled. Follow-up: Patients were followed prospectively after completion of rituximab therapy through regular clinical and laboratory assessments. The mean follow-up duration after the last rituximab infusion was 5.1 years (range: 6 months-8 years). treatment response definitions: Complete remission was defined according to International Pediatric Nephrology Association recommendations as a urine protein-to-creatinine ratio (UPCR) ≤20 mg/mmol (≤0.2 mg/mg) or negative/trace proteinuria on dipstick testing on at least three consecutive occasions. Partial remission was defined as a UPCR >20 mg/mmol but <200 mg/mmol together with serum albumin ≥30 g/L. No response was defined as failure to achieve either complete or partial remission. Genetic evaluation: Genetic testing was performed in all patients with focal segmental glomerulosclerosis (FSGS), classic minimal change disease (MCD), and MCD with immunoglobulin M (IgM) deposition. No pathogenic or likely pathogenic variants associated with monogenic SRNS were identified in the tested patients. Genetic testing was not performed in patients with IgA nephropathy, membranous nephropathy, C1q nephropathy, or dense deposit disease (DDD). Twenty-four children with SRNS were included (13 males and 11 females; age range 2-12 years). Histopathological diagnoses included FSGS in nine patients (37.5%), MCD in 4 (16.7%), MCD with IgM deposition in 6 (25.0%), DDD in 2 (8.3%), membranous nephropathy in 1 (4.2%), IgA nephropathy in 1 (4.2%), and C1q nephropathy in 1 (4.2%). Overall, 10 patients (41.7%) achieved complete remission and 3 (12.5%) achieved partial remission, predominantly among patients with MCD and MCD with IgM deposition. Responses were uncommon among patients with FSGS. Eleven patients (45.8%), all of whom were non-responders, progressed to end-stage kidney disease. No major adverse effects of rituximab were observed; mild infusion reactions occurred in three patients and mild cellulitis in one patient. In this cohort of children with refractory SRNS, favorable responses to rituximab were observed predominantly among patients with CNI-resistant MCD and MCD with IgM deposition, whereas responses among patients with FSGS were uncommon. These findings suggest that renal histopathology may help identify patients more likely to benefit from rituximab therapy; however, the small sample size, heterogeneous histopathological distribution, and observational study design preclude definitive conclusions. Larger prospective multicenter studies incorporating comprehensive genetic evaluation are required to determine whether histopathology can serve as a reliable predictor of rituximab responsiveness.
2026-08-20 | Beyond Defense: Kidney Mysteries in Inborn Errors of Immunity
Inborn errors of immunity (IEI), formerly termed primary immunodeficiencies, are increasingly recognized as disorders of immune dysregulation rather than infection susceptibility alone. With over 500 validated genes in the 2024 International Union of Immunological Societies (IUIS) classification and approximately one-quarter of patients presenting without infection, autoimmunity, autoinflammation, lymphoproliferation, and malignancy are now core features. The kidney is affected across at least 22 IEI categories, yet renal involvement remains under-recognized. This review proposes a mechanistic framework for IEI-associated kidney disease, encompassing: complement dysregulation (C3 glomerulopathy, atypical hemolytic uremic syndrome from CFH/CFI/C3 variants); immune complex–mediated and monogenic lupus nephritis (C1q, C2, C4, DNASE1L3, and TREX1 defects); autoinflammatory and type I interferonopathy–driven nephropathy; infection-related glomerulonephritis (common variable immunodeficiency [CVID], chronic granulomatous disease); lymphoproliferative and immune-dysregulation syndromes causing interstitial nephritis (ALPS, CTLA-4 and LRBA deficiency); and syndromic IEI with intrinsic structural disease. We outline a stepwise diagnostic approach integrating clinical red flags, complement and immune profiling, kidney biopsy with immunofluorescence and electron microscopy, and genetic testing, emphasizing that genetic diagnosis should precede immunosuppression. The therapeutic landscape is shifting from empirical immunosuppression toward precision medicine, including complement inhibitors (iptacopan, pegcetacoplan, Food and Drug Administration–approved for C3 glomerulopathy in 2025), JAK inhibitors for interferonopathies, leniolisib for activated PI3Kδ syndrome, CTLA4-Ig agents, and curative hematopoietic stem cell transplantation and emerging gene therapy. An illustrative case from Europe’s largest kidney transplant center illustrates a girl with Schimke immuno-osseous dysplasia (SMARCAL1 mutation) presenting with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis who underwent kidney transplantation following bone marrow transplant. Recognizing IEI in unexplained nephropathy, combining biopsy with complement and genetic profiling, and early nephrology–immunology collaboration are key to improving renal outcomes and enabling potentially curative therapy.
2026-07-28 | Obinutuzumab as a Rescue and Maintenance Strategy in Children with Difficult-to-Treat Nephrotic Syndrome After Rituximab-Based Treatment Failure or Intolerance: A Preliminary Single-Center Real-World Retrospective Study.
This preliminary study aimed to describe the effectiveness and safety of obinutuzumab as a rescue and maintenance anti-CD20 strategy in children with difficult-to-treat nephrotic syndrome after failure or intolerance of rituximab-based multi-target immunosuppression. This exploratory single-center retrospective real-world study included consecutive children who received obinutuzumab between April 2024 and January 2025. Nine patients were included in the safety set, and eight who completed treatment and had follow-up data comprised the efficacy set. The primary outcome was 12-month relapse-free survival. Secondary outcomes included annualized relapse rate, peripheral B-cell depletion, glucocorticoid-free status, reduction or discontinuation of background immunosuppression, and safety. Median follow-up in the efficacy set was 1.24 years (IQR 1.01-1.67). No relapses occurred after obinutuzumab in this small efficacy set, corresponding to an observed 12-month relapse-free proportion of 8/8 (100%; exact 95% CI 63.1-100) and reducing the annualized relapse rate from 2.50 to 0 episodes/person-year. All eight efficacy-set patients achieved complete peripheral B-cell depletion and remained depleted at 6 months. At last follow-up, seven had discontinued both glucocorticoids and all non-obinutuzumab immunosuppressants, while one had discontinued glucocorticoids with a reduced dose of mycophenolate mofetil. In the safety set, one child developed severe anaphylactic shock during the first infusion; infectious events were limited to CTCAE grade 1-2 events. In this exploratory, hypothesis-generating study, obinutuzumab was associated with a favorable relapse profile, sustained peripheral B-cell depletion, and reduction of background immunosuppression in a highly selected pediatric population. Larger prospective studies are required to confirm these preliminary observations and define long-term safety.
2026-07-12 | Kidney Survival in Children With Steroid-Resistant Nephrotic Syndrome Treated by Rituximab.
Kidney outcomes in children with steroid-resistant nephrotic syndrome (SRNS) following rituximab remain unclear. We conducted an international retrospective cohort study across 23 centers in 17 countries, including children with SRNS who did not respond to calcineurin inhibitors (CNIs) and subsequently, received rituximab. Patients with genetic variants were excluded. The primary outcome was kidney survival. We analyzed data on 151 children (53% males; median age at onset: 6.8 years; primary vs. secondary SRNS: 54% vs. 46%; focal segmental glomerulosclerosis [FSGS]: 62%). All subjects received CNIs before rituximab (0-3 months: 21%; 3-6 months: 26%; 6-12 months: 26%; > 12 months: 26%). Upon rituximab, 73 subjects (48%) had normal kidney function, 47 (31%) had chronic kidney disease (CKD)2, and 31 (21%) had CKD3. Twenty-eight (19%) developed kidney failure. Overall kidney survival was 82.7%, 75.8%, and 72.3% at 3, 5, and 7 years post-rituximab. Baseline CKD staging before rituximab was associated with kidney survival at 5 years (log-rank P < 0.001); CKD stage 1, 91.7%; CKD stage 2, 70.4%; and CKD stage 3, 35.5%). The predictive factors for inferior kidney survival were CKD2 (adjusted hazard ratio [HRadj]: 2.7, 95% confidence interval [CI]: 1.5-4.9, P < 0.001), lower baseline serum albumin (log-rank P = 0.01; HRadj: 0.88, 95% CI: 0.81-0.95; P < 0.001) and FSGS (log-rank P = 0.03; HRadj: 3.4, 95% CI: 1.1-10.0; P < 0.001). Nonremission at 6 months was associated with inferior kidney survival (61.2% at 5 years), compared with complete remission (CR) or partial remission (PR) (100% at 5 years) (log-rank P = 0.01; HRadj: 14.1, 95% CI: 2.2-93.5, P = 0.01). Duration of prior calcineurin inhibition and SRNS type were not significant predictors. Kidney survival of SRNS following add-on rituximab is 70% to 80% over 3 to 7 years. Nonresponse, preexisting CKD, lower albumin, and FSGS predict inferior kidney survivals.
2026-06-26 | Monogenic variants drive low recurrence risk in pediatric steroid-resistant nephrotic syndrome after kidney transplantation: a high-consanguinity cohort.
Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of stage 5 chronic kidney disease (CKD 5) in children and carries a substantial risk of post-transplant disease recurrence. Data from the Arabian Peninsula are sparse. This retrospective cohort study included all paediatric patients (aged < 18 years) who underwent a first kidney transplant at King Fahad Specialist Hospital-Dammam between January 2008 and December 2023 with a confirmed diagnosis of SRNS, focal segmental glomerulosclerosis (FSGS), congenital nephrotic syndrome, or a pathogenic monogenic variant known to cause SRNS. Patients were classified as having genetic or non-genetic SRNS according to next-generation sequencing results. Primary outcomes were post-transplant recurrence rate and graft survival. Secondary outcomes included estimated glomerular filtration rate (eGFR) values and treatment response. Among 208 paediatric kidney transplant recipients, 60 (28.8%) had CKD 5 attributable to SRNS/FSGS. Genetic testing (performed in 59/60 patients, 98.3%) identified pathogenic variants in 44 patients (74.6%); NPHS2 was most prevalent (28.8%). Post-transplant recurrence occurred in 6 patients (10%): 5 of 15 in the non-genetic group (33%) and 1 of 44 in the genetic group (2.3%) (p < 0.001). All six patients with recurrence received plasmapheresis; five also received rituximab. Complete remission was achieved in 5 patients (83%) and partial remission in 1 (17%). The 5-year graft survival rate was 98% overall-100% in the genetic group versus 93% in the non-genetic group (log-rank p = 0.21). The eGFR at 5 years was significantly higher in the genetic group (73.5 ± 17.6 vs. 60.6 ± 22.9 mL/min/1.73 m2, p = 0.049). SRNS/FSGS accounts for approximately 29% of paediatric CKD 5 in this cohort and is characterised by a high prevalence of monogenic variants reflecting regional consanguinity. Genetic testing reliably stratifies recurrence risk: non-genetic SRNS carries a substantially higher recurrence rate, yet combined plasmapheresis and rituximab achieves remission in most affected patients. Graft outcomes are comparable to those seen in other CKD 5 aetiologies.
other
2026-09-03 | Rapidly progressive steroid-resistant focal segmental glomerulosclerosis associated with an INF2 exon 6 variant.
Variants in the inverted formin-2 (INF2) gene are a known cause of hereditary focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth disease. We report a case of rapidly progressive FSGS associated with a rare INF2 variant. A 12-year-old boy developed proteinuria and was diagnosed with FSGS at age 14 following a renal biopsy. Steroid therapy and subsequent immunosuppressive treatments, including plasma exchange, were ineffective. At age 15, a heterozygous missense variant in exon 6 of the INF2 gene (c.763G>A, p.Asp255Asn) was identified. Despite conservative management, the patient progressed to end-stage kidney disease at age 17. Although exon 6 variants are rarely reported, the present case showed a relatively aggressive renal course.
2026-07-09 | Genetic mutation patterns in Indonesian children with primary steroid-resistant nephrotic syndrome.
Approximately 10-30% of pediatric cases of steroid-resistant nephrotic syndrome (SRNS) have pathogenic monogenic variants, particularly in primary SRNS. Identifying these variants aids in predicting outcomes, guiding treatment, and enabling genetic counseling. In Indonesia, data on genetic mutation patterns in pediatric SRNS are still limited. A cross-sectional study was conducted using whole-exome sequencing (WES) to detect variants of genetic origin in children diagnosed with primary SRNS at Indonesia's National Referral Hospital, Cipto Mangunkusumo. We assessed the relationship between genetic findings and clinical features, including age at onset, treatment response, kidney biopsy, and kidney function. Among 60 children with primary SRNS, 9 subjects (15%) harbored pathogenic or likely pathogenic variants across 8 genes (CUBN, AVIL, TRPC6, INF2, COL4A4, LAMA5, INVS, and FGA). Variants included stop-gained (n = 4), missense (n = 4), splice site (n = 1), and frameshift (n = 1), with both autosomal recessive and dominant inheritance observed. Two subjects had compound heterozygous variants. Most variant-positive subjects were male (6/9), had disease onset before age 3, and showed diverse histology (FSGS, MCD, or mesangial/membranoproliferative lesions). Four showed extrakidney features: peripheral neuropathy, high myopia, microcephaly with short stature, and hearing loss. While 53.3% responded to cyclosporin, over half remained in non-remission. This study reveals the genetic and phenotypic heterogeneity of primary SRNS in Indonesian children. The identification of diverse pathogenic variants underscores the utility of WES, even in cases responsive to cyclosporin. Genetic testing should be integrated into routine SRNS evaluation, especially in atypical presentations or early-onset of the disease.
2026-04-01 | Kidney diseases related to COL4A3, COL4A4 and COL4A5 gene variations and their pathogenic mechanisms
Collagen Ⅳ is the core structural protein of the glomerular basement membrane, composed of α chains encoded by the COL4A3, COL4A4, and COL4A5 genes, which assemble into the α3α4α5 trimer. It plays a crucial role in maintaining the structural integrity and filtration function of the glomerular basement membrane. Variations in these three genes can lead to a spectrum of inherited kidney diseases, with Alport syndrome being the most representative. Clinically, Alport syndrome is characterized by hematuria, progressive renal dysfunction, sensorineural hearing loss, and ocular abnormalities, with inheritance patterns including X-linked, autosomal recessive, and autosomal dominant. Additionally, variations in the COL4A3-COL4A5 genes are closely associated with various kidney diseases, such as thin basement membrane nephropathy (TBMN), familial IgA nephropathy, focal segmental glomerulosclerosis (FSGS), steroid-resistant nephrotic syndrome (SRNS), and end-stage renal disease (ESRD) of unknown etiology. In recent years, with the widespread application of high-throughput sequencing technologies, genetic testing has increasingly demonstrated its value in disease diagnosis, prognosis assessment, and precision medicine. This article systematically reviews the clinical manifestations, molecular genetic mechanisms, and clinical management strategies of COL4A3-COL4A5-related kidney diseases, aiming to provide a theoretical foundation and practical guidance for early diagnosis and individualized treatment of these conditions.
2026-01-23 | Identification of monogenic variants in steroid-resistant and steroid-sensitive nephrotic syndrome.
Steroid-resistant nephrotic syndrome (SRNS) constitutes the second most common cause of chronic kidney disease (CKD) in children. A monogenic cause can be identified in approximately 25% of SRNS cases. In contrast, steroid-sensitive or steroid-dependent nephrotic syndrome (SSNS/SDNS) is typically attributed to multifactorial or immunological causes and rarely linked to monogenic etiology. We performed exome sequencing (ES) in 237 families, including 183 with SRNS and 54 with SSNS/SDNS. A (likely) pathogenic variant in a known SRNS gene was identified in 29/183 individuals with SRNS (15.8%). Additionally, 6/183 (3.3%) individuals with SRNS carried pathogenic variants in phenocopy genes-genes associated with diseases that clinically mimic SRNS. The diagnostic yield was significantly higher in individuals with ≥ 50 Mb homozygosity-by-descent (HBD) (44.7% vs. 8.5%) and in those with SRNS disease onset before 1 year of age (41.9%). In individuals with SSNS/SDNS, we found a likely causative variant in only 1 of 54 probands. A genetic cause was established in 19.1% of SRNS patients (15.8% in known SRNS genes and 3.3% in phenocopy genes), but only 1.9% of non-steroid-resistant cases.
2025-12-30 | Steroid-Resistant Nephrotic Syndrome and Chronic Kidney Disease Associated with 6p Duplication Syndrome: A Case Report
6p duplication syndrome is a rare chromosomal disorder with a wide range of clinical features, including developmental delay, craniofacial dysmorphism, cardiac and skeletal anomalies, and renal involvement such as congenital anomalies of the kidney and urinary tract, proteinuria, and glomerular dysfunction. Reports of glomerular pathology are very limited. We describe a 14-year-old female with a 6p25.4q35 duplication presenting with obesity, intellectual disability, skeletal anomalies, and steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis and CKD. Genetic analysis unified her multisystemic findings under a single diagnosis and clarified the prognosis given her treatment resistance. This case highlights that glomerular disease can be part of the 6p duplication spectrum and underscores the diagnostic and prognostic value of genetic testing in patients with treatment-resistant nephrotic syndrome.
proteins
2026-05-29 | Biallelic pathogenic variants in FLNB are associated with paediatric steroid-resistant nephrotic syndrome via podocyte cytoskeletal dysfunction.
Steroid-resistant nephrotic syndrome (SRNS) is a severe paediatric kidney disease and a leading cause of end-stage kidney disease in children, with a high genetic contribution. While over 80 monogenic causes of SRNS have been identified, a significant proportion of affected patients still lack a clear genetic diagnosis, indicating that additional causative genes remain to be discovered. Through whole-exome sequencing of a paediatric SRNS cohort, we identified three probands carrying biallelic FLNB pathogenic variants. Sanger sequencing was performed for familial cosegregation verification and ACMG classification. Expression of Filamin B, Nephrin and Synaptopodin in renal tissues was assessed by immunohistochemistry/immunofluorescence. Wild-type and patient-derived variant FLNB plasmids were constructed and transfected into HEK293T cells and immortalised human podocytes (HPCs). The effects of these variants on protein expression, localisation and cytoskeletal organisation were assessed by western blotting and immunofluorescence. FLNB expression in HPCs was silenced using shRNA to evaluate the impact on podocyte marker proteins, cytoskeletal integrity and migratory capacity. A zebrafish flnb knockdown model was employed to validate its effects on renal development. All three probands presented with isolated SRNS without skeletal developmental abnormalities, and renal tissues showed significantly reduced Filamin B protein expression. In vitro, p.L117P and p.M1803L variants led to markedly reduced protein expression, while p.R470L and p.K2586R induced perinuclear aggregation of Filamin B accompanied by F-actin rearrangement. FLNB silencing led to downregulation of Nephrin and Synaptopodin, cytoskeletal disorganisation and impaired cell migration. Zebrafish flnb knockdown exhibited pericardial oedema, defective nephron development and abnormal podocyte foot processes. We report for the first time that biallelic FLNB pathogenic variants are associated with paediatric SRNS by disrupting Filamin B expression, cytoskeletal integrity and podocyte function, providing evidence that FLNB is a novel monogenic cause of SRNS.
2025-12-12 | Immune mechanisms and immunomodulatory therapies in steroid-resistant nephrotic syndrome.
Steroid-resistant nephrotic syndrome (SRNS) is a complex and refractory kidney disease generally causing chronic kidney dysfunction, characterized by persistent proteinuria despite prolonged corticosteroid therapy. This review comprehensively explores the mechanisms of immunity driving SRNS, mainly focusing on the complex function network within immune cells, pro-inflammatory cytokines, and podocyte injury. Current immunosuppressive therapies show limited efficacy, prompting exploration of precision immunomodulatory strategies. Emerging approaches include IL-17 or low-dose IL-12 modulation, proteasome or CD38 blockade, C5/factor B inhibition, and Rho kinase or caspase inhibition. Additionally, personalized strategies leveraging genetic profiling and biomarker-guided therapies are advancing tailored interventions. These targeted therapies address SRNS heterogeneity while minimizing systemic immunosuppression, offering new promise for halting disease progression. Future directions emphasize combinatorial regimens and mechanistic stratification to optimize therapeutic outcomes.
2025-09-25 | Genetic evidence for repurposing GLP-1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti-inflammatory pathways beyond glycaemic control.
Despite observational links between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and kidney benefits, causal mechanisms remain unclear. This study aims to dissect genetic causality and mediation pathways underlying the effects of GLP-1RAs on chronic kidney disease (CKD) and related renal outcomes. Using large-scale Genome - Wide Association Study (GWAS) data, we applied two-sample Mendelian randomisation (MR) to estimate the causal effects of GLP-1RAs on CKD, estimated glomerular filtration rate (eGFR) and subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome and chronic glomerulonephritis), with sensitivity analyses. The glycaemic markers (glycated haemoglobin [HbA1c] and blood glucose), type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) served as positive controls. Mediation MR assessed body mass index (BMI), lipids, glycaemic markers and inflammatory proteins. Data were sourced from MRC Integrative Epidemiology Unit Open Genome - Wide Association Studies OpenGWAS, FinnGen, GWAS Catalogue and cohort-specific studies. Positive control analyses revealed that genetically predicted GLP-1R activation was associated with reduced levels of HbA1c (p = 4.93E-15) and blood glucose (p = 9.73E-5), as well as a decreased risk of T2DM (p = 2.45E-4) and DN (p = 6.35E-4), fully validating the reliability of the genetic instruments. Genetic proxies for GLP-1R activation lowered risks of CKD (odds ratio [OR] = 0.83, p = 9.22E-9), immunoglobulin A nephropathy (IgAN) (OR = 0.70, p = 2.11E-3) and kidney function preservation (β = 0.01, p = 9.11E-3), but showed null effects on other CKD subtypes. Mediation analyses indicated that fibroblast growth factor 23 (FGF23) suppression mediated 26.57% of the effect on eGFR and 13.50% of CKD protection, whereas metabolic traits (BMI: 2.08% for CKD, 5.51% for eGFR; high-density lipoprotein: 0.79% for CKD, 2.34% for eGFR; HbA1c: 8.25% for eGFR) partially explained the benefits on CKD and eGFR. Only BMI exhibited a mediation effect on IgAN. Sensitivity analyses confirmed minimal pleiotropy. This study provides robust genetic evidence for repurposing GLP-1RAs in CKD and IgAN through anti-inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.
2025-04-15 | Glucagon-like peptide-1 receptor agonists, inflammation, and kidney diseases: evidence from Mendelian randomization.
It has been proved that glucagon-like peptide-1 receptor (GLP1R) agonists have positive effects on renal outcomes in diabetic patients. However, it remains unknown whether GLP1R agonists could provide similar protection against other kidney diseases. We performed two-sample Mendelian randomization (MR) analyses to determine the causal effects of GLP1R agonists on multiple kidney diseases. Exposure to GLP1R agonist was proxied by the available cis-eQTLs for GLP1R. Primary outcomes included the risk assessment for diabetic nephropathy, IgA nephropathy, membranous nephropathy, nephrotic syndrome, chronic kidney disease, acute glomerulonephritis, chronic glomerulonephritis and calculus of kidney/ureter. Type 2 diabetes and body mass index were used as positive control. Two-stage network MR analyses were conducted to assess the mediation effect of inflammatory proteins on the relationships between GLP1R agonists and kidney diseases. After meta-analyses of both discovery and validation cohorts, genetically proxied GLP1R agonist was found to significantly associated with a decreased risk of diabetic nephropathy (OR = 0.72, 95%CI = 0.54-0.97, p = 0.031) and IgA nephropathy (OR = 0.58, 95%CI = 0.36-0.94, p = 0.027). Two-stage network MR revealed that there was an indirect effect of GLP1R agonist on IgA nephropathy through signaling lymphocytic activation molecule family member 1 (SLAMF1), with a mediated proportion of 34.27% (95% CI, 1.47-67.03%, p = 0.041) of the total effect. The findings of current study presented genetic proof for the potential protective effects of GLP1R agonists in the development of diabetic nephropathy and IgA nephropathy, offering a novel sight for future mechanistic and clinical applications.
2024-06-19 | The Protective Role of KANK1 in Podocyte Injury.
Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.
small molecules
2026-08-03 | NEPHROTIC SYNDROME IN SAUDI CHILDREN: A SYSTEMATIC REVIEW OF CLINICAL CHARACTERISTICS, MANAGEMENT AND OUTCOMES
Background: Paediatric Nephrotic Syndrome (NS) is a major chronic disorder characterized by heavy proteinuria, hypoalbuminemia, hyperlipidaemia, and peripheral edema. While minimal change disease (MCD) is the predominant histopathology globally, paediatric populations in Saudi Arabia demonstrate distinct generic patterns, higher rates of consanguinity, and a varying prevalence of steroid-resistant nephrotic syndrome. (SRNS). Methods: A systematic literature search was conducted across Medline/PubMed, EMBASE, and reginal databases following PRISMA guidelines. Observational cohort studies, retrospective reviews, and clinicopathological studies focusing on paediatric primary nephrotic syndrome in Saudi Arabia evaluated. Results: Synthesis of included studies indicates a median age of presentation between 3 and 5.5 years, with a male-to-female ratio ranging from 1.5:1 to 2.3:1. Initial responsiveness to corticosteroid therapy ranges between 70% and 85%. However, among biopsy-proven steroid-resistant cases, Focal Segmental Glomerulosclerosis (FSGS) is the single most common histopathological pattern (39-54%), followed by IgM nephropathy, Mesangioproliferative Glomerulonephritis (MesPGN), and MCD variants. Familial clustering is noted in up to 6-12% of cases, strongly correlated with high rates of consanguinity. Calcineurin inhibitors (tacrolimus, cyclosporine) and mycophenolate mofetil remain the primary second-line immunosuppressive protocols are key to optimizing long-term renal outcomes. Conclusion: Saudi children with nephrotic syndrome demonstrate a high burden of focal segmental glomerulosclerosis, elevated risk of steroid dependency or resistance, and significant risk of infectious complications (predominantly peritonitis and urinary tract infections). Early genetic screening for podocyte gene mutations and aggressive second -line immunosuppressive protocols are key to optimizing long-term renal outcomes. Keywords: Paediatric Nephrotic Syndrome, Saudi Arabia, Minimal Change Disease, Focal segmental Glomerulosclerosis, Steroid-Resistant Nephrotic Syndrome, Immunosuppression.
2026-07-28 | A multi-national study examined the response sustainability to calcineurin inhibitors and long-term kidney survivals in children with genetic podocytopathies.
While calcineurin inhibitors (CNI) reduce proteinuria in a subgroup of children with genetic podocytopathies, previous reports suggest that the response is short-lived and of no benefit to long-term outcomes. Here, we assess CNI response sustainability and the association between different patterns of response preservation and kidney survival. We performed a retrospective cohort study of patients aged 0-18 years with genetic podocytopathies treated with CNI for at least three months from 34 pediatric nephrology centers worldwide. Response status was defined in accordance with International Pediatric Nephrology Association Clinical Practice Recommendations. We analyzed 136 patients with genetic podocytopathies over a median follow-up period of 42.1 months (between CNI initiation and last follow-up or commencement of kidney replacement therapy, whichever occurred first). At least partial response was attained in 28% and 22% of patients at six months post-CNI initiation and last follow-up, respectively. Compared to non-response group, patients with at least partial response at six months had significantly lower urine protein-to-creatinine ratios across various time points post-CNI. 71%, 11% and 18% exhibited no response, non-sustained and sustained response, respectively, throughout the observation period. Both sustained and non-sustained responses were significantly associated with superior kidney survival compared to no response. Importantly, no patients with sustained response developed kidney failure over a follow-up period of 42 (interquartile range 19-62) months. Patients with non-sustained response had a 92% lower risk of kidney failure compared to non-responders. A subset of children with genetic podocytopathies experienced a sustained response to CNI, and none developed kidney failure. Children with non-sustained response still demonstrated superior kidney survival compared to non-responders. Our findings may support a trial of CNI in genetic podocytopathies, and continuing therapy among those showing clinical response.
2026-07-12 | Kidney outcomes of coenzyme Q10 supplementation in patients with genetically confirmed CoQ10 nephropathy in Japan.
Coenzyme Q10 (CoQ10) nephropathy is a rare mitochondrial kidney disease caused by defects in CoQ10 biosynthesis and represents a unique form of steroid-resistant nephrotic syndrome with a disease-specific therapy. However, data on treatment outcomes of this disease in Japanese patients remain limited. We conducted a retrospective observational study of Japanese patients. Patients with a genetically confirmed diagnosis of CoQ10 nephropathy who received CoQ10 supplementation and had available longitudinal clinical data were included. Changes in the urinary protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate before and after treatment were evaluated, and adverse events were assessed. Twelve patients were included in the analysis. The median age at treatment initiation was 9.0 years, and COQ8B was the predominant causative gene (n = 11). One patient harbored a COQ6 variant. CoQ10 supplementation was initiated at a median dose of 10.0 mg/kg/day. The median UPCR decreased from 1.66 g/gCr at baseline to 0.19 g/gCr at 12 months, and 6/7 (86%) patients with available 12-month data achieved a ≥ 50% reduction in proteinuria. Kidney function remained stable, and no patients progressed to end-stage kidney disease during a median follow-up of 28.8 months. Adverse events were mild and did not lead to treatment discontinuation. In Japanese patients with CoQ10 nephropathy, CoQ10 supplementation was associated with a substantial reduction in proteinuria and stabilization of kidney function. These findings indicate the importance of early genetic diagnosis and prompt initiation of targeted therapy for this treatable hereditary kidney disease.
2026-06-06 | Update on APOL1 and chronic kidney diseases in children.
Chronic kidney disease (CKD) is a major global health burden that disproportionately impacts people of recent African ancestry. The discovery of risk variants in the apolipoprotein L1 (APOL1) gene has transformed the understanding of racial disparities in CKD. In particular, APOL1 variants have been associated with increased risk of focal segmental glomerulosclerosis, virus-associated nephropathy, and other glomerular diseases in Black adults. While approximately 10-15% of Black Americans have a high-risk APOL1 genotype, disease penetrance is variable and is likely mediated by additional genetic and environmental "second hits." Variants in APOL1 have also been implicated in kidney transplant outcomes and pregnancy complications, underscoring its broad clinical relevance. Advances in therapeutic strategies, including small molecule inhibitors of APOL1 pore function, APOL1 antisense oligonucleotides, and JAK-STAT pathway modulation, offer promise for targeted interventions in adult populations. Emerging data in children highlight similar genotype-phenotype associations, with evidence of high-risk APOL1 genotype impacting steroid-resistant nephrotic syndrome and CKD progression. However, pediatric studies remain limited and underpowered, leaving critical gaps in the understanding of disease epidemiology, mechanisms, and long-term outcomes. This review will explore current knowledge of APOL1 kidney disease (AMKD) with a particular focus on pediatric populations and highlight the need for inclusion of children in future studies.
2026-03-05 | Epigenetic mechanisms and steroid-resistant nephrotic syndrome: The future potential for SRNS diagnosis.
Nephrotic syndrome (NS) is commonly managed with glucocorticoid (GC) therapy, yet about 10%-30% of children do not achieve remission after an adequate initial steroid course and are classified as steroid-resistant nephrotic syndrome (SRNS); in adults, proportions are generally higher and heterogeneous across histologies. Currently, genetic testing can identify causative mutations in 30% of SRNS cases, highlighting the need for complementary pre-treatment stratification approaches. This review synthesizes human evidence linking epigenetic dysregulation to GC responsiveness, highlighting differential DNA methylation patterns in genes such as NLRP3 and SOCS3. Simultaneously, the expression levels of microRNAs (miRNAs) such as miR-142 and miR-30 have been shown to be associated with the efficacy of GC treatment. We propose a multi-biomarker integrative analysis strategy that combines methylation profiles with miRNA expression and emerging histone modification signals for pre-treatment risk stratification and prediction of therapeutic response, thereby reducing ineffective steroid exposure and enabling mechanism-informed management pending prospective validation.
gene therapies
2026-03-28 | Advances in SRNS Gene Research: From Precision Classification to Precision Diagnosis and Treatment.
To clarify the genetic classification, diagnostic strategies, and precision treatment pathways of steroid-resistant nephrotic syndrome (SRNS), this review systematically reviews the genetic stratification system of SRNS by integrating recent advances in genetic testing technologies and pathogenesis research. It contains the pathogenic mechanisms, diagnostic protocols, and therapeutic correlations of different genetic subtypes, while summarizing current progress and clinical challenges in gene therapy. Results indicate SRNS can be categorized into genetic (38-58%) and non-genetic/immune-mediated (40-60%). A stepwise diagnostic system comprising core proteinuria gene panel testing, whole-genome sequencing (WGS), whole-exome sequencing (WES), and supplementary multi-omics/long-range sequencing is proposed, suited for populations with "typical phenotypes and moderate genetic risk", "atypical phenotypes and high genetic suspicion", and "complex structural/non-coding region variants" respectively. Pathogenic mechanisms directly determine therapeutic strategies: COQ2/PDSS2 mutations respond to coenzyme Q10 suplementation, while NPHS1 mutations necessitate early renal transplantation. Adeno-associated virus (AAV)-mediated gene therapy and CRISPR-Cas editing show preclinical promise but face challenges including incomplete detection coverage and clinical translation difficulties. Genetic technologies are driving SRNS management transformation from "empirical treatment" to "mechanism-oriented precision diagnosis and therapy". Future efforts should focus on overcoming genetic testing limitations and gene therapy translation bottlenecks to enhance diagnostic and therapeutic efficacy.
2026-03-06 | Molecular mechanisms in podocytopathies: finding suitable targets for a new era of glomerular gene therapy.
Podocytopathies encompass a spectrum of glomerular disorders driven by structural and functional impairments in podocytes: specialized cells critical for maintaining the glomerular filtration barrier. Dysregulation of key podocyte components-such as slit-diaphragm proteins (nephrin, podocin), cytoskeletal regulators (ACTN4, TRPC6), and adhesion complexes (integrins, dystroglycan)-leads to proteinuria and progressive glomerulosclerosis. Current therapies often fail to address underlying genetic or molecular defects, particularly in hereditary or refractory cases. Gene therapy has emerged as a transformative approach, leveraging adeno-associated viral (AAV) vectors, CRISPR-based editing, and RNA modulation to correct pathogenic mutations or restore disrupted pathways. Recent advances in capsid engineering, tissue-specific promoters, and delivery strategies have enhanced podocyte targeting while minimizing off-target effects. Preclinical successes, including AAV-mediated rescue of NPHS2-associated nephrotic syndrome and complement modulation in IgA nephropathy, highlight the therapeutic potential. However, challenges such as immune responses, vector biodistribution, and disease heterogeneity remain. This review synthesizes the molecular mechanisms underlying podocytopathies, evaluates current gene-therapy strategies, and discusses translational hurdles and future directions, including patient-derived organoid models and combinatorial therapies. By bridging mechanistic insights with innovative gene-based interventions, this work underscores the promise of precision medicine in revolutionizing the treatment of podocytopathies.
2026-02-17 | Treatment outcomes and ongoing pediatric trials in steroid-resistant nephrotic syndrome.
Despite an increasing number of therapeutic options for pediatric patients with steroid-resistant nephrotic syndrome (SRNS), treatment resistance and risk of progression to kidney failure are still high. Children with monogenic forms of SRNS and resistance to non-steroidal immunosuppressants are at the highest risk. Advances in the understanding of SRNS pathogenesis have enabled the development of novel therapies that target genetic, immunologic, and metabolic mechanisms of disease development and progression. In this review, we summarize select contemporary cohort study findings, novel therapeutic agents and their mechanistic targets, and eight recent and ongoing clinical trials for pediatric patients with SRNS.
2025-11-12 | A CPEB2/ANGPTL3 feedback loop promotes the progression of podocyte injury in nephrotic syndrome.
Podocyte injury is the primary pathology responsible for 70-90% of nephrotic syndrome (NS) in children, a condition closely associated with the aberrant expression of Angiopoietin-like-3 (ANGPTL3). The regulatory mechanism by which ANGPTL3 is upregulated during NS progression remains elusive. In this study, we found that ANGPTL3 can be regulated by Cytoplasmic polyadenylation element binding protein 2 (CPEB2) through translational control, and conversely, CPEB2 can be transcriptionally regulated in response to ANGPTL3 signaling as a feedback loop. Exposure to puromycin aminonucleoside (PAN) or adriamycin (ADR) dose-dependently increased the expression of both CPEB2 and ANGPTL3 in MPC-5 cells. Ectopic overexpression of CPEB2 in MPC-5 cells significantly promoted cell apoptosis and migration, which could be abrogated by knockdown of ANGPTL3. Mechanistically, the regulation of ANGPTL3 by CPEB2 was attributed to translational promotion. CPEB2 could directly bind the 3' untranslated coding region (UTR) of ANGPTL3 mRNA, thereby promoting the recruitment of ANGPTL3 transcripts to the translation initiation complexes. Consequently, polysomal profiling suggested that the abundance of ANGPTL3 transcripts in actively high-translating polysomes was dramatically increased upon CPEB2 overexpression. On the other hand, ANGPTL3 signaling could increase the mRNA stability of CPEB2, thereby promoting the mRNA expression of CPEB2. Furthermore, the role of CPEB2/ANGPTL3 in podocyte injury was validated in vivo. Depletion of CPEB2 with adeno-associated virus (AAV9)-shCPEB2 significantly decreased the expression of ANGPTL3, and consequently mitigated albuminuria and histopathological injury in ADR-induced NS mice. In conclusion, this study highlighted the CPEB2/ANGPTL3 feedback loop as a novel mechanism contributing to the progression of podocyte injury.
2025-10-01 | Utility of Genetic Testing in CKD with Nephrotic-Range Proteinuria
Introduction: Recent advancements in genetics are transforming clinical practice in all medical fields, including nephrology. Case Description: We present a 55-year-old female with a past medical history of obesity, hypertension, and a BRCA-1 variant of uncertain significance (which she underwent hysterectomy and salpingo-oophorectomy for), referred for chronic kidney disease (CKD) with nephrotic proteinuria. Kidney biopsy was inconclusive and complicated by post-procedural bleeding requiring hospitalization. Genetic testing revealed a pathogenic variant in COL4A4. While she had no overt signs of Alport’s syndrome, including family history, ophthalmic or otologic complications, additional testing revealed mild sensorineural hearing loss. Discussion: This case exemplifies the emerging potential of genetic testing for the evaluation of CKD with nephrotic proteinuria. Generally, kidney biopsies are the “gold standard” workup when the etiology of a nephrotic proteinuria is unclear on initial evaluation. However, due to advancements in less invasive secondary work-up, such as serologic testing, clinicians can often solidify a diagnosis and treatment plan for select patients with glomerular diseases without a biopsy. Genetic testing ought to become a more common, minimally invasive tool to avoid unnecessary or risky biopsies. In fact, current KDIGO guidelines for glomerular diseases dictate that conditions such as Alport’s, Fabry, and familial FSGS can be treated without a confirmatory biopsy; notably, these diseases are all detectable on a genetic panel. Moreover, genetic testing is a more sensitive and accurate diagnostic tool than using a combination of clinical features, family history, and biopsy results in some conditions: Alport’s syndrome is an example of this phenomenon. Due to its elusive clinical nature, guidelines suggest testing for COL4A3–COL4A5 genes in patients with persistent proteinuria >0.5 g/d, steroid-resistant nephrotic syndrome, or FSGS. Furthermore, ongoing genetic research in conditions that cause nephrotic range proteinuria, such as FSGS and steroid-resistant nephrotic syndrome, suggests an optimistic future where genetic testing may complement or eliminate the need for a biopsy. Currently, kidney biopsy remains an invaluable and relatively safe procedure to evaluate nephrotic-range proteinuria. However, our case highlights the value of genetic testing as a less invasive and risky tool.
antibodies
2026-09-03 | Outcome of children treated with rituximab for steroid-resistant nephrotic syndrome: Renal histopathology as a response marker.
Steroid-resistant nephrotic syndrome (SRNS) in children remains a major therapeutic challenge. Although calcineurin inhibitors (CNIs) are commonly used as first-line therapy, a substantial proportion of patients fail to achieve remission, and prolonged use may result in nephrotoxicity. Rituximab has emerged as a potential therapeutic option for refractory SRNS; however, treatment responses appear variable, and the influence of underlying renal histopathology remains incompletely understood. The objective of the study was to evaluate the association between renal histopathological findings and clinical response to rituximab in children with CNI-resistant SRNS. Study design and setting: This prospective observational study was conducted between 2011 and 2020 at a university-affiliated tertiary pediatric nephrology center. The study aimed to evaluate the efficacy of rituximab in children with CNI-resistant SRNS and to examine the association between renal histopathological findings and treatment response. Twenty-four children aged 2-12 years were enrolled. Follow-up: Patients were followed prospectively after completion of rituximab therapy through regular clinical and laboratory assessments. The mean follow-up duration after the last rituximab infusion was 5.1 years (range: 6 months-8 years). treatment response definitions: Complete remission was defined according to International Pediatric Nephrology Association recommendations as a urine protein-to-creatinine ratio (UPCR) ≤20 mg/mmol (≤0.2 mg/mg) or negative/trace proteinuria on dipstick testing on at least three consecutive occasions. Partial remission was defined as a UPCR >20 mg/mmol but <200 mg/mmol together with serum albumin ≥30 g/L. No response was defined as failure to achieve either complete or partial remission. Genetic evaluation: Genetic testing was performed in all patients with focal segmental glomerulosclerosis (FSGS), classic minimal change disease (MCD), and MCD with immunoglobulin M (IgM) deposition. No pathogenic or likely pathogenic variants associated with monogenic SRNS were identified in the tested patients. Genetic testing was not performed in patients with IgA nephropathy, membranous nephropathy, C1q nephropathy, or dense deposit disease (DDD). Twenty-four children with SRNS were included (13 males and 11 females; age range 2-12 years). Histopathological diagnoses included FSGS in nine patients (37.5%), MCD in 4 (16.7%), MCD with IgM deposition in 6 (25.0%), DDD in 2 (8.3%), membranous nephropathy in 1 (4.2%), IgA nephropathy in 1 (4.2%), and C1q nephropathy in 1 (4.2%). Overall, 10 patients (41.7%) achieved complete remission and 3 (12.5%) achieved partial remission, predominantly among patients with MCD and MCD with IgM deposition. Responses were uncommon among patients with FSGS. Eleven patients (45.8%), all of whom were non-responders, progressed to end-stage kidney disease. No major adverse effects of rituximab were observed; mild infusion reactions occurred in three patients and mild cellulitis in one patient. In this cohort of children with refractory SRNS, favorable responses to rituximab were observed predominantly among patients with CNI-resistant MCD and MCD with IgM deposition, whereas responses among patients with FSGS were uncommon. These findings suggest that renal histopathology may help identify patients more likely to benefit from rituximab therapy; however, the small sample size, heterogeneous histopathological distribution, and observational study design preclude definitive conclusions. Larger prospective multicenter studies incorporating comprehensive genetic evaluation are required to determine whether histopathology can serve as a reliable predictor of rituximab responsiveness.
2026-08-20 | Beyond Defense: Kidney Mysteries in Inborn Errors of Immunity
Inborn errors of immunity (IEI), formerly termed primary immunodeficiencies, are increasingly recognized as disorders of immune dysregulation rather than infection susceptibility alone. With over 500 validated genes in the 2024 International Union of Immunological Societies (IUIS) classification and approximately one-quarter of patients presenting without infection, autoimmunity, autoinflammation, lymphoproliferation, and malignancy are now core features. The kidney is affected across at least 22 IEI categories, yet renal involvement remains under-recognized. This review proposes a mechanistic framework for IEI-associated kidney disease, encompassing: complement dysregulation (C3 glomerulopathy, atypical hemolytic uremic syndrome from CFH/CFI/C3 variants); immune complex–mediated and monogenic lupus nephritis (C1q, C2, C4, DNASE1L3, and TREX1 defects); autoinflammatory and type I interferonopathy–driven nephropathy; infection-related glomerulonephritis (common variable immunodeficiency [CVID], chronic granulomatous disease); lymphoproliferative and immune-dysregulation syndromes causing interstitial nephritis (ALPS, CTLA-4 and LRBA deficiency); and syndromic IEI with intrinsic structural disease. We outline a stepwise diagnostic approach integrating clinical red flags, complement and immune profiling, kidney biopsy with immunofluorescence and electron microscopy, and genetic testing, emphasizing that genetic diagnosis should precede immunosuppression. The therapeutic landscape is shifting from empirical immunosuppression toward precision medicine, including complement inhibitors (iptacopan, pegcetacoplan, Food and Drug Administration–approved for C3 glomerulopathy in 2025), JAK inhibitors for interferonopathies, leniolisib for activated PI3Kδ syndrome, CTLA4-Ig agents, and curative hematopoietic stem cell transplantation and emerging gene therapy. An illustrative case from Europe’s largest kidney transplant center illustrates a girl with Schimke immuno-osseous dysplasia (SMARCAL1 mutation) presenting with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis who underwent kidney transplantation following bone marrow transplant. Recognizing IEI in unexplained nephropathy, combining biopsy with complement and genetic profiling, and early nephrology–immunology collaboration are key to improving renal outcomes and enabling potentially curative therapy.
2026-07-28 | Obinutuzumab as a Rescue and Maintenance Strategy in Children with Difficult-to-Treat Nephrotic Syndrome After Rituximab-Based Treatment Failure or Intolerance: A Preliminary Single-Center Real-World Retrospective Study.
This preliminary study aimed to describe the effectiveness and safety of obinutuzumab as a rescue and maintenance anti-CD20 strategy in children with difficult-to-treat nephrotic syndrome after failure or intolerance of rituximab-based multi-target immunosuppression. This exploratory single-center retrospective real-world study included consecutive children who received obinutuzumab between April 2024 and January 2025. Nine patients were included in the safety set, and eight who completed treatment and had follow-up data comprised the efficacy set. The primary outcome was 12-month relapse-free survival. Secondary outcomes included annualized relapse rate, peripheral B-cell depletion, glucocorticoid-free status, reduction or discontinuation of background immunosuppression, and safety. Median follow-up in the efficacy set was 1.24 years (IQR 1.01-1.67). No relapses occurred after obinutuzumab in this small efficacy set, corresponding to an observed 12-month relapse-free proportion of 8/8 (100%; exact 95% CI 63.1-100) and reducing the annualized relapse rate from 2.50 to 0 episodes/person-year. All eight efficacy-set patients achieved complete peripheral B-cell depletion and remained depleted at 6 months. At last follow-up, seven had discontinued both glucocorticoids and all non-obinutuzumab immunosuppressants, while one had discontinued glucocorticoids with a reduced dose of mycophenolate mofetil. In the safety set, one child developed severe anaphylactic shock during the first infusion; infectious events were limited to CTCAE grade 1-2 events. In this exploratory, hypothesis-generating study, obinutuzumab was associated with a favorable relapse profile, sustained peripheral B-cell depletion, and reduction of background immunosuppression in a highly selected pediatric population. Larger prospective studies are required to confirm these preliminary observations and define long-term safety.
2026-07-12 | Kidney Survival in Children With Steroid-Resistant Nephrotic Syndrome Treated by Rituximab.
Kidney outcomes in children with steroid-resistant nephrotic syndrome (SRNS) following rituximab remain unclear. We conducted an international retrospective cohort study across 23 centers in 17 countries, including children with SRNS who did not respond to calcineurin inhibitors (CNIs) and subsequently, received rituximab. Patients with genetic variants were excluded. The primary outcome was kidney survival. We analyzed data on 151 children (53% males; median age at onset: 6.8 years; primary vs. secondary SRNS: 54% vs. 46%; focal segmental glomerulosclerosis [FSGS]: 62%). All subjects received CNIs before rituximab (0-3 months: 21%; 3-6 months: 26%; 6-12 months: 26%; > 12 months: 26%). Upon rituximab, 73 subjects (48%) had normal kidney function, 47 (31%) had chronic kidney disease (CKD)2, and 31 (21%) had CKD3. Twenty-eight (19%) developed kidney failure. Overall kidney survival was 82.7%, 75.8%, and 72.3% at 3, 5, and 7 years post-rituximab. Baseline CKD staging before rituximab was associated with kidney survival at 5 years (log-rank P < 0.001); CKD stage 1, 91.7%; CKD stage 2, 70.4%; and CKD stage 3, 35.5%). The predictive factors for inferior kidney survival were CKD2 (adjusted hazard ratio [HRadj]: 2.7, 95% confidence interval [CI]: 1.5-4.9, P < 0.001), lower baseline serum albumin (log-rank P = 0.01; HRadj: 0.88, 95% CI: 0.81-0.95; P < 0.001) and FSGS (log-rank P = 0.03; HRadj: 3.4, 95% CI: 1.1-10.0; P < 0.001). Nonremission at 6 months was associated with inferior kidney survival (61.2% at 5 years), compared with complete remission (CR) or partial remission (PR) (100% at 5 years) (log-rank P = 0.01; HRadj: 14.1, 95% CI: 2.2-93.5, P = 0.01). Duration of prior calcineurin inhibition and SRNS type were not significant predictors. Kidney survival of SRNS following add-on rituximab is 70% to 80% over 3 to 7 years. Nonresponse, preexisting CKD, lower albumin, and FSGS predict inferior kidney survivals.
2026-06-26 | Monogenic variants drive low recurrence risk in pediatric steroid-resistant nephrotic syndrome after kidney transplantation: a high-consanguinity cohort.
Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of stage 5 chronic kidney disease (CKD 5) in children and carries a substantial risk of post-transplant disease recurrence. Data from the Arabian Peninsula are sparse. This retrospective cohort study included all paediatric patients (aged < 18 years) who underwent a first kidney transplant at King Fahad Specialist Hospital-Dammam between January 2008 and December 2023 with a confirmed diagnosis of SRNS, focal segmental glomerulosclerosis (FSGS), congenital nephrotic syndrome, or a pathogenic monogenic variant known to cause SRNS. Patients were classified as having genetic or non-genetic SRNS according to next-generation sequencing results. Primary outcomes were post-transplant recurrence rate and graft survival. Secondary outcomes included estimated glomerular filtration rate (eGFR) values and treatment response. Among 208 paediatric kidney transplant recipients, 60 (28.8%) had CKD 5 attributable to SRNS/FSGS. Genetic testing (performed in 59/60 patients, 98.3%) identified pathogenic variants in 44 patients (74.6%); NPHS2 was most prevalent (28.8%). Post-transplant recurrence occurred in 6 patients (10%): 5 of 15 in the non-genetic group (33%) and 1 of 44 in the genetic group (2.3%) (p < 0.001). All six patients with recurrence received plasmapheresis; five also received rituximab. Complete remission was achieved in 5 patients (83%) and partial remission in 1 (17%). The 5-year graft survival rate was 98% overall-100% in the genetic group versus 93% in the non-genetic group (log-rank p = 0.21). The eGFR at 5 years was significantly higher in the genetic group (73.5 ± 17.6 vs. 60.6 ± 22.9 mL/min/1.73 m2, p = 0.049). SRNS/FSGS accounts for approximately 29% of paediatric CKD 5 in this cohort and is characterised by a high prevalence of monogenic variants reflecting regional consanguinity. Genetic testing reliably stratifies recurrence risk: non-genetic SRNS carries a substantially higher recurrence rate, yet combined plasmapheresis and rituximab achieves remission in most affected patients. Graft outcomes are comparable to those seen in other CKD 5 aetiologies.
other
2026-09-03 | Rapidly progressive steroid-resistant focal segmental glomerulosclerosis associated with an INF2 exon 6 variant.
Variants in the inverted formin-2 (INF2) gene are a known cause of hereditary focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth disease. We report a case of rapidly progressive FSGS associated with a rare INF2 variant. A 12-year-old boy developed proteinuria and was diagnosed with FSGS at age 14 following a renal biopsy. Steroid therapy and subsequent immunosuppressive treatments, including plasma exchange, were ineffective. At age 15, a heterozygous missense variant in exon 6 of the INF2 gene (c.763G>A, p.Asp255Asn) was identified. Despite conservative management, the patient progressed to end-stage kidney disease at age 17. Although exon 6 variants are rarely reported, the present case showed a relatively aggressive renal course.
2026-07-09 | Genetic mutation patterns in Indonesian children with primary steroid-resistant nephrotic syndrome.
Approximately 10-30% of pediatric cases of steroid-resistant nephrotic syndrome (SRNS) have pathogenic monogenic variants, particularly in primary SRNS. Identifying these variants aids in predicting outcomes, guiding treatment, and enabling genetic counseling. In Indonesia, data on genetic mutation patterns in pediatric SRNS are still limited. A cross-sectional study was conducted using whole-exome sequencing (WES) to detect variants of genetic origin in children diagnosed with primary SRNS at Indonesia's National Referral Hospital, Cipto Mangunkusumo. We assessed the relationship between genetic findings and clinical features, including age at onset, treatment response, kidney biopsy, and kidney function. Among 60 children with primary SRNS, 9 subjects (15%) harbored pathogenic or likely pathogenic variants across 8 genes (CUBN, AVIL, TRPC6, INF2, COL4A4, LAMA5, INVS, and FGA). Variants included stop-gained (n = 4), missense (n = 4), splice site (n = 1), and frameshift (n = 1), with both autosomal recessive and dominant inheritance observed. Two subjects had compound heterozygous variants. Most variant-positive subjects were male (6/9), had disease onset before age 3, and showed diverse histology (FSGS, MCD, or mesangial/membranoproliferative lesions). Four showed extrakidney features: peripheral neuropathy, high myopia, microcephaly with short stature, and hearing loss. While 53.3% responded to cyclosporin, over half remained in non-remission. This study reveals the genetic and phenotypic heterogeneity of primary SRNS in Indonesian children. The identification of diverse pathogenic variants underscores the utility of WES, even in cases responsive to cyclosporin. Genetic testing should be integrated into routine SRNS evaluation, especially in atypical presentations or early-onset of the disease.
2026-04-01 | Kidney diseases related to COL4A3, COL4A4 and COL4A5 gene variations and their pathogenic mechanisms
Collagen Ⅳ is the core structural protein of the glomerular basement membrane, composed of α chains encoded by the COL4A3, COL4A4, and COL4A5 genes, which assemble into the α3α4α5 trimer. It plays a crucial role in maintaining the structural integrity and filtration function of the glomerular basement membrane. Variations in these three genes can lead to a spectrum of inherited kidney diseases, with Alport syndrome being the most representative. Clinically, Alport syndrome is characterized by hematuria, progressive renal dysfunction, sensorineural hearing loss, and ocular abnormalities, with inheritance patterns including X-linked, autosomal recessive, and autosomal dominant. Additionally, variations in the COL4A3-COL4A5 genes are closely associated with various kidney diseases, such as thin basement membrane nephropathy (TBMN), familial IgA nephropathy, focal segmental glomerulosclerosis (FSGS), steroid-resistant nephrotic syndrome (SRNS), and end-stage renal disease (ESRD) of unknown etiology. In recent years, with the widespread application of high-throughput sequencing technologies, genetic testing has increasingly demonstrated its value in disease diagnosis, prognosis assessment, and precision medicine. This article systematically reviews the clinical manifestations, molecular genetic mechanisms, and clinical management strategies of COL4A3-COL4A5-related kidney diseases, aiming to provide a theoretical foundation and practical guidance for early diagnosis and individualized treatment of these conditions.
2026-01-23 | Identification of monogenic variants in steroid-resistant and steroid-sensitive nephrotic syndrome.
Steroid-resistant nephrotic syndrome (SRNS) constitutes the second most common cause of chronic kidney disease (CKD) in children. A monogenic cause can be identified in approximately 25% of SRNS cases. In contrast, steroid-sensitive or steroid-dependent nephrotic syndrome (SSNS/SDNS) is typically attributed to multifactorial or immunological causes and rarely linked to monogenic etiology. We performed exome sequencing (ES) in 237 families, including 183 with SRNS and 54 with SSNS/SDNS. A (likely) pathogenic variant in a known SRNS gene was identified in 29/183 individuals with SRNS (15.8%). Additionally, 6/183 (3.3%) individuals with SRNS carried pathogenic variants in phenocopy genes-genes associated with diseases that clinically mimic SRNS. The diagnostic yield was significantly higher in individuals with ≥ 50 Mb homozygosity-by-descent (HBD) (44.7% vs. 8.5%) and in those with SRNS disease onset before 1 year of age (41.9%). In individuals with SSNS/SDNS, we found a likely causative variant in only 1 of 54 probands. A genetic cause was established in 19.1% of SRNS patients (15.8% in known SRNS genes and 3.3% in phenocopy genes), but only 1.9% of non-steroid-resistant cases.
2025-12-30 | Steroid-Resistant Nephrotic Syndrome and Chronic Kidney Disease Associated with 6p Duplication Syndrome: A Case Report
6p duplication syndrome is a rare chromosomal disorder with a wide range of clinical features, including developmental delay, craniofacial dysmorphism, cardiac and skeletal anomalies, and renal involvement such as congenital anomalies of the kidney and urinary tract, proteinuria, and glomerular dysfunction. Reports of glomerular pathology are very limited. We describe a 14-year-old female with a 6p25.4q35 duplication presenting with obesity, intellectual disability, skeletal anomalies, and steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis and CKD. Genetic analysis unified her multisystemic findings under a single diagnosis and clarified the prognosis given her treatment resistance. This case highlights that glomerular disease can be part of the 6p duplication spectrum and underscores the diagnostic and prognostic value of genetic testing in patients with treatment-resistant nephrotic syndrome.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
6 orphan drug designations for Genetic steroid-resistant nephrotic syndrome, including 1 approved therapy.
6 orphan drug designations for Genetic steroid-resistant nephrotic syndrome, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Repagermanium | small molecules | EMA | Scendea (NL) B.V. | |
Propagermanium | small molecules | EMA | Scendea (NL) B.V. | |
4-Chloro-N-[5-methyl-2-(7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbonyl)-3-pyridinyl]-3-(trifluoromethyl)benzenesulfonamide, sodium salt | small molecules | FDA | ChemoCentryx, Inc. | |
propagermanium and irbesartan | small molecules | FDA | Dimerix Bioscience Ltd. | |
4’-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2’-(ethoxymethyl)-[1,1’-biphenyl]-2-sulfonamide | small molecules | EMA | Vifor France S.A. | |
sparsentan [Filspari] | small molecules | FDA | Approved | Travere Therapeutics, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.