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
508 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:
508 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:
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.
2026-07-28 | 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 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.
2026-07-12 | 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.
2026-08-03 | 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.
2026-07-28 | 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 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.
2026-07-12 | 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.
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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Repagermanium | small molecules | EMA | 2024-02-19 | — | Scendea (NL) B.V. |
Propagermanium | small molecules | EMA | 2018-11-19 | — | 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 | 2018-09-12 | — | ChemoCentryx, Inc. |
propagermanium and irbesartan | small molecules | FDA | 2015-12-09 | — | 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 | 2015-11-11 | — | Vifor France S.A. |
sparsentan [Filspari] | small molecules | FDA | 2015-01-05 | 2026-04-13 | Travere Therapeutics, Inc. |
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.