RARE DISEASE
Idiopathic steroid-sensitive nephrotic syndrome
Idiopathic steroid-sensitive nephrotic syndrome
Idiopathic steroid-sensitive nephrotic syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Idiopathic steroid-sensitive nephrotic syndrome (SSNS) is a pediatric-onset glomerular disorder characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. It typically responds to initial corticosteroid therapy but exhibits relapses in 40-60% of cases, often requiring steroid-sparing immunosuppressants. While renal prognosis is generally favorable, long-term morbidity arises from treatment side effects and relapses [1][3][6][17].
Burden
30-50% experience frequent relapses, leading to high cumulative steroid exposure with risks of obesity, growth impairment, and osteoporosis [9][11].
Significant caregiver psychological distress (17-31%) and healthcare utilization during relapses [9][16].
~15% develop secondary steroid resistance in adulthood, increasing chronic kidney disease risk [4][12].
Categories: rare renal diseases, rare transplant-related disorders
Research Papers
611 drug discovery papers about Idiopathic steroid-sensitive nephrotic syndrome, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
611 drug discovery papers about Idiopathic steroid-sensitive nephrotic syndrome, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-09 | Clinical and Pathological Faces of IgM Deposition in Children with Idiopathic Nephrotic Syndrome: A Single Center Experience.
Immunoglobulin M nephropathy (IgMN) is a pathological term defining glomerulonephritis with IgM deposition. The clinical significance is still a matter of debate. The aim was to evaluate children with IgM nephropathy (IgMN) in terms of clinical and pathological features, along with treatment responses and outcomes. The children with idiopathic nephrotic syndrome (INS) who underwent kidney biopsy at our center (n=41) were evaluated retrospectively. Twenty-one children with IgMN were included. The female to male ratio was 0.9, the median age was 3.5 years in the study group. The mean disease duration and follow-up periods were 11.8 and 11.3years, respectively. At admission, 14% of the patients had hypertension, and 19% had microscopic hematuria. Steroid-dependent nephrotic syndrome (SDNS) was observed in 62% of the patients at admission and 81% at last visit. The patients with IgM (≥2+) depositions had more SDNS than those with IgM (1+). The most common light microscopic diagnosis was mesangial proliferative glomerulonephritis (MesPGN) (47.6%). Focal segmental glomerulosclerosis (FSGS) elevated significantly from 14% at initial biopsy to 57% at follow-up biopsies. Patients who progressed to FSGS mostly had C3 co-deposition, high IgM intensity (≥2+), diagnosis of MesPGN, and SDNS clinic. The most frequently used adjuvant agent was cyclosporine-A (n=19) with mean duration of 68 months. It provided lower relapse rates. Rituximab (n=4) showed 75% remission rate. None of the patients had needed renal replacement treatment. Two patients who were steroid-resistant at admission had FSGS in their first biopsies, acted as multi-drug resistance at follow-up, and ended up in Stage-2 chronic kidney disease (CKD). This study shows IgMN is mainly presented with SDNS clinic and MesPGN pathology. Evolution to FSGS may be related to steroid resistance, MesPGN, high IgM intensity, and C3 co-deposition.
2026-05-18 | Kidney biopsy during pregnancy: indications, complications, results and therapeutic impact.
The diagnosis of kidney disease can be challenging during pregnancy. A kidney biopsy (KB) may be proposed, but there is little recent data available to assess the risk/benefit ratio of this procedure during pregnancy. In this French nationwide survey, we analysed the indications, complications, histological diagnoses, treatments, and obstetric outcomes of pregnant women who underwent native KB between 2006 and 2025. We gathered the medical records of 76 patients, with a median age of 29.5 [range 18-42] years, including 2 with twin pregnancies. KB was performed at a median gestational age of 13.5 [range 4-26] weeks. The main indications for KB were: nephrotic syndrome without AKI (40.8%) and non-nephrotic proteinuria without AKI (40.8%). KB led to a diagnosis in 72 (94.7%) patients. The main histological diagnoses were lupus nephritis (43%), focal segmental glomerulosclerosis (13%), membranous nephropathy (13%), IgA nephropathy (12%), and idiopathic nephrotic syndrome consistent with minimal change disease (5%). One patient experienced bleeding requiring transfusion. Specific treatment was initiated in 48 (63.2%) patients after KB: corticosteroids (35.5%), hydroxychloroquine (27.6%), azathioprine (18.4%), calcineurin inhibitor (13.2%), rituximab (2.6%) and belimumab (1.3%). There was a high incidence of preeclampsia (16.4%), small for gestational age (21.3%) and intrauterine fetal death (9.0%) in this cohort. Preterm birth and low birth weight occurred in 65.0% and 56.7% of cases, respectively. When considered necessary to establish a diagnosis during pregnancy, kidney biopsy performed in the first two trimesters appears to be safe, with a high diagnostic yield and a significant impact on therapeutic decision-making and patient management.
2026-03-20 | Mycophenolate mofetil versus prednisone for the initial treatment of idiopathic steroid-sensitive nephrotic syndrome in children in Germany (INTENT): a multicentre, open-label, randomised, controlled, parallel-group, non-inferiority, phase 3 trial.
Prolonged glucocorticoid therapy is the standard initial treatment for idiopathic nephrotic syndrome in children, but is associated with marked toxic effects. We aimed to assess whether a novel treatment protocol with mycophenolate mofetil is as effective as standard therapy with prednisone, while reducing the burden of glucocorticoid-related side-effects. INTENT was a multicentre, open-label, randomised, controlled, parallel-group, non-inferiority, phase 3 trial done in 37 community, municipal, and university hospitals in Germany. Patients aged 1-10 years with a first episode of steroid-sensitive nephrotic syndrome were randomly assigned (1:1) by a centralised web-based tool to receive either mycophenolate mofetil or prednisone (standard treatment), after remission induced by prednisone or prednisolone at a dose of 60 mg/m2 body surface area (maximum 80 mg/day) within 28 days. Block randomisation (block size of eight) was stratified by age (<7 years or ≥7 years). Mycophenolate mofetil was given at 1200 mg/m2 body surface area per day, twice daily, as a suspension (200 mg/mL) for a total treatment duration of 12 weeks. Prednisone was administered once, twice, or three times daily for 6 weeks at 60 mg/m2 body surface area per day (maximum 80 mg). Thereafter, prednisone was given for a further 6 weeks at 40 mg/m2 body surface area (maximum 60 mg) once daily in the morning on alternate days. The primary endpoint was the occurrence of a treated relapse during the 24-months of follow-up in the modified intention-to-treat population. The non-inferiority margin was 15%. This trial is registered with the European Union Drug Regulating Authorities Clinical Trials database (EudraCT 2014-001991-76) and has been completed. Between Oct 12, 2015, and April 23, 2021, 497 patients were screened for eligibility, 272 of whom were randomly assigned (136 to each group). The modified intention-to-treat population comprised 269 patients, of whom 173 (64%) were boys and 96 (36%) were girls (median age 4·0 years [IQR 2·0-5·0]). Mycophenolate mofetil was non-inferior to prednisone for the primary endpoint of treated relapse (106 [79·1%] of 134 vs 101 [74·8%] of 135; difference 4·3% [90% CIs -4·2 to 12·7]; p=0·019). At the end of the first 12 weeks of treatment, fewer glucocorticoid-related side-effects were observed in the mycophenolate mofetil group than the prednisone group, including arterial hypertension (78 [59·1%] of 132 vs 115 [87·1%] of 132; difference -28·0% [95% CI -37·7 to -17·5]), lower BMI (BMI Z score 0·16 [SD 0·85] vs 1·41 [1·02]; difference -1·24 [-1·47 to -1·02]), and fewer psychological abnormalities (37 [27·8%] of 133 vs 77 [57·9%] of 133; difference -30·1% [-40·9 to -18·4]). More patients in the mycophenolate mofetil group than in the prednisone group developed infections (93 [69·9%] of 133 vs 74 [55·6%] of 133; difference 14·3% [2·7 to 25·5]) and there was no statistically significant difference in the number of patients who developed at least one gastrointestinal disorder (22 [16·5%] of 133 vs 13 [9·8%] of 133; difference 6·8% [-1·5 to 14·8]). Our findings suggest that mycophenolate mofetil is non-inferior to standard prednisone treatment, with reduced glucocorticoid-related toxic effects. These findings could modify the initial standard of care for patients with steroid-sensitive nephrotic syndrome. German Federal Ministry of Education and Research.
2026-03-04 | A Retrospective Cohort Analysis of Short-Term Outcomes of the Mycophenolate Mofetil-Based Triple Regimen for the Treatment of Calcineurin Inhibitor-Resistant Childhood Nephrotic Syndrome: A Single-Center Experience.
Background Idiopathic nephrotic syndrome (INS) is a heterogeneous group of disorders. A variable number of children do not respond to the conventional first line of treatment and are at risk of progression and complications of nephrotic syndrome. There is limited literature on the use of a combination of alternative immunosuppressive agents in children with calcineurin inhibitor (CNI)-resistant nephrotic syndrome (NS). This study is designed to review short-term outcomes of children who have failed to respond to CNI with documented adequate levels and preserved renal function. Methods Of the 490 registered children receiving CNI, retrospective data were reviewed for 37 patients who received mycophenolate mofetil (MMF) along with conventional CNI and steroids after demonstration of CNI resistance with adequate drug levels. Using the predesigned proforma, clinical, histopathological, and laboratory parameters were collected. Outcomes were classified as complete, partial, and no response. Results The median age of the study participants was 10 years (interquartile range (IQR): 7.75-13.2), with a male predominance of 62%. A total of 24 out of 37 (65%) children responded to the addition of MMF, with half of them achieving complete remission (CR). With the addition of MMF to the conventional regimen, the improvement in serum albumin was statistically significant (OR: 9.29, 95% CI: 1.66-51.74; p = 0.011). Conclusion This retrospective study demonstrates the short-term efficacy of MMF-based triple regimen in achieving remission in pediatric CNI-resistant nephrotic syndrome and is a cost-effective treatment option. Larger, prospective studies with longer follow-up are, however, required to confirm these findings.
2026-03-03 | Unraveling BCR Repertoire Diversity and its Impact on Glucocorticoid Therapy in Pediatric Idiopathic Nephrotic Syndrome.
AIM: Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children, but its underlying mechanisms remain unclear. Although glucocorticoids (GC) are the first-line treatment, approximately 10% of INS cases are steroid-resistant (SRNS), and 50% may progress to refractory nephrotic syndrome (RNS). B cells play a crucial role in INS pathogenesis, treatment, and prognosis. This study aims to explore B-cell receptor repertoire (BCRR) characteristics in INS patients to identify molecular signatures associated with disease outcomes and develop early risk prediction models for RNS and SRNS. METHODS: A case-control study was conducted using peripheral blood samples from 40 initial diagnosed INS patients and 56 age-matched healthy controls. BCRR was sequenced using dimer-avoided multiplex PCR, followed by Illumina NovaSeq sequencing. Immunoglobulin heavy chain (IGH) sequences were mapped and analyzed for diversity, clone expansion and shared clone, isotype usage, class-switch recombination (CSR), IGHV/J gene usage, CDR3 length and somatic hypermutation (SHM). Additionally, a prospective cohort study was conducted on INS patients, with BCRR measured at baseline and follow-up to track changes in response to treatment. Longitudinal analysis was performed to identify specific B-cell clones and predict treatment resistance. RESULTS: The BCRR of INS patients exhibited lower evenness compared to controls, with significant increases in the usage of IGHM/D mutated and IgE/IgG12 isotypes. Public B-cell clones, including five specific CDR3 amino acid sequences, were identified across INS patients. NRNS patients showed increased clonal expansion with specific CDR3 sequences characters on IGHV5-51_IGHJ6 sequences and shorter CDR3 lengths, suggesting strong and focused autoimmune responses. In contrast, RNS and SRNS patients exhibited enhanced IgE-mediated immune responses, characterized by increased IgE BCRR diversity, decreased evenness and increased CSR. Early prediction models were developed based on BCRR parameters, successfully distinguishing between RNS and NRNS, SRNS and SSNS patients. CONCLUSION: B-cell-mediated humoral immunity plays a pivotal role in INS pathogenesis, with distinct immune profiles associated with clinical outcomes. Non- refractory nephrotic syndrome (NRNS) patients exhibit clonal expansion with antigen-driven immune responses, whereas SRNS and RNS patients demonstrate persistent IgE-mediated responses that are resistant to GC but sensitive to second-line immunosuppressants. These findings offer new insights into the mechanisms of steroid resistance and provide a basis for early diagnosis and personalized treatment strategies in INS.
proteins
2026-06-19 | IgM Hyposialylation Modulates Podocyte Vulnerability in Patients With Idiopathic Nephrotic Syndrome.
Altered Ig glycosylation has been implicated in antibody-mediated podocytopathies; however, the functional relevance of IgM sialylation remains poorly defined. Previous evidence suggests that circulating cationic or hyposialylated IgM may contribute to podocyte vulnerability in idiopathic nephrotic syndrome (iNS). Serum IgM from 86 pediatric and adult patients with podocytopathies, 20 patients with membranous nephropathy (MN), 20 patients with lupus nephritis (LN), and 30 healthy controls were analyzed by lectin-based enzyme-linked immunosorbent assay (ELISA) using biotinylated lectins to assess terminal N-glycan residues, including Sambucus nigra agglutinin (SNA) and Ricinus communis agglutinin I (RCA-I). Serum levels of the sialyltransferase ST6GAL1 and the sialidases neuraminidase-1 (NEU1) and neuraminidase-3 (NEU3) were quantified. Cultured human podocytes were exposed to native, desialylated, or resialylated IgM and analyzed by confocal microscopy, quantitative proteomics, phosphoproteomics, and metabolic assays. IgM from patients with iNS showed reduced SNA binding, which inversely correlated with proteinuria and circulating NEU1/NEU3 levels. In paired samples, SNA reactivity decreased during relapse and increased during remission. ST6GAL1 was undetectable across all groups, whereas phospholipase A2 receptor 1(PLA2R1)-positive MN displayed reduced RCA-I binding. Podocytes exposed to hyposialylated or desialylated IgM exhibited disorganization of the actin cytoskeleton, reduced nephrin signal, increased lipid peroxidation, and decreased ATP levels. Resialylated IgM displayed podocyte morphological and metabolic features not statistically distinguishable from those observed under control conditions. Proteomic and phosphoproteomic analyses highlighted modulation of mitogen-activated protein kinase (MAPK)-, mechanistic Target of Rapamycin (mTOR-), adenosine monophosphate-activated protein kinase (AMPK), and cytoskeleton-related pathways. IgM sialylation status tracks disease activity and modulates podocyte structural, metabolic, and signaling responses, supporting immune glycan remodeling as a disease-associated modifier of podocyte vulnerability in iNS.
2024-03-26 | Swollen Feet: Considering the Paradoxical Roles of Interleukins in Nephrotic Syndrome
Interleukins are a family of 40 bioactive peptides that act through cell surface receptors to induce a variety of intracellular responses. While interleukins are most commonly associated with destructive, pro-inflammatory signaling in cells, some also play a role in promoting cellular resilience and survival. This review will highlight recent evidence of the cytoprotective actions of the interleukin 1 receptor (IL-1R)- and common gamma chain receptor (IL-Rγc)-signaling cytokines in nephrotic syndrome (NS). NS results from the injury or loss of glomerular visceral epithelial cells (i.e., podocytes). Although the causes of podocyte dysfunction vary, it is clear that pro-inflammatory cytokines play a significant role in regulating the propagation, duration and severity of disease. Pro-inflammatory cytokines signaling through IL-1R and IL-Rγc have been shown to exert anti-apoptotic effects in podocytes through the phosphoinositol-3-kinase (PI-3K)/AKT pathway, highlighting the potential utility of IL-1R- and IL-Rγc-signaling interleukins for the treatment of podocytopathy in NS. The paradoxical role of interleukins as drivers and mitigators of podocyte injury is complex and ill-defined. Emerging evidence of the cytoprotective role of some interleukins in NS highlights the urgent need for a nuanced understanding of their pro-survival benefits and reveals their potential as podocyte-sparing therapeutics for NS.
2023-10-01 | Acthar® Gel Treatment for Patients with Autoimmune and Inflammatory Diseases: An Historical Perspective and Characterization of Clinical Evidence
Acthar® Gel (repository corticotropin injection) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that is believed to have both steroidogenic and nonsteroidogenic immunomodulatory effects via activation of melanocortin receptors in various cells throughout the body. Since 1952, Acthar has been approved by the US Food and Drug Administration to treat a variety of autoimmune and inflammatory diseases. Since 2014, Mallinckrodt Pharmaceuticals has conducted a large number of preclinical, clinical, and real-world-evidence studies of Acthar for the treatment of rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, multiple sclerosis relapse, ophthalmic disorders, sarcoidosis, and nephrotic syndrome. To date, Acthar has been the subject of more than 500 publications, many of which demonstrate the safety and efficacy of Acthar in patients with inflammatory diseases for whom standard treatments were ineffective or intolerable. Here, we review the history of Acthar and the findings of studies that have investigated the mechanism of action, safety, efficacy, and real-world effectiveness of Acthar for the treatment of inflammatory diseases. Acthar® Gel is an anti-inflammatory drug that directly affects the immune system in a manner that differs from other anti-inflammatory drugs, such as corticosteroids. Since 1952, Acthar has been approved by the U.S. Food and Drug Administration to treat a variety of diseases involving inflammation. The commercial rights to produce Acthar have changed hands several times over the years, beginning with Armour Pharmaceuticals and most recently ending with Mallinckrodt Pharmaceuticals in 2014. Since then, Mallinckrodt has conducted multiple studies in animals to demonstrate the function of Acthar compared with other anti-inflammatory drugs. Further, several clinical trials in humans and studies of hospital or clinical practice records have confirmed the safety and effectiveness of Acthar as a treatment for many inflammatory diseases.
2023-03-09 | Real-word adrenocorticotropic hormone treatment for childhood-onset nephrotic syndrome
Current first-line anti-proteinuric treatments do not produce a satisfactory therapeutic effect in a considerable number of patients with nephrotic syndrome (NS). Interest in adrenocorticotropic hormone (ACTH) for the treatment of NS has recently been revived. The present study investigated the efficacy and safety of ACTH treatment in children with frequent relapsing NS (FRNS), steroid-dependent NS (SDNS), and steroid-resistant NS (SRNS).The ACTH treatment group was comprised of NS patients receiving ACTH treatment. Patients with serum cortisol concentrations <85.3 nmol/L and who had not received ACTH treatment previously were enrolled in the control group from January 2018 to January 2021. The maintenance dose of prednisone, the number of disease recurrences, the time of first disease relapse, immunosuppressant use, serum cortisol levels, and adverse events were recorded in both groups.Fifty-one patients were included in the ACTH group, and twenty-one patients were enrolled in the control group. Concurrent treatment with one or more immunosuppressive and/or cytotoxic treatments occurred in 92.2% and 85.7% of patients in the ACTH and control groups, respectively, throughout the study period. A greater reduction in the prednisone maintenance dose was observed in the ACTH group compared with the control group after 1 year of follow up (0.603 ± 0.445 mg/kg vs. 0.267 ± 0.500 mg/kg, p = 0.006). During the one-year study period, fewer participants experienced one or more disease relapses in the ACTH group (45.1%) compared to the control group (76.2%, odds ratio = 3.896, p = 0.016). The number of disease recurrences per patient in the ACTH group was less than that in the control group (median difference = -1, p = 0.006). The mean length of remission was 8.902 m and 7.905 m in the ACTH group and control group, respectively. A log-rank test showed a longer relapse free survival for patients in the ACTH group (p = 0.046), but the Breslow test showed no significant difference between groups (p = 0.104). Ten patients in the ACTH group successfully discontinued all drug therapies. No patients in the control group were able to discontinue drug therapy as of February 2022.ACTH, combined with multiple drugs, is effective at reducing the prednisone maintenance dose and may effectively prevent disease relapses in childhood NS.
2021-10-15 | Consequences of insurance denials among U.S. patients prescribed repository corticotropin injection (Acthar Gel) for nephrotic syndrome.
Repository corticotropin injection (RCI; Acthar Gel) is indicated to induce a diuresis or a remission of proteinuria in nephrotic syndrome (NS) without uremia of the idiopathic type or that due to lupus erythematosus. This study compares patient characteristics and measurable healthcare resource utilization (HCRU) between NS patients who received a prescription for RCI and then were either approved or denied treatment by their insurers. A retrospective analysis of adults with NS from January 2015 to December 2018 was conducted using a de-identified open-source claims database. Patients were included in the study if they had ≥1diagnosis associated with NS, were age 18+, and had medical claims activity at some point in the year preceding ("baseline") and year following ("follow up") their first approved or denied RCI prescription. Baseline characteristics were reported with p-values indicating the significance of characteristics between cohorts. To assess outcomes, approved and denied patients were matched (1:1) using propensity-matching to account for underlying differences. Overall, 1,232 patients met inclusion criteria for the study. At baseline, approved patients were older than denied patients (mean age 53.9 vs. 48.4) and had higher rates of comorbidities. A greater proportion of approved patients required inpatient admissions (34.1 vs. 28.0%) and "high" doses of corticosteroids (CS) (26.2 vs. 20.7%) at baseline. Matched outcomes showed directionally more denied patients with inpatient admissions compared to approved (64 vs. 52) and a greater utilization of deep vein thrombosis ultrasound (12.2 vs. 6.6%) and dialysis (10.5 vs. 6.1%). Matched, denied patients had directionally greater CS use during follow-up both in the number of patients receiving CS (104 vs. 95) and the average annualized daily dose (4.1 vs. 3.4 mg). Patients denied access to RCI treatment had directionally higher HCRU compared to matched, approved counterparts. Thus, the results of this study may aid providers and payers in evaluating scenarios where RCI may be beneficial and improve quality of care for NS patients.
cell therapies
2026-07-03 | Cord blood-derived mesenchymal stromal cells in children with steroid-dependent nephrotic syndrome: a prospective phase II study.
Children with steroid-dependent nephrotic syndrome (SDNS) require long-term immunosuppressive (IS) treatment, significantly impacting their quality of life. Cord-blood-derived mesenchymal stromal cells (CB-MSCs) are multipotent stem cells with proven immunomodulatory properties. We conducted an adaptive, open-label, single-arm, phase II trial with an adaptive second part to evaluate the efficacy of CB-MSCs in children aged 3-18 years with SDNS in remission for ≥6 months on IS therapy. In Part 1, patients received three intravenous infusions of CB-MSCs (1.5 × 10⁶/kg) at 1-2-week intervals, with rapid IS tapering and discontinuation after the third infusion. The primary endpoint was relapse-free survival at 6 months post-IS withdrawal, with a threshold of <4/11 relapsing patients. In the adaptive Part 2, IS was discontinued before the first infusion to enhance CB-MSCs activity, and the dose was increased to 2 × 10⁶/kg, with a booster fourth infusion. A historical cohort of SDNS children tapering IS under standard care served as a post-hoc control. In Part 1, 9 patients were enrolled, and 7/9 (78%) relapsed, failing to meet the prespecified efficacy threshold. In Part 2, 11 patients were enrolled; 9 (82%) were in remission at 2 weeks post-third infusion and received the boosted dose. However, 6/11 (55%) relapsed within 6 months, with no significant difference in relapse-free survival compared to Part 1 (P = .25). Historical controls had significantly better relapse-free survival (P = .0007). In children with SDNS, this novel therapy with CB-MSCs was safe but failed to improve relapse-free survival 6 months after IS withdrawal.
2024-12-23 | Stem Cells Derived From Human Deciduous Exfoliated Teeth Ameliorate Adriamycin-induced Nephropathy In Rats By Modulating The Th17/Treg Balance.
Idiopathic Nephrotic Syndrome (INS) is a common kidney disease in children, and the main clinical manifestations are hypoproteinaemia, proteinuria, hyperlipidaemia, and oedema. Mesenchymal Stem Cells (MSCs) are involved in tissue repair, protection against fibrosis, and immune modulation but have rarely been studied in INS. This study aimed to explore the therapeutic potential of stem cells derived from human exfoliated deciduous teeth (SHEDs) in INS using an adriamycin-induced nephropathy (AN) rat model. AN was induced in Sprague‒Dawley rats, and SHEDs were transplanted via the tail vein in single (SHED-s) and multidose (SHED-m) regimens. Cell migration assays were used to track the SHED distribution. Weight, urine protein, and serum biochemical assays were also performed. HE and Masson staining were used to observe glomerular and tubular damage, as well as the degree of fibrosis. Immunohistochemistry was used to label T lymphocytes and podocytes, and structural changes in podocytes were observed by electron microscopy. ELISA was used to measure the levels of inflammatory factors. Flow cytometry was used to analyse the balance of Th17 cells and Tregs. The mRNA expression of Th17- and Treg-associated cytokines and specific transcription factors was examined by RT‒PCR. SHEDs directly migrated to damaged tissues, suggesting a targeted therapeutic effect. SHED transplantation significantly reduced proteinuria and reversed biochemical abnormalities in rats with AN. Both single and multidose SHED treatments could inhibit glomerular and tubular damage and delay the progression of fibrosis caused by adriamycin. SHEDs exerted a protective effect on podocytes. Additionally, this treatment inhibited inflammatory responses and corrected immune imbalances, as evidenced by decreased T lymphocyte infiltration, reduced serum levels of IL-6, TNF-a, and IL-1β, and modulation of the Th17/Treg balance. In the AN rat model, SHED partly suppressed the development of inflammation and alleviated kidney injury, and immune regulation may be the underlying mechanism.
2023-09-22 | A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome
BACKGROUNDSevere forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects.METHODSWe performed a phase I open-label trial assessing safety and feasibility of autologous bone marrow-derived MSCs (BM-MSCs) in children and young adults with severe forms of steroid-dependent nephrotic syndrome. Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy, and immunomodulatory effects in vivo were monitored for 12 months.RESULTSSixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (P = 0.02) and number of relapses was reduced (P = 0.002) after BM-MSC infusion, compared with the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared with baseline (P < 0.05). No treatment benefit was observed in adults.In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction in total CD19+, mature, and memory B cells and an increase in regulatory T cells in vivo up to 3-6 months following BM-MSC infusionCONCLUSIONTreatment with autologous BM-MSCs is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit.TRIAL REGISTRATIONEudraCT 2016-004804-77.FUNDINGAIFA Ricerca Indipendente 2016-02364623.
2022-08-23 | First clinical application of cord blood mesenchymal stromal cells in children with multi-drug resistant nephrotic syndrome.
Children with multi-drug resistant idiopathic nephrotic syndrome (MDR-INS) usually progress to end-stage kidney disease with a consistent risk of disease recurrence after transplantation. New therapeutic options are needed for these patients. Mesenchymal stromal cells (MSCs) are multipotential non-hematopoietic cells with several immunomodulatory properties and growing clinical applications. Cord blood-derived MSC have peculiar anti-inflammatory and immunosuppressive properties. We aimed at assessing safety and efficacy of cord-blood-derived MSCs (CB-MSCs) in children with MDR-INS. Prospective, open-label, single arm phase I-II pilot study. Pediatric patients with MDR-INS, resistant to at least two lines of therapy, were enrolled. Allogenic CB-MSCs were administered intravenously on days 0, 14, and 21 at a dose of 1.5 × 106 cells/kg. Patients were followed for at least 12 months. The primary outcomes were safety and toxicity. The secondary outcome was remission at 12 months evaluated by urinary protein/urinary creatinine ratio (uPr/uCr). Circulating regulatory T cells (Tregs) were monitored. Eleven pediatric patients with MDR-INS (10 females, median age 13 years) resistant to a median of 3 previous lines of therapy were enrolled. All patients completed the CB-MSC infusion schedule. No patient experienced any infusion-related adverse event or toxicity. Nine patients were assessable for efficacy. At the 12 months follow-up after the treatment, the median uPr/uCr did not change significantly from baseline (8.13 vs. 9.07; p = 0.98), while 3 patients were in partial or complete remission. A lower baseline uPr/uCr was a predictor of remission (2.55 vs. 8.74; p = 0.0238). Tregs count was not associated with CB-MSCs therapy. CB-MSCs are safe and may have a role in the immunosuppressive therapy of pediatric patients with MDR-INS. This preliminary experience paves the way toward further phase II studies addressing MSC efficacy in immune-mediated kidney diseases.
2020-11-25 | Novel Diagnostic and Therapeutic Techniques Reveal Changed Metabolic Profiles in Recurrent Focal Segmental Glomerulosclerosis
Abstract Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead early recurrence of FSGS and kidney failure after kidney transplantation. In the past three decades, many research endeavors were undertaken to identify these unknown factors. Even though some potential candidates have been recently discussed in the literature, “the” actual factor remains elusive. Therefore, there is an increased demand in FSGS research for the use of novel technologies that allow us to study FSGS from a yet unexplored angle. Here, we report the successful treatment of recurrent FSGS in a patient after living related kidney transplantation by removal of circulating factors with CytoSorb apheresis. Interestingly, the classical published circulating factors were all in normal range in this patient but early disease recurrence in the transplant kidney and immediate response to CytoSorb apheresis were still suggestive for pathogenic circulating factors. To proof the functional effects of the patient’s serum on podocytes and the glomerular filtration barrier we used a podocyte cell culture model and a proteinuria model in zebrafish to detect pathogenic effects on the podocytes actin cytoskeleton inducing a functional phenotype. We then performed Raman spectroscopy in the <50 kD serum fraction, on cultured podocytes treated with the FSGS serum and in kidney biopsies of the same patient at the time of transplantation and at the time of disease recurrence. The analysis revealed changes in podocyte metabolom induced by the FSGS serum as well as in focal glomerular and parietal epithelial cell regions in the FSGS biopsy. Several altered Raman spectra were identified in the fractionated serum and metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, which were supported by disturbances in the Raman spectra. Our novel innovative analysis reveals changed lipid metabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.
antibodies
2026-07-06 | Expression of PD-1 on T cells and its predictive value for steroid resistance in children with idiopathic nephrotic syndrome.
Programmed cell death protein 1 (PD-1) plays a pivotal role in regulating T-cell responses. Its expression profile and clinical significance in pediatric idiopathic nephrotic syndrome (INS), particularly in steroid-resistant nephrotic syndrome (SRNS), remain unclear. PD-1 expression on CD3⁺, CD4⁺, and CD8⁺T cells was quantified by flow cytometry in 65 treatment-naive children with idiopathic nephrotic syndrome (INS): steroid-sensitive (SSNS, n = 54), steroid-resistant (SRNS, n = 11), as well as in healthy controls (HC, n = 30). Group differences, clinical correlations and PD-1's predictive value for SRNS were analyzed. Circulating T subsets, including CD3⁺PD-1⁺ T cells, CD4⁺PD-1⁺T cells, and CD8⁺PD-1⁺T were detected with multiparameter flow cytometry. The percentage of CD4⁺PD-1⁺ T cells was significantly higher in SRNS (10.77 ± 4.62%) compared to both SSNS (5.14 ± 1.99%, P = 0.000) and HC (6.36 ± 2.02%, P = 0.028). CD3⁺PD-1⁺ T cells were also elevated in SRNS (8.13 ± 3.12%) versus SSNS (4.67 ± 1.82%, P = 0.001). No significant difference was found in CD8⁺PD-1⁺ T cells. Multivariate logistic regression identified an elevated percentage of CD4⁺PD-1⁺ T cells as an independent risk factor for SRNS (OR = 2.236, P = 0.002). Receiver operating characteristic (ROC) analysis showed that CD4⁺PD-1⁺ T cell cutoff > 7.385% predicted SRNS with an area under the curve (AUC) of 0.891, sensitivity of 81.8%, and specificity of 87.0%. Overexpression of PD-1, predominantly on CD4⁺ T cells, is associated with steroid resistance in pediatric INS. Elevated CD4⁺PD-1⁺ T cells may serve as a predictive biomarker for SRNS, offering a potential tool for early identification and a rationale for exploring PD-1 pathway modulation.
2026-04-01 | Rituximab in a desensitization protocol as a rescue therapy in severe nephrotic syndrome-a case report.
Idiopathic nephrotic syndrome is the most common glomerulopathy in children, and minimal change disease (MCD) is the most common histological pattern. First-line treatment involves glucocorticosteroids, but frequent relapses and steroid dependence may lead to steroid-related complications. Rituximab (RTX) is recommended in cases of lack of response or treatment side effects, reducing relapse rates and limiting the need for other medications. The mechanism of RTX involves B-cell depletion through various cytotoxic mechanisms. Its efficacy in nephrotic syndrome (NS) may stem from its influence on cytokines produced by B cells and a further effect on the podocyte cytoskeleton has been postulated. The present case describes a 19-year-old male with NS resulting from MCD, with a frequently relapsing, steroid-dependent, multidrug-resistant disease. He experienced a hypersensitivity reaction to RTX after the third dose, which contraindicated therapy continuation with traditional infusion. Due to the limited therapeutic options, a 12-step RTX desensitization protocol was adopted, allowing for safe administration of subsequent doses, achievement of remission, and gradual discontinuation of glucocorticosteroids.
2026-01-21 | A New Hope for Treating Podocytopathies: Emerging Role of Anti-Nephrin Antibody.
The etiology of primary podocytopathies including childhood nephrotic syndrome, minimal change disease, primary FSGS as well as recurrent FSGS had long remained elusive. The development of robust anti-nephrin autoantibody detection methods, the identification of these antibodies in idiopathic nephrotic syndrome, and the demonstration of their causal role in podocytopathy have led to a paradigm shift in our understanding of these diseases, offering new insights into pathophysiology and promising improved diagnostic, prognostic, and therapeutic approaches. Prognostication and risk stratification on the basis of anti-nephrin antibody detection as well as personalized therapeutic strategies including therapies targeting antibody-producing B cells or even antigen-specific depletion of autoreactive B cells could markedly improve treatment outcomes and patient quality of life in the future. In this review, we explore the prevalence of anti-nephrin antibodies in various glomerular diseases, current treatment options for primary podocytopathies, and how the emerging evidence of anti-nephrin antibody-mediated podocytopathy could influence future treatment approaches for affected patients.
2026-01-15 | Endothelial cell-released CD93 contributes to podocyte injury in idiopathic nephrotic syndrome.
Idiopathic nephrotic syndrome (INS) is a podocyte disease triggered by immune-derived factors. Endothelial activation occurs in this context, but whether the activated endothelium contributes to podocyte injury is unknown. We tested the hypothesis that CD93, a protein primarily expressed in the endothelium, is a contributory factor of podocyte injury. We studied 460 patients with INS and 150 with other podocytopathies. CD93 was analyzed in kidney tissue, urine, and serum samples. We tested the efficacy of CD93 blockade in vitro and in vivo and investigated the relationship between soluble CD93 and clinical outcomes in human INS. CD93 was highly expressed by glomerular endothelial cells (GEnCs) in human INS, and INS sera stimulated cultured human GEnCs to release CD93. Mechanistically, soluble CD93 mediated podocyte activation via β1 integrin/FAK signaling in cultured human podocytes. CD93 blockade mitigated the activation of cultured human podocytes and albumin permeability in human GEnC-podocyte cocultures as well as albuminuria, glomerulosclerosis, and podocyte loss in two models of nephrotic syndrome: podocyte-specific transforming growth factor-β1 signaling (PodTgfbr1) mice and adriamycin-treated mice. Cd93 knockout mice showed less proteinuria and glomerulosclerosis, compared with controls, after adriamycin injection. In patients with INS, soluble CD93 was high in urine in ~90% and 50% of patients in relapse and remission, respectively. High urinary CD93 was associated with faster decline in kidney function and slower response to immunosuppression. Soluble and glomerular CD93 was also elevated in other podocytopathies. We conclude that soluble CD93 contributes to podocyte injury.
2025-12-18 | Daratumumab combined with anti-CD20 therapy in pediatric and adult refractory idiopathic nephrotic syndrome: single-center experience.
Refractory idiopathic nephrotic syndrome (INS), in native kidneys or post-transplant, represents a major therapeutic challenge due to its high risk of progressing to end-stage renal disease. Patients often resist anti-CD20 therapy and require prolonged apheresis. Daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells, has demonstrated promising efficacy in case reports when combined with anti-CD20, but evidence remains limited. We conducted a single-center retrospective study including four patients (two pediatric, two adult, including one renal transplant) with INS refractory to conventional therapies (corticosteroids, calcineurin inhibitors, mycophenolate mofetil, anti-CD20 antibodies, and/or apheresis). All Patients received daratumumab combined with anti-CD20 therapy at University Hospital of La Réunion between 2022 and 2025. Clinical and laboratory data were extracted from medical records. Renal response was defined as complete remission (CR) or partial remission (PR). The mean patient age was 20 ± 13 years (range: 8-40), with a male-to-female ratio of 3:1. Median follow-up after daratumumab administration was 5 months (range: 2-12). All patients achieved CR with a median time to response of 25 days (range: 14-30). Previously apheresis-dependent patients were able to discontinue sessions. Two patients developed infections (herpetic and SARS-CoV-2 pneumonia complicated by pneumococcal bacteremia), all resolving favorably. Renal function remained stable. Combined daratumumab and anti-CD20 therapy appears to be an effective rescue strategy for refractory INS, in native kidneys and post-transplant. It induces rapid and sustained remission, enabling discontinuation of apheresis. Prospective studies are warranted to optimize treatment regimens and identify predictive biomarkers of response.
other
2025-05-22 | Association between SIRT-1 and SERPINA4 gene polymorphisms and the risk of idiopathic nephrotic syndrome among Egyptian children.
Idiopathic nephrotic syndrome (INS) is the primary cause of chronic glomerular dysfunction in children. Despite extensive research, its pathophysiology remains unclear, particularly in cases that are resistant to steroids. This research evaluated the impact of SIRT-1 (rs2273773) and SERPINA4 (rs2093266) gene variants on Egyptian children's susceptibility to INS and response to steroid therapy. Genetic polymorphisms of SIRT-1 (rs2273773) and SERPINA4 (rs2093266) were screened in 135 INS children and a similar number of healthy volunteers using real-time PCR. Concerning SIRT-1 rs2273773 genotypes, the cases showed markedly greater CT, TT genotypes, and T allele incidences than the reference group, which increased the risk of INS by 2.01-, 4.03-, and 1.88-folds, respectively. Regarding SERPINA4 rs2093266 genotypes, the cases exhibited notably higher GA, AA genotypes, and the A allele frequencies than controls, which enlarged the risk of INS by 3.1-, 5.47-, and 2.82-folds, respectively. The frequency of GA and AA genotypes and the presence of the A allele of SERPINA4 rs2093266 were considerably higher in steroid-resistant versus steroid-sensitive cases. The logistic regression model stated the serum creatinine, blood urea nitrogen, and the SERPINA4 rs2093266 polymorphism as independent contributors to the risk for steroid resistance in INS cases. SIRT-1 (rs2273773) and SERPINA4 (rs2093266) gene polymorphisms significantly attributed to the risk of developing INS in Egyptian children. Furthermore, the SERPINA4 (rs2093266) polymorphism has a strong correlation with steroid resistance, suggesting that it could be a target for treatment to avoid severe renal problems and adverse steroid effects.
2024-02-09 | Nephrotic Syndrome: A Review
Nephrotic syndrome (NS) is characterized by hypoalbuminemia, severe proteinuria, and peripheral edema, frequently in conjunction with hyperlipidemia. Individuals usually show symptoms of weariness and swelling, but no signs of serious liver damage or cardiac failure. With characteristic medical symptoms and evidence of hypoalbuminemia and severe proteinuria, NS can be diagnosed. The majority of NS episodes are classified as unexplained or primary; the most prevalent histopathological subgroups of primary NS in people are focal segmental glomerulosclerosis and membraneous nephropathy. Thrombosis of the veins with high cholesterol levels is a significant NS risk. Acute renal damage and infection are further possible side effects. The pathobiochemistry of NS involves alterations in genes that affect the selectivity of the kidneys and abnormalities in proteins related to podocytes. Understanding the molecular mechanisms that influence these processes is crucial to developing specific and targeted therapeutic approaches. The need for invasive renal biopsies throughout the diagnosis process may be lessened by the development of non-invasive nephrotic syndrome biomarkers, such as microRNAs. Corticosteroids are frequently used as the initial line of defense in NS treatment. However, some individuals need other treatments since a resistant type of NS also exists. The use of calcineurin inhibitors, mycophenolate mofetil, and rituximab is mentioned in the text, along with current research to identify safer and more efficient therapeutic choices. The complicated kidney condition NS has several underlying causes and symptoms. For the diagnosis of this ailment as well as the creation of focused therapies, an understanding of the pathophysiology and the identification of possible biomarkers are essential.
2022-05-09 | Human pluripotent stem cell-derived kidney organoids for personalized congenital and idiopathic nephrotic syndrome modeling.
Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo podocyte characteristics are a prerequisite to resolve NS pathogenesis. The detailed characterization of organoid podocytes resulting from a hybrid culture protocol showed a podocyte population that resembles adult podocytes and was superior compared with 2D counterparts, based on single-cell RNA sequencing, super-resolution imaging and electron microscopy. In this study, these next-generation podocytes in kidney organoids enabled personalized idiopathic nephrotic syndrome modeling, as shown by activated slit diaphragm signaling and podocyte injury following protamine sulfate, puromycin aminonucleoside treatment and exposure to NS plasma containing pathogenic permeability factors. Organoids cultured from cells of a patient with heterozygous NPHS2 mutations showed poor NPHS2 expression and aberrant NPHS1 localization, which was reversible after genetic correction. Repaired organoids displayed increased VEGFA pathway activity and transcription factor activity known to be essential for podocyte physiology, as shown by RNA sequencing. This study shows that organoids are the preferred model of choice to study idiopathic and congenital podocytopathies.
2022-01-31 | Influenza virus vaccination in pediatric nephrotic syndrome significantly reduces rate of relapse and influenza virus infection as assessed in a nationwide survey.
Although vaccination may precipitate relapses of nephrotic syndrome (NS) in children with idiopathic NS, no data are available regarding NS activity regarding influenza (flu) virus infections and NS relapses after receiving inactivated flu vaccines. We conducted a nationwide study of children aged 6 months to 15 years with idiopathic NS to assess the relationship between NS relapse, flu vaccination, and flu infections. We used a multivariate Poisson regression model (MPRM) to calculate the risk ratio (RR) for flu infection and for NS relapse in children with and without flu vaccination. Data of 306 children were assessed. The MPRM in all 306 children showed a significantly lower RR for flu infection (RR: 0.21, 95% confidence interval CI 0.11-0.38) and for NS relapse (RR: 0.22, 95% CI 0.14-0.35) in children receiving flu vaccination compared with unvaccinated children. In an additional MPRM only among 102 children receiving flu vaccination, they had a significantly lower risk for NS relapse during the post-vaccination period (RR: 0.31. 95% CI 017-0.56) compared with the pre-vaccination period. Although our study was observational, based on the favorable results of flu vaccinations regarding flu infections and NS relapse, the vaccine may be recommended for children with NS.
2022-01-31 | CMIP interacts with WT1 and targets it on the proteasome degradation pathway.
The Wilms tumor 1 suppressor gene, WT1, is expressed throughout life in podocytes and is essential for their function. Downregulation of WT1 has been reported in podocyte diseases but the underlying mechanisms remain unclear. Podocyte injury is the hallmark of idiopathic nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults. An increase in the abundance of Cmaf-inducing protein (CMIP) has been found to alter podocyte function, but it is not known whether CMIP affects WT1 expression. Transcriptional and post-transcriptional regulation of WT1in the presence of CMIP was studied using transient transfection, mouse models, and siRNA handling. We showed that overproduction of CMIP in the podocyte was consistently associated with a downregulation of WT1 according to two mechanisms. We found that CMIP prevented the NF-kB-mediated transcriptional activation of WT1. We demonstrated that CMIP interacts directly with WT1 through its leucine-rich repeat domain. Overexpression of CMIP in the M15 cell line induced a downregulation of WT1, which was prevented by lactacystin, a potent proteasome inhibitor. We showed that CMIP exhibits an E3 ligase activity and targets WT1 to proteasome degradation. Intravenous injection of Cmip-siRNA specifically prevented the repression of Wt1 in lipopolysaccharides-induced proteinuria in mice. These data suggest that CMIP is a repressor of WT1 and might be a critical player in the pathophysiology of some podocyte diseases. Because WT1 is required for podocyte integrity, CMIP could be considered a therapeutic target in podocyte diseases.
small molecules
2026-06-09 | Clinical and Pathological Faces of IgM Deposition in Children with Idiopathic Nephrotic Syndrome: A Single Center Experience.
Immunoglobulin M nephropathy (IgMN) is a pathological term defining glomerulonephritis with IgM deposition. The clinical significance is still a matter of debate. The aim was to evaluate children with IgM nephropathy (IgMN) in terms of clinical and pathological features, along with treatment responses and outcomes. The children with idiopathic nephrotic syndrome (INS) who underwent kidney biopsy at our center (n=41) were evaluated retrospectively. Twenty-one children with IgMN were included. The female to male ratio was 0.9, the median age was 3.5 years in the study group. The mean disease duration and follow-up periods were 11.8 and 11.3years, respectively. At admission, 14% of the patients had hypertension, and 19% had microscopic hematuria. Steroid-dependent nephrotic syndrome (SDNS) was observed in 62% of the patients at admission and 81% at last visit. The patients with IgM (≥2+) depositions had more SDNS than those with IgM (1+). The most common light microscopic diagnosis was mesangial proliferative glomerulonephritis (MesPGN) (47.6%). Focal segmental glomerulosclerosis (FSGS) elevated significantly from 14% at initial biopsy to 57% at follow-up biopsies. Patients who progressed to FSGS mostly had C3 co-deposition, high IgM intensity (≥2+), diagnosis of MesPGN, and SDNS clinic. The most frequently used adjuvant agent was cyclosporine-A (n=19) with mean duration of 68 months. It provided lower relapse rates. Rituximab (n=4) showed 75% remission rate. None of the patients had needed renal replacement treatment. Two patients who were steroid-resistant at admission had FSGS in their first biopsies, acted as multi-drug resistance at follow-up, and ended up in Stage-2 chronic kidney disease (CKD). This study shows IgMN is mainly presented with SDNS clinic and MesPGN pathology. Evolution to FSGS may be related to steroid resistance, MesPGN, high IgM intensity, and C3 co-deposition.
2026-05-18 | Kidney biopsy during pregnancy: indications, complications, results and therapeutic impact.
The diagnosis of kidney disease can be challenging during pregnancy. A kidney biopsy (KB) may be proposed, but there is little recent data available to assess the risk/benefit ratio of this procedure during pregnancy. In this French nationwide survey, we analysed the indications, complications, histological diagnoses, treatments, and obstetric outcomes of pregnant women who underwent native KB between 2006 and 2025. We gathered the medical records of 76 patients, with a median age of 29.5 [range 18-42] years, including 2 with twin pregnancies. KB was performed at a median gestational age of 13.5 [range 4-26] weeks. The main indications for KB were: nephrotic syndrome without AKI (40.8%) and non-nephrotic proteinuria without AKI (40.8%). KB led to a diagnosis in 72 (94.7%) patients. The main histological diagnoses were lupus nephritis (43%), focal segmental glomerulosclerosis (13%), membranous nephropathy (13%), IgA nephropathy (12%), and idiopathic nephrotic syndrome consistent with minimal change disease (5%). One patient experienced bleeding requiring transfusion. Specific treatment was initiated in 48 (63.2%) patients after KB: corticosteroids (35.5%), hydroxychloroquine (27.6%), azathioprine (18.4%), calcineurin inhibitor (13.2%), rituximab (2.6%) and belimumab (1.3%). There was a high incidence of preeclampsia (16.4%), small for gestational age (21.3%) and intrauterine fetal death (9.0%) in this cohort. Preterm birth and low birth weight occurred in 65.0% and 56.7% of cases, respectively. When considered necessary to establish a diagnosis during pregnancy, kidney biopsy performed in the first two trimesters appears to be safe, with a high diagnostic yield and a significant impact on therapeutic decision-making and patient management.
2026-03-20 | Mycophenolate mofetil versus prednisone for the initial treatment of idiopathic steroid-sensitive nephrotic syndrome in children in Germany (INTENT): a multicentre, open-label, randomised, controlled, parallel-group, non-inferiority, phase 3 trial.
Prolonged glucocorticoid therapy is the standard initial treatment for idiopathic nephrotic syndrome in children, but is associated with marked toxic effects. We aimed to assess whether a novel treatment protocol with mycophenolate mofetil is as effective as standard therapy with prednisone, while reducing the burden of glucocorticoid-related side-effects. INTENT was a multicentre, open-label, randomised, controlled, parallel-group, non-inferiority, phase 3 trial done in 37 community, municipal, and university hospitals in Germany. Patients aged 1-10 years with a first episode of steroid-sensitive nephrotic syndrome were randomly assigned (1:1) by a centralised web-based tool to receive either mycophenolate mofetil or prednisone (standard treatment), after remission induced by prednisone or prednisolone at a dose of 60 mg/m2 body surface area (maximum 80 mg/day) within 28 days. Block randomisation (block size of eight) was stratified by age (<7 years or ≥7 years). Mycophenolate mofetil was given at 1200 mg/m2 body surface area per day, twice daily, as a suspension (200 mg/mL) for a total treatment duration of 12 weeks. Prednisone was administered once, twice, or three times daily for 6 weeks at 60 mg/m2 body surface area per day (maximum 80 mg). Thereafter, prednisone was given for a further 6 weeks at 40 mg/m2 body surface area (maximum 60 mg) once daily in the morning on alternate days. The primary endpoint was the occurrence of a treated relapse during the 24-months of follow-up in the modified intention-to-treat population. The non-inferiority margin was 15%. This trial is registered with the European Union Drug Regulating Authorities Clinical Trials database (EudraCT 2014-001991-76) and has been completed. Between Oct 12, 2015, and April 23, 2021, 497 patients were screened for eligibility, 272 of whom were randomly assigned (136 to each group). The modified intention-to-treat population comprised 269 patients, of whom 173 (64%) were boys and 96 (36%) were girls (median age 4·0 years [IQR 2·0-5·0]). Mycophenolate mofetil was non-inferior to prednisone for the primary endpoint of treated relapse (106 [79·1%] of 134 vs 101 [74·8%] of 135; difference 4·3% [90% CIs -4·2 to 12·7]; p=0·019). At the end of the first 12 weeks of treatment, fewer glucocorticoid-related side-effects were observed in the mycophenolate mofetil group than the prednisone group, including arterial hypertension (78 [59·1%] of 132 vs 115 [87·1%] of 132; difference -28·0% [95% CI -37·7 to -17·5]), lower BMI (BMI Z score 0·16 [SD 0·85] vs 1·41 [1·02]; difference -1·24 [-1·47 to -1·02]), and fewer psychological abnormalities (37 [27·8%] of 133 vs 77 [57·9%] of 133; difference -30·1% [-40·9 to -18·4]). More patients in the mycophenolate mofetil group than in the prednisone group developed infections (93 [69·9%] of 133 vs 74 [55·6%] of 133; difference 14·3% [2·7 to 25·5]) and there was no statistically significant difference in the number of patients who developed at least one gastrointestinal disorder (22 [16·5%] of 133 vs 13 [9·8%] of 133; difference 6·8% [-1·5 to 14·8]). Our findings suggest that mycophenolate mofetil is non-inferior to standard prednisone treatment, with reduced glucocorticoid-related toxic effects. These findings could modify the initial standard of care for patients with steroid-sensitive nephrotic syndrome. German Federal Ministry of Education and Research.
2026-03-04 | A Retrospective Cohort Analysis of Short-Term Outcomes of the Mycophenolate Mofetil-Based Triple Regimen for the Treatment of Calcineurin Inhibitor-Resistant Childhood Nephrotic Syndrome: A Single-Center Experience.
Background Idiopathic nephrotic syndrome (INS) is a heterogeneous group of disorders. A variable number of children do not respond to the conventional first line of treatment and are at risk of progression and complications of nephrotic syndrome. There is limited literature on the use of a combination of alternative immunosuppressive agents in children with calcineurin inhibitor (CNI)-resistant nephrotic syndrome (NS). This study is designed to review short-term outcomes of children who have failed to respond to CNI with documented adequate levels and preserved renal function. Methods Of the 490 registered children receiving CNI, retrospective data were reviewed for 37 patients who received mycophenolate mofetil (MMF) along with conventional CNI and steroids after demonstration of CNI resistance with adequate drug levels. Using the predesigned proforma, clinical, histopathological, and laboratory parameters were collected. Outcomes were classified as complete, partial, and no response. Results The median age of the study participants was 10 years (interquartile range (IQR): 7.75-13.2), with a male predominance of 62%. A total of 24 out of 37 (65%) children responded to the addition of MMF, with half of them achieving complete remission (CR). With the addition of MMF to the conventional regimen, the improvement in serum albumin was statistically significant (OR: 9.29, 95% CI: 1.66-51.74; p = 0.011). Conclusion This retrospective study demonstrates the short-term efficacy of MMF-based triple regimen in achieving remission in pediatric CNI-resistant nephrotic syndrome and is a cost-effective treatment option. Larger, prospective studies with longer follow-up are, however, required to confirm these findings.
2026-03-03 | Unraveling BCR Repertoire Diversity and its Impact on Glucocorticoid Therapy in Pediatric Idiopathic Nephrotic Syndrome.
AIM: Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children, but its underlying mechanisms remain unclear. Although glucocorticoids (GC) are the first-line treatment, approximately 10% of INS cases are steroid-resistant (SRNS), and 50% may progress to refractory nephrotic syndrome (RNS). B cells play a crucial role in INS pathogenesis, treatment, and prognosis. This study aims to explore B-cell receptor repertoire (BCRR) characteristics in INS patients to identify molecular signatures associated with disease outcomes and develop early risk prediction models for RNS and SRNS. METHODS: A case-control study was conducted using peripheral blood samples from 40 initial diagnosed INS patients and 56 age-matched healthy controls. BCRR was sequenced using dimer-avoided multiplex PCR, followed by Illumina NovaSeq sequencing. Immunoglobulin heavy chain (IGH) sequences were mapped and analyzed for diversity, clone expansion and shared clone, isotype usage, class-switch recombination (CSR), IGHV/J gene usage, CDR3 length and somatic hypermutation (SHM). Additionally, a prospective cohort study was conducted on INS patients, with BCRR measured at baseline and follow-up to track changes in response to treatment. Longitudinal analysis was performed to identify specific B-cell clones and predict treatment resistance. RESULTS: The BCRR of INS patients exhibited lower evenness compared to controls, with significant increases in the usage of IGHM/D mutated and IgE/IgG12 isotypes. Public B-cell clones, including five specific CDR3 amino acid sequences, were identified across INS patients. NRNS patients showed increased clonal expansion with specific CDR3 sequences characters on IGHV5-51_IGHJ6 sequences and shorter CDR3 lengths, suggesting strong and focused autoimmune responses. In contrast, RNS and SRNS patients exhibited enhanced IgE-mediated immune responses, characterized by increased IgE BCRR diversity, decreased evenness and increased CSR. Early prediction models were developed based on BCRR parameters, successfully distinguishing between RNS and NRNS, SRNS and SSNS patients. CONCLUSION: B-cell-mediated humoral immunity plays a pivotal role in INS pathogenesis, with distinct immune profiles associated with clinical outcomes. Non- refractory nephrotic syndrome (NRNS) patients exhibit clonal expansion with antigen-driven immune responses, whereas SRNS and RNS patients demonstrate persistent IgE-mediated responses that are resistant to GC but sensitive to second-line immunosuppressants. These findings offer new insights into the mechanisms of steroid resistance and provide a basis for early diagnosis and personalized treatment strategies in INS.
proteins
2026-06-19 | IgM Hyposialylation Modulates Podocyte Vulnerability in Patients With Idiopathic Nephrotic Syndrome.
Altered Ig glycosylation has been implicated in antibody-mediated podocytopathies; however, the functional relevance of IgM sialylation remains poorly defined. Previous evidence suggests that circulating cationic or hyposialylated IgM may contribute to podocyte vulnerability in idiopathic nephrotic syndrome (iNS). Serum IgM from 86 pediatric and adult patients with podocytopathies, 20 patients with membranous nephropathy (MN), 20 patients with lupus nephritis (LN), and 30 healthy controls were analyzed by lectin-based enzyme-linked immunosorbent assay (ELISA) using biotinylated lectins to assess terminal N-glycan residues, including Sambucus nigra agglutinin (SNA) and Ricinus communis agglutinin I (RCA-I). Serum levels of the sialyltransferase ST6GAL1 and the sialidases neuraminidase-1 (NEU1) and neuraminidase-3 (NEU3) were quantified. Cultured human podocytes were exposed to native, desialylated, or resialylated IgM and analyzed by confocal microscopy, quantitative proteomics, phosphoproteomics, and metabolic assays. IgM from patients with iNS showed reduced SNA binding, which inversely correlated with proteinuria and circulating NEU1/NEU3 levels. In paired samples, SNA reactivity decreased during relapse and increased during remission. ST6GAL1 was undetectable across all groups, whereas phospholipase A2 receptor 1(PLA2R1)-positive MN displayed reduced RCA-I binding. Podocytes exposed to hyposialylated or desialylated IgM exhibited disorganization of the actin cytoskeleton, reduced nephrin signal, increased lipid peroxidation, and decreased ATP levels. Resialylated IgM displayed podocyte morphological and metabolic features not statistically distinguishable from those observed under control conditions. Proteomic and phosphoproteomic analyses highlighted modulation of mitogen-activated protein kinase (MAPK)-, mechanistic Target of Rapamycin (mTOR-), adenosine monophosphate-activated protein kinase (AMPK), and cytoskeleton-related pathways. IgM sialylation status tracks disease activity and modulates podocyte structural, metabolic, and signaling responses, supporting immune glycan remodeling as a disease-associated modifier of podocyte vulnerability in iNS.
2024-03-26 | Swollen Feet: Considering the Paradoxical Roles of Interleukins in Nephrotic Syndrome
Interleukins are a family of 40 bioactive peptides that act through cell surface receptors to induce a variety of intracellular responses. While interleukins are most commonly associated with destructive, pro-inflammatory signaling in cells, some also play a role in promoting cellular resilience and survival. This review will highlight recent evidence of the cytoprotective actions of the interleukin 1 receptor (IL-1R)- and common gamma chain receptor (IL-Rγc)-signaling cytokines in nephrotic syndrome (NS). NS results from the injury or loss of glomerular visceral epithelial cells (i.e., podocytes). Although the causes of podocyte dysfunction vary, it is clear that pro-inflammatory cytokines play a significant role in regulating the propagation, duration and severity of disease. Pro-inflammatory cytokines signaling through IL-1R and IL-Rγc have been shown to exert anti-apoptotic effects in podocytes through the phosphoinositol-3-kinase (PI-3K)/AKT pathway, highlighting the potential utility of IL-1R- and IL-Rγc-signaling interleukins for the treatment of podocytopathy in NS. The paradoxical role of interleukins as drivers and mitigators of podocyte injury is complex and ill-defined. Emerging evidence of the cytoprotective role of some interleukins in NS highlights the urgent need for a nuanced understanding of their pro-survival benefits and reveals their potential as podocyte-sparing therapeutics for NS.
2023-10-01 | Acthar® Gel Treatment for Patients with Autoimmune and Inflammatory Diseases: An Historical Perspective and Characterization of Clinical Evidence
Acthar® Gel (repository corticotropin injection) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that is believed to have both steroidogenic and nonsteroidogenic immunomodulatory effects via activation of melanocortin receptors in various cells throughout the body. Since 1952, Acthar has been approved by the US Food and Drug Administration to treat a variety of autoimmune and inflammatory diseases. Since 2014, Mallinckrodt Pharmaceuticals has conducted a large number of preclinical, clinical, and real-world-evidence studies of Acthar for the treatment of rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, multiple sclerosis relapse, ophthalmic disorders, sarcoidosis, and nephrotic syndrome. To date, Acthar has been the subject of more than 500 publications, many of which demonstrate the safety and efficacy of Acthar in patients with inflammatory diseases for whom standard treatments were ineffective or intolerable. Here, we review the history of Acthar and the findings of studies that have investigated the mechanism of action, safety, efficacy, and real-world effectiveness of Acthar for the treatment of inflammatory diseases. Acthar® Gel is an anti-inflammatory drug that directly affects the immune system in a manner that differs from other anti-inflammatory drugs, such as corticosteroids. Since 1952, Acthar has been approved by the U.S. Food and Drug Administration to treat a variety of diseases involving inflammation. The commercial rights to produce Acthar have changed hands several times over the years, beginning with Armour Pharmaceuticals and most recently ending with Mallinckrodt Pharmaceuticals in 2014. Since then, Mallinckrodt has conducted multiple studies in animals to demonstrate the function of Acthar compared with other anti-inflammatory drugs. Further, several clinical trials in humans and studies of hospital or clinical practice records have confirmed the safety and effectiveness of Acthar as a treatment for many inflammatory diseases.
2023-03-09 | Real-word adrenocorticotropic hormone treatment for childhood-onset nephrotic syndrome
Current first-line anti-proteinuric treatments do not produce a satisfactory therapeutic effect in a considerable number of patients with nephrotic syndrome (NS). Interest in adrenocorticotropic hormone (ACTH) for the treatment of NS has recently been revived. The present study investigated the efficacy and safety of ACTH treatment in children with frequent relapsing NS (FRNS), steroid-dependent NS (SDNS), and steroid-resistant NS (SRNS).The ACTH treatment group was comprised of NS patients receiving ACTH treatment. Patients with serum cortisol concentrations <85.3 nmol/L and who had not received ACTH treatment previously were enrolled in the control group from January 2018 to January 2021. The maintenance dose of prednisone, the number of disease recurrences, the time of first disease relapse, immunosuppressant use, serum cortisol levels, and adverse events were recorded in both groups.Fifty-one patients were included in the ACTH group, and twenty-one patients were enrolled in the control group. Concurrent treatment with one or more immunosuppressive and/or cytotoxic treatments occurred in 92.2% and 85.7% of patients in the ACTH and control groups, respectively, throughout the study period. A greater reduction in the prednisone maintenance dose was observed in the ACTH group compared with the control group after 1 year of follow up (0.603 ± 0.445 mg/kg vs. 0.267 ± 0.500 mg/kg, p = 0.006). During the one-year study period, fewer participants experienced one or more disease relapses in the ACTH group (45.1%) compared to the control group (76.2%, odds ratio = 3.896, p = 0.016). The number of disease recurrences per patient in the ACTH group was less than that in the control group (median difference = -1, p = 0.006). The mean length of remission was 8.902 m and 7.905 m in the ACTH group and control group, respectively. A log-rank test showed a longer relapse free survival for patients in the ACTH group (p = 0.046), but the Breslow test showed no significant difference between groups (p = 0.104). Ten patients in the ACTH group successfully discontinued all drug therapies. No patients in the control group were able to discontinue drug therapy as of February 2022.ACTH, combined with multiple drugs, is effective at reducing the prednisone maintenance dose and may effectively prevent disease relapses in childhood NS.
2021-10-15 | Consequences of insurance denials among U.S. patients prescribed repository corticotropin injection (Acthar Gel) for nephrotic syndrome.
Repository corticotropin injection (RCI; Acthar Gel) is indicated to induce a diuresis or a remission of proteinuria in nephrotic syndrome (NS) without uremia of the idiopathic type or that due to lupus erythematosus. This study compares patient characteristics and measurable healthcare resource utilization (HCRU) between NS patients who received a prescription for RCI and then were either approved or denied treatment by their insurers. A retrospective analysis of adults with NS from January 2015 to December 2018 was conducted using a de-identified open-source claims database. Patients were included in the study if they had ≥1diagnosis associated with NS, were age 18+, and had medical claims activity at some point in the year preceding ("baseline") and year following ("follow up") their first approved or denied RCI prescription. Baseline characteristics were reported with p-values indicating the significance of characteristics between cohorts. To assess outcomes, approved and denied patients were matched (1:1) using propensity-matching to account for underlying differences. Overall, 1,232 patients met inclusion criteria for the study. At baseline, approved patients were older than denied patients (mean age 53.9 vs. 48.4) and had higher rates of comorbidities. A greater proportion of approved patients required inpatient admissions (34.1 vs. 28.0%) and "high" doses of corticosteroids (CS) (26.2 vs. 20.7%) at baseline. Matched outcomes showed directionally more denied patients with inpatient admissions compared to approved (64 vs. 52) and a greater utilization of deep vein thrombosis ultrasound (12.2 vs. 6.6%) and dialysis (10.5 vs. 6.1%). Matched, denied patients had directionally greater CS use during follow-up both in the number of patients receiving CS (104 vs. 95) and the average annualized daily dose (4.1 vs. 3.4 mg). Patients denied access to RCI treatment had directionally higher HCRU compared to matched, approved counterparts. Thus, the results of this study may aid providers and payers in evaluating scenarios where RCI may be beneficial and improve quality of care for NS patients.
cell therapies
2026-07-03 | Cord blood-derived mesenchymal stromal cells in children with steroid-dependent nephrotic syndrome: a prospective phase II study.
Children with steroid-dependent nephrotic syndrome (SDNS) require long-term immunosuppressive (IS) treatment, significantly impacting their quality of life. Cord-blood-derived mesenchymal stromal cells (CB-MSCs) are multipotent stem cells with proven immunomodulatory properties. We conducted an adaptive, open-label, single-arm, phase II trial with an adaptive second part to evaluate the efficacy of CB-MSCs in children aged 3-18 years with SDNS in remission for ≥6 months on IS therapy. In Part 1, patients received three intravenous infusions of CB-MSCs (1.5 × 10⁶/kg) at 1-2-week intervals, with rapid IS tapering and discontinuation after the third infusion. The primary endpoint was relapse-free survival at 6 months post-IS withdrawal, with a threshold of <4/11 relapsing patients. In the adaptive Part 2, IS was discontinued before the first infusion to enhance CB-MSCs activity, and the dose was increased to 2 × 10⁶/kg, with a booster fourth infusion. A historical cohort of SDNS children tapering IS under standard care served as a post-hoc control. In Part 1, 9 patients were enrolled, and 7/9 (78%) relapsed, failing to meet the prespecified efficacy threshold. In Part 2, 11 patients were enrolled; 9 (82%) were in remission at 2 weeks post-third infusion and received the boosted dose. However, 6/11 (55%) relapsed within 6 months, with no significant difference in relapse-free survival compared to Part 1 (P = .25). Historical controls had significantly better relapse-free survival (P = .0007). In children with SDNS, this novel therapy with CB-MSCs was safe but failed to improve relapse-free survival 6 months after IS withdrawal.
2024-12-23 | Stem Cells Derived From Human Deciduous Exfoliated Teeth Ameliorate Adriamycin-induced Nephropathy In Rats By Modulating The Th17/Treg Balance.
Idiopathic Nephrotic Syndrome (INS) is a common kidney disease in children, and the main clinical manifestations are hypoproteinaemia, proteinuria, hyperlipidaemia, and oedema. Mesenchymal Stem Cells (MSCs) are involved in tissue repair, protection against fibrosis, and immune modulation but have rarely been studied in INS. This study aimed to explore the therapeutic potential of stem cells derived from human exfoliated deciduous teeth (SHEDs) in INS using an adriamycin-induced nephropathy (AN) rat model. AN was induced in Sprague‒Dawley rats, and SHEDs were transplanted via the tail vein in single (SHED-s) and multidose (SHED-m) regimens. Cell migration assays were used to track the SHED distribution. Weight, urine protein, and serum biochemical assays were also performed. HE and Masson staining were used to observe glomerular and tubular damage, as well as the degree of fibrosis. Immunohistochemistry was used to label T lymphocytes and podocytes, and structural changes in podocytes were observed by electron microscopy. ELISA was used to measure the levels of inflammatory factors. Flow cytometry was used to analyse the balance of Th17 cells and Tregs. The mRNA expression of Th17- and Treg-associated cytokines and specific transcription factors was examined by RT‒PCR. SHEDs directly migrated to damaged tissues, suggesting a targeted therapeutic effect. SHED transplantation significantly reduced proteinuria and reversed biochemical abnormalities in rats with AN. Both single and multidose SHED treatments could inhibit glomerular and tubular damage and delay the progression of fibrosis caused by adriamycin. SHEDs exerted a protective effect on podocytes. Additionally, this treatment inhibited inflammatory responses and corrected immune imbalances, as evidenced by decreased T lymphocyte infiltration, reduced serum levels of IL-6, TNF-a, and IL-1β, and modulation of the Th17/Treg balance. In the AN rat model, SHED partly suppressed the development of inflammation and alleviated kidney injury, and immune regulation may be the underlying mechanism.
2023-09-22 | A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome
BACKGROUNDSevere forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects.METHODSWe performed a phase I open-label trial assessing safety and feasibility of autologous bone marrow-derived MSCs (BM-MSCs) in children and young adults with severe forms of steroid-dependent nephrotic syndrome. Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy, and immunomodulatory effects in vivo were monitored for 12 months.RESULTSSixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (P = 0.02) and number of relapses was reduced (P = 0.002) after BM-MSC infusion, compared with the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared with baseline (P < 0.05). No treatment benefit was observed in adults.In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction in total CD19+, mature, and memory B cells and an increase in regulatory T cells in vivo up to 3-6 months following BM-MSC infusionCONCLUSIONTreatment with autologous BM-MSCs is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit.TRIAL REGISTRATIONEudraCT 2016-004804-77.FUNDINGAIFA Ricerca Indipendente 2016-02364623.
2022-08-23 | First clinical application of cord blood mesenchymal stromal cells in children with multi-drug resistant nephrotic syndrome.
Children with multi-drug resistant idiopathic nephrotic syndrome (MDR-INS) usually progress to end-stage kidney disease with a consistent risk of disease recurrence after transplantation. New therapeutic options are needed for these patients. Mesenchymal stromal cells (MSCs) are multipotential non-hematopoietic cells with several immunomodulatory properties and growing clinical applications. Cord blood-derived MSC have peculiar anti-inflammatory and immunosuppressive properties. We aimed at assessing safety and efficacy of cord-blood-derived MSCs (CB-MSCs) in children with MDR-INS. Prospective, open-label, single arm phase I-II pilot study. Pediatric patients with MDR-INS, resistant to at least two lines of therapy, were enrolled. Allogenic CB-MSCs were administered intravenously on days 0, 14, and 21 at a dose of 1.5 × 106 cells/kg. Patients were followed for at least 12 months. The primary outcomes were safety and toxicity. The secondary outcome was remission at 12 months evaluated by urinary protein/urinary creatinine ratio (uPr/uCr). Circulating regulatory T cells (Tregs) were monitored. Eleven pediatric patients with MDR-INS (10 females, median age 13 years) resistant to a median of 3 previous lines of therapy were enrolled. All patients completed the CB-MSC infusion schedule. No patient experienced any infusion-related adverse event or toxicity. Nine patients were assessable for efficacy. At the 12 months follow-up after the treatment, the median uPr/uCr did not change significantly from baseline (8.13 vs. 9.07; p = 0.98), while 3 patients were in partial or complete remission. A lower baseline uPr/uCr was a predictor of remission (2.55 vs. 8.74; p = 0.0238). Tregs count was not associated with CB-MSCs therapy. CB-MSCs are safe and may have a role in the immunosuppressive therapy of pediatric patients with MDR-INS. This preliminary experience paves the way toward further phase II studies addressing MSC efficacy in immune-mediated kidney diseases.
2020-11-25 | Novel Diagnostic and Therapeutic Techniques Reveal Changed Metabolic Profiles in Recurrent Focal Segmental Glomerulosclerosis
Abstract Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead early recurrence of FSGS and kidney failure after kidney transplantation. In the past three decades, many research endeavors were undertaken to identify these unknown factors. Even though some potential candidates have been recently discussed in the literature, “the” actual factor remains elusive. Therefore, there is an increased demand in FSGS research for the use of novel technologies that allow us to study FSGS from a yet unexplored angle. Here, we report the successful treatment of recurrent FSGS in a patient after living related kidney transplantation by removal of circulating factors with CytoSorb apheresis. Interestingly, the classical published circulating factors were all in normal range in this patient but early disease recurrence in the transplant kidney and immediate response to CytoSorb apheresis were still suggestive for pathogenic circulating factors. To proof the functional effects of the patient’s serum on podocytes and the glomerular filtration barrier we used a podocyte cell culture model and a proteinuria model in zebrafish to detect pathogenic effects on the podocytes actin cytoskeleton inducing a functional phenotype. We then performed Raman spectroscopy in the <50 kD serum fraction, on cultured podocytes treated with the FSGS serum and in kidney biopsies of the same patient at the time of transplantation and at the time of disease recurrence. The analysis revealed changes in podocyte metabolom induced by the FSGS serum as well as in focal glomerular and parietal epithelial cell regions in the FSGS biopsy. Several altered Raman spectra were identified in the fractionated serum and metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, which were supported by disturbances in the Raman spectra. Our novel innovative analysis reveals changed lipid metabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.
antibodies
2026-07-06 | Expression of PD-1 on T cells and its predictive value for steroid resistance in children with idiopathic nephrotic syndrome.
Programmed cell death protein 1 (PD-1) plays a pivotal role in regulating T-cell responses. Its expression profile and clinical significance in pediatric idiopathic nephrotic syndrome (INS), particularly in steroid-resistant nephrotic syndrome (SRNS), remain unclear. PD-1 expression on CD3⁺, CD4⁺, and CD8⁺T cells was quantified by flow cytometry in 65 treatment-naive children with idiopathic nephrotic syndrome (INS): steroid-sensitive (SSNS, n = 54), steroid-resistant (SRNS, n = 11), as well as in healthy controls (HC, n = 30). Group differences, clinical correlations and PD-1's predictive value for SRNS were analyzed. Circulating T subsets, including CD3⁺PD-1⁺ T cells, CD4⁺PD-1⁺T cells, and CD8⁺PD-1⁺T were detected with multiparameter flow cytometry. The percentage of CD4⁺PD-1⁺ T cells was significantly higher in SRNS (10.77 ± 4.62%) compared to both SSNS (5.14 ± 1.99%, P = 0.000) and HC (6.36 ± 2.02%, P = 0.028). CD3⁺PD-1⁺ T cells were also elevated in SRNS (8.13 ± 3.12%) versus SSNS (4.67 ± 1.82%, P = 0.001). No significant difference was found in CD8⁺PD-1⁺ T cells. Multivariate logistic regression identified an elevated percentage of CD4⁺PD-1⁺ T cells as an independent risk factor for SRNS (OR = 2.236, P = 0.002). Receiver operating characteristic (ROC) analysis showed that CD4⁺PD-1⁺ T cell cutoff > 7.385% predicted SRNS with an area under the curve (AUC) of 0.891, sensitivity of 81.8%, and specificity of 87.0%. Overexpression of PD-1, predominantly on CD4⁺ T cells, is associated with steroid resistance in pediatric INS. Elevated CD4⁺PD-1⁺ T cells may serve as a predictive biomarker for SRNS, offering a potential tool for early identification and a rationale for exploring PD-1 pathway modulation.
2026-04-01 | Rituximab in a desensitization protocol as a rescue therapy in severe nephrotic syndrome-a case report.
Idiopathic nephrotic syndrome is the most common glomerulopathy in children, and minimal change disease (MCD) is the most common histological pattern. First-line treatment involves glucocorticosteroids, but frequent relapses and steroid dependence may lead to steroid-related complications. Rituximab (RTX) is recommended in cases of lack of response or treatment side effects, reducing relapse rates and limiting the need for other medications. The mechanism of RTX involves B-cell depletion through various cytotoxic mechanisms. Its efficacy in nephrotic syndrome (NS) may stem from its influence on cytokines produced by B cells and a further effect on the podocyte cytoskeleton has been postulated. The present case describes a 19-year-old male with NS resulting from MCD, with a frequently relapsing, steroid-dependent, multidrug-resistant disease. He experienced a hypersensitivity reaction to RTX after the third dose, which contraindicated therapy continuation with traditional infusion. Due to the limited therapeutic options, a 12-step RTX desensitization protocol was adopted, allowing for safe administration of subsequent doses, achievement of remission, and gradual discontinuation of glucocorticosteroids.
2026-01-21 | A New Hope for Treating Podocytopathies: Emerging Role of Anti-Nephrin Antibody.
The etiology of primary podocytopathies including childhood nephrotic syndrome, minimal change disease, primary FSGS as well as recurrent FSGS had long remained elusive. The development of robust anti-nephrin autoantibody detection methods, the identification of these antibodies in idiopathic nephrotic syndrome, and the demonstration of their causal role in podocytopathy have led to a paradigm shift in our understanding of these diseases, offering new insights into pathophysiology and promising improved diagnostic, prognostic, and therapeutic approaches. Prognostication and risk stratification on the basis of anti-nephrin antibody detection as well as personalized therapeutic strategies including therapies targeting antibody-producing B cells or even antigen-specific depletion of autoreactive B cells could markedly improve treatment outcomes and patient quality of life in the future. In this review, we explore the prevalence of anti-nephrin antibodies in various glomerular diseases, current treatment options for primary podocytopathies, and how the emerging evidence of anti-nephrin antibody-mediated podocytopathy could influence future treatment approaches for affected patients.
2026-01-15 | Endothelial cell-released CD93 contributes to podocyte injury in idiopathic nephrotic syndrome.
Idiopathic nephrotic syndrome (INS) is a podocyte disease triggered by immune-derived factors. Endothelial activation occurs in this context, but whether the activated endothelium contributes to podocyte injury is unknown. We tested the hypothesis that CD93, a protein primarily expressed in the endothelium, is a contributory factor of podocyte injury. We studied 460 patients with INS and 150 with other podocytopathies. CD93 was analyzed in kidney tissue, urine, and serum samples. We tested the efficacy of CD93 blockade in vitro and in vivo and investigated the relationship between soluble CD93 and clinical outcomes in human INS. CD93 was highly expressed by glomerular endothelial cells (GEnCs) in human INS, and INS sera stimulated cultured human GEnCs to release CD93. Mechanistically, soluble CD93 mediated podocyte activation via β1 integrin/FAK signaling in cultured human podocytes. CD93 blockade mitigated the activation of cultured human podocytes and albumin permeability in human GEnC-podocyte cocultures as well as albuminuria, glomerulosclerosis, and podocyte loss in two models of nephrotic syndrome: podocyte-specific transforming growth factor-β1 signaling (PodTgfbr1) mice and adriamycin-treated mice. Cd93 knockout mice showed less proteinuria and glomerulosclerosis, compared with controls, after adriamycin injection. In patients with INS, soluble CD93 was high in urine in ~90% and 50% of patients in relapse and remission, respectively. High urinary CD93 was associated with faster decline in kidney function and slower response to immunosuppression. Soluble and glomerular CD93 was also elevated in other podocytopathies. We conclude that soluble CD93 contributes to podocyte injury.
2025-12-18 | Daratumumab combined with anti-CD20 therapy in pediatric and adult refractory idiopathic nephrotic syndrome: single-center experience.
Refractory idiopathic nephrotic syndrome (INS), in native kidneys or post-transplant, represents a major therapeutic challenge due to its high risk of progressing to end-stage renal disease. Patients often resist anti-CD20 therapy and require prolonged apheresis. Daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells, has demonstrated promising efficacy in case reports when combined with anti-CD20, but evidence remains limited. We conducted a single-center retrospective study including four patients (two pediatric, two adult, including one renal transplant) with INS refractory to conventional therapies (corticosteroids, calcineurin inhibitors, mycophenolate mofetil, anti-CD20 antibodies, and/or apheresis). All Patients received daratumumab combined with anti-CD20 therapy at University Hospital of La Réunion between 2022 and 2025. Clinical and laboratory data were extracted from medical records. Renal response was defined as complete remission (CR) or partial remission (PR). The mean patient age was 20 ± 13 years (range: 8-40), with a male-to-female ratio of 3:1. Median follow-up after daratumumab administration was 5 months (range: 2-12). All patients achieved CR with a median time to response of 25 days (range: 14-30). Previously apheresis-dependent patients were able to discontinue sessions. Two patients developed infections (herpetic and SARS-CoV-2 pneumonia complicated by pneumococcal bacteremia), all resolving favorably. Renal function remained stable. Combined daratumumab and anti-CD20 therapy appears to be an effective rescue strategy for refractory INS, in native kidneys and post-transplant. It induces rapid and sustained remission, enabling discontinuation of apheresis. Prospective studies are warranted to optimize treatment regimens and identify predictive biomarkers of response.
other
2025-05-22 | Association between SIRT-1 and SERPINA4 gene polymorphisms and the risk of idiopathic nephrotic syndrome among Egyptian children.
Idiopathic nephrotic syndrome (INS) is the primary cause of chronic glomerular dysfunction in children. Despite extensive research, its pathophysiology remains unclear, particularly in cases that are resistant to steroids. This research evaluated the impact of SIRT-1 (rs2273773) and SERPINA4 (rs2093266) gene variants on Egyptian children's susceptibility to INS and response to steroid therapy. Genetic polymorphisms of SIRT-1 (rs2273773) and SERPINA4 (rs2093266) were screened in 135 INS children and a similar number of healthy volunteers using real-time PCR. Concerning SIRT-1 rs2273773 genotypes, the cases showed markedly greater CT, TT genotypes, and T allele incidences than the reference group, which increased the risk of INS by 2.01-, 4.03-, and 1.88-folds, respectively. Regarding SERPINA4 rs2093266 genotypes, the cases exhibited notably higher GA, AA genotypes, and the A allele frequencies than controls, which enlarged the risk of INS by 3.1-, 5.47-, and 2.82-folds, respectively. The frequency of GA and AA genotypes and the presence of the A allele of SERPINA4 rs2093266 were considerably higher in steroid-resistant versus steroid-sensitive cases. The logistic regression model stated the serum creatinine, blood urea nitrogen, and the SERPINA4 rs2093266 polymorphism as independent contributors to the risk for steroid resistance in INS cases. SIRT-1 (rs2273773) and SERPINA4 (rs2093266) gene polymorphisms significantly attributed to the risk of developing INS in Egyptian children. Furthermore, the SERPINA4 (rs2093266) polymorphism has a strong correlation with steroid resistance, suggesting that it could be a target for treatment to avoid severe renal problems and adverse steroid effects.
2024-02-09 | Nephrotic Syndrome: A Review
Nephrotic syndrome (NS) is characterized by hypoalbuminemia, severe proteinuria, and peripheral edema, frequently in conjunction with hyperlipidemia. Individuals usually show symptoms of weariness and swelling, but no signs of serious liver damage or cardiac failure. With characteristic medical symptoms and evidence of hypoalbuminemia and severe proteinuria, NS can be diagnosed. The majority of NS episodes are classified as unexplained or primary; the most prevalent histopathological subgroups of primary NS in people are focal segmental glomerulosclerosis and membraneous nephropathy. Thrombosis of the veins with high cholesterol levels is a significant NS risk. Acute renal damage and infection are further possible side effects. The pathobiochemistry of NS involves alterations in genes that affect the selectivity of the kidneys and abnormalities in proteins related to podocytes. Understanding the molecular mechanisms that influence these processes is crucial to developing specific and targeted therapeutic approaches. The need for invasive renal biopsies throughout the diagnosis process may be lessened by the development of non-invasive nephrotic syndrome biomarkers, such as microRNAs. Corticosteroids are frequently used as the initial line of defense in NS treatment. However, some individuals need other treatments since a resistant type of NS also exists. The use of calcineurin inhibitors, mycophenolate mofetil, and rituximab is mentioned in the text, along with current research to identify safer and more efficient therapeutic choices. The complicated kidney condition NS has several underlying causes and symptoms. For the diagnosis of this ailment as well as the creation of focused therapies, an understanding of the pathophysiology and the identification of possible biomarkers are essential.
2022-05-09 | Human pluripotent stem cell-derived kidney organoids for personalized congenital and idiopathic nephrotic syndrome modeling.
Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo podocyte characteristics are a prerequisite to resolve NS pathogenesis. The detailed characterization of organoid podocytes resulting from a hybrid culture protocol showed a podocyte population that resembles adult podocytes and was superior compared with 2D counterparts, based on single-cell RNA sequencing, super-resolution imaging and electron microscopy. In this study, these next-generation podocytes in kidney organoids enabled personalized idiopathic nephrotic syndrome modeling, as shown by activated slit diaphragm signaling and podocyte injury following protamine sulfate, puromycin aminonucleoside treatment and exposure to NS plasma containing pathogenic permeability factors. Organoids cultured from cells of a patient with heterozygous NPHS2 mutations showed poor NPHS2 expression and aberrant NPHS1 localization, which was reversible after genetic correction. Repaired organoids displayed increased VEGFA pathway activity and transcription factor activity known to be essential for podocyte physiology, as shown by RNA sequencing. This study shows that organoids are the preferred model of choice to study idiopathic and congenital podocytopathies.
2022-01-31 | Influenza virus vaccination in pediatric nephrotic syndrome significantly reduces rate of relapse and influenza virus infection as assessed in a nationwide survey.
Although vaccination may precipitate relapses of nephrotic syndrome (NS) in children with idiopathic NS, no data are available regarding NS activity regarding influenza (flu) virus infections and NS relapses after receiving inactivated flu vaccines. We conducted a nationwide study of children aged 6 months to 15 years with idiopathic NS to assess the relationship between NS relapse, flu vaccination, and flu infections. We used a multivariate Poisson regression model (MPRM) to calculate the risk ratio (RR) for flu infection and for NS relapse in children with and without flu vaccination. Data of 306 children were assessed. The MPRM in all 306 children showed a significantly lower RR for flu infection (RR: 0.21, 95% confidence interval CI 0.11-0.38) and for NS relapse (RR: 0.22, 95% CI 0.14-0.35) in children receiving flu vaccination compared with unvaccinated children. In an additional MPRM only among 102 children receiving flu vaccination, they had a significantly lower risk for NS relapse during the post-vaccination period (RR: 0.31. 95% CI 017-0.56) compared with the pre-vaccination period. Although our study was observational, based on the favorable results of flu vaccinations regarding flu infections and NS relapse, the vaccine may be recommended for children with NS.
2022-01-31 | CMIP interacts with WT1 and targets it on the proteasome degradation pathway.
The Wilms tumor 1 suppressor gene, WT1, is expressed throughout life in podocytes and is essential for their function. Downregulation of WT1 has been reported in podocyte diseases but the underlying mechanisms remain unclear. Podocyte injury is the hallmark of idiopathic nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults. An increase in the abundance of Cmaf-inducing protein (CMIP) has been found to alter podocyte function, but it is not known whether CMIP affects WT1 expression. Transcriptional and post-transcriptional regulation of WT1in the presence of CMIP was studied using transient transfection, mouse models, and siRNA handling. We showed that overproduction of CMIP in the podocyte was consistently associated with a downregulation of WT1 according to two mechanisms. We found that CMIP prevented the NF-kB-mediated transcriptional activation of WT1. We demonstrated that CMIP interacts directly with WT1 through its leucine-rich repeat domain. Overexpression of CMIP in the M15 cell line induced a downregulation of WT1, which was prevented by lactacystin, a potent proteasome inhibitor. We showed that CMIP exhibits an E3 ligase activity and targets WT1 to proteasome degradation. Intravenous injection of Cmip-siRNA specifically prevented the repression of Wt1 in lipopolysaccharides-induced proteinuria in mice. These data suggest that CMIP is a repressor of WT1 and might be a critical player in the pathophysiology of some podocyte diseases. Because WT1 is required for podocyte integrity, CMIP could be considered a therapeutic target in podocyte diseases.
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Drug Discovery Landscape
2 orphan drug designations for Idiopathic steroid-sensitive nephrotic syndrome.
2 orphan drug designations for Idiopathic steroid-sensitive nephrotic syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
obinutuzumab | antibodies | FDA | 2021-11-22 | — | Genentech, Inc. |
Atrasentan | small molecules | FDA | 2016-09-29 | — | AbbVie Inc. |
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