Objective: To analyze the risk factors for poor prognosis in children with steroid-resistant nephrotic syndrome (SRNS) and to construct and validate a prognostic model. Methods: A retrospective cohort study was conducted. Clinical data of 456 children with SRNS who were initially diagnosed and hospitalized at the Children's Hospital of Chongqing Medical University from January 2009 to December 2024 was collected, including general information, laboratory and pathological indicators, gene types, treatment, and prognosis. Follow-up was conducted for more than 12 months. The endpoint event was defined as a decrease in the estimated glomerular filtration rate (eGFR) of more than 30% compared to the baseline for three consecutive times (with an interval of at least one month between each measurement). The patients were divided into the event group and the non-event group based on whether the endpoint event occurred. Independent sample t-test, Mann-Whitney U test, test χ2, or Fisher's exact probability test were used for comparison between groups. Multivariate Logistic regression was used to rank the importance of variables to screen for characteristic variables. The top 6 ranked characteristic variables were used to construct four machine learning models using Python: extreme gradient boosting, random forest, support vector machine, and logistic regression. The area under the receiver operating characteristic curve (AUC), accuracy, specificity, sensitivity, and F1 score were used to evaluate the discrimination and performance of the models. Calibration curves and clinical decision curves were drawn to assess the prediction accuracy and clinical net benefit of the models. The Shapley Additive Explanations (SHAP) method was applied to analyze the contribution of features. Results: Among the 456 children, 306 were male and 150 were female. The age of onset was 4.1 (2.3, 8.0) years, and the follow-up time was 2.2 (1.0, 4.0) years. There were 195 cases (42.7%) in the event group and 261 cases (57.3%) in the non-event group. The time of occurrence of the endpoint event in the event group was 1.0 (0.5, 2.5) years. Univariate analysis showed that there were statistically significant differences between the two groups in initial serum creatinine, initial eGFR, eGFR change rate after 3 months of treatment, gender, calcineurin inhibitor (CNI) treatment response, gene variation, white blood cell count, absolute monocyte count, blood urea nitrogen, and urine red blood cells (all P<0.05). The top 6 characteristic variables, including the eGFR change rate after 3 months of treatment, genetic variation, baseline eGFR, CNI treatment responsiveness, gender and baseline serum creatinine (the AUC decrease percentages of 20.1%, 9.4%, 1.6%, 1.0%, 0.3% and 0.1% respectively after permutation test). Among the four machine learning models, the random forest model performed the best (test set AUC was 0.77 (95%CI 0.73-0.81), accuracy 73.9%, specificity 78.5%, sensitivity 71.2%, and F1 score 68.9%). The Hosmer-Lemeshow test showed that the predicted risk and actual risk of the random forest model were in good agreement (χ2=7.72, P=0.461); the clinical decision curve showed that the random forest model performed best and had the highest net benefit within a certain threshold range (0-0.5). Through SHAP, it was determined that the eGFR change rate after 3 months of treatment, initial eGFR, gene variation, and CNI treatment response were important predictors of poor prognosis in SRNS (average SHAP absolute values were 0.18, 0.08, 0.07 and 0.02, respectively). Conclusions: A random forest model was constructed based on machine learning and explained using the SHAP method. The eGFR change rate after 3 months of treatment, initial eGFR, gene variation, and CNI treatment response are important factors affecting prognosis.

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

Serial thoracentesis is an established management strategy for hepatic hydrothorax (HH) patients who are intolerant to diuretics or not candidates for transjugular intrahepatic portosystemic shunt (TIPS) placement, but it carries a risk of complications. The role of indwelling pleural catheters (IPCs) in HH management remains controversial. This study aims to evaluate the safety and efficacy of IPCs compared with serial thoracentesis in patients with HH. We conducted a retrospective, propensity-matched cohort study using US population-based data, aged 18 to 89 years with HH secondary to cirrhosis of any etiology. Exclusion criteria included malignancy, congestive heart failure, nephrotic syndrome, chronic kidney disease, TIPS placement, or pleural effusions due to causes other than hepatic hydrothorax. Patients were stratified into 2 cohorts: (1) HH managed with IPCs placement and (2) HH managed with serial thoracentesis. After 1:1 propensity score matching, multivariate regression analysis was performed to evaluate primary and secondary outcomes over 18 months following the index intervention. All-cause mortality at 18 months was comparable between the IPCs and serial thoracentesis cohorts (odds ratio [OR]: 0.662, 95% CI: 0.434-1.108). However, patients in the serial thoracentesis group demonstrated higher odds of emergency room visits (OR: 2.273, 95% CI: 1.423-3.631), urgent care visits (OR: 1.581, 95% CI: 1.464-2.531), hepatic encephalopathy (OR: 2.351, 95% CI: 1.354-4.084), pneumonia (OR: 1.889, 95% CI: 1.075-3.320), liver transplantation (OR: 2.744, 95% CI: 1.276-5.897), and hypokalemia (OR: 2.028, 95% CI: 1.136-3.619) compared with the IPCs cohort. IPCs placement was associated with a lower risk of emergency room and urgent care visits, hepatic encephalopathy, pneumonia, hypokalemia, and reduced need for liver transplantation compared with serial thoracentesis in patients with HH.

Spatio-temporal analysis deciphers the energy metabolism disorders in depression based on stable isotope-resolved metabolomics.

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

Advances in antigen discovery and autoantibody profiling have reshaped the classification of autoimmune kidney diseases, moving beyond purely histologic definitions. The identification of podocyte-targeting autoantibodies has transformed the understanding of nephrotic syndrome, prompting renewed interest in autoimmune mechanisms underlying podocytopathies. Recent reports of nephrin autoantibodies in minimal change disease, the most common cause of nephrotic syndrome in children, suggested a potential antigen-defined subset, but findings have been inconsistent. In this issue of the JCI, Pecoraro and colleagues advance the field by systematically interrogating anti-nephrin antibodies across a diverse nephrotic syndrome cohort using human-based and orthogonal approaches. Their results highlight critical limitations in assay specificity and cohort heterogeneity while raising the question of the clinical utility of anti-nephrin antibodies in the care of patients with minimal change disease. More broadly, this study underscores the need for collaboration to establish standardized assays and rigorously phenotyped cohorts.

Emerging roles of S100 proteins in podocyte biology and disease: A mini review.

Navigating the methodological, ethical, and operational challenges of Trials within Cohorts (TwiCs): insights from a French pediatric research-based cohort.

Minimal change disease (MCD) is a common cause of nephrotic syndrome in adults, with limited evidence available on its treatment and prognosis. In this study, we retrospectively included the clinical characteristics and treatment results of adult MCD patients in our center and explored and analyzed potential risk factors for relapse in MCD patients. We included 51 adult MCD patients with a median age of 29 years, and 30 were men. Among them, 16 patients (31.37%) had acute kidney injury (AKI) at presentation. The average urinary protein excretion was 6.39 ± 5.54 g. Notably, 29 (59%) patients had hematuria; 16 (31.37%) patients developed AKI; and 25 patients (49.02%) experienced at least 1 relapse. 13 patients (25.49%) experienced 2 relapses, and 9 patients (17.65%) experienced 3 or more relapses during the observation period. Compared with non-relapse patients, relapse patients were younger (mean age, 18 years (18 - 32 years)), and fewer patients (n = 8, 32%) had positive urinary red blood cells. The time from treatment to remission and baseline albumin, renal function, urine protein quantification, and other laboratory indicators did not significantly differ between the two groups (all, p > 0.05). Single and multivariate logistic regression analysis revealed age of onset, drug-related adverse effects during treatment, and AKI as the risk factors for relapse. This study identified young age at onset, treatment-related adverse effects, and AKI as independent risk factors for relapse in adult-onset MCD patients. Rituximab may be an effective treatment for relapsed MCD patients.

The purpose of this study was to clarify the characteristics of newly diagnosed systemic lupus erythematosus (SLE) patients with or without kidney involvement in Japan. We used electronic data of SLE patients in the National Database of Designated Intractable Diseases of Japan who newly registered between 2015 and 2017. We analyzed patients within one year of disease onset. Kidney involvement was defined as any of the following: urinary protein ≥ 0.5g/day, granular casts, a clinical diagnosis of nephrotic syndrome, acute or chronic renal failure, or rapidly progressive glomerulonephritis, an estimated glomerular filtration rate (eGFR) < 60mL/min/1.73 m2, lupus nephritis confirmed by renal biopsy, or hemodialysis. Among 2315 SLE patients, 1088 (47.0%) had kidney involvement. Patients with kidney involvement more frequently exhibited symptoms such as pulmonary hemorrhage, pulmonary infarction and disturbance of consciousness, pericarditis, and hemolytic anemia whereas manifestations such as arthritis, aseptic meningitis, discoid rash, photosensitivity, and Raynaud's phenomenon were less common compared with those without kidney involvement. Anti-DNA antibody positivity was higher and complement levels (C3, C4, and CH50) were lower in patients with kidney involvement. In addition, concomitant glucocorticoid pulse therapy and immunosuppressive drugs were more frequently used in patients with kidney involvement. In this nationwide cohort, nearly half of newly diagnosed Japanese patients with SLE had kidney involvement and showed a distinct pattern of systemic manifestations, autoantibody profiles, and treatment intensity. These findings provide important insights into the epidemiology and pathophysiology of kidney involvement in SLE in Japan.

Purtscher-like retinopathy is a rare occlusive microvasculopathy that causes acute, painless visual loss and characteristic retinal lesions. Although typically trauma-related, it can occur in systemic conditions such as nephrotic syndrome (NS), driven by hypercoagulability, complement activation, and microembolization. We report a 3-year-old girl with steroid-resistant NS presenting with sudden vision loss, including inability to fixate and intermittent exotropia, without trauma or hypertension. Fundoscopy revealed bilateral peripapillary retinal whitening with periarteriolar sparing, cotton wool spots, and intraretinal hemorrhages. Laboratory tests showed hypoalbuminemia (1.7g/dL) and nephrotic-range proteinuria; kidney biopsy suggested podocytopathy. She was receiving prednisolone and cyclosporine (trough 84 ng/mL), which was discontinued due to concern for drug-induced vasculopathy. Treatment included intravenous methylprednisolone pulses followed by oral tapering. Whole-exome sequencing identified a de novo pathogenic WT1 variant (c.1447 + 5G > A), establishing a genetic etiology (NPHS4) for steroid-resistant nephrotic syndrome in this patient. At 6 months, visual acuity improved from light perception to counting fingers at a distance of 2m. This case highlights the need to consider Purtscher-like retinopathy in NS patients with acute vision loss, particularly in the context of steroid resistance or calcineurin inhibitor therapy. Prompt ophthalmologic evaluation and careful medication review are critical to prevent permanent visual impairment and to optimize recovery.

To assess the linear growth in patients with idiopathic nephrotic syndrome receiving corticosteroid therapy. Two hundred forty-five cases, aged 1-18 y of both gender [53 - first episode nephrotic syndrome (FENS), 50 - infrequent relapsing (IRNS), 68 - frequent relapsing (FRNS), 46 - steroid dependent (SDNS) and 28 - steroid resistant (SRNS)] were included. Height Z-score, cumulative dose of prednisolone and steroid-related side-effects were recorded. Median age at onset of disease was 3.8 y [interquartile range (IQR) 3-7] and median duration of follow-up was 4 mo (IQR 3, 10). Overall, 97 cases (39.5%) showed short stature (height Z-score <-2) after therapy; 27 had short stature before and 70 (28.5%) new cases (20 IRNS + 31 FRNS + 17 SDNS + 2 SRNS) developed after treatment. Median height Z-score showed significant reduction (-1.9 vs. -2.3, P <0.001) after therapy. Cumulative steroid dose (mg/m2) significantly decreased the height velocity in 50 cases (31 FRNS + 17 SDNS + 2 SRNS), who received steroid over prolonged period (r = -0.322, p = 0.023). Age at onset of disease (r = -0.328, p = 0.020) and duration of steroid therapy (r = -0.338, p = 0.016) significantly correlated with change in height Z-scores. Younger age of onset of disease and duration of steroid therapy had significant relationship with linear growth.

Rituximab is recommended as the first-line treatment for moderate- to high-risk primary membranous nephropathy (PMN). Obinutuzumab, a highly humanized anti-CD20 monoclonal antibody, has been shown to exhibit enhanced efficacy in laboratory studies. This study aimed to investigate the efficacy, side effects, and potential remission predictors of obinutuzumab in PMN treatment. This retrospective cohort study included PMN patients who presented with nephrotic syndrome and who were treated with obinutuzumab (1g on day 1 and day 28 in the majority of patients) between March 2022 and December 2023. Logistic regression, Kaplan-Meier curve analysis, and the log-rank test were used to assess treatment effectiveness and predictors of remission. Safety profiles were also recorded and analyzed. A total of 66 PMN patients, with a mean age of 50 ± 13 years, were enrolled, and 48 (72.7%) were male. The average follow-up duration was 18.1 ± 8.0 months. During the follow-up period, 60 patients (90.9%) achieved clinical remission, including 31 (47.0%) who achieved complete remission. The median time to the first recorded partial response (PR) was 4 (IQR 2 ~ 8) months. The anti-phospholipase A2 receptor antibody (aPLA2Rab) decrease rate during the first month of treatment was 88.3% (IQR 68.0%~95.7%). In total, 47/52 (90.4%) patients in the low aPLA2Rab group (aPLA2Rab < 150 RU/ml) and 13/14 (92.9%) in the high aPLA2Rab group (aPLA2Rab ≥ 150 RU/ml) achieved clinical remission. The remission rate of the low aPLA2Rab group did not significantly differ from that of the high aPLA2Rab group (HR = 1.656, 95% CI 0.895 ~ 3.065; P = 0.108). Decrease in aPLA2Rab at month-1 was associated with complete remission (OR = 1.033, 95% CI 1.003 ~ 1.063; P = 0.033) and had a predictive value for complete remission (AUC = 0.734, 95% CI 0.606 ~ 0.862; P = 0.002), and patients were more likely to achieve complete remission when the decrease rate exceeded 90.8%, with a sensitivity of 65.5% and a specificity of 75.8%. No serious adverse events were observed; the most common were mild infusion-related reactions (48.5%). Obinutuzumab rapidly and persistently reduces serum aPLA2Rab levels in PMN patients, leading to a favorable clinical remission rate. Decrease in aPLA2Rab at month-1 after treatment can predict clinical remission of PMN.

Idiopathic membranous nephropathy (IMN) is one of the main causes of adult nephrotic syndrome. A subset of untreated or inadequately treated patients eventually progress to end-stage renal disease (ESRD), posing a significant clinical challenge. Although the discovery of novel podocyte target antigens has deepened our understanding of IMN pathogenesis, the precise molecular mechanisms remain incompletely elucidated, and effective targeted therapies are still lacking. Animal models play an irreplaceable role in uncovering IMN pathogenesis and developing effective therapies. In recent years, with a deeper understanding of IMN, researchers have successfully established various animal models, including Heymann nephritis (HN), cationic bovine serum albumin (C-BSA), Aminopeptidase A (APA), thrombospondin type 1 domain-containing 7A (THSD7A)-related, and phospholipase A2 receptor (PLA2R)-related IMN models. These models have substantially advanced the simulation of pathological human IMN features. Notably, the development of human PLA2R1-related animal models marks a landmark breakthrough in this field, as these models are the first to recapitulate the immunopathological processes driven by a key human autoantigen in experimental animals. However, current animal models have their own limitations and still cannot fully replicate the complex pathological process of human IMN. This review summarizes recent progress in animal IMN models, analyzes their methods, pathological features, strengths, and limitations, and discusses future directions. Future model development should integrate advanced multi-omics and artificial intelligence (AI) to achieve greater accessibility and precision, enabling the construction of multidimensional models encompassing genetics, environment, and immunity, thereby enabling a leap from "disease simulation" to "personalized treatment".

Steroid-resistant nephrotic syndrome (SRNS) remains a major clinical challenge due to its heterogeneous etiologies and poor response to conventional immunosuppressive therapy. Anti-nephrin IgG has been associated with podocyte injury and proteinuria, suggesting a potential pathogenic role in SRNS. This case series was conducted to present real-world data on the evaluation of nephrin-IgG immunofluorescence colocalization in pediatric SRNS in a low-resource setting, and to examine whether this approach may inform treatment selection in routine clinical practice. We describe four pediatric patients with SRNS who underwent kidney biopsy following persistent proteinuria despite immunosuppressive therapy. Case 1showed severe hypoalbuminemia and anasarca with preserved renal function after full dose steroid;Case 2remained edematous with nephrotic range proteinuria after seven cycle of cyclophosphamide;Case 3progressed to chronic kidney disease despite cyclophosphamide and mycophenolate mofetil;Case 4 had normal kidney function and no edema, despite steroid resistant. Nephrin-IgG co-localization was observed in all cases. Clinical outcomes were heterogeneous, and assessment of treatment response was limited by resource constraints and loss to follow-up. These findings are exploratory in nature and suggest the potential applicability of nephrin-IgG co-localization in a low-resource setting, warranting further investigation.

The need for kidney biopsy in suspected primary membranous nephropathy with typical clinical presentation and positive anti-PLA2R antibodies.

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

Abstract Nephrotic syndrome (NS) is a major cause of end-stage renal disease. Treating NS relies on immunosuppressants, which have numerous side effects. Therefore, there is an urgent need to identify effective and safe alternative treatments for NS. Angiopoietin-like protein 3 (ANGPTL3) exacerbates proteinuria, whereas interleukin (IL)-22 has a reparative effect on renal cells. In the present study, we developed a bifunctional anti-ANGPTL3/IL22 fusion protein and validated its efficacy in an adriamycin-induced nephropathy in mice. The fusion protein significantly decreased the urinary albumin-to-creatinine ratio, serum creatinine, blood urea nitrogen, and total cholesterol levels while increasing serum albumin levels. Pathological renal damage was also alleviated. These therapeutic effects were accompanied by the preservation of mitochondrial integrity, reduced apoptosis, and inhibited autophagy. Finally,We humanized the fusion protein to facilitate its potential clinical translation. In conclusion, our results revealed that the anti-ANGPTL3/IL22 bifunctional fusion protein ameliorates NS by protecting mitochondria, inhibiting apoptosis and suppressing autophagy, highlighting a novel therapeutic approach for NS.

To evaluate the efficacy and safety of rituximab (RTX) in children with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS) after treatment with prednisone combined with standard doses of mycophenolate mofetil and a calcineurin inhibitor. A retrospective analysis was conducted on clinical data from pediatric patients admitted to the Department of Pediatric Nephrology, Peking University First Hospital from January 1, 2014 to December 31, 2023. These patients had received prednisone plus standard doses of mycophenolate mofetil and a calcineurin inhibitor but still presented with FRNS or SDNS. Outcomes included remission rate, relapse rate, reduction or discontinuation of steroids and oral immunosuppressants after RTX treatment, and adverse events following RTX. Eighteen patients were enrolled, receiving 63 courses of RTX treatment. None presented with FRNS or SDNS after RTX treatment. Among them, 11 patients experienced no relapse from the first RTX dose to the last follow-up. After RTX administration, the duration of use of all immunosuppressants and the relapse frequency were significantly reduced (P<0.05). Most RTX-related adverse events were mild. RTX demonstrates good efficacy and safety in children with FRNS or SDNS after treatment with three immunosuppressive agents.

Sphingosine-1-phosphate lyase (SPL) insufficiency syndrome (SPLIS), also known as nephrotic syndrome type 14, is an autosomal recessive multisystem disorder caused by loss-of-function mutations in SGPL1, encoding the enzyme responsible for the terminal degradation of sphingosine-1-phosphate (S1P). We investigated a patient carrying a previously undescribed c.1084T>A (p.Ser362Thr) SGPL1 variant and analyzed the metabolic and cellular consequences of SPL deficiency, using patient fibroblasts, SGPL1-KO HEK293T cells, and Sgpl1–/– and Sgpl1rosa+fl/fl mice. Metabolic stable isotope labeling revealed that SPL deficiency does not invariably result in S1P accumulation. Instead, SPL-deficient cells maintain near-normal S1P levels through (a) feedback regulation of de novo sphingolipid synthesis via the ORMDL–ceramide axis and (b) increased diversion of excess ceramides into glycosphingolipids. However, perturbation of sphingolipid homeostasis, either by exogenous sphingolipid load or disruption of compensatory regulation, induces pathological intracellular S1P accumulation. In vivo, Sgpl1–/– mice had pronounced urinary S1P excretion and renal S1P enrichment, accompanied by cytoskeletal disorganization and impaired epithelial morphogenesis. Mechanistically, we identify aberrant Rho/ROCK signaling as a key mediator of S1P-driven cytoskeletal dysregulation. Pharmacological ROCK inhibition with fasudil mitigated renal cytoskeletal defects in Sgpl1–/– and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture. These findings redefine the metabolic consequences of SPL deficiency and identify S1P-driven Rho/ROCK hyperactivation as a tractable therapeutic target in SPLIS.