Focal segmental glomerulosclerosis (FSGS) is a progressive glomerular disease characterized by podocyte injury, proteinuria, and risk of kidney failure. Until recently, no medicines had been approved by the FDA or European Medicines Agency, with management focused on supportive care and proteinuria reduction. This supplement explores the burden of FSGS from a clinical, humanistic, and economic perspective, informed by the results of 3 systematic literature reviews. FSGS is associated with poorer quality of life and high health care costs, and these outcomes are correlated with disease severity. Kidney Disease: Improving Global Outcomes guidelines recommend monitoring estimated glomerular filtration rate (eGFR) for kidney function; however, it is acknowledged that given the variable decline in FSGS, eGFR is not an ideal trial end point. Consequently, proteinuria reduction has become the preferred surrogate efficacy end point, as supported by the International Society of Glomerular Disease's global Proteinuria and Other Biomarkers as Endpoints for Clinical Trials in Kidney Disease initiative and subsequent FDA endorsement. Available treatments, such as glucocorticoids or calcineurin inhibitors, are limited in efficacy and safety. Among emerging medicines, sparsentan, a dual endothelin and angiotensin receptor antagonist (DEARA), has demonstrated consistent and significant reductions in proteinuria among patients with primary and genetic FSGS resulting in its approval by the FDA to reduce proteinuria in adult and pediatric patients aged 8 years and older with FSGS without nephrotic syndrome. In the phase 2 DUET clinical trial (NCT01613118), those treated with sparsentan showed a urine protein-creatinine ratio reduction of -35.6% (95% CI, -46.3% to -24.6%) vs baseline at 240 weeks. Sparsentan also showed greater reductions in proteinuria vs irbesartan, a standard renin-angiotensin system agent, along with a comparable safety profile in the phase 3 DUPLEX trial (NCT03493685). In model-based projections among real-world registry cohorts, sustained reductions in proteinuria are associated with lower long-term risk of kidney failure. These findings align with the PARASOL-FSGS initiative, supporting the role of proteinuria reduction as a key end point, facilitating pragmatic trial designs to address the persistent treatment gap in FSGS.

Background Recurrence of focal segmental glomerulosclerosis (rFSGS) remains a major complication and a challenge to study treatment efficacy due to lack of granular data in a sufficient sample size. Aggregated data from electronic health records can provide such data. Methods We applied computational phenotypes to data from 11 large pediatric health systems in the USA, to identify treatments used and remission outcomes in children with rFSGS after renal transplantation. Additional data were collected by chart review. We performed both linear and non-linear multivariable Cox regression analyses with penalized splines to allow for time-varying predictors. Based on effect sizes from the hazard ratios, we then calculated a sample size needed for a future randomized clinical trial. Results Plasmapheresis was used in 101/107 (94%) patients, followed by anti-CD20 agents in 84 (78%), Low-Density-Lipoprotein (LDL)-apheresis in 22 (20%) and CTLA4Igs in 8 (7%). In linear multivariable models, complete remission was associated with more plasmapheresis sessions. In non-linear models, more doses or sessions of all the above treatments were associated with complete remission or any remission (partial or complete). Penalized spline curves for complete or any remission showed greatest yield within 5 doses of anti-CD20 agents but increasing yield with more doses/sessions of CTLA4Igs or LDL-apheresis. Based on observed hazard ratios, a prospective randomized trial of plasmapheresis vs LDL-apheresis would require 155 participants to have 80% power. Conclusions Increased doses/sessions or additional therapies for rFSGS associated with more favorable outcomes. Non-linear modelling identified when further increases did not improve outcomes.

The mechanisms leading to the formation of sclerotic lesions in focal segmental glomerulosclerosis (FSGS) remain incompletely understood; however, podocyte detachment and loss are considered key pathogenic events. Ubiquitin-specific protease 40 (USP40) is a deubiquitylating enzyme expressed in podocytes. In the present study, we investigated the role of USP40 in podocytes, focusing on its impact on the adhesion molecule integrin β1, which is essential for anchoring podocytes to the glomerular basement membrane. When USP40 knockout mice were subjected to an experimental FSGS model, they exhibited significantly more severe proteinuria and glomerulosclerosis than control mice, along with a marked reduction in podocyte number and integrin β1 expression. Consistently, knockdown of USP40 in cultured podocytes resulted in decreased integrin β1 expression and impaired adhesive properties compared with sham-treated cells. In HEK293 cells transfected with ubiquitin constructs, USP40 suppressed integrin β1 monoubiquitylation. In a separate internalization assay, USP40 prevented the clathrin-mediated endocytosis of integrin β1. In USP40 knockout mice, clathrin-coated vesicles colocalizing with integrin β1 were more frequently observed in podocyte foot processes than in control mice. Together, these findings suggest that USP40 functions as a deubiquitylating enzyme that stabilizes integrin β1 at the podocyte plasma membrane by preventing its endocytosis. We therefore propose that the USP40-integrin β1 axis represents a potential therapeutic target for FSGS.

Podocyte injury is a characteristic feature of focal segmental glomerulosclerosis (FSGS) that leads to the development of nephrosis as its loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium levels; an excess or shortage of calcium influx in these cells may result in foot process effacement, apoptosis, and nephron degeneration. A key protein responsible for the regulation of calcium flux is the canonical transient receptor potential 6 (TRPC6) expressed in podocytes. Several mutations in the TRPC6 gene have been associated with FSGS. Here we present a systematically optimized inducible FSGS model system in human induced pluripotent stem cells (hiPSCs). We generated and phenotypically characterized three transgenic hiPSC lines with regulatable overexpression of TRPC6 wild-type and FSGS-associated gain-of-function (GoF, P112Q) and loss-of-function (LoF, G757D) mutations. Moreover, these cell lines were differentiated into induced podocytes (ipodocytes). We assessed the impact of TRPC6 GoF and LoF mutants on calcium influx in combination with TRPC6 agonists and antagonists. Our data showed relative calcium responses consistent with the GoF and LoF phenotypes. Transgenic iPSC-based models, like the one presented here, are instrumental to studying disease mechanisms in vitro and investigating the outcomes of, and possible therapeutic interventions for, this complex disease.

This case highlights the importance of considering primary glomerular diseases in the differential diagnosis of nephrotic-range proteinuria during pregnancy, particularly when clinical features are atypical for Preeclampsia. The use of angiogenic biomarkers, such as the sFlt-1/PlGF ratio, proved valuable for excluding Preeclampsia and guiding further diagnostic evaluation.

Background and aims The incidence and prevalence of acute kidney disease (AKD), including acute kidney injury (AKI) and proteinuria, are increased in cancer patients. This study aimed to investigate the variety of renal histopathological lesions in cancer patients and their associations with systemic anticancer therapies (SACT) before and after 2017, the year when new SACTs like immune checkpoint inhibitors and target therapies were generally introduced, as well as the role of kidney biopsy (KB) in guiding treatment decisions. Material and methods This retrospective cohort study included adult cancer patients who underwent kidney biopsy for AKD at a single center over a 14-year period. Clinical, laboratory, and renal histopathological data were collected, and therapeutic options were evaluated. The study cohort was stratified into three groups - (i) SACT-related AKD, (ii) cancer-related AKD, and (iii) non-SACT/non-cancer-related AKD - based on clinical judgment by the treating nephrologist, allowing detailed characterization of AKD patterns. Results Fifty-five patients (61.8% men; mean age 64.7±9.9 years) were included. At diagnosis, median serum creatinine was 2.2 mg/dl (interquartile range (IQR) 1.6-4) and proteinuria 1.3 g/24h (IQR 0.25-4). Most patients (63.6%) were receiving SACT. Glomerulopathies were the most frequent lesions (43.6%), with focal segmental glomerulosclerosis (FSGS) predominating (29%). Acute interstitial nephritis (AIN), acute tubular injury (ATI), and mixed AIN/ATI were identified in 21.8%, 12.7%, and 9.1% of cases, respectively, while renal tumor infiltration occurred in 7.3%. AKD was attributed to SACT in 41.8%, most commonly immunotherapy (52.2%), and AIN was the prevailing lesion (82.6%). A significant shift in histopathological patterns was observed after 2017 (p=0.006), with higher frequencies of glomerulonephritis (51.3% vs. 25%) and acute tubulointerstitial nephritis (25.6% vs. 12.5%). Among patients receiving targeted treatment based on KB findings, including corticosteroid therapy, all experienced favorable renal outcomes. Conclusions This study highlights the expanding spectrum of kidney injury in cancer patients, the influence of modern SACT on renal pathology, and the critical role of kidney biopsy in guiding individualized management strategies.

Introduction. End-stage renal disease exhibits a disproportionate prevalence among Black individuals and older adults within the United States and worldwide. A significant genetic contributor to this disparity is the Apolipoprotein L1 (APOL1) gene, found exclusively in populations of African ancestry. Materials and Method. We aim to perform a narrative review regarding the current understanding of APOL1 and its complex role in kidney disease pathogenesis. Results. The G1 and G2 APOL1 risk alleles are strongly associated with an elevated risk for non-diabetic chronic kidney disease (CKD), including hypertensive nephropathy, focal segmental glomerulosclerosis, and HIV-associated nephropathy, in individuals who are homozygous or compound heterozygous for these variants. While 10-15% of African Americans carry two APOL1 risk alleles, approximately 80% remain disease-free, suggesting incomplete penetrance and the involvement of additional risk factors. In this condition, renal damage could be induced through different mechanisms such as altered cellular ion transport, mitochondrial dysfunction, and the requirement for additional stressors or "second hits". Conclusion. The increased susceptibility to end-stage renal disease (ESRD) in individuals of African ancestry is influenced by variations in the APOL1 gene.

Townes-Brocks syndrome (TBS) is an autosomal dominant hereditary disorder caused by SALL1 variants, characterized by auricular malformations, anal anomalies, and limb deformities, often accompanied by kidney dysfunction. We describe a case of TBS, which was suspected after birth, in a 27-year-old man presenting with progressive kidney dysfunction and obesity. At age 16, school urinalysis revealed proteinuria and impaired kidney function. A kidney biopsy at that time showed a perihilar variant focal segmental glomerulosclerosis (FSGS) lesion, and the patient was treated with angiotensin II receptor blocker and sodium/glucose cotransporter 2 inhibitor. Kidney function gradually declined, prompting a second biopsy at age 27, which revealed progressive FSGS lesions and interstitial fibrosis/tubular atrophy. Genetic analysis identified a pathogenic SALL1 variant, confirming the diagnosis. This case demonstrates the mechanistic link between SALL1 variants, congenital renal hypoplasia, impaired podocyte repair, and obesity-related hyperfiltration, culminating in rapid development of FSGS. Longitudinal histopathological analysis through repeated biopsy was essential for understanding this progression. The integration of sequential renal biopsies and genetic analysis provided unique pathophysiological insight and diagnostic clarity in TBS-associated kidney disease. In patients with TBS and congenital nephron reduction, weight control is particularly important to mitigate obesity-related hyperfiltration injury.