Genetic Focal Segmental Glomerulosclerosis Research Articles

Ex Vivo-Derived Human-Induced Pluripotent Stem Cell (hiPSC) Podocytes from a Patient with Genetic Focal Segmental Glomerulosclerosis with an INF2 Mutation

Ex Vivo-Derived Human-Induced Pluripotent Stem Cell (hiPSC) Podocytes from a Patient with Genetic Focal Segmental Glomerulosclerosis with an INF2 Mutation

Outcomes of the DUPLEX Trial in Patients with Genetic Focal Segmental Glomerulosclerosis (gFSGS)

Outcomes of the DUPLEX Trial in Patients with Genetic Focal Segmental Glomerulosclerosis (gFSGS)

#1442 Retrospective evaluation of etiology, clinical and laboratory findings in patients diagnosed with secondary and genetic FSGS

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a glomerulonephritis characterized by segmental sclerosis in at least one of the glomeruli and may develop due to primary, secondary, genetic etiology. We compared clinical, histopathological, and laboratory findings, treatment options, and response to treatment in patients with secondary and genetic FSGS. Method This study analyzed 172 patients with secondary and genetic FSGS at our Glomerular Diseases Clinic (1987-2022). Criteria included at least 16 weeks of follow-up, absence of other primary glomerular diseases, and age over 18. Retrospective data were collected on demographics, diagnosis, renal biopsies, genetic tests, imaging, treatments, treatment responses, end-stage renal disease (ESRD) development, and transplantation. The focus was on predicting genetic FSGS and ESRD. Results 103 of our patients were female (59.8%), and the mean age at diagnosis was 38.46 ± 13.75 years. Of these patients, 29 were diagnosed with genetic FSGS and 141 with non-genetic secondary FSGS. Forty-one patients with non-genetic secondary FSGS were obese, and 21 had a single kidney. The patients had a median follow-up of 78 (38-134) months. 28 patients developed ESRD during follow-up, 16 of whom underwent renal transplantation. Familial renal disease (p < 0.001), familial ESRD (p < 0.001), and hematuria at diagnosis (p = 0.005) were more common in patients with genetic FSGS. Comparison of genetic FSGS and non-genetic secondary FSGS patients shown in Figure 1. The number of glomeruli with global sclerosis (p = 0.006) and C3 accumulation (p = 0.048) on renal biopsy was more frequent in patients with ESRD. Comparison of ESRD and non-ESRD patients are shown in Figure 2. Conclusion Differentiating genetic and non-genetic secondary FSGS is vital in clinical practice. For those with a family history of renal disease, hematuria, or unresponsive to immunosuppressive therapy, consider genetic FSGS and request genetic testing. Patients with secondary FSGS, diagnosed with high creatinine, a substantial presence of sclerosing glomeruli on biopsy, and C3 accumulation, should be closely monitored for ESRD.

#1389 Identification of serum lipidomic profile in nephrotic syndrome patients

Abstract Background and Aims Nephrotic syndrome describes a collection of symptoms, mainly heavy proteinuria leading to kidney function loss, that can be caused by different underlying kidney diseases. Common primary causes of nephrotic syndrome include focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD) and membranous nephropathy (MN). Nephrotic syndrome is often characterized by plasma lipid abnormalities with elevations in cholesterol, triglycerides and lipoproteins. Here we set out to generate a detailed lipidomic analysis of FSGS, MCD and MN patient's plasma to find lipid changes common to nephrotic syndrome or specific for the underlying disease. Method For this lipidomic study, we included patients with primary FSGS (2 cohorts with n = 5), genetic FSGS (n = 5), MCD (n = 5) and MN (n = 5) in whom serum had been collected at the time they presented at our center with active nephrotic syndrome. We compared the serum lipidome of nephrotic syndrome patients with age matched healthy controls (n = 5), and with age matched patients with familial hypercholesterolemia (n = 5) who, like patients with nephrotic syndrome, have significantly elevated lipid values. Serum was analyzed using the Shotgun Lipidomics platform by Lipotype GmbH (Dresden, Germany), as previously described [1]. Results The lipidomic profile of patients with nephrotic syndrome was markedly different compared to control groups (Fig. 1A). In particular, lower levels of lyso-phophatidylcholine (LPC) and higher concentrations of phosphatidylethanolamine (PE) and lyso-PE (LPE) compared to control groups were most prominent (Fig. 1B). Subspecies analysis identified LPC 16:0;0 to be highly downregulated in patients with nephrotic syndrome (Fig. 2A), whereas LPE 18:0;0 and nearly all PE subspecies were increased compared to control groups (Fig. 2B and C). The lipidomic profile was largely comparable between different underlying diseases and we could not identify lipid classes specifically different for certain diseases. Conclusion Our lipidomic data show that patients with nephrotic syndrome have a distinct lipid profile compared to healthy controls or other disease controls. We identified LPCs, PEs and LPEs to be changed in nephrotic syndrome. We could not identify lipids specific for certain diseases underlying nephrotic syndrome, but rather identified a general nephrotic syndrome lipid profile. This suggests that lipid changes are rather a consequence of disease manifestation in these patients with various underlying causes. Further research should focus on confirming this lipid profile in larger cohorts and unraveling the mechanisms leading to the observed lipid changes.

#1166 ACTION3 pivotal Phase 3 & open-label extension study assessing DMX-200 in adult & paediatric patients with focal segmental glomerulosclerosis (FSGS)

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a major cause of glomerular disease that affects both adults and children. FSGS can rapidly progress to end-stage kidney disease. Lack of safe and effective treatment represents a significant unmet need for patients with FSGS. Development of treatments has been hampered by complexities including the rare nature of the disease, varying drivers of pathogenesis, and the evolving diagnostic and clinical trial designs, necessitating innovative research approaches. DMX-200 (repagermanium) is a C-C motif chemokine receptor 2 (CCR2) pathway inhibitor. Activation of the angiotensin II type 1 receptor (AT1R) and CCR2 have been independently implicated in the pathogenesis and progression of FSGS. These receptors form a functional complex so inhibition of both receptors may provide an efficient approach to FSGS treatment. In vivo data shows co-administration of DMX-200 and the angiotensin receptor blocker (ARB) irbesartan demonstrated a synergistic reduction in proteinuria, macrophage infiltration, and podocyte loss compared with vehicle or either antagonist alone. A subsequent Phase 2a cross-over study (NCT03649152) in N = 8 patients with biopsy-proven primary FSGS showed that the combination of DMX-200 and irbesartan (compared to placebo) was well tolerated with most patients experiencing a reduction in proteinuria. Based on these data, the global Phase 3 study (ACTION3) was initiated to confirm the proteinuria lowering effects of DMX-200 and assess effects on eGFR decline. ACTION3 is a randomised, placebo-controlled, double-blind, long-duration study of FSGS patients and on completion will provide a resource for the wider nephrology community and advocacy groups on the natural history of FSGS patients and the effects of a CCR2-inhibitor on the background of an ARB. Here we present the baseline data from the first 90 patients enrolled in ACTION3 at 12th January 2024. Method The ACTION3 (NCT05183646) study is a pivotal Phase 3, multicentre study of the efficacy and safety of DMX-200, 120 mg twice daily compared with placebo in adult patients with biopsy-proven FSGS receiving maximal tolerated ARB, with persistent proteinuria >1.5g/ day and eGFR >25 ml/min/1.73 m2. The study plans to enroll approximately 286 patients with primary FSGS, genetic FSGS and FSGS of undetermined cause with the primary objective of evaluating the efficacy of DMX-200 in percent change in 24-hour urine PCR and eGFR slope. The initial 104-week randomized period will be extended in a 2-year open label extension study. A futility analysis by an Independent Data Monitoring Committee following the first 72 patients completing 35 weeks of treatment confirm that continuation of the study is non-futile. Results The study is actively recruiting at 71 sites in 11 countries listed in Table 1. Demographic data of randomised patients is listed in Table 2. Patients are predominantly male (65%), with an average age of 46.6 yrs. and mean eGFR 56.3 ± 27.6 (ml/min/1.73 m2). The study is expanding recruitment into additional countries in the Asia Pacific, Europe, and Latin American regions. Further, the study protocol has sought and received regulatory approval to enroll adolescent patients aged 12-18 in Argentina, Mexico, UK and the US. Conclusion DMX-200 (repagermanium) has shown encouraging signs of safety and efficacy in combination with an ARB for the treatment of FSGS. The contributing countries and baseline characteristics of the patients enrolled in ACTION3 are similar to the populations studied in other recent FSGS trials. No clinically significant safety concerns have been observed in patients enrolled to date in the ACTION3 Phase 3 study.

A Review of Focal Segmental Glomerulosclerosis Classification With a Focus on Genetic Associations

Focal segmental glomerulosclerosis (FSGS) defines a distinct histological pattern observed in kidney tissue, that is linked to several distinct underlying causes, all converging on the common factor of podocyte injury. It presents a considerable challenge in terms of classification due to its varied underlying causes and the limited correlation between histopathology and clinical outcomes. Critically, precise nomenclature is key to describe and delineate the pathogenesis, subsequently guiding the selection of suitable and precision therapies. A proposed pathomechanism-based approach has been suggested for FSGS classification. This approach differentiates between primary, secondary, genetic, and undetermined causes, aiming to provide clarity. Genetic FSGS from monogenic mutations can emerge during childhood or adulthood, and it is advisable to conduct genetic testing in cases where there is a family history of chronic kidney disease, nephrotic syndrome, or resistance to treatment. Genome-wide association studies have identified several genetic risk variants, such as in apolipoprotein L1 (APOL1), which play a role in the development of FSGS. Currently, no specific treatments have been approved to treat genetic FSGS; however, interventions targeting underlying cofactor deficiencies have shown potential in some cases. Furthermore, encouraging results have emerged from a phase 2 trial investigating inaxaplin, a novel small molecule APOL1 channel inhibitor, in APOL1-associated FSGS.

Immediate Recurrence of Genetic Focal Segmental Glomerulosclerosis PostKidney Transplant

Recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation is a serious concern with poor allograft outcomes. Possible circulating permeability factors are postulated as pathogenetic factors leading to recurrence. Genetic FSGS is said to have a negligible risk of posttransplant recurrence. Here, we describe an unfortunate patient of genetic FSGS (pathogenic genetic variant) who had a recurrence within hours after transplant and presented with a sudden onset of anuria. The patient did not respond to plasma exchange and subsequently underwent allograft nephrectomy.

Clinicopathological Outcomes in Focal Segmental Glomerulosclerosis: A Retrospective Cohort Study

Introduction: Focal Segmental Glomerulosclerosis (FSGS) is a nephrotic syndrome with a variety of clinicopathological presentations and varied responses to treatment. Hence, this study attempts to classify FSGS based on clinical presentation and pathological findings on kidney biopsy, which is essential for appropriate treatment and avoidance of inappropriate use of immunosuppressants. Aim: To analyse clinicopathological findings and responses to immunosuppressants in FSGS. Materials and Methods: A retrospective cohort study was conducted at Department of Nephrology, Vydehi Institute of Medical Sciences and Research Centre Bengaluru, Karnataka, India, to analyse clinicopathological parameters such as urine analysis, 24-hour urine protein, serum creatinine, serum albumin, lipid profile, renal biopsy details, and response to treatment in 97 patients. The study was planned, analysed, and executed between January 2023 and February 2023. All variables were expressed as mean±standard deviation or percentage. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) software version 16.0. Results: Among a total of 97 patients, 64% were males. Sudden onset oedema was observed in 90% of the cases, while nephrotic proteinuria was seen in 71%. The Not Otherwise Specified (NOS) variant was noted in 60% of the cases. Complete remission was observed in 61%, suggesting a possible primary FSGS. Persistent nephrotic proteinuria with a poor response to therapy was noted in 32%, indicating a possible secondary/genetic FSGS, despite adequate immunosuppressive therapy. Therefore, differentiating between primary and secondary forms of FSGS has therapeutic and prognostic implications. Accurate diagnosis of each form of FSGS is vital to avoid unnecessary immunosuppressive-based therapy and establish appropriate treatment. Conclusion: Resistance to steroid therapy was observed in one-third of FSGS patients. It is likely that unrecognised genetic FSGS or secondary FSGS were included among the study group of primary FSGS, leading to misinterpretation of treatment responses in primary FSGS. Hence, a clinicopathological approach for correctly differentiating between primary FSGS, secondary (maladaptive, viral, or toxic) FSGS, and genetic FSGS helps in making correct treatment decisions.

The most common founder pathogenic variant c.868G > A (p.Val290Met) in the NPHS2 gene in a representative adult Czech cohort with focal segmental glomerulosclerosis is associated with a milder disease and its underdiagnosis in childhood.

Genetic focal segmental glomerulosclerosis (FSGS) is caused by pathogenic variants in a broad spectrum of genes that have a variable representation based on subjects' ethnicity and/or age. The most frequently mutated autosomal recessive gene in FSGS is NPHS2. In this study, we analyzed the spectrum of NPHS2 variants and their associated phenotype in Czech adult FSGS patients. A representative cohort of 234 adult patients with FSGS, derived from 225 families originating from all regions of Czechia, was analyzed by massively parallel sequencing. In this study, we focused on the comprehensive analysis of the NPHS2 gene. The histological classification of FSGS followed the Columbia classification. We detected seven (3%) cases bearing homozygous or compound heterozygous pathogenic NPHS2 variants. A single pathogenic variant c.868G > A (p.Val290Met) was found in the majority of NPHS2-positive cases (86%; 6 out of 7) in histologically confirmed instances of FSGS. Its allele frequency among unrelated NPHS2-associated FSGS patients was 50% (6/12), and Haplotype analysis predicted its origin to be a result of a founder effect. There is an identical V290M-related haplotype on all V290M alleles spanning a 0,7 Mb region flanking NPHS2 in Central European FSGS populations. The phenotype of the p.Val290Met NPHS2-associated FSGS demonstrated a later onset and a much milder course of the disease compared to other NPHS2 pathogenic variants associated with FSGS. The mean age of the FSGS diagnosis based on kidney biopsy evaluation was 31.2 ± 7.46 years. In 50% of all cases, the initial disease manifestation of proteinuria occurred only in adulthood, with 83% of these cases not presenting with edemas. One-third (33%) of the studied subjects progressed to ESRD (2 out of 6) at the mean age of 35.0 ± 2.82 years. We identified the most prevalent pathogenic variant, p.Val290Met, in the NPHS2 gene among Czech adult FSGS patients, which has arisen due to a founder effect in Central Europe. The documented milder course of the disease associated with this variant leads to the underdiagnosis in childhood. We established the histopathological features of the NPHS2-associated adult FSGS cases based on the Columbia classification. This might improve patient stratification and optimize their treatment.

A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence

Possible roles of anti-nephrin antibodies in post-transplant recurrent focal segmental glomerulosclerosis (FSGS) have been reported recently. To confirm these preliminary results, we performed a multi-institutional study of 22 Japanese pediatric kidney transplant recipients with FSGS including eight genetic FSGS and 14 non-genetic (presumed primary) FSGS. Eleven of the 14 non-genetic FSGS patients had post-transplant recurrent FSGS. Median (interquartile range) plasma levels of anti-nephrin antibodies in post-transplant recurrent FSGS measured using ELISA were markedly high at 899 (831, 1292) U/mL (cut-off 231 U/mL) before transplantation or during recurrence. Graft biopsies during recurrence showed punctate IgG deposition co-localized with nephrin that had altered localization with increased nephrin tyrosine phosphorylation and Src homology and collagen homology A expressions. Graft biopsies after remission showed no signals for IgG and a normal expression pattern of nephrin. Anti-nephrin antibody levels decreased to 155 (53, 367) U/mL in five patients with samples available after remission. In patients with genetic FSGS as in those with non-genetic FSGS without recurrence, anti-nephrin antibody levels were comparable to those of 30 control individuals, and graft biopsies had no signals for IgG and a normal expression pattern of nephrin. Thus, our results suggest that circulating anti-nephrin antibodies are a possible candidate for circulating factors involved in the pathogenesis of post-transplant recurrent FSGS, and that this may be mediated by nephrin phosphorylation. Larger studies including other ethnicities are required to confirm this finding.

#4635 CIRCULATING NEPHRIN AUTOANTIBODIES IN PATIENTS WITH POST-TRANSPLANT RECURRENCE OF PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Abstract Background and Aims Post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) is a major challenge in the field of nephrology and kidney transplantation. Primary FSGS is thought to be caused by circulating factors (CFs) that injure podocytes, but these factors remain unknown despite intensive efforts to identify them. Recently, one post-transplant recurrent FSGS patient with pretransplant nephrin autoantibodies was reported (Watts AJB et al, JASN 33:238, 2022). Furthermore, we reported very early post-transplant recurrence changes of podocytes and possible roles of circulating nephrin autoantibodies in a patient with FSGS recurrence (Hattori M et al, AJT 22:2478, 2022). To confirm these preliminary results, we examined the autoantibodies to nephrin and the punctate deposition of IgG colocalized with nephrin using stocked plasma samples and grafted kidney biopsy specimens of the patients with FSGS recurrence. Method This study was approved by the local Ethics Committee of Tokyo Women's Medical University (approval no. 2021-0184). The clinical and research activities reported here are consistent with the Principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism”. From 1989 to 2022, a total of 78 patients with FSGS underwent kidney transplantation in our institution, and 16 patients experienced post-transplant recurrence of FSGS. Since the stoked plasma samples were available in 14 out of 16 patients, these 14 patients were included in this study. All 14 patients showed immediate post-transplant recurrence and had no pathogenic variants in FSGS-related genes including NPHS1. Circulating anti-nephrin autoantibodies were measured using the ELISA methods based on the Watts's report with one modification, that is, recombinant extracellular domain of human nephrin was obtained commercially (R&D systems, USA). To validate the ELISA system, circulating anti-nephrin autoantibodies were also measured in 9 genetic FSGS patients, 13 membranous nephropathy (MN) patients, 4 lupus nephritis (LN) patients, and 13 healthy controls. Dual immunofluorescence (IF) staining of nephrin and IgG and image acquisition using the two-dimensional structured illumination microscopy mode with a Nikon microscope were performed as previously reported (Hattori M et al, AJT 22:2478, 2022). Results The cut-off level of anti-nephrin antibody calculated from the results of a total 30 cases including 13 MN patients, 4 LN patients, and 13 healthy controls using Frey's formula (J Immunol Method, 1998) was 172.2 U/mL All 14 recurrent patients enrolled in this study had higher titter than the cut-off level and the mean ± SD of the anti-nephrin antibody level in these patients was 939.9 ± 261.8 U/mL. In contrast, the mean anti-nephrin antibody level in patients with genetic FSGS was 98.6 ± 77.3 U/mL, which was comparable with healthy controls. The IF staining of graft biopsy specimens showed punctate depositions of IgG colocalized with nephrin in all 14 recurrent patients. Conclusion The autoantibodies to nephrin in plasma samples and the punctate deposition of IgG colocalized with nephrin in grafted kidney biopsy specimens were observed in all 14 patients with post-transplant recurrent FSGS. Further studies in larger numbers of patients as well as in patients of other ethnicities are clearly required to confirm this surprising result; however, circulating nephrin autoantibodies could be a possible candidate for CFs in the pathogenesis of recurrent FSGS.

#5919 PATIENT-SPECIFIC HUMAN INDUCED PLURIPOTENT STEM CELL (HIPSC)-DERIVED PODOCYTES

Abstract Background and Aims Podocytes typically represent a distinct morphology with long, interdigitating primary and secondary foot processes wrapping around glomerular capillaries forming the filtration unit of the kidney. In glomerular diseases like genetic focal segmental glomerulosclerosis (FSGS), podocyte alterations are often related to dysfunction of the glomerular filtration barrier and the development of proteinuria. Genetic mutations in podocyte relevant genes, important for foot process or actin cytoskeleton dynamics, are known to induce severe podocyte injury. Analysis of podocyte alterations ex vivo is limited because of their inability to proliferate due to their terminal differentiated state and limited access to primary podocytes. Instead, immortalized podocytes regained proliferation capacity by insertion of a thermosensitive SV40 large T antigen and are useful for many research questions. However, these podocytes usually do not express all podocyte marker and foot process development is often restricted. Since we aim to characterize personalized podocytes from patients suffering from genetic FSGS ex vivo, we generated podocytes from dermal fibroblasts via reprogramming into hiPSCs and subsequent differentiation into hiPSC-derived podocytes keeping the patients’ genetic background. Method Dermal fibroblasts were outgrown from a skin punch biopsy from a patient or a healthy donor and subsequently reprogrammed into hiPSCs by electroporation of the common OKSM plasmids and finally differentiated into podocytes. Cells were characterized phenotypically regarding morphology and marker expression using RNA bulk sequencing, western blot, qPCR and immunofluorescence staining. Potential functional alterations of diseased podocytes regarding actin cytoskeleton were assessed by actin polymerization assay. Results Patient-specific podocytes could be generated ex vivo by reprogramming dermal fibroblasts into hiPSCs and subsequently differentiating them into mature podocytes representing the patients’ background. During this process, cell morphology changed from spindle-like fibroblasts to small and round hiPSCs growing in colonies and representing a high nuclei-to body ratio as well as high proliferation rate. During differentiation, hiPSCs were induced into intermediate mesoderm, resulting in increased cell size and decreased proliferation rate terminating in 300 nm large star-shaped podocytes developing a distinct network of long primary and secondary foot processes. Patient-derived hiPSC-podocytes with a mutation in the INF2 gene lacked filamentous actin and only develop a limited number of only short foot processes compared to hiPSC-podocytes derived from a healthy control donor. Moreover, expression of actin cytoskeleton associated genes like SYNPO, ACTN4 and CD2AP was decreased while other actin isoforms, cortactin and the GTPase RhoA were increased in diseased patient-specific podocytes. Actin polymerization assay showed that polymerization process itself was not altered in healthy and diseased hiPSC-podocytes. Conclusion Analysis of patient-specific podocytes is possible ex vivo via differentiation of hiPSCs, generated from patients’ dermal fibroblasts by episomal reprogramming, into hiPSC-derived podocytes, with the potential to study alterations of disease-specific mutations regarding phenotypical and functional behavior in a personalized manner. The use of hiPSCs bypasses the limitation of restricted podocyte cell number and has the advantage of maintaining the patients’ genetic background at podocyte cell level. This enables future large-scale experiments regarding intercell-cell communication and interaction in glomerular three-dimensional co-cultures or via treatment with therapeutic substances or stress factors.

Adult-Onset Genetic Focal Segmental Glomerulosclerosis: A Tale of Two Mutations

Focal segmental glomerulosclerosis (FSGS) is a kidney histologic lesion that may be caused by multiple aetiologies and pathophysiological mechanisms, with podocyte injury and depletion as the common denominator. FSGS may be subdivided into different subclasses: primary, secondary, genetic and unknown forms. Notwithstanding the overlapping clinical and histological characteristics across the different forms of FSGS, their management and response to treatment are strikingly different. Genetic FSGS may be suggested by the appearance of nephrotic syndrome during childhood, but it may also present in adulthood, where the diagnosis is rather challenging due to widely variable clinical and histological phenotypes. Herein we present the case of a 34-year-old female with a family history of chronic kidney disease of undetermined aetiology, referred for a Nephrology consultation due to haematoproteinuria and de novo arterial hypertension. Complementary evaluation revealed a urinary protein/creatinine ratio of 4.3 g/g and albumin/creatinine ratio of 3.9 g/g with hypoalbuminaemia. Kidney biopsy revealed lesions of FSGS, associated with extensive foot process effacement. The constellation of findings and family history of kidney disease raised the suspicion of a genetic cause, therefore genetic testing was performed. Two variants in the NPHS2 gene [c.686G>A, p.(Arg229Gln) and c.855_856del, p(Arg286Thrfs*17)] were found in compound heterozygosity, compatible with the diagnosis of genetic FSGS. This case highlights the importance of a detailed evaluation of patients with FSGS lesions in order to identify the FSGS form, given its therapeutic and prognostic impact, including after kidney transplantation.

Генетический фокальный сегментарный гломерулосклероз, диагностированный у взрослых. Клинические наблюдения

Генетический фокальный сегментарный гломерулосклероз, диагностированный у взрослых. Клинические наблюдения

Clinical, Pathological, and Genetic Characteristics in Patients with Focal Segmental Glomerulosclerosis.

Approximately 30% of children with steroid-resistant nephrotic syndrome (SRNS) have causative monogenic variants. SRNS represents glomerular disease resulting from various etiologies, which lead to similar patterns of glomerular damage. Patients with SRNS mainly exhibit focal segmental glomerulosclerosis (FSGS). There is limited information regarding associations between histologic variants of FSGS (diagnosed using on the Columbia classification) and monogenic variant detection rates or clinical characteristics. Here, we report FSGS characteristics in a large population of affected patients. This retrospective study included 119 patients with FSGS, diagnosed using the Columbia classification; all had been referred to our hospital for genetic testing from 2016 to 2021. We conducted comprehensive gene screening of all patients using a targeted next-generation sequencing panel that included 62 podocyte-related genes. Data regarding patients' clinical characteristics and pathologic findings were obtained from referring clinicians. We analyzed the associations of histologic variants with clinical characteristics, kidney survival, and gene variant detection rates. The distribution of histologic variants according to the Columbia classification was 45% (n=53) FSGS not otherwise specified, 21% (n=25) cellular, 15% (n=18) perihilar, 13% (n=16) collapsing, and 6% (n=7) tip. The median age at end stage kidney disease onset was 37 years; there were no differences in onset age among variants. We detected monogenic disease-causing variants involving 12 of the screened podocyte-related genes in 34% (40 of 119) of patients. The most common genes were WT1 (23%), INF2 (20%), TRPC6 (20%), and ACTN4 (10%). The perihilar and tip variants had the strongest and weakest associations with detection of monogenic variants (83% and 0%, respectively; P<0.001). We revealed the distributions of histologic variants of genetic FSGS and nongenetic FSGS in a large patient population. Detailed data concerning gene variants and pathologic findings are important for understanding the etiology of FSGS.

Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease.

Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high-dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.

Efficacy and Safety of ACE Inhibitor and Angiotensin Receptor Blocker Therapies in Primary Focal Segmental Glomerulosclerosis Treatment: A Systematic Review and Meta-Analysis

Rationale and ObjectiveAngiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy (renin-angiotensin-aldosterone system [RAAS] inhibitor) to control proteinuria in primary and genetic focal segmental glomerulosclerosis (FSGS) follows guidelines based on other proteinuria-related kidney diseases. There is no consensus on the efficacy and safety of RAAS inhibitor therapies in primary and genetic FSGS. This systematic review assessed the effects of RAAS inhibitor therapy on kidney outcomes in these patients.Study DesignSystematic review of randomized controlled trials, interventional nonrandomized studies, observational studies, and retrospective studies.Setting & Study PopulationsPatients with primary and genetic FSGS.Selection Criteria for StudiesPubMed, Cochrane Library, and Embase.Data Extraction2 investigators independently screened studies and extracted data.Analytical ApproachResults were summarized as the ratio of means (ROM) between baseline and follow-up measurements or as the hazard ratio using random-effects models.Results30 publications were selected; 5 were controlled trials (4 randomized controlled trials). 8 assessed RAAS inhibitor monotherapy, while the rest studied RAAS inhibitors in combination with other drugs, mainly immunosuppressants. On average, a 32% proteinuria reduction (ROM, 0.68; 95% CI, 0.47-0.98) and no change in creatinine clearance (ROM, 0.95; 95% CI, 0.77-1.16) from baseline to the last reported follow-up was observed in patients treated with RAAS inhibitor monotherapy. When a RAAS inhibitor was combined with other drugs, a 72% proteinuria reduction was observed from baseline to the last reported follow-up (ROM, 0.24; 95% CI, 0.08-0.75). The published data did not allow for the assessment of the effects of RAAS inhibitor monotherapy on estimated glomerular filtration rate and end-stage kidney disease risks.LimitationsLarge study heterogeneity in design, patient populations, and treatment regimens. No access to individual patient-level data.ConclusionsThis review supports the tendency to observe a proteinuria reduction with RAAS inhibitors in patients with primary FSGS. RAAS inhibitor monotherapy was associated with maintained kidney function, as shown by no change in creatinine clearance. Strong evidence to quantify the effects of RAAS inhibitor monotherapy on end-stage kidney disease and glomerular filtration rate was lacking. Larger, well-designed clinical trials are needed to better understand the effects of RAAS inhibitors on primary FSGS.

Clinical, pathological, and genetic characteristics of cases with asymptomatic proteinuria not manifesting nephrotic syndrome at onset: a single-center retrospective study.

Cases with asymptomatic proteinuria (ASP) not manifesting nephrotic syndrome often pathologically show focal segmental glomerulosclerosis (FSGS). However, characteristics of those cases had not been intensively studied so far. We retrospectively reviewed clinical, pathological, and genetic characteristics of 37 children (median age, 9.3years) who underwent renal biopsy for persistent isolated proteinuria (urine protein-to-creatinine ratio: UP/C, > 0.2g/g) between 2003 and 2019. Targeted next-generation sequencing (NGS) was utilized for all patients with FSGS, excluding those with secondary FSGS. At biopsy, all patients with FSGS (N = 14) had UP/C ≥ 0.5g/g and the median UP/C was significantly higher in those with FSGS than those with minor glomerular abnormalities (MGA) (N = 23) (1.49 vs. 0.53g/g, P < 0.001). Causative variants were found in seven patients with FSGS (TRPC6, WT1, ACTN4, and INF2 in 3, 2, 1, and 1 patient, respectively): all gene variants were in genes manifesting autosomal dominant inheritance mode. The proportion of the perihilar variant was significantly higher in the genetic FSGS patients than in the non-genetic FSGS patients (4/7 vs. 0/7, P < 0.05). Kaplan-Meier analysis showed that the renal survival rate after ASP diagnosis was significantly lower in the genetic FSGS patients than in the non-genetic FSGS and the MGA patients (P < 0.001). UP/C was a simple and useful predictive parameter for the diagnosis of FSGS. APS without nephrotic syndrome at onset may be associated with autosomal dominant causes of FSGS, especially in those with the perihilar variant.

Degree of foot process effacement in patients with genetic focal segmental glomerulosclerosis: a single-center analysis and review of the literature

Determining the cause of focal segmental glomerulosclerosis (FSGS) has crucial implications for evaluating the risk of posttransplant recurrence. The degree of foot process effacement (FPE) on electron micrographs (EM) of native kidney biopsies can reportedly differentiate primary FSGS from secondary FSGS. However, no systematic evaluation of FPE in genetic FSGS has been performed. In this study, percentage of FPE and foot process width (FPW) in native kidney biopsies were analyzed in eight genetic FSGS patients and nine primary FSGS patients. All genetic FSGS patients showed segmental FPE up to 38% and FPW below 2000 nm, while all primary FSGS patients showed diffuse FPE above 88% and FPW above 3000 nm. We reviewed the literature which described the degree of FPE in genetic FSGS patients and identified 38 patients with a description of the degree of FPE. The degree of FPE in patients with mutations in the genes encoding proteins associated with slit diaphragm and cytoskeletal proteins was varied, while almost all patients with mutations in other FSGS genes showed segmental FPE. In conclusion, the present study suggests that the degree of FPE in native kidney biopsies may be useful for differentiating some genetic FSGS patients from primary FSGS patients.

MO246ESTIMATING DELAY IN TIME TO ESKD FOR TREATMENT EFFECTS ON PROTEINURIA IN IGA NEPHROPATHY AND FSGS*

Abstract Background and Aims Reduction in proteinuria is associated with lower risk of end-stage kidney disease (ESKD) in IgA nephropathy (Thompson et al, 2019) and focal segmental glomerulosclerosis (FSGS) (Troost et al, 2017). Sparsentan, a dual endothelin receptor and angiotensin II receptor antagonist, is in phase 3 clinical trials in IgA nephropathy (PROTECT) and FSGS (DUPLEX), that are powered to detect a treatment benefit on proteinuria-based endpoints versus standard of care angiotensin receptor blockade (irbesartan). In this study, we aim to estimate the delay in time to ESKD conferred by the hypothesized treatment effect of sparsentan on proteinuria in these phase 3 trials; for PROTECT, a 30% reduction in urine protein to creatine ratio (UP/C) vs irbesartan in IgA nephropathy patients, and for DUPLEX, 30% more patients achieving the new FSGS Partial Remission Endpoint (UP/C &amp;lt;1.5 g/g associated with a 40% reduction in UP/C) versus irbesartan. Methods We analysed individual patient level data from two UK registries: the first is provided by Leicester General Hospital, UK and consists of IgAN patients, and the second is the UK National Registry of Rare Kidney Disease (RaDaR) Nephrotic Syndrome cohort, with access provided by the University of Bristol, UK, including FSGS patients. IgAN patients with urine total protein value ≥1.0 g/day or UP/C ≥1.0 g/g and eGFR &amp;gt;30 mL/min at the initiation of renin-angiotensin system blockade (RASB) were identified, as were patients with primary or genetic FSGS with UP/C ≥1.5 g/g and eGFR ≥30 mL/min. The time to ESKD (eGFR &amp;lt;15 mL/min, initiation of dialysis, transplantation) or death from any cause over the patient follow-up period was analysed using accelerated failure time modelling; Weibull, Log Logistic and Log Normal distributions were applied with the fitted survivor function reported from the model with the lowest AIC. The time gained for a given reduction in risk in ESKD/death and 5-year survival was estimated under proportional hazards. Results A 30% reduction in proteinuria in IgAN patients confers a 50% lower risk of ESKD, extending the median time to ESKD by 10.7 years, from 12.4 to 23.1 years; 5-year ESKD free survival rate is also increased, from 77.7% to 88.1%. Similarly, ongoing analysis in FSGS patients indicates 30% more patients achieving the FSGS Partial Remission Endpoint confers lower risk for ESKD and increase in 5-year ESKD free survival. Conclusion The data from the Leicester General Hospital, UK and RaDaR provide invaluable insight into the longer-term natural history of IgAN and FSGS patients and time to ESKD. Therapeutic interventions that reduce proteinuria and the risk of ESKD can confer important and clinically meaningful extensions in the time patients are alive and free from ESKD.