Secondary Focal Segmental Glomerulosclerosis Research Articles

#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.

#1004 Single-nucleus RNA sequencing identifies upregulated antigen presentation, apoptosis, mTORC1 signaling and EMT in primary FSGS podocytes

Abstract Background and Aims Primary focal segmental glomerulosclerosis (FSGS) is associated with irreversible podocyte damage, but the underlying cause and pathophysiology are incompletely understood. Furthermore, diagnostic markers that allow reliable differentiation between primary and secondary FSGS subtypes are lacking. We applied single-nucleus RNA-sequencing (snRNA-seq) on podocytes of patients with primary or secondary (maladaptive) FSGS, to identify subtype-specific differentially expressed genes and pathways. Method We used droplet-based snRNA-seq (10X Genomics Chromium) on cryopreserved kidney biopsy cores from human patients with newly diagnosed primary FSGS (n = 9, all nephrotic), maladaptive FSGS (n = 9, not nephrotic), proteinuric controls (PLA2R-positive membranous nephropathy (PLA2R+ MN), n = 3), and healthy controls (pre-perfusion biopsies, n = 4). Differential gene expression (DGE) analysis was done with a pseudobulk method provided by the EdgeR R-package to reduce bias and false discoveries. The fGSEA R-package was used for subsequent gene set enrichment analysis. Results We identified a total of 120 751 high-quality nuclei, of which 2 471 were podocytes (Fig. 1A). DGE analysis identified the top 20 differentially expressed genes (DEGs) per diagnosis (Fig. 1B). Remarkably, primary FSGS podocytes showed more transcriptional similarity to PLA2R+ MN podocytes, compared to maladaptive FSGS podocytes. This underscores the heterogeneity of patients with FSGS and shows that heavy proteinuria, regardless of the underlying diagnosis, may be associated with a distinct transcriptional profile in podocytes. Upregulated genes in primary FSGS podocytes included TIMP1, BTG2, ZNF44, EHD4, ZNF250, ECM1, SEMA4G, PHLDB1, and HDAC5. Upregulation of the matrix metalloproteinase inhibitor TIMP1 may possibly contribute to the development of glomerulosclerosis. Upregulation of BTG2 has previously been found to be pathogenic in FSGS by promoting epithelial-mesenchymal transition (EMT)-induced podocyte injury [1]. Next, gene set enrichment analysis on the identified DEGs in primary FSGS podocytes showed upregulation of pathways involved in antigen presentation (driven by upregulation of HLA-A, HLA-B, HLA-C, HLA-E and B2M), mTORC1 signaling, apoptosis and EMT (Fig. 1C). In maladaptive FSGS, upregulated pathways were mainly involved in extracellular matrix interaction. This may correlate with the significantly higher degree of chronic damage on kidney biopsy in the maladaptive FSGS patients (median Mayo Clinic Chronicity Score of 6.0, IQR [4.0-7.0]) vs. primary FSGS (2.0, [1.0-4.0]) and PLA2R+ MN (1, IQR [1.0-1.5]) (Kruskal-Wallis test, P = 0.007). Conclusion Our results corroborate previous studies that implicate apoptosis, mTORC1 signaling, EMT and auto-immunity in primary FSGS. Our future work will focus on cell-cell interactions within the glomerular niche and validation studies of candidate podocyte-specific genes.

Long-term outcomes of adults with FSGS in the German Chronic Kidney Disease cohort.

Focal segmental glomerulosclerosis (FSGS) can lead to kidney failure in adults. This study examines the progression of FSGS in the German Chronic Kidney Disease (GCKD) cohort. The GCKD study (N=5217), a prospective cohort, included 159 patients with biopsy-confirmed FSGS recruited from 2010 to 2012. Baseline was defined as the first study visit. Adjudicated endpoints included a composite kidney endpoint (CKE), including an estimated glomerular filtration rate (eGFR) decrease >40%, eGFR <15ml/min/1.73m2 or initiation of kidney replacement therapy and combined major adverse cardiovascular events (MACE), including non-fatal myocardial infarction or stroke and all-cause mortality. Associations between baseline demographics, laboratory data, comorbidity and CKE and MACE were analysed using the Cox proportional hazards regression model. The mean age at baseline was 52.1±13.6years, with a disease duration of 4.72years (quartile 1: 1; quartile 3: 6) before joining the study. The median urinary albumin:creatinine ratio (UACR) at baseline was 0.7g/g (IQR 0.1;1.8), while mean eGFR was 55.8±23ml/min/1.73m2. Based on clinical and pathological features, 69 (43.4%) patients were categorized as primary FSGS, 55 (34.6%) as secondary FSGS and 35 (22%) as indeterminate. Over a follow-up of 6.5years, 44 patients reached the composite kidney endpoint and 16 individuals had at least one MACE. UACR ≥0.7g/g was strongly associated with both the composite kidney endpoint {hazard ratio [HR] 5.27 [95% confidence interval (CI) 2.4-11.5]} and MACE [HR 3.37 (95% CI 1.05-10.82)] compared with <0.7g/g, whereas a higher eGFR at baseline (per 10ml/min) was protective for both endpoints [HR 0.8 (95% CI 0.68-0.95) and HR 0.63 (95% CI 0.46-0.88), respectively]. Patients with secondary FSGS experienced a greater rate of eGFR decline than patients with primary FSGS. Lower eGFR and higher albuminuria are key risk factors for kidney disease progression and cardiovascular events in patients with FSGS.

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.

Clinical Characteristics and Histopathology in Adults With Focal Segmental Glomerulosclerosis

Rationale & ObjectiveFew data are available regarding histological features at the time of focal segmental glomerulosclerosis (FSGS) diagnosis among diverse real-world populations. This study describes clinical and histological characteristics, and correlates of histological disease severity, in adults with FSGS who underwent a clinical kidney biopsy. Study DesignReal-world cohort study with data derived from health records. Setting& Participants: Adults with FSGS by kidney biopsies from Arkana Laboratories during 1 January 2016 to 31 May 2020. ExposuresRace, CKD stage, nephrotic proteinuria, age, sex, and hypertension. OutcomesSevere histological disease, defined as global glomerulosclerosis in >50% of glomeruli and >25% interstitial fibrosis and tubular atrophy (IFTA). Analytical ApproachDemographic, clinical, and histological characteristics were compared between race groups. Correlates of severe disease were analyzed by multiple logistic regression. ResultsAmong 2,011 patients with FSGS, 40.6% were White and 23.6% Black. White patients were older (52.8 versus 45.5 years, P < 0.001) with higher estimated glomerular filtration rate (eGFR) than Black patients (53.5 versus 43.1 ml/min/1.73 m2, P < 0.001). A higher proportion of Black patients had global glomerulosclerosis ≥50% (32.1% versus 14.6%, P < 0.001) or IFTA >50% (34.6% versus 14.7%, P < 0.001). Severe histological disease was more likely in Black patients (odds ratio 2.46; 95% confidence interval 1.59, 3.79; P < 0.001). A higher proportion of patients with nephrotic than non-nephrotic proteinuria exhibited diffuse foot process effacement. LimitationsUnequal representation across United States (US) regions, missing demographic and clinical data, and lack of data on primary versus secondary FSGS, treatments, or outcomes. ConclusionsBlack patients were more frequently diagnosed at younger age with lower eGFR and more severe histological disease compared with White patients. Timelier identification of FSGS could increase the opportunity for therapeutic intervention, especially for high-risk patients, to mitigate disease progression and complications.

Histomorphological Patterns of Focal Segmental Glomerulosclerosis and Their Clinical Correlation in Tertiary Care Hospitals in Bangladesh

Background: Being one of the commonest glomerular diseases in adults and a major etiology of the nephrotic syndrome, Focal Segmental Glomerulosclerosis (FSGS) gradually progresses towards end-stage renal disease (ESRD). According to pathogenesis, FSGS can be classified into primary or secondary ones and in both instances, histomorphological findings are nearly indistinguishable. Five histomorphological variants of primary as well as secondary focal segmental sclerosis have already been accepted, for instance, NOS (not otherwise specified), tip, cellular, perihilar, and collapsing variants. Nonetheless, primary FSGS is a diagnosis of exclusion and all the time, primary and secondary FSGS can not be distinguished discernibly. For this reason, correlation with clinical and biochemical parameters are extremely important. The present study was undertaken to identify various histomorphological patterns of FSGS by light microscopy and immunofluorescence study at tertiary care hospitals in Bangladesh as well as to correlate those patterns with clinical, biochemical parameters and additional histologic findings. Methods: This is an observational &amp; cross sectional study which was conducted among 57 paraffin blocks of renal biopsy specimens of histologically confirmed FSGS cases including all age groups and both sexes, which were collected from department of Pathology, BSMMU &amp; Kidney foundation hospital &amp; research institute, Mirpur, Dhaka. Renal biopsies received for light microscopy only and biopsies that contained less than eight glomeruli were exluded from the study . Routine Haematoxylin &amp; Eosin (H&amp;E), Periodic Acid Schiff (PAS), Jones silver &amp; Masson’s trichrome stains were used to evaluate renal biopsy specimens &amp; histomorphological patterns of FSGS were identified. Data regarding clinical &amp; biochemical parameters were collected from patient’s medical records. Statistical analyses were performed by SPSS-22. Result: In our study, it was observed that, among 57 biopsies, 35(61.4%) biopsies were diagnosed as NOS, 12(21.1%) biopsies as perihilar, 4(7.0%) biopsies as tip, 3(5.3%) biopsies as collapsing and 3(5.3%) biopsies as cellular variant. No clinical and biochemical parameters were significantly associated with these histomorphological patterns of FSGS. Regarding additional histologic features, thick walled blood vessels was significantly associated with histomorphological patterns. Conclusion: This study was conducted on only two tertiary level hospitals in Bangladesh, therefore, the result may not reflect the exact scenario of Bangladesh. It is the need of the moment to mention the histomorphological patterns of FSGS in renal histopathology reports. Moreover, logistic support is a necessity to institute nephro-pathology section in the pathology department of all the tertiary care hospitals in order to identify renal glomerular disease precisely. Sir Salimullah Med Coll J 2023; 31: 26-33

A pilot study of anti-nephrin antibodies in podocytopaties among adults.

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are podocytopathies characterized by damage to the glomerular filtration barrier, leading to proteinuria and nephrotic syndrome. The production of anti-podocyte antibodies has been proposed as potential circulating factors contributing to the development of these conditions. The aim of the study is to evaluate the levels of anti-nephrin antibodies in patients with podocytopathies and healthy subjects. In this study, a total of 77 patients with active glomerulopathy and 11 healthy subjects were included. Forty one patients were diagnosed with FSGS, 11 with MCD, and 25 with MN. To measure the levels of anti-nephrin antibodies, enzyme-linked immunosorbent assay was used. The levels of antibodies to nephrin were significantly higher in patients with MCD 61.2 [28.9-66.3] ng/mL and FSGS 32.5 [17.2-58.4] ng/mL compared to MN 20.3 [14.4-38.4] and healthy individuals 15.3 [12-18.9] ng/mL, p < .05. In patients with primary FSGS, the levels of antibodies to nephrin were significantly higher 45.2 [20-64.3] ng/mL compared to patients with secondary FSGS 26.7 [11.2-44.1] ng/mL, p < .05. There were no significant differences in the remission rate between the anti-nephrin antibodies positive and negative groups (log-rank test: p = .158). The level of anti-nephrin antibodies was found to be significantly higher in patients with MCD and pFSGS compared to those with sFSGS, MN, and healthy subjects. Anti-nephrin antibodies in MCD and primary FSGS may be associated with the severity of podocytopathies, however they did not have an impact on the response to therapy.

Focal Segmental Sclerosis Associated with the Novel Multi-tyrosine Kinase Inhibitor Ponatinib: A Case Report.

Ponatinib is a novel multi-tyrosine kinase inhibitor (TKI) with potent inhibitory activity against refractory chronic myeloid leukemia (CML). Despite its high clinical efficacy, ponatinib induces various adverse events due to its multi-target characteristic. However, renal complications associated with ponatinib are rare. A 76-year-old woman had a history of chronic myeloid leukemia (CML) resistant to imatinib and nilotinib. Our patient developed proteinuria and renal function deterioration during treatment with ponatinib but not with imatinib or nilotinib. We herein report the first case of a patient with secondary focal segmental glomerulosclerosis (FSGS) with partial glomerular collapse induced by ponatinib treatment.

#3476 CHARACTERISTICS AND SURVIVAL DATA OF PATIENTS WITH PRIMARY FOCAL SEGMENTAL SEGMENTAL GLOMERULOSCLEROSIS: TSN-GOLD MULTI-CENTER STUDY

Abstract Background and Aims We aimed to investigate the characteristics and survival data of biopsy-proven primary focal segmental glomerulosclerosis (FSGS) in adult patients across Turkey. Method Patients with primary FSGS were included by retrospectively scanning the database of the Turkish Society of Nephrology Glomerular Diseases Study Group (TSN-GOLD). Demographic and laboratory data of the patients at baseline, sixth month, first year, and third year were recorded. Patients with secondary FSGS, missing data were excluded. Results The study included 1668 patients with primary FSGS who met the criteria. 1386 patients were included. The mean age of the patients was 41.16±13.88 years, and 712 patients (51.4%) were male. The total follow-up period from the biopsy date was 37.63±40.45 (IQR:1-249) months. The mean blood pressure of the patients, respectively; 130.43±17.63/81.47±10.85 mmHg, serum creatinine 1.29±1.28 mg/dl, e-GFR: 86.10±42.70 ml/min/1.73 m2, serum albumin: 3.41±0.92 g/dl and proteinuria amount was 4687±4658 g/day. Microscopic hematuria was detected in 40.2% of the patients. The rate of admission with nephrotic syndrome was .45.7%. In light microscopy, the mean glomeruli count was 17.36±10.58, with 3.32±4.08 global sclerosis and 0.08±065 glomeruli had segmental sclerosis. Mesangial proliferation was found in 53.1% of the patients and interstitial inflammation was found in 69.7% of the patients. Interestingly, the most common immunoglobulin staining was IgM (19.3%) in the immunofluorescent microscope. The rate of receiving immunosuppressive therapy was 36%. A positive correlation was found in terms of serum creatinine, albumin, and proteinuria in the 3-year follow-up (p&amp;lt;0.001). In the univariate analysis, the group with e-GFR&amp;lt;60 ml/min/1.73 m2 was older, hypertensive, uremic, anemic, had more interstitial fibrosis/tubular atrophy and less interstitial inflammation and mesangial proliferation (p&amp;lt;0.001). In terms of quantitative proteinuria, Patients with proteinuria &amp;gt;3.5 g/day were more hypertensive, hyperlipidemic, hypoalbuminemic and anemic (p&amp;lt;0.05). Conclusion Our study presented important data on the status of patients with national primary FSGS. Approximately one-third of patients receive immunosuppressive therapy. The most important factors determining the prognosis of primary FSGS are the initial nephrotic proteinuria and the degree of renal function.

Focal Segmental Glomerulosclerosis and Renal Failure Secondary to Protein Kinase C Delta Deficiency in an Adolescent Male

Introduction: The autoimmune lymphoproliferative syndrome (ALPS)-like condition, Protein Kinase C-delta (PRKCD) deficiency, is associated with a lupus-like presentation, recurrent infections, and reduced B-cell function with hypogammaglobulinemia in addition to prominent lymphadenopathy and splenomegaly. Renal manifestations previously reported include nephrotic syndrome and glomerulonephritis. Focal segmental glomerulosclerosis (FSGS) and significant end-stage renal disease requiring dialysis have not been previously described in those with PRKCD deficiency.Case Study: We describe a now 21-year-old male of Palestinian descent with consanguineous parents who initially presented at 15 months of age with arthritis, splenomegaly, neutrophilic rash, and recurrent fevers. At 7 years of age, the patient was hospitalized with hepatosplenomegaly, diffuse adenopathy, and post-obstructive pneumonitis secondary to hilar adenopathy. He was subsequently given a diagnosis of presumed ALPS, although FAS mutation testing was negative, and started on mycophenolate with improvement in symptomology. He underwent additional comprehensive genetic testing when he was 18 years old with results revealing a novel homozygous PRKCD variant (c. 1872 1 G > A) leading to a presumed donor splice site defect. [Display omitted] Starting at 19 years of age, the patient was noted to have a steadily rising serum creatinine and profound proteinuria. Kidney biopsy revealed chronic immune complex glomerulonephritis with capillary loop and mesangial immune deposits and changes consistent with secondary FSGS. (Figure 1A&B). He was started on an angiotensin-converting enzyme (ACE) inhibitor for antiproteinuric effects, though this was discontinued due to persistent hyperkalemia. A subsequent renal biopsy performed 5 months later in the clinical setting of rapid deterioration of GFR and worsening proteinuria showed worsening FSGS with prominent podocytopathy (Figure 1 C&D). Mycophenolate and IVIG therapy were discontinued given a lack of efficacy and to preserve renal function. Unfortunately, his creatinine continued to rise, and he progressed to end-stage renal disease necessitating dialysis. He is currently being considered for kidney transplantation. ConclusionSevere FSGS leading to renal failure is an uncommon diagnosis in adolescents and has not previously been described in those with PRKCD deficiency. Our case thus broadens the phenotypic and pathologic renal manifestations of the disorder and emphasizes the need for comprehensive multidisciplinary care of individuals affected by ALPS-like conditions.

Differentiating Primary and Secondary Focal Segmental Glomerulosclerosis Using Non-Invasive Urine Biomarkers

Differentiating Primary and Secondary Focal Segmental Glomerulosclerosis Using Non-Invasive Urine Biomarkers

Renal Transplantation in Pure Autonomic Failure.

Renal Transplantation in Pure Autonomic Failure.

MO064: Expression Studies on Magi2 in Different FSGS Models

Abstract BACKGROUND AND AIMS MAGI2 is a tight junction protein and member of the membrane-associated guanylate kinase (MAGUK) family. In the glomerulus, it is exclusively expressed in podocytes and interacts with the slit diaphragm protein nephrin. Recent studies and podocyte-specific MAGI2 knockout mice have demonstrated the essential role of this protein in the glomerulus. The aim of this work was to study the expression of MAGI2 in different focal segmental glomerulosclerosis (FSGS) mouse models, in the GlomAssay, in a FSGS-like zebrafish model, and in human biopsies of patients suffering from minimal change disease and FSGS. Additionally, using CRISPR/Cas9 knockout of magi2 and nephrin in zebrafish, we investigated the influence of both proteins on each other’s localization. METHOD We used nephrotoxic serum (NTS) as well as uninephrectomy DOCA/salt-induced hypertension as murine models. The podocyte-specific nitroreductase/metronidazole zebrafish model was used to induce FSGS-like disease in zebrafish upon partial podocyte-depletion. MAGI2 expression was evaluated in kidney biopsies of patients affected by minimal change disease (MCD), primary and secondary FSGS. Slides were imaged using confocal laser scanning and super-resolution 3D-structured illumination microscopy (3D-SIM). Filtration slit density (FSD) was measured on human biopsies by PEMP (podocyte exact morphology measurement procedure). MAGI2/nephrin ratio measurements were performed with a customized macro for the ImageJ-based platform FIJI. Magi2 expression was studied in the GlomAssay. To evaluate the interaction between magi2 and nephrin in the zebrafish model, the respective proteins were knocked-out using CRISPR/Cas9. The knockout was validated by RT–PCR and the expression of these two proteins in both lines was analyzed by immunofluorescence staining. Proteinuria was assessed using the excretion of eGFP-tagged vitamin D-binding protein from the vasculature and reuptake in proximal tubule cells. RESULTS MAGI2 was expressed in a linear pattern along the filtration slit and colocalized with nephrin in all three species investigated (human, mouse and zebrafish) (3D-SIM in Fig. 1). MAGI2 was significantly downregulated in NTS-induced nephritis, as well as in uninephrectomized and DOCA/salt-treated mice. In the GlomAssay, Magi2 was significantly downregulated in dedifferentiated podocytes after 6 days in cell culture due to podocyte dedifferentiation. A reduction of MAGI2 was found in human biopsies of patients suffering from primary FSGS, but not in MCD and secondary FSGS, respectively. In addition, we found that magi2 was downregulated in zebrafish larvae using our FSGS-like zebrafish model. When we examined the effect of nephrin on magi2 expression and vice versa, we found that magi2 expression was unchanged in nephrin-KO larvae, whereas nephrin expression was significantly reduced in MAGI2a-KO larvae. CONCLUSION Here, we have shown that the expression of MAGI2 in the glomerulus of different species such as zebrafish, mice and humans is associated with the expression of nephrin. By using knockout larvae, we showed that nephrin expression is dependent on Magi2 and not vice versa. Since the expression of Magi2 seems to be specifically regulated depending on the podocytopathy investigated, we propose a role for MAGI2 to distinguish between different glomerulopathies.

Unusual association of Gitelman syndrome with early diagnosis and glomerular proteinuria; a case report

Gitelman syndrome is an autosomal recessive hereditary tubulopathy whose main alteration is at the sodium-chloride symporter in the distal convoluted tubule, characterized by metabolic alkalosis, normotension, hypokalemia, hypomagnesemia and hypocalciuria. Proteinuria and glomerular hyperfiltration (especially at the beginning of clinical course) are not characteristic manifestations of this disease. We present the case of a 25-year-old female with recent diagnosis of Gitelman syndrome who presented with hyperfiltration and glomerular proteinuria, leading to a renal biopsy, which showed hypertrophy of juxtaglomerular apparatus and mesangial proliferation. In electron microscopy focal podocyte detachment was evidenced, which was compatible with secondary focal segmental glomerulosclerosis (FSGS). This case of association of tubulopathy with secondary glomerulopathy of early presentation, shows the final pathway in this disease, when generating sustained renal ischemia due to the increased activity of renin-angiotensin-aldosterone system (RAAS). Renal biopsy and electron microscopy proved to be useful to define prognosis, early recognition of progression and adjust treatment in this patient.

Parietal epithelial cells maintain the epithelial cell continuum forming Bowman's space in focal segmental glomerulosclerosis.

ABSTRACTIn the glomerulus, Bowman's space is formed by a continuum of glomerular epithelial cells. In focal segmental glomerulosclerosis (FSGS), glomeruli show segmental scarring, a result of activated parietal epithelial cells (PECs) invading the glomerular tuft. The segmental scars interrupt the epithelial continuum. However, non-sclerotic segments seem to be preserved even in glomeruli with advanced lesions. We studied the histology of the segmental pattern in Munich Wistar Frömter rats, a model for secondary FSGS. Our results showed that matrix layers lined with PECs cover the sclerotic lesions. These PECs formed contacts with podocytes of the uninvolved tuft segments, restoring the epithelial continuum. Formed Bowman's spaces were still connected to the tubular system. In biopsies of patients with secondary FSGS, we also detected matrix layers formed by PECs, separating the uninvolved from the sclerotic glomerular segments. PECs have a major role in the formation of glomerulosclerosis; we show here that in FSGS they also restore the glomerular epithelial cell continuum that surrounds Bowman's space. This process may be beneficial and indispensable for glomerular filtration in the uninvolved segments of sclerotic glomeruli.

Interventions for focal segmental glomerulosclerosis in adults.

Focal segmental glomerulosclerosis (FSGS) can be separated into primary, genetic or secondary causes. Primary disease results in nephrotic syndrome while genetic and secondary forms may be associated with asymptomatic proteinuria or with nephrotic syndrome. Overall only about 20% of patients with FSGS experience a partial or complete remission of nephrotic syndrome with treatment. FSGS progresses to kidney failure in about half of the cases. This is an update of a review first published in 2008. To assess the benefits and harms of immunosuppressive and non-immunosuppressive treatment regimens in adults with FSGS. We searched the Cochrane Kidney and Transplant Register of Studies to 21 June 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Randomised controlled trials (RCTs) and quasi-RCTs of any intervention for FSGS in adults were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non-immunosuppressive agents were assessed. At least two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Fifteen studies (560 participants) were included. No studies specifically evaluating corticosteroids compared with placebo or supportive therapy were identified. Studies evaluated participants with steroid-resistant FSGS. Five studies (240 participants) compared cyclosporin with or without prednisone with different comparators (no specific treatment, prednisone, methylprednisolone, mycophenolate mofetil (MMF), dexamethasone). Three small studies compared monoclonal antibodies (adalimumab, fresolimumab) with other agents or placebo. Six single small studies compared rituximab with tacrolimus, cyclosporin plus valsartan with cyclosporin alone, MMF with prednisone, chlorambucil plus methylprednisolone and prednisone with no specific treatment, different regimens of dexamethasone and CCX140-B (an antagonist of the chemokine receptor CCR2) with placebo. The final study (109 participants) compared sparsentan, a dual inhibitor of endothelin Type A receptor and of the angiotensin II Type 1 receptor, with irbesartan. In the risk of bias assessment, seven and five studies were at low risk of bias for sequence generation and allocation concealment, respectively. Four studies were at low risk of performance bias and 14 studies were at low risk of detection bias. Thirteen, six and five studies were at low risk of attrition bias, reporting bias and other bias, respectively. Of five studies evaluating cyclosporin, four could be included in our meta-analyses (231 participants). Cyclosporin with or without prednisone compared with different comparators may increase the likelihood of complete remission (RR 2.31, 95% CI 1.13 to 4.73; I² = 1%; low certainty evidence) and of complete or partial remission (RR 1.64, 95% CI 1.10 to 2.44; I² = 19%) but not of partial remission (RR 1.36, 95% CI 0.78 to 2.39, I² = 22%). In Individual studies, cyclosporin with prednisone versus prednisone may increase the likelihood of partial (49 participants: RR 7.96, 95% CI 1.09 to 58.15) or complete or partial remission (49 participants: RR 8.85, 95% CI 1.22 to 63.92) but not of complete remission. The remaining individual comparisons may make little or no difference to the likelihood of complete remission, partial remission or complete or partial remission compared with no treatment, methylprednisolone, MMF, or dexamethasone. Individual study data and combined data showed that cyclosporin may make little or no difference to the outcomes of chronic kidney disease or kidney failure. It is uncertain whether cyclosporin compared with these comparators in individual or combined analyses makes any difference to the outcomes of hypertension or infection. MMF compared with prednisone may make little or no difference to the likelihood of complete remission (33 participants: RR 1.05, 95% CI 0.58 to 1.88; low certainty evidence), partial remission, complete or partial remission, glomerular filtration rate, or infection. It is uncertain whether other interventions make any difference to outcomes as the certainty of the evidence is very low. It is uncertain whether sparsentan reduces proteinuria to a greater extent than irbesartan. No RCTs, which evaluated corticosteroids, were identified although the KDIGO guidelines recommend corticosteroids as the first treatment for adults with FSGS. The studies identified included participants with steroid-resistant FSGS. Treatment with cyclosporin for at least six months was more likely to achieve complete remission of proteinuria compared with other treatments but there was considerable imprecision due to few studies and small participant numbers. In future studies of existing or new interventions, the investigators must clearly define the populations included in the study to provide appropriate recommendations for patients with primary, genetic or secondary 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.

POS-121 REGIONAL REFERENCE SERVICE GLOMERULAR DISEASES PROFILE - EIGHT-YEAR ANALYSIS

Glomerular diseases are an important etiology of chronic kidney disease and are associated with significant morbidity and mortality related to its clinical evolution. Epidemiological variations of clinical presentation and conduct are frequent. The aim of the study was to make a clinical and/or histopathological characterization of the cases followed up at the Glomerulopathy outpatient clinic of the Nephrology service of a tertiary hospital, a reference for the region, whether or not undergoing renal biopsy. Retrospective analysis of the medical records of patients referred and treated between June 2012 and June 2020. We collected demographic data, clinical presentation and histopathological reports of renal biopsies. Descriptive analysis of sociodemographic data was performed. For a better understanding of the sample, patients were divided into primary vs secondary glomerulopathies and patients with renal biopsy vs without renal biopsy. 350 patients were evaluated, 80.3% underwent renal biopsy. The mean age of all patients at diagnosis of glomerulopathy was 38.5 years (±16.3), with a predominance of females (57.1%) and white race (71.4%). Regarding the characterization of the renal disease presented, 59.7% were defined as primary glomerulopathies. In patients without renal biopsy, the main presentation was isolated hematuria (34.8%) and in biopsied patients, the main presentation was nephrotic syndrome (39.1%). In cases with biopsy, the most frequent primary glomerulopathy was Membranous Nephropathy (23.4%), followed by IgA Nephropathy (22.8%) and Primary Focal Segmental Glomerulosclerosis (21.6%). Among the secondary glomerulopathies, the most frequent was Lupus Nephritis (49.6%), followed by Secondary Focal Segmental Glomerulosclerosis (11.1%) and ANCA-Associated Vasculitis (5.2%). Considering all cases of biopsied glomerulopathies (primary and secondary), the most frequent was lupus nephritis (23.8%). In a specific analysis, 72 patients with renal involvement by lupus were evaluated, with a mean age at diagnosis of 32.4 years (±16.2), predominantly female (76.4%) and white (56.9%). The most frequent initial clinical presentation was nephritic-nephrotic syndrome (26.4%). In the histopathological evaluation, the most frequent class of lupus nephritis was IV (45.8%), followed by classes V (29.2%), III (18.1%) and II (1.4%). Lupus podocytopathy represented 5.5% of cases. During follow-up, 29.2% of patients with lupus nephritis underwent more than one kidney biopsy. A better characterization of the profile of glomerulopathies is essential in planning actions to meet the needs of this specific group of kidney diseases. Cases of lupus nephritis are highlighted, the most frequent glomerular disease in the study population, with a predominance of young patients and with more severe histopathological involvement (about half of the cases with Class IV lupus nephritis).

A Life-Changing Diagnosis of Focal Segmental Glomerulosclerosis in a Young Hispanic Male

Focal segmental glomerulosclerosis is a nephrotic syndrome characterized by significant proteinuria on urinalysis and sclerosis in parts of at least one glomerulus on biopsy. While primary cases are on the rise over the past two decades, it is important to rule out etiologies that cause secondary focal segmental glomerulosclerosis such as HIV and Hepatitis B. The prevalence of this disease over the past few decades has been notably higher in men and in particular African Americans. Here, we discuss a case of a 25-year-old Hispanic man who was found to have focal segmental glomerulosclerosis after initially presenting with facial and upper and lower extremity swelling.

The spectrum of biopsy-proven glomerular diseases in a tertiary Hospital in Southern Brazil

BackgroundThe prevalence and distribution of glomerular diseases differ among countries, and the indication to perform a kidney biopsy varies among centres. In this study, we assessed the prevalence of primary and secondary glomerulopathies based on histological diagnoses, and the correlation between glomerulopathies and demographic and clinical data was evaluated.MethodsIn this study, 1051 kidney biopsies were retrospectively reviewed between 2000 and 2018. Patient demographic, clinical and laboratory data were assessed. The prevalence of primary glomerulonephritis (PG) and secondary glomerulopathies (SG), as well as tubulointerstitial diseases (TIDs), hereditary nephropathies (HNs) and other diagnoses, were determined. The frequency of primary and secondary glomerulopathies was evaluated by age group, and the temporal variation in frequencies across three time periods (2000-2005, 2006-2011, and 2012-2018) was reported.ResultsThe prevalence of SG predominated (52.4%), followed by PG (29.6%), other diagnoses (10.7%), TID (6.6%) and HN (1.1%). Among the primary forms of glomerular disease, focal segmental glomerulosclerosis (FSGS) was the most common (37.3%), followed by IgA nephropathy (IgAN, 24.4%), membranous nephropathy (MN, 18.6%) and minimal change disease (MCD, 8.4%). Lupus nephritis (LN, 41.1%) was most common in patients with SG, followed by diabetic kidney disease (DKD, 17.8%), systemic vasculitis (SV, 10.2%) and secondary FSGS (2nd FSGS, 10%). Nephrotic syndrome was the most common clinical presentation in patients with PG and also in patients with DRD and 2nd FSGS, whereas in patients with IgAN and SV, nephritic syndrome was the main presentation. For the age group between 18 and 50 years, LN, FSGS and IgAN predominated; for patients aged between 51 and 65 years, the proportion of DKD and 2nd FSGS increased, and SV was more common in patients > 65 years. The temporal variation in PG across the three time periods showed a statistically significant increase in IgAN (p = 0.001) and a reduction in FSGS over time (p < 0.001). In SG, there was a reduction in LN (p = 0.027) and an increase in DKD (p < 0.001) over time, with a tendency for 2nd FSGS to decrease over time (p = 0.053).ConclusionsIn the studied kidney biopsy registry, FSGS and IgAN were the most prevalent diagnoses in patients with PG, and LN and DKD were the most prevalent in patients with SG. Nephrotic syndrome was the major indication for biopsy. When comparing the temporal variation in glomerulopathies, there was a reduction in FSGS and an increase in IgAN in patients with PGs over time, and for patients with SGs, there was a reduction in LN with an increase in cases of DKD over time.