A novel truncating PAX2 mutation in a boy with renal coloboma syndrome with focal segmental glomerulosclerosis causing rapid progression to end-stage kidney disease

Background: Focal segmental glomerulosclerosis (FSGS) is a heterogeneic glomerular disease. Risk factors for end- stage kidney disease (ESKD) and impact of immunosuppression treatment (IST) has varied in previously published cohorts. These cohorts were limited by relatively small case numbers, short follow up, lack of racial/ethnic diversity, a mix of adult and pediatric patients, lack of RAAS inhibition, or lack of subgroup analysis of IST. Methods: We compared demographics, clinical characteristics, histopathology and IST to long term renal survival in a large, ethnically diverse, adult cohort of 338 biopsy-proven FSGS cases with long term follow up in the era of RAAS inhibition using data from the United States Department of Defense health care network. Results: Multivariate analysis showed that nephrotic range proteinuria (NRP), estimated glomerular filtration rate <60 ml/min/1.73m2, hypoalbuminemia, interstitial fibrosis and tubular atrophy, and interstitial inflammation at diagnosis as well as the absence of remission were all associated with worse long term renal survival. IgM, C3, and a combination of IgM/C3 immunofluorescence staining were not associated with reduced renal survival. IST was not associated with improved renal survival in the whole cohort, or in a subgroup with NRP. However, IST was associated with better renal survival in a subgroup of FSGS cases with both NRP and hypoalbuminemia and hypoalbuminemia alone. Conclusion: Our study suggests that IST should be reserved for FSGS patients with nephrotic syndrome. It also introduces interstitial inflammation as a potential risk factor for ESKD and does not support the proposed pathogenicity of IgM and complement activation.

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Kidney Outcome in Primary Focal Segmental Glomerulosclerosis (FSGS) by Using a Predictive Model

10.21203/rs.2.11407/v1 ◽

2019 ◽

Author(s):

Shahrzad Ossareh ◽

Mansoureh Yahyaei ◽

Mojgan Asgari ◽

Hanri Afghahi

Keyword(s):

Kidney Disease ◽

Predictive Model ◽

Focal Segmental Glomerulosclerosis ◽

Interstitial Fibrosis ◽

Cox Model ◽

End Stage Kidney Disease ◽

Model Interaction ◽

Segmental Glomerulosclerosis ◽

End Stage ◽

Adjusted Model

Abstract Background: Focal segmental glomerulosclerosis (FSGS) is one of the important causes of end stage kidney disease (ESKD). We evaluated the risk factors of progression of primary FSGS to chronic kidney disease (CKD) or ESKD with a predictive model including clinical and histological predictors. Methods: 201 patients with primary FSGS (59% male, mean age: 38±15 years), were studied. Time-dependent Cox model and C statistics were used for the predictive model. Interaction and correlation between independent variables were estimated. Results: During 55±27 months of follow-up, 82 patients (41%) developed CKD (46) or ESKD (36) patients. In adjusted model, 1 unit of higher serum creatinine (SCr) at baseline (HR:1.39, 95%CI: 1.15-1.70) and 1% increase in glomeruli with segmental glomerulosclerosis (SGS) (HR: 1.03, 95% CI: 1.02-1.04) or interstitial fibrosis/tubular atrophy (IF/TA) (HR: 1.03, 95% CI: 1.01-1.05) increased the risk of CKD/ESKD. In adjusted model, higher baseline proteinuria and collapsing variant were not associated with risk of CKD/ESKD. By adding SGS and IF/TA scores to baseline SCr in the model, discrimination by C statistics was 0.83 (95%CI: 0.77-0.90). Median renal survival was 3.1 years (95% CI: 2.2-4.1 years) in patients with highest risks score (baseline eGFR<25 ml/min/1.73 m2+ IF/TA/SGS> 50%), and 8.1 years (95% CI: 7.7-8.6 years).in those with lowest score (baseline eGFR>75 ml/min/1.73 m2+ IF/TA/SGS <5%). Conclusion: In primary FSGS, higher baseline SCr, increased SGS and IF/TA, but not baseline proteinuria and collapsing pathology, were the predictors for CKD/ESKD. These findings indicated the importance of timely detection and referral in prognosis of primary FSGS. Keywords: Focal segmental glomerulosclerosis, End stage kidney disease, Pathology

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Disease causing mutations in inverted formin 2 regulate its binding to G-actin, F-actin capping protein (CapZ α-1) and profilin 2

Bioscience Reports ◽

10.1042/bsr20150252 ◽

2016 ◽

Vol 36 (1) ◽

Cited By ~ 13

Author(s):

Ruth Rollason ◽

Matthew Wherlock ◽

Jenny A. Heath ◽

Kate J. Heesom ◽

Moin A. Saleem ◽

...

Keyword(s):

Kidney Disease ◽

Focal Segmental Glomerulosclerosis ◽

End Stage Kidney Disease ◽

Capping Protein ◽

Segmental Glomerulosclerosis ◽

Actin Capping Protein ◽

End Stage ◽

Actin Capping

Mutations in inverted formin 2 (INF2) cause focal segmental glomerulosclerosis (FSGS) a major cause of end-stage kidney disease. In the present study, we show that disease associated mutations reduce INF2 auto-inhibition and cause increased binding to monomeric G-actin, profilin 2 and the F-actin capping protein, CapZ α-1.

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Clinical and laboratory features that differentiate familial from sporadic focal segmental glomerulosclerosis in adolescents and adults

Journal of Rare Diseases Research & Treatment ◽

10.29245/2572-9411/2021/1.1199 ◽

2021 ◽

Vol 6 (1) ◽

pp. 1-5

Author(s):

Maria Goretti Polito ◽

Michelle Tiveron Passos ◽

Danilo Euclides Fernandes ◽

Gianna Mastroianni-Kirsztajn

Keyword(s):

Serum Albumin ◽

Focal Segmental Glomerulosclerosis ◽

Steroid Resistance ◽

End Stage Kidney Disease ◽

Steroid Resistant ◽

Best Management ◽

Segmental Glomerulosclerosis ◽

Laboratory Features ◽

Adolescents And Adults ◽

End Stage

Background: Focal segmental glomerulosclerosis (FSGS) is an important cause of end-stage kidney disease in children and adults. Although most cases are sporadic (s), familial (f) presentation is also described. The purpose of the present study was to establish clinical and laboratory profiles of fFSGS vs. primary sFSGS, contributing to the distinguishing diagnosis in clinical practice and best management, in particular when mutation analysis is not available. Methods: Demographic, clinical and laboratorial parameters were studied in 124 patients 12 years and older with FSGS, subdivided in sFSGS (n=89) and fFSGS (n=35). Results: General and clinical features were similar, as well as serum creatinine at disease presentation. Proteinuria levels were more frequently ≥ 3g/day in sFSGS (63.8%) than in fFSGS (44%, p=0.080), and serum albumin levels were < 3.0 g/dL in 45.8% and 20%, respectively (p=0.046). The groups were statistically different regarding steroid resistance, corresponding to 60% in sFSGS and 100% in fFSGS (p=0.001). Conclusions: The studied groups were clinically similar, except that proteinuria tended to be higher (nephrotic range) and serum albumin was lower in sFSGS vs. fFSGS. In addition, all treated fFSGS patients were steroid resistant. At presentation it is important to characterize if the patient has fFSGS, that will contribute to further disease management, and disease history will be the first clue for such differential diagnosis.

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Chronic kidney disease: a review of proteomic and metabolomic approaches to membranous glomerulonephritis, focal segmental glomerulosclerosis, and IgA nephropathy biomarkers

Proteome Science ◽

10.1186/s12953-019-0155-y ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 4

Author(s):

Amir Taherkhani ◽

Reyhaneh Farrokhi Yekta ◽

Maede Mohseni ◽

Massoud Saidijam ◽

Afsaneh Arefi Oskouie

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Iga Nephropathy ◽

Focal Segmental Glomerulosclerosis ◽

Membranous Glomerulonephritis ◽

Renal Diseases ◽

Segmental Glomerulosclerosis ◽

Therapeutic Procedures ◽

Definition Of ◽

End Stage

AbstractChronic Kidney Disease (CKD) is a global health problem annually affecting millions of people around the world. It is a comprehensive syndrome, and various factors may contribute to its occurrence. In this study, it was attempted to provide an accurate definition of chronic kidney disease; followed by focusing and discussing on molecular pathogenesis, novel diagnosis approaches based on biomarkers, recent effective antigens and new therapeutic procedures related to high-risk chronic kidney disease such as membranous glomerulonephritis, focal segmental glomerulosclerosis, and IgA nephropathy, which may lead to end-stage renal diseases. Additionally, a considerable number of metabolites and proteins that have previously been discovered and recommended as potential biomarkers of various CKDs using ‘-omics-’ technologies, proteomics, and metabolomics were reviewed.

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Kidney Outcome in Primary Focal Segmental Glomerulosclerosis (FSGS) by Using a Predictive Model

10.21203/rs.2.11407/v3 ◽

2020 ◽

Author(s):

Shahrzad Ossareh ◽

Mansoureh Yahyaei ◽

Mojgan Asgari ◽

Hanri Afghahi

Keyword(s):

Kidney Disease ◽

Predictive Model ◽

Focal Segmental Glomerulosclerosis ◽

Interstitial Fibrosis ◽

Cox Model ◽

Tubular Atrophy ◽

Model Interaction ◽

Segmental Glomerulosclerosis ◽

End Stage ◽

Adjusted Model

Abstract Background: Focal segmental glomerulosclerosis (FSGS) is one of the important causes of end stage kidney disease (ESKD). We evaluated the risk factors of progression of primary FSGS to chronic kidney disease (CKD) or ESKD with a predictive model including clinical and histological predictors.Methods: 201 patients with primary FSGS (59% male, mean age: 38±15 years), were studied. Time-dependent Cox model and C statistics were used for the predictive model. Interaction and correlation between independent variables were estimated.Results: During 55±27 months of follow-up, 82 patients (41%) developed CKD (46) or ESKD (36) patients. In adjusted model, 1 unit of higher serum creatinine (SCr) at baseline (HR:1.39, 95%CI: 1.15-1.70) and 1% increase in glomeruli with segmental glomerulosclerosis (SGS) (HR: 1.03, 95% CI: 1.02-1.04) or interstitial fibrosis/tubular atrophy (IF/TA) (HR: 1.03, 95% CI: 1.01-1.05) increased the risk of CKD/ESKD. In adjusted model, higher baseline proteinuria and collapsing variant were not associated with risk of CKD/ESKD. By adding SGS and IF/TA scores to baseline SCr in the model, discrimination by C statistics was 0.83 (95%CI: 0.77-0.90). Median renal survival was 3.1 years (95% CI: 2.2-4.1 years) in patients with highest risks score (baseline eGFR<25 ml/min/1.73 m2+ IF/TA/SGS> 50%), and 8.1 years (95% CI: 7.7-8.6 years).in those with lowest score (baseline eGFR>75 ml/min/1.73 m2+ IF/TA/SGS <5%).Conclusion: In primary FSGS, higher baseline SCr, increased SGS and IF/TA, but not baseline proteinuria and collapsing pathology, were the predictors for CKD/ESKD. These findings indicated the importance of timely detection and referral in prognosis of primary FSGS.

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Update on Recurrent Focal Segmental Glomerulosclerosis in Kidney Transplantation

Nephron ◽

10.1159/000510748 ◽

2020 ◽

pp. 1-6

Author(s):

Jun Shoji ◽

Akiko Mii ◽

Mika Terasaki ◽

Akira Shimizu

Keyword(s):

Kidney Transplantation ◽

Focal Segmental Glomerulosclerosis ◽

Rapid Progression ◽

Segmental Glomerulosclerosis ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

History Of ◽

Stage Renal Disease ◽

End Stage

Background: Focal segmental glomerulosclerosis (FSGS) is a clinicopathological syndrome characterized by nephrotic-range proteinuria with high incidence of progression to end-stage renal disease (ESRD). In primary FSGS, 40–60% of patients develop ESRD within 10–20 years. Summary: Recurrence of FSGS after kidney transplantation is frequent and is associated with poor allograft survival. The risk factors for recurrent FSGS include onset of FSGS during childhood, rapid progression of primary FSGS to ESRD, history of recurrent FSGS in previous allograft, and diffuse mesangial hypercellularity or collapsing variant of FSGS in the native kidney. The early histological findings of recurrent FSGS consist of unremarkable glomerular changes on light microscopy but significant podocyte effacement on electron microscopy; the loss of foot processes with eventual dropout of podocytes leads to the development of segmental lesions in the glomerulus. Experimental and clinical data suggest the existence of circulating permeability factors, such as soluble urokinase-type plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor-1 (CLCF-1), CD40 axis, and apolipoprotein A-Ib (ApoA-Ib), in the pathogenesis of recurrent FSGS. These biomarkers including circulating permeability factors may facilitate earlier diagnosis of FSGS posttransplant and may guide in the development of novel therapies that may be more effective and improve long-term outcomes in kidney transplantation. Key Messages: Several studies have suggested the possible circulating permeability factors, such as suPAR, CLCF-1, CD40 axis, and ApoA-Ib, in the pathogenesis and disease progression of FSGS and recurrent FSGS. Further studies should be performed to elucidate the true essential biomarker(s) associated with the onset and progression of FSGS as well as recurrent FSGS.

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Diverse Renal Phenotypes Observed in a Single Family with a Genetic Mutation in Paired Box Protein 2

Case Reports in Nephrology and Dialysis ◽

10.1159/000445679 ◽

2016 ◽

Vol 6 (1) ◽

pp. 61-69 ◽

Cited By ~ 3

Author(s):

Yoichi Iwafuchi ◽

Tetsuo Morioka ◽

Takashi Morita ◽

Toshio Yanagihara ◽

Yuko Oyama ◽

...

Keyword(s):

Focal Segmental Glomerulosclerosis ◽

Genetic Mutation ◽

Single Family ◽

Renal Anomalies ◽

Renal Hypoplasia ◽

Exon 2 ◽

Segmental Glomerulosclerosis ◽

Renal Coloboma Syndrome ◽

Stage Renal Disease ◽

End Stage

A common renal phenotype of paired box protein 2 (PAX2) mutations is renal coloboma syndrome. We report a single family with diverse renal phenotypes associated with PAX2 mutation. The proband presented steroid-resistant focal segmental glomerulosclerosis with optic coloboma, whereas his two sons showed severe renal hypoplasia with end-stage renal disease, with or without optic coloboma. In all three cases, a heterozygous PAX2 genetic mutation was identified (exon 2; NM_003987.3:c.76dupG, p.Val26Glyfs*28). Based on histopathological findings of the proband, we hypothesized that autophagic dysfunction was associated with the pathophysiology of the focal segmental glomerulosclerosis with PAX2 mutation. Detailed funduscopic examination - including the optic disc - might be useful for the diagnosis of renal anomalies associated with PAX2 mutation.

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