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

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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Recent Advances in Treatments of Primary Focal Segmental Glomerulosclerosis in Children

BioMed Research International ◽

10.1155/2016/3053706 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Kyoung Hee Han ◽

Seong Heon Kim

Keyword(s):

Focal Segmental Glomerulosclerosis ◽

Calcineurin Inhibitors ◽

Steroid Treatment ◽

Renal Survival ◽

Steroid Resistant ◽

Segmental Glomerulosclerosis ◽

Risk Of Progression ◽

Traditional Therapies ◽

Stage Renal Disease ◽

End Stage

Focal segmental glomerulosclerosis (FSGS) is a nephrotic syndrome. Up to around 80% of cases of primary FSGS are resistant to steroid treatment. A large proportion of patients with steroid-resistant FSGS progress to end-stage renal disease. The purpose of treatment is to obtain a complete remission of proteinuria, a necessary step that precedes improved renal survival and reduces the risk of progression to chronic kidney disease. When this is not possible, the secondary goal is a partial remission of proteinuria. Reduction or remission of proteinuria is the most important factor predictive of renal survival. We will review the current updated strategies for treatment of primary FSGS in children, including traditional therapies consisting of corticosteroids and calcineurin inhibitors and novel therapies such as rituximab, abatacept, adalimumab, and fresolimumab.

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The podocin V260E mutation predicts steroid resistant nephrotic syndrome in black South African children with focal segmental glomerulosclerosis

Communications Biology ◽

10.1038/s42003-019-0658-1 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Melanie A. Govender ◽

June Fabian ◽

Errol Gottlich ◽

Cecil Levy ◽

Glenda Moonsamy ◽

...

Keyword(s):

Nephrotic Syndrome ◽

South African ◽

Focal Segmental Glomerulosclerosis ◽

Steroid Resistance ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Black South African ◽

African Children ◽

Segmental Glomerulosclerosis ◽

South African Children

AbstractIn black African children with focal segmental glomerulosclerosis (FSGS) there are high rates of steroid resistance. The aim was to determine genetic associations with apolipoprotein L1 (APOL1) renal risk variants and podocin (NPHS2) variants in 30 unrelated black South African children with FSGS. Three APOL1 variants were genotyped and the exons of the NPHS2 gene sequenced in the cases and controls. APOL1 risk alleles show a modest association with steroid sensitive nephrotic syndrome (SSNS) and steroid resistant nephrotic syndrome (SRNS). The NPHS2 V260E variant was present in SRNS cases (V/V = 5; V/E = 4; E/E = 11), and was absent in SSNS cases. Haplotype analysis suggests a single mutation origin for V260E and it was associated with a decline in kidney function over a 60-month period (p = 0.026). The V260E variant is a good predictor of autosomal recessive SRNS in black South African children and could provide useful information in a clinical setting.

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Focal Segmental Glomerulosclerosis, Risk Factors for End Stage Kidney Disease, and Response to Immunosuppression

Kidney360 ◽

10.34067/kid.0006172020 ◽

2020 ◽

pp. 10.34067/KID.0006172020

Author(s):

Benjamin M. Forster ◽

Robert Nee ◽

Dustin J. Little ◽

Peter J. Greasley ◽

James B. Hughes ◽

...

Keyword(s):

Risk Factors ◽

Kidney Disease ◽

Focal Segmental Glomerulosclerosis ◽

Renal Survival ◽

End Stage Kidney Disease ◽

Interstitial Inflammation ◽

Segmental Glomerulosclerosis ◽

End Stage

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

CEN Case Reports ◽

10.1007/s13730-019-00419-y ◽

2019 ◽

Vol 9 (1) ◽

pp. 19-23 ◽

Cited By ~ 1

Author(s):

Ken Saida ◽

Koichi Kamei ◽

Naoya Morisada ◽

Masao Ogura ◽

Kentaro Ogata ◽

...

Keyword(s):

Kidney Disease ◽

Focal Segmental Glomerulosclerosis ◽

Rapid Progression ◽

End Stage Kidney Disease ◽

Segmental Glomerulosclerosis ◽

Renal Coloboma Syndrome ◽

End Stage

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Case Report: Novel Dietary Supplementation Associated With Kidney Recovery and Reduction in Proteinuria in a Dialysis Dependent Patient Secondary to Steroid Resistant Minimal Change Disease

Frontiers in Pediatrics ◽

10.3389/fped.2021.614948 ◽

2021 ◽

Vol 9 ◽

Author(s):

Rasheed A. Gbadegesin ◽

Loren P. Herrera Hernandez ◽

Patrick D. Brophy

Keyword(s):

Nephrotic Syndrome ◽

Kidney Disease ◽

Minimal Change Disease ◽

Minimal Change ◽

Steroid Resistance ◽

Small Subset ◽

Disease Course ◽

End Stage Kidney Disease ◽

Steroid Resistant ◽

End Stage

Minimal change disease (MCD) is the most common cause of nephrotic syndrome worldwide. For decades, the foundation of the treatment has been corticosteroids. However, relapse rate is high and up to 40% of patients develop frequent relapsing/steroid dependent course and one third become steroid resistant. This requires treatment with repeated courses of corticosteroids, and second and third line immunomodulators increasing the incidence of drug related adverse effects. More recently, there have been reports of a very small subset of Nephrotic Syndrome (NS) patients who are initially steroid sensitive and later become secondarily steroid resistant. The disease course in this small subset is often protracted leading ultimately to end stage kidney disease requiring dialysis or kidney transplantation. Unfortunately, patients with this disease course do not do well post transplantation because 80% of them will develop disease recurrence that will ultimately lead to graft failure. Few approaches have been tried over many years to reduce the frequency of relapses, and steroid dependence and there is absolutely no therapeutic intervention for patients who develop secondary steroid resistance. Nonetheless, their therapeutic index is low, evidencing the need of a safer complementary treatment. Several hypotheses, including an oxidative stress-mediated mechanism, and immune dysregulation have been proposed to date to explain the underlying mechanism of Minimal Change Disease (MCD) but its specific etiology remains elusive. Here, we report a case of a 54-year-old man with steroid and cyclosporine resistant MCD. The patient rapidly progressed to end stage kidney disease requiring initiation of chronic dialysis. Intradialytic parenteral nutrition (IDPN), albumin infusion along with a proprietary dietary supplement, as part of the supportive therapy, led to kidney function recovery and complete remission of MCD without relapses.

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Prevalence, Genetics, and Clinical Features of Patients Carrying Podocin Mutations in Steroid-Resistant Nonfamilial Focal Segmental Glomerulosclerosis

Journal of the American Society of Nephrology ◽

10.1681/asn.v12122742 ◽

2001 ◽

Vol 12 (12) ◽

pp. 2742-2746 ◽

Cited By ~ 1

Author(s):

Gianluca Caridi ◽

Roberta Bertelli ◽

Alba Carrea ◽

Marco Di Duca ◽

Paolo Catarsi ◽

...

Keyword(s):

Renal Failure ◽

Nephrotic Syndrome ◽

Focal Segmental Glomerulosclerosis ◽

Founder Effect ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

End Stage Renal Failure ◽

Segmental Glomerulosclerosis ◽

End Stage ◽

Nphs2 Gene

ABSTRACT. Podocin mutations (NPHS2 gene) are responsible for the autosomal recessive form of steroid-resistant nephrotic syndrome. As a result of a screening for these gene alterations in a cohort of Italian patients with nonfamilial nephrotic syndrome and histologic focal segmental glomerulosclerosis (FSGS), nine patients with NPHS2 gene homozygous or composite heterozygous mutations were found. In addition to the previously described defects, two novel mutations at exon 4 were identified (frameshift, L169P); four single nucleotide polymorphisms (SNPs) and one dinucleotide repeat were also identified. On the basis of haplotype analysis, a founder effect was suggested for the 419delG mutation, the most frequently observed in the patients studied. Patients carrying NPHS2 mutations and without a family history of nephrotic syndrome were indistinguishable from those with idiopathic FSGS on the basis of the clinical phenotype. Two of the nine patients had normal renal function at 3 and 10 yr of age, despite the presence of the nephrotic syndrome. The other seven had reached end-stage renal failure at a mean age of 9.6 yr (range, 4 to 17 yr) and had received renal allografts. In those presenting with end-stage renal failure, the clinical and laboratory features both before and after transplantation were similar, including the age at onset, the amount of proteinuria, and the absence of any response to steroids and other immunosuppressants. Finally, two children presented recurrence of mild proteinuria after transplantation, which promptly remitted after plasmapheresis combined with cyclophosphamide. These data demonstrate that podocin mutations in nonfamilial cases of steroid-resistant nephrotic syndrome are frequent and may be due in one case to a founder effect. The pretransplantation and posttransplantation outcomes in the group of patients with mutations of the podocin gene are similar to classical idiopathic FSGS, including the possibility of recurrence of proteinuria that is mild and responsive to plasmapheresis. These observations support a role of molecular screening of the podocin gene in patients with nephrotic syndrome before immunosuppressive treatment is started.

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Focal Segmental Glomerulosclerosis

Journal of the American Society of Nephrology ◽

10.1681/asn.v1091900 ◽

1999 ◽

Vol 10 (9) ◽

pp. 1900-1907

Author(s):

MELVIN M. SCHWARTZ ◽

JONI EVANS ◽

RAY BAIN ◽

STEPHEN M. KORBET

Keyword(s):

Serum Creatinine ◽

Focal Segmental Glomerulosclerosis ◽

End Stage Renal Disease ◽

Poor Response ◽

Steroid Treatment ◽

Response To Treatment ◽

Therapeutic Trial ◽

Segmental Glomerulosclerosis ◽

Stage Renal Disease ◽

End Stage

Abstract. The cellular lesion (CELL), seen in some patients with primary focal segmental glomerulosclerosis (FSGS), comprises proliferation, hypertrophy, and pathologic changes in the cells overlying the glomerular scar. The prognosis of the cellular lesion was retrospectively studied in 100 patients with FSGS (43 had FSGS-CELL and 57 had FSGS without the cellular lesion (classic segmental scar [CS]). Patients with the FSGS-CELL lesion were more often black and severely proteinuric and developed more end-stage renal disease (ESRD). Nephrotic patients with FSGS-CELL (n = 39) were more proteinuric at presentation than patients with FSGS-CS (n = 36). ESRD developed more frequently in patients with the FSGS-CELL (17 of 39, 44% versus 5 of 36, 14%, P = 0.005), and patients with extensive FSGS-CELL (≥ 20% glomeruli) were mainly black (94%), severely nephrotic (67%, >10 g/d), and had a poor response to treatment (23% remission). In nephrotic patients, initial serum creatinine, interstitial expansion ≥20%, and CELL independently predicted ESRD. However, the rates of remission in treated nephrotic patients with FSGS-CELL and FSGS-CS were the same (9 of 17, 53% versus 17 of 39, 52%), and patients in both groups who achieved a remission had a 5-yr survival of 100%. Steroid treatment was the only variable that predicted remission. Patients with the FSGS-CELL have an increased prevalence of ESRD, but the improved prognosis associated with remission is so significant that a therapeutic trial is warranted in all nephrotic FSGS patients, regardless of the presence of the cellular lesion.

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