A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis
Haiyang YuMykyta ArtomovSebastian BrählerM. StänderGhaidan A. ShamsanMatthew G. SampsonJ. Michael WhiteMatthias KretzlerJeffrey H. MinerSanjay JainCheryl A. WinklerRobi D. MitraJeffrey B. KoppMark J. DalyAndréy S. Shaw
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Abstract:
Focal segmental glomerulosclerosis (FSGS) is a syndrome that involves kidney podocyte dysfunction and causes chronic kidney disease. Multiple factors including chemical toxicity, inflammation, and infection underlie FSGS; however, highly penetrant disease genes have been identified in a small fraction of patients with a family history of FSGS. Variants of apolipoprotein L1 (APOL1) have been linked to FSGS in African Americans with HIV or hypertension, supporting the proposal that genetic factors enhance FSGS susceptibility. Here, we used sequencing to investigate whether genetics plays a role in the majority of FSGS cases that are identified as primary or sporadic FSGS and have no known cause. Given the limited number of biopsy-proven cases with ethnically matched controls, we devised an analytic strategy to identify and rank potential candidate genes and used an animal model for validation. Nine candidate FSGS susceptibility genes were identified in our patient cohort, and three were validated using a high-throughput mouse method that we developed. Specifically, we introduced a podocyte-specific, doxycycline-inducible transactivator into a murine embryonic stem cell line with an FSGS-susceptible genetic background that allows shRNA-mediated targeting of candidate genes in the adult kidney. Our analysis supports a broader role for genetic susceptibility of both sporadic and familial cases of FSGS and provides a tool to rapidly evaluate candidate FSGS-associated genes.Keywords:
Candidate gene
Focal segmental glomerulosclerosis (FSGS) is an aggressive disease often leading to renal failure. It might be difficult to distinguish FSGS from minimal change disease (MCD) when renal biopsies from patients with nephrotic syndrome do not indicate sclerotic lesions. Based on the rat model study, reducing podocyte density (average podocyte number per glomerular volume), which suggests relative podocyte depletion, could be seen in FSGS, but not MCD. Here, we compared the following histological parameters of FSGS and MCD in renal biopsy specimens of nephrotic patients.
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Nephrotic syndrome is one of the most common childhood kidney diseases. It is mostly found in the age group of 2 to 8 years. Around 10%–15% of nephrotic syndrome cases are non-responders of steroid treatment (SRNS). Angiotensin converting enzyme (ACE) (I/D) gene association studies are important for detecting kidney disease and herein we assessed the association of ACE (I/D) polymorphism with nephrotic syndrome in South Indian children. We recruited 260 nephrotic syndrome (162 boys and 98 girls) and 218 (140 boys and 78 girls) control subjects. ACE I/D polymorphism was analyzed by PCR using genotype allele specific primers. In ACE (I/D), we did not find significant association for the ungrouped data of nephrotic syndrome children and the control subjects. Kidney biopsies were done in 86 nephrotic syndrome cases (minimal change disease, n = 51; focal segmental glomerulosclerosis, n = 27; diffuse mesangial proliferation, n = 8). We segregated them into the minimal change disease / focal segmental glomerulosclerosis groups and observed that the ACE 'D' allele was identified with borderline significance in cases of focal segmental glomerulosclerosis and the 'Ⅰ' allele was assessed as having very weak association in cases of minimal change disease. 'Ⅱ' genotype was weakly associated with minimal change disease. Gender specific analysis revealed weak association of 'ID' genotype with female nephrotic syndrome in females. Dominant expression of DD genotype was observed in males with nephrotic syndrome. Our finding indicated that ACE (I/D) has moderate association with focal segmental glomerulosclerosis. However, due to the limited number of biopsy proven focal segmental glomerulosclerosis subjects enrolled, further studies are required to confirm these results.
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Introduction: Nephrotic syndrome is the most common chronic renal disease in children. Mostly, it is controlled by steroids. Many underlying pathologies exist in patients with steroid-resistant nephrotic syndrome (SRNS). Among them are ‘focal segmental glomerulosclerosis (FSGS) and ‘minimal change disease’ (MCD). Examining patients’ clinicopathologic characteristics can be helpful by giving an insight into the etiology of steroid resistance and determining patient prognosis. Material and Methods : This cross-sectional study was performed in ‘Children’s Medical Center’ between 2001 and 2011. From 150 patients biopsied, seventy-one children with SRNS, aged 1-14 years, were included. Results: Among 150 patients biopsied, 71 children (47.3%) had steroid-resistant nephrotic syndrome. Forty-four (62%) of these were boys. Upon pathologic investigation of SRNS cases, FSGS came in first, with the highest prevalence at a rate of 32.4%, and MGN came in last, at a rate of 5.6%. The mean age of disease onset was 4.7 years and the mean age of undergoing biopsy was six years. Conclusions: In this study, the predominant pathologic pattern of steroid-resistant nephrotic syndrome was FSGS, a finding similar to that of most studies conducted in this field. MCD was observed in 21.1% of patients, which indicates the variety in reporting renal lesions, particularly, regarding the diagnoses of MCD, mesangio-proliferative glomerulonephritis and early stages of FSGS. Keywords : Steroid-resistant; Nephrotic syndrome; Child.
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Membranous Nephropathy
Nephrology
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Focal segmental glomerulosclerosis (FSGS) is a glomerular disease defined by a characteristic histologic pattern that occurs either as a primary kidney disease (primary FSGS) or as a result of a systemic illness (secondary FSGS). Proteinuria, often in the nephrotic range, is the hallmark of FSGS. The occurrence of nephrotic syndrome after an insect sting is rarely reported in the literature. We present a case of nephrotic syndrome with focal segmental glomerulosclerosis with a glomerular tip lesion developing after an insect bite.A 51-year-old Caucasian female was bitten by an insect on her left leg, which immediately became swollen. Generalized edema developed and she was admitted for further investigations. Urinary 24-h protein excretion was 7 g. Percutaneous renal biopsy was performed and showed focal segmental glomerulosclerosis of the tip variant. Nephrotic syndrome was steroid-resistant, and when we added cyclophosphamide for 8 weeks complete remission was achieved. There was no relapse of the disease during the 2-month follow-up.This report demonstrates the useful role of cyclophosphamide in the treatment of steroid-resistant nephrotic syndrome due to FSGS with glomerular tip lesion. A causal relationship between the insect bite and the nephrotic syndrome is suggested and an immune response could be responsible for the nephrotic syndrome.
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Nephrosis
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The treatment of primary nephrotic syndrome such as minimal change nephropathy, membranous nephropathy, and focal segmental glomerulosclerosis nephropathy remains challenging. Whilst most cases of idiopathic nephrotic syndrome respond to steroid therapy and experience a limited number of relapses prior to complete remission, some cases suffer from frequent relapses and become steroid dependent or are primarily steroid resistant. Treatment options are limited to immunosuppressive drugs with significant side effect profiles. New modalities targeting novel pathways in the pathogenesis of nephrotic syndrome are actively sought. Here we report the case of a patient with steroid dependent focal segmental glomerulosclerosis (FSGS) nephrotic syndrome with a favourable response to a novel proteasome inhibitor saquinavir.
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