scholarly journals Higher Urine Exosomal miR-193a Is Associated With a Higher Probability of Primary Focal Segmental Glomerulosclerosis and an Increased Risk of Poor Prognosis Among Children With Nephrotic Syndrome

2021 ◽  
Vol 9 ◽  
Author(s):  
Lixia Wang ◽  
Jie Wang ◽  
Zhimin Wang ◽  
Jianhua Zhou ◽  
Yu Zhang
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Release Mechanism ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Operating Characteristics ◽  
Glomerular Diseases ◽  
Calcium Dependent ◽  
Segmental Glomerulosclerosis ◽  
Increased Risk ◽  
Stage Renal Disease

Background: In children, focal segmental glomerulosclerosis (FSGS) is one of the most common primary glomerular diseases leading to end-stage renal disease. Exosomes facilitate communication between cells by transporting proteins and microRNAs. We aimed to investigate the utility of urine exosomal miR-193a for diagnosis and prognosis estimation among patients with primary FSGS, and preliminarily explore the regulation mechanism of exosome secretion from podocytes.Methods: Specimens of urine were obtained from patients with primary FSGS, minimal change nephropathy (MCN) and IgA nephropathy (IgAN), followed by exosome isolation. We quantified urine exosomal miR-193a based on quantitative reverse transcription-polymerase chain reaction, and evaluated its applicability using area-under-receiver-operating-characteristics curves (AUROCs). The semiquantitative glomerulosclerosis index (GSI) was used to evaluate the degree of glomerulosclerosis according to the method of Raij et al. We further used FAM-labeled miR-193a-5p to examine exosome shuttling using confocal microscopy for visualization, and explored the regulation mechanism of exosomes release from podocytes using Fluo-3AM dye.Results: Urine exosomal miR-193a levels were significantly higher in patients with primary FSGS than those with MCN and IgAN. The AUROCs for discriminating between primary FSGS and MCN or IgAN were 0.85 and 0.821, respectively. Urine exosomal miR-193a levels positively correlated with GSI in patients with primary FSGS. We further found that kidney tissues from these patients had increased CD63 expression involving podocytes in non-sclerotic tufts. Exosomes from cultured podocytes could transport miR-193a-5p to recipient cells, potentially through a calcium-dependent release mechanism.Conclusion: Urine exosomal miR-193a might be harnessed as a non-invasive marker for diagnosis and outcome assessment among patients with primary FSGS. Exosomes were potential vehicles for miRNAs shuttling between podocytes, and released from podocytes in a calcium-dependent manner.

scholarly journals Challenges in primary focal segmental glomerulosclerosis diagnosis: from the diagnostic algorithm to novel biomarkers

2020 ◽  
Author(s):  
Conxita Jacobs-Cachá ◽  
Ander Vergara ◽  
Clara García-Carro ◽  
Irene Agraz ◽  
Nestor Toapanta-Gaibor ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Focal Segmental Glomerulosclerosis ◽  
Graft Function ◽  
Experimental Studies ◽  
Diagnostic Algorithm ◽  
Disease Recurrence ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
Stage Renal Disease

Abstract Primary or idiopathic focal segmental glomerulosclerosis (FSGS) is a kidney entity that involves the podocytes, leading to heavy proteinuria and in many cases progresses to end-stage renal disease. Idiopathic FSGS has a bad prognosis, as it involves young individuals who, in a considerably high proportion (∼15%), are resistant to corticosteroids and other immunosuppressive treatments as well. Moreover, the disease recurs in 30–50% of patients after kidney transplantation, leading to graft function impairment. It is suspected that this relapsing disease is caused by a circulating factor(s) that would permeabilize the glomerular filtration barrier. However, the exact pathologic mechanism is an unsettled issue. Besides its poor outcome, a major concern of primary FSGS is the complexity to confirm the diagnosis, as it can be confused with other variants or secondary forms of FSGS and also with other glomerular diseases, such as minimal change disease. New efforts to optimize the diagnostic approach are arising to improve knowledge in well-defined primary FSGS cohorts of patients. Follow-up of properly classified primary FSGS patients will allow risk stratification for predicting the response to different treatments. In this review we will focus on the diagnostic algorithm used in idiopathic FSGS both in native kidneys and in disease recurrence after kidney transplantation. We will emphasize those potential confusing factors as well as their detection and prevention. In addition, we will also provide an overview of ongoing studies that recruit large cohorts of glomerulopathy patients (Nephrotic Syndrome Study Network and Cure Glomerulonephropathy, among others) and the experimental studies performed to find novel reliable biomarkers to detect primary FSGS.

scholarly journals Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q10

2013 ◽  
Vol 305 (8) ◽  
pp. F1228-F1238 ◽  
Author(s):  
David L. Gasser ◽  
Cheryl A. Winkler ◽  
Min Peng ◽  
Ping An ◽  
Louise M. McKenzie ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Cell Lines ◽  
Coenzyme Q ◽  
Lymphoblastoid Cell Lines ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Collapsing Glomerulopathy ◽  
Segmental Glomerulosclerosis ◽  
Increased Risk ◽  
Common Causes

Focal segmental glomerulosclerosis (FSGS) and collapsing glomerulopathy are common causes of nephrotic syndrome. Variants in >20 genes, including genes critical for mitochondrial function, have been associated with these podocyte diseases. One such gene, PDSS2, is required for synthesis of the decaprenyl tail of coenzyme Q10 (Q10) in humans. The mouse gene Pdss2 is mutated in the kd/kd mouse model of collapsing glomerulopathy. We examined the hypothesis that human PDSS2 polymorphisms are associated with podocyte diseases. We genotyped 377 patients with primary FSGS or collapsing glomerulopathy, together with 900 controls, for 9 single-nucleotide polymorphisms in the PDSS2 gene in a case-control study. Subjects included 247 African American (AA) and 130 European American (EA) patients and 641 AA and 259 EA controls. Among EAs, a pair of proxy SNPs was significantly associated with podocyte disease, and patients homozygous for one PDSS2 haplotype had a strongly increased risk for podocyte disease. By contrast, the distribution of PDSS2 genotypes and haplotypes was similar in AA patients and controls. Thus a PDSS2 haplotype, which has a frequency of 13% in the EA control population and a homozygote frequency of 1.2%, is associated with a significantly increased risk for FSGS and collapsing glomerulopathy in EAs. Lymphoblastoid cell lines from FSGS patients had significantly less Q10 than cell lines from controls; contrary to expectation, this finding was independent of PDSS2 haplotype. These results suggest that FSGS patients have Q10 deficiency and that this deficiency is manifested in patient-derived lymphoblastoid cell lines.

scholarly journals Focal Segmental Glomerulosclerosis

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.

scholarly journals Novel Haplotype Indicator for End-Stage Renal Disease Progression among Saudi Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-6
Author(s):  
Cyril Cyrus ◽  
Shahanas Chathoth ◽  
Chittibabu Vatte ◽  
Nafie Alrubaish ◽  
Othman Almuhanna ◽  
...  
Keyword(s):  
Renal Disease ◽  
End Stage Renal Disease ◽  
Haplotype Analysis ◽  
Taqman Assay ◽  
Rapid Progression ◽  
High Morbidity ◽  
Glomerular Diseases ◽  
Increased Risk ◽  
Stage Renal Disease ◽  
End Stage

Background. End-stage renal disease (ESRD) is the result of hypertensive nephrosclerosis and chronic glomerular diseases and is associated with high morbidity and mortality. There are strong heritable components in the manifestation of the disease with a genetic predisposition to renal disorders, including focal segmental glomerulosclerosis and arterionephrosclerosis. Recent studies in genetics have examined modifiable risk factors that contribute to renal disease, and this has provided a deep insight into progressive kidney disease. Single-nucleotide polymorphisms at the proximity of SHROOM3, CST3, SLC7A9, and MYH9 genes have been associated with an increased risk of developing CKD and ESRD. Methods. A total of 160 CKD patients and 189 control subjects of Saudi origin participated in the study. Eight polymorphisms (SHROOM3-rs9992101, rs17319721; SLC7A9-rs4805834; MYH9-rs4821480, rs4821481, rs2032487, rs3752462; CST3-rs13038305) were genotyped using TaqMan assay, and the haplotype analysis was done using the HaploView 4.2 software. Results. Haplotype analysis revealed a novel haplotype “E6”-GTTT to be associated significantly with an increased risk for ESRD (p=0.0001) and CKD (p=0.03). Conclusion. CKD is often silent until symptomatic uremia during the advanced stages of the disease. The newly identified haplotype will help recognize patients at risk for a rapid progression of CKD to ESRD. Accurate detection and mapping of the genetic variants facilitates improved risk stratification and development of improved and targeted therapeutic management for CKD.

scholarly journals P0372RITUXIMAB IN IDIOPATHIC FOCAL SEGMENTAL GLOMERULOSCLEROSIS OF THE ADULT: A MULTICENTRE RETROSPECTIVE SURVEY OF 31 PATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Martina Tedesco ◽  
Isabella Pisani ◽  
Marco Allinovi ◽  
Giovanni Casazza ◽  
Lucia Del Vecchio ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Focal Segmental Glomerulosclerosis ◽  
Immunosuppressive Treatment ◽  
Case Series ◽  
Post Transplantation ◽  
Steroid Resistant ◽  
Segmental Glomerulosclerosis ◽  
Steroid Dependent ◽  
Stage Renal Disease

Abstract Background and Aims Idiopathic Focal Segmental Glomerulosclerosis (FSGS) is a rare glomerulonephritis often complicated by a chronic relapsing course frequently characterized by dependency or resistance to immunosuppressive treatment. Moreover, about half of the patients with active disease would develop end-stage renal disease within 10 years from the diagnosis, highlighting the need of novel therapeutic approaches. Rituximab (RTX), a chimeric monoclonal antibody against CD20, showed promising results in pediatric steroid-dependent/frequently relapsing FSGS and in post-transplantation recurrence. However, evidence about its role in the FSGS of the adult is still lacking with small case series suggesting conflicting results. In this study we assess the efficacy of RTX in the largest cohort of adults with FSGS currently available in literature. Methods Adults with biopsy proven idiopathic FSGS treated with RTX were retrospectively identified among several Italian nephrology units. Response to RTX was evaluated at 3, 6, 12 months and, when available, during the long-term follow-up. A positive response (POR) was defined as: (1) proteinuria <3.5 g/die with a decrease >50% compared to baseline, (2) stable renal function (3) decreased or stable dose of glucocorticoids and other immunosuppressants. Severe Adverse Events (SAEs) have been recorded. Results 31 patients have been identified: 18 steroid-dependent, 11 steroid-resistant, and 2 patients with major contraindication to steroid therapy. RTX has been administered at a median of 87 months (IQR 54–96) from the diagnoses using heterogeneous schedules of administration. Overall, the POR rate at 6 months was 52% (steroid-dependent=69%; steroid-resistant=22%). At univariate analyses, POR to RTX at 6 months was associated to the steroid-dependent status (p=0.0347) and a proteinuria at RTX <5 g/die (p=0.0173); a trend towards better response was observed in patients with IgG at RTX <500 mg/dl (p=0.0774). Over the first year of follow-up, the proteinuria and serum albumin significantly improved (respectively, p=0.0021 and p=0.0277 at 12 months), while serum creatinine remained stable (figure). Among treated patients, the median dose of prednisone decreased from 15 mg/die (IQR 12.5–25) at baseline to 10 mg/die (IQR 5–15) at 12 months, while the proportion of patients free from glucocorticoids respectively increased from 42% to 54%. Six patients have been retreated within a year since the first RTX: of these only the 2 patients who have experienced a POR to the first administration obtained a further POR after retreatment. After the 12th month, 11 patients have been followed for a median time of 17 months (IQR 15–33.5): of the 5/11 with a POR at the 12th month, 2/5 maintained a POR without needing further immunosuppression, 2/5 maintained a POR with a pre-emptive RTX based maintenance treatment, 1/5 experienced a relapse successfully managed with RTX needing then a pre-emptive RTX based maintenance therapy able to allow a persistent POR. Overall, 9 SAEs have been recorded with requirement of hospital admission for clinical deterioration being the most frequent. Conclusion RTX may be an option in the FSGS of the adult, especially in the steroid-dependent patients and the ones with less severe nephrotic syndrome. In the responders, a RTX based maintenance therapy may be required.

scholarly journals Recent Advances in Treatments of Primary Focal Segmental Glomerulosclerosis in Children

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
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.

scholarly journals Circulating Permeability Factors in Primary Focal Segmental Glomerulosclerosis: A Review of Proposed Candidates

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Eva Königshausen ◽  
Lorenz Sellin
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Kidney Diseases ◽  
Individual Treatment ◽  
Pathogenic Role ◽  
Urokinase Plasminogen Activator Receptor ◽  
Permeability Factor ◽  
Segmental Glomerulosclerosis ◽  
Long Time ◽  
Stage Renal Disease ◽  
End Stage

Primary focal segmental glomerulosclerosis (FSGS) is a major cause of the nephrotic syndrome and often leads to end-stage renal disease. This review focuses on circulating permeability factors in primary FSGS that have been implicated in the pathogenesis for a long time, partly due to the potential recurrence in renal allografts within hours after transplantation. Recently, three molecules have been proposed as a potential permeability factor by different groups: the soluble urokinase plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor-1 (CLCF-1), and CD40 antibodies. Both CLCF-1 and CD40 antibodies have not been validated by independent research groups yet. Since the identification of suPAR, different studies have questioned the validity of suPAR as a biomarker to distinguish primary FSGS from other proteinuric kidney diseases as well as suPAR’s pathogenic role in podocyte damage. Researchers have suggested that cleaved molecules of suPAR have a pathogenic role in FSGS but further studies are needed to determine this role. In future studies, proposed standards for the research of the permeability factor should be carefully followed. The identification of the permeability factor in primary FSGS would be of great clinical relevance as it could influence potential individual treatment regimen.

scholarly journals Soluble Urokinase Receptors in Focal Segmental Glomerulosclerosis: A Review on the Scientific Point of View

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Andreas Kronbichler ◽  
Moin A. Saleem ◽  
Björn Meijers ◽  
Jae Il Shin
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Point Of View ◽  
Soluble Form ◽  
Glomerular Diseases ◽  
Segmental Glomerulosclerosis ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
End Stage

Focal segmental glomerulosclerosis (FSGS) is one of the primary glomerular disorders in both children and adults which can progress to end-stage renal failure. Although there are genetic and secondary causes, circulating factors have also been regarded as an important factor in the pathogenesis of FSGS, because about 40% of the patients with FSGS have recurrence after renal transplantation. Soluble urokinase-type plasminogen activator receptor (suPAR) is a soluble form of uPAR, which is a membrane-bound protein linked to GPI in various immunologically active cells, including podocytes. It has recently been suggested as a potential circulating factor in FSGS by in vitro podocyte experiments, in vivo mice models, and human studies. However, there have also been controversies on this issue, because subsequent studies showed conflicting results. suPAR levels were also increased in patients with other glomerular diseases and were inversely correlated with estimated glomerular filtration rate. Nevertheless, there has been no balanced review on this issue. In this review, we compare the conflicting data on the involvement of suPAR in the pathogenesis of FSGS and shed light on interpretation by taking into account many points and the potential variables and confounders influencing serum suPAR levels.

scholarly journals Proteomic profile of mesothelial exosomes isolated from peritoneal dialysis effluent of children with focal segmental glomerulosclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maurizio Bruschi ◽  
Edoardo La Porta ◽  
Isabella Panfoli ◽  
Giovanni Candiano ◽  
Andrea Petretto ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Kidney Disease ◽  
Focal Segmental Glomerulosclerosis ◽  
Mass Spectrometry Analysis ◽  
Causative Role ◽  
Focal Segmental Glomerular Sclerosis ◽  
Segmental Glomerulosclerosis ◽  
Potential Biomarker ◽  
Increased Risk ◽  
Peritoneal Dialysis Effluent

AbstractPeritoneal dialysis (PD) is the worldwide recognized preferred dialysis treatment for children affected by end-stage kidney disease (ESKD). However, due to the unphysiological composition of PD fluids, the peritoneal membrane (PM) of these patients may undergo structural and functional alterations, which may cause fibrosis. Several factors may accelerate this process and primary kidney disease may have a causative role. In particular, patients affected by steroid resistant primary focal segmental glomerulosclerosis, a rare glomerular disease leading to nephrotic syndrome and ESKD, seem more prone to develop peritoneal fibrosis. The mechanism causing this predisposition is still unrecognized. To better define this condition, we carried out, for the first time, a new comprehensive comparative proteomic mass spectrometry analysis of mesothelial exosomes from peritoneal dialysis effluent (PDE) of 6 pediatric patients with focal segmental glomerular sclerosis (FSGS) versus 6 patients affected by other primary renal diseases (No FSGS). Our omic study demonstrated that, despite the high overlap in the protein milieu between the two study groups, machine learning allowed to identify a core list of 40 proteins, with ANXA13 as most promising potential biomarker, to distinguish, in our patient population, peritoneal dialysis effluent exosomes of FSGS from No FSGS patients (with 100% accuracy). Additionally, the Weight Gene Co-expression Network Analysis algorithm identified 17 proteins, with PTP4A1 as the most statistically significant biomarker associated to PD vintage and decreased PM function. Altogether, our data suggest that mesothelial cells of FSGS patients are more prone to activate a pro-fibrotic machinery. The role of the proposed biomarkers in the PM pathology deserves further investigation. Our results need further investigations in a larger population to corroborate these findings and investigate a possible increased risk of PM loss of function or development of encapsulating peritoneal sclerosis in FSGS patients, thus to eventually carry out changes in PD treatment and management or implement new solutions.

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