scholarly journals Podocyte foot process effacement as a diagnostic tool in focal segmental glomerulosclerosis

2008 ◽  
Vol 74 (12) ◽  
pp. 1568-1576 ◽  
Author(s):  
Jeroen K.J. Deegens ◽  
Henry B.P.M. Dijkman ◽  
George F. Borm ◽  
Eric J. Steenbergen ◽  
José G. van den Berg ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Diagnostic Tool ◽  
Segmental Glomerulosclerosis ◽  
Foot Process Effacement ◽  
Foot Process

scholarly journals Degree of foot process effacement in patients with genetic focal segmental glomerulosclerosis: a single-center analysis and review of the literature

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kiyonobu Ishizuka ◽  
Kenichiro Miura ◽  
Taeko Hashimoto ◽  
Naoto Kaneko ◽  
Yutaka Harita ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Cytoskeletal Proteins ◽  
Systematic Evaluation ◽  
Review Of The Literature ◽  
Segmental Glomerulosclerosis ◽  
Native Kidney ◽  
Foot Process Effacement ◽  
Genes Encoding ◽  
Foot Process ◽  
Almost All

AbstractDetermining the cause of focal segmental glomerulosclerosis (FSGS) has crucial implications for evaluating the risk of posttransplant recurrence. The degree of foot process effacement (FPE) on electron micrographs (EM) of native kidney biopsies can reportedly differentiate primary FSGS from secondary FSGS. However, no systematic evaluation of FPE in genetic FSGS has been performed. In this study, percentage of FPE and foot process width (FPW) in native kidney biopsies were analyzed in eight genetic FSGS patients and nine primary FSGS patients. All genetic FSGS patients showed segmental FPE up to 38% and FPW below 2000 nm, while all primary FSGS patients showed diffuse FPE above 88% and FPW above 3000 nm. We reviewed the literature which described the degree of FPE in genetic FSGS patients and identified 38 patients with a description of the degree of FPE. The degree of FPE in patients with mutations in the genes encoding proteins associated with slit diaphragm and cytoskeletal proteins was varied, while almost all patients with mutations in other FSGS genes showed segmental FPE. In conclusion, the present study suggests that the degree of FPE in native kidney biopsies may be useful for differentiating some genetic FSGS patients from primary FSGS patients.

scholarly journals Mechanical challenges and cytoskeletal impairments in focal segmental glomerulosclerosis

2018 ◽  
Vol 314 (5) ◽  
pp. F921-F925 ◽  
Author(s):  
Di Feng ◽  
Clark DuMontier ◽  
Martin R. Pollak
Keyword(s):  
Blood Flow ◽  
Focal Segmental Glomerulosclerosis ◽  
Kidney Injury ◽  
Future Research ◽  
Disease States ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
The Face ◽  
Foot Process ◽  
Future Research Directions

Focal segmental glomerulosclerosis (FSGS) is a histologically defined form of kidney injury typically mediated by podocyte dysfunction. Podocytes rely on their intricate actin-based cytoskeleton to maintain the glomerular filtration barrier in the face of mechanical challenges resulting from pulsatile blood flow and filtration of this blood flow. This review summarizes the mechanical challenges faced by podocytes in the form of stretch and shear stress, both of which may play a role in the progression of podocyte dysfunction and detachment. It also reviews how podocytes respond to these mechanical challenges in dynamic fashion through rearranging their cytoskeleton, triggering various biochemical pathways, and, in some disease states, altering their morphology in the form of foot process effacement. Furthermore, this review highlights the growing body of evidence identifying several mutations of important cytoskeleton proteins as causes of FSGS. Lastly, it synthesizes the above evidence to show that a better understanding of how these mutations leave podocytes vulnerable to the mechanical challenges they face is essential to better understanding the mechanisms by which they lead to disease. The review concludes with future research directions to fill this gap and some novel techniques with which to pursue these directions.

scholarly journals Proteolytic program-dependent functions are impaired in INF2-mediated focal segmental glomerulosclerosis

2019 ◽  
Author(s):  
Balajikarthick Subramanian ◽  
Justin Chun ◽  
Chandra Perez ◽  
Paul Yan ◽  
Isaac Stillman ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Segmental Glomerulosclerosis ◽  
Terminal Fragment ◽  
Cathepsin Proteases ◽  
Foot Process ◽  
Inhibitory Domain ◽  
Altered Regulation ◽  
Actin Regulatory Proteins ◽  
And Function ◽  
Mutant Polypeptides

AbstractRegulation of the actin cytoskeleton is critical for normal glomerular podocyte structure and function. Altered regulation of the podocyte cytoskeleton can lead to proteinuria, reduced kidney filtration function and focal segmental glomerulosclerosis (FSGS). Mutations in inverted formin 2 (INF2), a member of the formin family of actin regulatory proteins, are the most common cause of autosomal dominant FSGS. INF2 is a multi-domain protein regulated by interaction between its N-terminal Diaphanous Inhibitory Domain (DID) and its C-terminal Diaphanous Auto-regulatory Domain (DAD). Although many aspects of the INF2 DID-DAD interaction are understood, it remains unclear why disease-causing mutations are restricted to the DID and how these mutations cause human disease. Here we report a proteolytic cleavage in INF2 that liberates the INF2 N-terminal DID to function independently of the INF2 C-terminal fragment containing the DAD domain. N-terminal DID region epitopes are differentially localized to podocyte foot process structures in normal glomeruli. This N-terminal fragment localization is lost in INF2-mediated FSGS, whereas INF2 C-terminal fragment epitopes localize to the podocyte cell body in both normal and disease conditions. INF2 cleavage is mediated by cathepsin proteases. In cultured podocytes, the wild-type INF2 N-terminal fragment localizes to membrane regions and promotes cell spreading, while these functions are impaired in a disease-associated INF2 mutant R218Q in the DID. These features are dependent on INF2-cleavage, with accompanying interaction of INF2 N-fragment with mDIA1. Our data suggest a unique cellular function of the DID dependent on INF2 cleavage and help explain the altered localization of FSGS-associated INF2 mutant polypeptides.

scholarly journals Melanocortin therapy ameliorates podocytopathy and proteinuria in experimental focal segmental glomerulosclerosis involving a podocyte specific non-MC1R-mediated melanocortinergic signaling

2020 ◽  
Vol 134 (7) ◽  
pp. 695-710
Author(s):  
Yingjin Qiao ◽  
Pei Wang ◽  
Mingyang Chang ◽  
Bohan Chen ◽  
Yan Ge ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Focal Segmental Glomerulosclerosis ◽  
De Novo ◽  
Protective Action ◽  
Clinical Effectiveness ◽  
Podocyte Injury ◽  
Segmental Glomerulosclerosis ◽  
Foot Process

Abstract The clinical effectiveness of adrenocorticotropin in inducing remission of steroid-resistant nephrotic syndrome points to a steroidogenic-independent anti-proteinuric activity of melanocortins. However, which melanocortin receptors (MCR) convey this beneficial effect and if systemic or podocyte-specific mechanisms are involved remain uncertain. In vivo, wild-type (WT) mice developed heavy proteinuria and kidney dysfunction following Adriamycin insult, concomitant with focal segmental glomerulosclerosis (FSGS) and podocytopathy, marked by loss of podocin and synaptopodin, podocytopenia and extensive foot process effacement on electron microscopy. All these pathologic findings were prominently attenuated by NDP-MSH, a potent non-steroidogenic pan-MCR agonist. Surprisingly, MC1R deficiency in MC1R-null mice barely affected the severity of Adriamycin-elicited injury. Moreover, the beneficial effect of NDP-MSH was completely preserved in MC1R-null mice, suggesting that MC1R is likely non-essential for the protective action. A direct podocyte effect seems to contribute to the beneficial effect of NDP-MSH, because Adriamycin-inflicted cytopathic signs in primary podocytes prepared from WT mice were all mitigated by NDP-MSH, including apoptosis, loss of podocyte markers, de novo expression of the podocyte injury marker desmin, actin cytoskeleton derangement and podocyte hypermotility. Consistent with in vivo findings, the podoprotective activity of NDP-MSH was fully preserved in MC1R-null podocytes. Mechanistically, MC1R expression was predominantly distributed to glomerular endothelial cells in glomeruli but negligibly noted in podocytes in vivo and in vitro, suggesting that MC1R signaling is unlikely involved in direct podocyte protection. Ergo, melanocortin therapy protects against podocyte injury and ameliorates proteinuria and glomerulopathy in experimental FSGS, at least in part, via a podocyte-specific non-MC1R-mediated melanocortinergic signaling.

Focal Segmental Glomerulosclerosis Superimposed on Transplant Glomerulopathy: Implications for Graft Survival

2021 ◽  
pp. 1-10
Author(s):  
Ying Zhu ◽  
Yun Fan ◽  
Feng Xu ◽  
Shaoshan Liang ◽  
Dandan Liang ◽  
...  
Keyword(s):  
Graft Survival ◽  
Focal Segmental Glomerulosclerosis ◽  
Cox Regression ◽  
Kidney Transplant Recipients ◽  
Segmental Glomerulosclerosis ◽  
Glomerular Endothelium ◽  
Foot Process ◽  
Independent Risk Factors ◽  
Allograft Loss ◽  
Transplant Glomerulopathy

<b><i>Introduction:</i></b> Transplant glomerulopathy (TG) is a morphological lesion resulting from chronic glomerular endothelium injury, and it is strongly associated with poor graft survival. TG coexisting with focal segmental glomerulosclerosis (FSGS) can be found in renal allograft biopsies, but few related studies are available. <b><i>Methods:</i></b> Consecutive kidney transplant recipients with biopsy-proven TG were studied retrospectively. Patients concomitant with FSGS were identified and compared with those without FSGS. The influence of FSGS on allograft outcomes was assessed using univariate and multivariate Cox regression models. <b><i>Results:</i></b> Of the 66 patients with TG, 40 (60.6%) had concomitant FSGS. TG patients with FSGS had higher proteinuria (median, 2.6 vs. 0.8 g/24 h, <i>p</i> &#x3c; 0.001) and serum creatinine levels (median, 2.5 vs. 2.1 mg/dL, <i>p</i> = 0.04), lower serum albumin levels, higher chronic glomerulopathy (cg) score, larger glomerular tuft area, lower number of podocytes, and higher incidences of podocyte hyperplasia, pseudotubule formation, and diffuse foot process effacement than those without FSGS (all <i>p</i> &#x3c; 0.05). The kidney allograft loss rate of patients with FSGS was higher than that of patients without FSGS (65.7% vs. 37.5%, <i>p</i> = 0.03). The presence of FSGS was independently associated with allograft loss in TG (hazard ratio (HR) = 3.42, 95% confidence interval (CI): 1.30–8.98, <i>p</i> = 0.01). Other independent predictors were proteinuria (HR = 1.18, 95% CI: 1.02–1.37, <i>p</i> = 0.02), estimated glomerular filtration rate (HR = 0.94, 95% CI: 0.91–0.97, <i>p</i> &#x3c; 0.001), and panel reactive antibody (HR = 3.99, 95% CI: 1.14–13.99, <i>p</i> = 0.03). Moreover, FSGS (odds ratio (OR) = 4.39, 95% CI: 1.29–14.92, <i>p</i> = 0.02) and cg (OR = 5.36, 95% CI: 1.56–18.40, <i>p</i> = 0.01) were independent risk factors for proteinuria. <b><i>Conclusion:</i></b> In this cohort of patients with TG, the presence of FSGS was strongly associated with more severe clinicopathological features and worse allograft survival.

scholarly journals A Specific Tubular ApoA-I Distribution Is Associated to FSGS Recurrence after Kidney Transplantation

2021 ◽  
Vol 10 (10) ◽  
pp. 2174
Author(s):  
Conxita Jacobs-Cachá ◽  
Natàlia Puig-Gay ◽  
Ander Vergara ◽  
Maria-Alejandra Gabaldon ◽  
Joana Sellarés ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Focal Segmental Glomerulosclerosis ◽  
Brush Border ◽  
Diagnostic Tool ◽  
Apical Membrane ◽  
Major Complication ◽  
Kidney Allograft ◽  
Tubular Cells ◽  
Apolipoprotein A ◽  
Segmental Glomerulosclerosis

A major complication of primary focal segmental glomerulosclerosis (FSGS) is its recurrence after kidney transplantation that happens in 30 to 40% of the patients. The diagnosis of these relapses is not always easy as the histological lesions are not highly specific and appear after the proteinuria increase. Currently, there are no accurate biomarkers to detect FSGS recurrence. Our group identified a modified form of Apolipoprotein A-I (ApoA-I), named ApoA-Ib, specifically present in the urine of recurrent FSGS patients after kidney transplantation. Aberrant forms of ApoA-I have also been described in the urine of native primary FSGS patients; this feature has been associated with prominent staining of ApoA-I at the apical membrane of the tubular cells. In this study, we aim to analyze the ApoA-I distribution in kidney allograft biopsies of recurrent FSGS patients. We detected ApoA-I by immunohistochemistry in kidney allograft biopsies of patients with FSGS relapse after kidney transplantation and in kidney allograft biopsies of patients with a disease different from FSGS in the native kidney (non-FSGS). In recurrent FSGS patients, ApoA-I was prominently localized at the brush border of the tubular cells, while in the non-FSGS patients, ApoA-I was found along the cytoplasm of the tubular cells. The localization of ApoA-I at the brush border of the tubular cells is a specific feature of primary FSGS in relapse. This suggests that ApoA-I staining in kidney biopsies, coupled with ApoA-Ib measurement in urine, could be used as a diagnostic tool of primary FSGS relapse after kidney transplantation due to its highly specific tubular distribution.

scholarly journals Focal Segmental Glomerulosclerosis in Related Miniature Schnauzer Dogs

2017 ◽  
Vol 55 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Wilson Yau ◽  
Lisa Mausbach ◽  
Meryl P. Littman ◽  
Rachel E. Cianciolo ◽  
Cathy A. Brown
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Creatinine Ratio ◽  
Urine Protein ◽  
Common Cause ◽  
Segmental Glomerulosclerosis ◽  
Dense Deposits ◽  
Glomerular Hypertension ◽  
Foot Process ◽  
Lipid Abnormalities ◽  
Arteriolar Hyalinosis

Focal segmental glomerulosclerosis (FSGS) recently has been recognized as a common cause of proteinuria in dogs in general, and in Miniature Schnauzer dogs in particular. This study describes the morphologic features present in the kidneys of 8 related proteinuric Miniature Schnauzer dogs. The FSGS, characterized by solidification of portions of the capillary tuft, affected 32% to 49% of examined glomeruli in these dogs. Synechiae, often accompanied by hyalinosis, were present in 13% to 54% of glomeruli and were more prevalent in older dogs. Seven of 8 dogs had arteriolar hyalinosis. Ultrastructurally, all dogs had evidence of a podocytopathy in the absence of electron-dense deposits, glomerular basement membrane splitting, or fibrils. All dogs had multifocal to extensive podocyte foot process effacement. Other podocyte changes included microvillous transformation, the presence of vacuoles or protein resorption droplets, cytoplasmic electron-dense aggregates, and occasional binucleation. Variable amounts of intraglomerular lipid were present in all dogs. All dogs were proteinuric, with measured values for the urine protein-to-creatinine ratio ranging from 1.2 to 6.5. Azotemia was mild to absent and dogs were euthanatized at 5.1 to 14 years of age, in all cases due to nonrenal diseases. The underlying cause of FSGS in these Miniature Schnauzer dogs has yet to be determined, but contributors likely include genetic podocytopathy, lipid abnormalities, and glomerular hypertension.

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