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.

scholarly journals Minimal Change Disease and IgA Deposition: Separate Entities or Common Pathophysiology?

2013 ◽  
Vol 2013 ◽  
pp. 1-3
Author(s):  
Brandon S. Oberweis ◽  
Aditya Mattoo ◽  
Ming Wu ◽  
David S. Goldfarb
Keyword(s):  
Iga Nephropathy ◽  
Minimal Change Disease ◽  
Minimal Change ◽  
Dramatic Improvement ◽  
Creatinine Ratio ◽  
Urine Protein ◽  
Common Cause ◽  
History Of ◽  
Foot Process

Introduction. Minimal Change Disease (MCD) is the most common cause of nephrotic syndrome in children, while IgA nephropathy is the most common cause of glomerulonephritis worldwide. MCD is responsive to glucocorticoids, while the role of steroids in IgA nephropathy remains unclear. We describe a case of two distinct clinical and pathological findings, raising the question of whether MCD and IgA nephropathy are separate entities or if there is a common pathophysiology.Case Report. A 19-year old man with no medical history presented to the Emergency Department with a 20-day history of anasarca and frothy urine, BUN 68 mg/dL, Cr 2.3 mg/dL, urinalysis 3+ RBCs, 3+ protein, and urine protein : creatinine ratio 6.4. Renal biopsy revealed hypertrophic podocytes on light microscopy, podocyte foot process effacement on electron microscopy, and immunofluorescent mesangial staining for IgA. The patient was started on prednisone and exhibited dramatic improvement.Discussion. MCD typically has an overwhelming improvement with glucocorticoids, while the resolution of IgA nephropathy is rare. Our patient presented with MCD with the uncharacteristic finding of hematuria. Given the improvement with glucocorticoids, we raise the question of whether there is a shared pathophysiologic component of these two distinct clinical diseases that represents a clinical variant.

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 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 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 Steroid Resistant Focal Segmental Glomerulosclerosis: Effect of Arterial Hyalinosis on Outcome: Single center study

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Amin R. Soliman ◽  
Hoda Maamoun ◽  
Haytham Soliman ◽  
Rabab Mahmoud Ahmed
Keyword(s):  
Mycophenolate Mofetil ◽  
Focal Segmental Glomerulosclerosis ◽  
Interstitial Fibrosis ◽  
Base Line ◽  
Steroid Resistant ◽  
Segmental Glomerulosclerosis ◽  
Significant Difference ◽  
One Year ◽  
Few Data ◽  
Arteriolar Hyalinosis

AbstractBackground: Few data with adequate evidence exists regards the effect of Cyclosporine (CsA) and mycophenolate mofetil (MMF) on pathological prognostic parameters in patients with steroid resistant focal segmental glomerulosclerosis (FSGS). The purpose of the present study is to compare the effect of cyclosporin and mycophenolate mofetil in addition to steroids on functional and histopathologic renal parameters in patients with steroid resistant FSGS one year after treatment.Material and methods: Thirty-seven adults with primary FSGS patients resistant to steroid therapy consecutively randomized to treatment with either MMF or cyclosporine. Low dose prednisolone added to both groups. Glomerular filtration rate (GFR) and blood pressure (BP) were determined at all examinations and a second renal biopsy was taken 12 months after treatment with either of cyclosporin and mycophenolate mofetil.Results: GFR significantly increased in MMF group p <0.01 after 6 months and unchanged after 12 months. On the other hand, GFR significantly decrease in CsA group p <0.001 after 6 months and reduced more after 12 months p <0.001 compared to base line levels. Significant difference of GFR between the 2 groups at 6 months p<0.001. The extent of proteinuria decreased significantly in CsA group after 12 months p <0.001. The extent of arteriolar hyalinosis increased significantly in CsA group (0.78 to 1.81 score, p <0.001) but was unchanged in MMF group (0.93 to 0.96 score), whereas interstitial fibrosis increased to same level in both groups (grade 3).Conclusion: Conversion to MMF in those patients may be superior to CsA as regard GFR after 12 months after treatment in spite presence of greater level of protein excretion. The increased arteriolar hyalinosis during CsA treatment most likely result in higher BP compared to MMF treatment in patients with FSGS resistant to steroids.

scholarly journals Repository corticotropin injection versus corticosteroids for protection against renal damage in a focal segmental glomerulosclerosis rodent model

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Kyle Hayes ◽  
Elizabeth Warner ◽  
Chris Bollinger ◽  
Dale Wright ◽  
Richard M. Fitch
Keyword(s):  
Renal Function ◽  
Focal Segmental Glomerulosclerosis ◽  
Renal Fibrosis ◽  
Kidney Injury ◽  
Receptor Activation ◽  
Urinary Biomarkers ◽  
Melanocortin Receptor ◽  
Urine Protein ◽  
Injury Score ◽  
Segmental Glomerulosclerosis

Abstract Background Focal segmental glomerulosclerosis (FSGS) causes renal fibrosis and may lead to kidney failure. FSGS and its common complication, proteinuria, are challenging to treat. Corticosteroids are ineffective in many patients with FSGS, and alternative treatments often yield suboptimal responses. Repository corticotropin injection (RCI; Acthar® Gel), a naturally sourced complex mixture of purified adrenocorticotropic hormone analogs and other pituitary peptides, may have beneficial effects on idiopathic FSGS via melanocortin receptor activation. Methods Two studies in a preclinical (female Sprague-Dawley rats) puromycin aminonucleoside FSGS model assessed the effect of RCI on renal function and morphology: an 8-week comparison of a single RCI dose with methylprednisolone (N = 27), and a 12-week chronic RCI dose range study (N = 34). Primary outcomes were proteinuria and renal pathology improvements for measures of renal fibrosis, tubular damage, glomerular injury, and total kidney injury score. Impact of RCI treatment was also determined by assessing urinary biomarkers for renal injury, podocyte expression of podoplanin (a biomarker for injury), podocyte effacement by electron microscopy, and histological staining for fibrosis biomarkers. Results Compared with saline treatment, RCI 30 IU/kg significantly reduced proteinuria, with a 38% reduction in peak mean urine protein levels on day 28 in the 8-week model, and RCI 10 IU/kg, 30 IU/kg, and 60 IU/kg reduced peak mean urine protein in the 12-week model by 18, 47, and 44%, respectively. RCI also showed significant dose-dependent improvements in fibrosis, interstitial inflammation, tubular injury, and glomerular changes. Total kidney injury score (calculated from histopathological evaluations) demonstrated statistically significant improvements with RCI 30 IU/kg in the 8-week study and RCI 60 IU/kg in the 12-week study. RCI treatment improved levels of urinary biomarkers of kidney injury (KIM-1 and OPN), expression of podoplanin, and podocyte morphology. RCI also reduced levels of desmin and fibrosis-associated collagen deposition staining. Methylprednisolone did not improve renal function or pathology in this model. Conclusions These results provide evidence supporting the improvement of FSGS with RCI, which was superior to corticosteroid treatment in this experimental model. To the authors’ knowledge, this is the first evidence that a drug for the treatment of FSGS supports podocyte recovery after repeated injury.

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