scholarly journals Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis

2019 ◽  
Vol 20 (3) ◽  
pp. 519 ◽  
Author(s):  
Jenny Frese ◽  
Matthias Kettwig ◽  
Hildegard Zappel ◽  
Johannes Hofer ◽  
Hermann-Josef Gröne ◽  
...  
Keyword(s):  
Renal Failure ◽  
Basement Membrane ◽  
Focal Segmental Glomerulosclerosis ◽  
Glomerular Basement Membrane ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Slit Diaphragm ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
Case Series Study

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases.

scholarly journals NPHS2 gene polymorphism aggravates renal damage caused by focal segmental glomerulosclerosis with COL4A3 mutation

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Liping Sun ◽  
Xinzhou Zhang ◽  
Zhen Wang
Keyword(s):  
Renal Failure ◽  
Basement Membrane ◽  
Gene Polymorphism ◽  
Focal Segmental Glomerulosclerosis ◽  
Glomerular Basement Membrane ◽  
Renal Damage ◽  
Single Gene ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
Nphs2 Gene

Abstract Focal segmental glomerulosclerosis (FSGS), a type of primary glomerular disease, is the leading cause of end-stage renal disease (ESRD). Several studies have revealed that certain single-gene mutations are involved in the pathogenesis of FSGS; however, the main cause of FSGS has not been fully elucidated. Homozygous mutations in the glomerular basement membrane gene can lead to early renal failure, while heterozygous carriers develop renal failure symptoms late. Here, molecular genetic analysis of clinical information collected from clinical reports and medical records was performed. Results revealed that nephrosis 2 (NPHS2) gene polymorphism aggravated renal damage in three FSGS families with heterozygous COL4A3 mutation, leading to early renal failure in index patients. Our findings suggest that COL4A3 and NPHS2 may have a synergistic effect on renal injury caused by FSGS. Further analysis of the glomerular filtration barrier could help assess the cause of kidney damage. Moreover, a detailed analysis of the glomerular basement membrane-related genes and podocyte structural proteins may help us better understand FSGS pathogenesis and provide insights into the prognosis and treatment of hereditary glomerulonephropathy.

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 The use of electron microscopy in the diagnosis of focal segmental glomerulosclerosis: are current pathological techniques missing important abnormalities in the glomerular basement membrane?

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1204
Author(s):  
Justin Davis ◽  
Alwie Tjipto ◽  
Katharine Hegerty ◽  
Andrew Mallett
Keyword(s):  
Electron Microscopy ◽  
Basement Membrane ◽  
Focal Segmental Glomerulosclerosis ◽  
Glomerular Basement Membrane ◽  
Type Iv Collagen ◽  
Histological Diagnosis ◽  
Ultrastructural Changes ◽  
Type Iv ◽  
Segmental Glomerulosclerosis ◽  
Two Samples

Background: There is an increasing appreciation that variants of the COL4A genes may be associated with the development of focal segmental glomerulosclerosis (FSGS). On electron microscopy, such variants may produce characteristic changes within the glomerular basement membrane (GBM). These changes may be missed if glomerular lesions histologically diagnosed as FSGS on light microscopy are not subjected to electron microscopy. Methods: We conducted a retrospective cohort analysis of all patients presenting to two hospitals who received a primary histological diagnosis of FSGS to see if these samples underwent subsequent electron microscopy. Each such sample was also scrutinised for the presence of characteristic changes of an underlying type IV collagen disorder Results: A total of 43 patients were identified. Of these, only 30 underwent electron microscopy. In two samples there were histological changes detected that might have suggested the underlying presence of a type IV collagen disorder. Around one in three biopsy samples that had a histological diagnosis of FSGS were not subjected to electron microscopy. Conclusion: Renal biopsy samples that have a histological diagnosis of primary FSGS not subjected to subsequent electron microscopy may potentially miss ultrastructural changes in the GBM that could signify an underlying type IV collagen disorder as the patient’s underlying disease process. This could potentially affect both them and their families’ investigative and management decisions given potential for implications for transplant, heritability and different disease pathogenesis. This represents a gap in care which should be reflected upon and rectified via iterative standard care and unit-level quality assurance initiatives.

scholarly journals An audit of electron microscopy in the diagnosis of focal segmental glomerulosclerosis: are current pathological techniques missing important abnormalities in the glomerular basement membrane?

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1204
Author(s):  
Justin Davis ◽  
Alwie Tjipto ◽  
Katharine Hegerty ◽  
Andrew Mallett
Keyword(s):  
Electron Microscopy ◽  
Basement Membrane ◽  
Focal Segmental Glomerulosclerosis ◽  
Glomerular Basement Membrane ◽  
Cohort Analysis ◽  
Collagen Iv ◽  
Histological Diagnosis ◽  
Ultrastructural Changes ◽  
Segmental Glomerulosclerosis ◽  
Two Samples

Background: There is an increasing appreciation that variants of the collagen IV genes may be associated with the development of focal segmental glomerulosclerosis (FSGS). On electron microscopy, such variants may produce characteristic changes within the glomerular basement membrane (GBM). These changes may be missed if glomerular lesions histologically diagnosed as FSGS on light microscopy are not subjected to electron microscopy. Methods: We conducted a retrospective cohort analysis of all patients presenting to two hospitals who received a primary histological diagnosis of FSGS to see if these samples underwent subsequent electron microscopy. Each such sample was also scrutinised for the presence of characteristic changes of an underlying collagen IV disorder Results: A total of 43 patients were identified. Of these, only 30 underwent electron microscopy. In two samples there were histological changes detected that might have suggested the underlying presence of a collagen IV disorder. Around one in three biopsy samples that had a histological diagnosis of FSGS were not subjected to electron microscopy. Conclusion: Renal biopsy samples that have a histological diagnosis of primary FSGS not subjected to subsequent electron microscopy may potentially miss ultrastructural changes in the GBM that could signify an underlying collagen IV disorder as the patient’s underlying disease process. This could potentially affect both them and their families’ investigative and management decisions given potential for implications for transplant, heritability and different disease pathogenesis. This represents a gap in care which should be reflected upon and rectified via iterative standard care and unit-level quality assurance initiatives.

scholarly journals COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

2007 ◽  
Vol 18 (11) ◽  
pp. 3004-3016 ◽  
Author(s):  
Konstantinos Voskarides ◽  
Loukas Damianou ◽  
Vassos Neocleous ◽  
Ioanna Zouvani ◽  
Stalo Christodoulidou ◽  
...  
Keyword(s):  
Renal Failure ◽  
Basement Membrane ◽  
Focal Segmental Glomerulosclerosis ◽  
Thin Basement Membrane Nephropathy ◽  
Segmental Glomerulosclerosis

scholarly journals An audit of electron microscopy in the diagnosis of focal segmental glomerulosclerosis – are current pathological techniques missing important abnormalities in the glomerular basement membrane?

2019 ◽  
Author(s):  
Justin Davis ◽  
Alwie Tjipto ◽  
Katharine Hegarty ◽  
Andrew Mallett
Keyword(s):  
Electron Microscopy ◽  
Basement Membrane ◽  
Focal Segmental Glomerulosclerosis ◽  
Glomerular Basement Membrane ◽  
Cohort Analysis ◽  
Collagen Iv ◽  
Histological Diagnosis ◽  
Ultrastructural Changes ◽  
Segmental Glomerulosclerosis ◽  
Two Samples

Abstract Background
There is an increasing appreciation that variants of the collagen IV genes may be associated with the development of focal segmental glomerulosclerosis (FSGS). On electron microscopy such variants may produce characteristic changes within the glomerular basement membrane (GBM). These changes may be missed if glomerular lesions histologically diagnosed as FSGS on light microscopy are not subjected to electron microscopy.
BFSMethods
We conducted a retrospective cohort analysis of all patients presenting to two hospitals who received a primary histological diagnosis of FSGS to see if these samples underwent subsequent electron microscopy. Each such sample was also scrutinised for the presence of characteristic changes of an underlying collagen IV disorder 
FSResults
A total of 43 patients were identified. Of these only 30 underwent electron microscopy. In two samples there were histological changes detected that might have suggested the underlying presence of a collagen IV disorder. Around one in three biopsy samples that had a histological diagnosis of FSGS were not subjected to electron microscopy.
BFSConclusion
Renal biopsy samples that have a histological diagnosis of primary FSGS not subjected to subsequent electron microscopy may potentially miss ultrastructural changes in the GBM that could signify an underlying collagen IV disorder as the patient’s underlying disease process. This could potentially affect both them and their families’ investigative and management decisions given potential for implications for transplant, heritability and different disease pathogenesis. This represents a gap in care which should be reflected upon and rectified via iterative standard care and unit-level quality assurance initiatives.

scholarly journals Expression of Nephrin in Pediatric Kidney Diseases

2001 ◽  
Vol 12 (2) ◽  
pp. 289-296
Author(s):  
JAAKKO PATRAKKA ◽  
VESA RUOTSALAINEN ◽  
ILKKA KETOLA ◽  
CHRISTER HOLMBERG ◽  
MARKKU HEIKINHEIMO ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Membranous Nephropathy ◽  
Staining Pattern ◽  
Kidney Diseases ◽  
Minimal Change ◽  
Slit Diaphragm ◽  
Segmental Glomerulosclerosis ◽  
Minimal Change Nephrosis ◽  
Pediatric Kidney Diseases

Abstract. Nephrin is a podocyte cell adhesion protein located at the slit diaphragm area of the kidney glomerulus. Mutations in the nephrin gene (NPHS1) lead to congenital nephrosis, suggesting that nephrin is essential for the glomerular filtration barrier. This prompted this study of the expression of nephrin in acquired pediatric kidney diseases usingin situhybridization and immunohistochemistry.In situhybridization for nephrin mRNA was performed in biopsy samples from patients with proteinuria caused by minimal change nephrosis, focal segmental glomerulosclerosis, and membranous nephropathy. The expression of nephrin mRNA was evaluated by grading the signal intensity visually and by counting the number of grains in separate glomeruli. No significant difference was observed in these samples as compared with controls. Immunostaining for nephrin was performed using antibodies directed against extra- and intracellular parts of the molecule. Nephrin staining gave a linear pattern along the glomerular capillary loops. In minimal change nephrosis, focal segmental glomerulosclerosis, and membranous nephropathy, the distribution of nephrin was similar to that in controls. In proliferative forms of glomerulonephritides (Henoch-Schönlein nephritis, IgA nephropathy, postinfectious and membranoproliferative glomerulonephritis), crescents and sclerotic lesions were negative for nephrin, and mesangial proliferation led to a scattered and sparse staining pattern. The staining pattern of nephrin was compared to that of ZO-1, a component of the cytoplasmic face of the slit diaphragm. The distributions of these two proteins in capillary tufts were similar in all disease entities studied. In conclusion, immunohistochemistry andin situhybridization did not reveal major alterations in the expression of nephrin in proteinuric kidney diseases in children. Further studies are needed for more precise evaluation of the role of nephrin in these diseases.

scholarly journals SARS-CoV-2 infection and recurrence of anti-glomerular basement disease: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Alexander Winkler ◽  
Emanuel Zitt ◽  
Hannelore Sprenger-Mähr ◽  
Afschin Soleiman ◽  
Manfred Cejna ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Plasma Cells ◽  
Rapidly Progressive Glomerulonephritis ◽  
Kidney Injury ◽  
Pulmonary Involvement ◽  
Pulmonary Haemorrhage ◽  
Basement Membranes ◽  
High Avidity ◽  
History Of

Abstract Background Anti-glomerular basement membrane disease (GBM) disease is a rare autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary haemorrhage. Recently, an association between COVID-19 and anti-glomerular basement membrane (anti-GBM) disease has been proposed. We report on a patient with recurrence of anti-GBM disease after SARS-CoV-2 infection. Case presentation The 31-year-old woman had a past medical history of anti-GBM disease, first diagnosed 11 years ago, and a first relapse 5 years ago. She was admitted with severe dyspnoea, haemoptysis, pulmonary infiltrates and acute on chronic kidney injury. A SARS-CoV-2 PCR was positive with a high cycle threshold. Anti-GBM autoantibodies were undetectable. A kidney biopsy revealed necrotising crescentic glomerulonephritis with linear deposits of IgG, IgM and C3 along the glomerular basement membrane, confirming a recurrence of anti-GBM disease. She was treated with steroids, plasma exchange and two doses of rituximab. Pulmonary disease resolved, but the patient remained dialysis-dependent. We propose that pulmonary involvement of COVID-19 caused exposure of alveolar basement membranes leading to the production of high avidity autoantibodies by long-lived plasma cells, resulting in severe pulmonary renal syndrome. Conclusion Our case supports the assumption of a possible association between COVID-19 and anti-GBM disease.

Sign in / Sign up

Export Citation Format

Share Document