Materiały źródłowe

• #1 Pathogenesis of Focal Segmental Glomerulosclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5122732/

  Focal segmental glomerulosclerosis (FSGS) is characterized by focal and segmental obliteration of glomerular capillary tufts with increased matrix. […] Primary or idiopathic FSGS is considered to be related to podocyte injury, and the pathogenesis of podocyte injury has been actively investigated. […] Several circulating factors affecting podocyte permeability barrier have been proposed, but not proven to cause FSGS. […] FSGS may also be caused by genetic alterations. […] The mode of inheritance and age of onset are different according to the gene involved. […] Recently, the role of parietal epithelial cells (PECs) has been highlighted. […] The pathogenesis of FSGS is very complex; however, understanding basic mechanisms of podocyte injury is important not only for basic research, but also for daily diagnostic pathology practice.

• #2 Pathogenesis of Focal Segmental Glomerulosclerosis

  https://www.jpatholtm.org/journal/view.php?doi=10.4132/jptm.2016.09.21

  Focal segmental glomerulosclerosis (FSGS) is characterized by focal and segmental obliteration of glomerular capillary tufts with increased matrix. FSGS is classified as collapsing, tip, cellular, perihilar and not otherwise specified variants according to the location and character of the sclerotic lesion. Primary or idiopathic FSGS is considered to be related to podocyte injury, and the pathogenesis of podocyte injury has been actively investigated. Several circulating factors affecting podocyte permeability barrier have been proposed, but not proven to cause FSGS. FSGS may also be caused by genetic alterations. These genes are mainly those regulating slit diaphragm structure, actin cytoskeleton of podocytes, and foot process structure. The mode of inheritance and age of onset are different according to the gene involved. Recently, the role of parietal epithelial cells (PECs) has been highlighted. Podocytes and PECs have common mesenchymal progenitors, therefore, PECs could be a source of podocyte repopulation after podocyte injury. Activated PECs migrate along adhesion to the glomerular tuft and may also contribute to the progression of sclerosis. Markers of activated PECs, including CD44, could be used to distinguish FSGS from minimal change disease. The pathogenesis of FSGS is very complex; however, understanding basic mechanisms of podocyte injury is important not only for basic research, but also for daily diagnostic pathology practice.

• #2 Pathogenesis of Focal Segmental Glomerulosclerosis

  https://www.jpatholtm.org/journal/view.php?doi=10.4132/jptm.2016.09.21

  There are several observations indicating that podocyte injury is at the center of the development of FSGS. First, podocyte injury is the earliest morphologic feature of FSGS. In recurrent FSGS in the allograft kidney, podocyte injury is detected by electron microscopy prior to the development of overt sclerosis. Second, there are animal models of podocyte-specific injury resulting in FSGS. NEP25 mice express human CD25 specifically on podocytes. Injection of immunotoxin which binds to human CD25 induced podocyte-specific injury and FSGS occurred a few weeks later. Rats expressing diphtheria toxin receptors on podocytes developed FSGS after diphtheria toxin injection. Third, histologic appearance of FSGS and clinical symptoms were in proportion with the number of injured podocytes. Therefore, the pathogenesis of podocyte injury is a key to understand the characteristics of FSGS.

• #3

  https://link.springer.com/article/10.1007/s00467-006-0357-2

  Focal segmental glomerulosclerosis (FSGS) is a major cause of idiopathic steroid-resistant nephrotic syndrome (SRNS) and end-stage kidney disease (ESKD). […] In recent years, animal models and studies of familial forms of nephrotic syndrome helped elucidate some mechanisms of podocyte injury and disease progression in FSGS. […] Alterations of normal glomerular structure and function have been found in FSGS. […] Normal function requires that the three major components of the glomerular filter (the endothelial cells, podocytes, and glomerular basement membrane) are intact and are able to provide a permselective filtration barrier. […] While the clinical presentation of FSGS is often heterogeneous, a characteristic feature of the disease is proteinuria, which implies the loss of this barrier.

• #3 Pathogenesis of Focal Segmental Glomerulosclerosis

  http://www.jpatholtm.org/journal/view.php?number=16647&view=citations

  There are several observations indicating that podocyte injury is at the center of the development of FSGS. First, podocyte injury is the earliest morphologic feature of FSGS. In recurrent FSGS in the allograft kidney, podocyte injury is detected by electron microscopy prior to the development of overt sclerosis. Second, there are animal models of podocyte-specific injury resulting in FSGS. NEP25 mice express human CD25 specifically on podocytes. Injection of immunotoxin which binds to human CD25 induced podocyte-specific injury and FSGS occurred a few weeks later. Rats expressing diphtheria toxin receptors on podocytes developed FSGS after diphtheria toxin injection. Third, histologic appearance of FSGS and clinical symptoms were in proportion with the number of injured podocytes. Therefore, the pathogenesis of podocyte injury is a key to understand the characteristics of FSGS.

• #4 Pathophysiology of focal segmental glomerulosclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1794138/

  Indeed, electron microscopy has shown distortion of the normal architecture (or effacement) of the foot processes of podocytes in FSGS. […] The connection between these projections of the epithelial cell and the underlying basement membrane can be disrupted, leading to the loss of nonspecific plasma proteins into the tubular filtrate. […] FSGS is characterized by increased extracellular matrix within the glomerular tuft with obliteration of the glomerular capillary lumen. […] It is possible that different mechanisms may play a role in the pathogenesis of each variant of FSGS. […] Key in the pathogenesis of FSGS is podocyte damage and loss. […] Injury to podocytes occurs by four major mechanisms: alteration of the components of the slit diaphragm or interference with its structure, dysregulation of the actin cytoskeleton, alteration of the glomerular basement membrane or its interactions with the podocyte, or alteration of the negative surface charge of the podocyte.

• #5

  https://link.springer.com/article/10.1007/s00467-006-0357-2

  Indeed, electron microscopy has shown distortion of the normal architecture (or effacement) of the foot processes of podocytes in FSGS. […] The connection between these projections of the epithelial cell and the underlying basement membrane can be disrupted, leading to the loss of nonspecific plasma proteins into the tubular filtrate. […] Insight into the pathogenesis of FSGS developed over the past decade from studies of genetic mutations in mice, models of progressive glomerulosclerosis, and identification of gene mutations in some familial forms of nephrotic syndrome. […] Key in the pathogenesis of FSGS is podocyte damage and loss. […] Injury to podocytes occurs by four major mechanisms: alteration of the components of the slit diaphragm or interference with its structure, dysregulation of the actin cytoskeleton, alteration of the glomerular basement membrane or its interactions with the podocyte, or alteration of the negative surface charge of the podocyte.

• #6 Pathophysiology of focal segmental glomerulosclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1794138/

  The ensuing reduction in podocyte number is felt to play an important role in the pathogenesis of FSGS. […] The initial insult to the podocyte leads to further damage mediated by cytokine release, mechanical stress, and further loss of polarity, resulting in sclerosis and scarring of the glomerulus. […] Genetic mutations seen in congenital forms of nephrotic syndrome and FSGS enabled researchers to identify specific gene mutations involved in podocyte damage. […] It is unclear how alteration of the slit diaphragm results in podocyte loss. […] Other proteins which are part of the slit diaphragm complex include: podocin, CD2-associated protein (CD2AP), FAT, ZO-1, P-cadherin, an LAP (leucine rich repeat and PDZ domain) protein, and MAGI-1. […] The role of the other components of the slit diaphragm in the pathophysiology of FSGS is not yet clear.

• #7

  https://link.springer.com/article/10.1007/s00467-006-0357-2

  Damage to podocytes triggers apoptosis and their detachment of podocytes from the glomerular basement membrane. […] The ensuing reduction in podocyte number is felt to play an important role in the pathogenesis of FSGS. […] The initial insult to the podocyte leads to further damage mediated by cytokine release, mechanical stress, and further loss of polarity, resulting in sclerosis and scarring of the glomerulus. […] Certain clinical variants of FSGS are suggestive of different mechanisms of injury to the podocyte. […] For example, a circulating factor which leads to glomerular basement membrane injury has been proposed in the pathogenesis of some types of FSGS. […] Another example of alternative mechanisms of injury is collapsing FSGS, which occurs in the setting of viruses such as HIV.

• #8

  https://link.springer.com/article/10.1007/s00467-006-0357-2

  Of great clinical importance is the mechanism by which the initial podocyte injury progresses to the final sclerotic lesion. […] As podocyte numbers decline, there is a relative exposure of the glomerular basement membrane. […] Factors resulting in the progression of FSGS to ESKD have also been the focus of recent research. […] Cytokines and vasoactive factors are believed to play a major role in the progression of FSGS. […] The overexpression of transforming growth factor (TGF) or its effector proteins, the Smads, leads to glomerulosclerosis in animal models. […] Mechanical stress is also believed to play a role in the progression of FSGS. […] Increased filtration due to the defects of the filtration barrier results in increased single-nephron glomerular filtration rate (SNGFR).

• #9 Pathogenesis of Focal Segmental Glomerulosclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5122732/

  There are several observations indicating that podocyte injury is at the center of the development of FSGS. […] Therefore, the pathogenesis of podocyte injury is a key to understand the characteristics of FSGS. […] Circulating permeability factors have been reckoned as the initiating factor of podocyte injury in primary FSGS and its recurrence after transplantation. […] Among the proposed circulating permeability factors, soluble urokinase receptor (suPAR) has been most thoroughly investigated. […] The presence of serum factors that can cause podocyte injury was suggested from the therapeutic effect of immunoadsorption therapy. […] Therefore, whether suPAR plays a role in the development of focal segmental lesions and its specificity to the primary FSGS are still open to further investigation.

• #10 Pathogenesis of Focal Segmental Glomerulosclerosis

  https://www.jpatholtm.org/journal/view.php?doi=10.4132/jptm.2016.09.21

  As for the pathophysiology of podocyte injury, several mechanisms have been proposed with supporting evidences. Circulating permeability factors have been reckoned as the initiating factor of podocyte injury in primary FSGS and its recurrence after transplantation. The presence of serum factors that can cause podocyte injury was suggested from the therapeutic effect of immunoadsorption therapy and observations that plasmapheresis could decrease the glomerular injury induced by patients serum. Further, serum of recurrent FSGS patients significantly increased albumin permeability of glomeruli in an in vitro test. Among the proposed circulating permeability factors, soluble urokinase receptor (suPAR) has been most thoroughly investigated. […] FSGS, as a podocytopathy, may be caused by mutation in several genes, which are important in maintaining podocyte morphology and function. Most of these genes can be categorized as those which are related with slit diaphragm structure, actin cytoskeleton of podocytes, or podocyte-glomerular basement membrane interaction through foot processes. In addition, a specific channel mutation has also been identified as a cause of FSGS. Alteration of these genes results in autosomal dominant or recessive congenital, infantile, or late onset nephrotic syndrome, some of which presents as FSGS histologically.

• #11 Pathogenesis of Focal Segmental Glomerulosclerosis

  http://www.jpatholtm.org/journal/view.php?number=16647&view=citations

  As for the pathophysiology of podocyte injury, several mechanisms have been proposed with supporting evidences. Circulating permeability factors have been reckoned as the initiating factor of podocyte injury in primary FSGS and its recurrence after transplantation. The presence of serum factors that can cause podocyte injury was suggested from the therapeutic effect of immunoadsorption therapy and observations that plasmapheresis could decrease the glomerular injury induced by patients serum. Further, serum of recurrent FSGS patients significantly increased albumin permeability of glomeruli in an in vitro test. Among the proposed circulating permeability factors, soluble urokinase receptor (suPAR) has been most thoroughly investigated. […] FSGS, as a podocytopathy, may be caused by mutation in several genes, which are important in maintaining podocyte morphology and function. Most of these genes can be categorized as those which are related with slit diaphragm structure, actin cytoskeleton of podocytes, or podocyte-glomerular basement membrane interaction through foot processes. In addition, a specific channel mutation has also been identified as a cause of FSGS. Alteration of these genes results in autosomal dominant or recessive congenital, infantile, or late onset nephrotic syndrome, some of which presents as FSGS histologically.

• #12 Pathophysiology and treatment of focal segmental glomerulosclerosis: the role of animal models | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/1471-2369-14-74

  In familial FSGS several genetic defects have been discovered, which account for 8% of FSGS causes. […] The affected genes encode important regulators of the actin cytoskeleton of podocytes and form an extensive list of factors. […] The first speculations about the existence of circulating permeability factors date from 1972. […] Recently, a case was reported in which a primary FSGS patient that received a kidney transplant developed marked proteinuria on the second day post transplantation. […] This study shows suPAR to be a circulating factor that can cause primary and recurrent FSGS and an important measurable risk factor for recurrent disease. […] The most frequently used animal model for FSGS is the reduced or remnant kidney model in rats. […] The remnant kidney model can cause podocyte damage through both hyperfiltration-hypertension and via the Ang II pathway, similar to what is seen in human FSGS.

• #13 suPAR and focal segmental glomerulosclerosis | Nefrología

  https://revistanefrologia.com/en-supar-focal-segmental-glomerulosclerosis-articulo-X2013251414053834

  In recent years, the nephrological community has witnessed very important discoveries in renal diseases, and within them, in glomerulonephritis. […] Nevertheless, one of the main subjects that needs clarification in this area is the identification of the permeabilizing circulating factor, which causes the nephrotic syndrome in primary or idiopathic FSGS. […] In 2011, a new candidate was proposed: soluble urokinase-type plasminogen activator receptor or suPAR. […] The molecular size of suPAR (20-50kDa) was similar to that which studies carried out years ago attributed to the circulating factor responsible for FSGS nephrotic syndrome. […] These studies stirred up great expectation, given that they presented solid data that indicated that suPAR could be the permeabilizing factor in a majority of primary FSGS cases and also because they demonstrated potential new therapeutic avenues on blocking this factor.

• #14 suPAR and focal segmental glomerulosclerosis | Nefrología

  https://revistanefrologia.com/en-supar-focal-segmental-glomerulosclerosis-articulo-X2013251414053834

  Nevertheless, subsequent studies have cast many doubts on the real significance of suPAR in the pathogenesis of FSGS. […] Therefore, despite the attractive aspects of suPAR as a potential permeabilizing factor, there are still many aspects that need to be clarified before attributing the predominant pathogenic role to it as initial studies suggested. […] In conclusion, it is obvious that the suPAR podocyte 3 integrin activation pathway is a very interesting area for exploring the pathogenesis of primary or idiopathic FSGS, but we are still far from being able to affirm that suPAR is the proteinuric circulating factor responsible for nephrotic syndrome in these patients. […] All of these data call into question the central pathogenic role of suPAR and its potential usefulness as a diagnostic biomarker. […] However, further studies are required in larger cohorts, in order to establish conclusions that can be applied to clinical practice in patients with nephrotic syndrome.

• #15 Pathogenesis of Focal Segmental Glomerulosclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5122732/

  FSGS, as a podocytopathy, may be caused by mutation in several genes, which are important in maintaining podocyte morphology and function. […] The mechanism of repopulation of podocytes after podocyte injury has been of great interest. […] Therefore, detecting activated PECs on Bowmans capsule or on the glomerular tuft could be an adjunctive diagnostic tool for early FSGS. […] The etiology and pathogenesis of FSGS are very complex.

• #16 Focal segmental glomerulosclerosis: molecular genetics and targeted therapies | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-015-0090-9

  Mutated NPHS1 was the first podocyte gene identified in congenital NS (CNS) of the Finnish type. […] This discovery revolutionized our understanding of the pathogenesis of NS/FSGS. […] Mutated INF2 is the most common cause of autosomal dominant (AD) FSGS. […] The risk variants G1 (S342G:I384M) and G2 (del.N388/Y389) are two coding variants in the APOL1 gene on chromosome 22q13. […] The mutant alleles confer protection against trypanosomal infections in AAs at the cost of an increased risk of kidney disease. […] Shalhoub first suggested the existence of a serum factor that causes FSGS in 1974. […] Savin et al. demonstrated that a serum protein with a molecular mass between 20 and 50 kD increases GFB permeability and induces post-transplantation recurrent FSGS. […] Glomerular hypertrophy and hyperfiltration can be associated with reduced nephron mass.

• #17 Focal segmental glomerulosclerosis – Wikipedia

  https://en.wikipedia.org/wiki/Focal_segmental_glomerulosclerosis

  A number of genes have been implicated in FSGS. These include: NPHS1, which encodes the protein nephrin that contributes to the filtration barrier; NPHS2, which encodes the protein podocin found in podocytes; and INF2, which encodes the actin-binding protein formin. […] The pathogenesis of HIV-associated FSGS is unclear, but may be due to the presence of the G1/G2 risk alleles of the APOL1 gene. There is some data to suggest that HIV can infect tubular epithelial cells and podocytes, but much remains to be known. […] Gain of function mutations in APOL1 have also been proposed to play a role in the pathogenesis of this disease.

• #18

  https://journals.lww.com/cjasn/fulltext/2017/03000/focal_segmental_glomerulosclerosis.18.aspx

  The identification of genetic variants in APOL1 in patients with FSGS has been an important discovery for FSGS and related diseases. Unlike certain genes that have not shown firm causality to FSGS, data are mounting for the role of APOL1. Although confirmatory data are required, the strength and consistency of the genetic association, the exclusion of other genetic variants in this genomic region, and the demonstration that the expression of the renal risk variants (but not the common allele) causes FSGS in transgenic mice are highly supportive of the role of APOL1 genetic variants as causal for FSGS.

• #19 Focal segmental glomerulosclerosis: molecular genetics and targeted therapies | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-015-0090-9

  Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2. […] In this review we focus on recent molecular insights into FSGS pathogenesis including results from our studies and discuss the effects on current treatment of patients with FSGS. […] It is clear that numerous podocyte gene products are required to construct the podocyte body and foot processes (FPs). […] Mutations in structural podocyte genes cause FSGS in humans. […] Human genetic studies in the past two decades have demonstrated that FSGS is primarily a podocytopathy with more than 20 mutated podocyte genes confidently implicated in the pathogenesis of NS/FSGS. […] These mutated genes can be divided into the following categories: (a) SD-associated molecules, (b) podocyte cytoskeleton related molecules, (c) podocyte transcription factors, and (d) adhesion and extracellular matrix molecules.

• #20

  https://omim.org/entry/603278

  A number sign (#) is used with this entry because of evidence that this form of progressive renal disease, referred to here as focal segmental glomerulosclerosis-1 (FSGS1), is caused by heterozygous mutation in the gene encoding alpha-actinin-4 (ACTN4; 604638) on chromosome 19q13. […] Focal segmental glomerulosclerosis (FSGS) is a pathologic finding in several renal disorders that manifest clinically as proteinuria and progressive decline in renal function. […] D’Agati et al. (2011) provided a detailed review of FSGS, emphasizing that the disorder results from defects of the podocyte. […] D’Agati et al. (2004) proposed a pathologic classification of FSGS, defining 5 morphologic variants based entirely on assessment of glomerular light microscopic alterations: collapsing variant, tip variant, cellular variant, perihilar variant, and 'not otherwise specified,’ with classification into a given category requiring that all preceding categories, as listed, be excluded. […] D’Agati et al. (2011) reviewed the pathogenesis of FSGS, with emphasis on loss of the glomerular filtration barrier due to defects in the podocyte.

• #21 Pathogenesis of Focal Segmental Glomerulosclerosis

  https://www.jpatholtm.org/journal/view.php?doi=10.4132/jptm.2016.09.21

  Recently, it has been suggested that parietal epithelial cells (PECs) lining Bowmans capsule play an important role in this process by migrating from their original site to replace injured podocytes. During glomerulogenesis, PECs and podocytes originate from common mesenchymal progenitors and finally have different phenotypes. Although little is known about the function of terminally differentiated PECs, they express tight junction molecules such as claudin-1, zonula occludens-1, and occludin and have barrier function against protein. Some PECs express both CD133 and CD24, which are known to be stem cell markers, and these cells have regenerative ability. More detailed study revealed that PECs show hierarchical differentiation according to their locations. PECs located at the urinary pole express CD133 and CD24 without the expression of podocyte markers. PECs of the vascular pole express podocyte markers without the expression of CD133 or CD24. In other areas, PECs express both CD133/CD24 and podocyte markers. CD133 and CD24-expressing PECs have the ability to ameliorate kidney injury by potentiating tubular regeneration and podocyte replacement, however, they can also contribute to glomerular injury such as glomerulosclerosis and crescent formation. Animal models and human posttransplant biopsies demonstrated that invasion of activated PECs through the adhesion sites of the capillary tuft contributed to the development of FSGS. The adhesion of the glomerular tuft to the Bowmans capsule as a bridge of PEC migration appears to occur at early stages of FSGS development. Therefore, detecting activated PECs on Bowmans capsule or on the glomerular tuft could be an adjunctive diagnostic tool for early FSGS. In support of this concept, CD44 as a marker of activated PECs successfully distinguished early primary FSGS and early post-transplant recurrence of FSGS from minimal change disease.

• #22 Pathophysiology of focal segmental glomerulosclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1794138/

  Certain clinical variants of FSGS are suggestive of different mechanisms of injury to the podocyte. […] For example, a circulating factor which leads to glomerular basement membrane injury has been proposed in the pathogenesis of some types of FSGS. […] Another example of alternative mechanisms of injury is collapsing FSGS, which occurs in the setting of viruses such as HIV. […] Of great clinical importance is the mechanism by which the initial podocyte injury progresses to the final sclerotic lesion. […] As podocyte numbers decline, there is a relative exposure of the glomerular basement membrane. […] Factors resulting in the progression of FSGS to ESKD have also been the focus of recent research. […] The overexpression of transforming growth factor (TGF) or its effector proteins, the Smads, leads to glomerulosclerosis in animal models.

• #23 Pathophysiology of focal segmental glomerulosclerosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1794138/

  Activation of the renin-angiotensin system upregulates TGF and is felt to further lead to the progression of disease. […] Mechanical stress is also believed to play a role in the progression of FSGS. […] The presence of plasma proteins in the tubular filtrate may directly injure the tubulointerstitium. […] The inflammatory infiltrate leads to mesangial matrix deposition, promoting the collapse of glomeruli. […] The beneficial effects of blocking the renin-angiotensin system may not be limited to their antiproteinuric or antihypertensive effects. […] With the increasing incidence of FSGS in children, these pathways of podocyte injury and disease progression provide important targets for future intervention.

• #24

  https://link.springer.com/article/10.1007/s00467-006-0357-2

  Another factor in the progression of FSGS is tubulointerstitial injury. […] The presence of plasma proteins in the tubular filtrate may directly injure the tubulointerstitium. […] The beneficial effects of blocking the renin-angiotensin system may not be limited to their antiproteinuric or antihypertensive effects. […] With the increasing incidence of FSGS in children, these pathways of podocyte injury and disease progression provide important targets for future intervention.

• #25 Focal segmental glomerulosclerosis – Wikipedia

  https://en.wikipedia.org/wiki/Focal_segmental_glomerulosclerosis

  Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of glomeruli and damage to renal podocytes. This process damages the filtration function of the kidney, resulting in protein presence in the urine due to protein loss. FSGS can be classified by the putative cause of damage to podocytes. Primary FSGS involves cases in which no cause is readily identifiable. It is presumed that a set of unidentified circulating factors in the blood contribute to podocyte damage in these cases. […] Secondary FSGS is caused by an identifiable stress or toxin that injures podocytes. Many causes of secondary FSGS contribute to podocyte injury through hyperfiltration, which is a scenario of excess filtration by renal glomeruli. Hyperfiltration can be caused by obesity, diabetes or loss of the contralateral kidney, among other causes.

• #26 Pathophysiology and treatment of focal segmental glomerulosclerosis: the role of animal models | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/1471-2369-14-74

  Studies using the remnant kidney model are conducted for the development of preventive treatment strategies as well as for gaining more insight in underlying pathologies. […] The reduction of renal mass is a secondary event to certain pathologies. […] Damage to glomerular vessels can also occur due to anti-phospholipid antibodies present in systemic lupus erythematosus (SLE) that occlude the glomerular vessels and result in chronic inflammation. […] These animal models are all good representations of secondary FSGS in humans. […] Adriamycin is known as an oncolytic antibiotic that can induce proteinuria from the second infusion onward. […] Both adriamycin and puromycin are used frequently to induce FSGS because of their strong dose-response effects. […] Virus induced animal models that are most often used in FSGS research are HIV-1 based models, in which transgenic mice express HIV-1 accessory genes such as Vpr.

• #27 Focal Segmental Glomerulosclerosis: Histopathology Discussion – European Medical Journal

  https://www.emjreviews.com/nephrology/article/focal-segmental-glomerulosclerosis-histopathology-discussion-j120121/

  In focal segmental glomerulosclerosis (FSGS), some (not all) glomeruli are affected with sclerosis (focal), and each diseased glomerulus is only partially affected (segmental). Sclerosis means renal vasculature is affected in a way similar to arteriosclerosis. Specifically, there occurs stiffness and obstruction in the vessels. Initially, juxtamedullary area is affected with sclerosis. As the disease advances, there is accumulation of glomerular collagen (Type IV). This proteinaceous material appears glassy pink on haematoxylin and eosin stain, and is called hyalinosis. FSGS is classified into primary FSGS, secondary FSGS, genetic FSGS, and FSGS of undetermined cause (FSGS-UC). If kidney biopsy reveals FSGS lesions, and patient has nephrotic syndrome (24 hours proteinuria 3.5 g and presence of serum albumin 30 g/L, with or without oedema), then there is more probability of primary FSGS. This is especially true if the electron microscopy shows diffuse foot process effacement. If the patient does not satisfy this criterion, then they should be investigated for secondary FSGS. Secondary FSGS could occur due to diabetic nephropathy, hypertensive nephrosclerosis, obesity, viral infections (including severe acute respiratory syndrome coronavirus 2, HIV, cytomegalovirus, EpsteinBarr virus, Hepatitis C virus, and Parvovirus B19), drug induced (including due to nonsteroidal anti-inflammatory drugs, steroids, calcineurin inhibitors, mammalian target of rapamycin inhibitors, and lithium), and reduced nephron number (as in sickle cell disease, age-related FSGS, renal dysplasia, and reflux nephropathy). Genetic testing to exclude genetic forms of FSGS (mutations in podocyte and glomerular basement membrane proteins) may be needed when subject does not meet the criteria for primary FSGS.

• #28 Pathophysiology and treatment of focal segmental glomerulosclerosis: the role of animal models | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/1471-2369-14-74

  Since podocytes were identified as the major cellular target in FSGS, new animal models were developed. […] These models all affect podocytes, either by targeting existing genes and their encoding proteins, or by the transfection of specific receptors on podocytes, which can specifically be targeted. […] Much of our knowledge on FSGS has come from a variety of animal models. […] Our inability to fully understand the pathogenesis and find curative treatment for FSGS may be due to the fact that almost all of the animal models used are based on the induction of secondary forms of FSGS.

• #29 Focal segmental glomerulosclerosis: molecular genetics and targeted therapies | BMC Nephrology | Full Text

  https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-015-0090-9

  This proposal is supported by recent studies that show defining patients by the underlying disease mechanism improves patient management. […] The potential efficacy of therapy must be considered in relation to the natural history of the disease. […] The rate of spontaneous remission among patients with NS is unknown. […] Most studies showed that untreated primary FSGS often followed a progressive course to ESRD. […] In a recent NIH-funded multicenter randomized FSGS Clinical Trial (FSGS-CT), the efficacy of a 12-month course of CSA was compared to a combination of MMF and oral pulse dexamethasone (DEX) in children and young adults with SR primary FSGS. […] In the era of personalized medicine, identifying FSGS-causing gene mutations and investigating their underlying molecular mechanisms have immense potential for the development of highly-targeted therapy.

• #30 Advances in FSGS Treatment from the Perspective of the Newest Mechanis | DDDT

  https://www.dovepress.com/advances-in-focal-segmental-glomerulosclerosis-treatment-from-the-pers-peer-reviewed-fulltext-article-DDDT

  Additional contributors including potentially pathogenic antibodies, deficits in autophagy, oxidative stress, and mitochondrial dysfunction play a role in this process. […] The unique structure of podocytes renders them susceptible to hemodynamic abnormalities. […] The activation of AMPK may represent a novel therapeutic target for podocyte-related diseases by promoting the renewal of autophagosomes. […] Recent findings suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors may benefit non-diabetic proteinuric chronic kidney disease (CKD) patients by mitigating hemodynamic injury. […] In preclinical models of FSGS, activation of inflammatory signaling pathways, including nuclear factor B (NF-B), P38 mitogen-activated protein kinase (MAPK), and Janus kinase-signal transducer and activator of transcription (JAK-STAT), has been observed, accompanied by a significant upregulation of related molecules such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-1 (IL-1). […] This suggests a vicious cycle of interactions. […] The mechanisms discussed in this review may represent other promising targets for the delay of podocyte injury, aiming to provide some references for the development of precision medicine approaches in the treatment of FSGS.

• #31 Pathogenesis of Focal Segmental Glomerulosclerosis

  http://www.jpatholtm.org/journal/view.php?number=16647&view=citations

  Recently, it has been suggested that parietal epithelial cells (PECs) lining Bowmans capsule play an important role in this process by migrating from their original site to replace injured podocytes. During glomerulogenesis, PECs and podocytes originate from common mesenchymal progenitors and finally have different phenotypes. […] The etiology and pathogenesis of FSGS are very complex. Current research is focusing on the role of podocytes and interaction with PECs. Understanding the mechanism of podocyte injury, its progression and possible recovery is important not only for basic research but also for daily diagnostic pathology practice.

• #32 Advances in FSGS Treatment from the Perspective of the Newest Mechanis | DDDT

  https://www.dovepress.com/advances-in-focal-segmental-glomerulosclerosis-treatment-from-the-pers-peer-reviewed-fulltext-article-DDDT

  Podocyte injury was widely recognized as a fundamental mechanism driving the progression of focal segmental glomerulosclerosis (FSGS). […] The role of mechanisms such as alterations in the actin cytoskeleton, oxidative stress, mitochondrial dysfunction, and inadequate autophagy within the microenvironment of podocyte injury have garnered increasing attention. […] This process can be conceptualized as an injury-protective strategy. […] Consequently, FSGS is not a distinct entity of glomerular disease but rather a pathological pattern characterized by podocyte injury. […] Identifying the precise mechanisms underlying podocyte loss during injury may have implications for the treatment of FSGS in resource-constrained settings, offering additional pharmacological targets for delaying the progression of glomerulosclerosis.

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