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Clinical Journal of the American... Mar 2017Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to... (Review)
Review
Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (, to rule out other primary glomerulopathies), and electron microscopy (, extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Apolipoprotein L1; Calcineurin Inhibitors; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Glucocorticoids; HIV Infections; Humans; Immunosuppressive Agents
PubMed: 28242845
DOI: 10.2215/CJN.05960616 -
Nephron 2020Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular injury, rather than a single disease, that is caused by diverse clinicopathological... (Review)
Review
Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular injury, rather than a single disease, that is caused by diverse clinicopathological entities with different mechanisms of injury with the podocyte as the principal target of lesion, leading to the characteristic sclerotic lesions in parts (i.e., focal) of some (i.e., segmental) glomeruli. The lesion of FSGS has shown an increasing prevalence over the past few decades and is considered the most common glomerular cause leading to ESKD. Primary FSGS, which usually presents with nephrotic syndrome, is thought to be caused by circulating permeability factors that have a main role in podocyte foot process effacement. Secondary forms of FSGS include maladaptive FSGS secondary to glomerular hyperfiltration such as in obesity or in cases of loss in nephron mass, virus-associated FSGS, and drug-associated FSGS that can result in direct podocyte injury. Genetic FSGS is increasingly been recognized and a careful evaluation of patients with atypical primary or secondary FSGS should be performed to exclude genetic causes. Unlike primary FSGS, secondary and genetic forms of FSGS do not respond to immunosuppression and tend not to recur after kidney transplantation. Distinguishing primary FSGS from secondary and genetic causes has a prognostic significance and is crucial for an appropriate management. In this review, we examine the pathogenesis, clinical approach to distinguish between the different causes, and current recommendations in the management of FSGS.
Topics: Adrenal Cortex Hormones; Diagnosis, Differential; Drug Resistance; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Transplantation; Nephrotic Syndrome; Plasmapheresis; Recurrence; Risk Factors
PubMed: 32721952
DOI: 10.1159/000508099 -
Nature Reviews. Nephrology Feb 2015Focal segmental glomerulosclerosis (FSGS) describes both a common lesion in progressive kidney disease, and a disease characterized by marked proteinuria and podocyte... (Review)
Review
Focal segmental glomerulosclerosis (FSGS) describes both a common lesion in progressive kidney disease, and a disease characterized by marked proteinuria and podocyte injury. The initial injuries vary widely. Monogenetic forms of FSGS are largely due to alterations in structural genes of the podocyte, many of which result in early onset of disease. Genetic risk alleles in apolipoprotein L1 are especially prevalent in African Americans, and are linked not only to adult-onset FSGS but also to progression of some other kidney diseases. The recurrence of FSGS in some transplant recipients whose end-stage renal disease was caused by FSGS points to circulating factors in disease pathogenesis, which remain incompletely understood. In addition, infection, drug use, and secondary maladaptive responses after loss of nephrons from any cause may also cause FSGS. Varying phenotypes of the sclerosis are also manifest, with varying prognosis. The so-called tip lesion has the best prognosis, whereas the collapsing type of FSGS has the worst prognosis. New insights into glomerular cell injury response and repair may pave the way for possible therapeutic strategies.
Topics: Animals; Glomerulosclerosis, Focal Segmental; Humans; Risk Factors
PubMed: 25447132
DOI: 10.1038/nrneph.2014.216 -
Journal of the American Society of... Mar 2018FSGS describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. Subclasses of FSGS include primary,... (Review)
Review
FSGS describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. Subclasses of FSGS include primary, genetic, and secondary forms, the latter comprising maladaptive, viral, and drug-induced FSGS. Despite sharing certain clinical and histologic features, these subclasses differ noticeably in management and prognosis. Without an accepted nongenetic biomarker that discriminates among these FSGS types, classification of patients is often challenging. This review summarizes the clinical and histologic features, including the onset and severity of proteinuria as well as the presence of nephrotic syndrome, that may aid in identifying the specific FSGS subtype. The FSGS lesion is characterized by segmental sclerosis and must be differentiated from nonspecific focal global glomerulosclerosis. No light microscopic features are pathognomonic for a particular FSGS subcategory. The characteristics of podocyte foot process effacement on electron microscopy, while helpful in discriminating between primary and maladaptive FSGS, may be of little utility in detecting genetic forms of FSGS. When FSGS cannot be classified by clinicopathologic assessment, genetic analysis should be offered. Next generation DNA sequencing enables cost-effective screening of multiple genes simultaneously, but determining the pathogenicity of a detected genetic variant may be challenging. A more systematic evaluation of patients, as suggested herein, will likely improve therapeutic outcomes and the design of future trials in FSGS.
Topics: Diagnosis, Differential; Genetic Testing; Glomerulosclerosis, Focal Segmental; Humans; Microscopy, Electron; Microscopy, Fluorescence; Nephrotic Syndrome; Podocytes; Proteinuria
PubMed: 29321142
DOI: 10.1681/ASN.2017090958 -
Clinical Journal of the American... Mar 2014FSGS is a lesion, not a disease. The separation into primary FSGS (a result of immunologic-mediated injury) versus secondary FSGS (related to a variety of causes) is... (Review)
Review
FSGS is a lesion, not a disease. The separation into primary FSGS (a result of immunologic-mediated injury) versus secondary FSGS (related to a variety of causes) is often difficult. Even when this particular issue is carefully evaluated, the therapeutic implications are not always apparent. Newer literature on both biomarker discovery and on the genetic basis of FSGS is reviewed in this context. In addition, the thorny implications of obesity as it relates to the FSGS lesion are discussed. An overall practical algorithmic approach to the management and treatment of the FSGS lesion that integrates these controversial overlap areas is suggested.
Topics: Biopsy; Genetic Markers; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Glomerulus; Predictive Value of Tests; Treatment Outcome
PubMed: 23990165
DOI: 10.2215/CJN.05810513 -
Nature Reviews. Nephrology Sep 2021Focal segmental glomerulosclerosis (FSGS) is not a specific disease entity but a lesion that primarily targets the podocyte. In a broad sense, the causes of the lesion... (Review)
Review
Focal segmental glomerulosclerosis (FSGS) is not a specific disease entity but a lesion that primarily targets the podocyte. In a broad sense, the causes of the lesion can be divided into those triggered by a presumed circulating permeability factor, those that occur secondary to a process that might originate outside the kidneys, those caused by a genetic mutation in a podocyte or glomerular basement membrane protein, and those that arise through an as yet unidentifiable process, seemingly unrelated to a circulating permeability factor. A careful attempt to correctly stratify patients with FSGS based on their clinical presentation and pathological findings on kidney biopsy is essential for sound treatment decisions in individual patients. However, it is also essential for the rational design of therapeutic trials in FSGS. Greater recognition of the pathophysiology underlying podocyte stress and damage in FSGS will increase the likelihood that the cause of an FSGS lesion is properly identified and enable stratification of patients in future interventional trials. Such efforts will facilitate the identification of effective therapeutic agents.
Topics: Animals; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Podocytes
PubMed: 34017116
DOI: 10.1038/s41581-021-00427-1 -
Advances in Experimental Medicine and... 2019Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes... (Review)
Review
Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes are prone to injuries; moreover, as a cell without proliferative potential, loss of podocytes is vital in the pathogenesis of glomerulosclerosis. Thus, sufficient understanding of factors and underlying mechanisms of podocyte injury facilitates the advancement of treating and prevention of glomerulosclerosis. The clinical symptom of podocyte injury is proteinuria, sometimes with loss of kidney functions progressing to glomerulosclerosis. Injury-induced changes in podocyte physiology and function are actually not a simple passive process, but a complex interaction of proteins that comprise the anatomical structure of podocytes at molecular levels. This chapter lists several aspects of podocyte injuries along with potential mechanisms, including glucose and lipid metabolism disorder, hypertension, RAS activation, micro-inflammation, immune disorder, and other factors. These aspects are not technically separated items, but intertwined with each other in the pathogenesis of podocyte injuries.
Topics: Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Inflammation; Lipid Metabolism Disorders; Podocytes; Proteinuria
PubMed: 31399967
DOI: 10.1007/978-981-13-8871-2_10 -
Pediatric Nephrology (Berlin, Germany) Jul 2011Focal and segmental glomerulosclerosis (FSGS) is an important cause of steroid-resistant nephrotic syndrome in adults and children. It is responsible for 5-20% of all... (Review)
Review
Focal and segmental glomerulosclerosis (FSGS) is an important cause of steroid-resistant nephrotic syndrome in adults and children. It is responsible for 5-20% of all cases of end-stage kidney disease (ESKD) in the United States. The pathogenesis of FSGS has not been fully elucidated; however, data from molecular studies of familial cases in the last two decades suggest that FSGS is a defect of the podocyte. The therapeutic agents available for treatment of FSGS are not very effective and only a small percentage of affected individuals will achieve complete remission. Recent data from molecular biology and molecular genetics has provided insight into the mechanisms of action of old agents and also identification of other novel therapeutic targets. This review focuses on recent advances in the molecular pathogenesis of FSGS and currently available therapeutic agents as well as potential novel therapies.
Topics: Genetic Predisposition to Disease; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Podocytes; Risk Factors; Stem Cell Transplantation; Treatment Outcome
PubMed: 21110043
DOI: 10.1007/s00467-010-1692-x -
Advances in Chronic Kidney Disease Mar 2014Glomerular diseases are major contributors to the global burden of end-stage kidney disease. The clinical course and outcome of these disorders are extremely variable... (Review)
Review
Glomerular diseases are major contributors to the global burden of end-stage kidney disease. The clinical course and outcome of these disorders are extremely variable and difficult to predict. The clinical trajectories range from a benign and spontaneously remitting condition to a symptomatic and rapidly progressive disease. The diagnosis is based entirely on the evaluation of kidney biopsy, but this invasive procedure carries multiple risks and often fails to predict the clinical course or responsiveness to treatment. However, more recent advances in genetics and molecular biology have facilitated elucidation of novel pathogenic mechanisms of these disorders. These discoveries fuel the development of novel biomarkers and offer prospects of noninvasive diagnosis and improved prognostication. Our review focuses on the most promising novel biomarkers that have recently emerged for the major types of glomerular diseases, including immunoglobulin A nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis.
Topics: Biomarkers; Genetic Markers; Glomerulonephritis; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Kidney
PubMed: 24602470
DOI: 10.1053/j.ackd.2013.12.002 -
The Journal of Histochemistry and... Sep 2019Focal segmental glomerulosclerosis (FSGS) presents with scar in parts of some glomeruli and often progresses to global and diffuse glomerulosclerosis. Podocyte injury is... (Review)
Review
Focal segmental glomerulosclerosis (FSGS) presents with scar in parts of some glomeruli and often progresses to global and diffuse glomerulosclerosis. Podocyte injury is the initial target in primary FSGS, induced by a circulating factor. Several gene variants, for example, APOL1, are associated with increased susceptibility to FSGS. Primary FSGS may be due to genetic mutation in key podocyte genes. Increased work stress after loss of nephrons, epigenetic mechanisms, and various profibrotic pathways can contribute to progressive sclerosis, regardless of the initial injury. The progression of FSGS lesions also involves crosstalk between podocytes and other kidney cells, such as parietal epithelial cells, glomerular endothelial cells, and even tubular epithelial cells. New insights related to these mechanisms could potentially lead to new therapeutic strategies to prevent progression of FSGS.
Topics: Animals; Apolipoprotein L1; Cicatrix; Disease Progression; Endothelial Cells; Epigenesis, Genetic; Epithelial Cells; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Kidney Tubules; Podocytes
PubMed: 31116068
DOI: 10.1369/0022155419850170