Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of

glomeruli ''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn". ''Glomerulus'' may refer to: * the filter ...

and damage to renal

podocyte Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. Bowman's capsule ...

s.Rosenberg, Avi Z.; Kopp, Jeffrey B. (2017-03-07). "Focal Segmental Glomerulosclerosis". ''Clinical Journal of the American Society of Nephrology''. 12 (3): 502–517. doi:10.2215/CJN.05960616.

ISSN An International Standard Serial Number (ISSN) is an eight-digit serial number used to uniquely identify a serial publication, such as a magazine. The ISSN is especially helpful in distinguishing between serials with the same title. ISSNs ...

1555-9041. PMC 5338705.

PMID PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine (NLM) at the National Institutes of Health maintain the ...

28242845.D'Agati V. The many masks of focal segmental glomerulosclerosis. Kidney Int. 1994 Oct;46(4):1223-41. doi: 10.1038/ki.1994.388. . This process damages the filtration function of the kidney, resulting in protein loss in the urine. FSGS is a leading cause of excess protein loss— nephrotic syndrome—in children and adults.Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis. 2004 Nov;44(5):815-25. . Signs and symptoms include

proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy (although this symptom ma ...

, water retention, and edema.Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am J Kidney Dis. 1995 Apr;25(4):534-42. doi: 10.1016/0272-6386(95)90120-5. .

Kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

is a common long-term complication of disease.Korbet SM, Schwartz MM, Lewis EJ. Primary focal segmental glomerulosclerosis: clinical course and response to therapy. Am J Kidney Dis. 1994 Jun;23(6):773-83. doi: 10.1016/s0272-6386(12)80128-4. . FSGS can be classified as primary versus secondary depending on whether a particular toxic or pathologic stressor can be identified as the cause.Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis. 1997 Nov;30(5):621-31. doi: 10.1016/s0272-6386(97)90485-6. . Diagnosis is established by renal biopsy,Kiffel J, Rahimzada Y, Trachtman H. Focal segmental glomerulosclerosis and chronic kidney disease in pediatric patients. Adv Chronic Kidney Dis. 2011 Sep;18(5):332-8. doi: 10.1053/j.ackd.2011.03.005. ; PMCID: PMC3709971. and treatment consists of glucocorticoids and other immune-modulatory drugs.Campbell KN, Tumlin JA. Protecting Podocytes: A Key Target for Therapy of Focal Segmental Glomerulosclerosis. Am J Nephrol. 2018;47 Suppl 1(Suppl 1):14-29. doi: 10.1159/000481634. Epub 2018 May 31. ; PMCID: PMC6589822. Response to therapy is variable, with a significant portion of patients progressing to end-stage kidney failure. FSGS is estimated to occur in 2-3 persons per million, with males and African peoples at higher risk .Tucker JK. Focal segmental glomerulosclerosis in African Americans. Am J Med Sci. 2002 Feb;323(2):90-3. doi: 10.1097/00000441-200202000-00006. .

Signs and symptoms

The most common symptoms are a result of abnormal loss of protein from the

glomerulus ''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn". ''Glomerulus'' may refer to: * the filter ...

of the kidney, and include: * Frothy urine (due to excess protein) * Excess water retention (pitting edema, due to loss of serum

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

) * Susceptibility to infection (due to loss of serum antibodies) Common signs are also due to loss of blood proteins by the glomerulus of the kidney, including: * Protein in the urine (often in the nephrotic syndrome-range of >3.5 g/day) * Low serum albumin (<3.5 g/dl) * Low serum antibodies * High serum cholesterol (compensatory by the liver to compensate for low serum

oncotic pressure Oncotic pressure, or colloid osmotic-pressure, is a form of osmotic pressure induced by the proteins, notably albumin, in a blood vessel's plasma (blood/liquid) that causes a pull on fluid back into the capillary. Participating colloids displace ...

) * Fatty casts in the urine (secondary to hypercholesterolemia)

Pathophysiology

FSGS is primarily a disease of the renal

, the site of filtration of ions and solutes.

Podocyte Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. Bowman's capsule ...

s are specialized cells lining the Bowman's capsule that contribute to the filtration barrier, preventing molecules larger than 5 nm from being filtered. FSGS involves damage to the renal podocytes such that larger molecules, most notably proteins, are filtered and lost through the kidney. Thus, many of the signs and symptoms of FSGS are related to protein loss. On histology, FSGS manifests as damage ( sclerosis) to segments of glomeruli; moreover, only a portion of glomeruli are affected.Nagata M, Kobayashi N, Hara S. Focal segmental glomerulosclerosis; why does it occur segmentally? Pflugers Arch. 2017 Aug;469(7-8):983-988. doi: 10.1007/s00424-017-2023-x. Epub 2017 Jun 29. . The focal and segmental nature of disease seen on histology help to distinguish FSGS from other types of glomerular sclerosis. FSGS can be classified by the putative cause of damage to podocytes. Primary FSGS involves cases in which no cause is readily identifiable.De Vriese AS, Sethi S, Nath KA, et al. Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach. J Am Soc Nephrol 2018; 29:759. 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.Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol. 2012 Feb 21;8(5):293-300. doi: 10.1038/nrneph.2012.19. . Hyperfiltration can be caused by obesity or loss of the contralateral kidney, among other causes. Secondary FSGS can also be caused by toxins, including steroids and heroin. A number of genes have been implicated in FSGS. These include: ''NPHS1'', which encodes the protein

nephrin Nephrin is a protein necessary for the proper functioning of the renal filtration barrier. The renal filtration barrier consists of fenestrated endothelial cells, the glomerular basement membrane, and the podocytes of epithelial cells. Nephrin is ...

that contributes to the filtration barrier; ''NPHS2'', which encodes the protein

podocin Podocin is a protein component of the filtration slits of podocytes. Glomerular capillary endothelial cells, the glomerular basement membrane and the filtration slits function as the filtration barrier of the kidney glomerulus. Mutations in the ...

found in podocytes; and ''INF2'', which encodes the actin-binding protein formin. The pathogenesis of HIV-associated FSGS is unclear, but may be primarily due to the presence of the G1/G2 risk alleles for APOL1. There is some data to suggest that HIV can infect tubular epithelial cells and podocytes, but much remains to be known.

Diagnosis

Diagnosis of FSGS is made by

renal biopsy Renal biopsy (also kidney biopsy) is a medical procedure in which a small piece of kidney is removed from the body for examination, usually under a microscope. Microscopic examination of the tissue can provide information needed to diagnose, moni ...

that includes at least 15 serial cuts with at least 8

.Schwartz MM, Korbet SM. Primary focal segmental glomerulosclerosis: pathology, histological variants, and pathogenesis. Am J Kidney Dis 1993; 22:874. Histologic features include sclerosis (scarring) of a portion (average: 15%) of the glomerular space, with only a portion of glomeruli manifesting any sclerosis. Other tests helpful in the diagnosis include urine protein, urinalysis, serum albumin, and serum lipids. A clinical picture of proteinuria, low blood protein levels (albumin, antibodies), and high blood cholesterol would support a diagnosis of FSGS, although these do not help to distinguish between FSGS and other causes of

Classification

Five mutually exclusive variants of focal segmental glomerulosclerosis may be distinguished by the pathologic findings seen on

: # Collapsing variant # Glomerular tip lesion variant # Cellular variant # Perihilar variant # Not otherwise specified (NOS) variant. Recognition of these variants may have

prognostic Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stable ...

value in individuals with primary focal segmental glomerulosclerosis. The collapsing variant is associated with higher rate of progression to end-stage renal disease, whereas the glomerular tip lesion variant has a low rate of progression to end-stage renal disease in most patients. Fogo AB. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol. 2015 Feb;11(2):76-87. doi: 10.1038/nrneph.2014.216. Epub 2014 Dec 2. ; PMCID: PMC4772430. The cellular variant shows similar clinical presentation to collapsing and glomerular tip variant but has intermediate outcomes between the other two variants.

Treatment

First-line treatment for primary FSGS consists of anti-inflammatory drugs. Specifically,

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every verteb ...

s are begun in patients manifesting with nephrotic-range proteinuria (>3.5 g/day).Chen YM, Liapis H. Focal segmental glomerulosclerosis: molecular genetics and targeted therapies. BMC Nephrol. 2015 Jul 9;16:101. doi: 10.1186/s12882-015-0090-9. ; PMCID: PMC4496884.Raina R, Wang J, Sharma A, Chakraborty R. Extracorporeal Therapies in the Treatment of Focal Segmental Glomerulosclerosis. Blood Purif. 2020;49(5):513-523. doi: 10.1159/000506277. Epub 2020 Feb 19. . For patients who maintain nephrotic-range proteinuria despite glucocorticoids, or for patients who demonstrate glucocorticoid intolerance,

calcineurin inhibitors Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified into ...

(e.g., tacrolimus) are initiated. Successful treatment is defined as a drop in proteinuria to sub-nephrotic ranges. The treatment of secondary FSGS involves addressing the particular toxic or stress agent.

Prognosis

The majority of untreated cases of FSGS will progress to

end-stage kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

.Deegens JK, Assmann KJ, Steenbergen EJ, Hilbrands LB, Gerlag PG, Jansen JL, Wetzels JF. Idiopathic focal segmental glomerulosclerosis: a favourable prognosis in untreated patients? Neth J Med. 2005 Nov;63(10):393-8. . Important prognostic factors include the degree of

and initial response to therapy. Patients with nephrotic-range (>3.5 g/day) proteinuria have over a 50% rate of progression to end-stage kidney disease at 10 years. Only 15% of patients with sub-nephrotic ranges of proteinuria progress to end-stage renal failure at 10 years. Initial response to therapy also dictates long-term outcomes. Those defined as having a "complete response" typically manifest a proteinuria of <300 mg/day; those with a "partial response" manifest a sub-nephrotic range of proteinuria, <3.5 g/day.Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC; Toronto Glomerulonephritis Registry Group. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. J Am Soc Nephrol. 2005 Apr;16(4):1061-8. doi: 10.1681/ASN.2004070593. Epub 2005 Feb 16. . Either complete or partial response is associated with 80% kidney survival at 10-years, compared with about 50% among non-responsive patients.

Epidemiology

FSGS accounts for 35% of all cases of nephrotic syndrome, making it one of the most common causes of nephrotic syndrome in the United States. FSGS accounts for 2% of all cases of kidney failure. African American patients have 4 times the likelihood of developing FSGS. Men are about 2 times as likely to develop FSGS as compared with women.

References

External links

{{DEFAULTSORT:Focal Segmental Glomerulosclerosis Kidney diseases Channelopathies Disorders causing edema