Focal segmental glomerulosclerosis

The most common symptoms are a result of abnormal loss of protein from the glomerulus of the kidney, and include:

• Frothy urine (due to excess protein)
• Excess water retention (pitting edema, due to loss of serum albumin)
• 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)
• Fatty casts in the urine (secondary to hypercholesterolemia)

File:Bowman's capsule and glomerulus.svg consists of a set of capillaries from which blood is filtered into Bowman's space. Large molecules, such as proteins, are usually too large to be filtered and instead are retained in the capillaries.]]

FSGS is primarily a disease of the renal glomerulus, the site of filtration of ions and solutes.{{cite journal |vauthors=Wallace MA |title=Anatomy and physiology of the kidney |journal=AORN J |volume=68 |issue=5 |pages=800, 803–16, 819–20; quiz 821–4 |date=November 1998 |pmid=9829131 |doi=10.1016/s0001-2092(06)62377-6 }}{{cite journal |vauthors=Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD |title=The glomerulus: the sphere of influence |journal=Clin J Am Soc Nephrol |volume=9 |issue=8 |pages=1461–9 |date=August 2014 |pmid=24875196 |pmc=4123398 |doi=10.2215/CJN.09400913 }} Podocytes are specialized cells lining the Bowman's capsule that contribute to the filtration barrier, preventing molecules larger than 5 nm from being filtered.{{cite journal |vauthors=Tojo A, Kinugasa S |title=Mechanisms of glomerular albumin filtration and tubular reabsorption |journal=Int J Nephrol |volume=2012 |pages=481520 |date=2012 |pmid=22685655 |pmc=3363986 |doi=10.1155/2012/481520 |doi-access=free }} FSGS involves damage to the renal podocytes such that larger molecules, most notably proteins, are filtered and lost through the kidney.{{cite journal |vauthors=Nagata M |title=Podocyte injury and its consequences |journal=Kidney Int |volume=89 |issue=6 |pages=1221–30 |date=June 2016 |pmid=27165817 |doi=10.1016/j.kint.2016.01.012 |doi-access=free }}{{cite journal |vauthors=Wang CS, Greenbaum LA |title=Nephrotic Syndrome |journal=Pediatr Clin North Am |volume=66 |issue=1 |pages=73–85 |date=February 2019 |pmid=30454752 |doi=10.1016/j.pcl.2018.08.006 }} Thus, many of the signs and symptoms of FSGS are related to protein loss.{{Cite web |title=Focal Segmental Glomerulosclerosis (FSGS) |url=https://my.clevelandclinic.org/health/diseases/21149-focal-segmental-glomerulosclerosis-fsgs |access-date=2022-06-30 |website=Cleveland Clinic}}

On histology, FSGS manifests as scarring (sclerosis) to segments of glomeruli; moreover, only a portion of glomeruli are affected.{{cite journal |vauthors=Ichikawa I, Fogo A |title=Focal segmental glomerulosclerosis |journal=Pediatr Nephrol |volume=10 |issue=3 |pages=374–91 |date=June 1996 |pmid=8792409 |doi=10.1007/BF00866790 }}{{cite journal |vauthors=Nagata M, Kobayashi N, Hara S |title=Focal segmental glomerulosclerosis; why does it occur segmentally? |journal=Pflugers Arch |volume=469 |issue=7–8 |pages=983–8 |date=August 2017 |pmid=28664408 |doi=10.1007/s00424-017-2023-x }} 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.{{cite journal |vauthors=De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC |title=Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach |journal=J Am Soc Nephrol |volume=29 |issue=3 |pages=759–774 |date=March 2018 |pmid=29321142 |pmc=5827609 |doi=10.1681/ASN.2017090958 }} It is presumed that a set of unidentified circulating factors in the blood contribute to podocyte damage in these cases.{{cite journal |vauthors=Rennke HG, Klein PS |title=Pathogenesis and significance of nonprimary focal and segmental glomerulosclerosis |journal=Am J Kidney Dis |volume=13 |issue=6 |pages=443–56 |date=June 1989 |pmid=2658558 |doi=10.1016/s0272-6386(89)80001-0 }}

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.{{cite journal |vauthors=Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW |title=Glomerular hyperfiltration: definitions, mechanisms and clinical implications |journal=Nat Rev Nephrol |volume=8 |issue=5 |pages=293–300 |date=February 2012 |pmid=22349487 |doi=10.1038/nrneph.2012.19 }} Hyperfiltration can be caused by obesity, diabetes or loss of the contralateral kidney, among other causes.

Secondary FSGS can also be caused by toxins, including anabolic steroids and heroin.{{cite journal |vauthors=Dubrow A, Mittman N, Ghali V, Flamenbaum W |title=The changing spectrum of heroin-associated nephropathy |journal=Am J Kidney Dis |volume=5 |issue=1 |pages=36–41 |date=January 1985 |pmid=3966467 |doi=10.1016/s0272-6386(85)80133-5 }}{{cite journal |vauthors=Kasiske BL, Crosson JT |title=Renal disease in patients with massive obesity |journal=Arch Intern Med |volume=146 |issue=6 |pages=1105–9 |date=June 1986 |doi=10.1001/archinte.1986.00360180095016 |pmid=3718096 }}

A number of genes have been implicated in FSGS. These include: NPHS1, which encodes the protein nephrin that contributes to the filtration barrier;{{cite journal |vauthors=Philippe A, Nevo F, Esquivel EL, Reklaityte D, Gribouval O, Tête MJ, Loirat C, Dantal J, Fischbach M, Pouteil-Noble C, Decramer S, Hoehne M, Benzing T, Charbit M, Niaudet P, Antignac C |title=Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome |journal=J Am Soc Nephrol |volume=19 |issue=10 |pages=1871–8 |date=October 2008 |pmid=18614772 |pmc=2551572 |doi=10.1681/ASN.2008010059 }} NPHS2, which encodes the protein podocin found in podocytes;{{cite journal |vauthors=Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C |title=NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome |journal=Nat Genet |volume=24 |issue=4 |pages=349–54 |date=April 2000 |pmid=10742096 |doi=10.1038/74166 }} and INF2, which encodes the actin-binding protein formin.{{cite journal |vauthors=Brown EJ, Schlöndorff JS, Becker DJ, Tsukaguchi H, Tonna SJ, Uscinski AL, Higgs HN, Henderson JM, Pollak MR |title=Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis |journal=Nat Genet |volume=42 |issue=1 |pages=72–6 |date=January 2010 |pmid=20023659 |pmc=2980844 |doi=10.1038/ng.505 }}

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.Chang, Anthony, Robbins & Cotran Pathologic Basis of Disease, Chapter 20, 895–952

Gain of function mutations in APOL1 have also been proposed to play a role in the pathogenesis of this disease.{{cite journal |vauthors=Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, Friedman D, Briggs W, Dart R, Korbet S, Mokrzycki MH, Kimmel PL, Limou S, Ahuja TS, Berns JS, Fryc J, Simon EE, Smith MC, Trachtman H, Michel DM, Schelling JR, Vlahov D, Pollak M, Winkler CA |title=APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy |journal=J Am Soc Nephrol |volume=22 |issue=11 |pages=2129–37 |date=November 2011 |pmid=21997394 |pmc=3231787 |doi=10.1681/ASN.2011040388 |url=}}

Diagnosis of FSGS is made by renal biopsy that includes at least fifteen serial cuts with at least eight glomeruli.{{cite journal |vauthors=Fuiano G, Comi N, Magri P, Sepe V, Balletta MM, Esposito C, Uccello F, Dal Canton A, Conte G |title=Serial morphometric analysis of sclerotic lesions in primary "focal" segmental glomerulosclerosis |journal=J Am Soc Nephrol |volume=7 |issue=1 |pages=49–55 |date=January 1996 |pmid=8808109 |doi=10.1681/ASN.V7149 }}{{cite journal |vauthors=Schwartz MM, Korbet SM |title=Primary focal segmental glomerulosclerosis: pathology, histological variants, and pathogenesis |journal=Am J Kidney Dis |volume=22 |issue=6 |pages=874–83 |date=December 1993 |pmid=8250036 |doi=10.1016/s0272-6386(12)70349-9 }} 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 proteinuria.

Image:Collapsing glomerulopathy - very high mag.jpg of the collapsing variant of FSGS (collapsing glomerulopathy). A collapsed glomerulus is seen at the top, right-of-centre. PAS stain. Kidney biopsy.]]

File:Histopathology of collapsing glomerulopathy.jpg

Five mutually exclusive variants of focal segmental glomerulosclerosis may be distinguished by the pathologic findings seen on renal biopsy:{{cite journal |vauthors=Thomas DB, Franceschini N, Hogan SL, Ten Holder S, Jennette CE, Falk RJ, Jennette JC |title=Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants |journal=Kidney Int |volume=69 |issue=5 |pages=920–6 |date=March 2006 |pmid=16518352 |doi=10.1038/sj.ki.5000160 |doi-access=free}}

1. Collapsing variant
2. Glomerular tip lesion variant
3. Cellular variant
4. Perihilar variant
5. Not otherwise specified (NOS) variant

Recognition of these variants may have prognostic 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.{{cite journal |author-link=Agnes Fogo |author=Fogo AB |title=Causes and pathogenesis of focal segmental glomerulosclerosis |journal=Nat Rev Nephrol |volume=11 |issue=2 |pages=76–87 |date=February 2015 |pmid=25447132 |pmc=4772430 |doi=10.1038/nrneph.2014.216 }} The cellular variant shows similar clinical presentation to collapsing and glomerular tip variant but has intermediate outcomes between the other two variants.

First-line treatment for primary FSGS consists of anti-inflammatory drugs. Specifically, glucocorticoids are begun in patients manifesting with nephrotic-range proteinuria (>3.5 g/day).{{cite journal |vauthors=Chen YM, Liapis H |title=Focal segmental glomerulosclerosis: molecular genetics and targeted therapies |journal=BMC Nephrol |volume=16 |pages=101 |date=July 2015 |pmid=26156092 |pmc=4496884 |doi=10.1186/s12882-015-0090-9 |doi-access=free }}{{cite journal |vauthors=Raina R, Wang J, Sharma A, Chakraborty R |title=Extracorporeal Therapies in the Treatment of Focal Segmental Glomerulosclerosis |journal=Blood Purif |volume=49 |issue=5 |pages=513–523 |date=2020 |pmid=32074606 |doi=10.1159/000506277 }} For patients who maintain nephrotic-range proteinuria despite glucocorticoids, or for patients who demonstrate glucocorticoid intolerance, calcineurin inhibitors (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.

The majority of untreated cases of FSGS will progress to end-stage kidney disease.{{cite journal |vauthors=Deegens JK, Assmann KJ, Steenbergen EJ, Hilbrands LB, Gerlag PG, Jansen JL, Wetzels JF |title=Idiopathic focal segmental glomerulosclerosis: a favourable prognosis in untreated patients? |journal=Neth J Med |volume=63 |issue=10 |pages=393–8 |date=November 2005 |pmid=16301760 }} Important prognostic factors include the degree of proteinuria and initial response to therapy.{{cn|date=December 2024}}

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.{{cite journal |vauthors=Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC |title=Focal and segmental glomerulosclerosis: definition and relevance of a partial remission |journal=J Am Soc Nephrol |volume=16 |issue=4 |pages=1061–8 |date=April 2005 |pmid=15716334 |doi=10.1681/ASN.2004070593 }} Either complete or partial response is associated with 80% kidney survival at 10 years, compared with about 50% among non-responsive patients.

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 four times the likelihood of developing FSGS. Men are about two times as likely to develop FSGS compared to women.

• Andy Cole
• Gary Coleman
• Sean Elliott
• Alonzo Mourning

• Glomerulonephritis
• Nephrotic syndrome

{{Medical resources

| ICD10 = {{ICD10|N|00||n|00}}–{{ICD10|N|08||n|00}} (with .1 suffix)

| ICD9 = {{ICD9|581.1}}

| OMIM = 603278

| OMIM_mult = {{OMIM|603965||none}} {{OMIM|607832||none}} {{OMIM|612551||none}} {{OMIM|613237||none}} {{OMIM|600995||none}}

| MedlinePlus = 000478

| eMedicineSubj = med

| eMedicineTopic = 2944

| MeshID = D005923

| SNOMED CT = 236403004

}}

{{Glomerular disease}}

{{DEFAULTSORT:Focal Segmental Glomerulosclerosis}}

Category:Kidney diseases

Category:Channelopathies

Category:Disorders causing edema