Focal segmental glomerulosclerosis | |
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Other names | focal glomerular sclerosis,[1] focal nodular glomerulosclerosis[1] |
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Light micrograph of focal segmental glomerulosclerosis, hilar variant. Kidney biopsy. PAS stain. | |
Specialty | Nephrology ![]() |
Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of glomeruli and damage to renal podocytes.[2][3] This process damages the filtration function of the kidney, resulting in protein presence in the urine due to protein loss.[3] FSGS is a leading cause of excess protein loss—nephrotic syndrome—in children and adults.[4] Signs and symptoms include proteinuria and edema.[2][5] Kidney failure is a common long-term complication of the disease.[5][6] FSGS can be classified as primary, secondary, or genetic, depending on whether a particular toxic or pathologic stressor or genetic predisposition can be identified as the cause.[7][8][9] Diagnosis is established by renal biopsy,[2][10] and treatment consists of glucocorticoids and other immune-modulatory drugs.[11] Response to therapy is variable, with a significant portion of patients progressing to end-stage kidney failure.[5] An American epidemiological study 20 years ago demonstrated that FSGS is estimated to occur in 7 persons per million, with males and African-Americans at higher risk .[12][13][7]
The most common symptoms are a result of abnormal loss of protein from the glomerulus of the kidney, and include:[2][5]
Common signs are also due to loss of blood proteins by the glomerulus of the kidney, including:[2][5][10]
FSGS is primarily a disease of the renal glomerulus, the site of filtration of ions and solutes.[14][15] Podocytes are specialized cells lining the Bowman's capsule that contribute to the filtration barrier, preventing molecules larger than 5 nm from being filtered.[16] FSGS involves damage to the renal podocytes such that larger molecules, most notably proteins, are filtered and lost through the kidney.[17][18] Thus, many of the signs and symptoms of FSGS are related to protein loss.[19]
On histology, FSGS manifests as scarring (sclerosis) to segments of glomeruli; moreover, only a portion of glomeruli are affected.[7][20][21] The focal and segmental nature of disease seen on histology help to distinguish FSGS from other types of glomerular sclerosis.[21]
FSGS can be classified by the putative cause of damage to podocytes. Primary FSGS involves cases in which no cause is readily identifiable.[22] It is presumed that a set of unidentified circulating factors in the blood contribute to podocyte damage in these cases.[22][23]
Secondary FSGS is caused by an identifiable stress or toxin that injures podocytes.[22] Many causes of secondary FSGS contribute to podocyte injury through hyperfiltration, which is a scenario of excess filtration by renal glomeruli.[24] Hyperfiltration can be caused by obesity, diabetes or loss of the contralateral kidney, among other causes.[24]
Secondary FSGS can also be caused by toxins, including anabolic steroids and heroin.[25][26]
A number of genes have been implicated in FSGS. These include: NPHS1, which encodes the protein nephrin that contributes to the filtration barrier;[27] NPHS2, which encodes the protein podocin found in podocytes;[28] and INF2, which encodes the actin-binding protein formin.[29]
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.[30]
Diagnosis of FSGS is made by renal biopsy that includes at least fifteen serial cuts with at least eight glomeruli.[31][32] Histologic features include sclerosis (scarring) of a portion (average: 15%) of the glomerular space, with only a portion of glomeruli manifesting any sclerosis.[32]
Other tests helpful in the diagnosis include urine protein, urinalysis, serum albumin, and serum lipids.[2] 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.[5][10]
Five mutually exclusive variants of focal segmental glomerulosclerosis may be distinguished by the pathologic findings seen on renal biopsy:[34]
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.[9] The cellular variant shows similar clinical presentation to collapsing and glomerular tip variant but has intermediate outcomes between the other two variants.[9]
First-line treatment for primary FSGS consists of anti-inflammatory drugs.[11] Specifically, glucocorticoids are begun in patients manifesting with nephrotic-range proteinuria (>3.5 g/day).[35][36] For patients who maintain nephrotic-range proteinuria despite glucocorticoids, or for patients who demonstrate glucocorticoid intolerance, calcineurin inhibitors (e.g., tacrolimus) are initiated.[36] Successful treatment is defined as a drop in proteinuria to sub-nephrotic ranges.[6]
The treatment of secondary FSGS involves addressing the particular toxic or stress agent.[35]
The majority of untreated cases of FSGS will progress to end-stage kidney disease.[37] Important prognostic factors include the degree of proteinuria 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.[6] Only 15% of patients with sub-nephrotic ranges of proteinuria progress to end-stage renal failure at 10 years.[6]
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.[38] Either complete or partial response is associated with 80% kidney survival at 10 years, compared with about 50% among non-responsive patients.[38]
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.[8] FSGS accounts for 2% of all cases of kidney failure.[4] African American patients have four times the likelihood of developing FSGS. Men are about two times as likely to develop FSGS compared to women.[12]