FOCAL SEGMENTAL GLOMERULOSCLEROSIS
Focal segmental glomerulosclerosis (FSGS) is a clinical pathologic syndrome in which there is proteinuria accompanied by glomerular scarring or sclerosis that occurs in a focal (i.e., subset of all glomeruli) and segmental (i.e., portion of each affected glomerulus) distribution. FSGS is a major cause of nephrotic syndrome in adults, and it can occur as a primary, idiopathic process or secondary to numerous systemic conditions, including viruses (HIV, parvovirus B19), medications (pamidronate, lithium, alpha interferon), inherited genetic diseases (mutations in podocyte proteins such as α-actinin-4 or podocin), heroin abuse, and any disorder that causes glomerular hyperﬁltration (such as morbid obesity or any congenital or acquired reduction in renal parenchymal mass, including renal agenesis, renal dysplasia, renal ablation, diabetic nephropathy, sickle cell anemia, or any advanced chronic kidney disease).
In the United States, FSGS is responsible for more cases of end-stage renal disease (ESRD) than any other primary glomerular disease. Its incidence has increased over past decades, for unknown reasons. It is more common in African Americans than Caucasians, possibly because of inherited genetic factors.
The pathogenesis of FSGS is poorly understood. In primary, idiopathic disease, it appears that a circulating permeability factor is responsible, a hypothesis supported by the fact that FSGS can rapidly recur in a transplanted allograft. Although the exact nature of the glomerular injury remains unknown, it appears probable that podocytes (visceral epithelial cells) are a major target, and that injury or loss of these cells leads to proteinuria and sclerosis.
The pathogenetic bases of secondary FSGS are likely diverse. In HIV-associated FSGS, for example, the virus is thought to directly infect podocytes and disrupt normal regulatory patterns. In hyperﬁltration states, increased glomerular pressure is thought to cause progressive endothelial and podocyte injury, ultimately leading to FSGS.
PRESENTATION AND DIAGNOSIS
All patients with FSGS have some degree of proteinuria, which may cause the nephrotic syndrome if severe (see Plate 4-7). On quantiﬁcation with a 24-hour collection or spot urine protein : creatinine ratio, the proteinuria may vary from less than 1 to more than 10 g/ day. A subset of patients will also be found to have hematuria. Laboratory evaluation of serum may reveal hypoalbuminemia and hypercholesterolemia if the proteinuria is in the nephrotic range. A subset of patients will have renal insufﬁciency, manifest as an elevated serum creatinine concentration.
The speciﬁc diagnosis of FSGS can only be established based on histopathologic ﬁndings. Renal biopsy should be performed in adults with nephrotic syndrome in the absence of an apparent cause (i.e., long-standing diabetes mellitus), or in children with unexplained nephrotic syndrome who do not respond to empiric treatment for MCD (see Plate 4-8).
Using light microscopy, glomerulosclerosis is seen in a focal and segmental distribution. Segmental occlusion of glomerular capillaries occurs as the end result of several pathologic changes, including hyalinosis (glasslike deposits resulting from subendothelial accumulation of plasma proteins), podocyte swelling, and accumulation of extracellular matrix. Foam cells may be seen trapped within the capillaries of the sclerotic segments. In addition, segmental adhesions may be seen between the sclerotic portions of the glomerular tuft and the adjacent lining of Bowman’s capsule.
Several histologic variants of FSGS can be distinguished, including classic FSGS (also known as FSGS not otherwise speciﬁed), perihilar variant, glomerular tip variant, cellular variant, and collapsing variant. It is unclear if these different subtypes have different pathophysiologic bases or merely represent different degrees of glomerular damage.
The perihilar variant of FSGS is characterized by the presence of perihilar hyalinosis and sclerosis in >50% of affected glomeruli. This variant can be seen in primary disease; however, if seen in the presence of glomerulomegaly, it suggests a secondary form related to glomerular hyperﬁltration. The glomerular tip variant is characterized by a focal lesion localized near the urinary pole of Bowman’s capsule, where the proximal tubule begins. The capillary lumina in this region appear obliterated secondary to the presence of foam cells and swollen endothelial cells, whereas the overlying podocytes appear hypertrophic and conﬂuent with adjacent parietal and tubular epithelial cells. Adhesions may be seen between the glomerular tuft and the urinary pole. The cellular variant is characterized by the presence of segmental endocapillary hypercellularity in at least one glomerulus that affects at least 25% of the tuft and results in occlusion of the capillary lumina. The inﬁltration of leukocytes, foam cells, and other cell types may result in karyorrhexis and other evidence of active inﬂammation. The collapsing variant is characterized by a segmental or global collapse of glomerular capillaries with signiﬁcant hypertrophy and hyperplasia of overlying podocytes, which often contain large intracytoplasmic protein resorption droplets. Unlike in other FSGS variants, hyalinosis and foam cells are generally not seen. This variant may occur as a primary phenomenon but is also the characteristic lesion of HIV-associated nephropathy (see Plate 4-55).
On immunoﬂuorescence, all types may reveal irregular positive staining for immunoglobulin M and complement factor C3 in the same focal, segmental distribution as the glomerulosclerosis. Strongly positive staining for antibodies or complement proteins in non-sclerotic glomeruli suggests an underlying immune complex glomerulonephritis. Electron microscopy of the sclerotic lesions in all subtypes reveals wrinkling and retraction of the glomerular basement membrane (GBM), subendothelial accumulation of hyaline material, diffuse foot process effacement, podocyte hypertrophy, and focal areas of podocyte detachment from the GBM.
If FSGS is diagnosed, patients should be screened for secondary causes that may otherwise be subclinical, such as HIV infection.
All patients with FSGS (both primary and secondary forms) should receive angiotensin-converting enzyme (ACE) inhibitors or aldosterone receptor blockers (ARBs) to reduce proteinuria and slow the progression to end-stage renal disease (ESRD). Hyperlipidemia, if present, should be treated with a cholesterol-lowering medication, such as a statin. Patients with edema may require diuretic therapy and should be encouraged to adopt a low-salt diet. Blood pressure should be aggressively controlled.
In cases of primary FSGS with subnephrotic proteinuria, the above conservative measures are often adequate. In cases with nephrotic syndrome, immunosuppression is warranted. Initial treatment is with high dose glucocorticoids for up to 6 months. About half of patients attain either full remission (<300 mg/ day of proteinuria) or partial remission (reduction in nephrotic rage proteinuria by > 50%) with glucocorticoids. For those patients who do not achieve remission, or who experience relapsing disease, cyclosporine or tacrolimus (both calcineurin inhibitors) can be used as second line agents as long as renal function is relatively intact.
In cases of secondary FSGS, treatment should focus on reversing the underlying cause, which may slow down or halt progression of the renal disease.
Overall, idiopathic FSGS has a signiﬁcantly higher rate of progression to ESRD than secondary forms. The clinical features that portend a poor prognosis include high levels of proteinuria (particularly if associated with nephrotic syndrome), impaired renal function, and failure to achieve remission (either complete or partial). The pathologic features that portend a poor prognosis include collapsing variant and high levels of interstitial ﬁbrosis. In contrast, the glomerular tip variant confers a more favorable prognosis, with a higher likelihood of attaining disease remission with steroids.
If appropriate treatment is not provided, a signiﬁcant portion of patients with primary FSGS will progress to ESRD. Only a small minority of patients experience complete spontaneous remission. Patients who progress to end-stage renal disease and receive a renal transplant are at risk for recurrent FSGS in the allograft.
C1q nephropathy is a rare but distinct cause of nephrotic syndrome with a clinical presentation and histopathologic ﬁndings that are very similar to what is seen with FSGS. Like FSGS, C1q nephropathy is also more common among African Americans. The pathogenesis is unknown but is likely immune-mediated. The major feature that distinguishes C1q nephropathy from FSGS is the presence of mesangial immune complex deposits that stain positive for C1q on immunoﬂuorescence. Staining is often positive for IgG, IgM, and C3 as well. There is no established treatment for C1q nephropathy. Some clinicians advise steroids, although the literature has offered mixed results regarding its efﬁcacy.