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.
PATHOPHYSIOLOGY
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.
TREATMENT
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.
PROGNOSIS
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
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.
