Agnes B. Fogo
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are both common causes of the nephrotic syndrome. Minimal change disease accounts for greater than 90% of cases of nephrotic syndrome in children, vs. 10% to 15% of adults with nephrotic syndrome (1). Focal segmental glomerulosclerosis has been increasing in incidence in the United States in both African Americans and in Hispanics, in both adult and pediatric populations (2-4). It is now the most common cause of nephrotic syndrome in adults in the U.S. Patients with FSGS may have hypertension and hematuria. Serologic studies, including complement levels, are typically within normal limits in both MCD and FSGS.
Minimal change disease shows normal glomeruli by light microscopy (Fig. 4.1). In FSGS, sclerosis involves some, but not all, glomeruli (focal), and the sclerosis affects a portion of, but not the entire, glomerular tuft (segmental) (Fig. 4.2) (1,5-7). Sclerosis is defined as increased matrix with obliteration of the capillary lumen. Uninvolved glomeruli in FSGS show no apparent lesions by light microscopy; FSGS may also entail hyalinosis, caused by insudation of plasma proteins, producing a smooth, glassy (hyaline) appearance (Fig. 4.3). Adhesions (synechiae) of the capillary tuft to Bowman's space are a very early sclerosing lesion.
Focal segmental glomerulosclerosis is diagnosed when even a single glomerulus shows segmental sclerosis. Therefore, samples must be adequate to detect these focal and segmental lesions. A biopsy with only 10 glomeruli has a 35% probability of missing a focal (10% involved) lesion, decreasing to 12% if 20 glomeruli are sampled (8). The juxtamedullary
region also should be included in the biopsy for optimal sampling, because that is where FSGS starts (5). Multiple step sections should also be examined to detect the focal segmental lesions.
Global glomerulosclerosis, in contrast to the segmental lesion, is not of special diagnostic significance in diagnosing FSGS. Globally sclerotic glomeruli may be normally seen at any age. In children, less than 1% global sclerosis is expected. The extent of global sclerosis increases with aging. Smith et al. (9) proffered the formula for normal percent of global sclerosis in adults of up to half the patient's age, minus 10, for example, up to 30% by age 80.
Morphologic variants of sclerosis appear to have differing prognosis (see below) (10,11). The most common type of FSGS, FSGS not otherwise specified (NOS), has no specific distinguishing features, and is characterized by segmental sclerosis, defined as increased matrix and obliteration of capillary lumina, often with hyalinosis in the absence of underlying immune complexes or other indicators of a secondary etiology by complete immunofluorescence/electron microscopy (IF/EM) evaluation; FSGS NOS is diagnosed by exclusion of specific subtypes as follows (Fig. 4.4): Collapsing variant of FSGS is characterized by collapse of the capillary loops and overlying podocyte proliferation, and has a particularly ominous prognosis (Fig. 4.5) (12,13). Even just one glomerulus with collapsing lesion is sufficient, we propose, to classify the process as collapsing variant FSGS. In the absence of collapsing lesions, the location of lesions, either peripheral or hilar, has significance as follows: The glomerular tip lesion is defined as sclerosis only affecting the tubular pole of the glomerulus, with adhesion of the tuft to the proximal tubule outlet (Fig. 4.6). There is often associated endocapillary hypercellularity and intracapillary foam cells (14-16). The
Hierarchical Classification _of FSGS_
cellular variant of FSGS is characterized by segmental proliferative podocyte reaction associated with early sclerosis and/or endocapillary hyper-cellularity and often intracapillary foam cells (17). It does not, per definition, involve the tubular pole. Predominantly hilar lesions, that is, more than half of sclerotic glomeruli with sclerosis with associated hyaline at the hilar pole, in the absence of collapsing lesions, have been proposed to represent a response to reduced renal mass, and may also be associated with secondary FSGS seen with arterionephrosclerosis (10,11).
Vascular sclerosis may be prominent late in the course of FSGS and is proportional to glomerular sclerosis. Tubular atrophy is often accompanied
by interstitial fibrosis, proportional to the degree of scarring in the glomerulus. In HIV nephropathy and collapsing glomerulopathy, tubular lesions are disproportionally severe, with cystic dilation and a more prominent infiltrate (18).
The presence of acute interstitial nephritis (i.e., edema, interstitial infiltrate of lymphocytes, plasma cells, and often eosinophils), and apparent MCD glomerular lesion (i.e., complete foot process effacement, no light microscopic lesions) suggest a drug-induced hypersensitivity etiology, in particular nonsteroidal antiinflammatory drug (NSAID) -related injury.
Surrogate markers of unsampled FSGS have been sought to suspect FSGS even when sclerosed glomeruli are not detected. Abnormal glomeru-lar enlargement (see below) appears to be an early indicator of the sclerotic process preceding overt sclerosis (19). Tubulointerstitial fibrosis in a young patient without sclerosis could also indicate possible unsampled FSGS.
There are no immune complex deposits in either MCD or FSGS. In FSGS, there may be nonspecific entrapment of immunoglobulin M (IgM) and C3 in sclerotic areas or areas where mesangial matrix is increased. IgM staining without deposits by EM does not appear to have specific diagnostic, prognostic, or etiologic significance (20).
Electron microscopy shows foot process effacement, vacuolization, and microvillous transformation of epithelial cells in both MCD and FSGS. In MCD, foot process effacement is typically extensive (Fig. 4.7). Foot process
effacement is often not complete in FSGS (20). However, the extent of foot process effacement does not allow precise distinction between the two disease processes. In secondary FSGS, foot process effacement is generally less than in idiopathic forms. In HIV-associated nephropathy (HIVAN), there are reticular aggregates in endothelial cell cytoplasm.
The pathogenesis of MCD appears related to abnormal cytokines, which only affect glomerular permeability and do not promote sclerogenic mechanisms. Minimal change disease has been associated with drug-induced hypersensitivity reactions, bee stings, Hodgkin's disease, and other venom exposure, implicating immune dysfunction as an initiating factor.
Glomerular hypertrophy may be marker of FSGS. Glomerular enlargement precedes overt glomerulosclerosis in FSGS (19). Patients with abnormal glomerular growth on initial biopsies that did not show overt sclerotic lesions subsequently developed overt glomerulosclerosis, documented in later biopsies. A cutoff of glomerular area larger than 50% more than normal for age indicated increased risk for progression. Of note, glomeruli grow until approximately age 18 years, so age-matched controls must be used in the pediatric population. Since tissue processing methods may influence the size of structures in tissue, it is imperative that each laboratory determines normal ranges for this parameter.
Recurrence of FSGS in the transplant has also shed light on its pathogenesis (21). Most recurrences occur within the first months after transplantation, but recurrence may be immediate. Foot process effacement is present when proteinuria recurs and precedes the development of sclerosis, typically by weeks to months. A circulating factor has been identified in patients with recurrent FSGS, which induces increased ex vivo glomerular permeability, and also a mild increase in proteinuria when injected in rats (22). Plasmapheresis induced remission in some patients with recurrent FSGS, but more often relapse occurred when plasmapheresis was stopped.
Differentiation markers of podocytes, including the Wilms' tumor WT-1 protein, podocalyxin, and synaptopodin, are retained when proteinuria is caused by MCD or membranous glomerulonephritis (GN), but disappeared (or were decreased in the case of synaptopodin) in the collapsing variant of FSGS or HIV-associated nephropathy, with lesser changes in typical FSGS. These observations point to a dysregulated phenotype of the podocyte in the pathogenesis of the collapsing and HIV-associated forms of FSGS (23).
Studies of the molecular biology of the podocyte and identification of genes mutated in rare familial forms of nephrotic syndrome or FSGS, such as nephrin, a-actinin-4, and podocin, have given important new insights into mechanisms of progressive glomerulosclerosis. The gene mutated for congenital nephrotic syndrome, nephrin (NPHS1) is localized to chromosome region 19q13 (24). The common mutations in this syndrome are called fin major and fin minor. Nephrin localizes to the slit diaphragm over the podocyte and is tightly associated with CD2-associated protein (CD2AP) (25). Nephrin functions as a zona occludens-type junction protein, and along with CD2AP is thought to provide a crucial role in receptor patterning and cytoskeletal polarity. Recent data also show that nephrin has signal transduction functions. Surprisingly, some patients develop nephrotic syndrome after transplantation, if the original disease was due to fin major mutations, which leads to complete loss of nephrin. The mechanism for recurrent nephrotic syndrome is not determined. Mice engineered to be deficient in CD2AP develop congenital nephrotic syndrome, similar to congenital nephrotic syndrome of the Finnish type. Recently, mutations of CD2AP, predicted to cause loss of function, have been detected in two adult patients with proteinuria and presumed FSGS without a family history of the disease (26).
Additional important genes interacting with the nephrin-CD2AP complex have been identified in rare cases of familial FSGS (27,28). Autosomal dominant FSGS is caused by mutation in a-actinin-4 (ACTN4), also localized to chromosome 19q13 (29). Patients with the ACTN4 mutation progress to end stage by age 30, with rare recurrence in the transplant. The ACTN4 mutation is hypothesized to cause altered actin cytoskeleton interaction, causing FSGS through a gain-of-function mechanism, contrasting with the loss-of-function mechanism implicated for disease caused by the nephrin mutation. Mice with knock-in of mutated ACTN4 indeed develop FSGS, supporting this hypothesis (30). Podocin, another podocyte-specific gene (NPHS2) is mutated in autosomal recessive FSGS with an early onset in childhood with rapid progression to end stage (31). Podocin is an integral stomatin protein family member and interacts with the CD2AP-nephrin complex, indicating that podocin could serve in the structural organization of the slit diaphragm. Patients with sporadic FSGS and podocin mutation showed recurrence of FSGS after transplant at the same rate as the general FSGS population (32). Recently, an overlap in the NPHS1/NPHS2 mutation spectrum has been detected, modifying the pheno-type of congenital nephrotic syndrome of the Finnish type to congenital FSGS when mutations in both are inherited. These findings further point to key functional interrelationships between NPHS1 and NPHS2 (33). Acquired FSGS also may involve alteration in expression of some of these key podocyte genes. Indeed, some patients with nonfamilial forms of FSGS have been found to have podocin mutations. Importantly, patients with such podocin mutations are generally resistant to steroid therapy (34,35).
Additional observations underscore the importance of the interactions between the podocyte and the underlying basement membrane. Dystrogly-can is an integral component of the GBM. Decreased dystroglycan staining was observed in patients with MCD (36). Dystroglycan expression was maintained in the nonsclerotic segments in FSGS, suggesting that MCD and FSGS are indeed different disease processes and not merely different stages of one disease.
Germline mutations of the WT-1 (Wilms' tumor) suppressor gene are found in Denys-Drash syndrome, a rare childhood disease with diffuse mesangial sclerosis, XY hermaphroditism, and a high risk of Wilms' tumor, with mutations usually of exon 9; and in Frasier syndrome, a disease with FSGS, XY hermaphroditism, and a high risk of gonadoblastoma, with mutations of intron 9 (37). Abnormal, lamellated basement membranes were observed in three patients with FSGS associated with Frasier syndrome, in whom studies for coexistent Alport syndrome were negative (38). Abnormal splice variants of WT-1 have rarely been associated with nonsyndromal cases of FSGS (39).
Minimal change disease patients typically respond to corticosteroids, with excellent long-term prognosis. In contrast, FSGS usually results in progressive decline of GFR. The finding of mesangial hypercellularity was proposed to indicate a subtype of primary MCD with poorer prognosis and increased risk for development of FSGS. However, several series have failed to confirm a definite clinical correlation of this morphologic variant. Thus, diffuse mesangial hypercellularity does not appear to impart a specific prognostic significance, and is rather regarded as a manifestation of an earlier stage of disease.
The proposed morphologic variants of FSGS appear to have prognostic significance (Table 4.1) (10,11). Collapsing FSGS has a poor prognosis with rapid loss of renal function and virtually no responsiveness to cor-ticosteroids alone (13). Series of patients with collapsing FSGS show
Key histologic feature
Possible prognostic implication
Collapse of tuft,
often podocyte hyperplasia
Sclerosis/adhesion at proximal
Sclerosis and hyalinosis
?May reflect a secondary
at vascular pole
type of FSGS
NOS, not otherwise specified.
NOS, not otherwise specified.
a strong preponderance of African Americans, and most patients were adults. The etiology has not yet been defined; however, a possible viral agent has been proposed. Evidence of parvovirus infection was increased in patients with collapsing glomerulopathy compared to controls, usual-type FSGS and HIVAN, suggesting an association (40). The drug pami-dronate also has been linked to the development of collapsing glomerulopathy (41). Collapsing lesions also have been seen in the transplant, linked to cyclosporine toxicity.
Clinically, patients with the cellular variant of FSGS have an abrupt onset of nephrotic syndrome. These patients typically show transition to progressively less cellular, more sclerotic lesions, becoming indistinguishable clinically and morphologically from classical FSGS. This cellular lesion may be an early abnormality seen by light microscopy (LM) when FSGS recurs in the transplant. This morphologic appearance is postulated to represent an early, active lesion (10,11).
Tip lesions, that is, glomerulosclerosis involving the proximal tubular pole of the glomerulus, and not extending past the mid-region, were proposed to represent an early lesion with good prognosis, although later follow-up has revealed a less than benign prognosis in some patients (14,15). Review of autopsy cases of children with MCD who died of overwhelming infection showed rare tip lesions, suggesting that the lesion may not be disease specific (16). Tips lesions can occur at any age. Patients typically present with nephrotic syndrome. In one recent series, patients with the tip lesion variant of FSGS were compared to FSGS NOS and MCD patients. After treatment with steroids alone in most of the tip lesion patients, with added cytotoxic therapy in about a third, over half had achieved remission, whereas only one of 29 in whom follow-up was available progressed to ESRD (15). Thus, the tip variant appears to have a better prognosis than FSGS NOS and to be more similar to MCD.
Predominantly hilar lesions, with glomerulosclerosis located at the vascular pole with associated hyaline, have been proposed to represent a response to reduced renal mass, and may also be associated with secondary FSGS seen with arterionephrosclerosis.
Secondary and Other Variant Forms of Focal Segmental Glomerulosclerosis
C1q nephropathy is best considered as a variant of FSGS-like disease, and presents as nephrotic syndrome (42,43). These patients are generally adolescent African Americans, steroid resistant, and some of those with sclerosis have developed end-stage renal disease. The median time to end stage from biopsy was 81 months in one recent series of 19 patients. Clinical or morphological findings of lupus nephritis are absent [e.g., no reticular aggregates, no clinical evidence of systemic lupus erythematosus (SLE)].
By light microscopy, there may be no lesions or focal segmental sclerosis. Tubular atrophy and interstitial fibrosis are proportional to sclerosis.
Immunofluorescence microscopy may show staining with IgG, IgM, C3, but by definition has prominent C1q. The pattern is most often mesangial, but capillary loop staining may also be present.
Electron microscopy shows electron-dense mesangial deposits, with occasional extension to subendothelial areas. There are no reticular aggregates.
Tubular atrophy and interstitial fibrosis were the best correlates of renal insufficiency at biopsy and at follow-up. The prognosis of those without sclerosis at time of biopsies awaits further follow-up studies.
Many insults to the kidney may result in secondary FSGS, either as the sole manifestation of injury or superimposed on other renal disease manifestations (6,10). The lesion of FSGS may be seen in association with, for example, substantial loss of nephron mass, diabetes, obesity, HIV infection, or heroin abuse. Hilar-type sclerosis may often manifest with these secondary forms of FSGS (see above). Secondary sclerosis also occurs in the chronic stage of many immune complex or proliferative diseases. In some of these settings, the morphologic appearance of sclerosis can indicate the nature of the initial insult: obesity-associated FSGS shows mild mesangial expansion, GBM thickening, subtotal foot process effacement, and marked glomerulomegaly (44). The course is more indolent than for idiopathic FSGS with less frequent nephrotic syndrome. In FSGS secondary to reflux nephropathy, there is frequently prominent periglomeru-lar fibrosis and thickening of Bowman's capsule and patchy interstitial scarring, in addition to the heterogeneous glomerulosclerosis. Focal segmental glomerulosclerosis associated with heroin use does not show pathognomonic features, although global glomerulosclerosis, epithelial cell changes, interstitial fibrosis, and tubular injury tend to be more prominent than in idiopathic cases of FSGS. In HIV-associated nephropathy, the tubules show severe injury, including cystic dilatation, out of proportion to the focal segmental glomerular scarring. Glomeruli show tuft collapse, and reticular aggregates are numerous in endothelial cells. Also, FSGS can develop in association with decreased renal mass, whether acquired or present at birth.
In summary, FSGS is a lesion with many manifestations and diverse mechanisms, including genetic, circulating factors, and environmental. Classification based on increasing understanding of these varying forms will likely lead to improved prognosis and, it is hoped, to treatments.
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