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Primary focal segmental glomerulosclerosis (FSGS) is a common glomerular disease in adults and ranks among the top causes of a primary glomerular disease causing end-stage renal disease (ESRD). Primary FSGS is, however, adiagnosis of exclusion that is reached after known causes of FSGS have been ruled out.
The distinction between primary versus secondary FSGS is not always obvious, resulting in a number of patients with secondary FSGS undergoing unnecessary and potentially harmful immunosuppressive therapy. In this article, we will review clinical history, laboratory evaluation and renal biopsy findings that may help the nephrologist to make a more accurate diagnosis and therapeutic decision when dealing with a patient who has proteinuria and an FSGS lesion on renal biopsy.
Is FSGS really focal?
FSGS is a pattern of glomerular injury characterized histologically by the presence of mesangial sclerosis, capillary obliteration with hyalinosis and intracapillary foam cells, with formation of adhesions between the glomerular tuft and Bowman’s capsule that occurs in parts (segmental) of some (focal) glomeruli.1
As such, FSGS is not a disease but rather a pattern of injury as a result of diverse pathological processes. For example, a focal necrotizing glomerulonephritis lesion in a patient with ANCA-associated vasculitis may heal as a FSGS lesion. Similarly, patients with Alport syndrome may develop a FSGS lesion that is indistinguishable from a patient with primary FSGS on light microscopy (LM) examination.
In patients with primary FSGS, however, the name focal is misleading because it fails to convey the true extent of the pathologic process. It should be also recognized that focal global glomerulosclerosis (FGGS) is not synonymous with FSGS and is most frequently a manifestation of aging per se, vascular injury from prolonged poorly managed hypertension, or a tubulopathy.2
In experimental models, lesions in podocytes involve the entire glomerular population but conventional LM examination shows that only a limited number of glomeruli have segmental sclerotic lesions. The use of serial-section with 3-D morphometric analysis in rats treated with adriamycin (a model of nephrotic syndrome) showed that up to 94% of the glomeruli were affected by sclerotic lesions.3
Conventional counting of glomeruli affected by sclerosis in single sections, however, greatly underestimated the percentage of sclerotic glomeruli (23%–39%). Similarly, 3-D glomerular morphology analysis in patients with subtotal nephrectomy showed that among 65 glomeruli examined, only 8% were normal, 42% revealed segmental sclerosis, and 51% showed global sclerosis.4
Also using 3-D analysis, Fogo et al evaluated the distribution of segmental sclerosis in patients (15 adults; 6 children) with idiopathic FSGS.5 After this serial section analysis, the percent of glomeruli involved by sclerosis increased from 32% to 48% in adults and from 12% to 23% in children.
Finally, Fuiano et al evaluated 14 biopsies from adults and sclerotic glomeruli rose from 31.5% to 71.8% on serial sectioning, and in the 57 glomeruli for which the whole glomerulus was available, it rose to 81.7%.6 These results confirmed that single-section evaluation overestimates the number of normal glomeruli and greatly underestimates the number of glomeruli classified as sclerotic.
This is easy to understand. Given that a glomerulus is a sphere with a top-to-bottom length of approximately 200 microns and that sections are usually cut at a thickness of 2 microns, a segmental lesion can be easily missed. Therefore, adequate quantification of the percentage of glomeruli affected by sclerosis can only be made by 3-D morphologic analysis of the entire glomerulus. These observations have led Stewart Cameron to state that “Perhaps we should drop the “focal” from the name, and simply call it “segmental sclerosis”.7
However, it remains to be explained why studies in humans do not show the same degree of segmental involvement (>90%) as in animal models. Part of the reason is that it takes time for the FSGS lesion to develop. Kriz and co-workers have shown loss of podocytes and adherence of the parietal epithelial cell to the denuded glomerular basement membrane is the key event in the formation of the FSGS lesion.8
As such, the primary event is the podocyte injury which can be seen initially only on electron microscopy (EM) examination as diffuse foot process effacement (see EM findings below) in an otherwise normal glomerulus on LM examination. Only with time a scar will form.
Indeed, it has been proposed that in some patients there is progression from diffuse segmental lesions at the tubular origin to diffuse multiple lesions throughout the glomerulus,9 and serial renal biopsies have shown progression of FSGS lesions both in native10–12 as well as in recurrent disease post kidney transplant.13
Understanding the extent of the pathological process makes it easier to explain to a patient with a proteinuria of >10g/24h and a renal biopsy containing 20 glomeruli, but only 4 showing a segmental scar, why he/she is likely to progress to ESRD if remission of proteinuria is not achieved.
Distinguishing primary from secondary FSGS
Distinguishing between primary versus secondary FSGS is crucial because presentation, prognosis, and therapeutic approach can vary significantly.2 As discussed, at the present time primary/idiopathic FSGS is a diagnosis of exclusion, once secondary causes—reduced renal mass, functional adaptation, infectious (e.g., HIV), drug-induced (e.g., pamidronate, interferons, anabolic steroids), and genetic (familial or sporadic)—have been ruled out.14
It should be noted that genetic mutations are a rare cause of FSGS presenting in adults to the point that routine genetic screening is not recommended in these group. For patients with primary FSGS, a putative circulating “permeability factor”, which is toxic to the podocyte, has been proposed as playing a role in its pathogenesis.15,16
The fact that administration of serum from FSGS patients into rats causes proteinuria supports the existence of such a factor in these patients.17 Unfortunately, to date, no such factor has been isolated and chemically purified or fulfilled Koch’s postulates for a causative agent.
In experimental animal models, chronic administration of the aminonucleoside puromycin, which is toxic to the podocyte, results in the development of proteinuria and FSGS lesions that are similar to the glomerular lesions found in human primary FSGS.18 In this model, EM examination shows that widespread foot process effacement and podocyte detachment from basement membranes is the initial lesion with formation of synechiae occurring at a later stage.18–20
In the unilateral nephrectomy post-adaptive model of secondary FSGS, however, there is glomerular tuft hypertrophy but podocyte cell numbers do notincrease.21 Rather, podocytes are forced to hypertrophy and stretch to cover a larger surface area. This results in podocyte attenuation, but foot processes are largely preserved.22,23 These data show that there are marked differences at the
EM levels between models of primary (toxic, permeability factor mediated) versus secondary forms of FSGS. Supporting the concept that primary FSGS is due to a “permeability factor” that is toxic to the podocyte is data fromrecurrent FSGS in kidney transplant showing diffuse foot process effacement as the initial pathological event that can be observed within minutes after reperfusion.24
In these patients, diffuse foot process effacement is followed by massive proteinuria developing within hours to days after kidney transplantation.25 With time, the characteristic FSGS lesion develops. Thus, foot process effacement is the earliest structural change and key initial event with an FSGS lesion developing “late” in the course of the pathological process.
More recently, the urokinase receptor (uPAR), which is integral to the maintenance of the slit diaphragm through its ability to form signaling complexes with other transmembrane proteins, including αvβ3 integrin, has been also found to be upregulated in FSGS.26 Research shows that uPAR can be released from the plasma membrane as a soluble molecule (suPAR) ranging from 20–50 kDa, depending on the degree of glycosylation and proteolytic cleavage.27,28 This molecular size is close to the putative circulating permeability factor discussed above, which has a predicted size range of 30 to 50 kDa.29
Activation of podocyte β3 integrin by high levels of suPAR leads to podocyte effacement, proteinuria, glomerular damage, and loss of renal function.16 Data show that suPAR is elevated in patients with FSGS and is highest in patients with post-transplantation recurrent disease.16,30
However, a number of recent studies have added skepticism to the specific pathogenic role of suPAR in “primary” FSGS (reviewed in Maas et al31), including the fact that a) suPAR levels are determined by the prevailing GFR level32; b) elevated suPAR levels have been reported in other glomerular diseases33,34; c) pre-transplant suPAR levels do not predict recurrence of FSGS following transplantation35,36; d) serum suPAR levels are higher in FSGS secondary to genetic mutations compared with primary FSGS;36 and e) serum suPAR levels do not differentiate between primary versus secondary forms of FSGS or other primary glomerular diseases.31,32