Saudi Journal of Kidney Diseases and Transplantation

: 2007  |  Volume : 18  |  Issue : 2  |  Page : 226--230

Pathogenesis of Focal and Segmental Glomerulosclerosis: A Review

Nabil Akash 
 Department of Nephrology, King Hussein Medical Center, Amman, Jordan

Correspondence Address:
Nabil Akash
P.O. Box 1362, Amman 11953

How to cite this article:
Akash N. Pathogenesis of Focal and Segmental Glomerulosclerosis: A Review.Saudi J Kidney Dis Transpl 2007;18:226-230

How to cite this URL:
Akash N. Pathogenesis of Focal and Segmental Glomerulosclerosis: A Review. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2023 Feb 4 ];18:226-230
Available from:

Full Text


The term Focal and Segmental Glomerulo­sclerosis (FSGS) implies that only a portion of the glomerulus (segmental) and only some of the glomeruli (focal) are involved. FSGS is a major cause of idiopathic nephrotic syndrome in adults and somewhat less common in children.[l] FSGS is characterized by protei­nuria, frequently in the nephrotic range, early onset of hypertension and azotemia, steroid resistance, progressive worsening of azotemia, and a characteristic glomerular lesion.[2],[3],[4] FSGS can be a primary disorder or secondary to other diseases [Table 1]; it is important to differentiate between the two as the patho­genesis and treatment of these disorders can differ significantly.[5] The diagnosis of FSGS is made from the history, from the onset and degree of proteinuria, and by light and electron microscopy. [Figure 1],[Figure 2].

Patients with primary FSGS usually present with acute onset nephrotic syndrome, while slowly increasing proteinuria and renal failure over time are characteristics of the secondary form, in which the proteinuria is usually in the non-nephrotic range. Electron micro­scopic findings are different in the two conditions; primary FSGS is associated with diffuse foot process fusion, while in the secondary form, these lesions tend to be focal and limited to the sclerotic area.[5]


Primary FSGS

The cause of primary FSGS is largely unknown, but it is likely to be a disease in which the primary injury affects the visceral epithelial cell {Podocyte}. Experimental models of Puromycine - induced FSGS have demonstrated that the earliest detectable abnormality involves the visceral epithelial cell with effacement of the foot processes.[6],[7] In vitro studies have shown that Puromycine is toxic to cultured visceral epithelial cells.[8] Upon exposure to Puromycine, these cells exhibit altered permeability and reduced adhesion to substrate, suggesting derangements in visceral cell metabolism that alter the composition and anionic charge of glomerular wall components.

In humans, the nature of visceral epithelial toxin remains unknown; a glomerular perme­ability factor of 60,000-160,000 Kd, which induces proteinuria and foot process fusion, has been synthesized in rats.[9] This factor demon­strates TNF-like activity in vitro, suggesting that it might be a lymphotoxin-related substance. A similar permeability factor of varying molecular weight has been isolated from the serum and urine of patients with minimal change disease, which is highly linked to FSGS.[10]

The rapid recurrence of the lesion in patients with primary FSGS who undergo kidney transplantation suggests the presence of one or more circulating factors [11],[12] that alter glomerular permeability to macromolecules. Recurrent FSGS occurs in 20-50% of grafts and is more common in the younger age group of patients and those in whom the disease has progressed rapidly to renal failure. [13],[14]

Savin, Sharma, and colleagues have described a permeability factor of 100-120 Kd in the serum of 30% of patients with FSGS and adult steroid-resistant nephrotic syndrome.[11],[12] The presence of this circulating factor underlies the rationale for the use of plasmapheresis in the treatment of recurrent FSGS in allografts.[15],[16] It appears that a majority of glomerulopathies, from the least proliferative, such as membra­nous, [17],[18] to the most exuberant crescentic glomerulonephritis,[19],[20] involve podocyte involvement and that FSGS is the final common pathway to glomerular obsolescence FSGS starts with podocyte injury [21], which drives the glomerular lesions from cellular proliferation to the build-up of fibrosis and scarring.

Familial FSGS

Several forms of familial FSGS are a result of genetic mutations of various membrane proteins expressed by the podocytes that are important in protein trafficking. Mutations of podocin {NPHS2 gene}, a-actinin 4, CD­associated protein, and nephrin, which were identified in the podocyte cell body and its foot processes, [22] have all been associated with the development of FSGS.

It has become known that various mutations of podocin {NPHS2 mutations} lead to steroid-resistant nephrotic syndrome, [23],[24],[25],[26] with the most common NPHS2 mutation occurring in chromosome Iq25-q31 and inherited in an autosomal recessive fashion.[24] Mutations of the acinin 4 gene are inherited in an autosomal dominant fashion with slowly developing renal disease [27],[28] and are linked to chromo­some 19q. [29]

The familial forms of FSGS are associated with steroid-resistance and with progression to end-stage renal disease. Nevertheless, unlike the sporadic forms of FSGS, these inherited forms do not recur after renal transplantation. Also, the pathogenesis of familial FSGS can differ from that of the sporadic form; while in the former, there is structural alteration in the podocyte, there is a circulating factor that damages podocytes in the latter.

Secondary FSGS

In the secondary form, damage to the glomerular capillary wall results from adaptive mechanisms following glomerular overwork. This can be either due to a reduced number of functioning nephrons or to increased function­nal stress on initially normal glomeruli that results in compensatory hypertrophy in the remaining glomeruli and intraglomerular hyper­tension. These functional adaptations eventually become maladaptive by leading to structural damage to the glomerular, endothelial, mesangial, and visceral cell components.[30],[31],[32]

Glomerular cell proliferation and the progressive accumulation of the extracellular matrix component due to the release of transforming growth factor {TGF-B} may contribute to the development of the sclerotic lesions. [33],[34],[35],[36]

The pathogenesis of HlV-associated nephro­pathy is not well known, but viral proteins could be toxic to podocytes, indicating that collapsing glomerulopathy might be caused by viral infection. Additionally, a possible viral etiology for FSGS has been strengthened by the presence of Parvovirus B19 in renal biopsies of patients with FSGS [37],[38] and by the occasional association of hepatitis C virus infection with FSGS.[39],[40]


FSGS represents the final common pathway for nephron degeneration in many forms of chronic progressive renal failure. The initial pathologic changes in FSGS are thought to occur in glomerular epithelial cells {podo­cytes}; podocyte damage is attributable to gene mutations, which is being recognized more frequently now. Therefore, when feasible, genetic screening for these mutations should become an integral part in the evaluation of patients with FSGS. In addition, identification of NPHS2 may save some of these patients from unnecessary steroid treatment and also allows the prediction of absence of disease recurrence after kidney transplantation.


1Haas M, Spargo BH, Coventry S. Increasing incidence of focal- segmental glomerulo­sclerosis among adult nephropathies: a 20­year renal biopsy study. Am J Kidney Dis 1995;26:740-50.
2Rich AR. A hitherto undescribed vulnerability of the juxtamedullary glomeruli in lipoid nephrosis. Bull Johns Hopkins Hosp 1957;100:173-86.
3White RH, Glascow EF, Mills RJ. Clinicopatholgical study of nephrotic syndrome in childhood. Lancet 1970;1:1353-5.
4Korbet SM, Schwartz MM, Lewis EJ. The prognosis of focal segmental glomerular sclerosis of adulthood. Medicine l986;65:304-11.
5Vivetti D, Agatti V. The many masks of focal segmental glomerulosclerosis.Kidney Int 1994;46:1223-41.
6Ryan GB, Karnovsky MJ. An ultrastructural study of the mechanisms of proteinuria in aminonucleoside nephrosis.Kidney Int 1975;8:219-32.
7Bertani T, Rocchi G, Sacchi G, Mecca G, Remuzzi G. Adriamycin induced glomerulo­sclerosis in the rat. Am J Kidney Dis 1986;7:12-9.
8Fishman JA, Karnovski MA. Effect of the aminonucleoside of puromycin on glomerular epithelial cells in vitro. Am J Pathol 1985;118:398-407.
9Koyama A, Fujisaki M, Kobayashi MJI, garashi M, Narita M. A glomerular permeability factor produced by human T cell hybridomas. Kidney Int 1991,40:453-60.
10Savin VJ. Mechanisms of proteinuria in non inflammatory glomerular diseases. Am J Kidney Dis 1993;21:347-62.
11Savin VJ, Chonko AM, Sharma R, Sharma M, Gunwar S. Factor present in serum of patients with minimal change nephritic syndrome or focal sclerosing glomerulopathy causes an immediate increase in glomerular protein permeability in vitro (abstract). J Am Soc Nephrol 1991;2:791.
12Sharma M, Shama R, Gunwar S, Vincenti F,Artero M, Savin V. Partial purification and characterization of circulating protein that increases albumin permeability in human focal segmental glomerulosclerosis. Am J Soc Nephrol 1992;3:751.
13Striegel JE, Sibley RK, Fryd DS, Mauer SM. Recurrence of focal segmental sclerosis in children following renal transplantation. Kidney Int 1986;30:S44­S50.
14Tejani A, Stablein DH. Recurrence of focal segmental glomerulosclerosis post­transplantation. A special report The North American Pediatric Renal Transplant Cooperative Study. J Am Soc Nephrol 1992;2:S258-63.
15Artero M, Biava C, Amend W, Tomlanovitch S, Vincenti F. Recurrent focal glomerulosclerosis:natural history and response to therapy. Am J Med 1992;92:375-83.
16Mowry J, Marik J, Cohen A, Hogg R, Sahny S, Ettenger R. Treatment of recurrent focal segmental glomerulosclerosis with high dose cyclosporine A and plasmapheresis. Transplant Proc 1993;25(1pt2):1345-6.
17Petermann AT, Krofft R, Blonski M et al. Podocyte that detach in experimental membranous nephropathy are viable. Kidney Int 2003;64:1222-31.
18Domoulin A, Hill GS, Montseney JJ, Meyrier A. Clinical and morphological prognostic factors in membranous nephropathy: significance of focal segmental glomerolosclerosis. Am J Kidney Dis 2003;41:38-48.
19Moeller MJ, Soofi A, Harman I. Podocyte populate cellular crescents in amurine model of inflammatory glomerulonephritis. J am Soc Nephrol 2004;15:61-7.
20Bariety J, Hill GS, Mandet C. Glomerular epithelial-mesenchymal transdifferentiation in pauci immune crescentic glomerulonephritis. Nephrol Dial Transplant 2003;18:1777-84.
21Pavenstadt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev 2003;253-307.
22Kerjaschki D. Caught flat- footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J Clin Invest 2001; 8:1583-7.
23Winn MP. Approach to the evaluation of heritable diseases and update on familial focal segmental glomerulosclerosis. Nephrol Dial Transplant 2003;18 Suppl 6:vil4-vi20.
24Boute N, Gribouval O, Roselli S, et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistance nephritic syndrome. Nat Genet 2000;24:349-54.
25Huber TB, Simons M, Hartleben B, et al. Molecular basis of the functional podocin­nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum Mol Genet 2003;12:3397-405.
26Caridi G, Bertelli R, Di Duca M. Broadening the spectrum of diseases related to podocin mutations. J Am Soc Nephrol 2003;14:1278-86.
27Kaplan JM, Kim SH, North KN, et al. Encoding alpha-actinin-4 causes familial focal segmental glomerulosclerosis. Nature Gen 2000;24:251-6.
28Kumatsuda A, Wakui H, Kigawa A, et al. Analysis of mutations in alpha actinin 4 and podocin genes of patients with chronic renal failure due to sporadic focal segmental glomerulosclerosis. Ren Fai, 2003;25:87-93.
29Mathis BJ, Kim SH, Calabrese K, et al. A locus for inherited focal segmental glomerulosclerosis maps to chromosome lq ql3. Kidney Int 1998;53:282-6.
30Rennke H, Klein PS. Pathogenesis and significance of non primary focal and segmental glomerulosclerosis. Am J Kidney Dis 1989;13:443-55.
31Kriz W, Elger M, Kretzler M, et al. The role of podocyte in the development of glomerular sclerosis.Kidney Int 1994;45:(suppl)S64-S72.
32Rennke HG. How does glomerular epithelial injury contribute to glomerular damage? Kidney Int 1994; 45(suppl):S58-S63.
33Floege G, Alpers CE, Burns MW, et al. Glomerular cell extracellular matrix accumulation and the development of glomerulosclerosis in the remnant kidney model.Lab Invest 1992:66(4):485-97.
34Sharma K, Ziadeh FN. The emerging role of transforming growth factor-b in kidney disease.Am J Physiol 1994;266:F 829-42.
35Habib R. Focal glomerular sclerosis. Kidney Int 1973;4:355-61.
36Cameron JS, Turner DR, Ogg CS, Chantler C,Williams DS. The long term prognosis of patients with focal segmental glomerulosclerosis. Clin Nephrol 1978;10:213-8.
37Tanawattanacharoen S, Falk RJ, Jennette JC, Kopp JB. Parvovirus B19 DNA in kidney tissue of patients with focal segmental glomerulosclerosis. Am J Kidney Dis 2000;35:1166-74.
38Moudgil A, Nast CC, Bagga A. Association of Parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney Int 2001;59:2126-33.
39Stehman-Breen C, Alpers CE, Fleet WP, Johnson RJ. Focal segmental sclerosis among patients infected with hepatitis C virus. Nephron 1999;81:37-40.
40Motta M, Malaguarnera M, Restuccia M, Romano M, Vinci E, Pistone G. Focal segmental glomerulosclerosis and hepatitis C virus: a report. Panminerva Med 2001;43:49-52.