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Primary and Secondary Focal Segmental Glomerulosclerosis:
Morphologic Classification and Clinical Correlation


Vivette D'Agati
Columbia University College of Physicians & Surgeons
New York, NY


FSGS is defined as a clinical-pathologic syndrome manifesting proteinuria, usually of nephrotic range, associated with lesions of focal and segmental glomerular sclerosis and foot process effacement [1, 2, 3, 4] . Early in the disease process, the pattern of glomerular sclerosis is focal, involving a subset of glomeruli, and segmental, involving a portion of the glomerular tuft. As the disease progresses, a more diffuse and global pattern of sclerosis evolves. Alterations of the podocyte constitute the major ultrastructural findings.

Table 1 - Etiologic Classification of FSGS

PRIMARY (IDIOPATHIC) FSGS
SECONDARY FSGS
1. Familial/Genetic
A. Mutations in α-actinin 4
B. Mutations in podocin
C. Mutations in WT-1
D. Mutations in β integrin
2. Virus-Associated
A. HIV-1 ("HIV-associated nephropathy")
B. Parvovirus B-19
3. Drug-Induced
A. Heroin ("Heroin nephropathy")
B. Interferon-α
C. Lithium
D. Pamidronate
4. Mediated by Adaptive Structural-Functional Responses
A. Reduced renal mass
Oligomeganephronia
Unilateral renal agenesis
Renal dysplasia
Reflux nephropathy
Sequela to cortical necrosis
Surgical renal ablation
Chronic allograft nephropathy
Any advanced renal disease with reduction in functioning nephrons
B. Initially normal renal mass
Hypertension
Atheroemboli or other acute vaso-occlusive processes
Obesity
Cyanotic congenital heart disease
Sickle cell anemia

The approach to a diagnosis of FSGS is problematic because the morphologic features are not specific and can occur in a variety of other conditions or superimposed on other glomerular processes [5, 6] . Primary (or idiopathic) FSGS must be differentiated from secondary forms with recognized etiologic associations including genetic mutations in podocyte-associated proteins (such as α-actinin-4, podocin, Wilm's tumor protein WT-1 and β integrin) [7, 8, 9, 10] , viruses (such as human immunodeficiency virus (HIV)-1 and parvovirus B19) [11, 12] and drug toxicities (such as heroin, interferon, lithium and pamidronate) [13, 14, 15, 16] . In addition, primary FSGS must be distinguished from the large group of secondary FSGS caused by structural-functional adaptations mediated by intrarenal vasodilatation, increased glomerular capillary pressures and plasma flow rates, and other maladaptive processes [6]. Such maladaptive glomerular alterations can arise through a reduction in the number of functioning nephrons (such as following unilateral renal agenesis, surgical ablation, oligomeganephronia, or any advanced primary renal disease) or by mechanisms that place hemodynamic stress on an initially normal nephron population (as in morbid obesity, cyanotic congenital heart disease and sickle cell anemia) [6]. Finally, primary and secondary forms of FSGS must also be differentiated from the non-specific pattern of focal and segmental glomerular scarring that can follow a variety of inflammatory, proliferative, thrombotic and hereditary conditions such as chronic glomerulonephritis, Alport syndrome, and mitochondrial cytopathies [6, 17, 18, 19] .

Table 2 - Morphologic Classification of FSGS

Variant Inclusion Criteria Exclusion Criteria
FSGS (NOS)
  • At least one glomerulus with segmental increase in matrix obliterating the capillary lumina.
  • There may be segmental glomerular capillary wall collapse without overlying podocyte hyperplasia.
  • Exclude perihilar, cellular, tip, and collapsing variants
    • Perihilar Variant
  • At least one glomerulus with perihilar hyalinosis, with or without sclerosis.
  • > 50% of glomeruli with segmental lesions must have perihilar sclerosis and/or hyalinosis.
  • Exclude cellular, tip, and collapsing variants
    • Cellular Variant
  • At least one glomerulus with segmental endocapillary hypercellularity occluding lumina, with or without foam cells and karyorrhexis.
  • Exclude tip and collapsing variants
    • Tip Variant
  • At least one segmental lesion involving the tip domain (outer 25% of tuft next to origin of proximal tubule).
  • The tubular pole must be identified in the defining lesion.
  • The lesion must have either an adhesion or confluence of podocytes with parietal or tubular cells at the tubular lumen or neck.
  • The tip lesion may be cellular or sclerosing.
  • Exclude collapsing variant
  • Exclude any perihilar sclerosis
    • Collapsing Variant
  • At least one glomerulus with segmental or global collapse and overlying podocyte hypertrophy and hyperplasia.
  • None

    • Primary FSGS and secondary FSGS comprise a number of morphologic subtypes that may have different prognostic and therapeutic implications. Historically, the early descriptions of Rich depicted discrete segmental scars with hyalinosis, predominantly affecting juxtamedullary glomeruli [1]. In the early 1980's, the pathologic heterogeneity of FSGS was increasingly appreciated. The lesions of FSGS differed both in their topographic location within the glomerular tuft and the quality of the endocapillary and extracapillary alterations.

    Schwartz and Lewis were the first to draw attention to the "cellular lesion" of FSGS in which endocapillary and extracapillary hypercellularity may be seen, including endocapillary foam cells, infiltrating leukocytes and pyknotic cellular debris [20]. They noted that cellular features correlated with a shorter time course from onset of clinical disease to renal biopsy, suggesting that they represent an early stage in the development of the segmental scars [20]. Although these investigators were the first to coin the term "cellular" FSGS, observations on this lesion were made as early as 1970 by Churg et al. [2] and 1975 by Velosa et al. [21].

    Following the emergence and recognition of HIV-associated nephropathy as a collapsing form of focal segmental glomerulosclerosis in the 1980's [11], there was increasing awareness that similar histologic lesions existed in some patients with primary FSGS, although these cases lacked endothelial tubulo-reticular inclusions at the ultrastructural level [22, 23, 24] . The relationship of this collapsing lesion to the previously described cellular lesion has been a point of contention, and clearly overlap exists between these forms with respect to the extracapillary cellularity caused by podocyte hyperplasia. Primary FSGS with collapsing features has been noted by several groups to be more prevalent in African Americans and to have more severe renal insufficiency at presentation, more severe markers of nephrotic syndrome, and a more rapidly progressive course to renal failure than non-collapsing forms [23, 24] . Secondary forms of FSGS with collapsing features have also been reported in association with parvovirus B19 infection [12], pamidronate toxicity [16], chronic allograft nephropathy with chronic transplant arteriopathy [25], atheroembolism [26], and other acute vaso-occlusive events.

    The importance of the location of the segmental lesions with respect to the perihilar and peripheral segments has also been debated. Perihilar lesions have been reported to be more common in adults vs. children with primary FSGS [27]. FSGS biopsy specimens with a predominance of perihilar lesions, especially when accompanied by glomerulomegaly, often represent secondary forms of FSGS mediated by glomerular hyperfiltration/hypertension or other adaptation after loss of renal mass. For example, this pattern is common in obesity-related glomerulopathy [28] and hypertensive nephrosclerosis with proteinuria [29]. It has been hypothesized that the predisposition for sclerosis to occur in the perihilar segment may relate to higher filtration pressures in the more proximal portions of the glomerular capillary bed [5].

    Lesions arising in the periphery at the tubular pole have been termed "tip lesions" by Howie and Brewer [30]. Evidence from several groups suggests that cases of tip lesion may have a clinical course more like that of minimal change disease with greater likelihood of steroid responsivity and more favorable outcome [31, 32, 33] . Most tip lesions have cellular features [33]. It is possible that this lesion arises through physical stress placed on the paratubular segment of the tuft in the setting of severe nephrotic syndrome and the flux of protein-rich filtrate towards the tubular pole, and a role for glomerular prolapse as a precursor to tip lesion formation has been proposed [34]. The existence of tip lesions in a variety of glomerular diseases manifesting proteinuria, (such as IgA nephropathy, membranous glomerulopathy, and diabetic nephropathy) would support this possibility [35]. The morphogenesis of this lesion and how it should be viewed within the minimal change disease-FSGS spectrum remain to be defined.

    In order to reach a consensus on the definition and classification of the histologic variants of primary and secondary FSGS, a group of renal pathologists convened at Columbia University. The pathologic criteria for five histologic variants of FSGS with possible pathophysiologic and prognostic significance were proposed based on the body of published literature: FSGS not otherwise specified (NOS), and perihilar, cellular, tip, and collapsing variants [36, 37] . These criteria encompass the spectrum of primary FSGS, as well as secondary forms. However, focal and segmental glomerular scarring following other primary glomerular diseases (such as immune-complex glomerulonephritis and hereditary nephritis) must be ruled out be immunofluorecence and electron microscopy. The morphologic classification is a working proposal that should provide a framework for subsequent refinements and modifications as our knowledge of the pathophysiology of FSGS grows.

    The classification proposed is based entirely on the glomerular light microscopic features, but requires immunofluorescence and electron microscopic examination to exclude other causes of sclerosis. It involves an assessment of both the location and the quality of the segmental lesions. Inclusion criteria for a given category can be either the presence of a single defining lesion (in the case of tip, cellular, and collapsing categories) or the percentage of segmental lesions with the defining characteristic (in the case of the perihilar variant). A hierarchical system of exclusion criteria is also applied (Table 2). FSGS (NOS) is the generic and most common form, which has been referred to in the past as FSGS of the classic or usual type. All the other variants may evolve into FSGS (NOS) in the course of disease progression.

    The approach to classification of FSGS can now designate a morphologic category (outlined in Table 2) and, wherever possible, an etiologic category (outlined in Table 1). The two classification systems are not mutually exclusive but can be applied together to a particular biopsy. This approach is analogous to the manner in which glomerulonephritis is described by a morphologic pattern (mesangial proliferative, endocapillary proliferative, extracapillary proliferative) and an etiologic modifier (consistent with IgA nephropathy, lupus nephritis, anti-GBM nephritis, etc). Similarly, following complete work-up it may be ascertained that a biopsy manifesting FSGS, collapsing variant represents primary FSGS, HIV-associated nephropathy, or pamidronate toxicity, for example. On clinical correlation, a biopsy showing FSGS, perihilar variant may prove to be primary FSGS, or to be secondary to obesity, renal agenesis, or reflux nephropathy, among others. Morphologic classification according to Table 2 does not eliminate the need to identify secondary causes of FSGS. As this working classification is applied routinely, it may facilitate the identification of new etiologic associations that typically manifest a particular pattern of sclerosis. Hopefully, it will provide a schema for the future application of more specific biomarkers of disease.

    References

    1. Rich AR: A hitherto undescribed vulnerability of the juxta-medullary glomeruli in lipoid nephrosis. Bull Johns Hopkins Hosp 100: 173-186, 1957

    2. Churg J, Habib R, White RH: Pathology of the nephrotic syndrome in children: a report for the International Study of Kidney Disease in Children. Lancet 760: 1299-1302. 1970.

    3. Habib R: Focal glomerulosclerosis. Kidney Int 4:355-361, 1973

    4. Southwest Pediatric Nephrology Study Group: Focal segmental glomerulosclerosis in children with idiopathic nephrotic syndrome. Kidney Int 27: 442-449, 1985

    5. D'Agati, V: The many masks of focal segmental glomerulosclerosis Kidney Int 46:1223-1241, 1994

    6. Rennke H, Klein PS: Pathogenesis and significance of non-primary focal and segmental glomerulosclerosis. Am J Kidney Dis 13: 443-455, 1989

    7. Kaplan JM, Kim SH, North KN, et al: Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24: 251-256, 2000

    8. Boute N, Gribouval O, Roselli S, et al: NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24: 349-354, 2000

    9. Denamur E, Bocquet N, Mougenot B, et al: Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases. J Am Soc Nephrol 10: 2219-2223, 1999

    10. Kambham N., Tanji N., Seigle RL et al: Congenital focal segmental glomerulosclerosis associated with β4 integrin mutation and epidermolysis bullosa. Am J Kid Dis 36: 190-196, 2000

    11. D'Agati V, Suh J-I, Carbone L, Appel GB: Pathology of HIV-associated nephropathy: A detailed morphologic and comparative study. Kidney Int 35: 1358-1370, 1989

    12. Moudgil A, Nast CC, Bagga A, et al: Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney Int 59: 2126-2133, 2001

    13. Rao TK, Nicastri AD, Friedman EA: Natural history of heroin-associated nephropathy. N Engl J Med 290: 19-23, 1974

    14. Shah M, Jenis EH, Mookerjee BK, et al: Interferon-alpha-associated focal segmental glomerulosclerosis with massive proteinuria in patients with chronic myeloid leukemia following high-dose chemotherapy. Cancer 83: 1938-1946, 1998

    15. Markowitz GS, Radhakrishnan J, Kambham N, et al: Lithium nephrotoxicity: a progressive combined glomerular and tubulo-interstitial nephropathy. J Am Soc Nephrol 11: 1439-1448, 2000

    16. Markowitz GS, Appel GB, Fine PL, et al: Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 12: 1164-1172, 2001

    17. Fogo AB: Glomerular hypertension, abnormal glomerular growth and progression of renal disease. Kidney Int 57 (Suppl 75): S15-S21, 2000

    18. Kashtan CE, Gubler MC, Sisson-Ross S, Mauer M: Chronology of renal scarring in males with Alport syndrome. Pediatr Nephrol 12: 269-274, 1998

    19. Guery B, Choukroun G, Noel LH, et al: The spectrum of systemic involvement in adults presenting with renal lesion and tRNA (Leu) gene mutation. J Am Soc Nephrol 14: 2099-2108, 2003

    20. Schwartz MM, Lewis EJ: Focal segmental glomerular sclerosis: The cellular lesion. Kidney Int 28: 968-974, 1985

    21. Velosa JA, Donadio JV, Holley KA: Focal sclerosing glomerulonephropathy: a clinicopathologic study. Mayo Clin Proc 50: 121-133, 1975

    22. Weiss MA, Daquioag E, Margolin EG, Pollak VE.: Nephrotic syndrome, progressive irreversible renal failure, and glomerular "collapse". A new clinico-pathologic entity? Am J Kidney Dis 7: 20-28, 1986

    23. Detwiler RK, Falk RJ, Hogan SL, Jennette JC: Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int 45: 1416-1424, 1994

    24. Valeri A, Barisoni L, Appel GB, D'Agati V: Idiopathic collapsing focal segmental glomerulosclerosis: A clinico-pathologic study. Kidney Int 50: 1734-1746, 1996

    25. Nadasdy T, Allen C, Aand MS: Zonal distribution of glomerular collapse in renal allografts: Possible role of vascular changes. Hum Pathol 33: 437-441, 2002

    26. Greenberg A, Bastacky SI, Iqbal A, et al: Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: Clinicopathological correlations. Am J Kid Dis 29: 334-344, 1997

    27. Fogo A, Glick AD, Horn SL, Horn RG: Is focal segmental glomerulosclerosis really focal? Distribution of lesions in adults and children. Kidney Int 47: 1690-1696, 1995

    28. Kambham N, Markowitz, GS, Valeri AM, et al: Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 59: 1498-1509, 2001

    29. Harvey JM, Howie AJ, Lee SJ, et al.: Renal biopsy findings in hypertensive patients with proteinuria. Lancet 340: 1435-1436, 1992

    30. Howie AJ, Brewer DB: The glomerular tip lesion: a previously undescribed type of segmental glomerular abnormality. J Pathol 142: 205-220, 1984

    31. Haas M, Yousefzadeh N: Glomerular tip lesion in minimal change nephropathy: a study of autopsies before 1950. Am J Kidney Dis 39: 1168-1175, 2002

    32. Beaman M, Howie AJ, Hardwicke J, et al: The glomerular tip lesion; a steroid responsive nephrotic syndrome. Clin Nephrol 27: 217-221, 1987

    33. Stokes MB, Markowitz GS, Lin J, Valeri AM, D'Agati VD: Glomerular tip lesion: A distinct entity within the minimal change disease/focal segmental glomeruosclerosis spectrum. Kidney Int 65: 1690-1702, 2004.

    34. Howie AJ, Ferreira MA, Majumdar A, Lipkin GW.: Glomerular prolapse as precursor of one type of segmental sclerosing lesions. J Pathol 190: 478-483, 2000

    35. Huppes W, Hene RJ, Kooiker CJ: The glomerular tip lesion: A distinct entity or not? J Pathol 154: 187-190, 1988

    36. D'Agati V.: Pathologic classification of focal segmental glomerulosclerosis. Semin Nephrol 23: 117-134, 2003

    37. D'Agati VD, Fogo AB, Bruijn JA, Jennette JC: Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kid Dis 43: 368-382, 2004.