Advertisement

Morphologic Variants of Focal Segmental Glomerulosclerosis and Their Significance

  • Michael B. Stokes
    Affiliations
    Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY
    Search for articles by this author
  • Vivette D. D'Agati
    Correspondence
    Address correspondence to Vivette D. D'Agati, MD, Department of Pathology, Columbia University, College of Physicians and Surgeons, Renal Pathology Laboratory, Room VC14-224, 630 West 168th Street, New York, NY 10032.
    Affiliations
    Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY
    Search for articles by this author
      Focal segmental glomerulosclerosis (FSGS) comprises a group of clinical-pathologic syndromes characterized by heavy proteinuria and segmental obliteration of glomerular capillaries by extracellular matrix. FSGS lesions display morphologic heterogeneity with respect to their relationship to the glomerular vascular and tubular poles, the presence of capillary collapse, and endocapillary and extracapillary hypercellularity. A working proposal, commonly referred to as the Columbia Classification, distinguishes 5 mutually exclusive morphologic variants: collapsing, tip, cellular, perihilar, and not otherwise specified (NOS), which can be applied to primary and secondary forms of FSGS. Several studies have documented significant differences in baseline clinical characteristics and outcomes between morphologic variants of primary FSGS, supporting that this classification may provide useful prognostic information. The association of certain variants with particular secondary causes of FSGS suggests pathogenetic relevance.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Advances in Chronic Kidney Disease
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • D'Agati V.D.
        • Kaskel F.J.
        • Falk R.J.
        Focal segmental glomerulosclerosis.
        N Engl J Med. 2011; 365: 2398-2411
        • Remuzzi A.
        • Mazerska M.
        • Gephardt G.N.
        • Novick A.C.
        • Brenner B.M.
        • Remuzzi G.
        Three-dimensional analysis of glomerular morphology in patients with subtotal nephrectomy.
        Kidney Int. 1995; 48: 155-162
        • Howie A.J.
        • Brewer D.B.
        The glomerular tip lesion: a previously undescribed type of segmental glomerular abnormality.
        J Pathol. 1984; 142: 205-220
        • Howie A.J.
        • Pankhurst T.
        • Sarioglu S.
        • Turhan N.
        • Adu D.
        Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion.
        Kidney Int. 2005; 67: 987-1001
        • Schwartz M.M.
        • Lewis E.J.
        Focal segmental glomerular sclerosis: the cellular lesion.
        Kidney Int. 1985; 28: 968-974
        • Schwartz M.M.
        • Korbet S.M.
        • Rydell J.
        • Borok R.
        • Genchi R.
        Primary focal segmental glomerular sclerosis in adults: prognostic value of histologic variants.
        Am J Kidney Dis. 1995; 25: 845-852
        • Weiss M.
        • Daquioag E.
        • Margolin E.
        • Pollak V.
        Nephrotic syndrome, progressive irreversible renal failure, and glomerular “collapse.” A new clinico-pathologic entity?.
        Am J Kidney Dis. 1986; 7: 20-28
        • Detwiler R.K.
        • Falk R.J.
        • Hogan S.L.
        • Jennette J.C.
        Collapsing glomerulopathy: a clinically and pathologically distinct variant of focal segmental glomerulosclerosis.
        Kidney Int. 1994; 45: 1416-1424
        • Valeri A.
        • Barisoni L.
        • Appel G.B.
        • Seigle R.
        • D'Agati V.
        Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study.
        Kidney Int. 1996; 50: 1734-1746
        • Laurinavicius A.
        • Hurwitz S.
        • Rennke H.G.
        Collapsing glomerulopathy in HIV and non-HIV patients: a clinicopathological and follow-up study.
        Kidney Int. 1999; 56: 2203-2213
        • D'Agati V.D.
        • Fogo A.B.
        • Bruijn J.A.
        • Jennette J.C.
        Pathologic classification of focal segmental glomerulosclerosis: a working proposal.
        Am J Kidney Dis. 2004; 43: 368-382
        • Barisoni L.
        • Kriz W.
        • Mundel P.
        • D'Agati V.
        The dysregulated podocyte phenotype: a novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy.
        J Am Soc Nephrol. 1999; 10: 51-61
        • Smeets B.
        • Angelotti M.L.
        • Rizzo P.
        • et al.
        Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis.
        J Am Soc Nephrol. 2009; 20: 2593-2603
        • Dijkman H.
        • Smeets B.
        • van der Laak J.
        • Steenbergen E.
        • Wetzels J.
        The parietal epithelial cell is crucially involved in human idiopathic focal segmental glomerulosclerosis.
        Kidney Int. 2005; 68: 1562-1572
        • D'Agati V.
        • Suh J.I.
        • Carbone L.
        • Cheng J.T.
        • Appel G.
        Pathology of HIV-associated nephropathy: a detailed morphologic and comparative study.
        Kidney Int. 1989; 35: 1358-1370
        • Moudgil A.
        • Nast C.C.
        • Bagga A.
        • et al.
        Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy.
        Kidney Int. 2001; 59: 2126-2133
        • Thaunat O.
        • Delahousse M.
        • Fakhouri F.
        • et al.
        Nephrotic syndrome associated with hemophagocytic syndrome.
        Kidney Int. 2006; 69: 1892-1898
        • Markowitz G.S.
        • Appel G.B.
        • Fine P.L.
        • et al.
        Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate.
        J Am Soc Nephrol. 2001; 12: 1164-1172
        • Markowitz G.S.
        • Nasr S.H.
        • Stokes M.B.
        • D'Agati V.D.
        Treatment with IFN-{alpha}, -{beta}, or -{gamma} is associated with collapsing focal segmental glomerulosclerosis.
        Clin J Am Soc Nephrol. 2010; 5: 607-615
        • Stokes M.B.
        • Davis C.L.
        • Alpers C.E.
        Collapsing glomerulopathy in renal allografts: a morphological pattern with diverse clinicopathologic associations.
        Am J Kidney Dis. 1999; 33: 658-666
        • Kopp J.B.
        • Nelson G.W.
        • Sampath K.
        • et al.
        APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy.
        J Am Soc Nephrol. 2011; 22: 2129-2137
        • Larsen C.P.
        • Beggs M.L.
        • Saeed M.
        • Walker P.D.
        Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy.
        J Am Soc Nephrol. 2013; 24: 722-725
        • Salvatore S.P.
        • Barisoni L.M.
        • Herzenberg A.M.
        • Chander P.N.
        • Nickeleit V.
        • Seshan S.V.
        Collapsing glomerulopathy in 19 patients with systemic lupus erythematosus or lupus-like disease.
        Clin J Am Soc Nephrol. 2012; 7: 914-925
        • Stokes M.B.
        • Markowitz G.S.
        • Lin J.
        • Valeri A.M.
        • D'Agati V.D.
        Glomerular tip lesion: a distinct entity within the minimal change disease/focal segmental glomerulosclerosis spectrum.
        Kidney Int. 2004; 65: 1690-1702
        • Chun M.J.
        • Korbet S.M.
        • Schwartz M.M.
        • Lewis E.J.
        Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants.
        J Am Soc Nephrol. 2004; 15: 2169-2177
        • Haas M.
        • Yousefzadeh N.
        Glomerular tip lesion in minimal change nephropathy: a study of autopsies before 1950.
        Am J Kidney Dis. 2002; 39: 1168-1175
        • Howie A.J.
        • Agarwal A.
        • Sebire N.J.
        • Trompeter R.S.
        Glomerular tip changes in childhood minimal change nephropathy.
        Pediatr Nephrol. 2008; 23: 1281-1286
        • Stokes M.B.
        • Valeri A.M.
        • Markowitz G.S.
        • D'Agati V.D.
        Cellular focal segmental glomerulosclerosis: clinical and pathologic features.
        Kidney Int. 2006; 70: 1783-1792
        • Thomas D.B.
        • Franceschini N.
        • Hogan S.L.
        • et al.
        Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants.
        Kidney Int. 2006; 69: 920-926
        • D'Agati V.D.
        Pathobiology of focal segmental glomerulosclerosis: new developments.
        Curr Opin Nephrol Hypertens. 2012; 21: 243-250
        • D'Agati V.D.
        • Alster J.M.
        • Jennette J.C.
        • et al.
        Association of histologic variants in FSGS clinical trial with presenting features and outcomes.
        Clin J Am Soc Nephrol. 2013; 8: 399-406
        • Kambham N.
        • Markowitz G.S.
        • Valeri A.M.
        • Lin J.
        • D'Agati V.D.
        Obesity-related glomerulopathy: an emerging epidemic.
        Kidney Int. 2001; 59: 1498-1509
        • Herlitz L.C.
        • Markowitz G.S.
        • Farris A.B.
        • et al.
        Development of focal segmental glomerulosclerosis after anabolic steroid abuse.
        J Am Soc Nephrol. 2010; 21: 163-172
        • McGraw M.
        • Poucell S.
        • Sweet J.
        • Baumal R.
        The significance of focal segmental glomerulosclerosis in oligomeganephronia.
        Int J Pediatr Nephrol. 1984; 5: 67-72
        • Bhathena D.B.
        • Julian B.A.
        • McMorrow R.G.
        • Baehler R.W.
        Focal sclerosis of hypertrophied glomeruli in solitary functioning kidneys of humans.
        Am J Kidney Dis. 1985; 5: 226-232
        • Hodgin J.B.
        • Rasoulpour M.
        • Markowitz G.S.
        • D'Agati V.D.
        Very low birth weight is a risk factor for secondary focal segmental glomerulosclerosis.
        Clin J Am Soc Nephrol. 2009; 4: 71-76
        • Harvey J.M.
        • Howie A.J.
        • Lee S.J.
        • et al.
        Renal biopsy findings in hypertensive patients with proteinuria.
        Lancet. 1992; 340: 1435-1436
        • Falk R.J.
        • Jennette J.C.
        Sickle cell nephropathy.
        Adv Nephrol Necker Hosp. 1994; 23: 133-147
        • Nagata M.
        • Kriz W.
        Glomerular damage after uninephrectomy in young rats. II. Mechanical stress on podocytes as a pathway to sclerosis.
        Kidney Int. 1992; 42: 148-160
        • Paik K.H.
        • Lee B.H.
        • Cho H.Y.
        • et al.
        Primary focal segmental glomerular sclerosis in children: clinical course and prognosis.
        Pediatr Nephrol. 2007; 22: 389-395
        • Deegens J.K.
        • Steenbergen E.J.
        • Borm G.F.
        • Wetzels J.F.
        Pathological variants of focal segmental glomerulosclerosis in an adult Dutch population-epidemiology and outcome.
        Nephrol Dial Transplant. 2008; 23: 186-192
        • Taneda S.
        • Honda K.
        • Uchida K.
        • et al.
        Histological heterogeneity of glomerular segmental lesions in focal segmental glomerulosclerosis.
        Int Urol Nephrol. 2012; 44: 183-196
        • Silverstein D.M.
        • Craver R.
        Presenting features and short-term outcome according to pathologic variant in childhood primary focal segmental glomerulosclerosis.
        Clin J Am Soc Nephrol. 2007; 2: 700-707
        • Rich A.R.
        A hitherto undescribed vulnerability of the juxtamedullary glomeruli in lipoid nephrosis.
        Bull Johns Hopkins Hosp. 1957; 100: 173-186
        • Meehan S.M.
        • Chang A.
        • Gibson I.W.
        • Kim L.
        • Kambham N.
        • Laszik Z.
        A study of interobserver reproducibility of morphologic lesions of focal segmental glomerulosclerosis.
        Virchows Arch. 2013; 462: 229-237
        • Barisoni L.
        • Schnaper H.W.
        • Kopp J.B.
        A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases.
        Clin J Am Soc Nephrol. 2007; 2: 529-542
        • Wyatt C.M.
        • Klotman P.E.
        • D'Agati V.D.
        HIV-associated nephropathy: clinical presentation, pathology, and epidemiology in the era of antiretroviral therapy.
        Semin Nephrol. 2008; 28: 513-522
        • Hahn B.H.
        • McMahon M.A.
        • Wilkinson A.
        • et al.
        American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.
        Arthritis Care Res (Hoboken). 2012; 64: 797-808
        • Lv J.
        • Shi S.
        • Xu D.
        • et al.
        Evaluation of the Oxford Classification of IgA nephropathy: a systematic review and meta-analysis.
        Am J Kidney Dis. 2013; 62: 891-899
        • El-Refaey A.M.
        • Bakr A.
        • Hammad A.
        • et al.
        Primary focal segmental glomerulosclerosis in Egyptian children: a 10-year single-centre experience.
        Pediatr Nephrol. 2010; 25: 1369-1373
        • Nada R.
        • Kharbanda J.K.
        • Bhatti A.
        • Minz R.W.
        • Sakhuja V.
        • Joshi K.
        Primary focal segmental glomerulosclerosis in adults: is the Indian cohort different?.
        Nephrol Dial Transplant. 2009; 24: 3701-3707
        • Gipson D.S.
        • Trachtman H.
        • Kaskel F.J.
        • et al.
        Clinical trial of focal segmental glomerulosclerosis in children and young adults.
        Kidney Int. 2011; 80: 868-878
        • Canaud G.
        • Dion D.
        • Zuber J.
        • et al.
        Recurrence of nephrotic syndrome after transplantation in a mixed population of children and adults: course of glomerular lesions and value of the Columbia Classification of histological variants of focal and segmental glomerulosclerosis (FSGS).
        Nephrol Dial Transplant. 2010; 25: 1321-1328