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Core Concepts in Parenchymal Kidney Disease pp 33–49Cite as

Focal and Segmental Glomerulosclerosis

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Abstract

Focal and segmental glomerulosclerosis (FSGS) is a pathologic diagnosis characterized by a signature pathologic lesion, grossly defined by the pathologic finding of sclerosis in parts of the tufts involving some but not all glomeruli. It can be primary or due to secondary causes. The incidence of FSGS has been increasing for unclear reasons and now it is the commonest glomerulonephritis underlying ESRD in the USA. Genetic studies have advanced our understanding of disease pathogenesis, pointing to injury in the podocyte as central to the disease. Despite this, our therapeutic options for primary FSGS remain limited and there is a lack of rigorous studies supporting current treatment practices. The mainstay of treatment for primary FSGS is glucocorticosteroids. Individuals who relapse are challenging to treat and there is very little data to guide practice. Regimens for these individuals include cyclophosphamide and cyclosporine.

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References

  1. Thomas DB, Franceschini N, Hogan SL, Ten Holder S, Jennette CE, Falk RJ, et al. Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney Int. 2006;69(5):920–6.

    PubMed  CAS  Google Scholar 

  2. Cameron JS. The enigma of focal segmental glomerulosclerosis. Kidney Int Suppl. 1996;57:S119–31.

    PubMed  CAS  Google Scholar 

  3. Simon P, Ramee MP, Boulahrouz R, Stanescu C, Charasse C, Ang KS, et al. Epidemiologic data of primary glomerular diseases in western France. Kidney Int. 2004;66(3):905–8.

    PubMed  Google Scholar 

  4. Briganti EM, Dowling J, Finlay M, Hill PA, Jones CL, Kincaid-Smith PS, et al. The incidence of biopsy-proven glomerulonephritis in Australia. Nephrol Dial Transplant. 2001;16(7):1364–7.

    PubMed  CAS  Google Scholar 

  5. Haas M, Spargo BH, Coventry S. Increasing incidence of focal-segmental glomerulosclerosis among adult nephropathies: a 20-year renal biopsy study. Am J Kidney Dis. 1995;26(5):740–50.

    PubMed  CAS  Google Scholar 

  6. Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis. 2004;44(5):815–25.

    PubMed  Google Scholar 

  7. Valeri A, Barisoni L, Appel GB, Seigle R, D’Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study. Kidney Int. 1996;50(5):1734–46.

    PubMed  CAS  Google Scholar 

  8. Barisoni L, D’Agati V. The changing epidemiology of focal segmental glomerulosclerosis in New York City. Mod Pathol. 1994;7:156A.

    Google Scholar 

  9. Filler G, Young E, Geier P, Carpenter B, Drukker A, Feber J. Is there really an increase in non-minimal change nephrotic syndrome in children? Am J Kidney Dis. 2003;42(6):1107–13.

    PubMed  Google Scholar 

  10. Soyibo AK, Shah D, Barton EN, Williams W, Smith R. Renal histological findings in adults in Jamaica. West Indian Med J. 2009;58(3):265–9.

    PubMed  CAS  Google Scholar 

  11. Arias LF, Henao J, Giraldo RD, Carvajal N, Rodelo J, Arbelaez M. Glomerular diseases in a Hispanic population: review of a regional renal biopsy database. Sao Paulo Med J. 2009;127(3):140–4.

    PubMed  Google Scholar 

  12. Polito MG, de Moura LA, Kirsztajn GM. An overview on frequency of renal biopsy diagnosis in Brazil: clinical and pathological patterns based on 9,617 native kidney biopsies. Nephrol Dial Transplant. 2010;25(2):490–6.

    PubMed  Google Scholar 

  13. Wahbeh AM, Ewais MH, Elsharif ME. Spectrum of glomerulonephritis in adult Jordanians at Jordan university hospital. Saudi J Kidney Dis Transpl. 2008;19(6):997–1000.

    PubMed  Google Scholar 

  14. Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976–1979 and 1995–1997. Am J Kidney Dis. 1997;30(5):621–31.

    PubMed  CAS  Google Scholar 

  15. Braden GL, Mulhern JG, O’Shea MH, Nash SV, Ucci Jr AA, Germain MJ. Changing incidence of glomerular diseases in adults. Am J Kidney Dis. 2000;35(5):878–83.

    PubMed  CAS  Google Scholar 

  16. Detwiler RK, Falk RJ, Hogan SL, Jennette JC. Collapsing glomerulopathy: a clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int. 1994;45(5):1416–24.

    PubMed  CAS  Google Scholar 

  17. D’Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis. 2004;43(2):368–82.

    PubMed  Google Scholar 

  18. D’Agati V. Pathologic classification of focal segmental glomerulosclerosis. Semin Nephrol. 2003;23(2):117–34.

    PubMed  Google Scholar 

  19. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241–50.

    PubMed  Google Scholar 

  20. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65(2):521–30.

    PubMed  Google Scholar 

  21. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):187–92.

    PubMed  CAS  Google Scholar 

  22. Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8(4):753–60.

    PubMed  CAS  Google Scholar 

  23. Solez K, Axelsen RA, Benediktsson H, Burdick JF, Cohen AH, Colvin RB, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int. 1993;44(2):411–22.

    PubMed  CAS  Google Scholar 

  24. Mongeau JG, Robitaille PO, Clermont MJ, Merouani A, Russo P. Focal segmental glomerulosclerosis (FSG) 20 years later. From toddler to grown up. Clin Nephrol. 1993;40(1):1–6.

    PubMed  CAS  Google Scholar 

  25. Schwartz MM, Lewis EJ. Focal segmental glomerular sclerosis: the cellular lesion. Kidney Int. 1985;28(6):968–74.

    PubMed  CAS  Google Scholar 

  26. Schwartz MM, Evans J, Bain R, Korbet SM. Focal segmental glomerulosclerosis: prognostic implications of the cellular lesion. J Am Soc Nephrol. 1999;10(9):1900–7.

    PubMed  CAS  Google Scholar 

  27. Korbet SM, Schwartz MM, Lewis EJ. Recurrent nephrotic syndrome in renal allografts. Am J Kidney Dis. 1988;11(3):270–6.

    PubMed  CAS  Google Scholar 

  28. Howie AJ, Brewer DB. The glomerular tip lesion: a previously undescribed type of segmental glomerular abnormality. J Pathol. 1984;142(3):205–20.

    PubMed  CAS  Google Scholar 

  29. Haas M, Yousefzadeh N. Glomerular tip lesion in minimal change nephropathy: a study of autopsies before 1950. Am J Kidney Dis. 2002;39(6):1168–75.

    PubMed  Google Scholar 

  30. Howie AJ, 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(3):987–1001.

    PubMed  Google Scholar 

  31. Weiss MA, Daquioag E, Margolin EG, Pollak VE. Nephrotic syndrome, progressive irreversible renal failure, and glomerular “collapse”: a new clinicopathologic entity? Am J Kidney Dis. 1986;7(1):20–8.

    PubMed  CAS  Google Scholar 

  32. Pappenheimer JR. Passage of molecules through capillary walls. Physiol Rev. 1953;33(3):387–423.

    PubMed  CAS  Google Scholar 

  33. Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008;88(2):451–87.

    PubMed  CAS  Google Scholar 

  34. Ballermann BJ, Stan RV. Resolved: capillary endothelium is a major contributor to the glomerular filtration barrier. J Am Soc Nephrol. 2007;18(9):2432–8.

    PubMed  Google Scholar 

  35. Rostgaard J, Qvortrup K. Sieve plugs in fenestrae of glomerular capillaries–site of the filtration barrier? Cells Tissues Organs. 2002;170(2–3):132–8.

    PubMed  Google Scholar 

  36. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129–36.

    PubMed  CAS  Google Scholar 

  37. Clement LC, Avila-Casado C, Mace C, Soria E, Bakker WW, Kersten S, et al. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med. 2011;17(1):117–22.

    PubMed  CAS  Google Scholar 

  38. Bolton GR, Deen WM, Daniels BS. Assessment of the charge selectivity of glomerular basement membrane using Ficoll sulfate. Am J Physiol. 1998;274(5 Pt 2):F889–96.

    PubMed  CAS  Google Scholar 

  39. Daniels BS, Hauser EB, Deen WM, Hostetter TH. Glomerular basement membrane: in vitro studies of water and protein permeability. Am J Physiol. 1992;262(6 Pt 2):F919–26.

    PubMed  CAS  Google Scholar 

  40. Deen WM, Lazzara MJ, Myers BD. Structural determinants of glomerular permeability. Am J Physiol Renal Physiol. 2001;281(4):F579–96.

    PubMed  CAS  Google Scholar 

  41. Zenker M, Aigner T, Wendler O, Tralau T, Muntefering H, Fenski R, et al. Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Hum Mol Genet. 2004;13(21):2625–32.

    PubMed  CAS  Google Scholar 

  42. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, et al. Positionally cloned gene for a novel glomerular protein–nephrin–is mutated in congenital nephrotic syndrome. Mol Cell. 1998;1(4):575–82.

    PubMed  CAS  Google Scholar 

  43. Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet. 2000;24(4):349–54.

    PubMed  CAS  Google Scholar 

  44. Boyer O, Benoit G, Gribouval O, Nevo F, Tete MJ, Dantal J, et al. Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. J Am Soc Nephrol. 2011;22(2):239–45.

    PubMed  CAS  Google Scholar 

  45. Brown EJ, Schlondorff JS, Becker DJ, Tsukaguchi H, Tonna SJ, Uscinski AL, et al. Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet. 2010;42(1):72–6.

    PubMed  CAS  Google Scholar 

  46. Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000;24(3):251–6.

    PubMed  CAS  Google Scholar 

  47. Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005;308(5729):1801–4.

    PubMed  CAS  Google Scholar 

  48. Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet. 2006;38(12):1397–405.

    PubMed  CAS  Google Scholar 

  49. Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, et al. Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science. 1999;286(5438):312–5.

    PubMed  CAS  Google Scholar 

  50. Rodewald R, Karnovsky MJ. Porous substructure of the glomerular slit diaphragm in the rat and mouse. J Cell Biol. 1974;60(2):423–33.

    PubMed  CAS  Google Scholar 

  51. Reiser J, Kriz W, Kretzler M, Mundel P. The glomerular slit diaphragm is a modified adherens junction. J Am Soc Nephrol. 2000;11(1):1–8.

    PubMed  CAS  Google Scholar 

  52. Schnabel E, Anderson JM, Farquhar MG. The tight junction protein ZO-1 is concentrated along slit diaphragms of the glomerular epithelium. J Cell Biol. 1990;111(3):1255–63.

    PubMed  CAS  Google Scholar 

  53. Inoue T, Yaoita E, Kurihara H, Shimizu F, Sakai T, Kobayashi T, et al. FAT is a component of glomerular slit diaphragms. Kidney Int. 2001;59(3):1003–12.

    PubMed  CAS  Google Scholar 

  54. Liu G, Kaw B, Kurfis J, Rahmanuddin S, Kanwar YS, Chugh SS. Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability. J Clin Invest. 2003;112(2):209–21.

    PubMed  CAS  Google Scholar 

  55. Gerke P, Huber TB, Sellin L, Benzing T, Walz G. Homodimerization and heterodimerization of the glomerular podocyte proteins nephrin and NEPH1. J Am Soc Nephrol. 2003;14(4):918–26.

    PubMed  CAS  Google Scholar 

  56. Pavenstadt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003;83(1):253–307.

    PubMed  CAS  Google Scholar 

  57. Kretzler M. Regulation of adhesive interaction between podocytes and glomerular basement membrane. Microsc Res Tech. 2002;57(4):247–53.

    PubMed  CAS  Google Scholar 

  58. Gubler MC. Podocyte differentiation and hereditary proteinuria/nephrotic syndromes. J Am Soc Nephrol. 2003;14 Suppl 1:S22–6.

    PubMed  Google Scholar 

  59. Ryan GB, Rodewald R, Karnovsky MJ. An ultrastructural study of the glomerular slit diaphragm in aminonucleoside nephrosis. Lab Invest. 1975;33(5):461–8.

    PubMed  CAS  Google Scholar 

  60. Charest PM, Roth J. Localization of sialic acid in kidney glomeruli: regionalization in the podocyte plasma membrane and loss in experimental nephrosis. Proc Natl Acad Sci U S A. 1985;82(24):8508–12.

    PubMed  CAS  Google Scholar 

  61. Kriz W. The pathogenesis of ‘classic’ focal segmental glomerulosclerosis-lessons from rat models. Nephrol Dial Transplant. 2003;18 Suppl 6:vi39–44.

    PubMed  Google Scholar 

  62. Sato Y, Wharram BL, Lee SK, Wickman L, Goyal M, Venkatareddy M, et al. Urine podocyte mRNAs mark progression of renal disease. J Am Soc Nephrol. 2009;20(5):1041–52.

    PubMed  CAS  Google Scholar 

  63. Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, et al. Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol. 2005;16(10):2941–52.

    PubMed  CAS  Google Scholar 

  64. Jalanko H. Congenital nephrotic syndrome. Pediatr Nephrol. 2009;24(11):2121–8.

    PubMed  Google Scholar 

  65. Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu J, Hasselbacher K, et al. Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics. 2007;119(4):e907–19.

    PubMed  Google Scholar 

  66. Liu L, Done SC, Khoshnoodi J, Bertorello A, Wartiovaara J, Berggren PO, et al. Defective nephrin trafficking caused by missense mutations in the NPHS1 gene: insight into the mechanisms of congenital nephrotic syndrome. Hum Mol Genet. 2001;10(23):2637–44.

    PubMed  CAS  Google Scholar 

  67. Koziell A, Grech V, Hussain S, Lee G, Lenkkeri U, Tryggvason K, et al. Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet. 2002;11(4):379–88.

    PubMed  CAS  Google Scholar 

  68. Beltcheva O, Martin P, Lenkkeri U, Tryggvason K. Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome. Hum Mutat. 2001;17(5):368–73.

    PubMed  CAS  Google Scholar 

  69. Gigante M, Monno F, Roberto R, Laforgia N, Assael MB, Livolti S, et al. Congenital nephrotic syndrome of the Finnish type in Italy: a molecular approach. J Nephrol. 2002;15(6):696–702.

    PubMed  CAS  Google Scholar 

  70. Patrakka J, Kestila M, Wartiovaara J, Ruotsalainen V, Tissari P, Lenkkeri U, et al. Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients. Kidney Int. 2000;58(3):972–80.

    PubMed  CAS  Google Scholar 

  71. Philippe A, Nevo F, Esquivel EL, Reklaityte D, Gribouval O, Tete MJ, et al. Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome. J Am Soc Nephrol. 2008;19(10):1871–8.

    PubMed  CAS  Google Scholar 

  72. Roselli S, Moutkine I, Gribouval O, Benmerah A, Antignac C. Plasma membrane targeting of podocin through the classical exocytic pathway: effect of NPHS2 mutations. Traffic. 2004;5(1):37–44.

    PubMed  CAS  Google Scholar 

  73. Holmberg C, Antikainen M, Ronnholm K, Ala Houhala M, Jalanko H. Management of congenital nephrotic syndrome of the Finnish type. Pediatr Nephrol. 1995;9(1):87–93.

    PubMed  CAS  Google Scholar 

  74. Caridi G, Trivelli A, Sanna-Cherchi S, Perfumo F, Ghiggeri GM. Familial forms of nephrotic syndrome. Pediatr Nephrol. 2010;25(2):241–52.

    PubMed  Google Scholar 

  75. Hinkes B, Vlangos C, Heeringa S, Mucha B, Gbadegesin R, Liu J, et al. Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome. J Am Soc Nephrol. 2008;19(2):365–71.

    PubMed  Google Scholar 

  76. Hildebrandt F, Heeringa SF. Specific podocin mutations determine age of onset of nephrotic syndrome all the way into adult life. Kidney Int. 2009;75(7):669–71.

    PubMed  CAS  Google Scholar 

  77. Nishibori Y, Liu L, Hosoyamada M, Endou H, Kudo A, Takenaka H, et al. Disease-causing missense mutations in NPHS2 gene alter normal nephrin trafficking to the plasma membrane. Kidney Int. 2004;66(5):1755–65.

    PubMed  CAS  Google Scholar 

  78. Caridi G, Perfumo F, Ghiggeri GM. NPHS2 (Podocin) mutations in nephrotic syndrome. Clinical spectrum and fine mechanisms. Pediatr Res. 2005;57(5 Pt 2):54R–61R.

    PubMed  CAS  Google Scholar 

  79. Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, et al. WT-1 is required for early kidney development. Cell. 1993;74(4):679–91.

    PubMed  CAS  Google Scholar 

  80. Wagner N, Wagner KD, Xing Y, Scholz H, Schedl A. The major podocyte protein nephrin is transcriptionally activated by the Wilms’ tumor suppressor WT1. J Am Soc Nephrol. 2004;15(12):3044–51.

    PubMed  Google Scholar 

  81. Chernin G, Vega-Warner V, Schoeb DS, Heeringa SF, Ovunc B, Saisawat P, et al. Genotype/phenotype correlation in nephrotic syndrome caused by WT1 mutations. Clin J Am Soc Nephrol. 2010;5(9):1655–62.

    PubMed  CAS  Google Scholar 

  82. Hasselbacher K, Wiggins RC, Matejas V, Hinkes BG, Mucha B, Hoskins BE, et al. Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders. Kidney Int. 2006;70(6):1008–12.

    PubMed  CAS  Google Scholar 

  83. Yao J, Le TC, Kos CH, Henderson JM, Allen PG, Denker BM, et al. Alpha-actinin-4-mediated FSGS: an inherited kidney disease caused by an aggregated and rapidly degraded cytoskeletal protein. PLoS Biol. 2004;2(6):e167.

    PubMed  Google Scholar 

  84. Weins A, Schlondorff JS, Nakamura F, Denker BM, Hartwig JH, Stossel TP, et al. Disease-associated mutant alpha-actinin-4 reveals a mechanism for regulating its F-actin-binding affinity. Proc Natl Acad Sci U S A. 2007;104(41):16080–5.

    PubMed  CAS  Google Scholar 

  85. Henderson JM, Al-Waheeb S, Weins A, Dandapani SV, Pollak MR. Mice with altered alpha-actinin-4 expression have distinct morphologic patterns of glomerular disease. Kidney Int. 2008;73(6):741–50.

    PubMed  CAS  Google Scholar 

  86. Santin S, Ars E, Rossetti S, Salido E, Silva I, Garcia-Maset R, et al. TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2009;24(10):3089–96.

    PubMed  CAS  Google Scholar 

  87. Gigante M, Caridi G, Montemurno E, Soccio M, d’Apolito M, Cerullo G, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626–34.

    PubMed  CAS  Google Scholar 

  88. Schlondorff J, Del Camino D, Carrasquillo R, Lacey V, Pollak MR. TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. Am J Physiol Cell Physiol. 2009;296(3):C558–69.

    PubMed  CAS  Google Scholar 

  89. Moller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, et al. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol. 2007;18(1):29–36.

    PubMed  CAS  Google Scholar 

  90. Krebs A, Rothkegel M, Klar M, Jockusch BM. Characterization of functional domains of mDia1, a link between the small GTPase Rho and the actin cytoskeleton. J Cell Sci. 2001;114(Pt 20):3663–72.

    PubMed  CAS  Google Scholar 

  91. Gupton SL, Eisenmann K, Alberts AS, Waterman-Storer CM. mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration. J Cell Sci. 2007;120(Pt 19):3475–87.

    PubMed  CAS  Google Scholar 

  92. Bindschadler M, McGrath JL. Formin’ new ideas about actin filament generation. Proc Natl Acad Sci U S A. 2004;101(41):14685–6.

    PubMed  CAS  Google Scholar 

  93. Yang C, Czech L, Gerboth S, Kojima S, Scita G, Svitkina T. Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells. PLoS Biol. 2007;5(11):e317.

    PubMed  Google Scholar 

  94. Chhabra ES, Ramabhadran V, Gerber SA, Higgs HN. INF2 is an endoplasmic reticulum-associated formin protein. J Cell Sci. 2009;122(Pt 9):1430–40.

    PubMed  CAS  Google Scholar 

  95. Sun H, Schlondorff JS, Brown EJ, Higgs HN, Pollak MR. Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2). Proc Natl Acad Sci U S A. 2011;108(7):2933–8.

    PubMed  CAS  Google Scholar 

  96. Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH, et al. CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science. 2003;300(5623):1298–300.

    PubMed  CAS  Google Scholar 

  97. Easterling RE. Racial factors in the incidence and causation of end-stage renal disease (ESRD). Trans Am Soc Artif Intern Org. 1977;23:28–33.

    CAS  Google Scholar 

  98. Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet. 2008;40(10):1175–84.

    PubMed  CAS  Google Scholar 

  99. Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet. 2008;40(10):1185–92.

    PubMed  CAS  Google Scholar 

  100. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329(5993):841–5.

    PubMed  CAS  Google Scholar 

  101. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet. 2010;128(3):345–50.

    PubMed  CAS  Google Scholar 

  102. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011;22(11):2129–37.

    PubMed  CAS  Google Scholar 

  103. O’Seaghdha CM, Parekh RS, Hwang SJ, Li M, Kottgen A, Coresh J, et al. The MYH9/APOL1 region and chronic kidney disease in European-Americans. Hum Mol Genet. 2011;20(12):2450–6.

    PubMed  Google Scholar 

  104. Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. J Am Soc Nephrol. 2005;16(4):1061–8.

    PubMed  Google Scholar 

  105. Gipson DS, Chin H, Presler TP, Jennette C, Ferris ME, Massengill S, et al. Differential risk of remission and ESRD in childhood FSGS. Pediatr Nephrol. 2006;21(3):344–9.

    PubMed  Google Scholar 

  106. Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am J Kidney Dis. 1995;25(4):534–42.

    PubMed  CAS  Google Scholar 

  107. Abrantes MM, Cardoso LS, Lima EM, Penido Silva JM, Diniz JS, Bambirra EA, et al. Predictive factors of chronic kidney disease in primary focal segmental glomerulosclerosis. Pediatr Nephrol. 2006;21(7):1003–12.

    PubMed  Google Scholar 

  108. Bakir AA, Share DS, Levy PS, Arruda JA, Dunea G. Focal segmental glomerulosclerosis in adult African Americans. Clin Nephrol. 1996;46(5):306–11.

    PubMed  CAS  Google Scholar 

  109. Meyrier A. E pluribus unum: the riddle of focal segmental glomerulosclerosis. Semin Nephrol. 2003;23(2):135–40.

    PubMed  Google Scholar 

  110. Meyrier A. Nephrotic focal segmental glomerulosclerosis in 2004: an update. Nephrol Dial Transplant. 2004;19(10):2437–44.

    PubMed  Google Scholar 

  111. Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE, Schultheiss M, et al. Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol. 2004;15(3):722–32.

    PubMed  Google Scholar 

  112. D’Agati VD, Jennette JC, Silva FG. Pathology of renal transplantation. In: D’Agati VD, Jennette JC, Silva FG, editors. Non-neoplastic kidney disease, Atlas of nontumor pathology. Washington, DC: American Registry of Pathology Press; 2005.

    Google Scholar 

  113. Colvin RB, Nickeleit V. Renal transplant pathology. In: Jennette JC, Olson JL, Scwarts MM, Silva FG, editors. Heptinstall’s pathology of the kidney. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 1347.

    Google Scholar 

  114. Artero M, Biava C, Amend W, Tomlanovich S, Vincenti F. Recurrent focal glomerulosclerosis: natural history and response to therapy. Am J Med. 1992;92(4):375–83.

    PubMed  CAS  Google Scholar 

  115. Pardon A, Audard V, Caillard S, Moulin B, Desvaux D, Bentaarit B, et al. Risk factors and outcome of focal and segmental glomerulosclerosis recurrence in adult renal transplant recipients. Nephrol Dial Transplant. 2006;21(4):1053–9.

    PubMed  Google Scholar 

  116. Ponticelli C, Glassock RJ. Posttransplant recurrence of primary glomerulonephritis. Clin J Am Soc Nephrol. 2010;5(12):2363–72.

    PubMed  Google Scholar 

  117. Shimizu A, Higo S, Fujita E, Mii A, Kaneko T. Focal segmental glomerulosclerosis after renal transplantation. Clin Transplant. 2011;25 Suppl 23:6–14.

    PubMed  Google Scholar 

  118. Weber S, Tonshoff B. Recurrence of focal-segmental glomerulosclerosis in children after renal transplantation: clinical and genetic aspects. Transplantation. 2005;80(1 Suppl):S128–34.

    PubMed  Google Scholar 

  119. Bertelli R, Ginevri F, Caridi G, Dagnino M, Sandrini S, Di Duca M, et al. Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin. Am J Kidney Dis. 2003;41(6):1314–21.

    PubMed  CAS  Google Scholar 

  120. Gipson DS, Gibson K, Gipson PE, Watkins S, Moxey-Mims M. Therapeutic approach to FSGS in children. Pediatr Nephrol. 2007;22(1):28–36.

    PubMed  Google Scholar 

  121. Cattran DC, Rao P. Long-term outcome in children and adults with classic focal segmental glomerulosclerosis. Am J Kidney Dis. 1998;32(1):72–9.

    PubMed  CAS  Google Scholar 

  122. Stirling CM, Mathieson P, Boulton-Jones JM, Feehally J, Jayne D, Murray HM, et al. Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis in five UK renal units. QJM. 2005;98(6):443–9.

    PubMed  CAS  Google Scholar 

  123. Banfi G, Moriggi M, Sabadini E, Fellin G, D’Amico G, Ponticelli C. The impact of prolonged immunosuppression on the outcome of idiopathic focal-segmental glomerulosclerosis with nephrotic syndrome in adults. A collaborative retrospective study. Clin Nephrol. 1991;36(2):53–9.

    PubMed  CAS  Google Scholar 

  124. Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants. J Am Soc Nephrol. 2004;15(8):2169–77.

    PubMed  Google Scholar 

  125. Pei Y, Cattran D, Delmore T, Katz A, Lang A, Rance P. Evidence suggesting under-treatment in adults with idiopathic focal segmental glomerulosclerosis. Regional Glomerulonephritis Registry Study. Am J Med. 1987;82(5):938–44.

    PubMed  CAS  Google Scholar 

  126. Pokhariyal S, Gulati S, Prasad N, Sharma RK, Singh U, Gupta RK, et al. Duration of optimal therapy for idiopathic focal segmental glomerulosclerosis. J Nephrol. 2003;16(5):691–6.

    PubMed  Google Scholar 

  127. Korbet SM, Schwartz MM, Lewis EJ. Primary focal segmental glomerulosclerosis: clinical course and response to therapy. Am J Kidney Dis. 1994;23(6):773–83.

    PubMed  CAS  Google Scholar 

  128. Cameron JS, Turner DR, Ogg CS, Chantler C, Williams DG. The long-term prognosis of patients with focal segmental glomerulosclerosis. Clin Nephrol. 1978;10(6):213–8.

    PubMed  CAS  Google Scholar 

  129. Velosa JA, Donadio Jr JV, Holley KE. Focal sclerosing glomerulonephropathy: a clinicopathologic study. Mayo Clin Proc. 1975;50(3):121–33.

    PubMed  CAS  Google Scholar 

  130. Beaufils H, Alphonse JC, Guedon J, Legrain M. Focal glomerulosclerosis: natural history and treatment. A report of 70 cases. Nephron. 1978;21(2):75–85.

    PubMed  CAS  Google Scholar 

  131. Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, Hallahan CW, Lubensky I, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124(5):477–84.

    PubMed  CAS  Google Scholar 

  132. Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, et al. Malignancies in Wegener’s granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol. 2008;35(1):100–5.

    PubMed  CAS  Google Scholar 

  133. Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA, Hoy WE, et al. A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int. 1999;56(6):2220–6.

    PubMed  CAS  Google Scholar 

  134. Ponticelli C, Rizzoni G, Edefonti A, Altieri P, Rivolta E, Rinaldi S, et al. A randomized trial of cyclosporine in steroid-resistant idiopathic nephrotic syndrome. Kidney Int. 1993;43(6):1377–84.

    PubMed  CAS  Google Scholar 

  135. Heering P, Braun N, Mullejans R, Ivens K, Zauner I, Funfstuck R, et al. Cyclosporine A and chlorambucil in the treatment of idiopathic focal segmental glomerulosclerosis. Am J Kidney Dis. 2004;43(1):10–8.

    PubMed  CAS  Google Scholar 

  136. Gipson DS, Trachtman H, Kaskel FJ, Greene TH, Radeva MK, Gassman JJ, et al. Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int. 2011;80(8):868–78.

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Victoria Charoonratana for the illustrations in Fig. 4.2.

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Authors and Affiliations

  1. Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Moumita Barua M.D.

  2. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Martin R. Pollak M.D.

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  1. Moumita Barua M.D.
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Correspondence to Martin R. Pollak M.D. .

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Editors and Affiliations

  1. Div. Nephrology & Hypertension, Mayo Clinic Dept. Internal Medicine, Rochester, Minnesota, USA

    Fernando C. Fervenza

  2. Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Julie Lin

  3. Mayo Clinic, Rochester, Minnesota, USA

    Sanjeev Sethi

  4. Renal Division, Brigham and Women's Hospital Harvard Medical School, Boston, Massachusetts, USA

    Ajay K. Singh

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Barua, M., Pollak, M.R. (2014). Focal and Segmental Glomerulosclerosis. In: Fervenza, F., Lin, J., Sethi, S., Singh, A. (eds) Core Concepts in Parenchymal Kidney Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8166-9_4

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