Conclusion

The most important message is that FSGS is a lesion and not a disease. The finding of an FSGS lesion is the start of an exploratory process leading to a diagnosis and not an end in itself. We propose that adult patients presenting with nephrotic syndrome, a FSGS lesion on LM, extensive foot process effacement (>80%) on EM examination and no factors associated with causing FSGS are likely to have primary/idiopathic FSGS.

Conversely, the presence of subnephrotic or nephrotic-range proteinuria, but no nephrotic syndrome, in a patient with segmental foot process effacement on EM suggests we are dealing with secondary FSGS, although the cause may not be obvious with the available diagnostic tools.

It should be understood that morphology alone (e.g. without any clinical information) makes it very difficult or impossible to reliably distinguish a primary from a secondary form of FSGS. Thus primary and secondary FSGS might be viewed as clinician-pathological entities and is important for clinicians to understand they have to integrate the pathological findings with clinical information to arrive at the most precise separation of primary from secondary FSGS.

Differentiating primary from secondary FSGS is crucial. Patients with primary FSGS should be considered for immunosuppressive treatment, whereas patients with secondary FSGS should be treated conservatively with therapy aimed at reducing BP and proteinuria.

Long-term follow-up is needed because clinical presentation and renal biopsy findings may suggest a primary FSGS going into spontaneous remission or a secondary FSGS progressing to full nephrotic syndrome. In this last group, a repeat renal biopsy should be considered.

HOW TO TAKE THE POST-TEST: To obtain CME credit, please click here after reading the article to take the post-test on myCME.com.

References

  1. D’Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis. 2004;43:368-382.
  2. Sethi S, Glassock RJ, Fervenza FC. Focal segmental glomerulosclerosis: towards a better understanding for the practicing nephrologist. Nephrol Dial Transplant. 2014; Epub ahead of print.
  3. Remuzzi A, Pergolizzi R, Mauer MS, Bertani T. Three-dimensional morphometric analysis of segmental
    glomerulosclerosis in the rat. Kidney Int. 1990;38:851-856.
  4. Remuzzi A, Mazerska M, Gephardt GN, et al. Threedimensional analysis of glomerular morphology in patients with subtotal nephrectomy. Kidney Int. 1995;48:155-162.
  5. Fogo A, Glick AD, Horn SL, Horn RG. Is focal segmental glomerulosclerosis really focal? Distribution of lesions in adults and children. Kidney Int. 1995;47:1690-1696.
  6. Fuiano G, Comi N, Magri P, Sepe V, et al. Serial morphometric analysis of sclerotic lesions in primary “focal” segmental glomerulosclerosis. J Am Soc Nephrol. 1996;7:49-55.
  7. Cameron, JS. The enigma of focal segmental glomerulosclerosis. Kidney Int Suppl 1996;57:S119-S131.
  8. Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int. 1998;54:687-697.
  9. Howie AJ. Segmental sclerosing glomerular lesions. Pediatr Nephrol. 1993;7:370-374.
  10. Hyman LR, Burkholder PM. Focal sclerosing glomerulonephropathy with segmental hyalinosis. A clinicopathologic analysis. Lab Invest. 1973;28:533-544.
  11. Velosa JA, Donadio JV Jr, Holley KE. Focal sclerosing glomerulonephropathy: a clinicopathologic study. Mayo Clin Proc. 1975;50:121-133.
  12. Howie AJ, Pankhurst T, Sarioglu S, et al. Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion. Kidney Int. 2005;67:987-1001.
  13. Hoyer JR, Vernier RL, Najarian JS, et al. Recurrence of idiopathic nephrotic syndrome after renal transplantation. Lancet. 1972;2:343-348.
  14. Korbet SM. Treatment of primary FSGS in adults. J Am Soc Nephrol. 2012;23:1769-1776.
  15. Savin VJ, Sharma R, Sharma M, et al. Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med. 1996;334:878-883.
  16. Wei C, El Hindi S, Li J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nature Med. 2011;17:952-960.
  17. Le Berre L, Godfrin Y, Lafond-Puyet L, et al. Effect of plasma fractions from patients with focal and segmental
    glomerulosclerosis on rat proteinuria. Kidney Int. 2000;58:2502-2511.
  18. Glasser RJ, Velosa JA, Michael AF. Experimental model of focal sclerosis. I. Relationship to protein excretion in aminonucleoside nephrosis. Lab Invest. 1977;36:519-526.
  19. Inokuchi S, Shirato I, Kobayashi N, et al. Re-evaluation of foot process effacement in acute puromycin aminonucleoside nephrosis. Kidney Int. 1996;50:1278-1287.
  20. Vernier RL, Papermaster BW, Good RA. Aminonucleoside nephrosis. I. Electron microscopic study of the renal lesion in rats. J Exp Med. 1959;109:115-126.
  21. D’Agati VD. Podocyte injury in focal segmental glomerulosclerosis: Lessons from animal models (a play in five acts). Kidney Int. 2008;73:399-406.
  22. 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.
  23. Nagata M, Scharer K, Kriz W. Glomerular damage after uninephrectomy in young rats. I. Hypertrophy and distortion of capillary architecture. Kidney Int. 1992;42:136-147.
  24. Chang JW, Pardo V, Sageshima J, et al. Podocyte foot process effacement in postreperfusion allograft biopsies correlates with early recurrence of proteinuria in focal segmental glomerulosclerosis. Transplantation. 2012;93:1238-1244.
  25. Cheong HI, Han HW, Park HW, et al. Early recurrent nephrotic syndrome after renal transplantation in children with focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2000;15:78-81.
  26. Wei C, Moller CC, Altintas MM, et al. Modification of kidney barrier function by the urokinase receptor. Nature Med. 2008;14:55-63.
  27. Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol. 2002;3:932-943.
  28. Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol. 2010;11:23-36.
  29. Sharma M, Sharma R, McCarthy ET, Savin VJ. “The FSGS factor:” enrichment and in vivo effect of activity from focal segmental glomerulosclerosis plasma. J Am Soc Nephrol. 1999;10:552-561.
  30. Alachkar N, Wei C, Arend LJ, et al. Podocyte effacement closely links to suPAR levels at time of posttransplantation focal segmental glomerulosclerosis occurrence and improves with therapy. Transplantation. 2013;96:649-656.
  31. Maas RJ, Deegens JK, Wetzels JF. Serum suPAR in patients with FSGS: trash or treasure? Pediatr Nephrol. 2013;28:1041-1048.
  32. Maas RJ, Wetzels JF, Deegens JK. Serum-soluble urokinase receptor concentration in primary FSGS. Kidney Int. 2012;81:1043-1044.
  33. Huang J, Liu G, Zhang YM, et al. Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis. Kidney Int. 2013;84:366-372.
  34. Bock ME, Price HE, Gallon L, Langman CB. Serum soluble urokinase-type plasminogen activator receptor levels and idiopathic FSGS in children: a single-center report. Clin J Am Soc Nephrol. 2013;8:1304-1311.
  35. Franco Palacios CR, Lieske JC, Wadei HM, et al. Urine but not serum soluble urokinase receptor (suPAR) may identify cases of recurrent FSGS in kidney transplant candidates. Transplantation. 2013;96:394-399.
  36. Wei C, Trachtman H, Li J, et al. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol. 2012;23:2051-2059.
  37. Glassock RJ, Fervenza FC, Hebert L, Cameron JS. Nephrotic syndrome redux. Nephrol Dial Transplant. 2014; Epub ahead of print.
  38. Gipson DS, Trachtman H, Kaskel FJ, et al. Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int. 2011;80:868-878.
  39. Fogo A, Breyer JA, Smith MC, et al. Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK Pilot Study Investigators. Kidney Int. 1997;51:244-252.
  40. Toto R. Proteinuria and hypertensive nephrosclerosis in African-Americans. Kidney Int. 2004;66:102-104.
  41. Cravedi P, Ruggenenti P, Remuzzi G. Proteinuria should be used as a surrogate in CKD. Nat Rev Nephrol. 2012;8:301-306.
  42. D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011;365:2398-2411.
  43. Powell HR. Relationship between proteinuria and epithelial cell changes in minimal lesion glomerulopathy. Nephron. 1976;16:310-317.
  44. Koop K, Eikmans M, Baelde HJ, et al. Expression of podocyte-associated molecules in acquired human kidney diseases. J Am Soc Nephrol. 2003;14:2063-2071.
  45. Black DA, Rose G, Brewer DB. Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br Med J. 1970;3:421-426.
  46. Praga M, Borstein B, Andres A, et al. Nephrotic proteinuria without hypoalbuminemia: clinical characteristics and response to angiotensinconverting enzyme inhibition. Am J Kidney Dis. 1994;17:330-338.
  47. Korbet SM. Primary focal segmental glomerulosclerosis. J Am Soc Nephrol. 1998;9:1333-1340.
  48. 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;15:2169-2177.
  49. Ponticelli C, Villa M, Banfi G, et al. Can prolonged treatment improve the prognosis in adults with focal segmental glomerulosclerosis? Am J Kidney Dis. 1999;34:618-625.
  50. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc. 1996;71:5-13.
  51. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2007;CD005590.
  52. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc. 2007;82:1052-1059.
  53. Cattran DC, Appel GB, Hebert LA, et al. A randomized trial of cyclosporine in patients with steroidresistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int. 1999;56:2220-2226.
  54. Duncan N, Dhaygude A, Owen J, et al. Treatment f focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy. Nephrol Dial Transplant. 2004;19:3062-3067.
  55. Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nature Med. 2008;14:931-938.
  56. Choi MJ, Eustace JA, Gimenez LF, et al. Mycophenolate mofetil treatment for primary glomerular diseases.[comment]. Kidney Int. 2002;61:1098-1114.
  57. Hogan J, Bomback AS, Mehta K, et al. Treatment of Idiopathic FSGS with Adrenocorticotropic Hormone Gel. Clin J Am Soc Nephrol. 2013;8;2072-2081.
  58. Fernandez-Fresnedo G, Segarra A, Gonzalez E, et al. Rituximab treatment of adult patients with steroidresistant focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2009;4:1317-1323.
  59. Schulman SL, Kaiser BA, Polinsky M, et al. Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: superiority of response to corticosteroid therapy over histopathologic patterns. J Pediatr. 1988;113:996-1001.
  60. Tumlin JA, Miller D, Near M, et al. A prospective, open-label trial of sirolimus in the treatment of focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2006;1:109-116.
  61. Cho ME, Hurley JK, Kopp JB. Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity. Am J Kidney Dis. 2007;49:310-317.
  62. Fervenza FC, Fitzpatrick PM, Mertz J, et al. Acute rapamycin nephrotoxicity in native kidneys of patients with chronic glomerulopathies. Nephrol Dial nsplant. 2004;19:1288-1292.
  63. Yu CC, Fornoni A, Weins A, et al. Abatacept in B7-1- positive proteinuric kidney disease. N Engl J Med. 2013;369:2416-2423.
  64. Cara-Fuentes G, Wei C, Segarra A, et al. CD80 and suPAR in patients with minimal change disease and focal segmental glomerulosclerosis: diagnostic and pathogenic significance. Pediatr Nephrol. 2013;Epub ahead of print.
  65. Garin EH, Mu W, Arthur JM, et al. Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int. 2010;78:296-302.
  66. Velosa JA, Holley KE, Torres VE, Offord KP. Significance of proteinuria on the outcome of renal function in patients with focal segmental glomerulosclerosis. Mayo Clin Proc. 1983;58:568-577.
  67. Troyanov S, Wall CA, Miller JA, et al. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. J Am Soc Nephrol. 2005;16:1061-1068.
  68. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int. 2012;2:139-274.
  69. Crook ED, Habeeb D, Gowdy O, et al. Effects of steroids in focal segmental glomerulosclerosis in a predominantly African-American population. Am J Med Sci. 2005;330:19-24.
  70. Fuchshuber A, Gribouval O, Ronner V, et al. Clinical and genetic evaluation of familial steroid-responsive nephrotic syndrome in childhood. J Am Soc Nephrol. 2001;12:374-378.
  71. Hinkes B, Wiggins RC, Gbadegesin R, et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet. 2006;38:1397-1405.
  72. Santin S, Garcia-Maset R, Ruiz P, et al. Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis. Kidney Int. 2009;76:1268-1276.
  73. Ruf RG, Lichtenberger A, Karle SM, et al. Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol. 2004;15:722-732.
  74. Santin S, Bullich G, Tazon-Vega B, et al. Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol. 2011;6:1139-1148.
  75. Santin S, Tazon-Vega B, Silva I, et al. Clinical value of NPHS2 analysis in early- and adult-onset steroidresistant nephrotic syndrome. Clin J Am Soc Nephrol. 2011;6:344-354.
  76. Mele C, Iatropoulos P, Donadelli R, et al. MYO1E mutations and childhood familial focal segmental glomerulosclerosis. Engl J Med. 2011;365:295-306.
  77. Buscher AK, Kranz B, Buscher R, et al. Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol. 2010;5:2075-2084.
  78. Hao X, Xie J, Ma J, et al. Increased risk of treatment failure and end-stage renal disease in familial focal segmental glomerular sclerosis.