Skip to main content

Advertisement

SpringerLink
Log in

Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Idiopathic nephrotic syndrome (INS) has been studied for decades in attempt to understand the physiopathological mechanisms explaining the disease. It is recognized as a multifactorial disease, with immunological components targeting kidney functions. Many hypotheses have been discussed or tested, including the role of a circulating factor, polymorphisms of genes implicated in lymphocyte maturation and differentiation, and DNA epigenetic modifications. In the present review, the data supporting these different (and probably combinatorial) hypotheses have been reviewed in order to identify and discuss the possible pathways implicated in the physiopathology of INS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Niaudet P (2004) Genetic forms of nephrotic syndrome. Pediatr Nephrol 19:1313–1318

    Article  PubMed  Google Scholar 

  2. Habib R, Kleinknecht C (1971) The primary nephrotic syndrome of childhood. Classification and clinicopathologic study of 406 cases. Pathol Annu 6:417–474

    PubMed  CAS  Google Scholar 

  3. International Study of Kidney Disease In Children (1978) Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. Kidney Int 13:159–165

    Article  Google Scholar 

  4. Arbeitsgemeinschaft für Pädiatrische Nephrologie (1988) Short versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Lancet 1:380–383

    Google Scholar 

  5. Hodson EM, Alexander SI (2008) Evaluation and management of steroid-sensitive nephrotic syndrome. Curr Opin Pediatr 20:145–150

    Article  PubMed  Google Scholar 

  6. McKinney PA, Feltbower RG, Brocklebank JT, Fitzpatrick MM (2001) Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire, UK. Pediatr Nephrol 16:1040–1044

    Article  PubMed  CAS  Google Scholar 

  7. Schlesinger ER, Sultz HA, Mosher WE, Feldman JG (1968) The nephrotic syndrome. Its incidence and implications for the community. Am J Dis Child 116:623–632

    PubMed  CAS  Google Scholar 

  8. Trompeter RS, Lloyd BW, Hicks J, White RH, Cameron JS (1985) Long-term outcome for children with minimal-change nephrotic syndrome. Lancet 1:368–370

    Article  PubMed  CAS  Google Scholar 

  9. Sahali D, Pawlak A, Le Gouvello S, Lang P, Valanciuté A, Remy P, Loirat C, Niaudet P, Bensman A, Guellaen G (2001) Transcriptional and post-transcriptional alterations of IkappaBalpha in active minimal-change nephrotic syndrome. J Am Soc Nephrol 12:1648–1658

    PubMed  CAS  Google Scholar 

  10. Araya C, Diaz L, Wasserfall C, Atkinson M, Mu W, Johnson R, Garin E (2009) T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol 24:1691–1698

    Article  PubMed  Google Scholar 

  11. Weaver ICG (2009) Epigenetic effects of glucocorticoids. Semin Fetal Neonatal Med 14:143–150

    Article  PubMed  Google Scholar 

  12. Barnes PJ (2010) Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol 120:76–85

    Article  PubMed  CAS  Google Scholar 

  13. Adcock IM (2000) Molecular mechanisms of glucocorticosteroid actions. Pulm Pharmacol Ther 13:115–126

    Article  PubMed  CAS  Google Scholar 

  14. Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2:556–560

    Article  PubMed  CAS  Google Scholar 

  15. Ulinski T, Aoun B (2010) Pediatric idiopathic nephrotic syndrome: treatment strategies in steroid-dependent and steroid-resistant forms. Curr Med Chem 17:847–853

    Article  PubMed  CAS  Google Scholar 

  16. Sellier-Leclerc A, Macher M, Loirat C, Guérin V, Watier H, Peuchmaur M, Baudouin V, Deschênes G (2010) Rituximab efficiency in children with steroid-dependent nephrotic syndrome. Pediatr Nephrol 25:1109–1115

    Article  PubMed  Google Scholar 

  17. Yap HK, Han EJ, Heng CK, Gong WK (2001) Risk factors for steroid dependency in children with idiopathic nephrotic syndrome. Pediatr Nephrol 16:1049–1052

    Article  PubMed  CAS  Google Scholar 

  18. Mansour H, Cheval L, Elalouf J, Aude J, Alyanakian M, Mougenot B, Doucet A, Deschênes G (2005) T-cell transcriptome analysis points up a thymic disorder in idiopathic nephrotic syndrome. Kidney Int 67:2168–2177

    Article  PubMed  CAS  Google Scholar 

  19. Audard V, Larousserie F, Grimbert P, Abtahi M, Sotto J, Delmer A, Boue F, Nochy D, Brousse N, Delarue R, Remy P, Ronco P, Sahali D, Lang P, Hermine O (2006) Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature. Kidney Int 69:2251–2260

    Article  PubMed  CAS  Google Scholar 

  20. Audard V, Zhang S, Copie-Bergman C, Rucker-Martin C, Ory V, Candelier M, Baia M, Lang P, Pawlak A, Sahali D (2010) Occurrence of minimal change nephrotic syndrome in classical Hodgkin lymphoma is closely related to the induction of c-mip in Hodgkin-Reed Sternberg cells and podocytes. Blood 115:3756–3762

    Article  PubMed  CAS  Google Scholar 

  21. Grimbert P, Valanciute A, Audard V, Pawlak A, Le Gouvelo S, Lang P, Niaudet P, Bensman A, Guellaën G, Sahali D (2003) Truncation of C-mip (Tc-mip), a new proximal signaling protein, induces c-maf Th2 transcription factor and cytoskeleton reorganization. J Exp Med 198:797–807

    Article  PubMed  CAS  Google Scholar 

  22. Yap HK, Cheung W, Murugasu B, Sim SK, Seah CC, Jordan SC (1999) Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. J Am Soc Nephrol 10:529–537

    PubMed  CAS  Google Scholar 

  23. Grimbert P, Audard V, Valanciute A, Pawlak A, Lang P, Guellaën G, Sahali D (2005) Abnormal RNA processing and altered expression of serin-rich proteins in minimal-change nephrotic syndrome. Pediatr Res 57:133–137

    Article  PubMed  CAS  Google Scholar 

  24. Sellier-Leclerc A, Duval A, Riveron S, Macher M, Deschenes G, Loirat C, Verpont M, Peuchmaur M, Ronco P, Monteiro RC, Haddad E (2007) A humanized mouse model of idiopathic nephrotic syndrome suggests a pathogenic role for immature cells. J Am Soc Nephrol 18:2732–2739

    Article  PubMed  Google Scholar 

  25. Lapillonne H, Leclerc A, Ulinski T, Balu L, Garnier A, Dereuddre-Bosquet N, Watier H, Schlageter M, Deschênes G (2008) Stem cell mobilization in idiopathic steroid-sensitive nephrotic syndrome. Pediatr Nephrol 23:1251–1256

    Article  PubMed  Google Scholar 

  26. Nagafuchi S, Katsuta H, Koyanagi-Katsuta R, Yamasaki S, Inoue Y, Shimoda K, Ikeda Y, Shindo M, Yoshida E, Matsuo T, Ohno Y, Kogawa K, Anzai K, Kurisaki H, Kudoh J, Harada M, Shimizu N (2006) Autoimmune regulator (AIRE) gene is expressed in human activated CD4+ T-cells and regulated by mitogen-activated protein kinase pathway. Microbiol Immunol 50:979–987

    PubMed  CAS  Google Scholar 

  27. Gavanescu I, Kessler B, Ploegh H, Benoist C, Mathis D (2007) Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity. Proc Natl Acad Sci USA 104:4583–4587

    Article  PubMed  CAS  Google Scholar 

  28. Long E, Wood KJ (2007) Understanding FOXP3: progress towards achieving transplantation tolerance. Transplantation 84:459–461

    Article  PubMed  CAS  Google Scholar 

  29. Shao XS, Yang XQ, Zhao XD, Li Q, Xie YY, Wang XG, Wang M, Zhang W (2009) The prevalence of Th17 cells and FOXP3 regulate T cells (Treg) in children with primary nephrotic syndrome. Pediatr Nephrol 24:1683–1690

    Article  PubMed  Google Scholar 

  30. Deschênes G, Doucet A (2009) Free immunoglobulin light chains: a role in minimal change disease. Biosci Hypotheses 2:135–142

    Article  Google Scholar 

  31. Garin EH (2000) Circulating mediators of proteinuria in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol 14:872–878

    Article  PubMed  CAS  Google Scholar 

  32. Hoyer JR, Vernier RL, Najarian JS, Raij L, Simmons RL, Michael AF (2001) Recurrence of idiopathic nephrotic syndrome after renal transplantation. J Am Soc Nephrol 12:1994–2002

    Google Scholar 

  33. Cochat P, Kassir A, Colon S, Glastre C, Tourniaire B, Parchoux B, Martin X, David L (1993) Recurrent nephrotic syndrome after transplantation: early treatment with plasmaphaeresis and cyclophosphamide. Pediatr Nephrol 7:50–54

    Article  PubMed  CAS  Google Scholar 

  34. Koyama A, Fujisaki M, Kobayashi M, Igarashi M, Narita M (1991) A glomerular permeability factor produced by human T cell hybridomas. Kidney Int 40:453–460

    Article  PubMed  CAS  Google Scholar 

  35. Ikeuchi Y, Kobayashi Y, Arakawa H, Suzuki M, Tamra K, Morikawa A (2009) Polymorphisms in interleukin-4-related genes in patients with minimal change nephrotic syndrome. Pediatr Nephrol 24:489–495

    Article  PubMed  Google Scholar 

  36. Vanden Berghe W, Ndlovu N, Hoya-Arias R, Dijsselbloem N, Gerlo S, Haegeman G (2006) Keeping up NF-[kappa]B appearances: epigenetic control of immunity or inflammation-triggered epigenetics. Biochem Pharmacol 72:1114–1131

    Article  Google Scholar 

  37. Alt FW, Rathbun G, Oltz E, Taccioli G, Shinkai Y (1992) Function and control of recombination-activating gene activity. Ann NY Acad Sci 651:277–294

    Article  PubMed  CAS  Google Scholar 

  38. Corneo B, Moshous D, Güngör T, Wulffraat N, Philippet P, Le Deist FL, Fischer A, de Villartay JP (2001) Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood 97:2772–2776

    Article  PubMed  CAS  Google Scholar 

  39. de Villartay J, Lim A, Al-Mousa H, Dupont S, Déchanet-Merville J, Coumau-Gatbois E, Gougeon M, Lemainque A, Eidenschenk C, Jouanguy E, Abel L, Casanova J, Fischer A, Le Deist F (2005) A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest 115:3291–3299

    Article  PubMed  Google Scholar 

  40. Klein U, Casola S, Cattoretti G, Shen Q, Lia M, Mo T, Ludwig T, Rajewsky K, Dalla-Favera R (2006) Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol 7:773–782

    Article  PubMed  CAS  Google Scholar 

  41. Lee GR, Fields PE, Flavell RA (2001) Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity 14:447–459

    Article  PubMed  CAS  Google Scholar 

  42. Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet 373:1905–1917

    Article  PubMed  CAS  Google Scholar 

  43. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu T, Corcoran L, Treuting P, Klein U, Rudensky AY (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458:351–356

    Article  PubMed  CAS  Google Scholar 

  44. Ransom RF, Lam NG, Hallett MA, Atkinson SJ, Smoyer WE (2005) Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int 68:2473–2483

    Article  PubMed  CAS  Google Scholar 

  45. Schönenberger E, Ehrich JH, Haller H, Schiffer M (2011) The podocyte as a direct target of immunosuppressive agents. Nephrol Dial Transplant 26:18–24

    Article  PubMed  Google Scholar 

  46. Wada T, Pippin JW, Marshall CB, Griffin SV, Shankland SJ (2005) Dexamethasone prevents podocyte apoptosis induced by puromycin aminonucleoside: role of p53 and Bcl-2-related family proteins. J Am Soc Nephrol 16:2615–2625

    Article  PubMed  CAS  Google Scholar 

  47. Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang J, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14:931–938

    Article  PubMed  CAS  Google Scholar 

  48. Mundel P, Reiser J (2010) Proteinuria: an enzymatic disease of the podocyte? Kidney Int 77:571–580

    Article  PubMed  CAS  Google Scholar 

  49. Shimada M, Araya C, Rivard C, Ishimoto T, Johnson RJ, Garin EH (2011) Minimal change disease: a “two-hit” podocyte immune disorder? Pediatr Nephrol 26:645–649

    Article  PubMed  Google Scholar 

  50. Zhang S, Kamal M, Dahan K, Pawlak A, Ory V, Desvaux D, Audard V, Candelier M, BenMohamed F, Mohamed FB, Matignon M, Christov C, Decrouy X, Bernard V, Mangiapan G, Lang P, Guellaën G, Ronco P, Sahali D (2010) c-mip impairs podocyte proximal signaling and induces heavy proteinuria. Sci Signal 3:ra39

    Google Scholar 

  51. Kamal M, Pawlak A, BenMohamed F, Valanciuté A, Dahan K, Candelier M, Lang P, Guellaën G, Sahali D (2010) C-mip interacts with the p85 subunit of PI3 kinase and exerts a dual effect on ERK signaling via the recruitment of Dip1 and DAP kinase. FEBS Lett 584:500–506

    Article  PubMed  CAS  Google Scholar 

  52. Clement LC, Avila-Casado C, Macé C, Soria E, Bakker WW, Kersten S, Chugh SS (2011) Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med 17:117–122

    Article  PubMed  CAS  Google Scholar 

  53. Okamoto K, Tokunaga K, Doi K, Fujita T, Suzuki H, Katoh T, Watanabe T, Nishida N, Mabuchi A, Takahashi A, Kubo M, Maeda S, Nakamura Y, Noiri E (2011) Common variation in GPC5 is associated with acquired nephrotic syndrome. Nat Genet 43:459–463

    Article  PubMed  CAS  Google Scholar 

  54. Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7:21–33

    Article  PubMed  CAS  Google Scholar 

  55. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159

    Article  PubMed  CAS  Google Scholar 

  56. Wong AHC, Gottesman II, Petronis A (2005) Phenotypic differences in genetically identical organisms: the epigenetic perspective. Hum Mol Genet 14 Spec No 1:R11–R18

    Google Scholar 

  57. Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447:433–440

    Article  PubMed  CAS  Google Scholar 

  58. Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 3:662–673

    Article  PubMed  CAS  Google Scholar 

  59. Rodenhiser D, Mann M (2006) Epigenetics and human disease: translating basic biology into clinical applications. CMAJ 174:341–348

    Article  PubMed  Google Scholar 

  60. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu Y, Plass C, Esteller M (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609

    Article  PubMed  CAS  Google Scholar 

  61. Szyf M, Weaver ICG, Champagne FA, Diorio J, Meaney MJ (2005) Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat. Front Neuroendocrinol 26:139–162

    Article  PubMed  CAS  Google Scholar 

  62. Migeon BR (2008) X inactivation, female mosaicism, and sex differences in renal diseases. J Am Soc Nephrol 19:2052–2059

    Article  PubMed  Google Scholar 

  63. Dwivedi RS, Herman JG, McCaffrey TA, Raj DSC (2011) Beyond genetics: epigenetic code in chronic kidney disease. Kidney Int 79:23–32

    Article  PubMed  Google Scholar 

  64. Barnes PJ (2009) Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 6:693–696

    Article  PubMed  CAS  Google Scholar 

  65. MacDonald NE, Wolfish N, McLaine P, Phipps P, Rossier E (1986) Role of respiratory viruses in exacerbations of primary nephrotic syndrome. J Pediatr 108:378–382

    Article  PubMed  CAS  Google Scholar 

  66. Stram Y, Kuzntzova L (2006) Inhibition of viruses by RNA interference. Virus Genes 32:299–306

    Article  PubMed  CAS  Google Scholar 

  67. Maekawa M, Watanabe Y (2007) Epigenetics: relations to disease and laboratory findings. Curr Med Chem 14:2642–2653

    Article  PubMed  CAS  Google Scholar 

  68. Guo L, Hu-Li J, Zhu J, Watson CJ, Difilippantonio MJ, Pannetier C, Paul WE (2002) In TH2 cells the Il4 gene has a series of accessibility states associated with distinctive probabilities of IL-4 production. Proc Natl Acad Sci USA 99:10623–10628

    Article  PubMed  CAS  Google Scholar 

  69. Adcock IM, Tsaprouni L, Bhavsar P, Ito K (2007) Epigenetic regulation of airway inflammation. Curr Opin Immunol 19:694–700

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Pediatric Pharmacology and Pharmacogenetics, Clinical Investigation Center CIC Inserm 9202, Hôpital Robert Debré, 48 Boulevard Sérurier, 75935, Paris Cedex 19, France

    Valéry Elie, May Fakhoury & Evelyne Jacqz-Aigrain

  2. Clinical Investigation Center (CIC) INSERM 9202, Hôpital Robert Debré, 48 Boulevard Sérurier, 75935, Paris Cedex 19, France

    May Fakhoury & Evelyne Jacqz-Aigrain

  3. Department of Pediatric Nephrology, Hôpital Robert Debré, 48 Boulevard Sérurier, 75935, Paris Cedex 19, France

    Georges Deschênes

Authors
  1. Valéry Elie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. May Fakhoury
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georges Deschênes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Evelyne Jacqz-Aigrain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Evelyne Jacqz-Aigrain.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elie, V., Fakhoury, M., Deschênes, G. et al. Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives. Pediatr Nephrol 27, 1249–1256 (2012). https://doi.org/10.1007/s00467-011-1947-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-011-1947-1

Keywords

Search

Navigation