Childhood Kidney Diseases

Korean Society of Pediatric Nephrology (대한소아신장학회)
권호 표지
DOI QR코드

DOI QR Code

Pathogenesis of Minimal Change Nephrotic Syndrome: A Review of the Underlying Molecular Mechanisms

  • Yang, Eun Mi (Department of Pediatrics, Chonnam National University Medical School)
  • Received : 2019.03.12
  • Accepted : 2019.04.16
  • Published : 2019.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Nephrotic syndrome (NS) is the most common glomerular disorder in childhood, and a vast majority of cases are idiopathic. The precise cause of this common childhood disease is not fully elucidated despite significant advancements in our understanding of podocyte biology. Idiopathic NS has been considered "a disorder of T-cell function" mediated by a circulating factor that alters podocyte function resulting in massive proteinuria since the last four decades. Several circulatory factors released from T-cells are considered to be involved in pathophysiology of NS; however, a single presumptive factor has not been defined yet. Extended evidence obtained by advances in the pathobiology of podocytes has implicated podocytes as critical regulator of glomerular protein filtration and podocytopathy. The candidate molecules as pathological mediators of steroid-dependent NS are CD80 (also known as B7-1), hemopexin, and angiopoietin-like 4. The "two-hit" hypothesis proposes that the expression of CD80 on podocytes and ineffective inhibition of podocyte CD80 due to regulatory T-cell dysfunction or impaired autoregulation by podocytes results in NS. Recent studies suggest that not only T cells but also other immune cells and podocytes are involved in the pathogenesis of MCNS.

Keywords

References

  1. Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet 2018;392:61-74. https://doi.org/10.1016/S0140-6736(18)30536-1
  2. Banh TH, Hussain-Shamsy N, Patel V, Vasilevska-Ristovska J, Borges K, Sibbald C, et al. Ethnic Differences in Incidence and Outcomes of Childhood Nephrotic Syndrome. Clin J AM Soc Nephrol 2016;11:1760-8. https://doi.org/10.2215/CJN.00380116
  3. Kaneko K, Tsuji S, Kimata T, Kitao T, Yamanouchi S, Kato S. Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes. World J Pediatr 2015;11:21-8. https://doi.org/10.1007/s12519-015-0003-9
  4. Mendonca AC, Oliveira EA, Froes BP, Faria LD, Pinto JS, Nogueira MM, et al. A predictive model of progressive chronic kidney disease in idiopathic nephrotic syndrome. Pediatr Nephrol 2015;30: 2011-20. https://doi.org/10.1007/s00467-015-3136-0
  5. Pais Pariya, Avner ED. Nephrotic syndrome. In: Klegman RM, Stanton BF, Geme III JWS, editros. Nelson textbook of pediatrics, 20th ed. Philadelphia: Elsevier, 2016:2521-6
  6. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of Tcell function. Lancet 1974;2:556-60. https://doi.org/10.1016/S0140-6736(74)91880-7
  7. Koyama A, Fujisaki M, Kobayashi M, Igarashi M, Narita M. A glomerular permeability factor produced by human T cell hybridomas. Kidney Int 1991;40:453-60. https://doi.org/10.1038/ki.1991.232
  8. Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, et al. Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 1996;334:878-83. https://doi.org/10.1056/NEJM199604043341402
  9. Araya CE, Wasserfall CH, Brusko TM, Mu W, Segal MS, Johnson RJ, et al. A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol 2006;21: 603-10. https://doi.org/10.1007/s00467-006-0026-5
  10. Kaneko K. Molecular mechanism in the pathogenesis of idiopathic nephrotic syndrome. . 1st ed. Tokyo: Springer, 2016.
  11. Daniel V, Trautmann Y, Konrad M, Nayir A, Scharer K. T-lymphocyte populations, cytokines and other growth factors in serum and urine of children with idiopathic nephrotic syndrome. Clin Nephrol. 1997;47:289-97.
  12. Neuhaus TJ, Wadhwa M, Callard R, Barratt TM. Increased IL-2, IL-4 and interferon-gamma (IFN-gamma) in steroid-sensitive nephrotic syndrome. Clin Exp Immunol 1995;100:475-9. https://doi.org/10.1111/j.1365-2249.1995.tb03725.x
  13. Mandreoli M, Beltrandi E, Casadei-Maldini M, Mancini R, Zucchelli A, Zucchelli P. Lymphocyte release of soluble IL-2 receptors in patients with minimal change nephropathy. Clin Nephrol 1992; 37:177-82.
  14. Garin EH, Blanchard DK, Matsushima K, Djeu JY. IL-8 production by peripheral blood mononuclear cells in nephrotic patients. Kidney Int 1994;45:1311-7. https://doi.org/10.1038/ki.1994.171
  15. Garin EH, West L, Zheng W. Effect of interleukin-8 on glomerular sulfated compounds and albuminuria. Pediatr Nephrol 1997;11: 274-9. https://doi.org/10.1007/s004670050276
  16. Souto MF, Teixeira AL, Russo RC, Penido MG, Silveira KD, Teixeira MM, et al. Immune mediators in idiopathic nephrotic syndrome: evidence for a relation between interleukin 8 and proteinuria. Pediatr Res 2008;64:637-42. https://doi.org/10.1203/PDR.0b013e318186ddb2
  17. Van Den Berg JG, Aten J, Annink C, Ravesloot JH, Weber E, Weening JJ. Interleukin-4 and -13 promote basolateral secretion of H(+) and cathepsin L by glomerular epithelial cells. Am J Physiol Renal Physiol 2002;282:F26-33. https://doi.org/10.1152/ajprenal.0102.2001
  18. Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG, et al. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol 2007;18:1476-85. https://doi.org/10.1681/ASN.2006070710
  19. Tain YL, Chen TY, Yang KD. Implications of serum TNF-beta and IL-13 in the treatment response of childhood nephrotic syndrome. Cytokine. 2003;21:155-9. https://doi.org/10.1016/S1043-4666(03)00017-6
  20. Suranyi MG, Guasch A, Hall BM, Myers BD. Elevated levels of tumor necrosis factor-alpha in the nephrotic syndrome in humans. Am J Kidney Dis 1993;21:251-9. https://doi.org/10.1016/S0272-6386(12)80742-6
  21. Matsumoto K, Kanmatsuse K. Elevated vascular endothelial growth factor levels in the urine of patients with minimal-change nephrotic syndrome. Clin Nephrol 2001;55:269-74.
  22. Cho MH, Lee HS, Choe BH, Kwon SH, Chung KY, Koo JH, et al. Interleukin-8 and tumor necrosis factor-alpha are increased in minimal change disease but do not alter albumin permeability. Am J Nephrol 2003;23:260-6. https://doi.org/10.1159/000072065
  23. Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, et al. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 2004;113:1390-7. https://doi.org/10.1172/JCI20402
  24. Gandhi NA, Pirozzi G, Graham NMH. Commonality of the IL-4/IL- 13 pathway in atopic diseases. Expert Rev Clin Immunol 2017;13:425-37. https://doi.org/10.1080/1744666X.2017.1298443
  25. Corren J. Role of interleukin-13 in asthma. Curr Allergy Asthma Rep 2013;13:415-20. https://doi.org/10.1007/s11882-013-0373-9
  26. Bertelli R, Bonanni A, Di Donato A, Cioni M, Ravani P, Ghiggeri GM. Regulatory T cells and minimal change nephropathy: in the midst of a complex network. Clin Exp Immunol 2016;183:166-74. https://doi.org/10.1111/cei.12675
  27. Shimada M, Araya C, Rivard C, Ishimoto T, Johnson RJ, Garin EH. Minimal change disease: a "two-hit" podocyte immune disorder? Pediatr Nephrol 2011;26:645-9. https://doi.org/10.1007/s00467-010-1676-x
  28. Le Berre L, Bruneau S, Naulet J, Renaudin K, Buzelin F, Usal C, et al. Induction of T regulatory cells attenuates idiopathic nephrotic syndrome. J Am Soc Nephrol 2009;20:57-67. https://doi.org/10.1681/ASN.2007111244
  29. Araya C, Diaz L, Wasserfall C, Atkinson M, Mu W, Johnson R, et al. T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol 2009;24:1691-8. https://doi.org/10.1007/s00467-009-1214-x
  30. Tellier S, Brochard K, Garnier A, Bandin F, Llanas B, Guigonis V, et al. Long-term outcome of children treated with rituximab for idiopathic nephrotic syndrome. Pediatr Nephrol 2013;28:911-8. https://doi.org/10.1007/s00467-012-2406-3
  31. Iijima K, Sako M, Kamei K, Nozu K. Rituximab in steroid-sensitive nephrotic syndrome: lessons from clinical trials. Pediatr Nephrol 2018;33:1449-55. https://doi.org/10.1007/s00467-017-3746-9
  32. Iharada A, Kaneko K, Tsuji S, Hasui M, Kanda S, Nishiyama T. Increased nitric oxide production by T- and B-cells in idiopathic nephrotic syndrome. Pediatr Nephrol 2009;24:1033-8. https://doi.org/10.1007/s00467-008-1092-7
  33. Elie V, Fakhoury M, Deschenes G, Jacqz-Aigrain E. Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives. Pediatr Nephrol 2012;27:1249-56. https://doi.org/10.1007/s00467-011-1947-1
  34. Bakker WW, van Dael CM, Pierik LJ, van Wijk JA, Nauta J, Borghuis T, et al. Altered activity of plasma hemopexin in patients with minimal change disease in relapse. Pediatr Nephrol 2005;20: 1410-5. https://doi.org/10.1007/s00467-005-1936-3
  35. Cheung PK, Klok PA, Baller JF, Bakker WW. Induction of experimental proteinuria in vivo following infusion of human plasma hemopexin. Kidney Int 2000;57:1512-20. https://doi.org/10.1046/j.1523-1755.2000.00996.x
  36. Lennon R, Singh A, Welsh GI, Coward RJ, Satchell S, Ni L, et al. Hemopexin induces nephrin-dependent reorganization of the actin cytoskeleton in podocytes. J Am Soc Nephrol 2008;19: 2140-9. https://doi.org/10.1681/ASN.2007080940
  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;17:117-22. https://doi.org/10.1038/nm.2261
  38. Clement LC, Mace C, Avila-Casado C, Joles JA, Kersten S, Chugh SS. Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat Med 2014;20:37-46. https://doi.org/10.1038/nm.3396
  39. Bertelli R, Bonanni A, Caridi G, Canepa A, Ghiggeri GM. Molecular and Cellular Mechanisms for Proteinuria in Minimal Change Disease. Front Med 2018;5:170. https://doi.org/10.3389/fmed.2018.00170
  40. Abbas AK, Sharpe AH. T-cell stimulation: an abundance of B7s. Nat Med 1999;5:1345-6. https://doi.org/10.1038/70905
  41. Garin EH, Diaz LN, Mu W, Wasserfall C, Araya C, Segal M, et al. Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol 2009;20:260-6. https://doi.org/10.1681/ASN.2007080836
  42. Garin EH, Mu W, Arthur JM, Rivard CJ, Araya CE, Shimada M, et al. Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int 2010;78:296-302. https://doi.org/10.1038/ki.2010.143
  43. Ling C, Liu X, Shen Y, Chen Z, Fan J, Jiang Y, et al. Urinary CD80 excretion is a predictor of good outcome in children with primary nephrotic syndrome. Pediatr Nephrol 2018;33:1183-7. https://doi.org/10.1007/s00467-018-3885-7
  44. Ishimoto T, Shimada M, Gabriela G, Kosugi T, Sato W, Lee PY, et al. Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice. Nephrol Dial Transplantation 2013;28:1439-46. https://doi.org/10.1093/ndt/gfs543