Child Kidney Dis.  2023 Jun;27(1):1-10. 10.3339/ckd.22.042.

Immunopathogenesis of childhood idiopathic nephrotic syndrome

• Cheong HI

• KMID: 2544231
• DOI: http://doi.org/10.3339/ckd.22.042

Abstract

Pediatric nephrotic syndrome (NS) is a clinical syndrome characterized by massive proteinuria, hypoalbuminemia, and generalized edema. Most childhood NS cases are idiopathic (with an unknown etiology). Traditional therapeutic approaches based on immunosuppressive agents largely support the key role of the immune system in idiopathic NS (INS), especially in the steroid-sensitive form. Although most previous studies have suggested the main role of T cell dysfunction and/or the abnormal secretion of certain glomerular permeability factors, recent studies have emphasized the role of B cells since the therapeutic efficacy of B cell depletion therapy in inducing and/or maintaining prolonged remission in patients with INS was confirmed. Furthermore, several studies have detected circulating autoantibodies that target podocyte proteins in a subset of patients with INS, suggesting an autoimmune-mediated etiology of INS. Accordingly, a new therapeutic modality using B cell-depleting drugs has been attempted, with significant effects in a subset of patients with INS. Currently, INS is considered an immune-mediated disorder caused by a complex interplay between T cells, B cells, soluble factors, and podocytes, which may vary among patients. More in-depth investigations of the pathogenic pathways of INS are required for an effective personalized therapeutic approach and to define precise targets for therapeutic intervention.

Keyword

Autoimmunity; B-lymphocytes; Etiology; Nephrotic syndrome

Reference

References

1. Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet. 2018; 392:61–74.

2. Barisoni L, Schnaper HW, Kopp JB. A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol. 2007; 2:529–42.

3. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet. 1974; 2:556–60.

4. Lagrue G, Xheneumont S, Branellec A, Hirbec G, Weil B. A vascular permeability factor elaborated from lymphocytes. I. Demonstration in patients with nephrotic syndrome. Biomedicine. 1975; 23:37–40.

5. Zimmerman SW. Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal glomerular sclerosis after renal transplantation. Clin Nephrol. 1984; 22:32–8.

6. 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.

7. Kienzl-Wagner K, Waldegger S, Schneeberger S. Disease recurrence: the sword of Damocles in kidney transplantation for primary focal segmental glomerulosclerosis. Front Immunol. 2019; 10:1669.

8. Hoyer JR, Vernier RL, Najarian JS, Raij L, Simmons RL, Michael AF. Recurrence of idiopathic nephrotic syndrome after renal transplantation. Lancet. 1972; 2:343–8.

9. Laufer J, Ettenger RB, Ho WG, Cohen AH, Marik JL, Fine RN. Plasma exchange for recurrent nephrotic syndrome following renal transplantation. Transplantation. 1988; 46:540–2.

10. Dantal J, Bigot E, Bogers W, Testa A, Kriaa F, Jacques Y, et al. Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med. 1994; 330:7–14.

11. Gallon L, Leventhal J, Skaro A, Kanwar Y, Alvarado A. Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. N Engl J Med. 2012; 366:1648–9.

12. Kemper MJ, Wolf G, Muller-Wiefel DE. Transmission of glomerular permeability factor from a mother to her child. N Engl J Med. 2001; 344:386–7.

13. Kitsou K, Askiti V, Mitsioni A, Spoulou V. The immunopathogenesis of idiopathic nephrotic syndrome: a narrative review of the literature. Eur J Pediatr. 2022; 181:1395–404.

14. Campbell RE, Thurman JM. The immune system and idiopathic nephrotic syndrome. Clin J Am Soc Nephrol. 2022; 17:1823–34.

15. Kemper MJ, Zepf K, Klaassen I, Link A, Muller-Wiefel DE. Changes of lymphocyte populations in pediatric steroid-sensitive nephrotic syndrome are more pronounced in remission than in relapse. Am J Nephrol. 2005; 25:132–7.

16. Baris HE, Baris S, Karakoc-Aydiner E, Gokce I, Yildiz N, Cicekkoku D, et al. The effect of systemic corticosteroids on the innate and adaptive immune system in children with steroid responsive nephrotic syndrome. Eur J Pediatr. 2016; 175:685–93.

17. Bhatia D, Sinha A, Hari P, Sopory S, Saini S, Puraswani M, et al. Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome. Pediatr Res. 2018; 84:520–6.

18. Liu LL, Qin Y, Cai JF, Wang HY, Tao JL, Li H, et al. Th17/Treg imbalance in adult patients with minimal change nephrotic syndrome. Clin Immunol. 2011; 139:314–20.

19. Stachowski J, Barth C, Michalkiewicz J, Krynicki T, Jarmolinski T, Runowski D, et al. Th1/Th2 balance and CD45-positive T cell subsets in primary nephrotic syndrome. Pediatr Nephrol. 2000; 14:779–85.

20. Park E, Chang HJ, Shin JI, Lim BJ, Jeong HJ, Lee KB, et al. Familial IPEX syndrome: different glomerulopathy in two siblings. Pediatr Int. 2015; 57:e59–61.

21. Hashimura Y, Nozu K, Kanegane H, Miyawaki T, Hayakawa A, Yoshikawa N, et al. Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr Nephrol. 2009; 24:1181–6.

22. Chen J, Qiao XH, Mao JH. Immunopathogenesis of idiopathic nephrotic syndrome in children: two sides of the coin. World J Pediatr. 2021; 17:115–22.

23. Cheung PK, Stulp B, Immenschuh S, Borghuis T, Baller JF, Bakker WW. Is 100KF an isoform of hemopexin? Immunochemical characterization of the vasoactive plasma factor 100KF. J Am Soc Nephrol. 1999; 10:1700–8.

24. 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.

25. 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.

26. Wei C, Moller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, et al. Modification of kidney barrier function by the urokinase receptor. Nat Med. 2008; 14:55–63.

27. Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med. 2011; 17:952–60.

28. Peng Z, Mao J, Chen X, Cai F, Gu W, Fu H, et al. Serum suPAR levels help differentiate steroid resistance from steroid-sensitive nephrotic syndrome in children. Pediatr Nephrol. 2015; 30:301–7.

29. Meijers B, Maas RJ, Sprangers B, Claes K, Poesen R, Bammens B, et al. The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. Kidney Int. 2014; 85:636–40.

30. Sinha A, Bajpai J, Saini S, Bhatia D, Gupta A, Puraswani M, et al. Serum-soluble urokinase receptor levels do not distinguish focal segmental glomerulosclerosis from other causes of nephrotic syndrome in children. Kidney Int. 2014; 85:649–58.

31. Delville M, Sigdel TK, Wei C, Li J, Hsieh SC, Fornoni A, et al. A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med. 2014; 6:256ra136.

32. Konigshausen E, Sellin L. Circulating permeability factors in primary focal segmental glomerulosclerosis: a review of proposed candidates. Biomed Res Int. 2016; 2016:3765608.

33. McCarthy ET, Sharma M, Savin VJ. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010; 5:2115–21.

34. Savin VJ, Sharma M, Zhou J, Gennochi D, Fields T, Sharma R, et al. Renal and hematological effects of CLCF-1, a B-cell-stimulating cytokine of the IL-6 family. J Immunol Res. 2015; 2015:714964.

35. 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.

36. Cara-Fuentes G, Segarra A, Silva-Sanchez C, Wang H, Lanaspa MA, Johnson RJ, et al. Angiopoietin-like-4 and minimal change disease. PLoS One. 2017; 12:e0176198.

37. 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.

38. Chugh SS, Clement LC, Mace C. New insights into human minimal change disease: lessons from animal models. Am J Kidney Dis. 2012; 59:284–92.

39. 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.

40. Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. 2001; 1:220–8.

41. Goldwich A, Burkard M, Olke M, Daniel C, Amann K, Hugo C, et al. Podocytes are nonhematopoietic professional antigen-presenting cells. J Am Soc Nephrol. 2013; 24:906–16.

42. Reiser J, Mundel P. Danger signaling by glomerular podocytes defines a novel function of inducible B7-1 in the pathogenesis of nephrotic syndrome. J Am Soc Nephrol. 2004; 15:2246–8.

43. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008; 322:271–5.

44. Mosser DM, Zhang X. Interleukin-10: new perspectives on an old cytokine. Immunol Rev. 2008; 226:205–18.

45. Cara-Fuentes G, Wasserfall CH, Wang H, Johnson RJ, Garin EH. Minimal change disease: a dysregulation of the podocyte CD80-CTLA-4 axis? Pediatr Nephrol. 2014; 29:2333–40.

46. 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.

47. 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.

48. Ling C, Liu X, Shen Y, Chen Z, Fan J, Jiang Y, et al. Urinary CD80 levels as a diagnostic biomarker of minimal change disease. Pediatr Nephrol. 2015; 30:309–16.

49. 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.

50. Yu CC, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, et al. Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med. 2013; 369:2416–23.

51. Dado D, Parikh S, Ayoub I, Rovin B, Nadasdy T, Hebert L. Abatacept efficacy in steroid-resistant minimal-change disease revealed by the speed of proteinuria reduction after the start of abatacept. Clin Nephrol. 2018; 89:376–80.

52. Minamikawa S, Nozu K, Maeta S, Yamamura T, Nakanishi K, Fujimura J, et al. The utility of urinary CD80 as a diagnostic marker in patients with renal diseases. Sci Rep. 2018; 8:17322.

53. Gonzalez Guerrico AM, Lieske J, Klee G, Kumar S, Lopez-Baez V, Wright AM, et al. Urinary CD80 discriminates among glomerular disease types and reflects disease activity. Kidney Int Rep. 2020; 5:2021–31.

54. Benigni A, Gagliardini E, Remuzzi G. Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med. 2014; 370:1261–3.

55. Alachkar N, Carter-Monroe N, Reiser J. Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med. 2014; 370:1263–4.

56. Arase N, Arase H. Cellular misfolded proteins rescued from degradation by MHC class II molecules are possible targets for autoimmune diseases. J Biochem. 2015; 158:367–72.

57. Benz K, Dotsch J, Rascher W, Stachel D. Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr Nephrol. 2004; 19:794–7.

58. Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2014; 384:1273–81.

59. Gauckler P, Shin JI, Alberici F, Audard V, Bruchfeld A, Busch M, et al. Rituximab in adult minimal change disease and focal segmental glomerulosclerosis: what is known and what is still unknown? Autoimmun Rev. 2020; 19:102671.

60. Audard V, Larousserie F, Grimbert P, Abtahi M, Sotto JJ, Delmer A, et al. Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature. Kidney Int. 2006; 69:2251–60.

61. Kofman T, Zhang SY, Copie-Bergman C, Moktefi A, Raimbourg Q, Francois H, et al. Minimal change nephrotic syndrome associated with non-Hodgkin lymphoid disorders: a retrospective study of 18 cases. Medicine (Baltimore). 2014; 93:350–8.

62. Chan EY, Webb H, Yu E, Ghiggeri GM, Kemper MJ, Ma AL, et al. Both the rituximab dose and maintenance immunosuppression in steroid-dependent/frequently-relapsing nephrotic syndrome have important effects on outcomes. Kidney Int. 2020; 97:393–401.

63. Colucci M, Oniszczuk J, Vivarelli M, Audard V. B-cell dysregulation in idiopathic nephrotic syndrome: what we know and what we need to discover. Front Immunol. 2022; 13:823204.

64. Wang CS, Liverman RS, Garro R, George RP, Glumova A, Karp A, et al. Ofatumumab for the treatment of childhood nephrotic syndrome. Pediatr Nephrol. 2017; 32:835–41.

65. Dossier C, Prim B, Moreau C, Kwon T, Maisin A, Nathanson S, et al. A global antiB cell strategy combining obinutuzumab and daratumumab in severe pediatric nephrotic syndrome. Pediatr Nephrol. 2021; 36:1175–82.

66. Shen P, Fillatreau S. Antibody-independent functions of B cells: a focus on cytokines. Nat Rev Immunol. 2015; 15:441–51.

67. Abdel-Hafez M, Shimada M, Lee PY, Johnson RJ, Garin EH. Idiopathic nephrotic syndrome and atopy: is there a common link? Am J Kidney Dis. 2009; 54:945–53.

68. Cho BS, Yoon SR, Jang JY, Pyun KH, Lee CE. Up-regulation of interleukin-4 and CD23/FcepsilonRII in minimal change nephrotic syndrome. Pediatr Nephrol. 1999; 13:199–204.

69. Kemper MJ, Meyer-Jark T, Lilova M, Muller-Wiefel DE. Combined T- and B-cell activation in childhood steroid-sensitive nephrotic syndrome. Clin Nephrol. 2003; 60:242–7.

70. Oniszczuk J, Beldi-Ferchiou A, Audureau E, Azzaoui I, Molinier-Frenkel V, Frontera V, et al. Circulating plasmablasts and high level of BAFF are hallmarks of minimal change nephrotic syndrome in adults. Nephrol Dial Transplant. 2021; 36:609–17.

71. Kim AH, Chung JJ, Akilesh S, Koziell A, Jain S, Hodgin JB, et al. B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. JCI Insight. 2017; 2:e81836.

72. Gbadegesin RA, Adeyemo A, Webb NJ, Greenbaum LA, Abeyagunawardena A, Thalgahagoda S, et al. HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome. J Am Soc Nephrol. 2015; 26:1701–10.

73. Debiec H, Dossier C, Letouze E, Gillies CE, Vivarelli M, Putler RK, et al. Transethnic, genome-wide analysis reveals immune-related risk alleles and phenotypic correlates in pediatric steroid-sensitive nephrotic syndrome. J Am Soc Nephrol. 2018; 29:2000–13.

74. Jia X, Yamamura T, Gbadegesin R, McNulty MT, Song K, Nagano C, et al. Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome. Kidney Int. 2020; 98:1308–22.

75. Ling C, Wang X, Chen Z, Fan J, Meng Q, Zhou N, et al. Altered B-lymphocyte homeostasis in idiopathic nephrotic syndrome. Front Pediatr. 2019; 7:377.

76. Ling C, Chen Z, Fan J, Sun Q, Wang X, Hua L, et al. Decreased circulating transitional B-cell to memory B-cell ratio is a risk factor for relapse in children with steroid-sensitive nephrotic syndrome. Nephron. 2021; 145:107–12.

77. Colucci M, Carsetti R, Cascioli S, Casiraghi F, Perna A, Rava L, et al. B cell reconstitution after rituximab treatment in idiopathic nephrotic syndrome. J Am Soc Nephrol. 2016; 27:1811–22.

78. Dantal J, Godfrin Y, Koll R, Perretto S, Naulet J, Bouhours JF, et al. Antihuman immunoglobulin affinity immunoadsorption strongly decreases proteinuria in patients with relapsing nephrotic syndrome. J Am Soc Nephrol. 1998; 9:1709–15.

79. Musante L, Candiano G, Bruschi M, Santucci L, Carnemolla B, Orecchia P, et al. Circulating anti-actin and anti-ATP synthase antibodies identify a sub-set of patients with idiopathic nephrotic syndrome. Clin Exp Immunol. 2005; 141:491–9.

80. Alachkar N, Gupta G, Montgomery RA. Angiotensin antibodies and focal segmental glomerulosclerosis. N Engl J Med. 2013; 368:971–3.

81. Jamin A, Berthelot L, Couderc A, Chemouny JM, Boedec E, Dehoux L, et al. Autoantibodies against podocytic UCHL1 are associated with idiopathic nephrotic syndrome relapses and induce proteinuria in mice. J Autoimmun. 2018; 89:149–61.

82. Sun Y, Zhang H, Hu R, Sun J, Mao X, Zhao Z, et al. The expression and significance of neuronal iconic proteins in podocytes. PLoS One. 2014; 9:e93999.

83. Meyer-Schwesinger C, Meyer TN, Munster S, Klug P, Saleem M, Helmchen U, et al. A new role for the neuronal ubiquitin C-terminal hydrolase-L1 (UCH-L1) in podocyte process formation and podocyte injury in human glomerulopathies. J Pathol. 2009; 217:452–64.

84. Liu Y, Wu J, Wu H, Wang T, Gan H, Zhang X, et al. UCH-L1 expression of podocytes in diseased glomeruli and in vitro. J Pathol. 2009; 217:642–53.

85. Ye Q, Zhang Y, Zhuang J, Bi Y, Xu H, Shen Q, et al. The important roles and molecular mechanisms of annexin A2 autoantibody in children with nephrotic syndrome. Ann Transl Med. 2021; 9:1452.

86. Ye Q, Zhou C, Wang D, Fu H, Wang J, Mao J. Seven novel podocyte autoantibodies were identified to diagnosis a new disease subgroup-autoimmune podocytopathies. Clin Immunol. 2021; 232:108869.

87. Watts AJ, Keller KH, Lerner G, Rosales I, Collins AB, Sekulic M, et al. Discovery of autoantibodies targeting nephrin in minimal change disease supports a novel autoimmune etiology. J Am Soc Nephrol. 2022; 33:238–52.

88. Caster DJ, Korte EA, Merchant ML, Klein JB, Wilkey DW, Rovin BH, et al. Autoantibodies targeting glomerular annexin A2 identify patients with proliferative lupus nephritis. Proteomics Clin Appl. 2015; 9:1012–20.

89. Chen P, Yan H, Tian Y, Xun Y, Shi L, Bao R, et al. Annexin A2 as a target endothelial cell membrane autoantigen in Behçet's disease. Sci Rep. 2015; 5:8162.

90. Salle V, Maziere JC, Brule A, Schmidt J, Smail A, Duhaut P, et al. Antibodies against the N-terminal domain of annexin A2 in antiphospholipid syndrome. Eur J Intern Med. 2012; 23:665–8.

91. Hayes MJ, Shao D, Bailly M, Moss SE. Regulation of actin dynamics by annexin 2. EMBO J. 2006; 25:1816–26.

92. Ye Q, Chen A, Lai EY, Mao J. Autoimmune podocytopathies: a novel sub-group of diseases from childhood idiopathic nephrotic syndrome. J Am Soc Nephrol. 2022; 33:653–4.

93. 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; 1:575–82.

94. Orikasa M, Matsui K, Oite T, Shimizu F. Massive proteinuria induced in rats by a single intravenous injection of a monoclonal antibody. J Immunol. 1988; 141:807–14.

95. Takeuchi K, Naito S, Kawashima N, Ishigaki N, Sano T, Kamata K, et al. New anti-nephrin antibody mediated podocyte injury model using a C57BL/6 mouse strain. Nephron. 2018; 138:71–87.

96. Holmberg C, Jalanko H. Congenital nephrotic syndrome and recurrence of proteinuria after renal transplantation. Pediatr Nephrol. 2014; 29:2309–17.

97. Kuusniemi AM, Qvist E, Sun Y, Patrakka J, Ronnholm K, Karikoski R, et al. Plasma exchange and retransplantation in recurrent nephrosis of patients with congenital nephrotic syndrome of the Finnish type (NPHS1). Transplantation. 2007; 83:1316–23.

98. Gadegbeku CA, Gipson DS, Holzman LB, Ojo AO, Song PX, Barisoni L, et al. Design of the nephrotic syndrome study network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney Int. 2013; 83:749–56.

99. Hada I, Shimizu A, Takematsu H, Nishibori Y, Kimura T, Fukutomi T, et al. A novel mouse model of idiopathic nephrotic syndrome induced by immunization with the podocyte protein Crb2. J Am Soc Nephrol. 2022; 33:2008–25.

100. Moller-Kerutt A, Rodriguez-Gatica JE, Wacker K, Bhatia R, Siebrasse JP, Boon N, et al. Crumbs2 is an essential slit diaphragm protein of the renal filtration barrier. J Am Soc Nephrol. 2021; 32:1053–70.