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Mechanisms of immune injury of the glomerulus

Author
Pierre Ronco, MD, PhD
Section Editors
Richard J Glassock, MD, MACP
Fernando C Fervenza, MD, PhD
Deputy Editor
Albert Q Lam, MD

INTRODUCTION

A large body of clinical, immunopathologic, and experimental data support the hypothesis that most forms of human glomerulonephritis (GN) result from immunologic mechanisms [1-6]. The etiologic agents in human GN are largely unknown with the exception of infection-related forms of disease, such as beta-hemolytic streptococci in poststreptococcal GN and hepatitis C virus in cryoglobulinemic membranoproliferative GN. (See "Group A streptococcus: Virulence factors and pathogenic mechanisms" and "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)", section on 'Etiology' and "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)", section on 'Renal disease'.)

It is likely that most precipitating factors, such as infections and drug and toxin exposures, initiate similar immune responses that result in GN via shared common pathways. The nature of the immune responses which lead to GN and the individuals who develop them are strongly influenced by immunogenetic phenotypes [7].

Glomerular injury of immune origin is mediated by the actions of multiple elements of both the innate and adaptive immune systems, resulting in diverse clinical and pathologic manifestations [2,3,8]. In addition, elements of the complement cascade and the complement regulatory systems can be involved in both the production and mediation of many glomerular diseases. A schematic depiction of the relationship among immune events, effector cells, mediator release, and eventual glomerular injury is shown in the figure (figure 1).

This topic will review the immune events that occur after antigen exposure and that lead to immune complex formation in glomeruli, T cell-mediated glomerular injury, and the glomerular response to immune injury and the mediators that are involved.

COMPONENTS OF THE NEPHRITOGENIC IMMUNE RESPONSE

The nephritogenic immune response includes both humoral and cellular components. The humoral, T helper cell 2 (Th2)-regulated immune response leads to B cell activation, immunoglobulin deposition, and complement activation in glomeruli. The cellular, T helper cell 1(Th1)-regulated immune response contributes to both the infiltration of circulating mononuclear inflammatory cells (including lymphocytes and macrophages) into glomeruli and to crescent formation. (See "T helper subsets: Differentiation and role in disease" and "Mechanisms of glomerular crescent formation", section on 'T cells'.)

                             

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Literature review current through: Jul 2017. | This topic last updated: Apr 09, 2017.
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References
Top
  1. Mathieson PW. Glomerulonephritis. Semin Immunopathol 2007; 29:315.
  2. Nangaku M, Couser WG. Mechanisms of immune-deposit formation and the mediation of immune renal injury. Clin Exp Nephrol 2005; 9:183.
  3. Chadban SJ, Atkins RC. Glomerulonephritis. Lancet 2005; 365:1797.
  4. Tipping PG, Kitching AR. Glomerulonephritis, Th1 and Th2: what's new? Clin Exp Immunol 2005; 142:207.
  5. Puri TS, Quigg RJ. The many effects of complement C3- and C5-binding proteins in renal injury. Semin Nephrol 2007; 27:321.
  6. Kurts C, Heymann F, Lukacs-Kornek V, et al. Role of T cells and dendritic cells in glomerular immunopathology. Semin Immunopathol 2007; 29:317.
  7. Kashtan C. Autotopes and allotopes. J Am Soc Nephrol 2005; 16:3455.
  8. van den Berg JG, Weening JJ. Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome. Clin Sci (Lond) 2004; 107:125.
  9. Hudson BG. The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family. J Am Soc Nephrol 2004; 15:2514.
  10. Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med 2003; 348:2543.
  11. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361:11.
  12. Kalaaji M, Fenton KA, Mortensen ES, et al. Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis. Kidney Int 2007; 71:664.
  13. O'Flynn J, Flierman R, van der Pol P, et al. Nucleosomes and C1q bound to glomerular endothelial cells serve as targets for autoantibodies and determine complement activation. Mol Immunol 2011; 49:75.
  14. Moura IC, Centelles MN, Arcos-Fajardo M, et al. Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J Exp Med 2001; 194:417.
  15. Stehman-Breen C, Johnson RJ. Hepatitis C virus-associated glomerulonephritis. Adv Intern Med 1998; 43:79.
  16. Debiec H, Lefeu F, Kemper MJ, et al. Early-childhood membranous nephropathy due to cationic bovine serum albumin. N Engl J Med 2011; 364:2101.
  17. Kitching AR, Hutton HL. The Players: Cells Involved in Glomerular Disease. Clin J Am Soc Nephrol 2016; 11:1664.
  18. Appel D, Kershaw DB, Smeets B, et al. Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 2009; 20:333.
  19. Shankland SJ, Smeets B, Pippin JW, Moeller MJ. The emergence of the glomerular parietal epithelial cell. Nat Rev Nephrol 2014; 10:158.
  20. Berger K, Schulte K, Boor P, et al. The regenerative potential of parietal epithelial cells in adult mice. J Am Soc Nephrol 2014; 25:693.
  21. Lazzeri E, Romagnani P. Podocyte biology: Differentiation of parietal epithelial cells into podocytes. Nat Rev Nephrol 2015; 11:7.
  22. Vivarelli M, Emma F, Pellé T, et al. Genetic homogeneity but IgG subclass-dependent clinical variability of alloimmune membranous nephropathy with anti-neutral endopeptidase antibodies. Kidney Int 2015; 87:602.
  23. Kerjaschki D, Exner M, Ullrich R, et al. Pathogenic antibodies inhibit the binding of apolipoproteins to megalin/gp330 in passive Heymann nephritis. J Clin Invest 1997; 100:2303.
  24. Tomas NM, Hoxha E, Reinicke AT, et al. Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy. J Clin Invest 2016; 126:2519.
  25. Couser WG, Salant DJ. In situ immune complex formation and glomerular injury. Kidney Int 1980; 17:1.
  26. Holthöfer H. Molecular architecture of the glomerular slit diaphragm: lessons learnt for a better understanding of disease pathogenesis. Nephrol Dial Transplant 2007; 22:2124.
  27. Kuusniemi AM, Qvist E, Sun Y, et al. Plasma exchange and retransplantation in recurrent nephrosis of patients with congenital nephrotic syndrome of the Finnish type (NPHS1). Transplantation 2007; 83:1316.
  28. Wang SX, Ahola H, Palmen T, et al. Recurrence of nephrotic syndrome after transplantation in CNF is due to autoantibodies to nephrin. Exp Nephrol 2001; 9:327.
  29. Couser WG. Basic and translational concepts of immune-mediated glomerular diseases. J Am Soc Nephrol 2012; 23:381.
  30. Hénique C, Papista C, Guyonnet L, et al. Update on crescentic glomerulonephritis. Semin Immunopathol 2014; 36:479.
  31. Ruseva MM, Vernon KA, Lesher AM, et al. Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency. J Am Soc Nephrol 2013; 24:43.
  32. Gale DP, de Jorge EG, Cook HT, et al. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 2010; 376:794.
  33. Chauvet S, Roumenina LT, Bruneau S, et al. A Familial C3GN Secondary to Defective C3 Regulation by Complement Receptor 1 and Complement Factor H. J Am Soc Nephrol 2016; 27:1665.
  34. Tipping PG, Holdsworth SR. Cytokines in glomerulonephritis. Semin Nephrol 2007; 27:275.
  35. Segerer S, Nelson PJ, Schlöndorff D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J Am Soc Nephrol 2000; 11:152.
  36. Chung AC, Lan HY. Chemokines in renal injury. J Am Soc Nephrol 2011; 22:802.
  37. Thurman JM, Nester CM. All Things Complement. Clin J Am Soc Nephrol 2016; 11:1856.
  38. Schreiber A, Xiao H, Jennette JC, et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol 2009; 20:289.
  39. Xiao H, Dairaghi DJ, Powers JP, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol 2014; 25:225.
  40. Naik A, Sharma S, Quigg RJ. Complement regulation in renal disease models. Semin Nephrol 2013; 33:575.
  41. Sogabe H, Nangaku M, Ishibashi Y, et al. Increased susceptibility of decay-accelerating factor deficient mice to anti-glomerular basement membrane glomerulonephritis. J Immunol 2001; 167:2791.
  42. Ma R, Cui Z, Hu SY, et al. The alternative pathway of complement activation may be involved in the renal damage of human anti-glomerular basement membrane disease. PLoS One 2014; 9:e91250.
  43. Nisihara RM, Magrini F, Mocelin V, Messias-Reason IJ. Deposition of the lectin pathway of complement in renal biopsies of lupus nephritis patients. Hum Immunol 2013; 74:907.
  44. Brandt J, Pippin J, Schulze M, et al. Role of the complement membrane attack complex (C5b-9) in mediating experimental mesangioproliferative glomerulonephritis. Kidney Int 1996; 49:335.
  45. Pickering MC, D'Agati VD, Nester CM, et al. C3 glomerulopathy: consensus report. Kidney Int 2013; 84:1079.
  46. Sethi S, Fervenza FC, Zhang Y, et al. Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int 2013; 83:293.
  47. Yang N, Nikolic-Paterson DJ, Ng YY, et al. Reversal of established rat crescentic glomerulonephritis by blockade of macrophage migration inhibitory factor (MIF): potential role of MIF in regulating glucocorticoid production. Mol Med 1998; 4:413.
  48. Lan HY, Yang N, Nikolic-Paterson DJ, et al. Expression of macrophage migration inhibitory factor in human glomerulonephritis. Kidney Int 2000; 57:499.
  49. Tesch GH, Maifert S, Schwarting A, et al. Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice. J Exp Med 1999; 190:1813.
  50. Hasegawa H, Kohno M, Sasaki M, et al. Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice. Arthritis Rheum 2003; 48:2555.
  51. Kulkarni O, Pawar RD, Purschke W, et al. Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice. J Am Soc Nephrol 2007; 18:2350.
  52. Segerer S, Henger A, Schmid H, et al. Expression of the chemokine receptor CXCR1 in human glomerular diseases. Kidney Int 2006; 69:1765.
  53. De Vriese AS, Endlich K, Elger M, et al. The role of selectins in glomerular leukocyte recruitment in rat anti-glomerular basement membrane glomerulonephritis. J Am Soc Nephrol 1999; 10:2510.
  54. Kitching AR, Ru Huang X, Turner AL, et al. The requirement for granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in leukocyte-mediated immune glomerular injury. J Am Soc Nephrol 2002; 13:350.
  55. Rops AL, van der Vlag J, Lensen JF, et al. Heparan sulfate proteoglycans in glomerular inflammation. Kidney Int 2004; 65:768.
  56. Segerer S, Schlöndorff D. Role of chemokines for the localization of leukocyte subsets in the kidney. Semin Nephrol 2007; 27:260.
  57. Devi S, Li A, Westhorpe CL, et al. Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus. Nat Med 2013; 19:107.
  58. Summers SA, Steinmetz OM, Ooi JD, et al. Toll-like receptor 9 enhances nephritogenic immunity and glomerular leukocyte recruitment, exacerbating experimental crescentic glomerulonephritis. Am J Pathol 2010; 177:2234.
  59. Summers SA, van der Veen BS, O'Sullivan KM, et al. Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis. Kidney Int 2010; 78:1263.
  60. Ito I, Yuzawa Y, Mizuno M, et al. Effects of a new synthetic selectin blocker in an acute rat thrombotic glomerulonephritis. Am J Kidney Dis 2001; 38:265.
  61. Johnson RJ, Couser WG, Chi EY, et al. New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system. J Clin Invest 1987; 79:1379.
  62. Kessenbrock K, Krumbholz M, Schönermarck U, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 2009; 15:623.
  63. Xiao H, Heeringa P, Liu Z, et al. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. Am J Pathol 2005; 167:39.
  64. Huugen D, van Esch A, Xiao H, et al. Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice. Kidney Int 2007; 71:646.
  65. Xiao H, Hu P, Falk RJ, Jennette JC. Overview of the Pathogenesis of ANCA-Associated Vasculitis. Kidney Dis (Basel) 2016; 1:205.
  66. Rastaldi MP, Ferrario F, Crippa A, et al. Glomerular monocyte-macrophage features in ANCA-positive renal vasculitis and cryoglobulinemic nephritis. J Am Soc Nephrol 2000; 11:2036.
  67. Timoshanko JR, Kitching AR, Semple TJ, et al. Granulocyte macrophage colony-stimulating factor expression by both renal parenchymal and immune cells mediates murine crescentic glomerulonephritis. J Am Soc Nephrol 2005; 16:2646.
  68. Shimizu H, Maruyama S, Yuzawa Y, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. J Am Soc Nephrol 2003; 14:1496.
  69. Kluger MA, Zahner G, Paust HJ, et al. Leukocyte-derived MMP9 is crucial for the recruitment of proinflammatory macrophages in experimental glomerulonephritis. Kidney Int 2013; 83:865.
  70. Lan HY, Bacher M, Yang N, et al. The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med 1997; 185:1455.
  71. Okada H, Moriwaki K, Konishi K, et al. Tubular osteopontin expression in human glomerulonephritis and renal vasculitis. Am J Kidney Dis 2000; 36:498.
  72. Huang J, Filipe A, Rahuel C, et al. Lutheran/basal cell adhesion molecule accelerates progression of crescentic glomerulonephritis in mice. Kidney Int 2014; 85:1123.
  73. Rogers NM, Ferenbach DA, Isenberg JS, et al. Dendritic cells and macrophages in the kidney: a spectrum of good and evil. Nat Rev Nephrol 2014; 10:625.
  74. Zhao L, David MZ, Hyjek E, et al. M2 macrophage infiltrates in the early stages of ANCA-associated pauci-immune necrotizing GN. Clin J Am Soc Nephrol 2015; 10:54.
  75. Han Y, Ma FY, Tesch GH, et al. Role of macrophages in the fibrotic phase of rat crescentic glomerulonephritis. Am J Physiol Renal Physiol 2013; 304:F1043.
  76. Koyama A, Fujisaki M, Kobayashi M, et al. A glomerular permeability factor produced by human T cell hybridomas. Kidney Int 1991; 40:453.
  77. Ooi JD, Kitching AR, Holdsworth SR. Review: T helper 17 cells: their role in glomerulonephritis. Nephrology (Carlton) 2010; 15:513.
  78. Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201:233.
  79. Paust HJ, Turner JE, Steinmetz OM, et al. The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis. J Am Soc Nephrol 2009; 20:969.
  80. Summers SA, Steinmetz OM, Li M, et al. Th1 and Th17 cells induce proliferative glomerulonephritis. J Am Soc Nephrol 2009; 20:2518.
  81. Gan PY, Steinmetz OM, Tan DS, et al. Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis. J Am Soc Nephrol 2010; 21:925.
  82. Krebs CF, Kapffer S, Paust HJ, et al. MicroRNA-155 drives TH17 immune response and tissue injury in experimental crescentic GN. J Am Soc Nephrol 2013; 24:1955.
  83. Ooi JD, Chang J, Hickey MJ, et al. The immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis. Proc Natl Acad Sci U S A 2012; 109:E2615.
  84. Perico N, Remuzzi G. Role of platelet-activating factor in renal immune injury and proteinuria. Am J Nephrol 1990; 10 Suppl 1:98.
  85. Camussi G, Tetta C, Coda R, et al. Platelet-activating factor-induced loss of glomerular anionic charges. Kidney Int 1984; 25:73.
  86. Barnes JL, Levine SP, Venkatachalam MA. Binding of platelet factor four (PF 4) to glomerular polyanion. Kidney Int 1984; 25:759.
  87. Mezzano S, Burgos ME, Ardiles L, et al. Glomerular localization of platelet factor 4 in streptococcal nephritis. Nephron 1992; 61:58.
  88. Johnson RJ, Raines EW, Floege J, et al. Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med 1992; 175:1413.
  89. Devi S, Kuligowski MP, Kwan RY, et al. Platelet recruitment to the inflamed glomerulus occurs via an alphaIIbbeta3/GPVI-dependent pathway. Am J Pathol 2010; 177:1131.
  90. Zachem CR, Alpers CE, Way W, et al. A role for P-selectin in neutrophil and platelet infiltration in immune complex glomerulonephritis. J Am Soc Nephrol 1997; 8:1838.
  91. Schlöndorff D. Putting the glomerulus back together: per aspera ad astra ("a rough road leads to the stars"). Kidney Int 2014; 85:991.
  92. Rabelink TJ, de Boer HC, van Zonneveld AJ. Endothelial activation and circulating markers of endothelial activation in kidney disease. Nat Rev Nephrol 2010; 6:404.
  93. Kang DH, Kanellis J, Hugo C, et al. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 2002; 13:806.
  94. Segal MS, Baylis C, Johnson RJ. Endothelial health and diversity in the kidney. J Am Soc Nephrol 2006; 17:323.
  95. Abboud HE. Mesangial cell biology. Exp Cell Res 2012; 318:979.
  96. Sacks S, Zhou W. New boundaries for complement in renal disease. J Am Soc Nephrol 2008; 19:1865.
  97. Ostendorf T, Kunter U, van Roeyen C, et al. The effects of platelet-derived growth factor antagonism in experimental glomerulonephritis are independent of the transforming growth factor-beta system. J Am Soc Nephrol 2002; 13:658.
  98. Eng E, Holgren C, Hubchak S, et al. Hypoxia regulates PDGF-B interactions between glomerular capillary endothelial and mesangial cells. Kidney Int 2005; 68:695.
  99. Griffin SV, Pichler R, Wada T, et al. The role of cell cycle proteins in Glomerular disease. Semin Nephrol 2003; 23:569.
  100. Ostendorf T, Rong S, Boor P, et al. Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 2006; 17:1054.
  101. Tan Y, Wang B, Keum JS, Jaffa AA. Mechanisms through which bradykinin promotes glomerular injury in diabetes. Am J Physiol Renal Physiol 2005; 288:F483.
  102. Sanz AB, Moreno JA, Sanchez-Nino MD, et al. TWEAKing renal injury. Front Biosci 2008; 13:580.
  103. Floege J, Eitner F, Alpers CE. A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol 2008; 19:12.
  104. Daha MR, van Kooten C. Deposition of IgA in primary IgA nephropathy: it takes at least four to tango. Nephrol Dial Transplant 2013; 28:794.
  105. Moura IC, Arcos-Fajardo M, Gdoura A, et al. Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy. J Am Soc Nephrol 2005; 16:2667.
  106. Berthelot L, Papista C, Maciel TT, et al. Transglutaminase is essential for IgA nephropathy development acting through IgA receptors. J Exp Med 2012; 209:793.
  107. Suzuki H, Suzuki Y, Narita I, et al. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol 2008; 19:2384.
  108. Tanaka H, Imaizumi T. Inflammatory chemokine expression via Toll-like receptor 3 signaling in normal human mesangial cells. Clin Dev Immunol 2013; 2013:984708.
  109. Couser WG, Johnson RJ. Mechanisms of progressive renal disease in glomerulonephritis. Am J Kidney Dis 1994; 23:193.
  110. Harding P, Balasubramanian L, Swegan J, et al. Transforming growth factor beta regulates cyclooxygenase-2 in glomerular mesangial cells. Kidney Int 2006; 69:1578.
  111. Schlöndorff D, Banas B. The mesangial cell revisited: no cell is an island. J Am Soc Nephrol 2009; 20:1179.
  112. Shankland SJ, Anders HJ, Romagnani P. Glomerular parietal epithelial cells in kidney physiology, pathology, and repair. Curr Opin Nephrol Hypertens 2013; 22:302.
  113. Smeets B, Angelotti ML, Rizzo P, et al. Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J Am Soc Nephrol 2009; 20:2593.
  114. Drew AF, Tucker HL, Liu H, et al. Crescentic glomerulonephritis is diminished in fibrinogen-deficient mice. Am J Physiol Renal Physiol 2001; 281:F1157.
  115. Ryu M, Migliorini A, Miosge N, et al. Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury. J Pathol 2012; 228:482.
  116. Henique C, Bollee G, Lenoir O, et al. Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor γ Essential for Resistance to Crescentic GN. J Am Soc Nephrol 2016; 27:172.
  117. Kietzmann L, Guhr SS, Meyer TN, et al. MicroRNA-193a Regulates the Transdifferentiation of Human Parietal Epithelial Cells toward a Podocyte Phenotype. J Am Soc Nephrol 2015; 26:1389.
  118. 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.
  119. Maas RJ, Deegens JK, Wetzels JF. Permeability factors in idiopathic nephrotic syndrome: historical perspectives and lessons for the future. Nephrol Dial Transplant 2014; 29:2207.
  120. Davin JC. The glomerular permeability factors in idiopathic nephrotic syndrome. Pediatr Nephrol 2016; 31:207.
  121. Hoyer JR, Vernier RL, Najarian JS, et al. Recurrence of idiopathic nephrotic syndrome after renal transplantation. Lancet 1972; 2:343.
  122. Ali AA, Wilson E, Moorhead JF, et al. Minimal-change glomerular nephritis. Normal kidneys in an abnormal environment? Transplantation 1994; 58:849.
  123. Cattran D, Neogi T, Sharma R, et al. Serial estimates of serum permeability activity and clinical correlates in patients with native kidney focal segmental glomerulosclerosis. J Am Soc Nephrol 2003; 14:448.
  124. Ghiggeri GM, Artero M, Carraro M, Perfumo F. Permeability plasma factors in nephrotic syndrome: more than one factor, more than one inhibitor. Nephrol Dial Transplant 2001; 16:882.
  125. Kemper MJ, Wolf G, Müller-Wiefel DE. Transmission of glomerular permeability factor from a mother to her child. N Engl J Med 2001; 344:386.
  126. Kemper MJ, Wei C, Reiser J. Transmission of glomerular permeability factor soluble urokinase plasminogen activator receptor (suPAR) from a mother to child. Am J Kidney Dis 2013; 61:352.
  127. Sellier-Leclerc AL, Duval A, Riveron S, et al. A humanized mouse model of idiopathic nephrotic syndrome suggests a pathogenic role for immature cells. J Am Soc Nephrol 2007; 18:2732.
  128. Yap HK, Cheung W, Murugasu B, et al. Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. J Am Soc Nephrol 1999; 10:529.
  129. Lai KW, Wei CL, Tan LK, et al. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol 2007; 18:1476.
  130. Clement LC, Avila-Casado C, Macé C, et al. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med 2011; 17:117.
  131. Chugh SS, Clement LC, Macé C. New insights into human minimal change disease: lessons from animal models. Am J Kidney Dis 2012; 59:284.
  132. Dantal J, Bigot E, Bogers W, 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.
  133. 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.
  134. Glassock RJ. Circulating permeability factors in the nephrotic syndrome: a fresh look at an old problem. J Am Soc Nephrol 2003; 14:541.
  135. Liu G, Kaw B, Kurfis J, et al. Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability. J Clin Invest 2003; 112:209.
  136. Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int 2005; 67:404.
  137. Wei C, El Hindi S, Li J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 2011; 17:952.
  138. Maas RJ, Deegens JK, Wetzels JF. Serum suPAR in patients with FSGS: trash or treasure? Pediatr Nephrol 2013; 28:1041.
  139. Wei C, Trachtman H, Li J, et al. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 2012; 23:2051.
  140. 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.
  141. Cathelin D, Placier S, Ploug M, et al. Administration of recombinant soluble urokinase receptor per se is not sufficient to induce podocyte alterations and proteinuria in mice. J Am Soc Nephrol 2014; 25:1662.
  142. Deegens JK, Wetzels JF. Glomerular disease: The search goes on: suPAR is not the elusive FSGS factor. Nat Rev Nephrol 2014; 10:431.
  143. Schlöndorff D. Are serum suPAR determinations by current ELISA methodology reliable diagnostic biomarkers for FSGS? Kidney Int 2014; 85:499.
  144. Wada T, Nangaku M. A circulating permeability factor in focal segmental glomerulosclerosis: the hunt continues. Clin Kidney J 2015; 8:708.
  145. Cara-Fuentes G, Clapp WL, Johnson RJ, Garin EH. Pathogenesis of proteinuria in idiopathic minimal change disease: molecular mechanisms. Pediatr Nephrol 2016; 31:2179.
  146. Nangaku M, Shankland SJ, Couser WG. Cellular response to injury in membranous nephropathy. J Am Soc Nephrol 2005; 16:1195.
  147. Cunningham PN, Quigg RJ. Contrasting roles of complement activation and its regulation in membranous nephropathy. J Am Soc Nephrol 2005; 16:1214.
  148. Ma H, Sandor DG, Beck LH Jr. The role of complement in membranous nephropathy. Semin Nephrol 2013; 33:531.
  149. Couser WG. Membranous nephropathy: a long road but well traveled. J Am Soc Nephrol 2005; 16:1184.
  150. Ronco P, Debiec H. Molecular pathomechanisms of membranous nephropathy: from Heymann nephritis to alloimmunization. J Am Soc Nephrol 2005; 16:1205.
  151. Farquhar MG, Saito A, Kerjaschki D, Orlando RA. The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J Am Soc Nephrol 1995; 6:35.
  152. Kerjaschki D, Ullrich R, Exner M, et al. Induction of passive Heymann nephritis with antibodies specific for a synthetic peptide derived from the receptor-associated protein. J Exp Med 1996; 183:2007.
  153. Ronco P, Debiec H. Pathogenesis of membranous nephropathy: recent advances and future challenges. Nat Rev Nephrol 2012; 8:203.
  154. Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient's care. Lancet 2015; 385:1983.
  155. Bally S, Debiec H, Ponard D, et al. Phospholipase A2 Receptor-Related Membranous Nephropathy and Mannan-Binding Lectin Deficiency. J Am Soc Nephrol 2016; 27:3539.
  156. Kerjaschki D, Schulze M, Binder S, et al. Transcellular transport and membrane insertion of the C5b-9 membrane attack complex of complement by glomerular epithelial cells in experimental membranous nephropathy. J Immunol 1989; 143:546.
  157. Schulze M, Donadio JV Jr, Pruchno CJ, et al. Elevated urinary excretion of the C5b-9 complex in membranous nephropathy. Kidney Int 1991; 40:533.
  158. Saran AM, Yuan H, Takeuchi E, et al. Complement mediates nephrin redistribution and actin dissociation in experimental membranous nephropathy. Kidney Int 2003; 64:2072.
  159. Mundel P, Shankland SJ. Podocyte biology and response to injury. J Am Soc Nephrol 2002; 13:3005.
  160. Cybulsky AV, Takano T, Papillon J, et al. Complement C5b-9 membrane attack complex increases expression of endoplasmic reticulum stress proteins in glomerular epithelial cells. J Biol Chem 2002; 277:41342.
  161. Wang L, Hong Q, Lv Y, et al. Autophagy can repair endoplasmic reticulum stress damage of the passive Heymann nephritis model as revealed by proteomics analysis. J Proteomics 2012; 75:3866.
  162. Cybulsky AV. The intersecting roles of endoplasmic reticulum stress, ubiquitin- proteasome system, and autophagy in the pathogenesis of proteinuric kidney disease. Kidney Int 2013; 84:25.
  163. Lv Q, Yang F, Chen K, Zhang Y. Autophagy protects podocytes from sublytic complement induced injury. Exp Cell Res 2016; 341:132.
  164. Kitzler TM, Papillon J, Guillemette J, et al. Complement modulates the function of the ubiquitin-proteasome system and endoplasmic reticulum-associated degradation in glomerular epithelial cells. Biochim Biophys Acta 2012; 1823:1007.
  165. Spicer ST, Tran GT, Killingsworth MC, et al. Induction of passive Heymann nephritis in complement component 6-deficient PVG rats. J Immunol 2007; 179:172.
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