Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The immune system and kidney disease: basic concepts and clinical implications

Nature Reviews Immunology volume 13, pages 738–753 (2013)Cite this article

Subjects

Key Points

  • Chronic kidney diseases are common in ageing populations and, if they progress to the end stage, are an economic burden because of the need for dialysis or transplantation. Immune mechanisms are centrally involved in the progression of kidney disease and their elucidation is an important research goal.

  • Recent studies have defined the immune mechanisms responsible for some previously unexplained kidney diseases. These may also be relevant to diseases affecting other organs.

  • Greater knowledge of immune homeostasis in the kidneys has identified features that render this organ susceptible to distinct types of immune-mediated damage; for example, kidney-specific damage-associated molecular patterns (DAMPs) and a predisposition to crystal formation.

  • The availability of well-characterized animal models and of biopsy samples from patients with renal disease makes the kidney an attractive model organ to analyse novel pathways of host defence, autoimmune injury, sterile inflammation and fibrosis.

  • The kidney has a central role in electrolyte homeostasis and the removal of toxins and so, when its function is compromised, normal immune effector cell function and intestinal microbial homeostasis are disturbed.

  • Kidney failure increases susceptibility to infection and promotes exaggerated inflammatory responses, both of which increase mortality. The underlying mechanisms responsible remain to be clarified.

Abstract

The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in rodent models and humans have uncovered several underlying mechanisms that can be used to explain the previously enigmatic immunopathology of many kidney diseases. These mechanisms include kidney-specific damage-associated molecular patterns that cause sterile inflammation, the crosstalk between renal dendritic cells and T cells, the development of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens. Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease. In this Review, we summarize the recent findings regarding the interactions between the kidneys and the immune system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Innate immune mechanisms in kidney inflammation.
Figure 2: Cellular immune response in experimental crescentic glomerulonephritis.
Figure 3: Local immune pathways in glomerulonephritis.
Figure 4: Consequences of chronic kidney disease with potential effects on systemic immunity.

Similar content being viewed by others

References

  1. Kaissling, B. & Le Hir, M. Characterization and distribution of interstitial cell types in the renal cortex of rats. Kidney Int. 45, 709–720 (1994).

    CAS  PubMed  Google Scholar 

  2. Kruger, T. et al. Identification and functional characterization of dendritic cells in the healthy murine kidney and in experimental glomerulonephritis. J. Am. Soc. Nephrol. 15, 613–621 (2004).

    PubMed  Google Scholar 

  3. Soos, T. J. et al. CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney Int. 70, 591–596 (2006).

    CAS  PubMed  Google Scholar 

  4. Woltman, A. M. et al. Quantification of dendritic cell subsets in human renal tissue under normal and pathological conditions. Kidney Int. 71, 1001–1008 (2007).

    CAS  PubMed  Google Scholar 

  5. Guilliams, M. et al. From skin dendritic cells to a simplified classification of human and mouse dendritic cell subsets. Eur. J. Immunol. 40, 2089–2094 (2010).

    CAS  PubMed  Google Scholar 

  6. Miller, J. C. et al. Deciphering the transcriptional network of the dendritic cell lineage. Nature Immunol. 13, 888–899 (2012).

    CAS  Google Scholar 

  7. Schraml, B. U. et al. Genetic tracing via expression history of DNGR-1 defines dendritic cells as a hematopoietic lineage. Cell 154, 843–858 (2013).

    CAS  PubMed  Google Scholar 

  8. Tittel, A. P. et al. Functionally relevant neutrophilia in CD11c diphtheria toxin receptor transgenic mice. Nature Methods 9, 385–390 (2012).

    CAS  PubMed  Google Scholar 

  9. Hochheiser, K. et al. Exclusive CX3CR1-dependence of kidney dendritic cells impacts glomerulonephritis progression. J. Clin. Invest. http://dx.doi.org/10.1172/JCI70143 (2013).

  10. Kim, K. W. et al. In vivo structure/function and expression analysis of the CX3C chemokine fractalkine. Blood 118, e156–e167 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Dong, X. et al. Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury. Kidney Int. 71, 619–628 (2007).

    CAS  PubMed  Google Scholar 

  12. Pindjakova, J. et al. Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction. Kidney Int. 81, 379–390 (2012).

    CAS  PubMed  Google Scholar 

  13. Merad, M., Ginhoux, F. & Collin, M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nature Rev. Immunol. 8, 935–947 (2008).

    CAS  Google Scholar 

  14. Nelson, P. J. et al. The renal mononuclear phagocytic system. J. Am. Soc. Nephrol. 23, 194–203 (2012). This paper summarizes the phenotypical range of mononuclear phagocytes in healthy and diseased kidneys.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Timoshanko, J. R., Kitching, R., Semple, T. J., Tipping, P. G. & Holdsworth, S. R. A pathogenetic role for mast cells in experimental crescentic glomerulonephritis. J. Am. Soc. Nephrol. 17, 150–159 (2006).

    CAS  PubMed  Google Scholar 

  16. Scandiuzzi, L. et al. Mouse mast cell protease-4 deteriorates renal function by contributing to inflammation and fibrosis in immune complex-mediated glomerulonephritis. J. Immunol. 185, 624–633 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gan, P. Y. et al. Mast cells contribute to peripheral tolerance and attenuate autoimmune vasculitis. J. Am. Soc. Nephrol. 23, 1955–1966 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Dong, X. et al. Antigen presentation by dendritic cells in renal lymph nodes is linked to systemic and local injury to the kidney. Kidney Int. 68, 1096–1108 (2005).

    CAS  PubMed  Google Scholar 

  19. Heymann, F. et al. Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury. J. Clin. Invest. 119, 1286–1297 (2009). This study shows that T cells can induce glomerular damage and that DC maturation drives glomerulonephritis progression.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Lukacs-Kornek, V. et al. The kidney-renal lymph node-system contributes to cross-tolerance against innocuous circulating antigen. J. Immunol. 180, 706–715 (2008).

    CAS  PubMed  Google Scholar 

  21. Gottschalk, C. et al. Batf3-dependent dendritic cells in the renal lymph node induce tolerance against circulating antigens. J. Am. Soc. Nephrol. 24, 543–549 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Bohle, A., Kressel, G., Muller, C. A. & Muller, G. A. The pathogenesis of chronic renal failure. Pathol. Res. Pract. 185, 421–440 (1989).

    CAS  PubMed  Google Scholar 

  23. Markovic-Lipkovski, J., Muller, C. A., Risler, T., Bohle, A. & Muller, G. A. Association of glomerular and interstitial mononuclear leukocytes with different forms of glomerulonephritis. Nephrol. Dial. Transplant. 5, 10–17 (1990).

    CAS  PubMed  Google Scholar 

  24. Risdon, R. A., Sloper, J. C. & De Wardener, H. E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet 2, 363–366 (1968).

    CAS  PubMed  Google Scholar 

  25. Kriz, W. & LeHir, M. Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int. 67, 404–419 (2005).

    PubMed  Google Scholar 

  26. Bohle, A., Mackensen-Haen, S. & Wehrmann, M. Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press. Res. 19, 191–195 (1996).

    CAS  PubMed  Google Scholar 

  27. Floege, J. & Grone, H. J. Progression of renal failure: what is the role of cytokines? Nephrol. Dial. Transplant. 10, 1575–1586 (1995).

    CAS  PubMed  Google Scholar 

  28. Abbate, M., Zoja, C. & Remuzzi, G. How does proteinuria cause progressive renal damage? J. Am. Soc. Nephrol. 17, 2974–2984 (2006).

    CAS  PubMed  Google Scholar 

  29. Niedermeier, M. et al. CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc. Natl Acad. Sci. USA 106, 17892–17897 (2009).

    CAS  PubMed  Google Scholar 

  30. Rock, K. L., Latz, E., Ontiveros, F. & Kono, H. The sterile inflammatory response. Annu. Rev. Immunol. 28, 321–342 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Yamanishi, Y. et al. TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury. J. Exp. Med. 207, 1501–1511 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Anders, H. J. Toll-like receptors and danger signaling in kidney injury. J. Am. Soc. Nephrol. 21, 1270–1274 (2010).

    CAS  PubMed  Google Scholar 

  33. Rosin, D. L. & Okusa, M. D. Dangers within: DAMP responses to damage and cell death in kidney disease. J. Am. Soc. Nephrol. 22, 416–425 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mulay, S. R. et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion. J. Clin. Invest. 123, 236–246 (2013). This paper identifies the role of the NLRP3 inflammasome in crystal nephropathy.

    CAS  PubMed  Google Scholar 

  35. Leemans, J. C. et al. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J. Clin. Invest. 115, 2894–2903 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wu, H. et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J. Clin. Invest. 117, 2847–2859 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Allam, R. et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J. Am. Soc. Nephrol. 23, 1375–1388 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362–366 (2010).

    CAS  PubMed  Google Scholar 

  39. Li, L. et al. Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury. J. Clin. Invest. 122, 3931–3942 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bonventre, J. V. & Yang, L. Cellular pathophysiology of ischemic acute kidney injury. J. Clin. Invest. 121, 4210–4221 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang, B., Ramesh, G., Uematsu, S., Akira, S. & Reeves, W. B. TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. J. Am. Soc. Nephrol. 19, 923–932 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Babelova, A. et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J. Biol. Chem. 284, 24035–24048 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Shigeoka, A. A. et al. An inflammasome-independent role for epithelial-expressed Nlrp3 in renal ischemia-reperfusion injury. J. Immunol. 185, 6277–6285 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Vilaysane, A. et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J. Am. Soc. Nephrol. 21, 1732–1744 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, W. et al. Inflammasome-independent NLRP3 augments TGF-β signaling in kidney epithelium. J. Immunol. 190, 1239–1249 (2013). This paper shows that NLRP3 and the adaptor protein ASC are needed for TGFβR1 signalling, which might contribute to kidney fibrosis.

    CAS  Google Scholar 

  46. Eddy, A. A. Scraping fibrosis: UMODulating renal fibrosis. Nature Med. 17, 553–555 (2011).

    CAS  PubMed  Google Scholar 

  47. Saemann, M. D. et al. Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J. Clin. Invest. 115, 468–475 (2005).

    PubMed  PubMed Central  Google Scholar 

  48. Darisipudi, M. N. et al. Uromodulin triggers IL-1β-dependent innate immunity via the NLRP3 Inflammasome. J. Am. Soc. Nephrol. 23, 1783–1789 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sethi, S. & Fervenza, F. C. Membranoproliferative glomerulonephritis — a new look at an old entity. N. Engl. J. Med. 366, 1119–1131 (2012).

    CAS  PubMed  Google Scholar 

  50. Fakhouri, F., Fremeaux-Bacchi, V., Noel, L. H., Cook, H. T. & Pickering, M. C. C3 glomerulopathy: a new classification. Nature Rev. Nephrol. 6, 494–499 (2010).

    CAS  Google Scholar 

  51. Chen, Q. et al. Combined C3b and factor B autoantibodies and MPGN type II. N. Engl. J. Med. 365, 2340–2342 (2011).

    CAS  PubMed  Google Scholar 

  52. Martinez-Barricarte, R. et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J. Clin. Invest. 120, 3702–3712 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gale, D. P. et al. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376, 794–801 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Bomback, A. S. & Appel, G. B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nature Rev. Nephrol. 8, 634–642 (2012).

    CAS  Google Scholar 

  55. Vivarelli, M., Pasini, A. & Emma, F. Eculizumab for the treatment of dense-deposit disease. N. Engl. J. Med. 366, 1163–1165 (2012).

    CAS  PubMed  Google Scholar 

  56. Daina, E., Noris, M. & Remuzzi, G. Eculizumab in a patient with dense-deposit disease. N. Engl. J. Med. 366, 1161–1163 (2012).

    CAS  PubMed  Google Scholar 

  57. Trachtman, H., Austin, C., Lewinski, M. & Stahl, R. A. Renal and neurological involvement in typical Shiga toxin-associated HUS. Nature Rev. Nephrol. 8, 658–669 (2012).

    CAS  Google Scholar 

  58. Morigi, M. et al. Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J. Immunol. 187, 172–180 (2011).

    CAS  PubMed  Google Scholar 

  59. Thurman, J. M. et al. Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 4, 1920–1924 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Lapeyraque, A. L. et al. Eculizumab in severe Shiga-toxin-associated HUS. N. Engl. J. Med. 364, 2561–2563 (2011).

    CAS  PubMed  Google Scholar 

  61. Noris, M., Mescia, F. & Remuzzi, G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nature Rev. Nephrol. 8, 622–633 (2012).

    CAS  Google Scholar 

  62. Legendre, C. M. et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 368, 2169–2181 (2013). This is a groundbreaking study showing that terminal complement inhibition (using eculizumab) abolishes complement-mediated thrombotic microangiopathy and results in a time-dependent improvement in renal function in patients with aHUS.

    CAS  PubMed  Google Scholar 

  63. Furlan, M. et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N. Engl. J. Med. 339, 1578–1584 (1998).

    CAS  PubMed  Google Scholar 

  64. Schreiber, A. et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J. Am. Soc. Nephrol. 20, 289–298 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Dixon, F. J. What are sensitized cells doing in glomerulonephritis? N. Engl. J. Med. 283, 536–537 (1970).

    CAS  PubMed  Google Scholar 

  66. Couser, W. G. Sensitized cells come of age: a new era in renal immunology with important therapeutic implications. J. Am. Soc. Nephrol. 10, 664–665 (1999).

    CAS  PubMed  Google Scholar 

  67. Bolton, W. K. What sensitized cells just might be doing in glomerulonephritis. J. Clin. Invest. 109, 713–714 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Sung, S. S. & Bolton, W. K. T cells and dendritic cells in glomerular disease: the new glomerulotubular feedback loop. Kidney Int. 77, 393–399 (2010).

    PubMed  Google Scholar 

  69. Tipping, P. G. & Holdsworth, S. R. T cells in crescentic glomerulonephritis. J. Am. Soc. Nephrol. 17, 1253–1263 (2006).

    PubMed  Google Scholar 

  70. Turner, J. E. et al. IL-17A production by renal γδ T cells promotes kidney injury in crescentic GN. J. Am. Soc. Nephrol. 23, 1486–1495 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Summers, S. A. et al. Th1 and Th17 cells induce proliferative glomerulonephritis. J. Am. Soc. Nephrol. 20, 2518–2524 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Paust, H. J. et al. The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis. J. Am. Soc. Nephrol. 20, 969–979 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Turner, J. E. et al. CCR6 recruits regulatory T cells and Th17 cells to the kidney in glomerulonephritis. J. Am. Soc. Nephrol. 21, 974–985 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Steinmetz, O. M. et al. The Th17-defining transcription factor RORγt promotes glomerulonephritis. J. Am. Soc. Nephrol. 22, 472–483 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Riedel, J. H. et al. Immature renal dendritic cells recruit regulatory CXCR6+ invariant natural killer T cells to attenuate crescentic GN. J. Am. Soc. Nephrol. 23, 1987–2000 (2012). This paper is one of the first descriptions of regulatory iNKT cells having an anti-inflammatory effect. It shows that immature renal DCs attract these cells via the CXCL16–CXCR6 axis to attenuate crescentic glomerulonephritis.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Panzer, U. et al. Chemokine receptor CXCR3 mediates T cell recruitment and tissue injury in nephrotoxic nephritis in mice. J. Am. Soc. Nephrol. 18, 2071–2084 (2007).

    CAS  PubMed  Google Scholar 

  77. Menke, J. et al. CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease. J. Am. Soc. Nephrol. 19, 1177–1189 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Chavele, K. M. et al. Mannose receptor interacts with Fc receptors and is critical for the development of crescentic glomerulonephritis in mice. J. Clin. Invest. 120, 1469–1478 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Wolf, D. et al. CD4+CD25+ regulatory T cells inhibit experimental anti-glomerular basement membrane glomerulonephritis in mice. J. Am. Soc. Nephrol. 16, 1360–1370 (2005). This is the first study to describe a role for T Reg cells in kidney disease.

    CAS  PubMed  Google Scholar 

  80. Paust, H. J. et al. Regulatory T cells control the Th1 immune response in murine crescentic glomerulonephritis. Kidney Int. 80, 154–164 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Ooi, J. D. et al. Endogenous foxp3+ T-regulatory cells suppress anti-glomerular basement membrane nephritis. Kidney Int. 79, 977–986 (2011).

    CAS  PubMed  Google Scholar 

  82. Hochheiser, K. et al. Kidney dendritic cells become pathogenic during crescentic glomerulonephritis with proteinuria. J. Am. Soc. Nephrol. 22, 306–316 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Feng, L. et al. Prevention of crescentic glomerulonephritis by immunoneutralization of the fractalkine receptor CX3CR1 rapid communication. Kidney Int. 56, 612–620 (1999).

    CAS  PubMed  Google Scholar 

  84. Goldwich, A. et al. Podocytes are nonhematopoietic professional antigen-presenting cells. J. Am. Soc. Nephrol. 24, 906–916 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, S., Kurts, C., Kontgen, F., Holdsworth, S. R. & Tipping, P. G. Major histocompatibility complex class II expression by intrinsic renal cells is required for crescentic glomerulonephritis. J. Exp. Med. 188, 597–602 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ryu, M. 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. 228, 448–494 (2012).

    Google Scholar 

  87. Neale, T. J., Tipping, P. G., Carson, S. D. & Holdsworth, S. R. Participation of cell-mediated immunity in deposition of fibrin in glomerulonephritis. Lancet 2, 421–424 (1988).

    CAS  PubMed  Google Scholar 

  88. Zaferani, A. et al. Identification of tubular heparan sulfate as a docking platform for the alternative complement component properdin in proteinuric renal disease. J. Biol. Chem. 286, 5359–5367 (2011).

    CAS  PubMed  Google Scholar 

  89. Macconi, D. et al. Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J. Am. Soc. Nephrol. 20, 123–130 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Ooi, J. D., Holdsworth, S. R. & Kitching, A. R. Advances in the pathogenesis of Goodpasture's disease: From epitopes to autoantibodies to effector T cells. J. Autoimmun. 31, 295–300 (2008).

    CAS  PubMed  Google Scholar 

  91. Reynolds, J. Strain differences and the genetic basis of experimental autoimmune anti-glomerular basement membrane glomerulonephritis. Int. J. Exp. Pathol. 92, 211–217 (2011).

    PubMed  PubMed Central  Google Scholar 

  92. Pedchenko, V. et al. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. N. Engl. J. Med. 363, 343–354 (2010). This paper clarifies the crucial importance of autoantigen conformation for autoantibody binding in anti-GBM disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Olaru, F. et al. Proteolysis breaks tolerance toward intact α345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for α345NC1 hexamers. J. Immunol. 190, 1424–1432 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Phelps, R. G. & Rees, A. J. The HLA complex in Goodpasture's disease: A model for analyzing susceptibility to autoimmunity. Kidney Int. 56, 1638–1653 (1999).

    CAS  PubMed  Google Scholar 

  95. Cairns, L. S. et al. The fine specificity and cytokine profile of T-helper cells responsive to the α3 chain of type IV collagen in Goodpasture´s disease. J. Am. Soc. Nephrol. 14, 2801–2812 (2003).

    CAS  PubMed  Google Scholar 

  96. Zou, J. et al. Healthy individuals have Goodpasture autoantigen-reactive T cells. J. Am. Soc. Nephrol. 19, 396–404 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Ooi, J. D. et al. The HLA-DRB1*15: 01-restricted Goodpasture's T cell epitope induces GN. J. Am. Soc. Nephrol. 24, 419–431 (2013). This study shows the crucial role of HLA-DR*15:01 in the autoimmune response to the α3(IV)NC1, which is the target of autoimmunity in anti-GBM disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Phelps, R. G., Jones, V. L., Coughlan, M., Turner, A. N. & Rees, A. J. Presentation of the Goodpasture autoantigen to CD4 T cells Is influenced more by processing constraints than by HLA class II peptide binding preferences. J. Biol. Chem. 273, 11440–11447 (1998).

    CAS  PubMed  Google Scholar 

  99. Kerjaschki, D. & Farquhar, M. G. Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J. Exp. Med. 157, 667–686 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Beck, L. H. Jr et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 361, 11–21 (2009). This seminal paper identifies PLA2R as the enigmatic autoantigen in membranous nephropathy.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Stahl, R., Hoxha, E. & Fechner, K. PLA2R autoantibodies and recurrent membranous nephropathy after transplantation. N. Engl. J. Med. 363, 496–498 (2010).

    PubMed  Google Scholar 

  102. Stanescu, H. C. et al. Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy. N. Engl. J. Med. 364, 616–626 (2011).

    CAS  PubMed  Google Scholar 

  103. Suzuki, H. et al. IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J. Clin. Invest. 118, 629–639 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Suzuki, H. et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J. Clin. Invest. 119, 1668–1677 (2009). This is a seminal paper indicating that glycan-specific autoantibodies are associated with IgA nephropathy and may represent a disease-specific marker and potential therapeutic target.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Berthoux, F. et al. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J. Am. Soc. Nephrol. 23, 1579–1587 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Goodnow, C. C. Multistep pathogenesis of autoimmune disease. Cell 130, 25–35 (2007).

    CAS  PubMed  Google Scholar 

  107. Hakkim, A. et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl Acad. Sci. USA 107, 9813–9818 (2010).

    CAS  PubMed  Google Scholar 

  108. Bosch, X. Systemic lupus erythematosus and the neutrophil. N. Engl. J. Med. 365, 758–760 (2011).

    CAS  PubMed  Google Scholar 

  109. Marshak-Rothstein, A. & Rifkin, I. R. Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu. Rev. Immunol. 25, 419–441 (2007).

    CAS  PubMed  Google Scholar 

  110. Guiducci, C. et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465, 937–941 (2010). This study shows that TLR7 and TLR9 signalling drives lupus nephritis by rendering DCs resistant to steroids.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Pawar, R. D. et al. Inhibition of Toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus. J. Am. Soc. Nephrol. 18, 1721–1731 (2007).

    CAS  PubMed  Google Scholar 

  112. Savarese, E. et al. U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 107, 3229–3234 (2006).

    CAS  PubMed  Google Scholar 

  113. Garcia-Romo, G. S. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 (2011).

    PubMed  PubMed Central  Google Scholar 

  114. Theofilopoulos, A. N., Baccala, R., Beutler, B. & Kono, D. H. Type I interferons (α/β) in immunity and autoimmunity. Annu. Rev. Immunol. 23, 307–336 (2005).

    CAS  PubMed  Google Scholar 

  115. Migliorini, A. & Anders, H. J. A novel pathogenetic concept-antiviral immunity in lupus nephritis. Nature Rev. Nephrology 8, 183–189 (2012).

    CAS  Google Scholar 

  116. Yung, S., Cheung, K. F., Zhang, Q. & Chan, T. M. Anti-dsDNA antibodies bind to mesangial annexin II in lupus nephritis. J. Am. Soc. Nephrol. 21, 1912–1927 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Mortensen, E. S. & Rekvig, O. P. Nephritogenic potential of anti-DNA antibodies against necrotic nucleosomes. J. Am. Soc. Nephrol. 20, 696–704 (2009).

    CAS  PubMed  Google Scholar 

  118. Weening, J. J. et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J. Am. Soc. Nephrol. 15, 241–250 (2004).

    PubMed  Google Scholar 

  119. Chen, M. & Kallenberg, C. G. ANCA-associated vasculitides — advances in pathogenesis and treatment. Nature Rev. Rheumatol 6, 653–664 (2010).

    CAS  Google Scholar 

  120. Kain, R. et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nature Med. 14, 1088–1096 (2008). This paper describes molecular mimicry of bacterial antigens underlying pauci-immune FNGN.

    CAS  PubMed  Google Scholar 

  121. Kain, R. et al. High prevalence of autoantibodies to hLAMP-2 in anti-neutrophil cytoplasmic antibody-associated vasculitis. J. Am. Soc. Nephrol. 23, 556–566 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Roth, A. J. et al. Anti-LAMP-2 antibodies are not prevalent in patients with antineutrophil cytoplasmic autoantibody glomerulonephritis. J. Am. Soc. Nephrol. 23, 545–555 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Kessenbrock, K. et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nature Med. 15, 623–625 (2009).

    CAS  PubMed  Google Scholar 

  124. Gou, S.-J., Yuan, J., Chen, M., Yu, F. & Zhao, M.-H. Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int. 83, 129–137 (2013).

    CAS  PubMed  Google Scholar 

  125. Schreiber, A. & Kettritz, R. The neutrophil in antineutrophil cytoplasmic autoantibody-associated vasculitis. J. Leukoc. Biol. http://dx.doi.org/10.1189/jlb.1012525 (2013).

  126. Abdulahad, W. H., Lamprecht, P. & Kallenberg, C. G. T-helper cells as new players in ANCA-associated vasculitides. Arthritis Res. Ther. 13, 236 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Velden, J. et al. Renal IL-17 expression in human ANCA-associated glomerulonephritis. Am. J. Physiol. Renal Physiol. 302, F1663–F1673 (2012).

    CAS  PubMed  Google Scholar 

  128. McKinney, E. F. et al. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nature Med. 16, 586–591 (2010).

    CAS  PubMed  Google Scholar 

  129. Lyons, P. A. et al. Genetically distinct subsets within ANCA-associated vasculitis. N. Engl. J. Med. 367, 214–223 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Jennette, J. C., Falk, R. J., Hu, P. & Xiao, H. Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu. Rev. Pathol. 8, 139–160 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Heeringa, P. & Little, M. A. In vivo approaches to investigate ANCA-associated vasculitis: lessons and limitations. Arthritis Res. Ther. 13, 204 (2011).

    PubMed  PubMed Central  Google Scholar 

  132. Kuligowski, M. P. et al. Antimyeloperoxidase antibodies rapidly induce α4-integrin-dependent glomerular neutrophil adhesion. Blood 113, 6485–6494 (2009).

    CAS  PubMed  Google Scholar 

  133. Little, M. A. et al. Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. PLoS ONE 7, e28626 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Ruth, A. J. et al. Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis. J. Am. Soc. Nephrol. 17, 1940–1949 (2006).

    CAS  PubMed  Google Scholar 

  135. Tan, D. S. et al. Thymic deletion and regulatory T cells prevent antimyeloperoxidase GN. J. Am. Soc. Nephrol. 24, 573–585 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Ooi, J. D. et al. The immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis. Proc. Natl Acad. Sci. USA 109, E2615–E2624 (2012).

    CAS  PubMed  Google Scholar 

  137. Gan, P. Y. et al. Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis. J. Am. Soc. Nephrol. 21, 925–931 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Tadema, H. et al. Bacterial DNA motifs trigger ANCA production in ANCA-associated vasculitis in remission. Rheumatology (Oxford) 50, 689–696 (2011).

    CAS  Google Scholar 

  139. Tadema, H., Kallenberg, C. G., Stegeman, C. A. & Heeringa, P. Reactivity against complementary proteinase-3 is not increased in patients with PR3-ANCA-associated vasculitis. PLoS ONE 6, e17972 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Vaziri, N. D. CKD impairs barrier function and alters microbial flora of the intestine: a major link to inflammation and uremic toxicity. Curr. Opin. Nephrol. Hypertens. 21, 587–592 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Lech, M., Rommele, C. & Anders, H. J. Pentraxins in nephrology: C-reactive protein, serum amyloid P and pentraxin-3. Nephrol. Dial. Transplant. 28, 803–811 (2013).

    CAS  PubMed  Google Scholar 

  142. Carrero, J. J. & Stenvinkel, P. Inflammation in end-stage renal disease — what have we learned in 10 years? Semin. Dial. 23, 498–509 (2010).

    PubMed  Google Scholar 

  143. Cohen, G. & Horl, W. H. Immune dysfunction in uremia — an update. Toxins 4, 962–990 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Weichhart, T. et al. Serum amyloid A in uremic HDL promotes inflammation. J. Am. Soc. Nephrol. 23, 934–947 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Anders, H. J., Andersen, K. & Stecher, B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 83, 1010–1016 (2013).

    CAS  PubMed  Google Scholar 

  146. Meyer, T. W. & Hostetter, T. H. Uremic solutes from colon microbes. Kidney Int. 81, 949–954 (2012).

    CAS  PubMed  Google Scholar 

  147. McIntyre, C. W. et al. Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 6, 133–141 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Hotchkiss, R. S., Coopersmith, C. M., McDunn, J. E. & Ferguson, T. A. The sepsis seesaw: tilting toward immunosuppression. Nature Med. 15, 496–497 (2009).

    CAS  PubMed  Google Scholar 

  149. Stearns-Kurosawa, D. J., Osuchowski, M. F., Valentine, C., Kurosawa, S. & Remick, D. G. The pathogenesis of sepsis. Annu. Rev. Pathol. 6, 19–48 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Oppermann, M. et al. Elevated plasma levels of the immunosuppressive complement fragment Ba in renal failure. Kidney Int. 40, 939–947 (1991).

    CAS  PubMed  Google Scholar 

  151. Pelajo, C. F., Lopez-Benitez, J. M. & Miller, L. C. Vitamin D and autoimmune rheumatologic disorders. Autoimmun Rev. 9, 507–510 (2010).

    CAS  PubMed  Google Scholar 

  152. Vaziri, N. D. Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin. Nephrol. 24, 469–473 (2004).

    CAS  PubMed  Google Scholar 

  153. Herrada, A. A. et al. Aldosterone promotes autoimmune damage by enhancing Th17-mediated immunity. J. Immunol. 184, 191–202 (2010).

    CAS  PubMed  Google Scholar 

  154. Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Madhur, M. S. et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension 55, 500–507 (2010).

    CAS  PubMed  Google Scholar 

  157. Machnik, A. et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nature Med. 15, 545–552 (2009).

    CAS  PubMed  Google Scholar 

  158. Harrison, D. G., Marvar, P. J. & Titze, J. M. Vascular inflammatory cells in hypertension. Front. Physiol. 3, 128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to all colleagues whose work could not be cited or discussed in greater detail due to space restrictions. The authors are supported by the German Research foundation (DFG Klinische Forschergruppe 228, SFB704 and TR57, Graduiertenkolleg 1202 and Excellence Cluster ImmunoSensation) and the EU Consortia INTRICATE and REDDSTAR.

Author information

Author notes

  1. Christian Kurts, Ulf Panzer, Hans-Joachim Anders and Andrew J. Rees: All authors contributed equally to this work.

Authors and Affiliations

  1. Institutes of Molecular Medicine and Experimental Immunology (IMMEI), Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Str. 25, Bonn, 53105, Germany

    Christian Kurts

  2. III. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, Hamburg, 20246, Germany

    Ulf Panzer

  3. Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians Universität München, Ziemssenstr. 1, München, 80336, Germany

    Hans-Joachim Anders

  4. Clinical Institute of Pathology, Medical University of Vienna, Währinger Gürtel 18–20, Vienna, A-1090, Austria

    Andrew J. Rees

Authors
  1. Christian Kurts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ulf Panzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans-Joachim Anders
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew J. Rees
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Christian Kurts, Ulf Panzer, Hans-Joachim Anders or Andrew J. Rees.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Animal models of immune-mediated kidney disease (PDF 281 kb)

PowerPoint slides

Glossary

Nephrons

Anatomically and functionally independent kidney units that each consist of one glomerulus and one tubule. The nephron delivers urine into collecting ducts that empty into the renal pelvis and, through the ureters, into the urinary bladder.

Glomerulus

An anatomical structure that is located in the kidney cortex and that filters blood into the tubular system.

Tubulointerstitium

The space between the tubuli and glomeruli, which contains capillaries, fibroblasts and dendritic cells, and thus is an important site for the progression of nephritis.

Bacterial pyelonephritis

A bacterial infection of the kidney, mostly due to uropathogenic Escherichia coli that ascend through the urethra, bladder and ureter into the kidneys.

Tubules

Hairpin-like structures that receive filtered blood. The tubular epithelium reabsorbs water, electrolytes, nutrients and proteins. Each nephron has a single tubule, which defines proximal and distal tubules as parts of the nephron.

Chronic kidney disease

(CKD). Chronic (and often progressive) impairment of renal functions, such as blood purification, barrier function of the glomerular filter, water, electrolyte and acid–base homeostasis, endocrine functions such as vitamin D processing, erythropoietin production and blood pressure regulation.

Uraemia

End-stage chronic kidney disease, the treatment of which requires dialysis or kidney transplantation.

Glomerulonephritis

A heterogeneous group of immune-mediated kidney diseases that initiate in the glomeruli.

Podocyte

A visceral epithelial cell that covers the glomerular capillaries in the Bowman's capsule. Podocytes are a component of the glomerular filtration barrier.

Fibrocytes

Monocyte-derived collagen-producing cells that have been suggested to contribute to kidney fibrosis.

Kidney fibrosis

The end stage of chronic kidney disease, when functional renal tissue has been replaced by fibrotic scar tissue and is usually accompanied by uraemia.

Inflammasome

An intracellular complex containing pattern recognition receptors that activate caspase 1. Caspase 1 activation induces pyroptotic cell death and interleukin-1β (IL-1β) and IL-18 secretion.

Haemolytic uraemic syndrome

(HUS). A group of diseases, which are induced by infection with Shiga toxin-producing bacteria, or by genetic or acquired defects in complement regulators, that are characterized by microvascular injury and thrombosis, which results in haemolytic anaemia, thrombocytopenia and organ dysfunction (kidney and often brain).

Thrombotic thrombocytopenic purpura

(TTP). A rare life-threatening disease, characterized by the development of platelet thrombi and microvascular injury, which results from either genetic or acquired defects of the enzyme a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), which has a unique role in the homeostasis of the coagulation system.

Anti-neutrophil cytoplasmic antibody

(ANCA). An autoantibody that is commonly found in pauci-immune focal necrotizing glomerulonephritis.

Crescentic glomerulonephritis

A rapidly progressive form of glomerulonephritis characterized by the hyperproliferation of parietal epithelial cells, which is driven by T cell and macrophage infiltrates and by plasma components leaking through the glomerular filter.

Delayed-type hypersensitivity

(DTH). An inappropriate T cell-initiated response to self or foreign antigens that is carried out by macrophages, eosinophils or cytotoxic T cells.

Proteinuria

The urinary loss of protein, which has numerous clinical consequences. Proteinuria is also used as a biomarker for renal filter dysfunction.

Anti-GBM disease

(Anti-glomerular basement membrane disease; also known as Goodpasture's disease). A severe form of crescentic glomerulonephritis caused by autoantibodies that are specific for the NC1 domain of the α3 chain of type IV collagen (α3(IV)NC1) in the GBM.

Membranous nephropathy

A glomerulonephritis form characterized by the subepithelial deposition of secretory phospholipase A2 receptor (PLA2R)-specific antibodies, which leads to podocyte injury and heavy proteinuria. It is the most common cause of the nephrotic syndrome in adults.

Nephrotic syndrome

A syndrome characterized by heavy proteinuria, hypoalbuminaemia and a loss of immunoglobulins, which results in humoral immunodeficiency, oedema, hyperlipidaemia and thrombosis. This syndrome results from damage to the glomerular filter, which causes the loss of proteins above 50 kDa in size from the circulation.

IgA nephropathy

The most common form of glomerulonephritis worldwide. It is characterized by the deposition of IgA-containing immune complexes in the mesangial compartment of glomeruli, which leads to mesangial cell-proliferative lesions, haematuria and proteinuria.

Pauci-immune focal necrotizing glomerulonephritis

(Pauci-immune FNGN). A highly inflammatory form of glomerulonephritis in which glomerular immune complex deposits are absent or scarce. It is commonly associated with small vessel vasculitis and with anti-neutrophil cytoplasmic antibodies.

NETosis

The formation and the release of neutrophil extracellular traps (NETs) by activated neutrophils to ensnare invading microorganisms. NETs enhance neutrophil killing of extracellular pathogens while minimizing damage to the host cells.

Humanized mice

Immunodeficient mice that are engrafted with human haematopoietic cells or tissues, or mice that transgenically express human genes.

Endotoxin tolerance

A transient state of hyporesponsiveness of the host or of cultured macrophages and/or monocytes to lipopolysaccharide (LPS) following previous exposure to LPS.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kurts, C., Panzer, U., Anders, HJ. et al. The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol 13, 738–753 (2013). https://doi.org/10.1038/nri3523

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3523

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing