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

Journal name:
Nature Reviews Immunology
Volume:
13,
Pages:
738–753
Year published:
DOI:
doi:10.1038/nri3523
Published online

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.

At a glance

Figures

  1. Innate immune mechanisms in kidney inflammation.
    Figure 1: Innate immune mechanisms in kidney inflammation.

    Renal cell necrosis or programmed forms of inflammatory cell death release damage-associated molecular patterns (DAMPs) into the extracellular space, where they activate pattern recognition receptors (PRRs). Renal dendritic cells and macrophages express numerous PRRs, whereas PRR expression is limited on renal non-immune cells. PRR ligation activates the cell, which results in cell type-specific consequences, such as the secretion of pro-inflammatory mediators that promote renal immunopathology. In the glomerulus, PRR activation in mesangial cells also stimulates their proliferation, for example, in mesangioproliferative forms of glomerulonephritis such as lupus nephritis, IgA nephropathy and hepatitis C virus-associated glomerulonephritis. PRR activation of endothelial and epithelial cells (including podocytes and tubular epithelial cells) in the glomerulus increases their permeability, which results in proteinuria, a clinically useful biomarker of glomerular vascular permeability, inflammation and damage. Moreover, the activation of endothelial and epithelial cells manifests as interstitial oedema and secretory dysfunction, for example, in septic acute kidney injury. CXCL2, CXC-chemokine ligand 2; GN, glomerulonephritis; HUS, haemolytic uraemic syndrome; IC-GN, immune complex glomerulonephritis; IFN, interferon; IL, interleukin; ROS, reactive oxygen species; TNF, tumour necrosis factor.

  2. Cellular immune response in experimental crescentic glomerulonephritis.
    Figure 2: Cellular immune response in experimental crescentic glomerulonephritis.

    The time-dependent changes in the pro-inflammatory and anti-inflammatory functions of leukocyte subsets during the course of experimental crescentic glomerulonephritis (a nephrotoxic nephritis model) are shown. a | The clinical outcome of the disease mainly depends on the balance between pro-inflammatory and anti-inflammatory immune cells. Whether this concept is relevant to human crescentic glomerulonephritis remains to be shown. Neutrophil recruitment to the kidney starts several hours after the induction of nephrotoxic nephritis and is partly mediated by interleukin-17A (IL-17A)-producing γδ T cells, which are activated by IL-23. The adaptive immune response is initiated by mature dendritic cells (DCs) that depend on CX3C-chemokine receptor 1 (CX3CR1) and CC-chemokine receptor 2 (CCR2). At earlier stages, immune responses that are mediated by CCR6-expressing T helper 17 (TH17) cells predominate, whereas at later stages, CXC-chemokine receptor 3 (CXCR3)+ TH1 cells are the prevailing mediators of renal tissue injury, as they produce cytokines such as interferon-γ (IFNγ), which activate macrophages. In addition, host antibodies against the heterologous antibodies form intrarenal immune complexes and thereby contribute to renal tissue damage. During the first days immature DCs attenuate crescentic glomerulonephritis by attracting regulatory invariant natural killer T (iNKT) cells via the CXC-chemokine ligand 16 (CXCL16)–CXCR6 axis, and these cells produce IL-4 and IL-10 and thereby might reduce the destructive TH1 and TH17 cell responses. At a later stage, CCR6+ and CCR7+ regulatory T (TReg) cells are recruited into the inflamed kidney and protect against an overwhelming TH1 cell- and TH17 cell-mediated immune response, at least partly through the local production of IL-10 and the expression of programmed cell death 1 ligand 1 (PDL1). b | Periodic acid-Schiff (PAS) staining of kidney sections from patients with acute crescentic glomerulonephritis shows glomerular and tubulointerstitial leukocyte infiltration. Irreversible kidney damage occurs along with glomerular sclerosis and tubulointerstitial fibrosis when the inflammatory response persists. IL-23R, IL-23 receptor; TNF, tumour necrosis factor. Image courtesy of U. Helmchen, Hamburg, Germany.

  3. Local immune pathways in glomerulonephritis.
    Figure 3: Local immune pathways in glomerulonephritis.

    Glomerular immunopathology often develops from intraglomerular complement activation via the classical (immune complex-related) or alternative (immune complex-independent) complement pathway. Immune complexes can form in different compartments of the glomerulus, which determines the resulting histopathological lesion, as different glomerular cell types are primarily activated in each compartment. The resulting histopathological lesions determine the classification of glomerulonephritis. Immune complex deposition in the mesangium activates mesangial cells, which leads to mesangioproliferative glomerulopathies, such as IgA nephropathy or lupus nephritis class I and II. Subendothelial immune complex deposits activate endothelial cells, as seen in lupus nephritis class III and IV. Subepithelial immune complex deposits preferentially activate the visceral glomerular epithelium — that is, podocytes — and usually cause massive proteinuria, as these cells are essential for the glomerular filtration barrier. As a result of the poor regeneration of podocytes compared with that of the other glomerular cell types, podocyte loss leads to progressive membranous nephropathy and end-stage renal disease. Primary membranous nephropathy mainly develops from autoimmunity against PLA2R, whereas secondary forms of this nephropathy represent renal manifestations of systemic disorders such as lupus nephritis. Hence, the level of proteinuria is an important prognostic biomarker and predictor of poor outcomes of glomerulopathies. Linear immune complex deposits indicate antibody binding to autoantigens within the glomerular basement membrane (GBM), for example, collagen IV antibodies in anti-GBM disease. Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis develops in the absence of immune complex deposits (known as pauci-immune), as it is driven by both ANCAs and cellular immunity. Complement component C3 glomerulopathies and atypical haemolytic uraemic syndrome (aHUS) develop from the aberrant activation of the alternative complement pathway. The boxes list in order the type of immune deposits, the glomerular structure that is primarily affected, the dominant clinical signs and the related disorders for each mechanism. α3(IV)NC1, non-collagenous 1 (NC1) domain of the α3 chain of type IV collagen; CKD, chronic kidney disease; LAMP2, lysosome-associated membrane protein 2; MPO, myeloperoxidase; PLA2R, secretory phospholipase A2 receptor; PR3, proteinase 3.

  4. Consequences of chronic kidney disease with potential effects on systemic immunity.
    Figure 4: Consequences of chronic kidney disease with potential effects on systemic immunity.

    Chronic kidney disease (CKD) has several immediate consequences (blue boxes), which are proposed to result in three main immunological alterations (red boxes) through intermediate steps. First, chronic stimulation of the renin–angiotensin–aldosterone system causes T helper 17 (TH17) cell polarization, through dendritic cell (DC) polarization and possibly through sodium retention. Second, uraemic intestinal barrier dysfunction, vitamin D deficiency and cytokine accumulation (which may be due to impaired protein catabolism, reduced uromodulin levels and chronic oxidative stress) result in systemic inflammation. Third, systemic immunosuppression results from the uraemic accumulation of toxic metabolic waste, the increased turnover of the components of the alternative complement pathway because of impaired protein catabolism, and in cases of extensive proteinuria, the urinary loss of proteins with immunological functions. This figure also integrates the key clinical consequences of CKD, which include hypertension, vascular damage and atherosclerosis, renal anaemia and bone loss (in bold). These mechanisms may alone or in concert affect general immunity.

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Author information

  1. All authors contributed equally to this work.

    • Christian Kurts,
    • Ulf Panzer,
    • Hans-Joachim Anders &
    • Andrew J. Rees

Affiliations

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

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

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

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

    • Andrew J. Rees

Competing interests statement

The authors declare no competing interests.

Corresponding authors

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Author details

  • Christian Kurts

    Christian Kurts trained as a specialist in internal medicine and nephrology at the Medical School of Hannover, Germany, and at the University Hospital Aachen, Germany. At the Walter and Eliza Hall Institute for Medical Research in Melbourne, Australia, he studied the immune mechanisms of cross-presentation and of cross-tolerance. Since 2003 he has been Professor at the University Clinic of Bonn, Germany; since 2013 as Executive Director of the Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Germany. His research focuses on cross-presentation, peripheral B cell and T cell tolerance and the role of dendritic cells in diseases, especially those affecting the kidneys. Christian Kurts' homepage.

  • Ulf Panzer

    Ulf Panzer is a nephrologist at the III. Medizinische Klinik of the University Medical Center in Hamburg, Germany. Since 2009 he has been Professor at the University of Hamburg and is leader of the Clinical Research Unit 228, Immunopathogenesis and Therapy of Glomerulonephritis, Hamburg. The focus of his research group is the function of chemokines and chemokine receptors in T cell trafficking in renal autoimmune disease, with a special focus on crescentic glomerulonephritis.

  • Hans-Joachim Anders

    Hans-Joachim Anders received his medical degree from the University of Wurzburg, Germany. He became a mentee of Detlef Schlöndorff at the University of Munich, Germany, where a trained as an internist and passed fellowship programmes and boards in nephrology and rheumatology. Currently, he is in charge of the Inner City Campus Nephrology Unit at the University of Munich. His laboratory team is interested in the molecular and cellular immune concepts of kidney injury and regeneration following a translational immunonephrology strategy. Therefore, conceptual mechanisms are studied in various forms of acute kidney injury and chronic kidney disease, including those occurring in lupus and diabetes. Hans-Joachim Anders' homepage.

  • Andrew J. Rees

    Andrew J. Rees qualified in medicine in Liverpool, UK, before training in nephrology and immunology in London, UK. He was Head of Nephrology at Royal Postgraduate Medical School, London, and then Regius Professor of Medicine at the University of Aberdeen, UK. In 2007 he moved to a Marie Curie Excellence Chair in the Clinical Institute of Pathology at the Medical University of Vienna, Austria. His major research interests are the immune mechanisms of glomerular disease and their translation to novel treatments.

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    Animal models of immune-mediated kidney disease

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