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.
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.
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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.
The authors declare no competing financial interests.
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.
An anatomical structure that is located in the kidney cortex and that filters blood into the tubular system.
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.
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.
End-stage chronic kidney disease, the treatment of which requires dialysis or kidney transplantation.
A heterogeneous group of immune-mediated kidney diseases that initiate in the glomeruli.
A visceral epithelial cell that covers the glomerular capillaries in the Bowman's capsule. Podocytes are a component of the glomerular filtration barrier.
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.
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.
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.
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.
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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
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