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The Immune System and Kidney Disease: Basic Concepts and Clinical Implications

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The Immune System and Kidney Disease: Basic Concepts and Clinical Implications REVIEWS The immune system and kidney disease: basic concepts and clinical implications Christian Kurts1, Ulf Panzer2, Hans-Joachim Anders3 and Andrew J. Rees4 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. Considerable progress has been made both in under- role of the cellular immune responses that drive renal 1Institutes of Molecular standing the basic immune mechanisms of kidney disease. Moreover, we summarize recent discoveries Medicine and Experimental disease and in translating these findings to clinical about complement- and antibody-mediated nephritis, Immunology (IMMEI), therapies. Sophisticated animal studies combined and we discuss kidney pathologies that are mediated Rheinische Friedrich- with the analysis of clinical samples have led to a pre- by renal autoantigen-specific antibodies, especially those Wilhelms-Universität, cise knowledge of the autoimmune targets and of the that are induced by crossreactive microorganism-specific Sigmund-Freud-Str. 25, 53105 Bonn, Germany. mechanisms responsible for kidney injury. Kidney antibodies. Finally, we describe how the disruption of 2III. Medizinische Klinik, diseases are highly prevalent and cost-intensive, kidney function and kidney pathologies can influence Universitätsklinikum but many discoveries in renal immunology are not systemic immune responses. Hamburg-Eppendorf, widely known in the immunological community, Martinistrasse 52, Kidney-resident immune cells 20246 Hamburg, Germany. although they are often relevant to diseases that affect 3Medizinische Klinik und other organs. In the kidneys, toxic waste products of metabolism are Poliklinik IV, Ludwig- In this Review, we discuss recent advances in our removed from the blood by nephrons. Each nephron Maximilians Universität understanding of immune-mediated kidney diseases, contains one glomerulus, which functions as a size- München, Ziemssenstr. 1, emphasizing those of particular relevance to the wider selective filter that retains molecules above ~50 kDa 80336 München, Germany. 4Clinical Institute of Pathology, immunology community and those that have led to a in the blood. Compounds of lower molecular mass Medical University of Vienna, better understanding of basic immunological mechan­ pass through the glomerular filter, enter the tubular Währinger Gürtel 18–20, isms. We have had to be selective in the topics consid- system and are excreted with the urine unless they A-1090 Vienna, Austria. ered and so have excluded a discussion of acute kidney are re­absorbed by the tubular epithelium (BOX 1). The e-mails: [email protected]; [email protected]; injury, kidney transplantation and alloimmunity, as kidneys produce several hormones that directly or [email protected] well as of systemic diseases with associated kidney indirectly affect immune responses, including vita- muenchen.de; andrew.rees@ disease, such as type 2 diabetes and hypertension, min D, which regulates bone homeostasis and phago- meduniwien.ac.at that are not primarily caused by the immune system, cyte function, erythropoietin, which is induced in All authors contributed despite the involvement of innate (and possibly adap- response to hypoxia to regulate erythropoiesis, and equally to this work. doi:10.1038/nri3523 tive) immune responses in the renal injury they cause. renin, which induces angiotensin and aldosterone to Published online Here, we discuss the innate immune mechanisms of regulate electrolyte balance, extracellular osmolarity 16 September 2013 kidney injury and introduce novel concepts about the and blood pressure. 738 | OCTOBER 2013 | VOLUME 13 www.nature.com/reviews/immunol © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Box 1 | Basic kidney anatomy and physiology The kidneys purify toxic metabolic waste products from the blood in several hundred thousand functionally independent units called nephrons. A nephron consists of one glomerulus and one double hairpin-shaped tubule that drains the filtrate into the renal pelvis. The glomeruli located in the kidney cortex are bordered by the Bowman’s capsule. They are lined with parietal epithelial cells and contain the mesangium with many capillaries to filter the blood. The glomerular filtration barrier consists of endothelial cells, the glomerular basement membrane and visceral epithelial cells (also known as podocytes). All molecules below the molecular size of albumin (that is, 68 kDa) pass the filter and enter the tubule, which consists of the proximal convoluted tubule, the loop of Henle and the distal convoluted tubule. An intricate countercurrent system forms a high osmotic gradient in the renal medulla that concentrates the filtrate. The tubular epithelial cells reabsorb water, small proteins, amino acids, carbohydrates and electrolytes, thereby regulating plasma osmolality, extracellular volume, blood pressure and acid–base and electrolyte balance. Non-reabsorbed compounds pass from the tubular system into the collecting ducts to form urine. The space between the tubules is called the interstitium and contains most Kidney of the intrarenal immune system, which mainly consists of dendritic cells, but also of macrophages and fibroblasts. Bowman’s capsule Ureter Glomerular basement membrane Podocyte Nephron Distal convoluted tubule Endothelial cell Proximal Mesangial convoluted cell Parietal tubule Glomerulus Bowman’s epithelial space cell Tubular Loop of Collecting epithelial Henle duct cell Ureter Nephrons Anatomically and functionally independent kidney units that Nature Reviews | Immunology each consist of one glomerulus Under homeostatic conditions, the resident that CX3CR1 might be a specific therapeutic target to and one tubule. The nephron immune cells of the kidneys include dendritic cells modulate DC numbers in the kidneys. In renal ischae- delivers urine into collecting ducts that empty into the renal (DCs) and macrophages, as well as a few lympho- mia (which is relevant in kidney transplantation) and 1–4 pelvis and, through the ureters, cytes . DCs are restricted to the tubulointerstitium and in ureteral obstruction, renal DCs promote tissue into the urinary bladder. are absent from the glomeruli1,2. In mice, kidney DCs injury by producing pro-inflammatory cytokines11,12. + + + + − − are CD11c CD11b F4/80 CX3CR1 CD8 CD205 and Basic leucine zipper transcriptional factor ATF-like 3 Glomerulus + An anatomical structure that have a transcriptome that is typical of DCs resident (BATF3)-dependent CD103 tissue DCs, which can 5,6 + is located in the kidney cortex in various non-lymphoid tissues . Kidney DCs are cross-present antigens to CD8 T cells, are rare and and that filters blood into the derived from monocytes and from common DC pre- their function in the kidney is unclear13. Macrophages tubular system. cursors (CDPs), but in contrast with other organs, are preferentially found in the renal medulla and cap- some CDP-derived kidney DCs express CD64 (also sule1 and have homeostatic and repair functions14. Tubulointerstitium 7 The space between the tubuli known as FcγRI) . Kidney DCs function as sentinels There are also mast cells in the kidney tubulointer- 3,8 15–17 and glomeruli, which contains in homeostasis, local injury and infection . They rap- stitium but their function is poorly understood . capillaries, fibroblasts and idly produce neutrophil-recruiting chemokines dur- In addition, the role of innate-like lymphocytes is dendritic cells, and thus ing bacterial pyelonephritis, which is the most prevalent currently unclear. Finally, the renal lymph nodes rep- is an important site for the 8 progression of nephritis. kidney infection . Neutrophils can also be recruited by resent a priming site for nephritogenic T cells during tubular epithelial cells, but not as quickly as by DCs. renal inflammation18,19. Bacterial pyelonephritis Mice lacking expression of CX3C-chemokine recep- Low-molecular-mass proteins can pass through the A bacterial infection of the tor 1 (CX3CR1) have a selective reduction in kidney glomerular filter but are reabsorbed and degraded by kidney, mostly due to DC numbers9. There is also a high renal expression of tubular epithelial cells. However, some of these proteins uropathogenic Escherichia coli 10, that ascend through the its ligand CX3C-chemokine ligand 1 (CX3CL1) which are captured by renal DCs or reach the renal lymph urethra, bladder and ureter suggests that the CX3CR1–CX3CL1 chemokine pair nodes by lymphatic drainage within seconds after filtra- into the kidneys. are important for DC recruitment to the kidney and tion20. Importantly, filtered proteins are concentrated in NATURE REVIEWS | IMMUNOLOGY VOLUME 13 | OCTOBER 2013 | 739 © 2013 Macmillan Publishers
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