The role of the immune system in kidney disease

Abstract

The immune system and the kidneys are closely linked. In health the kidneys contribute to immune homeostasis, while components of the immune system mediate many acute forms of renal disease and play a central role in progression of chronic kidney disease. A dysregulated immune system can have either direct or indirect renal effects. Direct immune-mediated kidney diseases are usually a consequence of autoantibodies directed against a constituent renal antigen, such as collagen IV in anti-glomerular basement membrane disease. Indirect immune-mediated renal disease often follows systemic autoimmunity with immune complex formation, but can also be due to uncontrolled activation of the complement pathways. Although the range of mechanisms of immune dysregulation leading to renal disease is broad, the pathways leading to injury are similar. Loss of immune homeostasis in renal disease results in perpetual immune cell recruitment and worsening damage to the kidney. Uncoordinated attempts at tissue repair, after immune-mediated disease or non-immune mediated injury, result in fibrosis of structures important for renal function, leading eventually to kidney failure. As renal disease often manifests clinically only when substantial damage has already occurred, new diagnostic methods and indeed treatments must be identified to inhibit further progression and promote appropriate tissue repair. Studying cases in which immune homeostasis is re-established may reveal new treatment possibilities.

Keywords: fibrosis; immune homeostasis; inflammation; kidney disease.

Figure 1

Molecular pathogenesis of anti‐glomerular basement membrane disease. An unknown stimulus directs production of anti‐glomerular basement membrane (GBM) autoantibodies. The principal target for the anti‐GBM antibodies [which are typically immunoglobulin IgG1 and 3 but sometimes IgA or IgM] is the NC1 domain of the alpha‐3 chain of type IV collagen [α3(IV) chain], one of six genetically distinct gene products found in basement membrane collagen. The antigen–antibody binding activates the complement cascade and further inflammatory cell recruitment leads to chronic inflammation and fibrosis.

Figure 2

Progression versus resolution of inflammatory processes in the kidney. Pathways following acute kidney injury and activation of the renal sentinel immune cells. Initial switch to inflammatory mononuclear phagocyte phenotype characterized by marked expression of the surface glycoprotein lymphocyte antigen 6 complex locus C (Ly6C^high). Phenotypic switch to the anti‐inflammatory phenotype (Ly6C^low) favours tissue repair and return to immune homeostasis. However, repeat or prolonged inflammation leads to necrosis of cells, fibrotic change and chronic kidney disease.

Figure 3

The central role of the immune system in renal pathology. CKD = chronic kidney disease; ESRD = end stage renal disease.