Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage

Abstract

The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney’s excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-β), p16ink4a, Wnt/β-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function.

Molecular Mechanisms of AKI in the Elderly: From Animal Models to Therapeutic Intervention

“…Interestingly, the authors found that classical and alternative pathways were significantly higher in the elderly, in contrast to lectin pathway activation [115]. Besides physiological and chronological aging, premature aging induced by AKI episodes could be modulated by complementary inhibition [108]. In a pig model of I/R we demonstrated that C1-INHIBITOR (C1-INH), an endogenous regulator of classical and lectin pathway, was able to protect from tubular senescence preserving the level of anti-aging protein Klotho and reducing cell cycle arrest proteins levels [70,81].…”

“…Complement system, an essential player of innate immune system is recognized as pivotal in several kidney diseases from glomerulonephritis (Lupus Nephritis, C3 glomerulopathy, IgAN) to AKI and further progression to CKD [107,108].…”

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

“…The C4d deposition has been considered the gold standard for ABMR diagnosis for several years, indicating activation of Classical pathway of Complement; however, all Complement pathways have been proved to be involved in ABMR, leading to recruitment and activation of leukocytes such as Natural Killer cells, monocytes/macrophages, and lymphocytes [ 97 ].…”

The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand?

“…Immunosenescence describes the process of progressive deterioration of the immune functions during aging due to a several causes such as: (i) reduced NK cell-mediated cytotoxicity and perforin release, (ii) altered TLRs and NODs activation on monocytes, decreased phagocytosis, ROS generation; increased basal production of proinflammatory cytokines; (iii) less efficient antigen presentation and phagocytosis by dendritic cells; reduced secretion of IFNγ and IL-12, (iv) systemic inflammaging as a state of chronic, low grade inflammation and the (v) thymic involution leading to reduced naïve T cell and increased memory cells in the elderly ( 158 – 160 ). Dysregulated functions associated to immunosenescence can include reduced responses to vaccination, lower antitumor ability of CD4, CD8 T cells and APC, increased systemic inflammation, as well as autoimmunity ( 79 ).…”