Immune checkpoint inhibitors (ICIs) are a novel class of immunotherapy drugs that have improved the treatment of a broad spectrum of cancers as metastatic melanoma, non-small lung cancer or renal cell carcinoma. These humanized monoclonal antibodies target inhibitory receptors (e.g. CTLA-4, PD-1, LAG-3, TIM-3) and ligands (PD-L1) expressed on T lymphocytes, antigen presenting cells and tumor cells and elicit an anti-tumor response by stimulating immune system. Nevertheless, the improved overall survival is complicated by the manifestation of Immune-related Adverse Effects (irAEs). During treatment with ICIs, the most common adverse kidney effect is represented by the development of acute kidney injury (AKI) with the acute tubulointerstitial nephritis as recurrent histological feature. The mechanisms involved in ICIs-induced AKI include the re-activation of effector T cells previously stimulated by nephrotoxic drugs (i.e. by antibiotics), the loss of tolerance versus self-renal antigens, the increased PD-L1 expression by tubular cells or the establishment of a pro-inflammatory milieu with the release of self-reactive antibodies. For renal transplant recipient treated with ICIs, the increased incidence of rejection is a serious concern. Therefore, the combination of ICIs with mTOR inhibitors represents an emerging strategy. Finally, it is relevant to anticipate which patients under ICIs would experience severe irAEs and from a kidney perspective, to predict patients with higher risk of AKI. Here, we provide a detailed overview of ICIs-related nephrotoxicity and the recently described multicenter studies. Several factors have been reported as biomarkers of ICIs-irAEs, in this review we speculate on potential biomarkers for ICIs-associated AKI.

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Sepsis remains a serious cause of morbidity and mortality in critically ill patients, with limited therapeutic options available. Of the several disorders connected with sepsis, acute kidney injury (AKI) is one of the major complications. The pathophysiology of sepsis-induced AKI is characterized by severe inflammation in renal parenchyma with endothelial dysfunction, intra-glomerular thrombosis and tubular injury. Endothelial dysfunction is regulated by several mechanisms implicated in cellular de-differentiation, such as endothelial-to-mesenchymal transition (EndMT). Gram-negative bacteria and their cell wall component lipopolysaccharides (LPSs) are frequently involved in the pathogenesis of AKI. The host recognition of LPS requires a specific receptor, which belongs to the Toll-like receptor (TLR) family of proteins, called TLR4, and two carrier proteins, namely the LPS-binding protein (LBP) and cluster of differentiation 14 (CD14). In particular, LBP is released as a consequence of Gram-negative infection and maximizes the activation of TLR4 signalling. Recent findings regarding the emerging role of LBP in mediating sepsis-induced AKI, and the possible beneficial effects resulting from the removal of this endogenous adaptor protein, will be discussed in this review.

Epigenetic mechanisms, such as DNA methylation, affect tubular maladaptive response after Acute Kidney Injury (AKI) and accelerate renal aging. Upon ischemia/reperfusion (I/R) injury, Complement activation leads to C5a release that mediates damage; however, little is known about the effect of C5a-C5a Receptor (C5aR) interaction in Renal Tubular Epithelial Cells (RTEC). Through a whole-genome DNA methylation analysis in cultured RTEC, we found that C5a induced aberrant methylation, particularly in regions involved in cell cycle control, DNA damage and Wnt signaling. The most represented genes were BCL9 , CYP1B1 and CDK6 . C5a stimulation of RTEC led to up-regulation of SA-β Gal and cell cycle arrest markers such as p53 and p21. C5a increased also IL-6 , MCP-1 and CTGF gene expression, consistent with SASP development. In accordance, in a swine model of renal I/R injury, we found the increased expression of Wnt4 and βcatenin correlating with SA-β Gal, p21, p16 and IL-6 positivity. Administration of Complement Inhibitor (C1-Inh), antagonized SASP by reducing SA-β Gal, p21, p16, IL-6 and abrogating Wnt4/βcatenin activation. Thus, C5a affects the DNA methylation of genes involved in tubular senescence. Targeting epigenetic programs and Complement may offer novels strategies to protect tubular cells from accelerated aging and to counteract progression to Chronic Kidney Disease

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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.

Pericytes are one of the principal sources of scar-forming myofibroblasts in chronic kidneys disease. However, the modulation of pericyte-to-myofibroblast transdifferentiation (PMT) in the early phases of acute kidney injury is poorly understood. Here, we investigated the role of complement in inducing PMT after transplantation. Using a swine model of renal ischemia/reperfusion (I/R) injury, we found the occurrence of PMT after 24 h of I/R injury as demonstrated by reduction of PDGFRβ+/NG2+ cells with increase in myofibroblasts marker αSMA. In addition, PMT was associated with significant reduction in peritubular capillary luminal diameter. Treatment by C1-inhibitor (C1-INH) significantly preserved the phenotype of pericytes maintaining microvascular density and capillary lumen area at tubulointerstitial level. In vitro, C5a transdifferentiated human pericytes in myofibroblasts, with increased αSMA expression in stress fibers, collagen I production, and decreased antifibrotic protein Id2. The C5a-induced PMT was driven by extracellular signal-regulated kinases phosphorylation leading to increase in collagen I release that required both non-canonical and canonical TGFβ pathways. These results showed that pericytes are a pivotal target of complement activation leading to a profibrotic maladaptive cellular response. Our studies suggest that C1-INH may be a potential therapeutic strategy to counteract the development of PMT and capillary lumen reduction in I/R injury.

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