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), p16^ink4a, 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.

Hemodialysis (HD) patient are known to be susceptible to a wide range of early and long-term complication such as chronic inflammation, infections, malnutrition, and cardiovascular disease that significantly affect the incidence of mortality. A large gap between the number of people with end-stage kidney disease (ESKD) and patients who received kidney transplantation has been identified. Therefore, there is a huge need to explore the underlying pathophysiology of HD complications in order to provide treatment guidelines. The immunological dysregulation, involving both the innate and adaptive response, plays a crucial role during the HD sessions and in chronic, maintenance treatments. Innate immune system mediators include the dysfunction of neutrophils, monocytes, and natural killer (NK) cells with signaling mediated by NOD-like receptor P3 (NLRP3) and Toll-like receptor 4 (TLR4); in addition, there is a significant activation of the complement system that is mediated by dialysis membrane-surfaces. These effectors induce a persistent, systemic, pro-inflammatory, and pro-coagulant milieu that has been described as inflammaging. The adaptive response, the imbalance in the CD4+/CD8+ T cell ratio, and the reduction of Th2 and regulatory T cells, together with an altered interaction with B lymphocyte by CD40/CD40L, have been mainly implicated in immune system dysfunction. Altogether, these observations suggest that intervention targeting the immune system in HD patients could improve morbidity and mortality. The purpose of this review is to expand our understanding on the role of immune dysfunction in both innate and adaptive response in patients undergoing hemodialysis treatment.

Glomerulonephritis are renal inflammatory processes characterized by increased permeability of the Glomerular Filtration Barrier (GFB) with consequent hematuria and proteinuria. Glomerular endothelial cells (GEC) and podocytes are part of the GFB and contribute to the maintenance of its structural and functional integrity through the release of paracrine mediators. Activation of the complement cascade and pro-inflammatory cytokines (CK) such as Tumor Necrosis Factor α (TNF-α) and Interleukin-6 (IL-6) can alter GFB function, causing acute glomerular injury and progression toward chronic kidney disease. Endothelial Progenitor Cells (EPC) are bone-marrow-derived hematopoietic stem cells circulating in peripheral blood and able to induce angiogenesis and to repair injured endothelium by releasing paracrine mediators including Extracellular Vesicles (EVs), microparticles involved in intercellular communication by transferring proteins, lipids, and genetic material (mRNA, microRNA, lncRNA) to target cells. We have previously demonstrated that EPC-derived EVs activate an angiogenic program in quiescent endothelial cells and renoprotection in different experimental models. The aim of the present study was to evaluate in vitro the protective effect of EPC-derived EVs on GECs and podocytes cultured in detrimental conditions with CKs (TNF-α/IL-6) and the complement protein C5a. EVs were internalized in both GECs and podocytes mainly through a L-selectin-based mechanism. In GECs, EVs enhanced the formation of capillary-like structures and cell migration by modulating gene expression and inducing the release of growth factors such as VEGF-A and HGF. In the presence of CKs, and C5a, EPC-derived EVs protected GECs from apoptosis by decreasing oxidative stress and prevented leukocyte adhesion by inhibiting the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin). On podocytes, EVs inhibited apoptosis and prevented nephrin shedding induced by CKs and C5a. In a co-culture model of GECs/podocytes that mimicked GFB, EPC-derived EVs protected cell function and permeselectivity from inflammatory-mediated damage. Moreover, RNase pre-treatment of EVs abrogated their protective effects, suggesting the crucial role of RNA transfer from EVs to damaged glomerular cells. In conclusion, EPC-derived EVs preserved GFB integrity from complement- and cytokine-induced damage, suggesting their potential role as therapeutic agents for drug-resistant glomerulonephritis.

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

Many advantages have been reported with the use of machine perfusion (MP) to rescue extended criteria donor (ECD) grafts, improving both short- and long-term post-liver transplantation (LT) outcomes. Acute kidney injury (AKI) is a common post-LT complication associated with these grafts and may compromise patient outcomes and increase LT-related costs. The aim of the study was to analyze the incidence of AKI in recipients of MP-treated grafts compared with those receiving conventionally cold-stored (SCS) grafts, both before and after a propensity score matching (PSM). From a prospectively maintained database, LT recipients of MP-treated grafts were compared with SCS grafts transplanted in the same study period (January 2022–May 2025). PSM was performed based on donor risk index (DRI), macrosteatosis (≥ or <30%), and recipient NaMELD score using a 3:1 (MP vs. SCS) ratio. Of the 177 consecutive LTs, 30 were performed with MP-treated grafts (MP group) and 147 using SCS (SCS group). The MP group displayed more marginal characteristics: older age (72 vs. 62 years, p = 0.02), higher proportion of DCD (10% vs. 0, p = 0.04), and higher frequency of moderate steatosis (macro ≥ 30%, 10% vs. 2.7%, p = 0.09). AKI rates were similar between groups (63% vs. 45.6%, p = 0.16), as was the distribution across AKI stages. After PSM, donor and recipient characteristics were balanced, and AKI rates remained similar between groups (58.6% vs. 47.1%, p = 0.39). Donor diabetes and recipient age were independent predictors of AKI in multivariate analysis (donor diabetes OR 3.29, 95% CI 1.347–8.030; recipient age: OR 1.06, 95% CI 1.015–1.097, both p < 0.05). MCP-1 and TNF-α levels measured in the perfusate fluid within the first minutes of perfusion were positively correlated with post-LT creatinine peak (MCP-1, p = 0.00023, R = 0.58; TNF-α, p = 0.0004, R = 0.57). In conclusion, machine perfusion remains a valuable strategy for rescuing ECD liver grafts. In the current era—characterized by increasing use of machine-perfused grafts and extended criteria donors—recipients demonstrate postoperative renal outcomes comparable to those receiving conventionally preserved grafts.