Fig. 1: Inflammaging is a key immune alteration in kidney failure that impairs vaccine responses.

Several factors associated with kidney failure and/or kidney replacement therapy — uraemia, intestinal permeability, oxidative stress, erythropoietin (EPO) and vitamin D deficiency, chronic kidney damage, bio-incompatibility of haemodialysis membranes and immunosuppressive therapy — contribute to immune alterations in patients. These factors interfere with processes involved in the generation of antigen-specific immune response, including antigen uptake and presentation by antigen-presenting cells (APCs), such as dendritic cells and/or macrophages, and the activation and proliferation of antigen-specific T and B cells. Moreover, the systemic changes that occur in patients with kidney failure act on immune cells to induce the production of the pro-inflammatory cytokines IL-1β, TNF, IFNγ, IL-6, IL-12, IL-18, CXC-chemokine ligand 10 (CXCL10), and the complement effector molecules C3a and C5a, while decreasing levels of anti-inflammatory IL-10. These alterations lead to the development of chronic systemic inflammation. In the long term, persistent immune cell activation can also induce exhaustion, which leads to functional impairment and contributes to premature ageing of the immune system. This process, termed inflammaging, is considered a hallmark of immune alteration in chronic kidney disease. Specifically, the effects of uraemia and microinflammation on thymic tissue accelerate the age-associated reduction in the generation of naive T cells and thus contribute to the loss of diversity in the T cell receptor repertoire. In addition, persistent immune activation expands the terminally differentiated effector T (T_EMRA) cell population. These highly differentiated T cells contain preformed pro-inflammatory molecules, are often self-reactive and can degranulate in response to unspecific signals, further contributing to inflammation.