Aspects of immune dysfunction in end-stage renal disease

Abstract

End-stage renal disease (ESRD) is associated with significantly increased morbidity and mortality resulting from cardiovascular disease (CVD) and infections, accounting for 50% and 20%, respectively, of the total mortality in ESRD patients. It is possible that these two complications are linked to alterations in the immune system in ESRD, as uremia is associated with a state of immune dysfunction characterized by immunodepression that contributes to the high prevalence of infections among these patients, as well as by immunoactivation resulting in inflammation that may contribute to CVD. This review describes disorders of the innate and adaptive immune systems in ESRD, underlining the specific role of ESRD-associated disturbances of Toll-like receptors. Finally, based on the emerging links between the alterations of immune system, CVD, and infections in ESRD patients, it emphasizes the potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population and the need for more studies in this area.

Figure 1.

Mortality caused by cardiovascular disease (A) and sepsis (B) of patients with end-stage renal disease (ESRD) treated by dialysis compared with the general population (GP). ^aBased on the figure by Foley et al. (2). ^bBased on the figure by Sarnak and Jaber (3).

Figure 2.

A schematic presentation of secreted, endocytic, and signaling pattern-recognition receptors. (A) The lectin pathway of complement activation. Mannose-binding lectin is a secreted pattern-recognition receptor specific for microbial carbohydrates. Binding of mannose-binding lectin to its microbial ligands leads to activation of the complement cascade. (B) Endocytic pattern-recognition receptors stick to pathogen specific cell walls and mediate phagocytosis. The pathogens are digested into antigenic peptides and presented to the major histocompatibility complex (MHC) class II molecules on the surface of APCs. This complex is recognized by T-cell receptors, which leads to T-cell activation. (C) Signaling pattern-recognition receptors, which are represented by Toll-like receptors, recognize pathogen-associated molecular patterns. The activation via these receptors mediates induction of cytokines and costimulatory molecules, for example CD80 and CD86, on the surface of APCs. Thus, pattern-recognition receptors of innate immunity system are instrumental for the adaptive immunity system.

Figure 3.

Potential links between the immune dysfunction in uremia, inflammation, infection, and increased risk of atherosclerosis and cardiovascular disease. We hypothesize that an immunosuppressed state, leading to increased susceptibility to infection, may lead to chronic inflammation and that inflammation may also ensue as a consequence of a state of immunoactivation. In addition, external factors, such as the dialysis procedure, dialysis access (blood or peritoneal) infections, medication, and PEW, may activate or inhibit the immune system.

Figure 4.

Possible impact of an impaired immune function in uremia on mortality. The right part of the figure demonstrates that dysfunction of the immune system may contribute to mortality, via increased susceptibility to infections and increased risk of cardiovascular disease. The left part of the figure shows an alternative scenario where an impairment in the immune function instead is associated with a lower degree of immunoactivation contributing to lower mortality through avoidance of potentially harmful consequences of an activated immune system.