Dendritic Cell Dysfunction in Patients with End-stage Renal Disease

Abstract

End-stage renal disease (ESRD) with immune disorder involves complex interactions between the innate and adaptive immune responses. ESRD is associated with various alterations in immune function such as a reduction in polymorphonuclear leukocyte bactericidal activity, a suppression of lymphocyte proliferative response to stimuli, and a malfunction of cell-mediated immunity at the molecular level. ESRD also increases patients' propensity for infections and malignancies as well as causing a diminished response to vaccination. Several factors influence the immunodeficiency in patients with ESRD, including uremic toxins, malnutrition, chronic inflammation, and the therapeutic dialysis modality. The alteration of T-cell function in ESRD has been considered to be a major factor underlying the impaired adaptive cellular immunity in these patients. However, cumulative evidence has suggested that the immune defect in ESRD can be caused by an Ag-presenting dendritic cell (DC) dysfunction in addition to a T-cell defect. It has been reported that ESRD has a deleterious effect on DCs both in terms of their number and function, although the precise mechanism by which DC function becomes altered in these patients is unclear. In this review, we discuss the effects of ESRD on the number and function of DCs and propose a possible molecular mechanism for DC dysfunction. We also address therapeutic approaches to improve immune function by optimally activating DCs in patients with ESRD.

Keywords: Antigen presenting cells; Costimulatory molecule; Dendritic cells; End-stage renal disease; Immunodeficiency.

Figure 1. Effect of kidney failure on dendritic cells and therapeutic approaches involving the modulation of dendritic cell maturation. The loss of kidney function causes an accumulation of uremic toxins and proinflammatory molecules, leading to chronic low grade inflammation and increased oxidative stress. Kidney failure also leads to disturbed renal metabolic and endocrinologic activities, resulting in abnormalities such as increased parathyroid hormone production and a decreased circulating concentration of erythropoietin. The results of these defects associated with renal failure have detrimental effects on dendritic cells. After sensing a foreign Ag via TLRs and then capturing and processing it, dendritic cells undergo maturation and begin to express Ag–MHCs and appropriate costimulatory molecules like CD80 and CD86 at the cell surface. This process is associated with T-cell activation. Several therapeutic modalities can induce the terminal differentiation of immature dendritic cells into their fully matured immunogenic form through activating TLRs or inducing the upregulation of costimulatory molecules. The red line and plus sign indicate activation. The blue line and minus sign indicate inhibition. EPO, erythropoietin; GM-CSF, granulocyte macrophage colony-stimulating factor; HD, hemodialysis; MHC, major histocompatibility complex; MPL, monophosphoryl lipid; TCR, T-cell receptor; TLR, Toll-like receptor.