Chronic Kidney Disease-Associated Immune Dysfunctions: Impact of Protein-Bound Uremic Retention Solutes on Immune Cells

Abstract

Regardless of the primary disease responsible for kidney failure, patients suffering from chronic kidney disease (CKD) have in common multiple impairments of both the innate and adaptive immune systems, the pathophysiology of which has long remained enigmatic. CKD-associated immune dysfunction includes chronic low-grade activation of monocytes and neutrophils, which induces endothelial damage and increases cardiovascular risk. Although innate immune effectors are activated during CKD, their anti-bacterial capacity is impaired, leading to increased susceptibility to extracellular bacterial infections. Finally, CKD patients are also characterized by profound alterations of cellular and humoral adaptive immune responses, which account for an increased risk for malignancies and viral infections. This review summarizes the recent emerging data that link the pathophysiology of CKD-associated immune dysfunctions with the accumulation of microbiota-derived metabolites, including indoxyl sulfate and p-cresyl sulfate, the two best characterized protein-bound uremic retention solutes.

Keywords: chronic kidney disease; immune system; uremic toxins.

Figure 1

Generation and impact of indoxyl sulfate (IS). During chronic kidney disease, dysbiosis increases tryptophanase-producing bacterial species that convert tryptophan into indol. IS is derived from indole hepatic metabolism. The loss of renal function lead to decreased excretion of IS. IS acts as AhR ligands, permitting its translocation into the nucleus of various cells, where it controls the expression of various genes. Abbreviations are; IS: indoxyl sulfate; AhR: aryl hydrocarbon receptor.

Figure 2

Schematic representation of chronic kidney disease (CKD)-associated immune dysfunctions. Chronic kidney disease and gut-microbiota dysbiosis lead to the accumulation of protein-bound uremic retention solutes (PBURS), including p-cresyl sulfate and indoxyl sulfate, which have an impact on innate and adaptive immune systems. PBURS impair endothelial cells function and induce chronic low-grade activation of innate immune effectors (monocytes and neutrophils). This toxic loop is responsible for accelerated atherosclerosis. Despite chronic activation, the antibacterial capacity of neutrophils is impaired by PBURS. PBURS also affect the adaptive immune system. CKD patients are characterized by defective dendritic cells (DCs), premature aging of T cells and impaired cellular and humoral responses, which in turn account for an increased risk for malignancies and viral infections. Abbreviations: DCs: dendritic cells; PBURS: protein-bound uremic retention solutes.