The intestine and the kidneys: a bad marriage can be hazardous

Abstract

The concept that the intestine and chronic kidney disease influence each other, emerged only recently. The problem is multifaceted and bidirectional. On one hand, the composition of the intestinal microbiota impacts uraemic retention solute production, resulting in the generation of essentially protein-bound uraemic toxins with strong biological impact such as vascular damage and progression of kidney failure. On the other hand, the uraemic status affects the composition of intestinal microbiota, the generation of uraemic retention solutes and their precursors and causes disturbances in the protective epithelial barrier of the intestine and the translocation of intestinal microbiota into the body. All these elements together contribute to the disruption of the metabolic equilibrium and homeostasis typical to uraemia. Several measures with putative impact on intestinal status have recently been tested for their influence on the generation or concentration of uraemic toxins. These include dietary measures, prebiotics, probiotics, synbiotics and intestinal sorbents. Unfortunately, the quality and the evidence base of many of these studies are debatable, especially in uraemia, and often results within one study or among studies are contradictory. Nevertheless, intestinal uraemic metabolite generation remains an interesting target to obtain in the future as an alternative or additive to dialysis to decrease uraemic toxin generation. In the present review, we aim to summarize (i) the role of the intestine in uraemia by producing uraemic toxins and by generating pathophysiologically relevant changes, (ii) the role of uraemia in modifying intestinal physiology and (iii) the therapeutic options that could help to modify these effects and the studies that have assessed the impact of these therapies.

Keywords: CKD; creatinine; haemodialysis; systematic review; uraemic toxins.

Fig. 1.

Main metabolic pathways involved in uraemic toxin generation. (A) ingestion via the gastrointestinal tract and direct unmodified uptake via the intestinal wall into the systemic circulation (e.g. advanced glycation end products); (B) gastrointestinal uptake of a precursor (e.g. an amino acid), that is transformed by the intestinal microbiota into another precursor (e.g. indole); after its uptake via the intestinal wall and portal vein, this precursor is further conjugated by the liver (e.g. indoxyl sulphate) before its transfer into the systemic circulation; (C) gastrointestinal uptake of a precursor (e.g. an amino acid), that is transformed by the intestinal microbiota into another precursor (e.g. indole); the precursor is conjugated during its uptake via the intestinal wall (e.g. indoxyl sulphate) and then passes into the systemic circulation via the liver without further modification; (D) endogenous generation without contribution of the gastro-intestinal tract (e.g. β₂-microglobulin). Modified from Schepers et al. [12].

Fig. 2.

The dual interference between the intestine and uraemia. The intestine is responsible for generating and absorbing uraemic toxins with a deleterious impact on body functions. Uraemia in its turn modifies intestinal functions with a further increase in uraemic toxin generation and pro-inflammatory modifications which again are deleterious to body functions.