The kidneys are key contributors to body homeostasis, by virtue of controlled excretion of excessive fluid, electrolytes, and toxic waste products. The syndrome of uremia equals the altered physiology due to irreversible loss of kidney function that is left uncorrected for, despite therapeutic intervention(s). The intestines and its microbial content are prime contributors to this syndrome. The intestinal barrier separates the self (or the so-called “milieu intérior”) from the environment. In the large intestine, the intestinal barrier keeps apart human physiology and the microbiota. The enterocytes and the extracellular mucin layer functions form a complex multilayered structure, facilitating complex bidirectional metabolic and immunological crosstalk. The current review focuses on the intestinal barrier in chronic kidney disease (CKD). Loss of kidney function results in structural and functional alterations of the intestinal barrier, contribution to the syndrome of uremia.

Patients with chronic kidney disease (CKD) are at increased risk of bone mineral density loss and vascular calcification. Bone demineralization and vascular mineralization often concur in CKD, similar to what observed in the general population. This contradictory association is commonly referred to as the ‘calcification paradox’ or the bone–vascular axis. Mounting evidence indicates that CKD-associated gut dysbiosis may be involved in the pathogenesis of the bone–vascular axis. A disrupted intestinal barrier function, a metabolic shift from a predominant saccharolytic to a proteolytic fermentation pattern, and a decreased generation of vitamin K may, alone or in concert, drive a vascular and skeletal pathobiology in CKD patients. A better understanding of the role of gut dysbiosis in the bone–vascular axis may open avenues for novel therapeutics, including nutriceuticals.

Background In haemodialysis, maintaining patency of the extracorporeal circuit requires the use of anticoagulants. Although (low molecular weight) heparins are the mainstay, these are not well tolerated in all patients. Alternative approaches include saline infusion, citrate-containing dialysate, regional citrate anticoagulation or the use of heparin-coated membranes. Asymmetric cellulose triacetate (ATA) dialysers have a low degree of platelet contact activation and might be an alternative to heparin-coated dialysers. The aim of this study was to test the clotting propensity of ATA when used without systemic anticoagulation. Methods We performed a Phase II pilot study in maintenance dialysis patients. The ‘Strategies for Asymmetrical Triacetate dialyzer heparin-Free Effective hemodialysis’ (SAFE) study was a two-arm open-label crossover study. In Arm A, patients were dialysed using 1.9 m2 ATA membranes in combination with a citrate-containing dialysate (1 mM). In Arm B, the ATA membrane was combined with high-volume predilution haemodiafiltration (HDF) without any other anticoagulation. The primary endpoint was the success rate to complete 4 h of haemodialysis without preterm clotting. Secondary endpoints included time to clotting and measures of dialysis adequacy. Results We scheduled 240 dialysis sessions (120/arm) in 20 patients. Patients were randomized 1:1 to start with Arm A or B. All patients crossed to the other arm halfway through the study. A total of 232 (96.7%) study treatments were delivered. Overall, 23 clotting events occurred, 7 in Arm A and 16 in Arm B. The success rate in Arm A (ATA + citrate-containing dialysate) was 90.8/94.0% [intention to treat (ITT)/as treated]. The success rate in Arm B (ATA + predilution HDF) was 83.3/86.2% (ITT/as treated). Time to clotting was borderline significantly better in Arm A (Mantel-Cox log rank P = 0.05). Conclusion ATA dialysers have a low clotting propensity and both predilution HDF and a citrate-containing dialysate resulted in high rates of completed dialysis sessions.

See related rapid communication, "Arginase-1 is Required for Macrophage-Mediated Renal Tubule Regeneration," on pages 1077-1086.

BACKGROUND AND AIMS Chronic kidney disease (CKD) patients present an increased plasma level of protein-bound solutes known as uraemic toxins. Their accumulation is associated with, amongst others, cardiovascular events. The gut microbiome plays an important role in the generation of part of the uraemic toxins. It has been postulated that proximal tubule cells in kidneys are able to sense augmented levels of gut microbial metabolites via receptors and signalling pathways [1]. According to the so-called remote sensing hypothesis, kidney tubular cells respond to uraemic toxins plasma variations modulating the activity of membrane transporters involved in their excretion. Indoxyl sulfate (IS) originates from the microbial fermentation of tryptophan, a diet-derived amino acid. Nonetheless, few studies have investigated whether gut generation, absorption and plasma retention of indolic uraemic toxins and kidney cells’ secretory mechanisms are affected by the protein content in the diet. METHOD A total of 18 Sprague–Dawley male rats (Janvier, Le Genest- St Isle, France) 7–8 weeks old (weighing 270–388 g) were induced with CKD utilizing 5/6 nephrectomy and were randomly assigned to a low protein (LP) (n = 10) or a high protein (HP) (n = 8) diet. A sham-operated control group for each diet was used (n = 7 and n = 8 respectively). 24 h-urine was collected after 7 weeks, and euthanasia was carried out after 8 weeks from the induction of the disease (Figure 1). Blood and colon samples were collected. Diffusion chambers were used to assess colon permeability to indole over time (t = 0, 60, 90, 120 min). Indole concentration was quantified by Kovacs assay. Blood creatinine and urea were determined with standard laboratory techniques. Total plasmatic and urinary IS concentrations were measured using LC-MS/MS. The fractional excretion (FE) i.e. the percentage of IS excreted relatively to the kidney filtered load, was calculated to assess IS remote sensing. RESULTS Plasmatic levels of IS were significantly higher (P <0.001) in CKD rats compared to sham rats. However, CKD rats on an HP diet showed no difference in plasma IS (P = 0.63) compared to rats on an LP diet. Conversely, 24-h urinary IS was significantly increased in CKD rats on a HP diet (P <0.001). The FE of IS was significantly higher (P = 0.005) in CKD rats on an HP diet (Figure 2) and correlated with 24 h-urinary IS (Spearman r = 0.51, P -value = 0.03) and with protein intake (Spearman r = 0.52, P-value = 0.03) in CKD rats. Therefore, CKD rodent models’ results suggest higher absorption and/or production of indole at the intestinal level when an HP is administered to CKD rats. Plus, they provide additional proof of the remote sensing theory of indole metabolites. The permeability of colon to indole evaluated ex vivo with the diffusion chamber technique, showed an increased apparent apical-to-basolateral transport of indole (P = 0.049) in CKD rats on an HP diet compared to that of sham rats on the same diet, again suggesting modulatory mechanisms affecting indole metabolites transporters uptake. CONCLUSION An HP diet in 5/6 nephrectomized CKD rats leads to increased production of indole in the colon and increased fractional excretion of IS. These results provide an additional proof of mechanisms of remote sensing and signalling of indole-derived uraemic toxins. To conclude, the adoption of a low protein diet remains recommended in chronic kidney disease.