In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches.

Background. In chronic kidney disease (CKD) patients, the ability to excrete a phosphate load is impaired. Compensatory increase in parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) promote phosphaturia. Serum FGF23 concentration is considered an early biomarker of excess phosphate load and high levels of FGF23 have been associated with increased mortality. In the present study, we have evaluated the changes in plasma FGF23 after treatment with the phosphate binder lanthanum carbonate in patients with CKD-3 and a normal serum phosphate concentration. Methods. Eighteen Caucasian CKD Stage 3a/3b patients with serum phosphate <4.5 mg/dL were recruited in a prospective longitudinal open-label study. Patients received a 4-week period of standardized phosphorus-restricted diet containing 0.8 g/Kg/day protein. Thereafter, the same diet was maintained and patients received lanthanum carbonate (750 mg with the three main meals) for 4 weeks. Results. No significant changes were observed in serum phosphate, however, lanthanum carbonate significantly decreased urinary excretion of phosphate and fractional excretion of phosphate (P < 0.004). This was accompanied by a significant decrease in carboxyterminal FGF23 (median percent change from baseline −21.8% (interquartile range −4.5, −30%), P = 0.025). No changes were observed in PTH. Conclusions. In conclusion, lanthanum carbonate reduced phosphate load, as assessed by urinary phosphate excretion, and also reduced plasma FGF23 in CKD-3 patients. This occurs in the presence of unchanged normal serum phosphate levels.

In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of death. Some uremic toxins are ingested with the diet, such as phosphate and star fruit-derived caramboxin. Others result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves. These nutrients include l-carnitine, choline/phosphatidylcholine, tryptophan and tyrosine, which are also sold over-the-counter as nutritional supplements. Physicians and patients alike should be aware that, in CKD patients, the use of these supplements may lead to potentially toxic effects. Unfortunately, most patients with CKD are not aware of their condition. Some of the dietary components may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins, such as trimethylamine N-Oxide (TMAO), p-cresyl sulfate, indoxyl sulfate and indole-3 acetic acid. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of death and cardiovascular disease and there is evidence that this association may be causal. Future developments may include maneuvers to modify gut processing or absorption of these nutrients or derivatives to improve CKD patient outcomes.

BACKGROUND: Bisphenol A (BPA) is a ubiquitous environmental toxin that accumulates in chronic kidney disease (CKD). Our aim was to explore the effect of chronic exposition of BPA in healthy and injured kidney investigating potential mechanisms involved. METHODS: In C57Bl/6 mice, administration of BPA (120 mg/kg/day, i.p for 5 days/week) was done for 2 and 5 weeks. To study BPA effect on CKD, a model of subtotal nephrectomy (SNX) combined with BPA administration for 5 weeks was employed. In vitro studies were done in human proximal tubular epithelial cells (HK-2 line). RESULTS: Chronic BPA administration to healthy mice induces inflammatory infiltration in the kidney, tubular injury and renal fibrosis (assessed by increased collagen deposition). Moreover, in SNX mice BPA exposure exacerbates renal lesions, including overexpression of the tubular damage biomarker Hepatitis A virus cellular receptor 1 (Havcr-1/KIM-1). BPA upregulated several proinflammatory genes and increased the antioxidant response [Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme Oxygenase-1 (Ho-1) and NAD(P)H dehydrogenase quinone 1 (Nqo-1)] both in healthy and SNX mice. The autophagy process was modulated by BPA, through elevated autophagy-related gene 5 (Atg5), autophagy-related gene 7 (Atg7), Microtubule-associated proteins 1A/1B light chain 3B (Map1lc3b/Lc3b) and Beclin-1 gene levels and blockaded the autophagosome maturation and flux (p62 levels). This autophagy deregulation was confirmed in vitro. CONCLUSIONS: BPA deregulates autophagy flux and redox protective mechanisms, suggesting a potential mechanism of BPA deleterious effects in the kidney.

Patients with renal impairment progressively lose the ability to excrete phosphorus. Decreased glomerular filtration of phosphorus is initially compensated by decreased tubular reabsorption, regulated by PTH and FGF23, maintaining normal serum phosphorus concentrations. There is a close relationship between protein and phosphorus intake. In chronic renal disease, a low dietary protein content slows the progression of kidney disease, especially in patients with proteinuria and decreases the supply of phosphorus, which has been directly related with progression of kidney disease and with patient survival. However, not all animal proteins and vegetables have the same proportion of phosphorus in their composition. Adequate labeling of food requires showing the phosphorus-to-protein ratio. The diet in patients with advanced-stage CKD has been controversial, because a diet with too low protein content can favor malnutrition and increase morbidity and mortality. Phosphorus binders lower serum phosphorus and also FGF23 levels, without decreasing diet protein content. But the interaction between intestinal dysbacteriosis in dialysis patients, phosphate binder efficacy, and patient tolerance to the binder could reduce their efficiency.