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.

Evidence is emerging for the inflammatory nature of many ageing-associated diseases, including atherosclerosis, vascular calcification, diabetes and chronic kidney disease (CKD), among others. Ageing itself results in chronic low-grade inflammation that promotes end-organ damage. Inflammatory organ damage, in turn, may contribute to inflammation. Recent research has identified the kidney-secreted hormone Klotho as a central player at the ageing–inflammation interface. Thus, systemic or local renal inflammation decreases kidney Klotho expression. Klotho down-regulation may be induced by specific cytokines such as tumour necrosis factor-α or TWEAK through the canonical activation of the inflammatory transcription factor nuclear factor kappa B (NFκB) and, specifically RelA. In addition, inflammatory cytokines lead to the epigenetic inactivation of Klotho transcription. Klotho itself has antioxidant and anti-inflammatory properties and the canonical NFκB component RelA is one of its targets. Klotho is a key regulator of phosphate balance and a role of phosphate in ageing has been shown. However, the potential relationship between phosphate and inflammation requires further clarification. A correct understanding of these interactions may lead to the design of novel therapeutic approaches to CKD and CKD-related inflammatory and ageing features as well as to inflammation/ageing in general.

Chronic kidney disease (CKD) expands the prior concept of chronic renal insufficiency by including patients with relatively preserved renal function, as assessed by the estimated glomerular filtration rate (eGFR), as even these early CKD stages are associated with an increased risk for all-cause death and cardiovascular death, CKD progression and acute kidney injury. A decreased eGFR (3 months. However, when eGFR is ≥60 mL/min/1.73 m², an additional criterion is required to diagnose CKD. In a recent clinical trial published in The New England Journal of Medicine, all 6190 participants were reported to have CKD: 47% had Stages 1 and 2 CKD and 53% had Stage 3 CKD. This illustrates a widespread misunderstanding of the concept of CKD. Moreover, CKD categories in this study were assigned based on the estimated creatinine clearance. Since both estimated creatinine clearance and creatinine clearance overestimate eGFR, this illustrates another frequent misunderstanding: equating GFR with creatinine clearance. In this commentary, we clarify the concept of CKD and of CKD categories for non-nephrologists. Assigning a diagnosis of CKD to a patient with normal renal function and absence of other evidence of CKD may have negative consequences for the individual (e.g. insurance and others) as well as for the medical community at large by creating confusion about the concept.

Chronic kidney disease (CKD) is a prevalent cause of morbidity and mortality worldwide. A hallmark of CKD progression is renal fibrosis characterized by excessive accumulation of extracellular matrix (ECM) proteins. In this study, we aimed to investigate the correlation of the urinary proteome classifier CKD273 and individual urinary peptides with the degree of fibrosis. In total, 42 kidney biopsies and urine samples were examined. The percentage of fibrosis per total tissue area was assessed in Masson trichrome stained kidney tissues. The urinary proteome was analysed by capillary electrophoresis coupled to mass spectrometry. CKD273 displayed a significant and positive correlation with the degree of fibrosis (Rho = 0.430, P = 0.0044), while the routinely used parameters (glomerular filtration rate, urine albumin-to-creatinine ratio and urine protein-to-creatinine ratio) did not (Rho = −0.222; −0.137; −0.070 and P = 0.16; 0.39; 0.66, respectively). We identified seven fibrosis-associated peptides displaying a significant and negative correlation with the degree of fibrosis. All peptides were collagen fragments, suggesting that these may be causally related to the observed accumulation of ECM in the kidneys. CKD273 and specific peptides are significantly associated with kidney fibrosis; such an association could not be detected by other biomarkers for CKD. These non-invasive fibrosis-related biomarkers can potentially be implemented in future trials.

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.

Introduction: The age-standardized death rate from diabetic kidney disease increased by 106% from 1990 to 2013, indicating that novel therapeutic approaches are needed, in addition to the renin-angiotensin system (RAS) blockers currently in use. Clinical trial results of anti-fibrotic therapy have been disappointing. However, promising anti-inflammatory drugs are currently on phase 1 and 2 randomized controlled trials. Areas covered: The authors review the preclinical, phase 1 and 2 clinical trial information of drugs tested for diabetic kidney disease that directly target inflammation as a main or key mode of action. Agents mainly targeting other pathways, such as endothelin receptor or mineralocorticoid receptor blockers and vitamin D receptor activators are not discussed. Expert opinion: Agents targeting inflammation have shown promising results in the treatment of diabetic kidney disease when added on top of RAS blockade. The success of pentoxifylline in open label trials supports the concept of targeting inflammation. In early clinical trials, the pentoxifylline derivative CTP-499, the CCR2 inhibitor CCX140-B, the CCL2 inhibitor emapticap pegol and the JAK1/JAK2 inhibitor baricitinib were the most promising drugs for diabetic kidney disease. The termination of trials testing the anti-IL-1β antibody gevokizumab in 2015 will postpone the evaluation of therapies targeting inflammatory cytokines.