Skeletal muscle atrophy, referred to as sarcopenia, is often observed in chronic kidney disease (CKD) patients, especially in patients who are undergoing hemodialysis. The purpose of this study was to determine whether uremic toxins are involved in CKD-related skeletal muscle atrophy. Among six protein-bound uremic toxins, indole containing compounds, indoxyl sulfate (IS) significantly inhibited proliferation and myotube formation in C2C12 myoblast cells. IS increased the factors related to skeletal muscle breakdown, such as reactive oxygen species (ROS) and inflammatory cytokines (TNF-α, IL-6 and TGF-β1) in C2C12 cells. IS also enhanced the production of muscle atrophy-related genes, myostatin and atrogin-1. These effects induced by IS were suppressed in the presence of an antioxidant or inhibitors of the organic anion transporter and aryl hydrocarbon receptor. The administered IS was distributed to skeletal muscle and induced superoxide production in half-nephrectomized (1/2 Nx) mice. The chronic administration of IS significantly reduced the body weights accompanied by skeletal muscle weight loss. Similar to the in vitro data, IS induced the expression of myostatin and atrogin-1 in addition to increasing the production of inflammatory cytokines by enhancing oxidative stress in skeletal muscle. These data suggest that IS has the potential to accelerate skeletal muscle atrophy by inducing oxidative stress-mediated myostatin and atrogin-1 expression.

BackgroundChronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS‐targeted intervention using AST‐120, which inhibits IS accumulation, or mitochondria‐targeted intervention using L‐carnitine or teneligliptin, a dipeptidyl peptidase‐4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice.MethodsThe in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6‐nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non‐treatment group and AST‐120, L‐carnitine, or teneligliptin treatment groups.ResultsIn C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC‐1α and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co‐incubation with an anti‐oxidant, ascorbic acid, L‐carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin‐6 and atrophy‐related factors such as myostatin and atrogin‐1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG‐1α and increased muscular autophagy, as reflected by decreased mitochondria‐rich type I fibres. An AST‐120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L‐carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level.ConclusionsOur results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS‐targeted and mitochondria‐targeted interventions for treating CKD‐induced muscle atrophy and decreased exercise endurance.

Background This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety. Methods We conducted our analysis using the MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials electronic databases searched on August 9, 2020. We calculated odds ratios (ORs) and 95% confidence intervals (CIs). Results Adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia with VCM trough concentrations ≥15 μg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47–0.85). The incidence of acute kidney injury (AKI) increased with increased trough concentrations and was significantly higher for trough concentrations ≥20 μg/mL compared to those at 15–20 μg/mL (OR 2.39, 95% CI 1.78–3.20). Analysis of the target area under the curve/minimum inhibitory concentration ratios (AUC/MIC) showed significantly lower treatment failure rates for high AUC/MIC (cut-off 400 ± 15%) (OR 0.28, 95% CI 0.18–0.45). The safety analysis revealed that high AUC value (cut-off 600 ± 15%) significantly increased the risk of AKI (OR 2.10, 95% CI 1.13–3.89). Our meta-analysis of differences in monitoring strategies included four studies. The incidence of AKI tended to be lower in AUC-guided monitoring than in trough-guided monitoring (OR 0.54, 95% CI 0.28–1.01); however, it was not significant in the analysis of mortality. Conclusions We identified VCM trough concentrations and AUC values that correlated with effectiveness and safety. Furthermore, compared to trough-guided monitoring, AUC-guided monitoring showed potential for decreasing nephrotoxicity.

The major cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease. Here, p-Cresyl sulfate (PCS), a uremic toxin, is considered to be a risk factor for cardiovascular disease in CKD. However, our understanding of the vascular toxicity induced by PCS and its mechanism is incomplete. The purpose of this study was to determine whether PCS enhances the production of reactive oxygen species (ROS) in vascular endothelial and smooth muscle cells, resulting in cytotoxicity. PCS exhibited pro-oxidant properties in human umbilical vein endothelial cells (HUVEC) and aortic smooth muscle cells (HASMC) by enhancing NADPH oxidase expression. PCS also up-regulates the mRNA levels and the protein secretion of monocyte chemotactic protein-1 (MCP-1) in HUVEC. In HASMC, PCS increased the mRNA levels of alkaline phosphatase (ALP), osteopontin (OPN), core-binding factor alpha 1, and ALP activity. The knockdown of Nox4, a subunit of NADPH oxidase, suppressed the cell toxicity induced by PCS. The vascular damage induced by PCS was largely suppressed in the presence of probenecid, an inhibitor of organic anion transporters (OAT). In PCS-overloaded 5/6-nephrectomized rats, plasma MCP-1 levels, OPN expression, and ALP activity of the aortic arch were increased, accompanied by the induction of Nox4 expression. Collectively, the vascular toxicity of PCS can be attributed to its intracellular accumulation via OAT, which results in an enhanced NADPH oxidase expression and increased ROS production. In conclusion, we found for the first time that PCS could play an important role in the development of cardiovascular disease by inducing vascular toxicity in the CKD condition.

Chronic kidney disease (CKD), a chronic catabolic condition, is characterized by muscle wasting and decreased muscle endurance. Many insights into the molecular mechanisms of muscle wasting in CKD have been obtained. A persistent imbalance between protein degradation and synthesis in muscle causes muscle wasting. During muscle wasting, high levels of reactive oxygen species (ROS) and inflammatory cytokines are detected in muscle. These increased ROS and inflammatory cytokine levels induce the expression of myostatin. The myostatin binding to its receptor activin A receptor type IIB stimulates the expression of atrogenes such as atrogin-1 and muscle ring factor 1, members of the muscle-specific ubiquitin ligase family. Impaired mitochondrial function also contributes to reducing muscle endurance. The increased protein-bound uremic toxin, parathyroid hormone, glucocorticoid, and angiotensin II levels that are observed in CKD all have a negative effect on muscle mass and endurance. Among the protein-bound uremic toxins, indoxyl sulfate, an indole-containing compound has the potential to induce muscle atrophy by stimulating ROS-mediated myostatin and atrogenes expression. Indoxyl sulfate also impairs mitochondrial function. Some potential therapeutic approaches based on the muscle wasting mechanisms in CKD are currently in the testing stages.