Anemia is a common complication of chronic kidney disease (CKD). There are various causes of renal anemia such as decreased production of erythropoietin, resistance to erythropoietin, shortened ...survival of red blood cells, and bone marrow fibrosis. Secondary hyperparathyroidism (SHPT) is a less recognized, but potentially significant cause of renal anemia in CKD patients. Parathyroid hormone (PTH) has been regarded as a uremic toxin that has multiple adverse effects, and its elevated levels have been associated with renal anemia in hemodialysis patients. Moreover, recent clinical studies have shown that the treatment of SHPT using either vitamin D receptor activators, calcimimetics, or parathyroidectomy leads to improvement of anemia, supporting the role of PTH in renal anemia. Emerging data have also indicated the involvement of bone‐derived fibroblast growth factor 23 in renal anemia. This review summarizes recent insights into the role of PTH in renal anemia and discusses the importance of treating SHPT in improving the control of renal anemia in hemodialysis patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The degree of oxidized cysteine (Cys) 34 in human serum albumin (HSA), as determined by high performance liquid chromatography (HPLC), is correlated with oxidative stress related pathological ...conditions. In order to further characterize the oxidation of Cys34-HSA at the molecular level and to develop a suitable analytical method for a rapid and sensitive clinical laboratory analysis, the use of electrospray ionization time-of-flight mass spectrometer (ESI-TOFMS) was evaluated. A marked increase in the cysteinylation of Cys34 occurs in chronic liver and kidney diseases and diabetes mellitus. A significant positive correlation was observed between the Cys-Cys34-HSA fraction of plasma samples obtained from 229 patients, as determined by ESI-TOFMS, and the degree of oxidized Cys34-HSA determined by HPLC. The Cys-Cys34-HSA fraction was significantly increased with the progression of liver cirrhosis, and was reduced by branched chain amino acids (BCAA) treatment. The changes in the Cys-Cys34-HSA fraction were significantly correlated with the alternations of the plasma levels of advanced oxidized protein products, an oxidative stress marker for proteins. The binding ability of endogenous substances (bilirubin and tryptophan) and drugs (warfarin and diazepam) to HSA purified from chronic liver disease patients were significantly suppressed but significantly improved by BCAA supplementation. Interestingly, the changes in this physiological function of HSA in chronic liver disease were correlated with the Cys-Cys34-HSA fraction. In conclusion, ESI-TOFMS is a suitable high throughput method for the rapid and sensitive quantification of Cys-Cys34-HSA in a large number of samples for evaluating oxidative stress related chronic disease progression or in response to a treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Cost-effectiveness analysis of booster fifth-dose DTaP vaccination.•Reflection of herd immunity from vaccinated preschool children to infants.•Booster DTaP is expected to reduce pertussis cases in ...preschool children.•Booster DTaP vaccination to preschool children would not be cost-effective in Japan.
Introduction: Japan currently recommends four doses of the diphtheria-tetanus-acellular pertussis (DTaP) vaccine in its routine vaccination program, but the introduction of a fifth dose is currently under consideration. An objective of the booster vaccination is to prevent severe cases of pertussis in infants through herd immunity. Thus, the aim of this analysis was to demonstrate the cost-effectiveness of a fifth-dose of the DTaP vaccine for 6-year-old children, taking herd immunity for unvaccinated infants into account.
An economic model analysis was conducted comparing the cost and effectiveness of the two strategies based on quality-adjusted life years (QALYs). We evaluated the incremental cost-effectiveness ratio (ICER) of the booster strategy to the no booster strategy. This model contained two sub-models: one for children aged 6 years or older and one for infants under 3 months old. Herd immunity for infants is modeled as when siblings in the same family are infected.
The ICER was JPY 71,605,491 (USD 656,931) per QALY gained from the societal perspective, and 7.10% of incremental QALYs (0.0000934) were from a reduction in infant infection. In the sensitivity analysis, no variables moved the ICER under the threshold (JPY 5,000,000 per QALY gained), and the duration of pertussis disease and the incidence rate of pertussis had a significant impact on the ICER. When the disease burden of pertussis decreased, the booster strategy resulted in fewer QALYs gained and greater costs compared with the no booster strategy.
The introduction of a DTaP booster vaccination to the routine immunization schedule can be expected to reduce the number of pertussis cases in the target population. However, our study showed that adding a booster vaccination for 6-year-old children to the schedule in Japan would not be cost-effective in terms of achieving herd immunity among unvaccinated infants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Chronic 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.
Methods
The 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.
Results
In 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.
Conclusions
Our 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.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Chronic kidney disease (CKD) patients with secondary hyperparathyroidism (SHPT) have an increased risk of cardiovascular disease (CVD). Cinacalcet is a calcimimetic that permits impaired endothelial ...functions to be recovered via inhibiting parathyroid hormone (PTH) production in SHPT patients. However, the underlying mechanism for its action remains unknown. The purpose of this study was to examine the effect of cinacalcet on the redox state of human serum albumin (HSA), a reliable marker for assessing endothelial oxidative damage in SHPT patients who were receiving hemodialysis. Cinacalcet was administered to six SHPT patients for a period of 8 weeks. After 4 weeks of treatment, cinacalcet significantly decreased the oxidized albumin ratio which is a ratio of reduced and oxidized forms of HSA via increasing reduced form of HSA. Moreover, the radical scavenging abilities of HSA that was isolated from SHPT patients were increased by cinacalcet, suggesting the recovery of the impaired vascular anti-oxidant ability. Interestingly, the oxidized albumin ratio in SHPT patients was significantly higher than that in hemodialysis patients. In addition, the changes of intact PTH levels were significantly correlated with the oxidized albumin ratio. It therefore appears that PTH may induce oxidative stress in SHPT patients. In fact, an active analogue of PTH increased the production of reactive oxygen species in human endothelial cells. Thus, cinacalcet exhibits anti-oxidative activity through its pharmacological action. Additionally, cinacalcet itself showed radical scavenging activity. In conclusion, cinacalcet improves the redox status of HSA by inhibiting PTH production and partially by its radical scavenging action.
Finding an appropriate carrier for antisense oligonucleotides (AS-ODNs) and improving the efficiency of their delivery to cells and organs has been critical for the translation of antisense therapy ...into practice for more than 30 years. We have used a β-glucan, schizophyllan (SPG), as a delivery tool to solve this issue. SPG forms a complex with AS-ODNs that can be taken up by cells expressing the β-glucan receptor Dectin-1. We used SPG/AS-DNA complexes containing four to ten ODNs with a relatively large distribution of molecular weights. We recently discovered a complex in which the number of AS-ODNs can be accurately controlled and denoted it as a quantized complex. Building on our previous work, this paper presents the biological properties of this new quantized complex, including its efficacy for cells expressing Dectin-1 and the mechanism behind its cellular uptake of gene-silenced AS-ODNs and immunostimulatory CpG-ODNs. We found that this new complex is also recognized by Dectin-1, and interestingly, is more effective than the conventional complexes, owing to its easier escape from the endocytotic pathway.In this study, we examined the efficiency of q1-complex and L-SPG complex in translocation to the cytoplasm. The results showed that the q1 complex can deliver YB-1-AS into the cytoplasm about three times more efficiently than the L-SPG complex.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Sarcopenia with chronic kidney disease (CKD) progression is associated with life prognosis. Oxidative stress has attracted interest as a trigger for causing CKD‐related muscular atrophy. ...Advanced oxidation protein products (AOPPs), a uraemic toxin, are known to increase oxidative stress. However, the role of AOPPs on CKD‐induced muscle atrophy remains unclear.
Methods
In a retrospective case–control clinical study, we evaluated the relationship between serum AOPPs levels and muscle strength in haemodialysis patients with sarcopenia (n = 26, mean age ± SEM: 78.5 ± 1.4 years for male patients; n = 22, mean age ± SEM: 79.1 ± 1.5 for female patients), pre‐sarcopenia (n = 12, mean age ± SEM: 73.8 ± 2.0 years for male patients; n = 4, mean age ± SEM: 74.3 ± 4.1 for female patients) or without sarcopenia (n = 12, mean age ± SEM: 71.3 ± 1.6 years for male patients; n = 7, mean age ± SEM: 77.7 ± 1.6 for female ). The molecular mechanism responsible for the AOPPs‐induced muscle atrophy was investigated by using 5/6‐nephrectomized CKD mice, AOPPs‐overloaded mice, and C2C12 mouse myoblast cells.
Results
The haemodialysis patients with sarcopenia showed higher serum AOPPs levels as compared with the patients without sarcopenia. The serum AOPPs levels showed a negative correlation with grip strength (P < 0.01 for male patients, P < 0.01 for female patients) and skeletal muscle index (P < 0.01 for male patients). Serum AOPPs levels showed a positive correlation with cysteinylated albumin (Cys‐albumin), a marker of oxidative stress (r2 = 0.398, P < 0.01). In the gastrocnemius of CKD mice, muscle AOPPs levels were also increased, and it showed a positive correlation with atrogin‐1 (r2 = 0.538, P < 0.01) and myostatin expression (r2 = 0.421, P < 0.05), but a negative correlation with PGC‐1α expression (r2 = 0.405, P < 0.05). Using C2C12 cells, AOPPs increased atrogin‐1 and myostatin expression through the production of reactive oxygen species via CD36/NADPH oxidase pathway, and decreased myotube formation. AOPPs also induced mitochondrial dysfunction. In the AOPPs‐overloaded mice showed that decreasing running time and hanging time accompanied by increasing AOPPs levels and decreasing cross‐sectional area in gastrocnemius.
Conclusions
Advanced oxidation protein products contribute to CKD‐induced sarcopenia, suggesting that AOPPs or its downstream signalling pathway could be a therapeutic target for the treatment of CKD‐induced sarcopenia. Serum AOPPs or Cys‐albumin levels could be a new diagnostic marker for sarcopenia in CKD.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Hyperuricemia occurs with increasing frequency among patients with hyperparathyroidism. However, the molecular mechanism by which the serum parathyroid hormone (PTH) affects serum urate levels ...remains unknown. This was studied in uremic rats with secondary hyperparathyroidism where serum urate levels were found to be increased and urate excretion in the intestine and kidney decreased, presumably due to down-regulation of the expression of the urate exporter ABCG2 in intestinal and renal epithelial membranes. These effects were prevented by administration of the calcimimetic cinacalcet, a PTH suppressor, suggesting that PTH may down-regulate ABCG2 expression. This was directly tested in intestinal Caco-2 cells where the expression of ABCG2 on the plasma membrane was down-regulated by PTH (1-34) while its mRNA level remained unchanged. Interestingly, an inactive PTH derivative (13-34) had no effect, suggesting that a posttranscriptional regulatory system acts through the PTH receptor to regulate ABCG2 plasma membrane expression. As found in an animal study, additional clinical investigations showed that treatment with cinacalcet resulted in significant reductions in serum urate levels together with decreases in PTH levels in patients with secondary hyperparathyroidism undergoing dialysis. Thus, PTH down-regulates ABCG2 expression on the plasma membrane to suppress intestinal and renal urate excretion, and the effects of PTH can be prevented by cinacalcet treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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