The clinical effectiveness and safety of traditional Chinese medicine uremic clearance granule combined with high-flux hemodialysis in the treatment of uremic pruritus: A protocol for systematic review and meta analysis.

BACKGROUND: Skin pruritus is a common complication in patients with uremia. When the hemodialysis time of patients is extended, and the probability of skin pruritus is greater. Patients often have the symptoms of skin pruritus intolerable, affecting the normal sleep and normal life of patients. The patients with uremic pruritus often constant scratching and pruritus skin, resulting in broken skin, and further symptoms such as infection, and subsequent skin shedding, prurigo nodularis, and other adverse complications, aggravating the patient's condition. Some patients will experience symptoms such as depression and insomnia due to skin pruritus, and simply scratching the skin lead to infection. Severely affected patients may even show suicidal tendency, endangering the physical and mental health of patients, and it is needed to give the effective treatment to patients. Hemodialysis is a common treatment for uremic pruritus, which can effectively relieve the pruritus symptoms of patients. The drugs can also relieve the symptoms and improve the degree of pruritus in patients. And some studies show that traditional Chinese medicine UCG combined with HFH in the treatment of uremic pruritus has a very good effect, Therefore, this study will systematically evaluate the clinical efficacy and safety of UCG combined with HFH and HFH alone in the treatment of uremic pruritus. METHODS: Use computer to search English and Chinese databases, English databases include: PubMed, Web of Science, EMbase, The Cochrane Library. Chinese databases include: CNKI, CBM, WanFang Data and VIP databases, collecting the RCT on the clinical effectiveness and safety of UCG combined with HFH and HFH alone in the treatment of uremic pruritus. The retrieval time is from the beginning of each database to May 1, 2021. In order to improve the retrieval rate of the literature, the references cited in the included research are also collected and screened. Set Chinese and English as the search language. Two members of the research group independently collected, included and excluded the literatures. In case of disagreement, consulting the third party to assist in the judgment. For the literature with missing data, the original author should be contacted as far as possible to obtain complete data. Two evaluators evaluate the bias risk of included studies according to the Cochrane Handbook bias risk assessment tool for RCT. RevMan 5.3 software is used for statistical analysis and the forest plot is drawn to show the outcome indicators and funnel plot is drawn to show the publication bias. RESULTS: This study evaluates the advantages and disadvantages of traditional Chinese medicine UCG combined with HFH and HFH alone in the treatment of uremic pruritus through the clinical effectiveness and safety-related indicators. CONCLUSION: This study will give a positive conclusion on the efficacy and safety of uremic clearance granule in the treatment of uremic pruritus, and the research results will be published in professional journals in the form of academic papers, thus benefiting more patients. ETHICS AND DISSEMINATION: This study belongs to meta-analysis and all data comes from academic papers published publicly in formal academic journals, so there are no ethical issues involved in this study and no ethical review or approval is required. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/W8P5G.

Optimized calcium supplementation approach in post-dilution CVVHDF using regional citrate anticoagulation.

BACKGROUND: Regional citrate anticoagulation has been recommended as first choice for anticoagulation of continuous renal replacement therapy. Precise calcium supplementation is important for the safety of regional citrate anticoagulation. In this study we aimed to provide an optimized calcium supplementation approach for regional citrate anticoagulation in post-dilution continuous venous-venous hemodiafiltration. METHODS: Twenty-seven patients receiving post-dilution continuous venous-venous hemodiafiltration anticoagulated by citrate were included in this study. The ionized calcium levels were monitored and maintained in the targeted range. After linear regression analysis of the clearance of non-protein bound calcium and calculating the ratio of the non-protein bound calcium concentration to total calcium concentration, we concluded the mathematical model for calcium supplementation. RESULTS: Positive correlations were found between the clearance of non-protein bound calcium and both dialysate flow rates (r = 0.647, p < 0.001) and ultrafiltration plus substitution fluid flow rates (r = 0.525, p = 0.005). The ratio of the non-protein bound calcium concentration to total calcium concentration values at the pre-filter point after infusion of citrate were constant about 0.83. Based on the clearance and the calcium ratio, the amount of extracorporeal calcium removal can be estimated with a simplified equation. CONCLUSIONS: We provided an optimized calcium supplementation approach for post-dilution continuous venous-venous hemodiafiltration anticoagulated by citrate which may help to estimate the amount of extracorporeal circuit removal of calcium with regard to different dosages of regional citrate anticoagulation.

Lack of Endothelial Nitric Oxide Synthase Accelerates Ectopic Calcification in Uremic Mice Fed an Adenine and High Phosphorus Diet.

Ectopic calcification is a risk of cardiovascular disease in chronic kidney disease (CKD) patients, and impaired endothelial nitric oxide synthase (eNOS) is involved in the CKD complications. However, whether eNOS dysfunction is a cause of ectopic calcification in CKD remains to be elucidated. To address this issue, we investigated the role of eNOS in ectopic calcification in mice with renal injury caused by an adenine and high-phosphorus (Ade + HP) diet. DBA/2J mice, a calcification-sensitive strain, were fed Ade + HP for 3 weeks. Expression levels of eNOS-related genes were reduced significantly in their calcified aorta. C57BL/6J is a calcification-resistant strain, and wild-type mice showed mild calcified lesions in the aorta and kidney when given an Ade + HP diet for 4 weeks. In contrast, a lack of eNOS led to the development of severe aortic calcification accompanied by an increase in runt-related transcription factor 2, an osteochondrogenic marker. Increased renal calcium deposition and the tubular injury score were remarkable in mice lacking eNOS-fed Ade + HP. Exacerbation of ectopic calcification by a lack of eNOS is associated with increased oxidative stress markers such as nicotinamide adenine dinucleotide phosphate oxidases. In conclusion, eNOS is critically important in preventing ectopic calcification. Therefore, the maintenance of eNOS is useful to reduce cardiovascular disease events and to improve prognosis in CKD patients.

The effects of omega-3 on the sleep quality of patients with uremic pruritus undergoing hemodialysis: a randomized crossover study.

OBJECTIVES: Information on sleep quality and its effective factors in the patients undergoing hemodialysis are important factors in future planning for improving sleep quality and ultimately the quality of life in these patients. The present study investigated the effect of omega-3 on the sleep quality of hemodialysis patients. METHODS: The 52 hemodialysis patients were randomized into two groups and underwent two different treatment modes (A and B). The first group was given omega-3 and cetirizine and the second group only received cetirizine for six weeks. After one week wash out, the study was followed by crossover treatment in both groups for six weeks. Sleep quality and pruritus severity were evaluated in patients before the intervention and at the end of each treatment period using the Pittsburgh Sleep Quality Index and the Yosipovitch Itch Questionnaire. The collected data was analyzed using repeated measures ANOVA and the Pearson correlation coefficient. RESULTS: The results of the study showed that majority of the patients (94.2%) had poor sleep quality (sleep score > 5 based on the questionnaire) and 5.8% of the patients had favorable sleep quality (sleep score < 5). Repeated measures ANOVA showed that sleep quality scores were different in two groups in phases 0, I and II (p <0.001). CONCLUSIONS: Sleep quality improved in both modes but more improvement was observed in mode A. Therefore, omega-3 fatty acids can be used as a suitable method for improving sleep quality in hemodialysis patients.

Parathyroid Hormone: A Uremic Toxin.

Parathyroid hormone (PTH) has an important role in the maintenance of serum calcium levels. It activates renal 1α-hydroxylase and increases the synthesis of the active form of vitamin D (1,25[OH]2D3). PTH promotes calcium release from the bone and enhances tubular calcium resorption through direct action on these sites. Hallmarks of secondary hyperparathyroidism associated with chronic kidney disease (CKD) include increase in serum fibroblast growth factor 23 (FGF-23), reduction in renal 1,25[OH]2D3 production with a decline in its serum levels, decrease in intestinal calcium absorption, and, at later stages, hyperphosphatemia and high levels of PTH. In this paper, we aim to critically discuss severe CKD-related hyperparathyroidism, in which PTH, through calcium-dependent and -independent mechanisms, leads to harmful effects and manifestations of the uremic syndrome, such as bone loss, skin and soft tissue calcification, cardiomyopathy, immunodeficiency, impairment of erythropoiesis, increase of energy expenditure, and muscle weakness.

Acupuncture Application in Chronic Kidney Disease and its Potential Mechanisms.

Chronic kidney disease (CKD) is an increasing major public health problem worldwide. The number of CKD patients on hemodialysis is growing rapidly as well. Acupuncture technique is one of the traditional Chinese medicine methods and has been used in a variety of diseases. Nowadays, the clinical application of acupuncture technique for CKD patients has become the focus for its effectiveness and security. In this paper, we will review the therapeutic effects and mechanisms of different acupuncture techniques for CKD patients. In patients with CKD, acupuncture improves renal function, reduces proteinuria, controls hypertension, corrects anemia, relieves pain, and controls many hemodialysis-related complications such as uremic pruritus, insomnia and fatigue. The mechanisms are related to the regulation of sympathetic nerve and the activation of bioactive chemicals. In conclusion, acupuncture is proved to be beneficial for CKD patients. More research, however, is needed to verify the potential mechanisms.

Establishment of colonic dialysis model in uremic rats by right nephrectomy and left partial nephrectomy.

BACKGROUND: Conventional treatments for patients suffering with end-stage renal disease (ESRD) has several disadvantages, highlighting the importance of other reproducible modalities such as colonic dialysis (CD). OBJECTIVES: The aim was to establish a CD model in uremic rats and evaluate the effect of two different peritoneal dialysis (PD) solutions. METHODS: Thirty-two male Wistar rats were randomly divided into four groups. After right nephrectomy and left partial nephrectomy, a Malone antegrade continence enema (MACE) stoma was created. Seven days after the procedure, blood sampling was performed. In group I (N = 8) no postoperative intervention was performed. In group II (N = 8), CD was started through the MACE stoma by a low osmolar PD solution. Rats of group III (N = 8) underwent the same procedure with a high osmolar PD solution. Rats of group IV (N = 8) underwent CD without nephrectomy in order to evaluate the feasibility of this technique. Mannitol and activated charcoal were also added to both PD solutions. Weekly blood sampling was performed in order to evaluate the plasma creatinine and blood urea nitrogen (BUN) level. RESULTS: In rats of the control group, the respective mean ± SD creatinine level was 1.5 ± 0.04 mg/dL, 7 days after the surgical procedure, but a lower creatinine level was found in groups II and III (0.8 ± 0.02 and 0.5 ± 0.03, respectively). Despite the fact that the creatinine level was in steady low states after regular CD in group II (1 ± 0.05) and group III (0.6 ± 0.02), it remained at higher levels in the control group (1.7 ± 0.08) 2 weeks postoperatively. Rats of group I did not survive until the third postoperative week, while the creatinine level was still lower in group III than in group II (0.6 ± 0.02 vs. 1.1 ± 0.03). Similar results were obtained for the BUN level at these timepoints. The mean ± SD survival period was 11 ± 2, 20 ± 3, and 33 ± 2 days in the animals of groups I, II, and III, respectively. DISCUSSION: To the best of our knowledge, this is the first study of CD establishment in a rat model. Unfortunately, the amount of protein loss, elevation of blood glucose levels, and electrolyte disturbance were not evaluated in the current study because of the limited amount of blood samples. Disturbance of these factors might be a cause of mortality in experimental groups undergoing CD while a significant decrease in BUN and creatinine levels was obtained. CONCLUSION: CD with an efficient PD solution through a MACE stoma may be a valuable option when conventional methods are not available.

Vitamin E protects against extraskeletal calcification in uremic rats fed high fat diets.

BACKGROUND: High fat diets are implicated in the pathogenesis of metabolic syndrome, obesity and renal disease. Previous studies have revealed that high fat diets promote vascular calcification in uremic rats. Moreover, vitamin E has been shown to prevent uremic calcifications in genetically obese Zucker rats fed standard diet. The objective of this study was to investigate the influence of vitamin E supplementation on the development of extraskeletal calcifications in non-obese (wild type) uremic rats fed high fat diets. METHODS: Wistar rats (n = 32) were preconditioned by feeding either a normal (NF) or high fat (HF) diet for 45 days and subsequently were subjected to 5/6 nephrectomy (Nx). Just before performing the first Nx step, a blood sample (Pre-Nx) was obtained. After Nx rats were switched to a diet with 0.9% phosphorus and supplemented with calcitriol. Also, after Nx, half of the rats from each group (NF and HF) were treated with vitamin E (VitE) in the diet (30,000 mg/kg) and the other half were maintained on basic VitE requirements (27 mg/kg). Thus, rats were allotted to four experimental groups: Nx-NF (n = 8), Nx-NF-VitE (n = 8), Nx-HF (n = 8) and Nx-HF-VitE (n = 8). At the time of sacrifice (day 66), blood and tissue samples were obtained. RESULTS: Feeding a HF diet for 45 days did not increase body weight but elicited hyperglycemia, hypertriglyceridemia, an increase in plasma fibroblast growth factor 23 and a reduction in plasma calcitriol concentrations. After Nx, rats fed HF diet showed substantial extraskeletal calcification with aortic calcium content that was higher than in rats fed NF diet. Supplementation with VitE significantly (p < 0.05) reduced aortic (from 38.4 ± 8.8 to 16.5 ± 1.4 mg/g), gastric (from 5.6 ± 2.7 to 1.2 ± 0.4 mg/g) and pulmonary (from 1.8 ± 0.3 to 0.3 ± 0.2 mg/g) calcium content in rats on HF diets. CONCLUSIONS: Uremic rats fed HF diets developed more severe extraosseous calcifications than their normocaloric-fed counterparts and dietary VitE supplementation protected against uremic calcifications in rats fed HF diets. Thus, eating energy-rich foods should be discouraged in patients with renal disease and their deleterious effect may be ameliorated with adequate antioxidant supply.

Curative effect of neutral macroporous resin hemoperfusion on treating hemodialysis patients with refractory uremic pruritus.

This study aims to investigate the efficacy and safety of neutral macroporous resin hemoperfusion in treating maintenance hemodialysis (MHD) patients with refractory uremic pruritus (RUP).Ninety patients were enrolled and were randomly divided into 3 groups: control group, experiment 1 group, and experiment 2 group. Clinical symptom scores of skin itching were recorded before and at 4 and 8 weeks after the treatment. In addition, serum parathyroid hormone (PTH), calcium (Ca), phosphorus (P), and C-reactive protein (CRP) were detected; and the calcium-phosphorus product ([Ca] × [P]) was calculated to compare the curative effect.VSA score, modified Duo pruritus score, and CRP: these indices decreased to some extent at 4 and 8 weeks after treatment in the 2 experiment groups, compared with pretreatment (P < 0.05); and differences among these 3 groups were statistically significant (P < 0.05). PTH, P, and [Ca] × [P]: these indices decreased to some extent at 4 and 8 weeks after treatment in the 2 experiment groups, compared with pretreatment (P < 0.05); and differences between the control and experiment 1 groups, as well as between the control and experiment 2 groups, were statistically significant (P < 0.05). However, the difference between the experiment 1 and experiment 2 groups were not statistically significant (P < 0.05).The effects of HA330 and HA130 resin hemoperfusion apparatus on secondary hyperparathyroidism and the disorder of calcium and phosphorus metabolism are similar. The mechanism may be related to its strong adsorption effect, and its capacity to widely remove inflammatory mediators, immune mediators, and endotoxins.

[Effects of auricular plaster therapy on quality of life in uremia patients after parathyroidectomy plus autograft].

OBJECTIVE: To observe the effects of auricular plaster therapy on quality of life in uremia patients after parathyroidectomy plus autograft (PTX+AT). METHODS: A total of 34 uremia patients complicated with secondary hyperparathyroidism (SHPT) who received PTX+AT were randomly divided into an observation group and a control group, 17 cases in each one. The patients in the control group were treated with calcium supplementation after surgery, 1 to 2 mg/kg an hour; one day after surgery, the patients were treated with oral administration of calcium carbonate before meals, 1.5 g, three times per day, and calcitriol (0.5 to 4 µg/d) was added if necessary. None-heparin hemodialysis was performed for one week after surgery. Besides calcium supplementation, patients in the observation group were treated with auricular plaster therapy at Shenmen (TF4), Jiaogan (AH6a), Neifenmi (CO18) and Shen (CO10). The laboratory indexes, including immunoreactive parathyroid hormone (iPTH), calcium, phosphorus, and SF-36 questionnaire, including 8 dimensions of physical function (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social function (SF), role-emotional (RE) and emotional well-being (EB), were observed before surgery and 1 week, 2 weeks, 4 weeks and 8 weeks after surgery in the two groups. RESULTS: The iPTH in the two groups was significantly decreased 1 week, 2 weeks, 4 weeks and 8 weeks after surgery, and the serum calcium and phosphorus were also improved to a certain degree (all P<0.05); however, the differences of iPTH, calcium and phosphorus between the two groups were not significant at each time point after surgery (all P>0.05).The PF, RP, BP, GH, VT, SF, RE and EB of SF-36 in the two groups before surgery were lower than the normal score; after surgery, each dimension of SF-36 were improved to some extent in the two groups (all P<0.05). Eight weeks after surgery, the improvement of PF, RP, BP, GH and EB in the observation group was superior to that in the control group (all P<0.05); however, in terms of VT, SF and RE, no significant difference was observed between the two groups (all P>0.05). CONCLUSION: The auricular plaster therapy can improve the physical and mental health, relieve pain and improve quality of life in patients with uremia after PTX+AT, which is superior to calcium carbonate alone.

Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.

Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-ß1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.

Cardiac effect of vitamin D receptor modulators in uremic rats.

Vitamin D receptor (VDR) modulators (VDRMs) are commonly used to control secondary hyperparathyroidism (SHPT) associated with chronic kidney disease, and are associated with beneficial outcomes in cardiovascular disease. In this study, we compared the cardiac effect of VS-105, a novel VDRM, with that of paricalcitol in 5/6 nephrectomized uremic rats. Male Sprague-Dawley rats were 5/6 nephrectomized, fed a standard diet for 4 weeks to establish uremia, and then treated (intraperitoneally, 3 times/week) with vehicle (propylene glycol), paricalcitol (0.025 and 0.15µg/kg), or VS-105 (0.05 and 0.3µg/kg) for 4 weeks. In uremic rats, neither VDRM (low and high doses) altered serum creatinine and phosphorus levels. Serum calcium was significantly higher with high dose paricalcitol compared to sham rats. PTH levels were significantly decreased with low dose paricalcitol and VS-105, and were further reduced in the high dose groups. Interestingly, serum FGF23 was significantly higher with high dose paricalcitol compared to sham rats, whereas VS-105 had no significant effect on FGF23 levels. Left ventricle (LV) weight and LV mass index determined by echocardiography were significantly suppressed in both high dose VDRM groups. This suppression was more evident with VS-105. Western blotting showed significant decreases in a fibrosis marker TGF-ß1 in both high dose VDRM groups (vs. vehicle) and Masson trichrome staining showed significant decreases in cardiac fibrosis in these groups. These results suggest that VS-105 is less hypercalcemic than paricalcitol and has favorable effects on SHPT and cardiac parameters that are similar to those of paricalcitol in uremic rats. The cardioprotective effect is a noteworthy characteristic of VS-105.

Effects of turmeric on uremic pruritus in end stage renal disease patients: a double-blind randomized clinical trial.

BACKGROUND: Uremic pruritus as a symptom that affects hemodialysis (HD) patients can decrease the quality of life and increase morbidity in these patients. The aim of this study was to evaluate the effects of turmeric on uremic pruritus in HD patients. SUBJECTS AND METHODS: This was a double-blind placebo-controlled trial conducted on 100 HD patients suffering from pruritus. Patients (mean age 53.3 ± 15.8 years) were randomized into two groups: turmeric and placebo. The pruritus score and biochemical determinants including high-sensitivity C-reactive protein (hs-CRP) were compared before and at the end of the study between the two groups. RESULTS: The mean decrease in hs-CRP was significantly higher in the turmeric than the placebo group (-0.8 ± 2.6 vs. 0.4 ± 8.7 mg/l, p = 0.012). Also reduction of pruritus scores was greater in the turmeric than the placebo group (13.6 ± 2.6 vs. 7.2 ± 2.6, p = 0.001). No side effect was observed during the study due to the use of turmeric. CONCLUSIONS: This study demonstrates the possible efficacy of turmeric in decreasing hs-CRP and uremic pruritus in end stage renal disease patients. Future studies are needed to further evaluate the efficacy and safety of turmeric.

Whole blood platelet aggregation and release reaction testing in uremic patients.

BACKGROUND: Platelet function analysis utilizing platelet-rich plasma and optical density based aggregometry fails to identify patients at risk for uremia associated complications. METHODS: We employed whole blood platelet aggregation analysis based on impedance as well as determination of ATP release from platelet granules detected by a chemiluminescence method. Ten chronic kidney disease (CKD) stage 4 or 5 predialysis patients underwent platelet evaluation. Our study aims to evaluate this platform in this patient population to determine if abnormalities could be detected. RESULTS: Analysis revealed normal aggregation and ATP release to collagen, ADP, and high-dose ristocetin. ATP release had a low response to arachidonic acid (0.37 ± 0.26 nmoles, reference range: 0.6-1.4 nmoles). Platelet aggregation to low-dose ristocetin revealed an exaggerated response (20.9 ± 18.7 ohms, reference range: 0-5 ohms). CONCLUSIONS: Whole blood platelet analysis detected platelet dysfunction which may be associated with bleeding and thrombotic risks in uremia. Diminished ATP release to arachidonic acid (an aspirin-like defect) in uremic patients may result in platelet associated bleeding. An increased aggregation response to low-dose ristocetin (a type IIb von Willebrand disease-like defect) is associated with thrombus formation. This platelet hyperreactivity may be associated with a thrombotic diathesis as seen in some uremic patients.

Uremic anorexia and gastrointestinal motility dysfunction correlate with the changes of ghrelin system in hypothalamus.

AIM: Ghrelin can act as a signal for meal initiation and play a role in the regulation of gastrointestinal (GI) motility via hypothalamic circuit. This study investigated the correlation between changes of hypothalamic ghrelin system and GI motility dysfunction and anorexia in rats with chronic renal failure (CRF). METHODS: Sprague-Dawley (SD) rats (male/female 1:1, 180 ± 20 g) were randomly classified into a CRF group and control group (n = 8 per group). 5/6 nephrectomy was used to construct the CRF model. When plasma creatinine concentration (PCr) and blood urea nitrogen (BUN) in the CRF group were twice higher than the normal, food intake (g/24 h) and gastrointestinal interdigestive myoelectric complex (IMC) were detected. Then all rats were killed for assessment of the mRNA expression of ghrelin and growth hormone secretagogue receptor (GHS-R) in hypothalamus using reverse transcription-polymerase chain reaction. Analysis of variance, Student-Newman-Keuls-q-test and Correlation Analysis were used to do statistical analysis. P < 0.05 was considered as statistically significant. RESULTS: Compared to the control group, the CRF group was obviously decreased in the food intake (g/24 h), the phase III duration and amplitude and the ghrelin and GHS-R expression in the hypothalamus (P < 0.05). There was a positive correlation between them (P < 0.05). CONCLUSION: Changes of ghrelin and GHS-R in the hypothalamus correlate with gastrointestinal motility dysfunction and anorexia in rats with CRF.

Maximal conservative therapy of calcific uremic ateriolopathy.

We present the case of a 61-year- old female patient in long-term hemodialysis who developed calcific uremic arteriolopathy (CUA) upon administration of the oral calcimimetic agent cinacalcet for treatment of secondary hyperparathyroidism. In May 2009, the baseline serum values were parathormone (PTH) 310 pg/ml, calcium 9.1 mg/dl and phosphorous 6.9 mg/dl. Necrotic wounds in the suprapubic fat tissue were successfully treated first, by correcting the calcium phosphorous product; second, through treatment with sodium thiosulfate and third, through intensive wound care with hyperbaric oxygen therapy and vacuum-assisted closure therapy, with no need for parathyroidectomy. Multiple factors have been described to play a role in the development of CUA. Based on the findings of this case, the treatment of CUA should be aimed at correcting different causes simultaneously.

Effect of dietary supplements in reducing probability of death for uremic crises in dogs affected by chronic kidney disease (masked RCCT).

Chitosan and alkalinizing agents can decrease morbidity and mortality in humans with chronic kidney disease (CKD). Whether this holds true in dog is not known. Objective of the study was to determine whether a commercial dietary supplement containing chitosan, phosphate binders, and alkalinizing agents (Renal), compared to placebo, reduces mortality rate due to uremic crises in dogs with spontaneous CKD, fed a renal diet (RD). A masked RCCT was performed including 31 azotemic dogs with spontaneous CKD. Dogs enrolled in the study were randomly allocated to receive RD plus placebo (group A; 15 dogs) or RD plus Renal (group B; 16 dogs). During a first 4-week period, all dogs were fed an RD and then randomized and clinically evaluated up to 44 weeks. The effects of dietary supplements on mortality rate due to uremic crises were assessed. At 44 weeks, compared to group A, dogs in group B had approximately 50% lower mortality rate due to uremic crises (P = 0.015). Dietary supplementation with chitosan, phosphate binders, and alkalinizing agents, along with an RD, is beneficial in reducing mortality rate in dogs with spontaneous CKD.

The effect of vitamin D derivatives on vascular calcification associated with inflammation.

BACKGROUND: Vitamin D sterols may modulate vascular response to inflammation and vascular calcification (VC). METHODS: Rat aortic rings (RARs) and human vascular smooth muscle cells (HVSMCs) were treated in vitro with phosphate (P), tumour necrosis factor alpha (TNF-α), calcitriol (CTR) and paricalcitol (PCT). Rats having undergone subtotal nephrectomy (Nx) (n = 66) on a high-phosphorus diet were treated with Escherichia coli lipopolysacharide (LPS) (40-400 µg/kg/day) or LPS plus CTR (80 ng/kg/48 h) or LPS plus PCT (240 ng/kg/48 h) for 14 days. RESULTS: In vitro, the addition of TNF-α to the medium increased the mineral content of RAR and HVSMC. Treatment with both vitamin D analogues decreased bone morphogenetic protein 2 but did not modify Runx-2. Calcification was prevented only by PCT. In vivo, treatment with LPS increased plasma levels of TNF-α, monocyte chemotactic protein-1 and interleukin-1alfa and induced calcification. The concomitant administration of LPS with either CTR or PCT led to a significant decrease in cytokine plasma levels and the decrease was more accentuated after treatment with PCT than with CTR. Rats treated with CTR showed an elevation in aortic Ca and marked Von Kossa staining; however, rats treated with PCT did not increase aortic Ca and did not show Von Kossa staining. CONCLUSION: Treatment with PCT resulted in more marked anti-inflammatory effect than treatment with CTR and, as opposed to CTR, PCT prevented VC.

Cinacalcet HCl prevents development of parathyroid gland hyperplasia and reverses established parathyroid gland hyperplasia in a rodent model of CKD.

BACKGROUND: Secondary hyperparathyroidism (sHPT) represents an adaptive response to progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease (CKD). It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Parathyroid hyperplasia in uremic rats can be prevented by calcium-sensing receptor (CaSR) activation with the calcimimetic cinacalcet (Sensipar®/Mimpara®); however, it is unknown, how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT. METHODS: We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT. RESULTS: Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia. In rats with established sHPT, cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia. The cinacalcet-mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin-dependent kinase inhibitor p21. Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium. CONCLUSIONS: The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating CaSR activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH.

Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats.

The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.