Cholesterol-Lowering Action of a Novel Nutraceutical Combination in Uremic Rats: Insights into the Molecular Mechanism in a Hepatoma Cell Line.

Appropriate nutraceutical combinations may represent a valid approach to prevent vascular calcification associated with chronic kidney disease (CKD). In the present study, we tested the effect of a new nutraceutical combination named RenaTris®, containing MK-7, magnesium carbonate, and Sucrosomial® Iron, on vascular calcification in uremic rats. Rats were randomly divided into three groups, i.e. control (high-phosphate diet), uremic (high-phosphate diet containing 0.5% adenine), and supplemented uremic diet (0.5% adenine, MK-7, magnesium carbonate, and Sucrosomial® Iron). After six weeks, sera and vascular calcification were examined. The uremic diet increased creatinine and phosphate levels and induced extensive vascular calcification. The uremic condition also induced a mild hypercholesterolemic condition (+52% of total cholesterol; p < 0.05). The supplemented uremic diet did not reduce creatinine, phosphate levels, or vascular calcification, however, we observed a significant hypocholesterolemic effect (-18.9% in supplemental uremic vs. uremic diet; p < 0.05). Similar to simvastatin, incubation of cultured human hepatoma cells (Huh7) with MK-7 significantly reduced cholesterol biosynthesis (-38%) and induced 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase and low-density lipoprotein receptor (LDLR) at both mRNA and protein levels. The effect of MK-7 on LDLR was counteracted by the co-incubation with squalene. Unlike simvastatin, MK-7 reduced PCSK9 in Huh7. These results indicated that the new nutraceutical combination significantly impacts cholesterol metabolism and its supplementation may help to control mild hypercholesterolemic conditions in CKD patients.

Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD.

The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis-mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.

Resveratrol supplementation reduces aortic atherosclerosis and calcification and attenuates loss of aerobic capacity in a mouse model of uremia.

The polyphenolic compound resveratrol (RSV) has been studied for its protective effects on a variety of conditions, including cardiovascular disease (CVD), reduced exercise capacity, and bone disease. Individuals with chronic kidney disease suffer from a variety of these comorbid conditions, but the efficacy of RSV supplementation in this population is unknown. The objective of this study was to determine the efficacy of resveratrol feeding on factors related to CVD, aerobic capacity, and bone health in a mouse model of uremia. At 8 weeks of age, 28 female apolipoprotein E⁻/⁻ mice underwent a two-step surgical procedure to induce uremia and were randomized to one of the two treatment groups for 16 weeks: 0.04% w/w resveratrol supplemented diet (group designated as RSV) (n=12) or control diet (group designated as CON) (n=16). Cardiovascular risk was determined by analysis of aortic atherosclerotic lesion area and aortic calcium, aerobic capacity was measured by maximal oxygen consumption/maximal aerobic capacity (VO(2max)) testing, and bone microarchitecture was assessed by microcomputed tomography. RSV animals had significantly fewer aortic atherosclerotic lesions at the site of the ascending aorta and lower aortic calcium at the branch of the coronary arteries compared with CON. Furthermore, there was a significant decline in VO(2max) from baseline to final testing in the CON group, but VO(2max) was preserved in the RSV group. Last, RSV had no significant effect on bone architecture. These data indicate that RSV supplementation improves vascular health and preserves aerobic capacity in a model of uremia, suggesting RSV supplementation could be examined as a therapeutic strategy for a critically ill population.

Caffeine decreases systemic urea in elite soccer players during intermittent exercise.

PURPOSE: We investigated the effects of caffeine on the ammonia and amino acid metabolism of elite soccer players. METHODS: In this double-blind randomized study, athletes (n = 19) received 5 mg·kg caffeine or lactose (LEx, control) and performed 45 min of intermittent exercise followed by an intermittent recovery test (Yo-Yo IR2) until exhaustion. The caffeine-supplemented athletes were divided into two groups (CEx and SCEx) depending on their serum caffeine levels (<900% and >10,000%, respectively). Data were analyzed by ANOVA and Tukey post hoc test (P < 0.05 was considered to be statistically significant). RESULTS: Caffeine supplementation did not significantly affect the performance (LEx = 12.3 ± 0.3 km·h, 1449 ± 378 m; CEx = 12.2 ± 0.5 km·h, 1540 ± 630 m; SCEx = 12.3 ± 0.5 km·h, 1367 ± 330 m). Exercise changed the blood concentrations of several amino acids and increased the serum concentrations of ammonia, glucose, lactate, and insulin. The LEx group showed an exercise-induced increase in valine (∼29%), which was inhibited by caffeine. Higher serum caffeine levels abolished the exercise-induced increase (∼24%-27%) in glutamine but did not affect the exercise-induced increase in alanine (∼110%-160%) and glutamate (42%-61%). In response to exercise, the SCEx subjects did not exhibit an increase in uremia and showed a significantly lower increase in their serum arginine (15%), citrulline (16%), and ornithine (ND) concentrations. CONCLUSIONS: Our data suggest that caffeine might decrease systemic urea by decreasing the glutamine serum concentration, which decreases the transportation of ammonia to the liver and thus urea synthesis.

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.

Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease.

INTRODUCTION: Uremic syndrome consists of nitrogenous waste retention, deficiency in kidney-derived hormones, and reduced acid excretion, and, if untreated, may progress to coma and eventual death. Previous experience suggests that oral administration of a probiotic formulation of selected microbial strains may extend renoprotection via intraintestinal extraction of toxic waste solutes in patients with chronic kidney disease (CKD)stages 3 and 4. This report presents preliminary data from a pilot study. METHODS: This was a 6-month prospective, randomized, double-blind, placebo-controlled crossover trial of a probiotic bacterial formulation conducted in four countries, at five institutions, on 46 outpatients with CKD stages 3 an nd 4: USA (n=10), Canada (n=113), Nigeria (n=115), and Argentina (n=8). Outcomes were compared using biochemical parameters:blood urea nitrogen (BUN), serum creatinine, and uric acid. General well-being was assessed as a secondary parameter by a quality of life (QQOL) questionnaire on a subjective scale of 1-10. RESULTS: Oral ingestion of probiotics (90 billion colony forming units [CFUs]/day) was well tolerated and safe during the entire trial period at all sites. BUN levels decreased in 29 patients (63%, P<0.05), creatinine levels decreased in 20 patients (43%, no statistical significance), and uric acid levels decreased in 15 patients (33%, no statistical significance). Almost all subjects expressed a perceived substantial overall improvement in QOL (86%, P<0.05). CONCLUSION: The main outcomes of this preliminary trial include a significant reduction of BUN, enhanced well-being, and absence of serious adverse effects, thus supporting the use of the chosen probiotic formulation for bowel-based toxic solute extraction. QOL and BUN levels showed statistically significant differences in outcome (P<0.05) between placebo and probiotic treatment periods at all four sites (46 patients). A major limitation of this trial is the small sample size nd elated inconsistencies.

Amelioration of cisplatin-induced nephrotoxicity by extracts of Hemidesmus indicus and Acorus calamus.

Administration of commonly used anticancer drug cisplatin [cis-diamminedichloroplatinum (II)] at pharmacologically relevant concentrations (12 mg/kg body weight) resulted in severe renal toxicity as evidenced from histopathological observations and biochemical alterations in the renal tissue. The extracts of medicinal plants Hemidesmus indicus L. (Apocynaceae) and Acorus calamus L. (Araceae) protected the renal tissue effectively from cisplatin-induced toxicity. Treatment of cisplatin-administered animals with the plant extracts could prevent the drug-induced oxidative damage in the renal tissue as evidenced from the decreased levels of lipid peroxidation and enhanced activities of the antioxidants in the renal tissue. Cisplatin treatment increased serum urea level to 41.3 +/- 2.86 mg/dL and administration of the extracts of H. indicus and A. calamus brought down the level to 34.54 +/- 0.37 and 30.12 +/- 0.95 mg/dL, respectively. Serum creatinine levels were increased to 1.1 +/- 0.02 mg/dL following cisplatin administration, and treatment with extracts of H. indicus and A. calamus brought this down to 0.76 +/- 0.09 and 0.61 +/- 0.06 mg/dL, respectively. The histopathological observations indicated that treatment with the H. indicus and A. calamus extracts restored the cisplatin-induced structural alterations in the renal tissue.

Effect of extract of Withania Somnifera on dehydration-induced oxidative stress-related uremia in male rats.

Dehydration or water deprivation in the body decreases urinary excretion and allows urea and other protein waste products to accumulate in the blood. The aim of the present study is to evaluate the association of uremia and oxidative stress by applying the herbal plant Withania somnifera (W. somnifera) (Aswagandha). The study was performed on male Wister strain rats in which, dehydration was achieved by water withdrawal. A total of 18 rats were studied and were randomly divided into three Groups: Group-1, control, Group-2, only dehydration and Group-3, dehydration + administration of aqueous root extract of W. somnifera, orally (50 mg/100 gm body weight/day) for 25 days. After 25 days of treatment, it was observed that the body weight of Group-3 animals had increased significantly, while that in Group-2 had decreased significantly. The liver enzymes in both blood and kidneys did not show any significant change in the three groups implying absence of any toxicity of the root extract. In Group-2 animals, the serum urea and creatinine levels increased sig-nificantly when compared with animals in Groups-1 and 3. The low levels of serum urea and crea-tinine in Group-3 animals indicates the protective effect of the plant extract against renal injury caused by dehydration. Dehydration-induced oxidative stress was established in our study by noting the low activities of super-oxide dismutase and catalase, both important antioxidant enzymes, in Group-2 animals; both enzymes were stabilized in animals of Groups-3 and 1. In conclusion, it is hypothesized that there is an antioxidative role of W. somnifera resulting in reducing the extent of renal injury as a result of oxidative stress.

[High-dose vitamin therapy as prophylaxis against porphyria cutanea uremica]. / Hochdosierte Vitamingabe zur Verhinderung einer Porphyria cutanea urämica?

50 Patients with chronic renal failure undergoing hemodialysis with or without porphyria cutanea tarda (PCT)-like skin changes were investigated. The total porphyrin amount in erythrocytes, plasma and dialysate and the distribution of porphyrin metabolites in plasma and dialysate were measured. In plasma, the group of patients with skin changes (referred as PCU = porphyria cutanea uremica) showed significantly increased uroporphyrin levels as compared to the non-symptomatic group. In addition, significant differences concerning the ratio uro-/coproporphyrin in plasma were shown: non-symptomatic patients with 0.87, as opposed to the PCU group with 3.7. Considerable differences between the level of vitamin ingestion were identified between the groups. Patients with PCU took distinctly less vitamins C, E and B than patients without symptoms.

Probiotic amelioration of azotemia in 5/6th nephrectomized Sprague-Dawley rats.

The present study was to test the hypothesis that, selected bacteria instilled into the gastrointestinal tract could help in converting nitrogenous wastes accumulated due to renal insufficiency into non-toxic compounds; thereby, ameliorating the biochemical imbalance. Herein we describe a prospective, blinded, placebo controlled pilot-study, using 5/6th nephrectomized Sprague Dawley rat, as a chronic renal failure model. The study group consisted of 36 nephrectomized and 7 non-nephrectomized (control) rats. After two-week nephrectomy stabilization, cohorts of six nephrectomized rats were fed casein-based diet plus one of the following regimens: (A) Control, (B) Placebo (casein-based diet without probiotics), (C) Bacillus pasteurii, (D) Sporolac(R), (E) Kibow cocktail, (F) CHR Hansen Cocktail, and (G) ECONORM. Subsequently, blood (retro-orbital) and urine (collected for measurements of blood urea-nitrogen and creatinine respectively), body weight and bacterial counts (feces) were obtained at regular intervals. The study end-points were to determine if any of the probiotic dietary supplements facilitated, (1) decreased blood concentrations of uremic toxins, (2) altered renal function, and (3) prolonged survival. After 16 weeks of treatment, regimens C and D significantly prolonged the life span of uremic rats, in addition to showing a reduction in blood urea-nitrogen levels, concluding that supplementation of probiotic formulation to uremic rats slows the progression of azotemia, which may correlate with prolonged life span of uremic rats. Derivative trials of probiotic treatment of larger animals and humans will further assess the potential role of probiotic formulations in delaying the onset and clinical severity of clinical illness at different stages of renal failure.

Does a low protein diet really slow down the rate of progression of chronic renal failure?

In this paper we present evidence from data obtained by different study groups, indicating that a low protein diet slows down the rate of progression of chronic renal failure. These data also demonstrate that the delay of progression is highly dependent on the underlying renal disease. In absolute terms, patients suffering from polycystic kidney disease experienced most benefit from a low protein diet, while in relative terms, the natural course of the renal disease of patients suffering from chronic glomerulonephritis is significantly more delayed than in other disease groups. Furthermore, a vegetarian diet seems to be superior to a meat-containing diet. Thus, we conclude that there are sufficient data from the literature to suggest that a low protein diet delays the progression of chronic renal failure.