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Clinical Calcium Nov 2011In chronic kidney disease (CKD) , phosphate retention and low 1, 25-dihydroxyvitamin D [1, 25 (OH) ₂D] due to a decrease in the number of functioning nephrons had long... (Review)
Review
In chronic kidney disease (CKD) , phosphate retention and low 1, 25-dihydroxyvitamin D [1, 25 (OH) ₂D] due to a decrease in the number of functioning nephrons had long been considered to contribute to the pathogenesis of secondary hyperparathyroidism (SHPT) . The discovery of fibroblast growth factor 23 (FGF23) drastically changed our understanding and provided new implication of the development of SHPT. In addition, CKD impairs the maintenance of normal 25-hydoxyvitamin D [25 (OH) D] levels which can act directly on the parathyroid glands to repress PTH synthesis. Active vitamin D therapy is widely used for the treatment of SHPT. However, the active form of vitamin D, 1, 25 (OH) ₂D and its analogs increase the calcium and phosphate levels by increasing the intestinal calcium and phosphate absorption. To suppress PTH secretion without these potential complications, several vitamin D analogs including paricalcitol, maxacalcitol and doxercalciferol are already in clinical use. A novel therapeutic concept in new vitamin D therapies are expected to improve patient outcome.
Topics: Calcium; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism, Secondary; Intestinal Absorption; Kidney Failure, Chronic; Parathyroid Hormone; Phosphates; Vitamin D
PubMed: 22040818
DOI: No ID Found -
Expert Opinion on Pharmacotherapy Dec 2011Disturbances of the bone and mineral metabolism are a common complication of chronic kidney disease (CKD); these disturbances are known as CKD-mineral bone disorder... (Review)
Review
INTRODUCTION
Disturbances of the bone and mineral metabolism are a common complication of chronic kidney disease (CKD); these disturbances are known as CKD-mineral bone disorder (CKD-MBD). A better understanding of the pathophysiological mechanisms of CKD-MBD, along with its negative impact on other organs and systems, as well as on survival, has led to a shift in the treatment paradigm of this disorder. The use of phosphate binders changed dramatically over the last decade when noncalcium-containing phosphate binders, such as sevelamer and lanthanum carbonate, became possible alternative treatments to avoid calcium overload. Vitamin D receptor activators, such as paricalcitol and doxercalciferol, with fewer calcemic and phosphatemic effects, have also been introduced to control parathormone production and the interest in native vitamin D supplementation has grown. Furthermore, a new drug class, the calcimimetics, has recently been introduced into the therapeutic arsenal for treating secondary hyperparathyroidism.
AREAS COVERED
This review discusses the advantages and disadvantages of the above pharmacological options to treat CKD-MBD.
EXPERT OPINION
The individual-based use of phosphate binders, vitamin D and calcimimetics, separately or in combination, constitute a reasonable approach to treat CKD-MBD. These treatments aim to achieve a rigorous control of phosphorus and parathormone levels, while avoiding calcium overload.
Topics: Animals; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcimimetic Agents; Humans; Hyperphosphatemia; Kidney Diseases; Phosphorus; Vitamin D
PubMed: 22017388
DOI: 10.1517/14656566.2011.626768 -
Journal of Renal Nutrition : the... May 2012Lipopolysaccharide or endotoxin constitutes most part of the outer portion of the cell wall in the gram-negative bacteria. Subclinical endotoxemia could contribute to...
OBJECTIVE
Lipopolysaccharide or endotoxin constitutes most part of the outer portion of the cell wall in the gram-negative bacteria. Subclinical endotoxemia could contribute to increased inflammation and mortality in hemodialysis (HD) patients. Endotoxin level and clinical effect are determined by its soluble receptor sCD14 and high-density lipoprotein. We examine the hypothesis that endotoxin level correlates with mortality.
METHODS
In this cohort study, endotoxin levels were measured in 306 long-term HD patients who were then followed up for a maximum of 42 months. Soluble CD14 and cytokines levels were also measured.
RESULTS
The mean (±SD) endotoxin level was 2.31 ± 3.10 EU/mL (minimum: 0.26 EU/mL, maximum: 22.94 EU/mL, interquartile range: 1.33 EU/mL, median: 1.27 EU/mL). Endotoxin correlated with C-reactive protein (r = 0.11, P < .04). On multivariate logistic regression analysis, high body mass index and low high-density lipoprotein (HDL) cholesterol levels were associated with higher endotoxemia (endotoxin below or above of median). In multivariate Cox regression analysis adjusted for case-mix and nutritional/inflammatory confounders, endotoxin levels in the third quartile versus first quartile were associated with a trend toward increased hazard ratio for death (hazard ratio: 1.83, 95% confidence interval: 0.93 to 3.6, P = .08).
CONCLUSIONS
In this HD cohort, we found associations between endotoxemia and C-reactive protein, body composition, and HDL. Moderately high endotoxin levels tended to correlate with increased mortality than the highest circulating endotoxin level. Additional studies are required to assess the effect of endotoxemia on mortality in dialysis population.
Topics: Adult; Aged; Blood Circulation; Body Composition; Body Mass Index; C-Reactive Protein; Cohort Studies; Endotoxemia; Endotoxins; Female; Humans; Inflammation; Lipoproteins, HDL; Male; Middle Aged; Multivariate Analysis; Nutritional Status; Protein-Energy Malnutrition; Renal Dialysis
PubMed: 21880509
DOI: 10.1053/j.jrn.2011.05.004 -
Nephron. Experimental Nephrology 2011Kidney disease patients experience declining calcitriol levels and develop secondary hyperparathyroidism (SHPT). Animal models of uremia based on 5/6 nephrectomy (NTX)...
BACKGROUND/AIMS
Kidney disease patients experience declining calcitriol levels and develop secondary hyperparathyroidism (SHPT). Animal models of uremia based on 5/6 nephrectomy (NTX) do not consistently reproduce this calcitriol deficiency. We developed an animal model, the NTX Cyp27b1-null mouse, which completely lacks endogenous calcitriol, and examined the suitability of this model for evaluation of treatment with vitamin D analogs in uremia.
METHODS
NTX was performed at 2 months of age. One week post-NTX, animals were treated for 4 weeks with vehicle; doxercalciferol at 30, 100 or 300 pg/g body weight (b.w.); or paricalcitol at 100, 300 or 1,000 pg/g b.w. by gavage 3 times per week.
RESULTS
Serum blood urea nitrogen and creatinine were elevated. Vehicle-treated NTX null mice had hypocalcemia and SHPT. Doxercalciferol at 100 or 300 pg/g b.w. normalized serum calcium and parathyroid hormone (PTH) levels. Paricalcitol at 300 or 1,000 pg/g normalized serum calcium, but PTH levels remained elevated. Osteomalacia was corrected by 100 pg/g b.w. of doxercalciferol or 1,000 pg/g b.w. of paricalcitol. The highest dose of doxercalciferol, but not of paricalcitol, significantly reduced osteitis fibrosa.
CONCLUSION
Our results reveal the differential efficacy of doxercalciferol and paricalcitol in this novel animal model incorporating both calcitriol deficiency and renal insufficiency.
Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Administration, Oral; Animals; Calcitriol; Calcium; Disease Models, Animal; Dose-Response Relationship, Drug; Ergocalciferols; Mice; Mice, Knockout; Osteitis; Osteomalacia; Parathyroid Hormone; Uremia
PubMed: 21849802
DOI: 10.1159/000329663 -
Journal of Renal Nutrition : the... Jan 2012The purpose of the 2 studies presented in this article was to determine the clinically appropriate dose of doxercalciferol capsules that is required to maintain similar... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The purpose of the 2 studies presented in this article was to determine the clinically appropriate dose of doxercalciferol capsules that is required to maintain similar intact parathyroid hormone control when converting from intravenous (IV) paricalcitol or doxercalciferol.
DESIGN
Both studies were multicenter, open-label, randomized designs comprising the following 3 periods: a screening period, a 5-week run-in period, and a 5-week treatment period.
SETTING
Dialysis centers in the United States.
PATIENTS
Patients with stage 5 chronic kidney disease receiving dialysis 3 times weekly for a minimum of 6 months and with recent intact parathyroid hormone measurements between 15.9 and 63.7 pmol/L (150 to 600 pg/mL) were included.
INTERVENTION
After a 5-week fixed-dose IV paricalcitol or doxercalciferol run-in period, subjects were randomized to doxercalciferol capsules for the 5-week treatment period. Conversion factors for the paricalcitol study were 0.5, 1.0, and 1.5 times the current paricalcitol dose. Conversion factors for the doxercalciferol study were 1.0, 1.5, and 2.0 times the current doxercalciferol injection dose.
RESULTS
The predicted conversion factor for paricalcitol injection to doxercalciferol capsules was 0.92, whereas the factor for doxercalciferol injection to doxercalciferol capsules was 1.49. No statistically significant changes in serum calcium and phosphorus levels were found in either study. The nature of adverse events was consistent with the administration of an active vitamin D therapy to patients with chronic kidney disease receiving dialysis.
CONCLUSION
The studies demonstrate patients on dialysis can be safely and effectively converted from IV paricalcitol or doxercalciferol to oral doxercalciferol.
Topics: Adult; Aged; Aged, 80 and over; Calcium; Capsules; Ergocalciferols; Female; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Renal Dialysis
PubMed: 21652220
DOI: 10.1053/j.jrn.2011.02.004 -
International Journal of Nephrology 2011Vitamin D deficiency appears to be an underestimated risk factor for cardiovascular disease in patients with chronic kidney disease. Evidence from both basic science and...
Vitamin D deficiency appears to be an underestimated risk factor for cardiovascular disease in patients with chronic kidney disease. Evidence from both basic science and clinical studies supports the possible protective role of vitamin D beyond its effect on mineral metabolism. Toxicity of pharmacologic doses of active vitamin D metabolites, in particular calcitriol, is mainly due to the possibility of positive calcium and phosphorus balance. Therefore, vitamin D analogs have been developed, which suppress PTH secretion and synthesis with reduced calcemic and phosphatemic effects. Observational studies suggest that in hemodialysis patients the use of a vitamin D receptor (VDR) activator, such as calcitriol, doxercalciferol, paricalcitol, or alfacalcidol, is associated with a reduced mortality when compared with nonusers of any VDR activator. In this article the existing literature on the topic is reviewed, although a more robust answer to the question of whether or not VDR activators have beneficial effects in hemodialysis patients will hopefully come from a randomized controlled trial.
PubMed: 21647319
DOI: 10.4061/2011/419524 -
British Journal of Pharmacology Sep 2011Vitamin D receptor (VDR) modulators (VDRMs) such as calcitriol, paricalcitol and doxercalciferol are commonly used to manage hyperparathyroidism secondary to chronic...
BACKGROUND AND PURPOSE
Vitamin D receptor (VDR) modulators (VDRMs) such as calcitriol, paricalcitol and doxercalciferol are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRM therapy may be associated with cardio-renal protective and survival benefits for CKD patients. However, hypercalcaemia remains a serious side effect for current VDRMs, which leads to the need for frequent dose titration and serum Ca (calcium) monitoring. Significant clinical benefits can be derived from a VDRM with cardiovascular protective effects without the hypercalcaemic liability.
EXPERIMENTAL APPROACH
Male Sprague-Dawley rats were 5/6 nephrectomized and 6 weeks later, after they had established uraemia, elevated parathyroid hormone levels, endothelial dysfunction and left ventricular hypertrophy, the rats were treated with VS-105, a novel VDRM. The effects of VS-105 were also tested in cultured HL-60 cells.
KEY RESULTS
VS-105 induced HL-60 cell differentiation with an EC₅₀ value at 11.8 nM. Treatment (i.p., 3× a week over a period of 2 weeks) of the 5/6 nephrectomized rats by VS-105 (0.004-0.64 µg·kg⁻¹) effectively suppressed serum parathyroid hormone without raising serum Ca or phosphate levels. Furthermore, 2 weeks of treatment with VS-105 improved endothelium-dependent aortic relaxation and attenuated left ventricular abnormalities in a dose range that did not affect serum Ca levels. Similar results were obtained when VS-105 was administered i.p. or by oral gavage.
CONCLUSIONS AND IMPLICATIONS
VS-105 exhibits an overall therapeutic product profile that supports expanded use in CKD to realize the cardiovascular protective effects of VDR activation.
Topics: Animals; Aorta; Calcitriol; Calcium; Cardiotonic Agents; Cell Differentiation; Drug Administration Routes; Endothelium; Ergocalciferols; HL-60 Cells; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Kidney Failure, Chronic; Male; Myocytes, Cardiac; Nephrectomy; Parathyroid Hormone; Phosphates; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Tumor Cells, Cultured; Vasodilation; Ventricular Dysfunction, Left
PubMed: 21557735
DOI: 10.1111/j.1476-5381.2011.01473.x -
Nephrology News & Issues Jan 2011Comparative Effectiveness Research (CER) has become positioned to inform health care decision-making with passage of the health care reform law, "Patient Protection and... (Comparative Study)
Comparative Study
Comparative Effectiveness Research (CER) has become positioned to inform health care decision-making with passage of the health care reform law, "Patient Protection and Affordability Care Act of 2010". As the name suggests, CER attempts to understand the relative efficacy between two therapies to allow clinicians, health care providers, and others to make rational decisions when evaluating therapeutic options. This is particularly relevant in the nephrology community as the dawn of bundled payments approaches. The current evidence base for CER studies is especially curtailed as a result of limited head-to-head clinical trials in patients with end-stage renal disease. Specifically, CER for available oral vitamin D agents approved for use in ESRD is lacking. The inclusion of oral vitamin D in the bundled payment system in 2011 may lead more clinicians to examine which oral vitamin D analog to prescribe to their patients, making this an especially timely topic.
Topics: Administration, Oral; Calcitriol; Comparative Effectiveness Research; Ergocalciferols; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Practice Guidelines as Topic; Survival Rate; United States; Vitamins
PubMed: 21291054
DOI: No ID Found -
American Journal of Physiology. Renal... Mar 2011Diet-induced obesity (DIO) and insulin resistance in mice are associated with proteinuria, renal mesangial expansion, accumulation of extracellular matrix proteins, and...
Diet-induced obesity (DIO) and insulin resistance in mice are associated with proteinuria, renal mesangial expansion, accumulation of extracellular matrix proteins, and activation of oxidative stress, proinflammatory cytokines, profibrotic growth factors, and the sterol regulatory element binding proteins, SREBP-1 and SREBP-2, that mediate increases in fatty acid and cholesterol synthesis. The purpose of the present study was to determine whether treatment of DIO mice with the vitamin D receptor (VDR) agonist doxercalciferol (1α-hydroxyvitamin D2) prevents renal disease. Our results indicate that treatment of DIO mice with the VDR agonist decreases proteinuria, podocyte injury, mesangial expansion, and extracellular matrix protein accumulation. The VDR agonist also decreases macrophage infiltration, oxidative stress, proinflammatory cytokines, and profibrotic growth factors. Furthermore, the VDR agonist also prevents the activation of the renin-angiotensin-aldosterone system including the angiotensin II type 1 receptor and the mineralocorticoid receptor. An additional novel finding of our study is that activation of VDR results in decreased accumulation of neutral lipids (triglycerides and cholesterol) and expression of adipophilin in the kidney by decreasing SREBP-1 and SREBP-2 expression and target enzymes that mediate fatty acid and cholesterol synthesis and increasing expression of the farnesoid X receptor. This study therefore demonstrates multiple novel effects of VDR activation in the kidney which prevent renal manifestations of DIO in the kidney.
Topics: Animals; Cytokines; Dietary Fats; Disease Models, Animal; Ergocalciferols; Extracellular Matrix Proteins; Kidney; Kidney Diseases; Lipid Metabolism; Macrophages; Male; Mice; NF-kappa B; Obesity; Podocytes; Proteinuria; Receptors, Calcitriol; Renin-Angiotensin System; Sterol Regulatory Element Binding Proteins
PubMed: 21209008
DOI: 10.1152/ajprenal.00338.2010 -
Journal of Molecular Endocrinology Apr 2011Vitamin D compounds regulate PTH at the transcriptional level, presumably via binding to the vitamin D receptor (VDR), but the exact mechanism is presently unclear. We...
Vitamin D compounds regulate PTH at the transcriptional level, presumably via binding to the vitamin D receptor (VDR), but the exact mechanism is presently unclear. We recently reported that the several vitamin D prohormones with low VDR affinity suppressed PTH, even when their activation was inhibited, raising the possibility that their actions may be VDR independent. To test this hypothesis, we developed a novel organ culture that allowed the assessment of activities of the prohormones on PTH release from wild-type and VDR-null thyroparathyroid explants. The cultures remained viable with respect to PTH release for at least 2 weeks. Full suppression of PTH by the native vitamin D hormone, 1α,25-dihydroxyvitamin D(3) [1α,25 (OH)(2)D(3)], required 2 days, consistent with a transcriptional mechanism, and was reversible, indicating that reduced PTH was not attributable to cell death. Inhibition of PTH release by 1α,25 (OH)(2)D(3) and two prohormones, 25-hydroxyvitamin D(3) and 1α-hydroxyvitamin D(2), was observed in explants from wild-type mice but not in those from VDR-null mice. These findings 1) are the first direct demonstration of the role of the VDR in regulation of PTH by 1α,25(OH)(2)D(3), 2) confirm that the suppressive actions of the vitamin D prohormones are mediated by the VDR, and 3) introduce a novel organ culture model that allows the ex vivo study of the function of parathyroid glands from transgenic animals.
Topics: Animals; Calcifediol; Calcitriol; Ergocalciferols; Gene Expression; Gene Expression Regulation; Mice; Mice, Transgenic; Organ Culture Techniques; Parathyroid Glands; Parathyroid Hormone; Receptors, Calcitriol; Transcription, Genetic
PubMed: 21169421
DOI: 10.1677/JME-10-0128