vitamin-d-2 and Kidney-Diseases

Bone disease is common in children with chronic kidney disease (CKD) and when untreated may result in bone deformities, bone pain, fractures and reduced growth rates. This is an update of a review first published in 2010.. This review aimed to examine the benefits (improved growth rates, reduced risk of bone fractures and deformities, reduction in PTH levels) and harms (hypercalcaemia, blood vessel calcification, deterioration in kidney function) of interventions (including vitamin D preparations and phosphate binders) for the prevention and treatment of metabolic bone disease in children with CKD.. We searched the Cochrane Kidney and Transplant Specialised Register to 8 September 2015 through contact with the Trial's Search Co-ordinator using search terms relevant for this review.. We included randomised controlled trials (RCTs) comparing different interventions used to prevent or treat bone disease in children with CKD stages 2 to 5D.. Data were assessed for study eligibility, risk of bias and extracted independently by two authors. Results were reported as risk ratios (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) was used. Statistical analyses were performed using the random-effects model.. This review included 18 studies (576 children); three new studies were added for this update. Adequate sequence generation and allocation concealment were reported in 12 and 11 studies respectively. Only four studies reported blinding of children, investigators or outcome assessors. Nine studies were at low risk of attrition bias and 12 studies were at low risk of selective reporting bias.Eight different interventions were compared. Two studies compared intraperitoneal (IP) with oral calcitriol. PTH levels were significantly lower with IP compared with oral calcitriol (1 study: MD -501.00 pg/mL, 95% CI -721.54 to -280.46) but the number of children with abnormal bone histology did not differ between treatments. Three studies compared intermittent with daily oral calcitriol. The change in mean height SDS (1 study: MD 0.13, 95% CI -0.22 to 0.48) and the percentage fall in parathyroid hormone (PTH) levels at eight weeks (1 study: MD -5.50%, 95% CI -32.37 to 21.37) and 12 months (1 study: MD -6.00% 95% CI -25.27 to 13.27) did not differ between treatments.Four studies compared active vitamin D preparations (calcitriol, paricalcitol, 1α-hydroxyvitamin D) with placebo or no specific treatment. One study reported vitamin D preparations significantly reduced PTH levels (-55.00 pmol/L, 95% CI -83.03 to -26.97). There was no significant difference in hypercalcaemia risk with vitamin D preparations compared with placebo or no specific treatment (4 studies, 103 children: RD 0.08 mg/dL, 95% CI -0.08 to 0.24). However, there was heterogeneity (I(2) = 55%) with one study showing a significantly greater risk of hypercalcaemia with intravenous (IV) calcitriol administration. Two studies (97 children) compared calcitriol with other vitamin D preparations and both found no significant differences in growth between preparations.Two studies compared ergocalciferol in patients with CKD and vitamin D deficiency. Elevated PTH levels developed significantly later in ergocalciferol treated children (1 study: hazard ratio 0.30, 95% CI 0.09 to 0.93) though the number with elevated PTH levels did not differ between groups (1 study, 40 children: RR 0.33, 95% CI 0.11 to 1.05).Two studies compared calcium carbonate with aluminium hydroxide as phosphate binders. One study (17 children: MD -0.86 SDS, 95% CI -2.24 to 0.52) reported no significant difference in mean final height SDS between treatments. Three studies compared sevelamer with calcium-containing phosphate binders. There were no. Bone disease, assessed by changes in PTH levels, is improved by all vitamin D preparations. However, no consistent differences between routes of administration, frequencies of dosing or vitamin D preparations were demonstrated. Although fewer episodes of high calcium levels occurred with the non-calcium-containing phosphate binder, sevelamer, compared with calcium-containing binders, there were no differences in serum phosphorus and calcium overall and phosphorus values were reduced to similar extents. All studies were small with few data available on patient-centred outcomes (growth, bone deformities) and limited data on biochemical parameters or bone histology resulting in considerable imprecision of results thus limiting the applicability to the care of children with CKD.

Topics: Aluminum Hydroxide; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcitriol; Calcium; Calcium Carbonate; Child; Chronic Disease; Ergocalciferols; Humans; Kidney Diseases; Parathyroid Hormone; Phosphorus; Polyamines; Randomized Controlled Trials as Topic; Sevelamer; Vitamin D

Proteinuria is the main predictor of chronic kidney disease progression. Drugs that block the renin-angiotensin-aldosterone (RAA) system reduce proteinuria and slow down the progression of the disease. However, their effect is suboptimal, and residual proteinuria persists as an important predictor of renal impairment. Vitamin D has pleiotropic effects that could have an impact on these parameters. In this study, we critically review the molecular and experimental bases that suggest an antiproteinuric effect of vitamin D receptor (VDR) activation and the available evidence on its antiproteinuric effect in clinical practice. In animal models, we have observed the antiproteinuric effect of VDR activation, which could be due to direct protective action on the podocyte or other pleiotropic effects that slow down RAA system activation, inflammation and fibrosis. Clinical trials have generally been conducted in patients with a vitamin D deficiency or insufficiency and the main trial (VITAL) did not demonstrate that paricalcitol improved the study's primary endpoint (decrease in the urine albumin to creatinine ratio). In this sense, the information available is insufficient to advise the use of native vitamin D or VDR activators as renoprotective antiproteinuric drugs beyond the experimental level. Two Spanish clinical trials and one Italian trial attempted to determine the effect of paricalcitol and vitamin D on residual proteinuria in various clinical circumstances (PALIFE, NEFROVID and PROCEED).

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcitriol; Clinical Trials as Topic; Cost-Benefit Analysis; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Ergocalciferols; Gene Expression Regulation; Humans; Kidney Diseases; Mice; Mice, Knockout; Multicenter Studies as Topic; Myocytes, Smooth Muscle; Phosphates; Podocytes; Proteinuria; Rats; Receptors, Calcitriol; Renal Dialysis; Renin-Angiotensin System; Vitamin D

Observational data indicate that newer vitamin D compounds such as paricalcitol can suppress serum intact parathyroid hormone (iPTH) and reduce proteinuria in patients with CKD. To systematically evaluate the efficacy and safety of paricalcitol for CKD, we conducted a meta-analysis of the published randomized controlled trials (RCTs).. MEDLINE, Embase, the Cochrane Library, and article reference lists were searched for RCTs that compared paricalcitol with placebo in the treatment of patients with stage 2-5 CKD. The quality of the studies was evaluated using the Jadad method. The results are summarized as risk ratios (RRs) for dichotomous outcomes or mean differences for continuous outcomes.. Nine studies (832 patients) were included. Compared with placebo, paricalcitol suppressed serum iPTH (RR, 6.37; 95% confidence interval [95% CI], 4.64-8.74; P<0.001) and reduced proteinuria (RR, 1.68; 95% CI, 1.25-2.25; P<0.001). Compared with the control group, the RR for hypercalcemia associated with paricalcitol use was 2.25 (95% CI, 0.81-6.26; P=0.12). Patients receiving paricalcitol therapy did not have an increased risk of endocrine system and cardiovascular system adverse effects (RR, 1.07; 95% CI, 0.84-1.36; P=0.58).. We confirm that paricalcitol suppresses iPTH and lowers proteinuria in patients with stage 2-5 CKD without an increased risk of adverse events. A trend toward increased hypercalcemia did not reach statistical significance, but may be clinically relevant. A randomized trial is needed to determine if paricalcitol affects the development of ESRD or mortality.

Topics: Biomarkers; Chi-Square Distribution; Chronic Disease; Ergocalciferols; Evidence-Based Medicine; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Diseases; Odds Ratio; Parathyroid Hormone; Proteinuria; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Severity of Illness Index; Treatment Outcome

Reduction in serum 1,25 (OH) (2)D level plays an important role in the pathophysiology of altered bone and mineral metabolism among patients with advanced stages of CKD. The use of vitamin D receptor activators (VDRA) has brought great progress in medical management of CKD-MBD. A number of observational studies have shown that the nonuse of VDRA, and low serum concentrations of 1,25 (OH) (2)D or 25 (OH) D are the predictors of poor clinical outcomes in CKD patients including dialysis patients, raising a possibility that the pleiotropic actions of vitamin D may be systemically involved in the poor survival of patients with CKD-MBD. Randomized controlled trials are needed to clarify whether or not VDRA could be beneficial in the protection of the cardiovascular system and good longevity.

Topics: Bone Diseases, Metabolic; Cardiovascular Diseases; Cholecalciferol; Chronic Disease; Ergocalciferols; Humans; Kidney Diseases; Minerals; Randomized Controlled Trials as Topic; Receptors, Calcitriol; Risk; Vitamin D

Abnormalities of bone mineral parameters (calcium, phosphate, vitamin D, and parathyroid hormone) are nearly always present in patients with chronic kidney disease (CKD). These typically consist of hypocalcemia, hyperphosphatemia, abnormalities of vitamin D metabolism, and secondary hyperparathyroidism, and are now defined as CKD mineral bone disorders (CKD-MBD). Currently, emerging evidence indicates that deficiencies in vitamin D receptor (VDR) activation play crucial roles in adversely affecting the cardiovascular health of CKD patients. VDRs are not restricted to skeletal tissue, but are instead widely expressed throughout the body at several sites, such as in cardiac tissue, vascular smooth muscle cells, endothelial cells, renal tissue, and cells of the immune system. Restoring the physiology and modulation of VDR activator levels results in correlative regulatory effects on mineral homeostasis, hypertension, cardiovascular disease, and vascular calcification, as well as a number of other endpoints in cardiac and renal pathology. Among the compounds available for treatment of CKD-MBD, paricalcitol is a selective VDR activator. The term 'selective' refers to paricalcitol being more selective in affecting VDR pathways in the parathyroid gland compared with bone and intestine. As such, paricalcitol's selectivity allows for a wider therapeutic window with effects beyond parathyroid hormone control and mineral management, and may explain, in part, the increased survival advantage with paricalcitol treatment.

Topics: Animals; Chronic Disease; Ergocalciferols; Humans; Kidney Diseases; Parathyroid Hormone; Receptors, Calcitriol

Cardiovascular (CV) morbidity and mortality are significantly higher in patients with chronic kidney disease (CKD). Mineral metabolism disorders, such as hyperphosphatemia, hypocalcemia, and vitamin D deficiency, have been deeply associated not only with bone disease, but also with vascular calcification and CV disease. In addition, the decrease in vitamin D production stimulates the renin-angiotensin-aldosterone system, resulting in vasoconstriction and salt and water retention, which further promotes arterial stiffening. Several studies have shown that supplementation with vitamin D ameliorates some of these issues and is associated with improved survival. However, vitamin D also elevates serum levels of calcium and phosphorus. Selective vitamin D receptor (VDR) activators, such as paricalcitol, provide similar efficacy but are not associated with elevated serum concentrations of calcium and phosphorus. By selectively activating VDR, paricalcitol should enhance cardiorenal protection and provide significant clinical benefit. Therefore, paricalcitol may offer a novel and interesting approach to supplement and potentially enhance the standard of care in CKD patients.

Topics: Animals; Cardiovascular Diseases; Chronic Disease; Ergocalciferols; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Diseases; Receptors, Calcitriol; Vitamin D Deficiency

Calcitriol is important in nephroprotective strategy in chronic disease of the kidneys (CDK). However, its long-term use often results in hypercalciemia with metastatic calcification. Compared to calcitriol, paricalcitol (zemplar)--metabolite of vitamin D2--leads to hypercalciemia less frequently, has a more potent nephroprotective effect and more rapidly decreases blood levels of parathyroid hormone. Paricalcitol in combination with lozartan has more pronounced nephroprotective effect. Morphological analysis detected inhibition of development of glomerulosclerosis and tubulointerstitial fibrosis. A cardioprotective effect of paricalcitol manifests with reduction of mortality from cardiovascular complications both at CDKpredialysis stage and in regular hemodialysis.

Topics: Angiotensin II Type 1 Receptor Blockers; Calcitriol; Cardiovascular Diseases; Chronic Disease; Ergocalciferols; Humans; Kidney Diseases; Losartan

The management of cyclosporine A (CsA)-induced nephrotoxicity remains one of the main challenges in kidney transplantation. The animal study by Park et al. proposes that paricalcitol, a vitamin D analog with renoprotective actions reported in other conditions, attenuates CsA-induced kidney injury via the suppression of inflammatory, fibrotic, and apoptotic factors. Before paricalcitol can be considered a feasible new therapeutic option for post-transplantation nephropathy, these interesting data require further studies assessing other mechanisms of CsA-induced nephrotoxicity.

Topics: Bone Density Conservation Agents; Cyclosporine; Ergocalciferols; Fibrosis; Humans; Kidney Diseases; Kidney Transplantation; Protective Agents

The articles providing answers to the questions on vascular calcification of most interest from a clinical point of view were selected. 1. How is it measured?: Studies showing the clinical utility of different tools to quantify it were analyzed. 2. What does it measure?: Both in dialysis patients and the general population, vascular calcification and arterial stiffness are prognostic factors for morbidity and mortality. Other markers such as fetuin-A are associated with mortality in patients on hemodialysis but not in patients in early stages of chronic kidney disease. 3. What causes it?: In two selected studies, it was demonstrated again that low bone turnover and diabetes cause cardiovascular disease and vascular calcification, respectively. 4. How is it treated?: There is still no clinical evidence of regression of vascular calcification. However, a prospective study in new hemodialysis patients showed that sevelamer compared to calcium compounds slows the progression of vascular calcification and confers greater survival. A study comparing both compounds in chronic hemodialysis patients showed that sevelamer only had a benefit on survival in patients older than 65 years. It remains to be demonstrated whether the good experimental results of paricalcitol and cinacalcet are confirmed in prospective clinical studies.

Topics: Aged; Animals; Atherosclerosis; Calcinosis; Chronic Disease; Cinacalcet; Coronary Artery Disease; Diabetes Complications; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Diseases; Mice; Mice, Knockout; Multicenter Studies as Topic; Naphthalenes; Polyamines; Randomized Controlled Trials as Topic; Renal Artery; Sevelamer; Tomography, Spiral Computed; Tomography, X-Ray Computed; Vascular Diseases

Disorders in calcium, phosphorus, and parathyroid hormone (PTH) are common in chronic kidney disease (CKD) and may be associated with poor outcomes including a higher rate of CKD progression and increased death risk. Although these abnormalities have been examined extensively in patients with CKD stage 5 who are receiving chronic maintenance dialysis, they have not been studied to the same extent at earlier stages of CKD, in spite of the much larger numbers of patients in the early CKD population. We summarize the available literature on outcomes associated with bone and mineral disorders in patients with CKD not yet receiving maintenance dialysis. We have reviewed novel data linking fibroblast growth factor 23 (FGF-23) to phosphorus and vitamin D homeostasis. More rapid CKD progression is linked to hyperphosphatemia and its associated hyperparathyroidism and vitamin D deficiency. Hence, hyperphosphatemia may play a central role in the diverse disorders characterizing CKD. We provide a brief overview of the available treatment recommendations for bone and mineral disorders, with an emphasis on areas needing further research.

Topics: Bone Density Conservation Agents; Chronic Disease; Comorbidity; Disease Progression; Ergocalciferols; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Humans; Hyperparathyroidism; Hyperphosphatemia; Kidney Diseases; Phosphorus; Vitamin D; Vitamin D Deficiency

Secondary hyperparathyroidism (SHPT) is a common and serious consequence of chronic kidney disease (CKD). SHPT is a complex condition characterised by a decline in 1,25-dihydroxyvitamin D and consequent vitamin D receptor (VDR) activation, abnormalities in serum calcium and phosphorus levels, parathyroid gland hyperplasia, elevated parathyroid hormone (PTH) secretion, and systemic mineral and bone abnormalities. There are three classes of drugs used for treatment of SHPT: (i) nonselective VDR activators or agonists (VDRAs); (ii) selective VDRAs; and (iii) calcimimetics. The VDRAs act on the VDR, whereas the calcimimetics act on the calcium-sensing receptor. Calcimimetics are commonly used in conjunction with VDRA therapy. By virtue of the differences in their chemical structure, the nonselective and selective VDRAs differ in their effects on gene expression, and ultimately parathyroid gland, bone and intestine function. Medications in all three classes are effective in suppression of PTH; however, clinical studies show that calcimimetics are associated with an unfavourable tolerability profile and hypocalcaemia, whereas nonselective VDRAs, and to a lesser extent selective VDRAs, are associated with dose-limiting hypercalcaemia and hyperphosphataemia. Selective VDRAs also have minimal undesirable effects on calcium absorption in the intestine, and calcium and phosphorus mobilisation in the bone compared with nonselective VDRAs. Calcium load in patients with CKD can lead to vascular calcification, accelerated progression of cardiovascular disease and increased mortality. High serum phosphorus levels are also associated with adverse effects on cardiorenal function and survival. Recent evidence suggests that VDRAs are associated with a survival benefit in CKD patients, with a more favourable effect with selective VDRAs than nonselective VDRAs. Paricalcitol, a selective VDRA, is reported to exert specific effects on gene expression in various cell types that are involved in vascular calcification and the development of coronary artery disease. This article examines the molecular mechanisms that determine selectivity of VDRAs, and reviews the evidence for clinical efficacy, safety and survival associated with the three drug classes used for treatment of SHPT in CKD patients.

Topics: Animals; Bone Density Conservation Agents; Calcitriol; Chronic Disease; Cinacalcet; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Diseases; Naphthalenes; Receptors, Calcitriol; Vitamin D

The 'classical' effects of vitamin D receptor activator or agonist (VDRA) therapy for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease primarily involves suppressive effects on the parathyroid gland, and regulation of calcium and phosphorus absorption in the intestine and mobilisation in bone. Observational studies in haemodialysis patients report improved cardiovascular and all-cause survival among those receiving VDRA therapy compared with those not on VDRA therapy. Among VDRAs, the selective VDRA paricalcitol has been associated with greater survival than nonselective VDRAs, such as calcitriol (1,25-dihydroxyvitamin D(3)). The survival benefits of paricalcitol appear to be linked, at least in part, to 'nonclassical' actions of VDRAs, possibly through VDRA-mediated modulation of gene expression. In cardiovascular tissues, VDRAs are reported to have beneficial effects such as anti-inflammatory and antithrombotic effects, inhibition of vascular smooth muscle cell proliferation, inhibition of vascular calcification and stiffening, and regression of left ventricular hypertrophy. VDRAs are also reported to negatively regulate the renin-angiotensin system, which plays a key role in hypertension, myocardial infarction and stroke. The selective VDRAs, paricalcitol and maxacalcitol, are associated with direct protective effects on glomerular architecture and antiproteinuric effects in response to renal damage. Paricalcitol regulates several cardiovascular and renal parameters more favourably than nonselective VDRAs. Complex nonclassical effects, which are not clearly understood, possibly contribute to the improved survival seen with VDRAs, especially paricalcitol.

Topics: Animals; Bone Density Conservation Agents; Calcitriol; Cardiovascular Diseases; Chronic Disease; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Diseases; Receptors, Calcitriol; Survival Rate

Secondary hyperparathyroidism is a common complication of patients with chronic kidney disease. Treatment with calcitriol, the active form of vitamin D, reduces parathyroid hormone levels, but may result in elevations in serum calcium and phosphorus. New vitamin D analogues have been developed to reduce parathyroid hormone secretion without concomitant hypercalcaemia and hyperphosphataemia. Recent data from studies with paricalcitol capsules, the oral formulation of 19-nor-1,25(OH)2D2, show a significant reduction in parathyroid hormone levels with no change in calcium and phosphorus levels when compared with placebo. Paricalcitol also compares favourably to other oral vitamin D analogues, effectively decreasing parathyroid secretion with less hypercalcaemia and hypercalciuria than other agents.

Topics: Capsules; Chronic Disease; Drug Administration Schedule; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Parathyroid Hormone; Randomized Controlled Trials as Topic; Vitamin D; Vitamins

Secondary hyperparathyroidism complicating chronic kidney disease requires therapy to minimize the effects of parathyroid hormone (PTH) on bone and other tissues. Low levels of calcitriol in blood play a major role in the initiation and maintenance of hyperparathyroidism. Accordingly, administration of calcitriol has been demonstrated to be an effective form of therapy. While this therapy is effective in controlling hyperparathyroidism, side effects of calcitriol, including increased intestinal absorption of calcium and phosphate, often complicate therapy by giving rise to hypercalcemia and hyperphosphatemia, which may be important risk factors for extraskeletal calcifications. Over the last several years, interest has turned toward vitamin D analogs, which may be able to affect parathyroid function with lesser effects on calcium and phosphorus in serum, and thereby, minimizing the undesirable toxicities of vitamin D therapy. Two vitamin D analogs are available in this country for the control of hyperparathyroidism in the setting of advanced kidney disease, and include 19-nor-1,25-dihydroxyvitamin D(2) (paricalcitol), and more recently, 1-alpha-hydroxyvitamin D(2) (doxercalciferol). 19-nor-1,25-dihydroxyvitamin D(2) is widely used and was evaluated extensively in animals, revealing that this vitamin D sterol had a selective effect on increasing PTH suppression, with lesser effects on calcium and phosphorus metabolism. These studies lead to clinical trials which showed the efficacy of this therapy in that PTH could be lowered satisfactorily in patients with calcium and phosphorus values within the normal range. The selectivity of 19-nor-1,25-dihydroxyvitamin D(2) seen in animals has also been found in humans, such that therapy with this sterol can achieve control of hyperparathyroidism with a wider therapeutic window than the predecessor, calcitriol. 1-alpha-hydroxyvitamin D(2) has recently been introduced, but in contrast to paracalcitol, there is little reason to believe that there is any selectivity in its actions in terms of suppressing PTH, compared with its ability to raise serum calcium or phosphorus in serum. However, this vitamin D sterol can effectively decrease PTH levels in patients with advanced renal failure. Comparative studies of paricalcitol and doxercalciferol have not been undertaken at the present time. Further studies on the mechanism of actions might explain the differences between these sterols and their effects on the intestinal abs

Topics: Animals; Bone and Bones; Calcitriol; Calcium; Chronic Disease; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Parathyroid Hormone; Vitamin D

Topics: 24,25-Dihydroxyvitamin D 3; 25-Hydroxyvitamin D 2; Animals; Calcitriol; Calcium; Chick Embryo; Dihydroxycholecalciferols; Dogs; Ergocalciferols; Female; Humans; Kidney Diseases; Liver Diseases; Pregnancy; Vitamin D; Vitamin D Deficiency

Topics: Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Feedback; Humans; Hypocalcemia; Kidney Diseases; Liver; Osteomalacia; Parathyroid Hormone; Rickets; Seasons; Ultraviolet Rays; Vitamin D

Topics: Bone Diseases; Calcium; Carcinoma; Cholecalciferol; Chromatin; Dihydroxycholecalciferols; Ergocalciferols; Homeostasis; Humans; Hydroxycholecalciferols; Intestinal Diseases; Intestinal Mucosa; Kidney; Kidney Diseases; Liver; Liver Diseases; Parathyroid Diseases; Receptors, Drug; Skin Diseases; Thyroid Neoplasms; Vitamin D Deficiency

Vitamin D (25-hydroxyvitamin D; 25[OH]D) deficiency is common in patients initiating long-term hemodialysis, but the safety and efficacy of nutritional vitamin D supplementation in this population remain uncertain.. This randomized, placebo-controlled, parallel-group multicenter trial compared two doses of ergocalciferol with placebo between October 2009 and March 2013. Hemodialysis patients (n=105) with 25(OH)D levels ≤32 ng/ml from 32 centers in the Northeast United States were randomly assigned to oral ergocalciferol, 50,000 IU weekly (n=36) or monthly (n=33), or placebo (n=36) for a 12-week treatment period. The primary endpoint was the achievement of vitamin D sufficiency (25[OH]D >32 ng/ml) at the end of the 12-week treatment period. Survival was assessed through 1 year.. Baseline characteristics were similar across all arms, with overall mean±SD 25(OH)D levels of 21.9±6.9 ng/ml. At 12 weeks, vitamin D sufficiency (25[OH]D >32 ng/ml) was achieved in 91% (weekly), 66% (monthly), and 35% (placebo) (P<0.001). Mean 25(OH)D was significantly higher in both the weekly (49.8±2.3 ng/ml; P<0.001) and monthly (38.3±2.4 ng/ml; P=0.001) arms compared with placebo (27.4±2.3 ng/ml). Calcium, phosphate, parathyroid hormone levels, and active vitamin D treatment did not differ between groups. All-cause and cause-specific hospitalizations and adverse events were similar between groups during the intervention period. Lower all-cause mortality among ergocalciferol-treated participants was not statistically significant (hazard ratio, 0.28; 95% confidence interval, 0.07 to 1.19).. Oral ergocalciferol can increase 25(OH)D levels in incident hemodialysis patients without significant alterations in blood calcium, phosphate, or parathyroid hormone during a 12-week period.

Topics: Administration, Oral; Adult; Aged; Biomarkers; Cause of Death; Dietary Supplements; Double-Blind Method; Ergocalciferols; Female; Hospitalization; Humans; Kidney Diseases; Male; Middle Aged; New England; Nutritional Status; Renal Dialysis; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency

Vitamin D has an important regulatory effect on the renin-angiotensin-aldosterone system, playing a central role in the regulation of proteinuria. We therefore studied the antiproteinuric effect of paricalcitol.. 36 patients with an estimated GFR of 30-90 mL/min/1.73 m² and proteinuria >400 mg/d with a stable dose of ACE inhibitor or ARB for at least 3 months were recruited. Patients received oral paricalcitol 1 µg/day for 12 months. Primary endpoint was decrease in proteinuria from baseline. Secondary endpoints were changes in creatinine, eGFR, serum levels of calcium, phosphorus, iPTH, 25(OH)vitD, C-Reactive Protein and blood presure.. Mean proteinuria was 2806 mg/d and fell to 2199 mg/d at month 6 (p<.0001) and 1931.5 mg/d at month 12 (P<.0001). Patients with >3000 mg/d baseline proteinuria (n=12) saw smaller relative reductions in proteinuria (5956.9±2492.6 mg/d to 4220.4±2613 mg/d at 12 months) than patients with <3000 mg/d baseline proteinuria (1371±627.5 mg/d to 821.3±491.5mg/d at 12 months). There were no changes in BP, eGFR and CRP. We observed significant changes in serum levels of calcium, phosphorus, iPTH, 25(OH) vitamin D.. Our study shows an important reduction in proteinuria with a low dose of oral paricalcitol in CKD, that is particularly robust with baseline proteinuria between 1-3 g/d.

Topics: Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; C-Reactive Protein; Calcium; Chronic Disease; Creatinine; Ergocalciferols; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Proteinuria; Treatment Outcome; Vitamin D

Paricalcitol and cinacalcet are common therapies for patients on haemodialysis with secondary hyperparathyroidism (SHPT). We conducted a multi-centre study in 12 countries to compare the safety and efficacy of paricalcitol and cinacalcet for the treatment of SHPT.. Patients aged ≥18 years with Stage 5 chronic kidney disease receiving maintenance haemodialysis and with intact parathyroid hormone (iPTH) 300-800 pg/mL, calcium 8.4-10.0 mg/dL (2.09-2.49 mmol/L) and phosphorus ≤6.5 mg/dL (2.09 mmol/L) were randomized within two strata defined by the mode of paricalcitol administration to treatment with paricalcitol- (intra-venous, US and Russian sites, IV stratum; oral, non-US and non-Russian sites, oral stratum) or cinacalcet-centred therapy. The primary endpoint is the proportion of patients in each treatment group who achieve a mean iPTH value of 150-300 pg/mL during Weeks 21-28 of treatment. Assuming efficacy response rates of 36 and 66% for cinacalcet and paricalcitol, respectively, and a 20% discontinuation rate, 124 subjects in each stratum were estimated to provide 81% power to detect a 30% absolute difference in the primary endpoint.. Of 746 patients screened, 272 (mean age, 63 years; mean iPTH, 509 pg/mL) were randomized. Mean duration of haemodialysis at baseline was 3.7 years. Comorbidities included hypertension (90.4%), Type 2 diabetes (40.4%), congestive heart failure (17.3%), coronary artery disease (34.6%) and gastrointestinal disorders (75%).. The study participants are representative of a multinational cohort of patients on haemodialysis with elevated iPTH. The study results will provide valuable information on the best available treatment of SHPT in patients on haemodialysis.

Topics: Adult; Aged; Aged, 80 and over; Bone Density Conservation Agents; Calcimimetic Agents; Cinacalcet; Cohort Studies; Disease Management; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Naphthalenes; Practice Guidelines as Topic; Renal Dialysis; Treatment Outcome; Vitamin D

Vitamin D deficiency is an important contributor to the development of hyperparathyroidism and is independently associated with cardiovascular and bone disease. The hypothesis was that nutritional vitamin D (ergocalciferol) supplementation in children with CKD stages 2-4 delays the onset of secondary hyperparathyroidism.. A randomized, double-blinded, placebo-controlled study in children with CKD2-4 who had 25-hydroxyvitamin D [25(OH)D] deficiency was conducted. Ergocalciferol (or a matched placebo) was given daily as per Kidney Disease Outcomes Quality Initiative guidelines. The primary endpoint was the time to development of hyperparathyroidism.. Seventy-two children were screened. Forty-seven children were 25(OH)D-deficient and randomly assigned to receive ergocalciferol or placebo. Twenty children in each arm completed the study; median follow-up was 12 months. Groups were well matched for age, race, estimated GFR, and season when recruited. Nine of 20 children on placebo and 3 of 20 children on ergocalciferol developed hyperparathyroidism (odds ratio, 4.64; 95% confidence interval, 1.02-21.00). The time to development of hyperparathyroidism was significantly longer with ergocalciferol treatment compared with placebo (hazard ratio, 0.30; 95% confidence interval, 0.09-0.93, P=0.05). With ergocalciferol treatment, normal 25(OH)D levels were achieved in all 8 children with CKD2, 8 of 11 children with CKD3, but not in the single patient with CKD4. There were no ergocalciferol-related adverse events. 25(OH)D levels >100 nmol/L were required to achieve normal levels of 1,25-dihydroxyvitamin D.. Ergocalciferol is an effective treatment that delays the development of secondary hyperparathyroidism in children with CKD2-3.

Topics: Adolescent; Analysis of Variance; Biomarkers; Chi-Square Distribution; Child; Child, Preschool; Chronic Disease; Dietary Supplements; Double-Blind Method; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kaplan-Meier Estimate; Kidney Diseases; London; Male; Odds Ratio; Placebos; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking.. To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2).. Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010.. Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112).. Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function.. Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group.. Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease.. clinicaltrials.gov Identifier: NCT00497146.

Topics: Aged; Chronic Disease; Double-Blind Method; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Treatment Outcome; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

In chronic kidney disease (CKD), left ventricular hypertrophy (LVH) is prevalent and is associated with increased cardiovascular morbidity and mortality. Vitamin D receptor (VDR) activation attenuates LVH progression in animal models.. PRIMO is a multinational, randomized, double-blinded trial with oral paricalcitol in subjects with stages 3-4 CKD, mild-to-moderate LVH and an LV ejection fraction >50%. The primary endpoint is change in the left ventricular mass index (LVMI) compared with placebo after 48 weeks of treatment. The main secondary endpoints are changes in diastolic function parameters. In this paper, we report baseline characteristics from this study.. LVMI was 33.0 ± 7.5 g/m(2.7) for males and 30.8 ± 7.2 g/m(2.7) for females (p = 0.04). LVMI correlated with systolic blood pressure (r = 0.24), urine albumin creatinine ratio (r = 0.39), troponin T (r = 0.29), high-sensitivity C-reactive protein (r = 0.25) and plasma levels of B-type brain natriuretic peptide (r = 0.22); all p < 0.01. In multiple linear regression, each remained independently associated with LVMI. The early diastolic velocity of the lateral mitral annulus (E') was 8.1 ± 2.4 cm/s. E' was inversely correlated with age in univariate (r = -0.14, p = 0.04) and multivariable (p = 0.02) analysis.. Among 227 multinational subjects with stages 3-4 CKD, baseline LVMI correlates with baseline blood pressure, urine albumin creatinine ratio and cardiac biomarkers, and baseline diastolic function correlates with age. This research was funded by Abbott Laboratories; ClinicalTrials.gov No. NCT00497146.

Topics: Administration, Oral; Aged; Blood Pressure; C-Reactive Protein; Creatinine; Double-Blind Method; Echocardiography; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Linear Models; Male; Middle Aged; Receptors, Calcitriol; Time Factors; Troponin T

Vitamin D receptor activation has been associated with increased serum creatinine and reduced estimated glomerular filtration rates, raising concerns that its use may be detrimental to kidney function. Here we studied the effect of vitamin D receptor activation on serum creatinine, creatinine generation, and its clearance. We measured baseline serum creatinine and 24-h urine creatinine in 16 patients with chronic kidney disease. The measurements were repeated every day for 7 days, during which time the patients received 2 μg paricalcitol, an orally active vitamin D receptor activator, every morning. At 4 days after stopping the vitamin analog, measurements were continued for 3 days. Geometric mean parathyroid hormone levels decreased from 77 pg/ml at baseline to 43 pg/ml at the end of treatment and significantly rebounded to 87 pg/ml following paricalcitol withdrawal, thereby supporting the biological efficacy of the analog dose used. With this therapy, the serum creatinine significantly increased at a rate of 0.010 mg/dl/day and urine creatinine at a rate of 17.6 mg/day. Creatinine and iothalamate clearances did not change, whereas urine albumin decreased insignificantly. Thus, short-term vitamin D receptor activation increases creatinine generation and serum creatinine, but it does not influence the glomerular filtration rate.

Topics: Administration, Oral; Aged; Albuminuria; Biomarkers; Chronic Disease; Creatinine; Drug Administration Schedule; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Indiana; Iothalamic Acid; Kidney; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Receptors, Calcitriol; Time Factors; Treatment Outcome

The optimal treatment of secondary hyperparathyroidism in chronic kidney disease (CKD) is unknown.. We conducted a randomized, blinded, 3-month trial in vitamin D-deficient CKD stage 3 and 4 patients with parathyroid hormone (PTH) values above the Kidney Disease Outcomes Quality Initiative target, comparing cholecalciferol (4000 IU/d x 1 month, then 2000 IU/d; n = 22) to doxercalciferol (1 microg/d; n = 25).. There was no difference in baseline demographics or lab tests, except a slightly higher estimated GFR (eGFR) in the doxercalciferol group. There was a significant increase in vitamin D level in the cholecalciferol group (14 +/- 6 to 37 +/- 10 ng/ml; P < 0.001) but no change in the doxercalciferol group. The PTH decreased by 27% +/- 34% in the doxercalciferol group (P = 0.002) and decreased by 10% +/- 31% in the cholecalciferol group (P = 0.16), but the difference between treatments was NS (P = 0.11). Similar results were found when absolute PTH change from baseline to end point was analyzed in a repeated-measures ANOVA model. The serum calcium and urine calcium excretions were not different. Additional non-mineral-related end points, albuminuria, and BP were evaluated, and although trends were present, this did not reach significance.. This prospective, randomized trial demonstrated a within-group reduction in PTH in the doxercalciferol-treated patients but no significant difference between the doxercalciferol and cholecalciferol patients. Larger, long-term studies are needed to demonstrate efficacy of mineral-related and non-mineral-related end points and safety.

Topics: Aged; Biomarkers; Calcium; Cholecalciferol; Chronic Disease; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Prospective Studies; Single-Blind Method; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Intermittent dosing of calcitriol for secondary hyperparathyroidism (SHPT) has been associated with greater parathyroid hormone (PTH) reduction with fewer calcemic and phosphatemic effects than daily (QD) dosing.. Secondary analyses of three randomized, double-blind, placebo-controlled multicenter studies in stage 3 and 4 chronic kidney disease (CKD) patients with SHPT were performed to compare three times per week (TIW) with QD dosing of paricalcitol. The pharmacokinetics of TIW and QD dosing of paricalcitol capsules were assessed in a separate group of healthy subjects.. Pharmacokinetics revealed similar steady state paricalcitol exposure between dosing regimens. In CKD patients, baseline data were similar between the TIW studies (n = 72, paricalcitol; n = 73, placebo) and QD studies (n = 35, paricalcitol; n = 40, placebo). Both dosing regimens resulted in similar efficacy (91%) for the primary end point of two consecutive > or = 30% decreases in intact PTH from baseline, but the QD regimen resulted in a greater percent reduction in intact PTH from baseline. The chances for developing increased serum calcium and phosphorus levels or Ca x P product were similar between paricalcitol and placebo groups for both treatment regimens. Furthermore, no difference in the risk for these elevations was detected between the TIW and QD regimens.. QD dosing of paricalcitol capsules is as efficacious as TIW dosing in achieving the primary end point (2 consecutive > or = 30% reductions in PTH) in stage 3 and 4 CKD patients with SHPT. Moreover, the QD regimen had no significant effect on hypercalcemia, hyperphosphatemia or Ca x P product as compared with placebo or intermittent dosing.

Topics: Adult; Aged; Aged, 80 and over; Calcium; Capsules; Chronic Disease; Double-Blind Method; Drug Administration Schedule; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Prospective Studies; Vitamins

Calcitriol lowers parathyroid hormone (PTH) levels in patients with chronic kidney disease (CKD) stages 3 and 4, but its use is limited by a low therapeutic index and concerns regarding hypercalcemia and acceleration of kidney disease. We evaluated doxercalciferol (1alpha-hydroxyvitamin D2) as an alternative therapy in a randomized, double-blinded, placebo-controlled, multicenter trial.. Fifty-five adults with stage 3 or 4 CKD and an intact PTH (iPTH) level greater than 85 pg/mL (ng/L) completed 8 baseline weeks, followed by 24 weeks of oral therapy with doxercalciferol or placebo. Pretreatment demographics and biochemical features did not differ between groups. Dosages were increased gradually if iPTH level was not decreased by 30% or greater and serum calcium and phosphorus levels were stable. Regular monitoring included plasma iPTH, serum calcium and phosphorus, urinary calcium, bone-specific serum markers, and serum lalpha,25-dihydroxyvitamin D levels. Glomerular filtration rate (GFR) was measured before and after treatment.. Mean plasma iPTH level decreased by 46% from baseline after 24 weeks of doxercalciferol treatment (P <0.001), but was unchanged with placebo. After 6 weeks, iPTH level reductions with doxercalciferol treatment exceeded those with placebo at all subsequent intervals (P <0.001). No clinically significant differences in mean serum calcium or phosphorus or urinary calcium levels or incidence of hypercalcemia, hyperphosphatemia, or hypercalciuria were noted between groups. Serum C- and N-telopeptide and bone-specific alkaline phosphatase levels decreased with doxercalciferol treatment relative to both baseline and placebo (P <0.01). Adverse-event rates and changes in GFR did not differ between groups.. Doxercalciferol is safe and effective in controlling secondary hyperparathyroidism of patients with CKD stages 3 and 4.

Topics: Aged; Calcium; Chronic Disease; Double-Blind Method; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphorus

The protective mechanism of paricalcitol remains unclear in renal ischemia-reperfusion (IR) injury. We investigated the renoprotective effects of paricalcitol in IR injury through the prostaglandin E

Topics: Animals; Apoptosis; Ergocalciferols; Kidney; Kidney Diseases; Male; Mice; Oxidative Stress; Proto-Oncogene Proteins c-akt; Receptors, Prostaglandin E, EP4 Subtype; Reperfusion Injury; Second Messenger Systems; Transcription Factor RelA

The aim of this study was to assess any potential additive effects of a treatment combining aliskiren with paricalcitol on reducing renal fibrosis. C57BL/6J mice were treated individually with aliskiren and/or paricalcitol until 7 days after initiation of unilateral ureteral obstruction (UUO).In obstructed kidneys of UUO mice, monotherapy with aliskiren or paricalcitol significantly attenuated interstitial fibrosis, collagen IV accumulation, and α-smooth muscle actin- and terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling-positive cells. The combination treatment showed additive efficacy in inhibition of these parameters. Renal NADPH oxidase (Nox)1 and Nox2 were significantly decreased by aliskiren or paricalcitol alone or in combination, while renal Nox4 expression was significantly reduced by paricalcitol mono- or combination treatment. Increased levels of p-Erk and p-p38 MAPK, and NF-κB in UUO kidneys were also significantly reduced by either aliskiren or paricalcitol treatment alone or in combination. Aliskiren or paricalcitol monotherapy significantly reduced the expression of (pro)renin receptor in UUO kidneys. In addition, aliskiren tended to augment renin expression in UUO kidneys, but paricalcitol reduced its expression level. The combination treatment effectively blocked both (pro)renin receptor and renin expression induced by aliskiren, and resulted in a further reduction of the renal expression of angiotensin II AT1 receptor. Aliskiren failed to increase the expression of vitamin D receptor in UUO kidneys, but the combination treatment restored its expression level. Taken together, a treatment combining aliskiren with paricalcitol better inhibits UUO-induced renal injury. The mechanism of this synergy may involve more profound inhibition of the intrarenal renin-angiotensin system.

Topics: Amides; Animals; Apoptosis; Collagen Type IV; Disease Progression; Drug Therapy, Combination; Ergocalciferols; Fibrosis; Fumarates; Inflammation Mediators; Kidney; Kidney Diseases; Male; Mice, Inbred C57BL; Myofibroblasts; Oxidative Stress; Receptors, Calcitriol; Renin; Renin-Angiotensin System; Treatment Outcome; Ureteral Obstruction

This study aimed to investigate the possible protective effect of paricalcitol on experimental amikacin-induced nephrotoxicity model in rats. Wistar albino rats (n = 32) were allocated into four equal groups of eight each, the control (Group C), paricalcitol (Group P), amikacin-induced nephrotoxicity (Group A), and paricalcitol-treated amikacin-induced nephrotoxicity (Group A + P) groups. Paricalcitol was given intra-peritoneally at a dose of 0.4 μg/kg/d for 5 consecutive days prior to induction of amikacin-induced nephrotoxicity. Intra-peritoneal amikacin (1.2 g/kg) was used to induce nephrotoxicity at day 4. Renal function parameters, oxidative stress biomarkers, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine/deoxyguanosine ratio), kidney histology, and vascular endothelial growth factor (VEGF) immunoexpression were determined. Group A + P had lower mean fractional sodium excretion (p < 0.001) as well as higher creatinine clearance (p = 0.026) than the amikacin group (Group A). Renal tissue malondialdehyde levels (p = 0.035) and serum 8-hydroxy-2'-deoxyguanosine/deoxyguanosine ratio (8-OHdG/dG ratio) (p < 0.001) were significantly lower; superoxide dismutase (p = 0.024) and glutathione peroxidase (p = 0.007) activities of renal tissue were significantly higher in group A + P than in group A. The mean scores of tubular necrosis (p = 0.024), proteinaceous casts (p = 0.038), medullary congestion (p = 0.035), and VEGF immunoexpression (p = 0.018) were also lower in group A + P when compared with group A. This study demonstrates the protective effect of paricalcitol in the prevention of amikacin-induced nephrotoxicity in an experimental model. Furthermore, it is the first study to demonstrate that paricalcitol improves oxidative DNA damage in an experimental acute kidney injury model.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amikacin; Animals; Anti-Bacterial Agents; Bone Density Conservation Agents; Deoxyguanosine; Disease Models, Animal; DNA Damage; Ergocalciferols; Kidney; Kidney Diseases; Kidney Function Tests; Malondialdehyde; Oxidative Stress; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A

Topics: Dietary Supplements; Ergocalciferols; Female; Humans; Kidney Diseases; Male; Renal Dialysis; Vitamin D; Vitamin D Deficiency

The COL4A3-/- mouse serves as animal model for progressive renal fibrosis. Using this animal model, the present study investigates the nephroprotective effects of Paricalcitol versus Calcitriol alone and on top of ACE-inhibitor therapy.. Eighty six mice were divided into six groups: (PC) with Paricalcitol 0.1 mcg/kg, (CA) Calcitriol 0.03 mcg/kg (dose equipotent), (PLAC) vehicle 0.1 mL i.p. five times per week, (ACE + PC) Paricalcitol plus Ramipril, (ACE + CA) Calcitriol plus Ramipril and (ACE + PLAC) vehicle plus Ramipril 10 mg/kg/day p.o. ACE therapy started pre-emptively in Week 4, PC/CA therapy was initiated in 6-week-old animals with ongoing renal fibrosis and lasted for 8 weeks. Four to six animals were sacrificed after 9.5 weeks and kidneys were further investigated using histological, immunohistological and Western-blot techniques. Survival until end-stage renal failure was determined in the remaining animals.. PC, but not CA, prolonged lifespan until renal failure by 13% compared with untreated controls (P = 0.069). ACE-inhibition prolonged lifespan by >50%. Added on top of ACE inhibition, ACE + PC (but not ACE + CA) even further prolonged lifespan by additional 18.0% (P < 0.01 versus ACE + PLAC) and improved renal function (blood urea nitrogen; P < 0.05 versus ACE + CA). Accumulation of extracellular matrix and renal scarring was decreased in PC and ACE + PC-treated mice.. The present study demonstrated a substantial nephroprotective and antifibrotic effect of the vitamin D-receptor activator Paricalcitol on top of early ACE inhibition in the COL4A3-/- model of progressive kidney fibrosis. The synergistic effect of Paricalcitol on top of RAAS-blockade might as well be valuable in other chronic kidney diseases.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoantigens; Bone Density Conservation Agents; Calcitriol; Collagen Type IV; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Ergocalciferols; Extracellular Matrix; Female; Fibrosis; Immunoblotting; Immunoenzyme Techniques; Kidney Diseases; Male; Mice; Mice, Knockout; Ramipril; Receptors, Calcitriol

The effect of vitamin D and renin-angiotensin-aldosterone system blockade medications in pathophysiology of contrast induced nephropathy (CIN) is controversial. The effects of paricalcitol (active vitamin D analogue) and losartan treatments in an experimental model of CIN were investigated in this study.. Thirty-six male Wistar albino rats were examined in five treatment groups. Placebo group (Group A; n = 4) received no active medication; control group (Group B; n = 8) received only contrast media (CM); Group C (n = 8) received paricalcitol; Group D (n = 8) received losartan and Group E (n = 8) received paricalcitol plus losartan. CIN was induced by NG-nitro-L-arginine methyl ester and indomethacin before iohexol injection. Renal histopathological findings were categorized and renal immunohistochemical examinations by caspase-3 rabbit primary antibody were performed.. Creatinine and cystatin C levels significantly increased in the treatment groups, compared to Group A. However, creatinine levels were not significantly increased in Groups C, D and E compared to Group B. Compared to Group B, a significant increase of cystatin C levels was observed in Group D (p < 0.01). In Group E, when paricalcitol treatment was added to losartan treatment, cystatin C levels were similar to Group B (p = 1.00). In histopathological and immunohistochemical examination frequency of Grade 2/3 tubular necrosis and renal caspase 3 activity scores were significantly higher in the losartan treatment group compared to the other treatment groups. The histopathological effects related to losartan treatment were found to be reversed when paricalcitol treatment was combined.. Our findings suggest that paricalcitol treatment counteracts increased contrast induced nephropathy caused by losartan. These findings warrant further clinical studies to investigate the benefit of paricalcitol in CIN prophylaxis.

Topics: Animals; Contrast Media; Disease Models, Animal; Drug Therapy, Combination; Ergocalciferols; Kidney Diseases; Losartan; Male; Rabbits; Rats; Rats, Wistar; Renin-Angiotensin System

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

The effect of paricalcitol on renal ischemia-reperfusion injury (IRI) has not been investigated. We examined whether paricalcitol is effective in preventing inflammation in a mouse model of IRI, and evaluated the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) pathways as a protective mechanism of paricalcitol.. Paricalcitol (0.3 μg/kg) was administered to male C57BL/6 mice 24 h before IRI. Bilateral kidneys were subjected to 23 min of ischemia, and mice were killed 72 h after IRI. The effects of paricalcitol on renal IRI were evaluated in terms of renal function, tubular necrosis, apoptotic cell death, inflammatory cell infiltration and inflammatory cytokines. The effects of paricalcitol on COX-2, PGE2 and its receptors were investigated.. Paricalcitol pretreatment improved renal function (decreased blood urea nitrogen and serum creatinine levels), tubular necrosis and apoptotic cell death in IRI-mice kidneys. The infiltration of inflammatory cells (T cells and macrophages), and the production of proinflammatory cytokines (RANTES, tumor necrosis factor-α, interleukin-1β and interferon-γ) were reduced in paricalcitol-treated mice with IRI. Paricalcitol up-regulated COX-2 expression, PGE2 synthesis and mRNA expression of receptor subtype EP4 in post-ischemic renal tissue. The cotreatment of a selective COX-2 inhibitor with paricalcitol restored functional injury and tubular necrosis in paricalcitol-treated mice with IRI.. Our study demonstrates that paricalcitol pretreatment prevents renal IRI via the inhibition of renal inflammation, and the up-regulation of COX-2 and PGE2 is one of the protective mechanisms of paricalcitol in renal IRI.

Topics: Animals; Blotting, Western; Bone Density Conservation Agents; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Ergocalciferols; Immunoenzyme Techniques; Inflammation; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Receptors, Calcitriol; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Topics: Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male

Vitamin D slows the progression of chronic kidney disease. Furthermore, activators of vitamin D receptors (VDR) have suppressant effects on the renin-angiotensin system, as well as anti-inflammatory and antifibrotic actions. This study aimed to evaluate the cytoprotective effects of paricalcitol, a VDR activator, at the mitochondrial level using an obstructive nephropathy model [unilateral ureteral obstruction (UUO)]. Rats subjected to UUO and controls were treated daily with vehicle or paricalcitol. The control group underwent a sham surgery. The treatment was done for 15 days (30 ng/kg). The following were determined: biochemical parameters; fibrosis; apoptosis; mitochondrial morphology; VDR, AT(1) receptor, and NADPH oxidase 4 expression; and NADPH oxidase activity (in total and in mitochondrial fractions from the renal cortex). VDR activation prevented fibrosis (20 ± 5 vs. 60 ± 10%) and the number of TUNEL-positive apoptotic cells (10 ± 3 vs. 25 ± 4) in UUO. Biochemical, histological, and molecular studies suggest mitochondrial injury. Electron microscopy revealed in UUO electronically luminous material in the nucleus. Some mitochondria were increased in size and contained dilated crests and larger than normal spaces in their interiors. These changes were not present with paricalcitol treatment. Additionally, high AT(1)-receptor mRNA and NADPH activity was reverted in mitochondrial fractions from obstructed paricalcitol-treated animals (0.58 ± 0.06 vs. 0.95 ± 0.05 relative densitometry units and 9,000 ± 800 vs. 15,000 ± 1,000 relative fluorescence units·μg protein(-1)·min(-1), respectively). These changes were consistent with an improvement in VDR expression (0.75 ± 0.05 vs. 0.35 ± 0.04 relative densitometry units). These results suggest that paricalcitol confers a protective effect and reveal, as well, a possible AT(1) receptor-dependent protective effect that occurs at the mitochondrial level.

Topics: Animals; Apoptosis; Cytoprotection; Ergocalciferols; Fibrosis; Kidney; Kidney Diseases; Mitochondria; Rats; Rats, Inbred WKY; Renin-Angiotensin System; Ureteral Obstruction

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

Topics: Ergocalciferols; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Ventricular Function, Left; Vitamin D Deficiency; Vitamins

The aim of the study was to assess the effect of paricalcitol on the experimental contrast-induced nephropathy (CIN) model. We hypothesised that paricalcitol may prevent CIN.. 32 Wistar albino rats were divided into four groups (n=8 each): control group, paricalcitol group, CIN group and paricalcitol plus CIN group. Paricalcitol (0.4 µg kg(-1) day(-1)) was given intraperitoneally for 5 consecutive days prior to induction of CIN. CIN was induced at day 4 by intravenous injection of indometacin (10 mg kg(-1)), Nω-nitro-L-arginine methyl ester (L-NAME, 10 mg kg(-1)) and meglumine amidotrizoate (6 ml kg(-1)). Renal function parameters, oxidative stress biomarkers, histopathological findings and vascular endothelial growth factor (VEGF) immunoexpression were evaluated.. The paricalcitol plus CIN group had lower mean serum creatinine levels (p=0.034) as well as higher creatinine clearance (p=0.042) than the CIN group. Serum malondialdehyde and kidney thiobarbituric acid-reacting substances levels were significantly lower in the paricalcitol plus CIN group than in the CIN group (p=0.024 and p=0.042, respectively). The mean scores of tubular necrosis (p=0.024), proteinaceous casts (p=0.038), medullary congestion (p=0.035) and VEGF immunoexpression (p=0.018) in the paricalcitol plus CIN group were also significantly lower.. This study demonstrates the protective effect of paricalcitol in the prevention of CIN in an experimental model.

Topics: Analysis of Variance; Animals; Antioxidants; Biomarkers; Contrast Media; Ergocalciferols; Immunohistochemistry; Kidney Diseases; Male; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Renal Agents; Vascular Endothelial Growth Factor A

Topics: Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Naphthalenes; Renal Dialysis; Vitamin D

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

Secondary hyperparathyroidism (SHPT) is a common problem among patients with chronic kidney disease (CKD) on haemodialysis. This study was conducted to assess the use, effectiveness and safety of intravenous paricalcitol in haemodialysis patients with various degrees of SHPT.. This observational, multicentre, prospective study was conducted in 14 Swedish dialysis centres from May 2007 to June 2008 and included 92 haemodialysis patients with a diagnosis of SHPT associated with CKD. The decision to initiate treatment with intravenous paricalcitol was made by the treating physician. No treatment algorithms were provided.. Mean patient age was 64 years. Of the 92 patients included, 74 had an intact parathyroid hormone (iPTH) level of >300 pg/ml at baseline. Median iPTH was 584 pg/ml in patients with a baseline PTH of >300 pg/ml. During follow-up there was a decrease in iPTH to 323 pg/ml at 6 months (-45%, p < 0.0001). In parallel, there was a small increase in serum calcium, but serum phosphorus and the calcium × phosphorus product remained unchanged.. This study showed that intravenous paricalcitol substantially and safely decreased iPTH in haemodialysis patients with a baseline iPTH above the Kidney Disease Outcomes Quality Initiative recommended target range (150-300 pg/ml) and had minimal impact on serum minerals.

Topics: Aged; Biomarkers, Pharmacological; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcium; Chronic Disease; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Observation; Parathyroid Hormone; Phosphorus; Prospective Studies; Renal Dialysis; Sweden

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.. 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.. 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.. 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; Heart Ventricles; HL-60 Cells; 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

Vitamin D receptor activation may have pleiotropic effects in a variety of tissues. Experimental studies with vitamin D receptor activation demonstrate an ability to delay progression of renal disease. In humans, vitamin D receptor activation reduces albuminuria. Yet some clinical studies demonstrate that patients receiving vitamin D supplementation have an elevation in serum creatinine and a decline in estimated glomerular filtration rate. These observations may be explainable by an effect of vitamin D receptor activation on creatinine metabolism.

Topics: Creatinine; Ergocalciferols; Female; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Male; Receptors, Calcitriol

Secondary hyperparathyroidism is a common complication in patients with chronic kidney disease. Treatment with paricalcitol, a selective vitamin D receptor (VDR) activator, has shown benefits in these patients by adequately reducing PTH levels with minimal changes in serum calcium and phosphorus. The aim of this study was to assess the effectiveness and safety of paricalcitol in chronic renal disease patients (CKD grades 3 and 4).. A study of our experience with paricalcitol was conducted in normal clinical practice in patients over 18 years diagnosed with grade 3 or 4 chronic kidney disease. Patients were periodically evaluated every 3 months. The primary endpoint of effectiveness was to obtain two consecutive decreases of ≥30% in iPTH with respect to baseline values. The secondary endpoints were fulfilment of the objectives in accordance with the Spanish Society of Nephrology (SEN) and Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, as well as the relationship between the effectiveness of the treatment and different patient variables. Safety was studied by means of hypercalcaemia events.. The primary study endpoint was achieved in 54.3% of patients. In addition, another 16.3% of patients had reduced iPTH by more than 30% at the 3rd visit. Therefore, 70.6% of patients reduced their iPTH levels by more than 30% in 6 months. The relationship between treatment success and both glomerular filtration rate and body mass index was significant. There were few adverse events, although hypercalcaemia was found in 5.4% of patients.. Treatment with paricalcitol is effective in controlling secondary hyperparathyroidism in non-dialysed patients with a wide safety margin.

Topics: Aged; Aged, 80 and over; Body Mass Index; Calcium; Chronic Disease; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Evaluation; Endpoint Determination; Ergocalciferols; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Vitamin D is thought to exert a protective effect on renal disease progression, but the underlying molecular mechanism remains unclear. We investigated whether paricalcitol ameliorates tubular dysfunction and fibrosis in gentamicin (GM)-induced renal injury. Two groups of rats were treated with GM (100 mg x kg(-1) x day(-1)), one of which was cotreated with paricalcitol (0.3 microg x kg(-1) x day(-1)) for 14 days and the other was not. The control group was treated with vehicle only. HK-2 cells were cultured with GM in the absence or presence of paricalcitol. Paricalcitol restored impaired renal function and the downregulated renal sodium transporters and aquaporin-1 expression caused by GM. ED-1-expressing monocyte/macrophage accumulation induced by GM was attenuated by paricalcitol treatment. Paricalcitol prevented upregulated inflammatory cytokines (TNF-alpha, IL-1beta, INF-gamma) and adhesion molecules (monocyte chemoattractant protein-1, ICAM-1, VCAM-1) induced by GM. In addition, paricalcitol effectively reversed TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) process and extracellular matrix accumulation in GM-induced nephropathy. Increased collagen deposition and fibrosis in GM-treated kidney were ameliorated by paricalcitol. Paricalcitol also attenuated the upregulated NF-kappaB and phosphorylated ERK1/2 expression in HK-2 cells cultured with GM. In conclusion, paricalcitol prevents GM-induced renal injury by inhibiting renal inflammation and fibrosis, the mechanism of which is the interruption of NF-kappaB/ERK signaling pathway and preservation of tubular epithelial integrity via inhibiting EMT process.

Topics: Animals; Aquaporin 1; Bone Density Conservation Agents; Carrier Proteins; Cell Adhesion Molecules; Cell Line; Cytokines; Ergocalciferols; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Gentamicins; Inflammation Mediators; Kidney Diseases; Kidney Tubules; Kidney Tubules, Proximal; Male; Nephritis; NF-kappa B; Rats; Rats, Sprague-Dawley; Sodium; Transforming Growth Factor beta1

Vitamin D deficiency is highly prevalent in chronic kidney disease. The aim of this study was to evaluate the effects of oral cholecalciferol supplementation on mineral metabolism, inflammation, and cardiac dimension parameters in long-term hemodialysis (HD) patients.. This 1-year prospective study included 158 HD patients. Serum levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], intact parathyroid hormone, and plasma brain natriuretic peptide as well as circulating bone metabolism and inflammation parameters were measured before and after supplementation. Baseline 25(OH)D and 1,25(OH)(2)D levels were measured twice (end of winter and of summer, respectively). Therapy with paricalcitol, sevelamer, and darbepoietin was evaluated.. There was an increase in serum 25(OH)D and 1,25(OH)(2)D levels after supplementation. Conversely, serum calcium, phosphorus, and intact parathyroid hormone were decreased. There was a reduction in the dosage and in the number of patients who were treated with paricalcitol and sevelamer. Darbepoietin use was also reduced, with no modification of hemoglobin values. Serum albumin increased and C-reactive protein decreased during the study. Brain natriuretic peptide levels and left ventricular mass index were significantly reduced at the end of the supplementation.. Oral cholecalciferol supplementation in HD patients seems to be an easy and cost-effective therapeutic measure. It allows reduction of vitamin D deficiency, better control of mineral metabolism with less use of active vitamin D, attenuation of inflammation, reduced dosing of erythropoiesis-stimulating agents, and possibly improvement of cardiac dysfunction.

Topics: Administration, Oral; Aged; Biomarkers; Bone Density Conservation Agents; Bone Remodeling; C-Reactive Protein; Calcitriol; Calcium; Chelating Agents; Cholecalciferol; Chronic Disease; Darbepoetin alfa; Dietary Supplements; Ergocalciferols; Erythropoietin; Female; Hematinics; Humans; Hypertrophy, Left Ventricular; Inflammation Mediators; Kidney Diseases; Male; Middle Aged; Natriuretic Peptide, Brain; Parathyroid Hormone; Phosphorus; Polyamines; Prospective Studies; Renal Dialysis; Serum Albumin; Sevelamer; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Despite its benefits, the clinical use of cyclosporine A (CsA) is limited by its nephrotoxic properties. Because paricalcitol (19-nor-1,25-hydroxyvitamin D(2)) has renoprotective effects, we tested whether it can blunt renal dysfunction and fibrosis in a rat model of CsA-induced nephropathy. Treatment with CsA decreased creatinine clearance, increased monocyte/macrophage infiltration, and increased the expression of inflammatory cytokines within the kidney. Paricalcitol reduced the decline in kidney function and pro-fibrotic changes and also blunted the increased transforming growth factor (TGF)-beta1 expression and Smad signaling. Using an in vitro model, we treated HK-2 cells with CsA and found that paricalcitol attenuated the CsA-induced increases in phosphorylated extracellular signal-regulated and c-Jun N-terminal kinases, and also prevented the activation of nuclear factor-kappaB. Paricalcitol effectively prevented TGF-beta1-induced epithelial-to-mesenchymal transitions and extracellular matrix accumulation as evidenced by attenuated collagen deposition and fibrosis in CsA-treated rats. In addition, paricalcitol decreased the number of TUNEL-positive nuclei and reduced the expression of pro-apoptotic markers in CsA-treated HK-2 cells. Thus, paricalcitol appears to attenuate CsA-induced nephropathy by suppression of inflammatory, pro-fibrotic, and apoptotic factors through inhibition of the nuclear factor-kappaB, Smad, and mitogen-activated protein kinase signaling pathways.

Topics: Animals; Apoptosis; Cyclosporine; Ergocalciferols; Fibrosis; Inflammation; Kidney Diseases; Protective Agents; Rats; Signal Transduction; Treatment Outcome

secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD) and a frequent cause of clinically significant bone disease. Non-selective vitamin D receptor (VDR) activator treatment has been used to treat the condition but is ineffective for many patients with hypercalcaemia and hyperphosphataemia and may precipitate worsening of their condition. Compared with non-selective VDR activator treatment, use of the VDR ligand paricalcitol may increase survival and reduce the risk of morbidities in patients with SHPT, which may have health economic consequences.. the objective of this study was to determine the cost effectiveness of paricalcitol versus a non-selective VDR activator for the treatment of SHPT in patients with CKD in the UK setting.. A Markov process model was developed employing data sources from the published literature, paricalcitol clinical trials and observational studies, official UK price/tariff lists and national population statistics. The comparator was alfacalcidol, a non-selective VDR activator medication. The primary perspective of the study was that of the UK National Health Service (NHS). The efficacy outcomes (reductions in SHPT, proteinuria, complications and mortality) were extrapolated to: number of life-years gained (LYG) and number of quality-adjusted life-years (QALYs). Clinical and economic outcomes were discounted at 3.5%. The year of costing for costs determined in the study was 2006.. the reference case analysis was a 10-year time horizon, based on a comparison of paricalcitol with a non-selective VDR activator, which is started in CKD stage 3 (moderate reduction in glomerular filtration rate [GFR] with kidney damage) and continued in CKD stage 4 (severe reduction in GFR) and CKD stage 5 (established kidney failure). The use of paricalcitol leads to an additional medical cost of pound3224 ($US5970). The health benefits of paricalcitol lead to an increase in LYG of 0.52 and a gain in QALYs of 0.465. Therefore the use of paricalcitol results in an incremental cost-effectiveness ratio of pound6933/QALY ($US12 840/QALY) from the primary perspective of the NHS. One-way sensitivity analyses and probabilistic sensitivity analyses confirmed the robustness of the model.. this model showed that the favourable clinical benefit of paricalcitol results in positive short- and long-term health economic benefits. This study suggests that the use of paricalcitol in patients with early CKD may be cost effective from the UK NHS perspective versus non-selective VDR activator medication.

Topics: Chronic Disease; Cost-Benefit Analysis; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Diseases; Markov Chains; Quality-Adjusted Life Years; Receptors, Calcitriol

Topics: alpha-2-HS-Glycoprotein; Blood Proteins; Chronic Disease; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Renal Dialysis; Time Factors; Treatment Outcome; Up-Regulation

Topics: Adolescent; Child; Ergocalciferols; Humans; Kidney Diseases; Vitamin D; Vitamin D Deficiency

Continuously emerging evidence indicates that defi ciencies in 25-hydroxyvitamin D and consequently vitamin D receptor (VDR) activation play crucial roles in adversely affecting cardiovascular (CV) health in the general population and those at high risk of CV disease, as well as in patients with chronic kidney disease (CKD). In CKD patients, a lack of VDR activation is one of the main pathophysiological factors contributing to secondary hyperparathyroidism (SHPT). However, this lack of VDR activation has numerous additional implications on CV and renal function, with SHPT being only one symptom of a much more extensive disorder. VDRs are widely expressed throughout the body with manifold activities that involve feedback loops within the CV, immune, and renal systems. Modulation of VDR activator levels results in correlative regulatory effects on mineral homeostasis, hypertension, vascular disease, and vascular calcifi cation, as well as a number of other endpoints in cardiac and renal pathology. Among compounds available for the treatment of SHPT, paricalcitol is a selective VDR activator. The term 'selective' refers to paricalcitol being more selective in affecting VDR pathways in the PTH gland compared with bone and intestine. As such, paricalcitol's selectivity allows for a wider therapeutic window with effects beyond PTH control and mineral management, and may explain, in part, the increased survival advantage with paricalcitol treatment.

Topics: Bone Density Conservation Agents; Cardiovascular Diseases; Chronic Disease; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Receptors, Calcitriol

Secondary hyperparathyroidism is a serious complication of chronic renal disease when function decline and is characterized by abnormalities in serum calcium and phosphate profile, along with a decline in calcitriol synthesis. A reduced density of specific receptors for vitamin D and calcium in several tissues and organs are also present, thus contributing to parathyroid hyperplasia and abnormal parathyroid hormone synthesis and secretion. This metabolic derangement is observable early in the course of chronic renal failure (stages 3 and 4) and on this basis it should also be treated early in order to avoid important clinical consequences. To afford secondary hyperparathyroidism, several strategies should be considered: phosphate oral intake control (diet and phosphate binders), adequate calcium oral intake, vitamin D receptor activation. More specifically, the concept of selective vitamin D receptor activation will be considered as well as its biological effects, the use of paricalcitol (a selective vitamin D receptor activator) given orally to patients on peritoneal dialysis, and stages 3 and 4 of chronic renal failure. Finally, we will consider a series of nonclassical interesting potential mechanisms of selective vitamin D receptor activation leading to reduced cardiovascular and all-cause mortality.

Topics: Bone Density Conservation Agents; Calcitriol; Chronic Disease; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Parathyroid Hormone; Peritoneal Dialysis; Phosphates; Receptors, Calcitriol

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Dietary Supplements; Ergocalciferols; Female; Humans; Hypertension; Kidney Diseases; Male; Parathyroid Hormone; Prospective Studies; Risk Assessment; Sensitivity and Specificity; Treatment Outcome

Several observational studies have indicated that vitamin D receptor activators (VDRA), including paricalcitol, are associated with greater survival in maintenance hemodialysis (MHD) patients; however, patients with higher serum parathyroid hormone (PTH), indicative of a more severe secondary hyperparathyroidism and higher death risk, are usually given higher VDRA dosages, which can lead to confounding by medical indication and attenuated survival advantage of high VDRA dosages. It was hypothesized that the ratio of the administered paricalcitol dosage to serum PTH level discloses better the underlying dosage-survival association.. The 3-yr mortality predictability of the administered paricalcitol during the first 3 mo of the cohort divided by averaged serum intact PTH during the same period was examined in 34,307 MHD patients from all DaVita dialysis clinics across the United States using Cox regression.. MHD patients were 60.8 +/- 15.4 yr of age and included 47% women, 34% black patients, and 47% patients with diabetes. Initially, the ratio of paricalcitol (mircrog/wk) to PTH (pg/ml) was divided into four groups: 0 (reference), 1 to <30, 30 to <60, and >60 x 10(-3). Unadjusted, case mix-adjusted (demographics, comorbidity, and Kt/V), and malnutrition-inflammation complex syndrome-adjusted models, the death rate ratio for the paricalcitol/PTH index groups, were 0.99, 0.95, and 0.92. Restricted cubic splines analyses were consistent with a linear relation.. Higher weekly paricalcitol dosage per each unit of serum PTH seems to have an incremental association with greater survival in MHD patients. The observed dosage-response phenomenon needs to be confirmed in clinical trials.

Topics: Aged; Biomarkers; Chronic Disease; Dose-Response Relationship, Drug; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Proportional Hazards Models; Receptors, Calcitriol; Renal Dialysis; Risk Assessment; Time Factors; Treatment Outcome; United States

Abnormalities in vitamin D metabolism play a major role in the pathogenesis of secondary hyperparathyroidism in chronic kidney disease. The gradual and progressive decline in 1,25-dihydroxyvitamin D in the course of chronic kidney disease is the result of several mechanisms that limit the ability of the failing kidney to maintain the levels of 1,25-dihydroxyvitamin D despite increasing levels of parathyroid hormone. Recent observations have indicated that chronic kidney disease seems to be associated with a high incidence of nutritional vitamin D insufficiency or deficiency as manifested by decreased levels of 25-hydroxyvitamin D. This contributes to the inability to maintain the levels of 1,25-dihydroxyvitamin D; therefore, current practice guidelines suggest repleting vitamin D status by the administration of native vitamin D as a first step in the therapy of the abnormalities of bone and mineral metabolism in chronic kidney disease. The efficacy of this therapy is extremely variable, and active vitamin D sterols may be required, especially as kidney disease progresses. The importance of the abnormal vitamin D metabolism is being investigated vigorously in view of the observations that vitamin D may have important biologic actions in many tissues in addition to bone and parathyroid. Thus, observational data have suggested potential survival benefits of vitamin D sterol administration in this clinical setting, and experimental data have suggested a potential beneficial effect of vitamin D sterols on the progression of kidney disease. Further work is required to define the mechanisms involved and to examine the effects of vitamin D therapy on outcomes in randomized, controlled trials.

Topics: Chronic Disease; Ergocalciferols; Evidence-Based Medicine; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Practice Guidelines as Topic; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Substantial data for the relative costs of hospitalisation in paricalcitol- and calcitriol-treated patients with chronic kidney disease stage 4 do not exist. The objective of this study was to compare the cost benefit of paricalcitol and calcitriol therapies in chronic kidney disease stage 4 from the perspective of a healthcare payer.. A range of methods were used to estimate the relative costs of hospitalisation in paricalcitol- and calcitriol-treated patients with chronic kidney disease stage 4, extrapolated from observed differences in hospitalisation costs in stage 5 patients. Different values and approaches were used to show a range of values and to show the specific hospitalisation benefit in terms of the all-cause hospitalisation rate and number of all-cause hospital days.. The annual dollar impact of use of paricalcitol instead of calcitriol on all-cause hospital admissions was calculated to be a reduction of $US1220-$US4476 and for all-cause number of hospital days a reduction of $US1816-$US8776. A total of 42 cost comparison estimates were generated to compare the cost benefit of calcitriol or paricalcitol. Of these 42 comparisons, 35 showed that the total cost of paricalcitol was lower than the total cost of calcitriol therapy. The cost advantage of paricalcitol over calcitriol substantially increased as patients progressed toward dialysis.. Cost analyses suggest that paricalcitol-treated patients have a lower total cost than calcitriol-treated patients.

Topics: Calcitriol; Calcium Channel Agonists; Cost-Benefit Analysis; Ergocalciferols; Hospitalization; Humans; Kidney Diseases; Vitamins

To determine the effect of various doses of vitamin D(2) and D(3), as well as ambulatory status (a surrogate for sun exposure), on 25-OH-D levels.. Cross-sectional study with multiple regression analysis.. A state veterans home for veterans and their spouses.. Three hundred two of 609 eligible residents.. Serum 25-OH-D and parathyroid hormone (PTH) level, supplemental dose of vitamins D(2) and D(3) per kilogram of body weight, and 3 levels of ambulatory status.. The mean 25-OH-D level was 28.6 + 9.2 ng/mL; 6.6% of subjects had values of 16 ng/mL or below. Thirty-two percent of participants had 25-OH-D levels below 30 ng/mL and PTH elevation based on stage of kidney disease, evidence that the suboptimal 25-OH-D level had physiologic consequences. Residents unable to transfer independently had 25-OH-D levels 1.6 ng/mL lower than those able to transfer independently. A regression analysis performed in residents unable to transfer independently (less likely to be exposed to the sun) demonstrated that the average increase in 25-OH-D level per 100 IU of D(3) in a 70-kg resident was 2.1 ng/mL versus 1.8 ng/mL for vitamin D(2).. Nursing home residents should receive at least 800-1000 IU of D(3) per day in an effort to maintain optimal vitamin D levels.

Topics: Aged; Aged, 80 and over; Bone Density Conservation Agents; Calcifediol; Cholecalciferol; Cross-Sectional Studies; Drug Monitoring; Ergocalciferols; Female; Geriatric Assessment; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Mobility Limitation; Nursing Homes; Parathyroid Hormone; Regression Analysis; Severity of Illness Index; Sunlight; Treatment Outcome; Veterans; Vitamin D Deficiency; Wisconsin

Topics: Calcitriol; Chronic Disease; Ergocalciferols; Humans; Kidney Diseases; Parathyroid Hormone; Peptide Fragments

The effects of calcitriol and paricalcitol on circulating levels of intact parathyroid hormone, parathyroid hormone-(1-84), the large carboxy-terminal-parathyroid hormone fragments, and the parathyroid hormone-(1-84)/carboxy-terminal-parathyroid hormone fragments were studied.. In the longitudinal study, 31 hemodialysis patients who were receiving intravenous calcitriol or paricalcitol were followed for 6 to 8 wk. After a washout period, patients were treated with the other vitamin D compound for 6 to 8 wk. Plasma intact parathyroid hormone and parathyroid hormone-(1-84) were measured, and the parathyroid hormone ratio was calculated. In the cross-sectional study, results of intact parathyroid hormone, parathyroid hormone-(1-84), and parathyroid hormone ratio were compared between patients who were treated with paricalcitol (n = 49) versus no vitamin D therapy (n = 44).. In the longitudinal study, the parathyroid hormone ratio was significantly lower in patients who were treated with calcitriol and higher with paricalcitol treatment compared with values that were obtained during washout. In the cross-sectional study, intact parathyroid hormone levels were identical in both groups, whereas parathyroid hormone-(1-84) and thus parathyroid hormone ratio values were higher in patients who were given paricalcitol than in patients who were not receiving vitamin D.. These data show that at similar intact parathyroid hormone values, the active parathyroid hormone-(1-84) compound is lower with calcitriol than with paricalcitol treatment. This finding might be relevant for choice of vitamin D compound in patients with stage 5 chronic kidney disease.

Topics: Adult; Aged; Calcitriol; Chronic Disease; Cross-Sectional Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Longitudinal Studies; Male; Middle Aged; Parathyroid Hormone; Peptide Fragments; Renal Dialysis

Topics: Acetates; Calcitriol; Calcium; Calcium Compounds; Chronic Disease; Cinacalcet; Clinical Trials, Phase III as Topic; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Naphthalenes; Parathyroid Hormone; Phosphorus; Randomized Controlled Trials as Topic

Paricalcitol is a less hypercalcemic vitamin D analog that has been shown to suppress secondary hyperparathyroidism and to prevent the associated histomorphometric changes in bone. In this study, we show that paricalcitol also ameliorates the renal insufficiency-induced loss of bone mineral and the mechanical competence of bone.. Renal bone disease is a common consequence of chronic renal insufficiency and the associated secondary hyperparathyroidism (SH). Paricalcitol [19-nor-1,25(OH)(2)D(2)] has been shown to ameliorate SH and prevent renal failure-induced histomorphometric changes in bone with minimal calcemic and phosphatemic activity. However, information about its efficacy on restoration of bone structural strength is lacking. In this study, we explored the effects of paricalcitol treatment on bone structure and strength in a model of advanced renal disease.. Forty-five 8-week-old rats were randomly assigned to either surgical 5/6 nephrectomy (NTX) or Sham-operation. After a 15-week postoperative disease progression period, the NTX rats were further allocated to uremic control (NTX) and treatment (NTX + paricalcitol) groups, the latter of which received paricalcitol for the subsequent 12 weeks. After 27 weeks, the animals were killed, plasma samples were collected, and both femora were excised for comprehensive analysis of the femoral neck and midshaft (pQCT and biomechanical testing).. High mortality that exceeded 30% was observed in both NTX groups. NTX induced over a 13-fold increase in plasma PTH, whereas this increase was only 5-fold after paricalcitol treatment. At the femoral neck, NTX was associated with an 8.1% decrease (p < 0.05) in vBMD and a 16% decrease in breaking load (p < 0.05) compared with the Sham group, whereas paricalcitol treatment completely prevented these changes. At the femoral midshaft, the NTX resulted in a 6.6% decrease in cortical BMD (p < 0.01 versus Sham), and this change was also prevented by paricalcitol.. Paricalcitol administration prevented renal insufficiency-associated decreases in BMD in the femoral neck and the femoral midshaft and restored bone strength in the femoral neck. Therefore, paricalcitol can efficiently ameliorate renal insufficiency-induced loss of bone mineral and mechanical competence of bone.

Topics: Animals; Aorta; Biomechanical Phenomena; Bone Density; Bone Diseases; Calcinosis; Ergocalciferols; Kidney; Kidney Diseases; Rats; Tomography, X-Ray Computed

Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.

Topics: Aged; Alkaline Phosphatase; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Female; Humans; Kidney Diseases; Male; Middle Aged; Multivariate Analysis; Parathyroid Hormone; Phosphorus; Predictive Value of Tests; Proportional Hazards Models; Renal Dialysis; Risk Factors; Survival Analysis; Time Factors

Topics: Chronic Disease; Ergocalciferols; Humans; Kidney Diseases; Proteinuria; Randomized Controlled Trials as Topic; Retrospective Studies

To survey the medical nutrition therapy practices of renal dietitians for the treatment of bone mineral metabolism.. To obtain data on phosphorus diet prescription levels. To determine allied team involvement for phosphate binder and Vitamin D therapies. To assess the frequency and target levels for monitoring serum calcium, phosphorus, -phosphorus product, intact PTH and alkaline phosphatase.. Two renal dietitians from the National Kidney Foundation-Council on Renal Nutrition developed a 5-question survey. This was posted on both the RenalRD Listserv and the NKF-CRN website from January 1 through February 15, 2001. Dietitians were asked to respond using facsimile, e-mail or reply by mail.. One hundred and thirty-one surveys were received representing all major dialysis providers in the United States, the British Virgin Islands, and Japan. Results included information for peritoneal and hemodialysis patients. Five different methods for dosing phosphate binders were determined. Prescribed phosphate binders included calcium acetate, sevelamer hydrochloride, and calcium carbonate. 108 out of 131 dietitian respondents (82.5%) have a medical protocol in place for vitamin D therapy. Of the respondents, 47% were directly responsible for implementing the vitamin D protocol. Paricalcitol was the most widely used form of IV Vitamin D. Biochemistry results were as follows: calcium, 16 different ranges from 8.0 mg/dL to 11.5 mg/dL; phosphorus, 13 different ranges from 2.5 mg/dL to 6.5 mg/dL; calcium-phosphorus product, 13 different ranges from 55-75; iPTH, 20 different ranges from 50-300 pg/mL; alkaline phosphatase, 18 different ranges from no records being monitored to a level of 500 mg/dL.. The survey revealed a large variability in the treatment of bone mineral metabolism. Improved clinical practice guidelines for the health care team are being developed with the National Kidney Foundation (NKF)-Kidney Disease Outcomes and Quality Initiative (KDOQI) bone disease management workgroup.

Topics: Acetates; Bone and Bones; Calcium Carbonate; Calcium Compounds; Dietetics; Epoxy Compounds; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Phosphates; Phosphorus, Dietary; Polyamines; Polyethylenes; Renal Dialysis; Sevelamer; Surveys and Questionnaires; Vitamin D

Identification of bone selective vitamin D analogues would provide an interesting substance class for the treatment of osteoporosis. The synthetic prodrug 1alpha-hydroxyvitamin D2 [1alpha(OH)D2] has been shown to combine equal bone-preserving activity with distinctly reduced calcemic effects relative to 1alpha-hydroxyvitamin D3 [1alpha(OH)D3] in 3-month-old ovariectomized (OVX) rats. Therefore, 1alpha(OH)D2 may be a bone-selective compound. The aim of this study was to compare the bone protective and the calcemic activities of chronically administered 1alpha(OH)D2 and 1alpha(OH)D3 in 6-month-old OVX rats over a broad dose range from ineffective to toxic doses. Ninety-six female 6-month-old Fischer-344 rats were used for this experiment. Eighty rats were bilaterally OVX, 8 rats were sham-operated (SHAM), and 8 rats were killed at the time of surgery as a baseline control. Groups of OVX rats received vehicle alone (n = 16) or daily doses in the diet of 0.025, 0.05, 0.1, and 0.2 microg of 1alpha(OH)D2 or 1alpha(OH)D3 per kg body weight (BW) per day (n = 8 each). After calcein double-labeling, all animals were killed 3 months post-OVX. Orally administered 1alpha(OH)D2 was significantly less toxic compared with 1alpha(OH)D3 in terms of BW gain and kidney calcium content. The effects of 1alpha(OH)D2 and 1alpha(OH)D3 on serum calcium and urinary calcium excretion were generally similar at all doses in this study. Both 1alpha(OH)D2 and 1alpha(OH)D3 prevented the estrogen deficiency-induced bone loss in OVX rats, and induced profound bone anabolic effects at high dosages. 1alpha(OH)D3 and 1alpha(OH)D2 also dose-dependently increased total bone mineral density (BMD), cortical area, and cortical thickness in the tibial diaphysis of OVX rats. Bone resorption as assessed by osteoclast numbers (Oc.Ns) in vertebral cancellous bone and urinary excretion of deoxypyridinoline (DPD) was dose-dependently suppressed by 1alpha(OH)D2 and 1alpha(OH)D3. These data show that although 1alpha(OH)D2 was slightly but significantly less toxic compared with 1alpha(OH)D3, it did not have increased skeletal effects at any dose. Taken together, our findings argue against selective metabolic activation of 1alpha(OH)D2 in bone.

Topics: Animals; Biotransformation; Bone and Bones; Bone Density; Calcinosis; Calcium; Creatinine; Ergocalciferols; Female; Hydroxycholecalciferols; Kidney Diseases; Lumbar Vertebrae; Organ Specificity; Osteocalcin; Osteoporosis; Ovariectomy; Phosphorus; Prodrugs; Rats; Rats, Inbred F344; Tibia; Urea; Weight Gain

Nephrocalcinosis (NC) detected by ultrasound is a recognized abnormality for some patients with X-linked hypophosphatemia (XLH) who received vitamin D2 and inorganic phosphate therapy, but is commonly observed in XLH patients treated with 1,25-dihydroxyvitamin D3 and inorganic phosphate supplementation. Nevertheless, long-term follow-up of kidney function in XLH patients with NC detected ultrasonographically has not been reported. We investigated two women with XLH, ages 31 (patient 1) and 39 (patient 2) years, each of whom had suffered at least one documented episode of vitamin D2-induced hypercalcemia and renal azotemia during childhood. Patient 2 had also been treated with inorganic phosphate. No medications for XLH had been taken during adulthood. Renal ultrasonography at our institution demonstrated marked bilateral medullary NC in both women. No other explanation was found for their NC that apparently occurred several decades earlier from medical therapy for XLH. Detailed studies (including creatinine clearance, beta2-microglobulin excretion, and fasting urinary osmolality and acidification) revealed no impairment of kidney function in either patient. Our findings indicate that subradiographic medullary NC acquired during medical therapy for XLH may persist for decades, but with no adverse renal sequelae. Definitive (long-term) assessment of kidney function in the XLH population with NC, however, will be necessary to fully understand the risk of current medical treatment for this most common heritable form of rickets.

Topics: Adult; Ergocalciferols; Family Health; Female; Humans; Hypophosphatemia, Familial; Kidney; Kidney Diseases; Kidney Medulla; Nephrocalcinosis; Time Factors; Uremia

Topics: Animals; Bone Development; Calcification, Physiologic; Calcitriol; Calcium; Child; Child, Preschool; Diuretics; Ergocalciferols; Growth; Humans; Hypophosphatemia; Infant; Infant, Newborn; Kidney Diseases; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Monitoring, Physiologic; Phosphates; Rickets

Because of the recently observed augmentation of medullary hypoxic injury by calcium in isolated perfused rat kidneys (Kidney Int 34:186-194, 1988), renal morphology of chronic, prolonged hypercalcemia was investigated in vivo. Rats were treated with repeated injections of vitamin D2 (400,000 units/week) for two to eight weeks. Chronic elevation of plasma calcium from 2.1 to 2.8 mmol/liter (P less than 0.001) was associated by a fall in maximal urine osmolality with no change in glomerular filtration rate. The most significant morphological alterations occurred in the inner stripe of the outer medulla; these changes were characterized by a sequence of active injury with subsequent destruction and atrophy of the medullary thick ascending limbs, fibroblastic and lymphocytic infiltration, and secondary dilatation of collecting ducts. Similar changes occurred in the medullary rays. These alterations were accompanied by increased renal prostanoid production and a predisposition to acute kidney failure from indomethacin. Because of its selective occurrence in zones of poorest oxygen supply, this inner stripe injury may derive from vulnerability to hypoxia and may play a role in some chronic nephropathies.

Topics: Animals; Chronic Disease; Ergocalciferols; Hypercalcemia; Hypoxia; Kidney Diseases; Kidney Medulla; Prostaglandins; Rats; Rats, Inbred Strains

Topics: Cholecalciferol; Ergocalciferols; Female; Humans; Hypercalcemia; Kidney; Kidney Diseases; Middle Aged; Parathyroid Hormone

This report describes a microassay for 1,25-dihydroxyvitamin D [1,25-(OH)2D] in plasma which does not require high performance liquid chromatography. The assay involves rapid extraction and preliminary purification on a C-18 Sep-Pak cartridge, followed by final purification on a silica Sep-Pak using hexane-isopropanol. Quantitation of 1,25-(OH)2D is achieved using a nonequilibrium assay employing 1,25-(OH)2D receptor from calf thymus. The method is sensitive to 1.5 pg/tube, with B50 occurring at 9 pg/tube and a useful assay range of 1.5-40 pg/tube. The intra- and interassay coefficients of variation are 6.5% and 11.5%, respectively, and the method is linear over a wide range of sample dilutions. In addition, this assay measures both 1,25-(OH)2D2 and 1,25-(OH)2D3 with equal affinity. The importance of using an assay with equal affinity for 1,25-(OH)2D2 and 1,25-(OH)2D3 is demonstrated by the findings that 25-hydroxyvitamin D2 (250HD2) constituted 38.9% of the total 25-OHD found in clinical samples (12.6 +/- 0.7 ng/ml 25-OHD2 vs. 20.1 +/- 0.5 ng/ml 25-OHD3; n = 807). Results of this new assay have been compared to those of the assay of Horst et al. (21), which employs Sephadex LH-20 and high performance liquid chromatography sample purification. The correlation coefficient was r2 = 0.96, and the slope was 1.05. Using this new assay, plasma 1,25-(OH)2D concentrations were as follows: normal adults, 37.4 +/- 2.2 pg/ml (n = 22); chronic renal failure, 10.6 +/- 1.5 pg/ml (n = 7); anephrics, undetectable (n = 10); infant cord blood, 22.9 +/- 4.4 pg/ml (n = 7); and hyperparathyroidism, 68.9 +/- 5.0 pg/ml (n = 13). This assay should be particularly useful in pediatric or other studies in which sample size is limited.

Topics: Adult; Animals; Biological Assay; Calcitriol; Cattle; Child; Child, Preschool; Chromatography; Cytosol; Ergocalciferols; Female; Fetal Blood; Humans; Hyperparathyroidism; In Vitro Techniques; Infant, Newborn; Kidney Diseases; Male; Microchemistry; Radioligand Assay; Thymus Gland

Serum 25-hydroxyvitamin D and immunoreactive parathyroid hormone concentrations were measured in normal elderly subjects living at home and in sick elderly patients in hospital. Normal old people tended to have high 25-hydroxyvitamin D and low parathyroid hormone concentrations; in the sick elderly this pattern was reversed. The raised serum parathyroid hormone concentrations in the sick elderly were not due to poor renal function and may have been a response to vitamin D deficiency. A high serum parathyroid hormone concentration in an elderly patient must be interpreted in the light of the patient's general health and nutritional state. Caution is needed in diagnosing primary hyperparathyroidism in this age group.

Topics: 25-Hydroxyvitamin D 2; Aged; Alkaline Phosphatase; Ergocalciferols; Female; Humans; Hyperparathyroidism; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone

Topics: Calcifediol; Calcitriol; Child; Cystinosis; Dihydrotachysterol; Ergocalciferols; Humans; Kidney Diseases; Vitamin D

Topics: Acidosis, Renal Tubular; Adult; Bicarbonates; Ergocalciferols; Female; Humans; Kidney Diseases; Middle Aged; Osteomalacia; Sodium

Topics: Adolescent; Calcium; Child; Chronic Kidney Disease-Mineral and Bone Disorder; Congenital Abnormalities; Drug Therapy; Dwarfism; Ear Deformities, Acquired; Ear, External; Ergocalciferols; Fractures, Bone; Humans; Kidney Diseases; Metabolism; Radiography

Topics: Adult; Ergocalciferols; Humans; Kidney Diseases; Kidney Tubules; Osteomalacia; Phosphates; Vitamin D; Vitamins

Topics: Absorption; Blood; Calcium; Calcium, Dietary; Creatine; Creatinine; Diet; Diet Therapy; Ergocalciferols; Gastrointestinal Tract; Hypercalcemia; Hyperparathyroidism; Inositol; Kidney Diseases; Kidney Function Tests; Metabolism; Pharmacology; Phosphates; Phytic Acid; Sarcoidosis; Sodium; Toxicology; Urine; Vitamin D

Topics: Alloxan; Calcinosis; Cholecalciferol; Dihydrotachysterol; Ergocalciferols; Islands; Islets of Langerhans; Kidney Diseases; Kidney Tubules; Nephrocalcinosis; Pancreas; Pathology; Rats; Research

Topics: Alkalies; Aluminum; Bicarbonates; Blood Chemical Analysis; Bone Diseases; Calcium; Ergocalciferols; Humans; Kidney Diseases; Kidney Failure, Chronic; Osteitis Fibrosa Cystica; Osteomalacia

Topics: Blood Protein Disorders; Calcium Metabolism Disorders; Ergocalciferols; Fractures, Spontaneous; Gastroenterology; Humans; Kidney Diseases; Kidney Glomerulus; Liver Cirrhosis; Osteomalacia; Osteoporosis; Phosphorus Metabolism Disorders; Rib Fractures; Vitamin D Deficiency

Topics: Cholestanes; Ergocalciferols; Humans; Kidney; Kidney Diseases; Vitamin D; Vitamins

Topics: Animals; Cortisone; Ergocalciferols; Kidney Diseases; Nephrocalcinosis; Rats; Vitamin D