vitamin-d-2 and Hyperphosphatemia

Previous studies have demonstrated the safety and efficacy of using Paricalcitol for the treatment of secondary hyperparathyroidism (SHPT) in patients on dialysis. The aim of the current meta-analysis was to assess the safety and efficacy of Paricalcitol for the management of SHPT in patients with chronic kidney disease (CKD) not yet on dialysis. A secondary aim was to determine if sufficient data was available to assess the effect of Paricalcitol for the management of proteinuria.. A meta-analysis was conducted using the Cochrane Collaboration's RevMan 4.2 software.. Paricalcitol is effective in lowering PTH in patients with CKD not yet on dialysis and is also effective in lowering proteinuria in diabetic CKD patients. However, we uncovered a safety signal identifying an elevated calcium phosphate product and a trend towards the development of hypercalcemia. A phosphate elevation was not demonstrated because the target used in the clinical studies was a P > 5.5 mg/dl, a value appropriate for dialysis patients and not CKD patients.. Although Paricalcitol is effective in lowering PTH, we advise caution in the use of any active Vitamin D analogues in patients with CKD because of the potential risk of exacerbating vascular calcification.

Topics: Bone Density Conservation Agents; Ergocalciferols; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Failure, Chronic; Proteinuria; Randomized Controlled Trials as Topic; Risk; Treatment Outcome; Vitamin D

The involvement of vitamin D deficiency in cardiovascular morbidity and mortality is attracting great interest. In patients with chronic kidney disease this association is stronger because vitamin D levels decrease as a result of renal progressive impairment. In chronic kidney disease secondary hyperparathyroidism commonly occurs in response to persistent hypocalcemia and hyperphosphatemia; moreover, parathyroid gland volume increases, vascular calcification is accelerated, and structural and functional modifications of the left ventricle are observed. These alterations entail both cardiac and renal involvement, resulting in cardio-renal syndrome. Recent studies concluded that vitamin D administration seems to have cardioprotective and renoprotective effects and improve peripheral vascular disease, vascular calcification, cardiac outcome, and blood pressure control. In clinical practice, therefore, the use of this hormone may play an important role in cardio-renal syndrome prevention.

Topics: Cardio-Renal Syndrome; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypocalcemia; Kidney; Parathyroid Glands; Parathyroid Hormone; Receptors, Calcitriol; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin D; Vitamin D Deficiency

Recent evidence suggests that the traditional syndromes known as renal osteodystrophy, secondary hyperparathyroidism, and vitamin D deficiency are related to mortality in persons with moderate to advanced chronic kidney disease (CKD). The so-called 'kidney bone disease', also known as 'mineral and bone disorders', is defined to include bone disorders, mineral disarrays, and vascular calcification. We have identified 14 common and clinically relevant conditions of contemporary nature that are related to the kidney bone disease, including calcitriol (active vitamin D) deficiency, 25(OH)-vitamin D deficiency, biochemical hyperparathyroidism, relatively low parathyroid hormone (PTH) level, increased serum alkaline phosphatase (hyperphosphatasemia), elevated fibroblast growth factor (FGF)-23, high turnover bone disease, adynamic bone disease, uremic osteoporosis, vascular calcification, hyper- and hypophosphatemia, and hyper- and hypocalcemia. We present a critical review of these 14 conditions with emphasis on patient survival and other pertinent clinical outcomes. We also review unresolved controversies surrounding the management of these conditions by administration of nutritional vitamin D (ergocalciferol and cholecalciferol), vitamin D receptor activators (calcitriol, alphacalcidiol, doxercalciferol), D-mimetics (paricalcitol, maxacalcitol), calcimimetics (cinacalcet), recombinant PTH (teriparatide), and receptor activator of nuclear factor-kappaB ligand modulators (denosumab); compare mortality predictability of PTH and alkaline phosphatase; and examine potential risks of bone disorders and mineral disarrays in CKD patients.

Topics: Alkaline Phosphatase; Calcinosis; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypocalcemia; Hypophosphatemia; Kidney Failure, Chronic; Minerals; Osteoporosis; Parathyroid Hormone; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency

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 common in chronic kidney disease (CKD) patients. Classically, SHPT is induced by hypocalcemia, hyperphosphatemia, and calcitriol deficiency, that cause not only renal osteodystrophy but also systemic toxicity, particularly cardiovascular disease.. Treatment with calcitriol, the active form of vitamin D, reduces serum parathyroid hormone (PTH) levels but may result in both hypercalcemia and hyperphosphatemia, increasing the risk of vascular calcification in CKD. Are the new vitamin D receptor activators (VDRAs) more useful in the treatment of SHPT for their reduced risk of hypercalcemia and hyperphosphatemia in haemodialysis (HD) patients?. In this review, we describe the new VDRA, paricalcitol (1,25-dihydroxy-19-nor-vitamin D2), which suppresses PTH secretion with minimal increases on serum calcium and phosphate levels.. In some animal models of CKD paricalcitol does not cause vascular calcification, while other VDRAs do. These data may account for the results seen in observational studies of HD patients, in which paricalcitol is associated with improved survival compared to calcitriol.

Topics: Animals; Bone Density Conservation Agents; Calcitriol; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypocalcemia; Kidney Failure, Chronic; Receptors, Calcitriol; Renal Dialysis

Elevated intact parathyroid hormone (iPTH) levels can contribute to morbidity and mortality in children with chronic kidney disease (CKD). We evaluated the pharmacokinetics, efficacy, and safety of oral paricalcitol in reducing iPTH levels in children with stages 3-5 CKD.. Children aged 10-16 years with stages 3-5 CKD were enrolled in two phase 3 studies. The stage 3/4 CKD study characterized paricalcitol pharmacokinetics and compared the efficacy and safety of paricalcitol with placebo followed by an open-label period. The stage 5 CKD study evaluated the efficacy and safety of paricalcitol (no comparator) in children with stage 5 CKD undergoing dialysis.. In the stage 3/4 CKD study, mean peak plasma concentration and area under the time curve from zero to infinity were 0.13 ng/mL and 2.87 ng•h/((or ng×h/))mL, respectively, for 12 children who received 3 μg paricalcitol. Thirty-six children were randomized to paricalcitol or placebo; 27.8% of the paricalcitol group achieved two consecutive iPTH reductions of ≥30% from baseline versus none of the placebo group (P = 0.045). Adverse events were higher in children who received placebo than in those administered paricalcitol during the double-blind treatment (88.9 vs. 38.9%; P = 0.005). In the stage 5 CKD study, eight children (61.5%) had two consecutive iPTH reductions of ≥30% from baseline, and five (38.5%) had two consecutive iPTH values of between 150 and 300 pg/mL. Clinically meaningful hypercalcemia occurred in 21% of children.. Oral paricalcitol in children aged 10-16 years with stages 3-5 CKD reduced iPTH levels and the treatment was well tolerated. Results support an initiating dose of 1 μg paricalcitol 3 times weekly in children aged 10-16 years.

Topics: Adolescent; Bone Density Conservation Agents; Calcium; Child; Double-Blind Method; Ergocalciferols; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Failure, Chronic; Male; Parathyroid Hormone; Phosphorus; Renal Dialysis; Treatment Outcome

Many patients with chronic kidney disease are prescribed vitamin D receptor agonists (VDRAs) for the management of secondary hyperparathyroidism. Oral phosphate binders may interact with, and potentially reduce the therapeutic activity of, oral VDRAs. This post hoc analysis of a Phase 3 study evaluated the pharmacodynamic effects of the iron-based phosphate binder sucroferric oxyhydroxide (SFOH) and sevelamer (SEV) carbonate on VDRA activity in dialysis patients.. One thousand and fifty nine patients were randomized to SFOH 1.0-3.0 g/day (n = 710) or SEV 2.4-14.4 g/day (n = 349) for up to 52 weeks. Potential interactions of SFOH and SEV with VDRAs were assessed using serum intact parathyroid hormone (iPTH) concentrations as a pharmacodynamic biomarker. Three populations of SFOH- and SEV-treated patients were analyzed: Population 1 (n = 187), patients taking concomitant stable doses of oral VDRAs only; Population 2 (n = 250), patients taking no concomitant VDRAs; Population 3 (n = 68), patients taking concomitant stable doses of intravenous paricalcitol only. Populations were compared using a mixed-effects model to obtain the least squares mean change in iPTH from baseline to Week 52. Differences between treatment groups were also compared.. In Population 1, iPTH decreased from baseline to Week 52 in the SFOH group (-25.3 pg/ml) but increased in the SEV group (89.8 pg/ml) (p = 0.02). In Population 2, iPTH increased to a similar extent in both treatment groups. In Population 3, iPTH concentrations in both treatment groups decreased to a similar degree (-29.6 and -11.4 pg/ml for SFOH and SEV, respectively; p = 0.87).. In contrast with SEV, SFOH did not appear to impact the iPTH-lowering effect of oral VDRAs.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Biomarkers, Pharmacological; Bone Density Conservation Agents; Chelating Agents; Drug Combinations; Drug Interactions; Ergocalciferols; Female; Ferric Compounds; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Male; Middle Aged; Parathyroid Hormone; Receptors, Calcitriol; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer; Sucrose

We compared the effects of calcitriol and doxercalciferol, in combination with either calcium carbonate or sevelamer, on bone, mineral, and fibroblast growth factor-23 (FGF-23) metabolism in patients with secondary hyperparathyroidism. A total of 60 pediatric patients treated with peritoneal dialysis were randomized to 8 months of therapy with either oral calcitriol or doxercalciferol, combined with either calcium carbonate or sevelamer. Bone formation rates decreased during therapy and final values were within the normal range in 72% of patients. A greater improvement in eroded surface was found in patients treated with doxercalciferol than in those given calcitriol. On initial bone biopsy, a mineralization defect was identified in the majority of patients which did not normalize with therapy. Serum phosphate concentrations were controlled equally well by both binders, but serum calcium levels increased during treatment with calcium carbonate, and serum parathyroid hormone levels were decreased by 35% in all groups. Baseline plasma FGF-23 values were significantly elevated and rose over fourfold with calcitriol and doxercalciferol, irrespective of phosphate binder. Thus, doxercalciferol is as effective as calcitriol in controlling serum parathyroid hormone levels and suppressing the bone formation rate. Sevelamer allows the use of higher doses of vitamin D. Implications of these changes on bone and cardiovascular biology remain to be established.

Topics: Adolescent; Bone and Bones; Bone Density Conservation Agents; Calcitriol; Calcium Carbonate; Chronic Kidney Disease-Mineral and Bone Disorder; Drug Therapy, Combination; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney Failure, Chronic; Longitudinal Studies; Male; Osteogenesis; Parathyroid Hormone; Polyamines; Sevelamer

Klotho plays an important role in the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Klotho is highly expressed in the kidney and parathyroid glands, but its presence in the vasculature is debated. Renal Klotho is decreased in CKD, but the effect of uremia on Klotho in other tissues is not defined. The effect of vitamin D receptor activator therapy in CKD on the expression of Klotho in various tissues is also in debate. In uremic rats (surgical 5/6th nephrectomy model), we compared 3 months of treatment with and without paricalcitol on Klotho immunostaining in the kidney, parathyroid glands, and aorta. With uremia, Klotho was unchanged in the parathyroid, significantly decreased in the kidney (66%) and the intimal-medial area of the aorta (69%), and significantly increased in the adventitial area of the aorta (67%) compared with controls. Paricalcitol prevented the decrease of Klotho in the kidney, increased expression in the parathyroid (31%), had no effect in the aortic media, but blunted the increase of Klotho in the aortic adventitia. We propose that fibroblasts are responsible for the expression of Klotho in the adventitia. In hyperplastic human parathyroid tissue from uremic patients, Klotho was higher in oxyphil compared with chief cells. Thus, under our conditions of moderate CKD and mild-to-moderate hyperphosphatemia in rats, the differential expression of Klotho and its regulation by paricalcitol in uremia is tissue-dependent.

Topics: Adventitia; Animals; Aorta; Bone Density Conservation Agents; Disease Models, Animal; Ergocalciferols; Female; Fibroblasts; Glucuronidase; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney; Klotho Proteins; Nephrectomy; Oxyphil Cells; Parathyroid Glands; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Tunica Intima; Uremia

Calcimimetics activate the calcium-sensing receptor (CaR) and reduce parathyroid hormone (PTH) by increasing the sensitivity of the parathyroid CaR to ambient calcium. The calcimimetic, cinacalcet, is effective in treating secondary hyperparathyroidism in dialysis patients [chronic kidney disease (CKD 5)], but little is known about its effects on stage 3-4 CKD patients. We compared cinacalcet and paricalcitol in uremic rats with creatinine clearances "equivalent" to patients with CKD 3-4. Uremia was induced in anesthetized rats using the 5/6th nephrectomy model. Groups were 1) uremic control, 2) uremic + cinacalcet (U+Cin; 15 mg x kg(-1) x day(-1) po for 6 wk), 3) uremic + paricalcitol (U+Par; 0.16 microg/kg, 3 x wk, ip for 6 wk), and 4) normal. Unlike U+Par animals, cinacalcet promoted hypocalcemia and marked hyperphosphatemia. The Ca x P in U+Cin rats was twice that of U+Par rats. Both compounds suppressed PTH. Serum 1,25-(OH)(2)D(3) was decreased in both U+Par and U+Cin rats. Serum FGF-23 was increased in U+Par but not in U+Cin, where it tended to decrease. Analysis of tibiae showed that U+Cin, but not U+Par, rats had reduced bone volume. U+Cin rats had similar bone formation and reduced osteoid surface, but higher bone resorption. Hypocalcemia, hyperphosphatemia, low 1,25-(OH)(2)D(3), and cinacalcet itself may play a role in the detrimental effects on bone seen in U+Cin rats. This requires further investigation. In conclusion, due to its effects on bone and to the hypocalcemia and severe hyperphosphatemia it induces, we believe that cinacalcet should not be used in patients with CKD without further detailed studies.

Topics: Animals; Biomarkers; Bone Resorption; Calcitriol; Calcium; Cinacalcet; Creatinine; Disease Models, Animal; Ergocalciferols; Female; Fibroblast Growth Factors; Hyperparathyroidism; Hyperphosphatemia; Hypocalcemia; Naphthalenes; Nephrectomy; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing; Renal Insufficiency, Chronic; Severity of Illness Index; Tibia; Uremia

Topics: Animals; Biomarkers; Bone Remodeling; Bone Resorption; Calcitriol; Cinacalcet; Ergocalciferols; Fibroblast Growth Factors; Humans; Hyperparathyroidism; Hyperphosphatemia; Hypocalcemia; Naphthalenes; Parathyroid Hormone; Rats; Renal Insufficiency, Chronic; Severity of Illness Index; Tibia; Treatment Outcome; Uremia

Patients with poor metabolic control receiving conventional hemodialysis are at risk for developing severe secondary hyperparathyroidism. We postulated that daily hemodialysis may be effective at controlling parathyroid hormone (PTH) in the setting of severe secondary hyperparathyroidism by improving the control of hyperphosphatemia and allowing increased use of vitamin D analogs. We present 5 patients with severe secondary hyperparathyroidism (median iPTH=1783 pg/mL) who were treated with 3-hour daily hemodialysis (3 hours x 6 times a week). Daily hemodialysis, at 1 year, was associated with a 70.4% reduction in median PTH (1783 pg/mL [interquartile range: 1321-1983]-472 pg/mL [334, 704], P<0.001). Additionally, there was an increase in paricalcitol dose from 0 mcg/d to 10.8 (2.00, 11.7) mcg/d, a 39% reduction in calcium x phosphorus product (80.3 +/- 26.8-48.9 +/- 14.0, P<0.01), a 52% reduction in serum phosphorus (9.90 +/- 2.34-4.75 +/- 0.79 mg/dL, P<0.0001), and a 17.6% increase in serum calcium (8.18 +/- 2.04-9.62 +/- 0.93 mg/dL, P<0.01). Three-hour daily hemodialysis with the use of high-dose paricalcitol is associated with improved control of severe secondary hyperparathyroidism.

Topics: Adult; Appointments and Schedules; Biomarkers; Bone Density Conservation Agents; Calcinosis; Combined Modality Therapy; Dose-Response Relationship, Drug; Ergocalciferols; Female; Heart Valve Diseases; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Minerals; Phosphates; Renal Dialysis; Severity of Illness Index