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American Journal of Nephrology 2015In patients with chronic kidney disease (CKD), impaired renal function leads to decreased vitamin D levels, which causes an increase in parathyroid hormone (PTH)... (Review)
Review
BACKGROUND
In patients with chronic kidney disease (CKD), impaired renal function leads to decreased vitamin D levels, which causes an increase in parathyroid hormone (PTH) production and contributes to the development of secondary hyperparathyroidism (SHPT). This may result in adverse clinical effects such as bone disorders, vascular calcification, cardiovascular disease, and increased mortality. Current treatment practices and associated outcomes with active vitamin D treatment in patients with CKD were reviewed with the objective to assess parameters (such as PTH and serum calcium levels) that may be used to define the failure of vitamin D treatment.
SUMMARY
Reports based on observational data have noted improved outcomes with active vitamin D treatment (calcitriol, paricalcitol, alfacalcidol, or doxercalciferol) in patients with CKD. Criteria for the identification of active vitamin D treatment failure are unclear from current guidelines, although up to 50% of patients may experience treatment failure eventually because of development of hypercalcemia or resistant SHPT, characterized by an elevated intact PTH (iPTH) level despite treatment. We propose a definition of vitamin D treatment failure as iPTH >600 pg/ml after 6 months of intravenous active vitamin D treatment and corrected total calcium serum levels >10.2 mg/dl, and review factors that may predict the response to vitamin D treatment. Key Message: Active vitamin D treatment failure is an important challenge in clinical practice. The aim of the proposed definition is to suggest a possible framework for hypothesis generation and to encourage further research into this common problem.
Topics: Bone Density Conservation Agents; Humans; Hyperparathyroidism, Secondary; Renal Insufficiency, Chronic; Treatment Failure; Vitamin D; Vitamin D Deficiency
PubMed: 26439891
DOI: 10.1159/000441095 -
The Journal of Steroid Biochemistry and... Nov 2016Arabinocytosine (AraC, also known as cytarabine) is one of the mainstays of AML therapy, but like other DNA damaging therapeutic agents it is rarely curative by itself....
Arabinocytosine (AraC, also known as cytarabine) is one of the mainstays of AML therapy, but like other DNA damaging therapeutic agents it is rarely curative by itself. There is an emerging realization that the therapeutic outcomes may be improved by combining AraC with other compounds. Here we report that the addition of a differentiating agent combination immediately following AraC damage to AML blasts, selectively increases the cell kill. The experiments were performed using cultured cells from established cell lines of AML (HL60 and U937). The cells were exposed to 100nM AraC, a concentration which produced approximately 25-50% cell kill, followed by a combination of 100nM 1alpha-hydroxyvitamin D2 (1-D2) and 10μM carnosic acid (CA), which together can serve as a powerful differentiating agent combination for AML cells, but are not toxic alone. AraC-induced cell death, measured by annexin V/propidium iodide, was significantly (p<0.01) increased by the 1-D2/CA combination in both cell lines, but not by 1-D2 or CA alone. The enhancement of cell death occurred by both apoptosis and necrosis, was associated with increased DNA damage and with higher levels of DNA damage response (DDR) activated marker Chk1, but the expression of p27, a cell cycle inhibitor protein, was not enhanced by 1-D2/CA. The principal finding is that a vitamin D analog 1-D2 combined with a plant-derived antioxidant CA can markedly augment the cytotoxic action of AraC, an anti-leukemia therapeutic agent.
Topics: Abietanes; Annexin A5; Antimetabolites, Antineoplastic; Antioxidants; Apoptosis; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Differentiation; Comet Assay; Cytarabine; DNA Damage; Ergocalciferols; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Phosphorylation; Propidium; U937 Cells
PubMed: 26319201
DOI: 10.1016/j.jsbmb.2015.08.023 -
PloS One 2015Osteocytic protein expression is dysregulated in CKD and is affected by changes in mineral metabolism; however the effects of active vitamin D sterol therapy on...
BACKGROUND
Osteocytic protein expression is dysregulated in CKD and is affected by changes in mineral metabolism; however the effects of active vitamin D sterol therapy on osteocyte protein expression in advanced CKD is unknown.
METHODS
Eleven pediatric patients with end stage kidney disease underwent bone biopsy, were treated for 8 months with doxercalciferol, and then underwent a second bone biopsy. Bone expression of fibroblast growth factor 23 (FGF23), dentin matrix protein 1 (DMP1), and sclerostin were determined by immunohistochemistry and quantified by Ariol Scanning. Western blot analysis and qRT-PCR was performed on bone abstracts of a subset of study subjects to determine the nature (i.e. size) of FGF23 and DMP1 in bone before and after therapy.
RESULTS
As assessed by immunohistochemistry, bone FGF23, DMP1 and sclerostin protein all increased with therapy. In the case of FGF23, this increase was due to an increase in the full-length molecule without the appearance of FGF23 fragments. DMP1 was present primarily in its full-length form in healthy controls while 57kDa and 37kDa fragments of DMP1 were apparent in bone of dialysis patients at baseline and the 57 kDa appeared to decrease with therapy.
CONCLUSION
Marked changes in osteocytic protein expression accompany doxercalciferol therapy, potentially impacting bone mineralization and the skeletal response to PTH. The effects of these bone changes on long-term outcomes remain to be determined.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Biopsy; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Bone and Bones; Child; Ergocalciferols; Extracellular Matrix Proteins; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gene Expression; Genetic Markers; Humans; Kidney Failure, Chronic; Male; Osteocytes; Osteolysis; Phosphoproteins; Renal Dialysis; Treatment Outcome
PubMed: 25774916
DOI: 10.1371/journal.pone.0120856 -
Peritoneal Dialysis International :... 2015Limited well-controlled research exists examining the impact of different formulations of oral vitamin D on clinical outcomes in dialysis patients, specifically those on... (Comparative Study)
Comparative Study
BACKGROUND
Limited well-controlled research exists examining the impact of different formulations of oral vitamin D on clinical outcomes in dialysis patients, specifically those on peritoneal dialysis. For this retrospective mortality analysis, we compared mortality rates of patients on 3 of the most commonly prescribed vitamin D agents.
METHODS
We examined 2 years (7/1/2008 to 6/30/2010) of oral medication records of peritoneal dialysis patients from a large US dialysis organization. Patients were identified whose physicians prescribed a single form of vitamin D (calcitriol, paricalcitol, or doxercalciferol) for ≥ 90% of all patient-months. We excluded incident patients (< 90 days on dialysis) and patients whose physicians treated < 5 peritoneal dialysis patients at a dialysis facility, and we assessed mortality.
RESULTS
The analysis inclusion criteria identified 1,707 patients. The subset in this analysis included 12.6% of all prevalent peritoneal dialysis patients and 11.8% of prevalent patient-months. Patients with physicians who predominately prescribed calcitriol had a lower mortality rate: 9.33 (confidence interval (CI) 7.06, 11.60) deaths per 100 patient-years than the doxercalciferol, 12.20 (CI 9.34, 15.06) or paricalcitol, 12.27 (CI 9.27, 15.28) groups. However, these differences were not statistically significant. A Cox proportional hazards model, adjusting for differences in age, vintage, gender, race, body mass index, and comorbidities also showed no significant differences.
CONCLUSIONS
For this peritoneal dialysis population, instrumental variable analyses showed no significant difference in mortality in patients taking the most common oral vitamin D formulations (calcitriol, doxercalciferol, paricalcitol).
Topics: Adult; Aged; Calcitriol; Cause of Death; Cohort Studies; Confidence Intervals; Dietary Supplements; Drug Administration Schedule; Ergocalciferols; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Prognosis; Proportional Hazards Models; Reference Values; Retrospective Studies; Risk Assessment; Survival Analysis; Treatment Outcome; Vitamin D
PubMed: 24584595
DOI: 10.3747/pdi.2012.00324 -
Clinical Drug Investigation Feb 2014The IMPACT SHPT [Improved Management of Intact Parathyroid Hormone (iPTH) with Paricalcitol-Centered Therapy Versus Cinacalcet Therapy with Low-Dose Vitamin D in... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The IMPACT SHPT [Improved Management of Intact Parathyroid Hormone (iPTH) with Paricalcitol-Centered Therapy Versus Cinacalcet Therapy with Low-Dose Vitamin D in Hemodialysis Patients with Secondary Hyperparathyroidism] study compared the effectiveness of paricalcitol and cinacalcet in the management of secondary hyperparathyroidism in haemodialysis patients but did not report the costs or cost effectiveness of these treatments.
AIM
The aim of this study was to compare the cost effectiveness of a paricalcitol-based regimen versus cinacalcet with low-dose vitamin D for management of secondary hyperparathyroidism in haemodialysis patients from a US payer perspective, using a 1-year time horizon.
METHODS
This was a post hoc cost-effectiveness analysis of data collected for US patients enrolled in the IMPACT SHPT study-a 28-week, randomized, open-label, phase 4, multinational study (ClinicalTrials.gov identifier: NCT00977080). Patients eligible for the IMPACT SHPT study were aged≥18 years with stage 5 chronic kidney disease, had been receiving maintenance haemodialysis three times weekly for at least 3 months before screening and were to continue haemodialysis during the study. Only US patients who reached the evaluation period (weeks 21-28) were included in this secondary analysis. US subjects in the IMPACT SHPT study were randomly assigned to receive intravenous paricalcitol, or oral cinacalcet plus fixed-dose intravenous doxercalciferol, for 28 weeks. Patients in the paricalcitol group could also receive supplemental cinacalcet for hypercalcaemia. The primary effectiveness endpoint in the IMPACT SHPT study was the proportion of subjects who achieved a mean intact parathyroid hormone (iPTH) level of 150-300 pg/mL during the evaluation period. In this secondary analysis, we estimated the incremental cost-effectiveness ratio (ICER), comparing paricalcitol-treated patients with cinacalcet-treated patients on the basis of this primary endpoint and several secondary endpoints. Costs were estimated by examining the dosage of the study drug (paricalcitol or cinacalcet) and phosphate binders used by each participant during the trial. Nonparametric bootstrap analysis was used to examine the accuracy of the ICER point estimates.
RESULTS
The percentages of patients achieving the treatment goal of a mean iPTH level between 150-300 pg/mL during weeks 21-28 of therapy were 56.9% in the paricalcitol group and 34.0% in the cinacalcet group (a difference of 23%, p=0.0235). Paricalcitol was also more effective for each of the secondary endpoints. When annualized, the total drug costs were US$10,153 in the paricalcitol group and US$15,967 in the cinacalcet group, a difference of US$5,814 (57.3%, p=0.0053). Because the paricalcitol-based treatment was less expensive and more effective, it was 'dominant', compared with cinacalcet, in this cost-effectiveness analyses. In our bootstrap analysis, 99.1% of bootstrap replicates for the ICER of the primary endpoint fell within the lower right quadrant of the cost-effectiveness plane-where paricalcitol is considered dominant. For all of the other endpoints, paricalcitol was dominant in 100% of replicates.
CONCLUSION
On the basis of dosing and effectiveness data from US patients in the IMPACT SHPT study, we found that a regimen of intravenous paricalcitol was more cost effective than cinacalcet plus low-dose vitamin D in the management of iPTH in patients with SHPT requiring haemodialysis.
Topics: Administration, Intravenous; Administration, Oral; Aged; Bone Density Conservation Agents; Cinacalcet; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Naphthalenes; Renal Dialysis; Treatment Outcome; United States; Vitamin D
PubMed: 24214232
DOI: 10.1007/s40261-013-0151-4 -
Endocrinology Dec 2013Calcium has recently been shown to regulate fibroblast growth factor 23 (FGF-23), a bone-derived phosphate and vitamin D-regulating hormone. To better understand the...
Calcium has recently been shown to regulate fibroblast growth factor 23 (FGF-23), a bone-derived phosphate and vitamin D-regulating hormone. To better understand the regulation of FGF-23 by calcium, phosphorus, 1,25 dihydroxyvitamin D3 [1,25(OH)2D], and PTH, we examined FGF-23 expression under basal conditions and in response to PTH, doxercalciferol, or high-calcium diet treatment in Gcm2(-/-) and Cyp27b1(-/-) mutant mice. Gcm2(-/-) mice exhibited low serum PTH and 1,25(OH)2D concentrations, hypocalcemia, and hyperphosphatemia, whereas Cyp27b1(-/-) mice had high PTH, undetectable 1,25(OH)2D, hypocalcemia, and hypophosphatemia. Serum FGF-23 levels were decreased in both mutant models. Doxercalciferol administration increased serum FGF-23 levels in both mutant models. PTH administration to Gcm2(-/-) mice also increased serum FGF-23 levels, in association with an increase in both 1,25(OH)2D and calcium concentrations. Multiple regression analysis of pooled data indicated that changes in FGF-23 were positively correlated with serum calcium and 1,25(OH)2D but not related to changes in serum phosphate concentrations. A high-calcium diet also increased serum FGF-23 concentrations in Cyp27b1(-/-) mice in the absence of 1,25(OH)2D and in Gcm2(-/-) mice with low PTH. The addition of calcium to the culture media also stimulated FGF-23 message expression in MC3T3-E1 osteoblasts. In addition, FGF-23 promoter activity in cultured osteoblasts was inhibited by the L-calcium-channel inhibitor nifedipine and stimulated by calcium ionophores. The effects of chronic low calcium to prevent 1,25(OH)2D and PTH stimulation of FGF-23 in these mutant mouse models suggest that suppression of FGF-23 plays an important physiological adaptive response to hypocalcemia.
Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Calcium; Cell Line; Dose-Response Relationship, Drug; Ergocalciferols; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gene Expression Regulation; Genotype; Mice; Mice, Knockout; Nuclear Proteins; Osteoblasts; Parathyroid Glands; Transcription Factors
PubMed: 24140714
DOI: 10.1210/en.2013-1627 -
Nefrologia : Publicacion Oficial de La... 2013There are few data in Argentina on the prevalence and management of bone and mineral metabolism (BMM) in patients with chronic kidney disease (CKD).
BACKGROUND
There are few data in Argentina on the prevalence and management of bone and mineral metabolism (BMM) in patients with chronic kidney disease (CKD).
OBJECTIVES AND METHODS
A survey was carried out in dialysis units in 2010 to measure the prevalence of and types of treatments for BMM disorders in Argentina. The data obtained was then compared to the published results from other large population studies. We recorded characteristics of dialysis centres and participating patients, the frequency of measurements and individual results for BMM biochemical markers, as well as the type of management used to control hyperphosphataemia and secondary hyperparathyroidism.
RESULTS
1210 patients from 25 dialysis centres in Argentina participated in the study (representing 4.7% of the country’s prevalent dialysis population in 2010). The mean patient age was 55.3±17.6 years, 60.8% were male, 3.3% were on peritoneal dialysis and 29.1% suffered diabetes. In all centres, phosphataemia and calcaemia were measured on a monthly basis, 60% of centres measured intact parathyroid hormone (iPTH) every 6 months, 36% every 3 to 4 months, and 4% annually. As recommended by K/DOQI, 51.6% of patients had adequate levels of calcium (8.4-9.5 mg/dl), 51.6% had adequate phosphorus (3.5-5.5 mg/dl) and 21.1% displayed acceptable iPTH levels (150-300 pg/ml). 24% had iPTH <150 pg/ml and 54.5% >300 pg/ml. iPTH ≥600 pg/ml was present in 28.3%, and 13.3% had values ≥1000 pg/ml. These figures differed from those published by the DOPPS II study, in which 51.1% of patients had iPTH <150 pg/ml, and only 26.7% had iPTH ≥300 pg/ml. Calcium-based phosphate binders were used in 83.6% of the patients, 5.6% used sevelamer and 4.0% used aluminium-containing compounds. To achieve control of hyperparathyroidism, oral or intravenous calcitriol was predominantly used (50.5%) with a small percentage of patients receiving paricalcitol or doxercalciferol.
CONCLUSIONS
The present study shows a high prevalence of secondary hyperparathyroidism, which differs from that published by other large population studies. There was a high proportion of patients with BMM markers outside the ranges suggested by K/DOQI. Mainly phosphate binders based on calcium and calcitriol continue to be used for the management of hyperphosphatemia and hyperparathyroidism respectively.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Argentina; Biomarkers; Bone and Bones; Calcitriol; Calcium; Child; Child, Preschool; Chronic Disease; Diabetic Nephropathies; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Peritoneal Dialysis; Phosphorus; Prevalence; Renal Dialysis; Young Adult
PubMed: 24089157
DOI: 10.3265/Nefrologia.pre2013.May.12009 -
Indian Journal of Nephrology Jul 2013This study was carried out to evaluate the efficacy and safety of doxercalciferol as therapy for secondary hyperparathyroidism (SHPT) in patients with chronic kidney...
This study was carried out to evaluate the efficacy and safety of doxercalciferol as therapy for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stage 4 in a prospective clinical trial. A total of 35 CKD-4 patients who had a baseline parathyroid hormone (iPTH) >150 pg/mL and had not received any vitamin D analog in the preceding 8 weeks were followed up at intervals of 6 weeks for 18 weeks on oral therapy with doxercalciferol. The starting dose was 1.5 μg/day, and the dose was increased in steps of 1 μg/day if iPTH did not decrease by at least 30% on the subsequent visit. Doxercalciferol was stopped temporarily if low iPTH (<70 pg/mL), hypercalcemia (>10.7 mg/dL), or severe hyperphosphatemia (>8.0 mg/dL) occurred, and was restarted at a lower dose on reversal of these abnormalities. Calcium acetate was the only phosphate binder used. Mean iPTH decreased by 35.4 ± 4.4% from 381.7 ± 31.3 pg/mL to 237.9 ± 25.7 pg/mL (P < 0.001). The proportion of patients who achieved 30% and 50% suppression of iPTH levels was 83% and 72%, respectively. Mean serum calcium, phosphorus, and calcium-phosphorus product values did not differ significantly from the baseline values. Four, two, and nine patients developed hypercalcemia, severe hyperphosphatemia, and high CaxP (>55), respectively. Almost all patients recovered to an acceptable level within 2 weeks of stopping doxercalciferol and adjusting the phosphate binder dose. In all, 21 patients required temporary stoppage of therapy. Most of them were restarted on therapy at a reduced dose during the study. It can, therefore, be concluded that doxercalciferol is effective in controlling SHPT in CKD-4 patients with an acceptable risk of hyperphosphatemia and hypercalcemia.
PubMed: 23960343
DOI: 10.4103/0971-4065.114492 -
Journal of Medical Economics Sep 2013The objective of this analysis was to compare costs of paricalcitol or cinacalcet plus low dose vitamin D, and of phosphate binders, in patients in the IMPACT SHPT... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
The objective of this analysis was to compare costs of paricalcitol or cinacalcet plus low dose vitamin D, and of phosphate binders, in patients in the IMPACT SHPT study; and to extrapolate those to estimate expected annual maintenance costs.
METHODS
IMPACT SHPT was a 28-week, randomized, open-label trial. Subjects from 12 countries received intravenous (IV) or oral paricalcitol, or oral cinacalcet plus fixed IV doxercalciferol or oral alfacalcidol. The primary end-point was the proportion of subjects who achieved a mean intact parathyroid hormone (iPTH) value of 150-300 pg/mL during weeks 21-28 (evaluation period). This study compares the costs of study drugs and phosphate binders among participants during the study and annualized. This analysis includes only those subjects that reached the evaluation period (134 in each group).
RESULTS
The mean total drug costs over the study period were €2606 (SD = €2000) in the paricalcitol group and €3034 (SD = €3006) in the cinacalcet group (difference €428, p = 0.1712). The estimated annualized costs were €5387 (SD = €4139) in the paricalcitol group and €6870 (SD = €6256) in the cinacalcet group (difference €1492, p = 0.0395). In addition, a significantly greater proportion (p = 0.010) of subjects in the paricalcitol arm (56.0%) achieved an iPTH of 150-300 pg/mL during the evaluation period compared to the cinacalcet arm (38.2%).
LIMITATIONS
This was a secondary analysis of the IMPACT SHPT study which was not designed or powered for costs as an outcome. The dosing of study drugs and phosphate binders in the IMPACT study may not reflect actual practice, and patients were followed for 28 weeks, while the treatment of SHPT is long-term.
CONCLUSION
Patients with SHPT requiring hemodialysis who were treated with a paricalcitol-based regimen for iPTH control had lower estimated annual drug costs compared to those treated with cinacalcet plus low-dose vitamin D.
Topics: Administration, Oral; Aged; Cinacalcet; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Drug Therapy, Combination; Ergocalciferols; Female; Follow-Up Studies; Health Care Costs; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Naphthalenes; Prospective Studies; Renal Dialysis; Treatment Outcome; Vitamin D
PubMed: 23834479
DOI: 10.3111/13696998.2013.823092 -
Journal of Chromatographic Science Jul 2014In the current study, injectable formulations containing Doxercalciferol as the active pharmaceutical ingredient are analyzed by using gradient-elution high-performance...
In the current study, injectable formulations containing Doxercalciferol as the active pharmaceutical ingredient are analyzed by using gradient-elution high-performance liquid chromatography with ultraviolet detection. Various related impurities and degradants are quantified by using solid-phase extraction (SPE) for enhanced sensitivity. The assay of possible related impurities and Doxercalciferol analogues present at trace quantities is performed by using Trans-1-α-hydroxy vitamin D2 (Doxercalciferol related degradation product/Impurity B) as standard and 1-β-hydroxy vitamin D2 (Doxercalciferol related degradation product/Impurity C) as internal standards for the SPE study. The current method is shown to be stability-indicating and free from interferences from any of the formulation excipients and potential degradation products and impurities. The validated method is shown to be reproducible, accurate, sensitive and selective.
Topics: Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Ergocalciferols; Reproducibility of Results; Solid Phase Extraction
PubMed: 23780943
DOI: 10.1093/chromsci/bmt073