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The D-vitamin metabolite 1,25(OH)2 D in serum is associated with disease activity and Anti-Citrullinated Protein Antibodies in active and treatment naïve, early Rheumatoid Arthritis Patients.
Herly, M, Stengaard-Pedersen, K, Vestergaard, P, Østergaard, M, Junker, P, Hetland, ML, Hørslev-Petersen, K, Ellingsen, T
Scandinavian journal of immunology. 2018;(3):e12704
Abstract
RATIONALE Sufficient levels of vitamin D seem to be essential for proper immune function, and low levels might be associated to disease activity in Rheumatoid Arthritis (RA). Most studies investigate only 25OHD and not the physiologically active vitamin D metabolite, 1,25(OH)2 D. OBJECTIVE To investigate associations between serum level of vitamin D metabolites and disease activity parameters in 160 inflammatory active and treatment naïve early RA patients. Serum level of vitamin D metabolites (25OHD2 , 25OHD3 and 1,25(OH)2 D) was measured by isotope dilution mass spectrometry and radio-immunoassays at baseline. Disease characteristics were gender, number of tender joints, number of swollen joints, DAS28-CRP, HAQ, VAS-scores, CRP, erosive status (Total Sharp Score; TSS), ACPA and IgM-RF-status. Associations were evaluated using Spearman's and Wilcoxon rank-sum tests. The study was registered in clinical trials; trial registration number: NCT00209859. FINDINGS Statistically significant inverse associations were found between the active metabolite 1,25(OH)2 D and DAS28-CRP (P = 0.004, rho = -0.23), HAQ (P = 0.005, rho = -0.22), CRP (P = 0.001, rho = -0.25), VASpatient-pain (P = 0.008, rho = -0.21), and a positive association was found to ACPA-status (P = 0.04). CONCLUSION The vitamin D metabolite 1,25(OH)2 D was inversely associated with disease activity and positively associated with ACPA in treatment naïve and inflammatory active early RA. The results indicate that in RA, both the degree of inflammatory activity, and the diagnostic sensitivity and specificity might affect-or might be affected by the level of vitamin 1,25(OH)2 D.
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Effect of Vitamin D Receptor Activation on the AGE/RAGE System and Myeloperoxidase in Chronic Kidney Disease Patients.
Torino, C, Pizzini, P, Cutrupi, S, Tripepi, R, Vilasi, A, Tripepi, G, Mallamaci, F, Zoccali, C
Oxidative medicine and cellular longevity. 2017;:2801324
Abstract
Vitamin D receptor (VDR) activation has been reported to increase circulating levels of the advanced glycation end products (AGE) and their decoy receptor (RAGE). However, until now, the effect of VDR activation on AGE and RAGE has not been tested in the setting of a randomized, double-blind clinical trial. We have therefore analyzed the effect of VDR activation by paricalcitol on pentosidine, S100A12/ENRAGE, and RAGE and on established biomarkers of oxidative stress like myeloperoxidase in CKD patients in the PENNY trial. At baseline, human S100A12/ENRAGE, RAGE, and myeloperoxidase, but not pentosidine, were intercorrelated, and the association between S100A12/ENRAGE and myeloperoxidase (r = 0.71, P < 0.001) was the strongest among these correlations. Paricalcitol failed to modify biomarkers of the AGE/RAGE system and myeloperoxidase in unadjusted and adjusted analyses by the generalized linear model (GLM). No effect modification by other risk factors was registered. Paricalcitol does not modify biomarkers of the AGE/RAGE system and myeloperoxidase in CKD patients. The apparent increase in RAGE levels by VDR activation reported in previous uncontrolled studies is most likely due to confounding factors rather than to VDR activation per se. This trial is registered with NCT01680198.
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Comparison of paricalcitol with maxacalcitol injection in Japanese hemodialysis patients with secondary hyperparathyroidism.
Akizawa, T, Akiba, T, Hirakata, H, Kinugasa, E, Tominaga, Y, Fukagawa, M, Yokoyama, K, Zhang, W, Linde, PG, Suzuki, M
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2015;(3):225-34
Abstract
Secondary hyperparathyroidism (SHPT) is one of the major complications of chronic kidney disease (CKD) and is associated with elevated serum intact parathyroid hormone (iPTH). Calcitriol, a non-selective vitamin D receptor agonist (VDRA) that suppresses iPTH is used for SHPT treatment, but its use is frequently complicated by hypercalcemia. Paricalcitol, a selective VDRA, demonstrated efficacy in iPTH suppression compared to maxacalcitol in a Phase 2 study (M11-609) in Japanese subjects. The current larger Phase 3 study (M11-517), evaluated the efficacy of intravenous paricalcitol injection compared to intravenous maxacalcitol injection with respect to iPTH and calcium control using a non-inferiority primary endpoint. In this double-blind, double-dummy, parallel-group study, eligible Japanese CKD subjects with SHPT on hemodialysis were randomized 1:1 to receive intravenous paricalcitol or intravenous maxacalcitol injections for 12 weeks. Dynamic allocation of subjects on the basis of screening iPTH levels was used to ensure equal distribution of subjects with iPTH <500 pg/mL and ≥500 pg/mL into the two treatment groups. 255 subjects were randomized to receive paricalcitol (N = 127) or maxacalcitol (N = 128). Primary efficacy analysis indicated that 27.7% in the paricalcitol group vs. 30.5% in the maxacalcitol group (95% CI -14.34% to 8.79%, P = 0.353) achieved target iPTH in the last 3 weeks without hypercalcemia during treatment, failing to achieve the non-inferiority margin of -5% that was set based upon agreement with the PMDA. Both intravenous paricalcitol and maxacalcitol were effective in reducing iPTH and provided similar safety profiles; however, non-inferiority for paricalcitol vs. maxacalcitol was not demonstrated.
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Paricalcitol- or cinacalcet-centred therapy affects markers of bone mineral disease in patients with secondary hyperparathyroidism receiving haemodialysis: results of the IMPACT-SHPT study.
Cozzolino, M, Ketteler, M, Martin, KJ, Sharma, A, Goldsmith, D, Khan, S
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2014;(4):899-905
Abstract
BACKGROUND In this Phase 4 international study, efficacy and safety of paricalcitol-centred therapy were compared with that of cinacalcet-centred therapy for the treatment of chronic kidney disease (CKD)-associated secondary hyperparathyroidism (SHPT) in patients undergoing haemodialysis (ClinicalTrials.gov identifier NCT00977080). METHODS Patients ≥ 18 years of age with Stage 5 CKD and SHPT [intact parathyroid hormone (iPTH) level of 300-800 pg/mL, calcium level of 8.4-10.0 mg/dL and phosphate concentration of ≤ 6.5 mg/dL] who were undergoing haemodialysis were included. Patients were randomized by mode of paricalcitol administration [i.e. intravenous (IV) or oral strata] to receive paricalcitol- or cinacalcet-centred therapy for ≤ 28 weeks. Changes in metabolic markers [total alkaline phosphatase (AP), bone-specific AP and fibroblast growth factor-23 (FGF-23)] and the proportion of patients in each treatment group who achieved an iPTH level of 150-300 pg/mL during Weeks 8, 16 and 21-28 as a composite value were evaluated. RESULTS Compared with cinacalcet-centred therapy, levels of both bone turnover markers were significantly reduced from baseline with IV and oral paricalcitol-centred treatment (P < 0.05 for both dosing strata) at Weeks 8, 16 and 28. Levels of FGF-23 were increased with paricalcitol versus cinacalcet-centred treatment. A greater proportion of patients receiving paricalcitol-centred therapy achieved target iPTH levels (i.e. 150-300 pg/mL) throughout the study in the IV and oral dosing strata compared with patients receiving cinacalcet-centred treatment. CONCLUSIONS In patients with CKD and SHPT undergoing haemodialysis, paricalcitol-centred therapy reduced circulating bone turnover markers and iPTH levels and increased FGF-23 levels compared with cinacalcet-centred treatment. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT00977080.
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Effects of paricalcitol on calcium and phosphate metabolism and markers of bone health in patients with diabetic nephropathy: results of the VITAL study.
Coyne, DW, Andress, DL, Amdahl, MJ, Ritz, E, de Zeeuw, D
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2013;(9):2260-8
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Abstract
BACKGROUND Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium-phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant risks of cardiovascular and bone disorders. Active vitamin D can suppress parathyroid hormone (PTH), but may raise serum calcium and phosphate concentrations. Paricalcitol, a selective vitamin D activator, suppressed PTH in CKD patients (stages 3 and 4) with secondary hyperparathyroidism (SHPT) with minimal changes in calcium and phosphate metabolism. METHODS The VITAL study enrolled patients with CKD stages 2-4. We examined the effect and relationship of paricalcitol to calcium and phosphate metabolism and bone markers in a post hoc analysis of VITAL. The study comprised patients with diabetic nephropathy enrolled in a double-blind, placebo-controlled, randomized trial of paricalcitol (1 or 2 μg/day). Urinary and serum calcium and phosphate, serum BAP, and intact PTH (iPTH) concentrations were measured throughout the study. RESULTS Baseline demographics and calcium, phosphate, PTH (49% with iPTH <70 pg/mL), and BAP concentrations were similar between groups. A transient, modest yet significant increase in phosphate was observed for paricalcitol 2 μg/day (+0.29 mg/dL; P < 0.001). Dose-dependent increases in serum and urinary calcium were observed; however, there were few cases of hypercalcemia: one in the 1-μg/day group (1.1%) and three in the 2-μg/day group (3.2%). Significant reductions in BAP were observed that persisted for 60 days after paricalcitol discontinuation (P < 0.001 for combined paricalcitol groups versus placebo). Paricalcitol dose-dependent reductions in iPTH were observed. Paricalcitol in CKD patients (±SHPT) was associated with modest increases in calcium and phosphate. CONCLUSION Paricalcitol reduces BAP levels, which may be beneficial for reducing vascular calcification. TRIAL REGISTRATION Trial is registered with ClinicalTrials.gov, number NCT00421733.
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Anti-inflammatory profile of paricalcitol in hemodialysis patients: a prospective, open-label, pilot study.
Navarro-González, JF, Donate-Correa, J, Méndez, ML, de Fuentes, MM, García-Pérez, J, Mora-Fernández, C
Journal of clinical pharmacology. 2013;(4):421-6
Abstract
Inflammation is a strong predictor of increased morbidity and mortality in hemodialysis (HD) patients. Paricalcitol, a selective vitamin D receptor activator used for prevention and treatment of secondary hyperparathyroidism, has shown anti-inflammatory properties in experimental studies, although clinical data are scarce. In an open-label, prospective, single center, pilot study, 25 stable HD patients, previously receiving calcitriol, completed 12 weeks of therapy with oral paricalcitol. Serum and peripheral blood mononuclear cell (PBMC) expression profiles of inflammatory cytokines were analyzed. Serum interleukin (IL)-1, IL-10, and IL-18 did not change, unlike high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and IL-6, which experienced a significant mean percent decrease of 14.3%, 4.7%, and 5%, respectively. There was a significant reduction in the TNF-α/IL-10 and the IL-6/IL-10 ratios (P < .05). Serum intact parathyroid hormone concentration experienced a mild but significant reduction. In addition, expression levels of TNF-α and IL-6 decreased by 19.1% (P < .01) and 17.5% (P < .001), respectively, whereas expression of IL-10 increased by 17.7% (P < .01) after treatment. In conclusion, paricalcitol administration to HD patients is associated with a beneficial effect on the inflammatory cytokine serum and gene expression profile of PBMC. This effect may contribute to the survival benefits of paricalcitol observed in clinical studies.
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Paricalcitol reduces proteinuria in non-dialysis chronic kidney disease patients.
Hojs, N, Bevc, S, Balon, BP, Hojs, R, Ekart, R
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2013;(4):368-72
Abstract
Existing treatment of proteinuria is not sufficient to halt the chronic kidney disease (CKD) epidemic. Therefore the aim of our study was to evaluate the effect of paricalcitol on proteinuria in non-dialysis CKD patients with secondary hyperparathyroidism treated according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Forty-one non-dialysis CKD patients with secondary hyperparathyroidism (iPTH >65 pg/mL), serum calcium <2.6 mmol/L, serum phosphate <1.8 mmol/L and proteinuria (>150 mg/day) were treated with paricalcitol 1 μg/day. Most were treated for 6 months, with the exception of three patients having iPTH <30 pg/mL after 3 months, in whom therapy was stopped. All patients were followed for 6 months. 24-h ambulatory blood pressure (24hABP) monitoring was performed at 0 and 6 months. Fixed doses of ACE inhibitors and/or ARBs and/or statins were kept for 3 months before and during the study. Forty-one patients (30 men, 11 women; age 62.44 ± 11.93 years) with different primary causes of CKD were enrolled in the study. Urinary albumin/creatinine ratio (UACR), 24-h urinary albuminuria (24hUA) and 24-h urinary quantitative proteinuria (24hUQP) were measured. Values at 0 and 6 months of these parameters were log-transformed for statistical analysis. After treatment with paricalcitol, statistically significant reduction (paired t-test) in 24hUA (P < 0.011) and 24hUQP (P < 0.0001) were found. The reduction of UACR was not significant (P = 0.074). In the observational period no statistically significant reduction in 24hABP was found. Treatment with 1 μg paricalcitol daily according to clinical practice in non-dialysis CKD patients with secondary hyperparathyroidism and proteinuria significantly reduces 24hUA and 24hUQP without significant change in 24hABP.
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Phase II open label, multi-center clinical trial of modulation of intermediate endpoint biomarkers by 1α-hydroxyvitamin D2 in patients with clinically localized prostate cancer and high grade pin.
Gee, J, Bailey, H, Kim, K, Kolesar, J, Havighurst, T, Tutsch, KD, See, W, Cohen, MB, Street, N, Levan, L, et al
The Prostate. 2013;(9):970-8
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Abstract
BACKGROUND Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention. Major risk factors for this disease have been associated with low serum levels of vitamin D. Here, we evaluate the biologic activity of a less calcemic vitamin D analog 1α-hydroxyvitamin D2 [1α-OH-D2] (Bone Care International, Inc.) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia (HG PIN). METHODS Patients with clinically organ-confined prostate cancer and HG PIN were randomized to 1α-OH-D2 versus placebo for 28 days prior to radical prostatectomy. Intermediate endpoint biomarkers included serum vitamin D metabolites, TGFß 1/2, free/total PSA, IGF-1, IGFBP-3, bFGF, and VEGF. Tissue endpoints included histology, MIB-1 and TUNEL staining, microvessel density and factor VIII staining, androgen receptor and PSA, vitamin D receptor expression and nuclear morphometry. RESULTS The 1α-OH-D2 vitamin D analog was well tolerated and could be safely administered with good compliance and no evidence of hypercalcemia over 28 days. While serum vitamin D metabolite levels only slightly increased, evidence of biologic activity was observed with significant reductions in serum PTH levels. TGF-ß2 was the only biomarker significantly altered by vitamin D supplementation. Whether reduced TGF-ß2 levels in our study is an early indicator of response to vitamin D remains unclear. CONCLUSIONS While further investigation of vitamin D may be warranted based on preclinical studies, results of the present trial do not appear to justify evaluation of 1α-OH-D2 in larger clinical prostate cancer prevention studies.
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The role of paricalcitol on proteinuria.
Aperis, G, Paliouras, C, Zervos, A, Arvanitis, A, Alivanis, P
Journal of renal care. 2011;(2):80-4
Abstract
Paricalcitol is a synthetic vitamin D analogue acting on vitamin D receptor (VDR). The result is inhibition of PTH synthesis and secretion. Paricalcitol appears also to block the renin-angiotensin-aldosterone system. We evaluated the role of paricalcitol in the management of proteinuria of various aetiology. A total of 19 patients participated. Most had diabetic nephropathy; however patients with other types of glomerulopathy leading to proteinuria were also included. Paricalcitol 1-2 μg daily, according to response, was administered for three months. Serum Ca, PO4, Ca × PO4, PTH, creatinine clearance and albumin, as well as 24 hour urine protein were measured before and after treatment. Five out of 19 patients did not respond to the treatment. The remaining 14 patients had an average 32.9% reduction of proteinuria. The drug was well tolerated. Paricalcitol appears to have a role in the treatment of proteinuria. However, our study raises a question regarding why some patients do not respond to paricalcitol. Patients with proteinuria due to diabetic nephropathy seem to respond better than patients with glomerulopathy.
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Short-term vitamin D receptor activation increases serum creatinine due to increased production with no effect on the glomerular filtration rate.
Agarwal, R, Hynson, JE, Hecht, TJ, Light, RP, Sinha, AD
Kidney international. 2011;(10):1073-9
Abstract
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.