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Clinical Therapeutics Nov 2019Diabetic nephropathy (DN) is a major complication of diabetes. Paricalcitol is a vitamin D analog that is typically used for secondary hyperparathyroidism in patients...
PURPOSE
Diabetic nephropathy (DN) is a major complication of diabetes. Paricalcitol is a vitamin D analog that is typically used for secondary hyperparathyroidism in patients with chronic kidney disease but may have some beneficial effect on DN. This review evaluates the effect of paricalcitol in combination with renin-angiotensin-aldosterone system inhibitor therapy in managing DN.
METHODS
A literature search was conducted of PubMed and ClinicalTrials.gov. Limits were set to include only clinical trials in humans written in English. The search terms used were paricalcitol and diabetic nephropathy. The following outcomes of kidney function and damage as well as adverse drug events were assessed and included: 24-h urine albumin excretion, serum phosphorus and calcium concentrations, urinary albumin excretion rates, estimated glomerular filtration rate, and markers of inflammation and endothelial function.
FINDINGS
Four studies with a total of 389 patients were identified for review through the process described above. Two of the 6 studies provide evidence of the effect of paricalcitol on DN by way of reduction in urine albumin to creatinine ratio and urinary albumin excretion rate when compared with placebo. One study reported an increase in serum phosphorous, 1 study observed a decrease in estimated glomerular filtration rate, and 1 study reported no effect on inflammatory markers or endothelial function.
IMPLICATIONS
The number of clinical trials examining the effect of paricalcitol in DN is small. The studies that have been completed enrolled <300 patients. Paricalcitol can reduce protein in the urine, but there is no compelling evidence that it preserves kidney function.
Topics: Diabetic Nephropathies; Ergocalciferols; Humans; Randomized Controlled Trials as Topic; Renin-Angiotensin System
PubMed: 31601446
DOI: 10.1016/j.clinthera.2019.09.009 -
Journal of the American Heart... May 2018Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear.
METHODS AND RESULTS
We conducted a systematic review and individual participant meta-analysis to examine the effect of vitamin D supplementation on flow-mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo-controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial-level meta-analysis was performed using random-effects models; individual participant meta-analyses used a 2-stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial-level meta-analysis, and 24 trials (2051 participants) contributed to individual-participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial-level meta-analysis showed no significant effect of supplementation on macrovascular measures (flow-mediated dilatation, 0.37% [95% confidence interval, -0.23 to 0.97]; carotid-femoral pulse wave velocity, 0.00 m/s [95% confidence interval, -0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial-level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues.
CONCLUSIONS
Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis.
Topics: Adolescent; Adult; Aged; Biomarkers; Cardiovascular Diseases; Dietary Supplements; Endothelium, Vascular; Female; Hemodynamics; Humans; Male; Middle Aged; Treatment Outcome; Vascular Stiffness; Vitamin D; Vitamin D Deficiency; Young Adult
PubMed: 29848497
DOI: 10.1161/JAHA.117.008273 -
PloS One 2016Vitamin D receptor activators (VDRAs) can protect against mineral bone disease, but they are reported to elevate serum creatinine (SCr) and may also reduce glomerular... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Vitamin D receptor activators (VDRAs) can protect against mineral bone disease, but they are reported to elevate serum creatinine (SCr) and may also reduce glomerular filtration rate (GFR).
METHODS
We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) to evaluate the effect of VDRAs on kidney function and adverse events. MEDLINE, EMBASE, the Cochrane Controlled Trials Register were searched for RCTs that evaluate vitamin D receptor activators (alfacalcidol, calcitriol, doxercalciferol, falecalcitriol, maxacalcitol and paricalcitol) up to March 2015.
RESULTS
We included 31 studies, all of which were performed between 1976 and 2015, which enrolled 2621 patients. Patients receiving VDRAs had lower eGFR (weighted mean difference WMD -1.29 mL/min /1.73 m2, 95% CI -2.42 to -0.17) and elevated serum creatinine (WMD 7.03 μmol/L, 95% CI 0.61 to 13.46) in sensitivity analysis excluding studies with dropout rate more than 30%. Subgroup analysis of the 5 studies that not use SCr-based measures did not indicated lower GFR in the VDRAs group(WMD -0.97 mL/min/1.73 m2, 95% CI -4.85 to 2.92). Compared with control groups, there was no difference in all-cause mortality (relative risk RR 1.41, 95% CI 0.58 to 3.80), cardiovascular disease (RR 0.84, 95% CI 0.42 to 1.71), and severe adverse events (RR 1.15, 95% CI 0.75 to 1.77) for the VDRAs groups. Episodes of hypercalcemia (RR 3.29, 95% CI 2.02 to 5.38) were more common in the VDRAs group than in the control group.
CONCLUSIONS
Administration of VDRAs increased serum creatinine levels. Subgroup analysis of studies that did not use SCr-based measures did not indicate a lower GFR in the VDRA group. Future studies with non-SCr-based measures are needed to assess whether the mild elevations of serum creatinine are of clinical significance.
Topics: Bone Density Conservation Agents; Bone Diseases; Cardiovascular Diseases; Creatinine; Databases, Factual; Glomerular Filtration Rate; Humans; Hypercalcemia; Receptors, Calcitriol
PubMed: 26812502
DOI: 10.1371/journal.pone.0147347 -
International Urology and Nephrology Apr 2016The goal of this systematic review is to evaluate the efficacy and safety of paricalcitol versus active non-selective vitamin D receptor activators (VDRAs) for secondary... (Meta-Analysis)
Meta-Analysis Review
Comparison between paricalcitol and active non-selective vitamin D receptor activator for secondary hyperparathyroidism in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.
PURPOSE
The goal of this systematic review is to evaluate the efficacy and safety of paricalcitol versus active non-selective vitamin D receptor activators (VDRAs) for secondary hyperparathyroidism (SHPT) management in chronic kidney disease (CKD) patients.
METHODS
PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), clinicaltrials.gov (inception to September 2015), and ASN Web site were searched for relevant studies. A meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs that assessed the effects and adverse events of paricalcitol and active non-selective VDRA in adult CKD patients with SHPT was performed using Review Manager 5.2.
RESULTS
A total of 10 trials involving 734 patients were identified for this review. The quality of included trials was limited, and very few trials reported all-cause mortality or cardiovascular calcification without any differences between two groups. Compared with active non-selective VDRAs, paricalcitol showed no significant difference in both PTH reduction (MD -7.78, 95% CI -28.59-13.03, P = 0.46) and the proportion of patients who achieved the target reduction of PTH (OR 1.27, 95% CI 0.87-1.85, P = 0.22). In addition, no statistical differences were found in terms of serum calcium, episodes of hypercalcemia, serum phosphorus, calcium × phosphorus products, and bone metabolism index.
CONCLUSIONS
Current evidence is insufficient, showing paricalcitol is superior to active non-selective VDRAs in lowering PTH or reducing the burden of mineral loading. Further trials are required to prove the tissue-selective effect of paricalcitol and to overcome the limitation of current research.
Topics: Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Randomized Controlled Trials as Topic; Receptors, Calcitriol; Renal Insufficiency, Chronic
PubMed: 26748501
DOI: 10.1007/s11255-015-1195-6 -
The Cochrane Database of Systematic... Nov 2015Bone 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.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
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.
OBJECTIVES
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.
SEARCH METHODS
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.
SELECTION CRITERIA
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 COLLECTION AND ANALYSIS
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.
MAIN RESULTS
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 significant differences in the final calcium, phosphorus or PTH levels between binders. More episodes of hypercalcaemia occurred with calcium-containing binders. One study reported no significant differences between calcitriol and doxercalciferol in bone histology or biochemical parameters.
AUTHORS' CONCLUSIONS
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
PubMed: 26561037
DOI: 10.1002/14651858.CD008327.pub2 -
Journal of Diabetes and Metabolic... 2015Nephropathy is one of the major complications of diabetes often leading to chronic kidney disease (CKD). Inflammation and oxidative stress are associated with...
Nephropathy is one of the major complications of diabetes often leading to chronic kidney disease (CKD). Inflammation and oxidative stress are associated with pathogenesis of diabetic nephropathy (DN) and found to be regulated by nuclear receptors such as vitamin D receptors (VDR). Vitamin D and its analogues have been effectively used in patients with CKD. The review attempts to summarize the available evidence on the role of vitamin D in DN. Electronic databases (MEDLINE, EMBASE, and Cochrane Library) were searched for studies assessing the role of vitamin D or its analogues on kidney function in type 2 diabetic patients. Studies evaluating kidney functions (urinary albumin/protein creatinine ratio, albuminuria and eGFR) were included and quality and risk of bias assessment performed. Additionally effect on 25 (OH) vitamin D, calcium and HbA1c were evaluated. The mean or its % change along with their standard deviation (SD) was used for reporting our results. RevMan (V5.2) was used for data analysis. Six studies included in this review evaluated the role of cholecalciferol, calcitriol and paricalcitol in patients with DN. Study designs differed (three randomized, one non-randomized and two uncontrolled trials) with varying degree of quality and risk of biases. Vitamin D analogues showed significant improvement in kidney function in two randomized studies. None of the studies reported significant incidences of hypercalcemia. Vitamin D analogues show significant improvement of kidney function in DN. Randomized controlled trials with longer duration, comparing the efficacy of vitamin D and its analogues are needed.
PubMed: 26180775
DOI: 10.1186/s40200-015-0186-6 -
Nephrology (Carlton, Vic.) Oct 2015Vitamin D deficient patients present an increased risk of cardiovascular disease. We conducted this systematic review and meta-analysis to evaluate the effect of active...
AIM
Vitamin D deficient patients present an increased risk of cardiovascular disease. We conducted this systematic review and meta-analysis to evaluate the effect of active vitamin D analogue on cardiovascular outcomes in predialysis chronic kidney disease.
METHODS
Pubmed, Embase, the Cochrane Library, CNKI, and article reference lists were searched for randomized controlled trials (RCTs) that compared active vitamin D analogues with placebo or no treatment for patients with predialysis chronic kidney disease. A meta-analysis was conducted using the standard methods consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Reviewer Manager Software, ver. 5.2, was used.
RESULTS
Seven RCTs (five studies with paricalcitol and two studies with calcitriol, 731 patients) were included. Compared with control groups, active vitamin D reduced the incidence of cardiovascular events (RR, 0.27; 95% CI, 0.13-0.59), induced an increase in those with proteinuria reduction (RR, 1.9; 95% CI, 1.34-2.71), but did not alter left ventricular mass index and systolic function (MD, 0.42 g/m ; 95% CI, -0.23-1.07 g/m , P = 0.21 for left ventricular mass index and MD, -0.33; 95% CI, -0.74-0.07, P = 0.1 for left ventricular ejection fraction). Neither systolic blood pressure nor diastolic blood pressure was reduced by active vitamin D (MD, 0.3 mmHg; 95% CI, -4.95-5.56 mmHg; MD, -0.24 mmHg; 95% CI: -6.21-5.72 mmHg, respectively). Increased probability of hypercalcaemia after paricalcitol therapy was found (RR, 7.85; 95% CI, 2.92-21.10).
CONCLUSION
Active vitamin D reduced the incidence of cardiovascular events and induced a reduction in proteinuria, but its long-term effect on cardiac structure and function needed further confirmation. Increased probability of hypercalcaemia after paricalcitol therapy was found.
PubMed: 25963841
DOI: 10.1111/nep.12505