The Effect of Magnesium Supplementation on Vascular Calcification in CKD: A Randomized Clinical Trial (MAGiCAL-CKD).

SIGNIFICANCE STATEMENT: Magnesium prevents vascular calcification in animals with CKD. In addition, lower serum magnesium is associated with higher risk of cardiovascular events in CKD. In a randomized, double-blinded, placebo-controlled trial, the authors investigated the effects of magnesium supplementation versus placebo on vascular calcification in patients with predialysis CKD. Despite significant increases in plasma magnesium among study participants who received magnesium compared with those who received placebo, magnesium supplementation did not slow the progression of vascular calcification in study participants. In addition, the findings showed a higher incidence of serious adverse events in the group treated with magnesium. Magnesium supplementation alone was not sufficient to delay progression of vascular calcification, and other therapeutic strategies might be necessary to reduce the risk of cardiovascular disease in CKD. BACKGROUND: Elevated levels of serum magnesium are associated with lower risk of cardiovascular events in patients with CKD. Magnesium also prevents vascular calcification in animal models of CKD. METHODS: To investigate whether oral magnesium supplementation would slow the progression of vascular calcification in CKD, we conducted a randomized, double-blinded, placebo-controlled, parallel-group, clinical trial. We enrolled 148 subjects with an eGFR between 15 and 45 ml/min and randomly assigned them to receive oral magnesium hydroxide 15 mmol twice daily or matching placebo for 12 months. The primary end point was the between-groups difference in coronary artery calcification (CAC) score after 12 months adjusted for baseline CAC score, age, and diabetes mellitus. RESULTS: A total of 75 subjects received magnesium and 73 received placebo. Median eGFR was 25 ml/min at baseline, and median baseline CAC scores were 413 and 274 in the magnesium and placebo groups, respectively. Despite plasma magnesium increasing significantly during the trial in the magnesium group, the baseline-adjusted CAC scores did not differ significantly between the two groups after 12 months. Prespecified subgroup analyses according to CAC>0 at baseline, diabetes mellitus, or tertiles of serum calcification propensity did not significantly alter the main results. Among subjects who experienced gastrointestinal adverse effects, 35 were in the group receiving magnesium treatment versus nine in the placebo group. Five deaths and six cardiovascular events occurred in the magnesium group compared with two deaths and no cardiovascular events in the placebo group. CONCLUSIONS: Magnesium supplementation for 12 months did not slow the progression of vascular calcification in CKD, despite a significant increase in plasma magnesium. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov ( NCT02542319 ).

Bone Turnover, Mineralization, and Volume Estimated by 18F-Sodium Fluoride PET/CT and Biomarkers in Chronic Kidney Disease: Mineral and Bone Disorder Compared with Bone Biopsy.

INTRODUCTION: Invasive bone biopsy to assess bone metabolism in patients with chronic kidney disease-mineral and bone disorder may be replaced by the noninvasive 18F-NaF PET/CT and biomarkers of bone metabolism. We aimed to compare parameters of bone turnover, mineralization, and volume assessed by bone biopsies with results derived from 18F-NaF PET/CT and biomarkers (bone-specific alkaline phosphatase, osteocalcin, fibroblast growth factor 23, and osteoprotegerin). METHODS: A cross-sectional study included 17 dialysis patients, and results from 18F-NaF PET/CT scans and the biomarkers were directly compared with the results of histomorphometric analyses of tetracycline double-labeled trans-iliac bone biopsies. RESULTS: Bone biopsies showed 40% high, 20% normal, and 40% low bone turnover. No biopsies had generalized abnormal mineralization, and the bone volume/total tissue volume was low in 80% and high in 7%. The pelvic skeletal plasma clearance (Ki) from 18F-NaF PET/CT correlated with bone turnover parameters obtained by bone biopsy (activation frequency: r = 0.82, p < 0.01; bone formation rate/bone surface: r = 0.81, p < 0.01), and Ki defined low turnover with high sensitivity (83%) and specificity (100%). CT-derived radiodensity correlated with bone volume, r = 0.82, p < 0.01. Of the biomarkers, only osteocalcin showed a correlation with turnover assessed by histomorphometry. CONCLUSION: In conclusion, 18F-NaF PET/CT may be applicable for noninvasive assessment of bone turnover and volume in CKD-MBD.

A systematic evaluation of five different image-derived input functions for the clinical implementation of 18F-NaF bone PET/CT in patients with chronic kidney disease-mineral and bone disorder.

Introduction: The aim of this study was to investigate the impact of the use of varying input parameters on resulting bone plasma clearance (Ki ) and other kinetic modelling parameters in a group of patients with chronic kidney disease-mineral and bone disorder (CKD-MBD). Methods: Raw PET/CT data and blood data were systematically analyzed using five different VOIs for the input functions in the left ventricle and in the thoracic aorta. Standardized VOIs were placed in four thoracic vertebrae and the results pooled and averaged. The basic image-derived input functions (IDIFs) were corrected for partial volume effect and spill-over and modified by substitution of the terminal image exponential with the corresponding plasma-exponentials derived from blood samples. Ki was then calculated using both a non-linear regression (NLR) analysis and a graphical Patlak analysis and compared. Results: Our original results were reproducible with an inter-observer difference of approximately 6%. The correction factors varied with the VOI volumes from 0.73 ± 0.17 for the largest LV-VOI (48.7 ± 25.3 cm3) to 0.99 ± 0.10 for the AO-VOI (3.4 ± 1.2 cm3). The mean NLR-Ki results varied between 0.0378 ± 0.0112 and 0.0432 ± 0.0095 ml/min ml-1 with a fixed vB and 0.0408 ± 0.0111 and 0.045 ± 0.0102 ml/min ml-1 with a free-fitted vB. The corresponding Patl-Ki -results varied between 0.0302 ± 0.0071 and 0.0325 ± 0.0070 ml/min ml-1, having lesser differences and variances. The input functions with least variance and mean differences compared with NLR results were derived from the left ventricle with a VOI volume of 19.2 ± 11.3 cm3 corrected for PVE and Bg with a mean Ki -difference: 0.0097 ± 0.0370 ml/min ml-1 and 95% confidence limits (-0.023 to 0.004). Conclusions: Our results indicated that a VOI with a volume of approximately 20 cm3 with a correction factor of 0.83 ± 0.13 results in Patlak results with the least variance and difference compared with the NLR results. The use of free-fitted vB in the NLR analysis showed the most robust results in all input series. The Patlak results were in comparison generally lower than the NLR results (-17.3% to -23.4%) but very robust across the various input series and with results comparable to previously published data and are therefore recommended for future analysis.