Magnesium Modifies the Impact of Calcitriol Treatment on Vascular Calcification in Experimental Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) patients are commonly treated with vitamin D analogs, such as calcitriol. Recent epidemiologic evidence revealed a significant interaction between vitamin D and magnesium, since an inverse relationship between vitamin D levels and mortality mainly occurs in patients with a high magnesium intake. The aim of the study was to assess the mechanisms involved by determining whether magnesium alone or combined with calcitriol treatments differentially impacts vascular calcification (VC) in male Sprague-Dawley rats with adenine-induced CKD. Treatment with moderate doses of calcitriol (80 mg/kg) suppressed parathyroid hormone to near or slightly below control levels. Given alone, this dose of calcitriol increased the prevalence of VC; however, when magnesium was given in combination, the severity of calcification was attenuated in the abdominal aorta (51% reduction), iliac (44%), and carotid arteries (46%) compared with CKD controls. The decreases in vascular calcium content were associated with a 20-50% increase in vascular magnesium. Calcitriol treatment alone significantly decreased TRPM7 protein (↓ to ∼11%), whereas the combination treatment increased both mRNA (1.7Â) and protein (6.8Â) expression compared with calcitriol alone. In summary, calcitriol increased VC in certain conditions, but magnesium prevented the reduction in TRPM7 and reduced the severity of VC, thereby increasing the bioavailable magnesium in the vascular microenvironment. These findings suggest that modifying the adverse effect profile of calcitriol with magnesium may be a plausible approach to benefiting the increasing number of CKD patients being prescribed calcitriol.

Acute Tissue Mineral Deposition in Response to a Phosphate Pulse in Experimental CKD

“…These ex vivo findings corroborate previous research demonstrating accelerated mineral uptake occurs after the initiation of VSMC transdifferentiation and VC. (22)(23)(24) This is consistent with our previous work, which demonstrates that in adenine-induced CKD there was significantly increased vascular RUNX2 and decreased SM-22, ie, transdifferentiation of VSMC toward osteoblast-like cells. (22) The finding of a strong correlation between phosphate accrual and FGF-23, in particular, across the vasculature, is consistent with this vascular maladaptation.…”

PTH suppression by calcitriol does not predict off‐target actions in experimental CKD

“…Furthermore, calcitriol upregulates several pro‐calcification genes in vasculature and can cause iatrogenic PTH over‐suppression leading to adynamic bone disease. Together, these observations provide some indirect evidence for the link between calcitriol treatments and the development of calcification that has been reported in experimental models 12,14–16 . It is noteworthy that pre‐clinical studies report discordant effects of calcitriol on VC that appear to be linked to dose.…”

Oral Magnesium Supplementation in Chronic Kidney Disease Stages 3 and 4: Efficacy, Safety, and Effect on Serum Calcification Propensity—A Prospective Randomized Double-Blinded Placebo-Controlled Clinical Trial

“… 15 In vitro calcifications induced by Ca and high concentrations of PO 4 can be prevented or reversed by adding or increasing Mg, which appears to be mediated by both upregulation of factors that inhibit calcification and downregulation of factors that promote calcification. 16 , 17 , 18 , 19 , 20 Also, 2 small clinical trials of Mg supplementation in end-stage renal disease have shown reduced progression of vascular calcification. 21 , 22 Thus, Mg supplementation could potentially be a therapeutic option to attenuate the progression of vascular calcification in CKD.…”