The first systematic review of trials of possible therapies to slow vascular calcification in chronic kidney disease (CKD) finds purported benefits from magnesium, sodium thiosulfate, and etidronate in patients on hemodialysis.

Investigators reviewed 77 clinical trials (63 randomized trials) involving 6898 patients with CKD stage 3-5D or who have received a kidney transplant. Trials differed with respect to baseline vascular calcification, study design (randomized and nonrandomized), study duration, imaging modality, and anatomic site.

Therapy involving magnesium, sodium thiosulfate, and etidronate appeared promising, but studies were small and of short duration, Nigel Toussaint, MBBS, PhD, of The Royal Melbourne Hospital, Victoria, Australia, and colleagues reported in the Journal of the American Society of Nephrology. Magnesium supplementation may downregulate promoters of vascular smooth muscle cell osteogenic differentiation, upregulate calcification inhibitors, and inhibit of hydroxyapatite crystal formation, the reviewers explained. Intravenous sodium thiosulfate may reduce progression of vascular calcification, but the mechanism of action is uncertain. The effects of antiresorptive agents, such as bisphosphonates and denosumab, are unclear. However, in 4 studies examining the bisphosphonate etidronate in patients on hemodialysis, all reported slowing of vascular calcification.

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Both intimal and medial vascular calcification are prevalent in patients with chronic kidney disease, the investigators noted. Cardiovascular calcification progresses rapidly, and increases mortality risk in the ESKD population, according to other research.

Trials of cinacalcet in the dialysis population showed possible slowing of vascular calcification, but studies were small and confounded by concomitant vitamin D treatment and maintenance of serum calcium. Use of vitamin D treatment alone showed no relevant benefit.

Trials of phosphate binders and changes in dialysis prescription, such as dialysate calcium, yielded conflicting results. Lipid-lowering and other potential antiatherosclerotic effects of HMG-CoA reductase inhibitors appeared effective in the general population, but less so in CKD.

“The studies highlight that there are multiple therapeutic targets to address the complex and multifactorial [vascular calcification] pathogenesis in CKD, and further trials need to be more adequately powered to determine whether any intervention is beneficial to attenuate [vascular calcification] progression in this population,” Dr Toussaint and colleagues wrote. “Choice of an effective intervention may need to be better tailored to baseline patient characteristics, such as presence of conventional cardiovascular risk factors, hyperphosphatemia, vitamin D deficiency, bone mineral density, and uremia.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Xu C, Smith ER, Tiong MK, Ruderman I, Toussaint ND. Interventions to attenuate vascular calcification progression in chronic kidney disease: a systematic review of clinical trials. J Am Soc Nephrol. 33(5):1011-1032. doi:10.1681/ASN.2021101327