Interventions To Attenuate Vascular Calcification Progression in Chronic Kidney Disease: A Systematic Review of Clinical Trials
Authors: Xu Chelsea , Smith Edward R. , Tiong Mark K. , Ruderman Irene , Toussaint Nigel D. 
Published: March 2022

Significance Statement
Vascular calcification is associated with cardiovascular morbidity and mortality in people with CKD. In this systematic review, we summarized evidence from randomized and nonrandomized clinical trials investigating effects of interventions that might attenuate progression of vascular calcification in CKD; interventions were compared with placebo, other comparators, or standard of care. We reviewed 77 heterogeneous clinical trials (63 randomized) involving 6898 participants. Therapy involving magnesium or sodium thiosulfate appears the most promising, with consistent findings of attenuation of vascular calcification progression, but evaluable studies were small and of short duration. Many other studies had inconclusive or conflicting outcomes. This study highlights the need for more definitive trials to evaluate interventions targeting vascular calcification in people with CKD, preferably in association with patient-centered outcomes.

Background
Vascular calcification is associated with cardiovascular morbidity and mortality in people with CKD. Evidence-based interventions that may attenuate its progression in CKD remain uncertain.

Methods
We conducted a systematic review of prospective clinical trials of interventions to attenuate vascular calcification in people with CKD, compared with placebo, another comparator, or standard of care. We included prospective clinical trials (randomized and nonrandomized) involving participants with stage 3–5D CKD or kidney transplant recipients; the outcome was vascular calcification measured using radiologic methods. Quality of evidence was determined by the Cochrane risk of bias assessment tool and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) method.

Results
There were 77 trials (63 randomized) involving 6898 participants eligible for inclusion (median sample size, 50; median duration, 12 months); 58 involved participants on dialysis, 15 involved individuals with nondialysis CKD, and 4 involved kidney transplant recipients. Risk of bias was moderate over all. Trials involving magnesium and sodium thiosulfate consistently showed attenuation of vascular calcification. Trials involving intestinal phosphate binders, alterations in dialysate calcium concentration, vitamin K therapy, calcimimetics, and antiresorptive agents had conflicting or inconclusive outcomes. Trials involving vitamin D therapy and HMG-CoA reductase inhibitors did not demonstrate attenuation of vascular calcification. Mixed results were reported for single studies of exercise, vitamin E–coated or high-flux hemodialysis membranes, interdialytic sodium bicarbonate, SNF472, spironolactone, sotatercept, nicotinamide, and oral activated charcoal.

Conclusions
Currently, there are insufficient or conflicting data regarding interventions evaluated in clinical trials for mitigation of vascular calcification in people with CKD. Therapy involving magnesium or sodium thiosulfate appears most promising, but evaluable studies were small and of short duration.