Reversal Of Arterial Disease by modulating Magnesium and Phosphate

This study is also registered through: https://www.clinicaltrialsregister.eu EudraCT Number: 2019-001306-23

Background: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Accumulating evidence suggests that CVD and mortality are partially driven by inflammation and an increased calcification, both features that affect arterial stiffness. Recently, clinical quantification of calcification propensity, i.e. the tendency to develop calcifications, has become feasible by measuring calciprotein particle (CPP) maturation time in-vitro from patient samples (T50). Besides their direct effect on vascular mineralization, CPP’s seem to induce inflammation, that contributes to vascular calcification and endothelial dysfunction, contributing to increased arterial stiffness as well. Importantly, both magnesium deficiency and excess phosphate are associated with increased arterial stiffness as can be measured by pulse wave velocity (PWV). The influences of lower magnesium and higher phosphate concentrations on arterial stiffness are possibly explained by their modulating, detrimental effect on endothelial function and their ability to aggravate CPP formation, respectively. Moreover, multiple observational studies among CKD patients have linked magnesium deficiency to cardiovascular events and mortality.
This study focuses on the role of magnesium as a powerful endogenous calcification inhibitor, examining the effect of magnesium supplementation on arterial stiffness and calcification propensity. In addition, we will determine whether phosphate-binding therapy in CKD patients without overt hyperphosphatemia can amplify the presumed beneficial effect of magnesium. By focusing on the role of magnesium and phosphate as targets that can modulate arterial stiffness, this research aims to improve cardiovascular outcomes in the CKD population. Moreover, the hypothesis will be tested, if the effects on arterial stiffness and inflammation are mediated by changes in calcification propensity. If this hypothesis can be confirmed, this will enable personalized medicine on this aspect of CKD, by directing interventions on the T50 score.

Primary Objective:
- Determine the effect of 24 weeks of oral magnesium supplementation and/or the phosphate binder sucroferric oxyhydroxide on arterial wall stiffness in CKD patients, as measured by pulse wave velocity.
Secondary Objectives:
- Determine the effect of 24 weeks of oral magnesium supplementation and/or the phosphate binder sucroferric oxyhydroxide on calcification propensity and vascular inflammation in CKD patients, measured by markers including T50, CPP concentrations, FGF-23, Klotho and hsCRP.
- Explore the effect of 24 weeks of oral magnesium supplementation and/or the phosphate binder sucroferric oxyhydroxide on vascular calcification and vascular inflammation, assessed by 18F-NaF-PET scans and 18F-FDG-PET, respectively, in a subsample of 40 participants.

Methods: A Randomized Controlled Trial, with a double blind magnesium citrate intervention and an open label sucroferric oxyhydroxide (phophate-binder) intervention in adult non-dialysis dependent CKD patients.

Intervention & Comparator:
- Magnesium 117mg 3dd (350 mg elemental magnesium a day, supplemented as magnesium citrate)
- Magnesium placebo (Mg-placebo) 3dd
- Magnesium 117mg 3dd + sucroferric oxyhydroxide (SFOH) 2dd 500mg
- Mg-Placebo 3dd + SFOH 2dd 500mg

Country of recruitment: The Netherlands

We hypothesize that 24 weeks of oral magnesium supplementation in patients with chronic kidney disease can improve vascular stiffness, through inhibiting calcification propensity and inflammation. In addition, we test the hypothesis that phosphate-binding therapy in these patients without overt hyperphosphatemia, amplifies the beneficial effects of magnesium.

- week 0, 12 and 24 measurement of PWV
- week 0, 12, 24 and 28 measurement of calcification propensity and additional laboratory measurements
- week 0 and 24 weeks biobank material storage (plasma, serum and urine)

Magnesium Citrate and Sucroferric Oxyhydroxide