Magnesium: a renewed player of vascular ageing in diabetic CKD patients?

Abstract

Chronic kidney disease (CKD) patients are prone to a higher cardiovascular morbidity and mortality compared with the general population [1]. Consistent results from the basic and clinical research showed that cardiovascular susceptibility in CKD is due, partially at least, to a considerable acceleration of the vascular ageing processes in the context of chronic kidney disease-mineral bone disorder syndrome (CKD-MBD) [2]. This premature cardiovascular senescence is mainly characterized by altered endothelial reactivity, followed by pathologic calcification of cardiac valves and medial layer in the arteries [3]. The consequent increase of arterial stiffness worsens the cardiac afterload, contributing to the onset of left ventricular hypertrophy and to the progressive increase of pulse pressure (PP) leading to a significant reduction of diastolic tissue perfusion. The metabolic pathways linked to this premature ageing involve the dysregulation of several systems such as inflammation, oxydative stress, insulin resistance and mineral metabolism [3]. The alterations of calcium (Ca) and phosphate (P) homeostasis in renal patients, mainly driven by a derangement of Klotho/fibroblast growth factor 23 (FGF23)—parathormone (PTH)—vitamin D axis, are considered pivotal triggers and regulators of vascular ageing rather than mere biomarkers of CKD-MBD syndrome [3]. Thus, P overload and hyperparathyroidism are well known targets of medical treatments, such as P binders, vitamin D and calcimimetics, although with still limited evidence-based advantages in terms of survival in renal patients [3, 4]. The tough hedge that is still keeping nephrologists far from a conclusive and winning approach against vascular ageing is reasonably related to the still partial comprehension of the molecular pathways involved in a so complex, multifactorial and extreme process. New biomarkers and new actors are thus needed to orient the scientific knowledge towards further intervention strategies against CKD-MBD. In the present issue of the Clinical Kidney Journal, Fragoso et al. [5] present the first observational data linking magnesium (Mg) and FGF23 levels to PP in 80 pre-dialysis type 2 CKD diabetic patients. This elegant cross-sectional analysis observed that a PP higher than 50 mmHg was independently associated with lower Mg and higher FGF23 levels [OR 0.550 (95% CI 0.305–0.727) and 1.239 (95% CI 1.001–2.082), respectively]. Consistent with previous results, Mg levels were also negatively correlated with PTH (P = 0.0001), c-term FGF23 (P = 0.0001), Ca levels (P = 0.026) and HOMA-IR (P = 0.003) as well. A growing body of evidence is supporting a cardinal role of Mg in several diseases linked to vascular ageing in CKD-MBD and diabetes. More specifically, low Mg levels were associated with low insulin resistance, poor endothelial reactivity, higher oxidative stress, increased intima-media thickness, vascular calcification, progression of CKD and mortality [6–9]. Although the common clinical experience depicted how Mg was directly involved in the altered Ca and PTH homeostasis, as in those cases of symptomatic hypocalcaemia secondary to severe hypomagnesaemia [10], the specific hormonal regulation of Mg balance and the specific pathways linking Mg to the pathophysiology of the mineral and vascular systems are still incompletely understood. Of note, altered Mg levels were associated with diabetes [7], menopause [11] and CKD [8], three conditions that share a common phenotype of accelerated vascular ageing, characterized by Monckeberg calcification and impaired bone metabolism (ranging from adynamic bone disease in diabetes to high bone turnover in osteoporotic menopausal women and certain CKD patients). Nevertheless, the maintenance of adequate intracellular Mg levels appears essential for life per se, considering that Mg is a fundamental co-enzyme of vital biochemical reactions as Krebs cycle and glycolysis [7] and it is essential for the maintenance of RNA and DNA stability [12]. Thus Mg may represent a cardinal biomarker and regulator of vascular ageing in humans, with special emphasis in CKD diabetic patients. Furthermore, nephrologists are called to a growing comprehension of Mg physiology, as a consequence of the renewed adoption of Mg as a P binder, now available in a single formulation together with calcium-acetate [13]. The data by Fragoso et al. [5] confirm the growing interest that nephrology community should point towards Mg metabolism with particular emphasis on CKD-MBD diabetic patients.