Magnesium Balance in Chronic Kidney Disease: Mineral Metabolism, Immunosuppressive Therapies and Sodium-Glucose Cotransporter 2 Inhibitors

Abstract

It is now widely recognized that maintaining magnesium (Mg) homeostasis is critical for health, especially in the context of chronic kidney disease (CKD). Patients with CKD commonly develop hyperphosphatemia and secondary hyperparathyroidism, which are controlled by therapies targeting intestinal phosphate absorption and circulating calcium levels or by modulating parathyroid calcium sensing. Notably, Mg supplementation may provide dual benefits by promoting bone formation and maintaining normal mineralization with slightly elevated serum levels. Importantly, low Mg levels are associated with mortality risk in CKD, highlighting the importance of maintaining adequate serum Mg levels in these patients. Particularly, kidney transplant (KT) patients have lower circulating Mg levels, likely due to interactions with immunosuppressive treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown survival benefits in CKD and increased serum Mg levels, suggesting that Mg regulation may contribute to these outcomes. Overall, Mg plays a key role in CKD-associated mineral and bone disorders (CKD-MBD). Thus, understanding the mechanisms underlying the alteration of Mg homeostasis in CKD could improve clinical outcomes. This review summarizes the basic and clinical studies demonstrating (1) the key actions of Mg in CKD-MBD, including secondary hyperparathyroidism and bone abnormalities; (2) the distinctive profile of KT patients for Mg homeostasis; and (3) the interaction between commonly used drugs, such as SGLT2 inhibitors or immunosuppressive treatments, and Mg metabolism, providing a broad understanding of both the key role of Mg in the context of CKD and the treatments that should be considered to manage Mg levels in CKD patients.

Keywords: CKD-MBD; SLGT2 inhibitors; chronic kidney disease; magnesium; renal transplant patients.

Figure 1

Magnesium effects on bone and mineral metabolism in the CKD context disease (a) Magnesium (Mg) supplementation acts as a “phosphate binder,” decreasing phosphate uptake in the gut while increasing circulating Mg levels. (b) At the vascular level, circulating Mg inhibits vascular calcification, thus preventing cardiovascular disease. (c) Ionized Mg activates the Calcium-Sensing Receptor (CaSR) in parathyroid cells and inhibits parathyroid hormone (PTH) production and secretion. (d) The Mg-induced PTH decrease could, in part, reduce bone remodeling; however, Mg exerts direct bone effects by increasing osteoblast activity and inhibiting osteoclastic action, while the Mg effects on mineralization may depend on the Mg range, with a probable deleterious effect if Mg levels are too high. Created in BioRender. Domínguez Coral, J. (2025) https://BioRender.com/biw1hmi.

Figure 2

Schematic representation of the mechanisms involved in renal magnesium absorption and the potential effects of some drugs commonly used for CKD treatment. In the kidneys, most of the magnesium (Mg) is filtered by the glomerulus, which is subsequently reabsorbed paracellularly in the proximal tubule and thick ascending limb, mediated by the sodium-potassium-2chloride cotransporter 2 (NKCC2). Moreover, Mg is reabsorbed from urine into the circulation in the distal tubule in a transcellular manner through the transient receptor potential cation channel, subfamily M, member 6 (TRPM6). In this way, there are certain mechanisms that may interfere with active Mg resorption, such as glucose resorption at the proximal tubule via sodium-dependent glucose cotransporter 2 (SGLT2) or pathways involved in immunomodulatory mechanisms such as calcineurin or mammalian target of rapamycin (mTOR), which inhibit NKCC2 and epidermal growth factor (EGF) signaling, being the latter a key inductor of the TRPM6 expression. Thus, inhibitors of the SGLT2, calcineurin, and mTOR pathways, which are used in CKD patients, modulate renal Mg resorption by regulating TRPM6 expression, impacting circulating Mg levels and its associated effects on systemic mineral and bone homeostasis. Created in BioRender. Domínguez Coral, J. (2025) https://BioRender.com/r05q12e.