Update on Chronic Kidney Disease Mineral and Bone Disorder in Cardiovascular Disease

Abstract

Chronic kidney disease mineral and bone disorder (MBD) encompasses changes in mineral ion and vitamin D metabolism that are widespread in the setting of chronic kidney disease and end-stage renal disease. MBD components associate with cardiovascular disease in many epidemiologic studies. Through impacts on hypertension, activation of the renin-angiotensin-aldosterone system, vascular calcification, endothelial function, and cardiac remodeling and conduction, MBD may be a direct and targetable cause of cardiovascular disease. However, assessment and treatment of MBD is rife with challenges owing to biological tensions between its many components, such as calcium and phosphorus with their regulatory hormones fibroblast growth factor 23 and parathyroid hormone; fibroblast growth factor 23 with its co-receptor klotho; and vitamin D with control of calcium and phosphorus. These complex interactions between MBD components hinder the simple translation to clinical trials, which ultimately are needed to prove the benefits of treating MBD. Deeper investigation using precision medicine tools and principles, including genomics and individualized risk assessment and therapy, may help move the field closer toward clinical applications. This review provides a high-level overview of conventional and precision epidemiology in MBD, potential mechanisms of cardiovascular disease pathogenesis, and guiding therapeutic principles for established and emerging treatments.

Keywords: Cardiovascular disease; fibroblast growth factor 23; klotho; mineral metabolism; phosphorus; vitamin D.

Figure 1.. Simplified Schematic of Mineral and Bone Disorder (MBD) Physiology in Chronic Kidney Disease.

Solid lines and arrows depict dominant physiologic effects on circulating MBD factors including: (1) effects of fibroblast growth factor 23 (FGF23) to lower serum phosphorus by inhibiting 1α-hydroxylase that converts 25-hydroxyvitamin D (25-D) to 1,25-dihydroxyvitamin D (1,25-D) and stimulating urinary phosphorus excretion; (2) effects of parathyroid hormone (PTH) to raise serum calcium by stimulating 1α-hydroxylase and increasing urinary calcium reabsorption and bone remodeling; (3) effects of vitamin D to promote gastrointestinal absorption of calcium and phosphorus and feedback on FGF23 (stimulation) and PTH (inhibition). Dashed lines and arrows depict additional non-dominant effects of FGF23 to increase urinary calcium reabsorption and PTH to increase urinary phosphorus excretion and FGF23 transcription. In each case, arrows (→) represent actions that raise the associated MBD factor whereas capped lines (┤) represent actions that lower the associated MBD factor. Altogether, the physiology encompasses major effects of FGF23 to reduce phosphorus and vitamin D and major effects of PTH to increase calcium and vitamin D, along with substantial redundancy, feedback, and crosstalk.

Figure 2.. Examples of Major Factors that Influence Mineral and Bone Disorder (MBD).

These factors may confound associations or interact to modify associations leading to heterogeneity across studies. FGF23, fibroblast growth factor 23; PTH, parathyroid hormone; Pi, inorganic phosphorus; Ca, calcium; Mg, magnesium.

Figure 3.. Theoretical Framework for Incorporating Genetic Data in Studies of Mineral and Bone Disorder (MBD) and Cardiovascular Disease.

In panel A genetic variants impact cardiovascular disease via effects on MBD intermediates without any other influences on cardiovascular disease pathways supporting causal inference. In panel B genetic variants may influence both MBD and other unrelated intermediate pathways leading to cardiovascular disease, demonstrating pleiotropy. Candidate genes with known primary biological effects on MBD and without other known unrelated biological effects may provide stronger causal inference (blue 3a) compared to genes with known pleiotropic effects (blue 3b). In panel C MBD related variants may interact with other patient and environmental factors to more strongly influence MBD and cardiovascular disease. Studies elucidating these effects may help identify subtle effects on common environmental exposures, explain across study heterogeneity, and allow personalized therapy. FGF23, fibroblast growth factor 23; PTH, parathyroid hormone; RAAS, renin angiotensin aldosterone system.