Role of Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (MBD) in the Pathogenesis of Cardiovascular Disease in CKD

Abstract

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Multiple factors account for the increased incidence of cardiovascular morbidity and mortality in patients with CKD. Traditional risk factors for atherosclerosis and arteriosclerosis, including age, hypertension, dyslipidemia, diabetes mellitus, and smoking, are also risk factors for CKD. Non-traditional risk factors specific for CKD are also involved in CVD pathogenesis in patients with CKD. Recently, CKD-mineral and bone disorder (CKD-MBD) has emerged as a key player in CVD pathogenesis in the context of CKD. CKD-MBD manifests as hypocalcemia and hyperphosphatemia in the later stages of CKD; however, it initially develops much earlier in disease course. The initial step in CKD-MBD involves decreased phosphate excretion in the urine, followed by increased circulating concentrations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH), which increase urinary phosphate excretion. Simultaneously, the serum calcitriol concentration decreases as a result of FGF23 elevation. Importantly, FGF23 and PTH cause left ventricular hypertrophy, arrhythmia, and cardiovascular calcification. More recently, calciprotein particles, which are nanoparticles composed of calcium, phosphate, and fetuin-A, among other components, have been reported to cause inflammation, cardiovascular calcification, and other clinically relevant outcomes. CKD-MBD has become one of the critical therapeutic targets for the prevention of cardiovascular events and is another link between cardiology and nephrology. In this review, we describe the role of CKD-MBD in the pathogenesis of cardiovascular disorders and present the current treatment strategies for CKD-MBD.

Keywords: CKD; CKD–MBD; Calcium; Cardiovascular disease; Phosphate.

Fig.1. Schema of the complex network of CKD–MBD mediators

The arrows represent the actions that increase the associated CKD–MBD mediators, while the capped lines represent the actions that decrease the associated CKD–MBD mediators. The overall impact of changes in each CKD–MBD parameter depends on the medical conditions of each patient. CKD–MBD, chronic kidney disease–mineral and bone disorder; CPP1, primary calciprotein particles; CPP2, secondary calciprotein particles; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone.

Fig.2. Calcium and inorganic phosphate flow exerted by multiple organs and CKD–MBD mediators

Calcium and inorganic phosphate balance are maintained by orchestration of the complex function exerted by the kidneys, parathyroid glands, bone, and gastrointestinal tract. This orchestration is mainly mediated by PTH, FGF23, and calcitriol (1,25-dihydroxyvitamin D). PTH downregulates sodium–phosphate transporters in the renal proximal tubules and increases urinary inorganic phosphate excretion. PTH also increases the absorption of calcium in the renal distal tubules, upregulates 1-α hydroxylase, and elevates calcitriol. FGF23 increases urinary inorganic phosphate excretion by downregulating sodium–phosphate transporters in the renal proximal tubules, and deactivates calcitriol. Calcitriol increases calcium and inorganic phosphate absorption via the gastrointestinal tract and calcium reabsorption via the renal proximal tubules. Calcitriol also increases FGF23 synthesis and secretion in bone. Calcitriol and PTH affect bone turnover and regulate bone mass, followed by changes in the amount of calcium/inorganic phosphate release into the bloodstream. Excessive calcium and inorganic phosphate accelerate cardiovascular calcification. Ca, calcium; CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineral and bone disorder; CPP1, primary calciprotein particles; CPP2, secondary calciprotein particles; FGF23, fibroblast growth factor 23; Pi, inorganic phosphate; PTH, parathyroid hormone; PTG, parathyroid gland.

Fig.3. Chronological changes in serum CKD–MBD mediators during CKD progression

CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineral and bone disorder; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone.

Fig.4. Risk factors and cell-mediated processes for CVC

Patients with CKD are at an elevated risk of cardiovascular calcification, including arterial intimal and medial calcification and cardiac valvular calcification. The reasons for the heightened risk of CVC are supposed to be accumulation of multiple risk factors, including traditional risk factors for atherosclerosis, uremia-related risk factors, and CKD–MBD. CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineral and bone disorder; CPPs, calciprotein particles; CVC, cardiovascular calcification; Mg, magnesium; PEW, protein-energy wasting; VSMCs, vascular smooth muscle cells; VICs, valvular interstitial cells.

Fig.5. Impact of CKD–MBD mediators on diverse cardiovascular disorders

In patients with CKD, as kidney function declines, relative phosphate overload develops and circulating concentrations of PTH and FGF23 increase, leading to the formation of CPPs. The serum concentrations of α-klotho, calcitriol, and calcidiol decrease. These abnormalities in CKD–MBD ultimately accelerate atherosclerosis, arteriosclerosis, hypertension, left ventricular hypertrophy, congestive heart failure, arrhythmia, and myocardial and cardiovascular calcification, all of which increase the risk of death. CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineral and bone disorder; CPPs, calciprotein particles; FGF23, fibroblast growth factor 23; PTG, parathyroid gland; PTH, parathyroid hormone.