The role of calcium and non calcium‐based phosphate binders in chronic kidney disease

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Changes associated with the development of Chronic Kidney Disease‐Mineral and Bone Disorder (CKD‐MBD) are often apparent by CKD stage 3 and are universal by the time patients require dialysis. Abnormal values of serum calcium and phosphate are the most commonly measured laboratory features of CKD‐MBD, but only occur at later CKD stages. More fundamental and usually unmeasured changes occur early in CKD, and involve endocrine axes controlling mineral homeostasis, and natural inhibitors and potentiators of vascular calcification (VC). Early hormonal changes include a reduction in soluble‐Klotho and an adaptive increase in the phosphaturic hormone fibroblast growth factor 23 (FGF23), followed by a reduction in 1,25‐dihydroxyvitamin D. The later increase in serum parathyroid hormone (PTH) further reduces tubular reabsorption of phosphate and helps to maintain normal serum phosphate values.
Despite these hormonal adaptations to CKD, serum phosphate values eventually rise, and the solubility limit of calcium and phosphate may be exceeded, at which point crystal development (nucleation) occurs. These crystals have potential to transform and grow into amorphous calcium phosphate and hydroxyapatite that can precipitate, causing damage to blood vessels and other soft tissues. Counterbalancing this process, the serum protein Fetuin‐A absorbs small (<1 nm diameter) calcium‐phosphate crystals.1 These molecules of Fetuin‐A aggregate to form primary and then secondary calciprotein particles (CPPs), which are colloidal nanoparticles of Fetuin‐A with a crystalline core. This process can be interpreted as a defence against potential vascular damage from calcium phosphate crystal deposition in CKD.2 CPPs inhibit crystal growth, reduce spontaneous crystal precipitation, and can be phagocytosed via scavenger receptors in the liver.3 However, there are caveats; Fetuin‐A is a negative acute phase reactant, and levels fall in patients with CKD. In addition, CPPs are themselves bioactive ligands that have the capacity to induce VC and renal tubular damage.4
Another potent defence against the development of VC involves the vitamin‐K2 dependent matrix‐Gla protein (MGP). MGP protects against crystal growth in matrix vesicles of vascular smooth muscle cells. The Gla residues of MGP bind strongly to insoluble calcium salts, and MGP also modulates the osteo‐inductive properties of bone morphogenic protein‐2.5 However, in patients with CKD, dietary vitamin K2 intake is often low, and patients are frequently treated with warfarin; both of which lead to undercarboxylation and inactivation of MGP. Levels of inactive dephosphorylated‐uncarboxylated‐MGP are high in patients with CKD and increase with dialysis vintage.
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