The interplay between mineral metabolism, vascular calcification and inflammation in Chronic Kidney Disease (CKD): challenging old concepts with new facts

Abstract

Chronic kidney disease (CKD) is one of the most powerful predictors of premature cardiovascular disease (CVD), with heightened susceptibility to vascular intimal and medial calcification associated with a high cardiovascular mortality. Abnormal mineral metabolism of calcium (Ca) and phosphate (P) and underlying (dys)regulated hormonal control in CKD-mineral and bone disorder (MBD) is often accompanied by bone loss and increased vascular calcification (VC). While VC is known to be a multifactorial process and a major risk factor for CVD, the view of primary triggers and molecular mechanisms complexity has been shifting with novel scientific knowledge over the last years. In this review we highlight the importance of calcium-phosphate (CaP) mineral crystals in VC with an integrated view over the complexity of CKD, while discuss past and recent literature aiming to highlight novel horizons on this major health burden. Exacerbated VC in CKD patients might result from several interconnected mechanisms involving abnormal mineral metabolism, dysregulation of endogenous calcification inhibitors and inflammatory pathways, which function in a feedback loop driving disease progression and cardiovascular outcomes. We propose that novel approaches targeting simultaneously VC and inflammation might represent valuable new prognostic tools and targets for therapeutics and management of cardiovascular risk in the CKD population.

Keywords: calciprotein particles; cardiovascular disease; chronic kidney disease; extracellular vesicles; vascular calcification and inflammation; vitamin K-dependent proteins.

Figure 1

Overview of calcium (Ca) and phosphate (P) homeostatic regulation. Red lines represent the main mechanisms of Ca regulation in a situation of hypocalcemia. Decreased Ca levels in serum increase 1,25D and PTH. Increased levels of 1,25D increase Ca absorption at the intestine and stimulate mineral exchange in bone increasing Ca efflux. Increased PTH stimulate mineral exchange in bone increasing Ca efflux, and increase Ca reabsorption in the kidney. Indirectly, high levels of PTH stimulate 1,25D with consequent increase in Ca absorption. Overall, the concerted action of PTH and 1,25D lead to increased serum Ca levels until the normal range by increasing Ca reabsorption at the intestine, increasing Ca from mineral exchange in bone, and increasing Ca reabsorption in the kidneys. Blue lines represent the main mechanisms of P regulation in a situation of hyperphosphatemia. High levels of serum P increase FGF-23 production in bone, which exerts several effects to promote a decrease in serum P. FGF-23 decreases P reabsorption and increases P excretion in the kidneys, and indirectly decreases P absorption at the intestine and P efflux from bone mineral exchange, through the inhibition of 1,25D and PTH.

Figure 2

Schematic representation of the mineralization paradox in CKD. As kidney functional declines, P retention occurs and FGF-23 highly increases, with consequent decrease in 1,25D levels. Dysregulated levels of 1,25D lead to increased levels of PTH and decreased levels of serum Ca. Low levels of serum Ca maintained by low 1,25D, constantly stimulate PTH production, often resulting in secondary hyperparathyroidism (SHPT) and bone resorption leading to decreased bone mineralization. However, increased Ca efflux from bone, and increased Ca reabsorption and decreased excretion in the kidneys originate a positive Ca balance, correlated with increased vascular calcification.

Figure 3

The vascular calcification-inflammation cycle. Calcium-phosphate (CaP) mineral is present in secondary calciprotein particles (CPP-II), in calcifying extracellular vesicles (cEVs) and in the extracellular matrix (ECM) of blood vessels. All these forms of CaP mineral are able to induce pro-inflammatory responses in immune and VSMs cells, and the osteogenic differentiation of VSMCs. In turn, macrophage pro-inflammatory responses contribute to increased vascular calcification through the release of cEVs and inducing osteogenic differentiation of VSMCs, while osteogenic VSMCs drive ECM calcification through the release of cEVs and increase in macrophage pro-inflammatory responses, in a vicious cycle.