Phosphate, Calcification in Blood, and Mineral Stress: The Physiologic Blood Mineral Buffering System and Its Association with Cardiovascular Risk

Abstract

Phosphate is an important cardiovascular risk factor and lowering elevated blood phosphate concentrations is a main therapeutic target in kidney patients. Phosphate is subject to the blood mineral buffering system which controls the precipitation of calcium and phosphate. Calciprotein particles (CPP), self-assembling complexes of calcium phosphate and serum proteins, are the nanomorphological correlates of this system. CPP1 are spherical, 50-100 nm in diameter, and contain amorphous mineral. CPP2 are oblongated, 100-200nm in the long axis, and they contain a crystalline mineral core. The relative abundance and biological activity of these particles are a matter of intense research, because they can cause oxidative stress, inflammation, and calcification in cellular assay. Therapeutically reducing this endogenous stressor by prolonging crystal formation time might improve patient outcome. This concise review article summarizes our current knowledge about the blood mineral buffering system and proposes Mineral Stress as a novel modifiable cardiovascular risk factor. It furthermore outlines possible implications this might have for improving patient care.

Figure 1

Schematic illustration of the Mineral Stress hypothesis. Mineral Stress is caused by excess calciprotein particles, which upon interaction with susceptible cells, tissues, and organs induce damage in the form of oxidative stress, inflammation, and calcification. These clinical problems then contribute to adverse outcome. CPP are formed by the blood mineral buffering system when calcium and phosphate concentrations are raised. Primary CPP (CPP1) occur earlier during excess mineral buffering, whereas CPP2 should not occur in sizeable amounts, because CPP in general are rapidly cleared from circulation. Longer crystal formation time in vitro has consistently been associated with better cardiovascular outcome in multiple clinical studies. Figure provided with courtesy from Calciscon AG.

Figure 2

Crystal formation time is a measure of calcium phosphate crystallization. Crystal formation time functionally measures the transformation from amorphous primary (CPP1) to crystalline secondary (CPP2) calciprotein particles. It provides an integrated “functional summary” of crystallization promoting and inhibiting substances in serum and thus gives an estimate of the likelihood of CPP2-formation. Figure provided with courtesy from Calciscon AG.