Novel pathologic link between hyperphosphatemia, generation of microparticles, and thrombotic risk

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. More than half of the patients with kidney diseases develop vascular complications at some stage of their disease progression. Hyperphosphatemia, high serum inorganic phosphate (Pi) levels, is a common biochemical abnormality in kidney patients and can exert damaging effects on endothelial cells lining the blood vessels.

Microparticles, small 100-1000nm in diameter cell membrane fragments, are released from cells under stress. While hyperphosphatemia can exert its damaging effect on cells of the vasculature by inducing soft-tissue calcification, we have proposed that Pi can exert functional effects on the cells of the blood vessels (especially endothelial cells), resulting in generation of MPs by a direct inhibition of phosphoprotein phosphatases resulting in cytoskeletal protein dysregulation and subsequent MP formation.

The mechanism of this Pi-induced cell stress and microparticle formation is elusive. In this study we have shown a novel mechanism by which Pi induces cell-stress, resulting in the generation of pro-coagulant forms of endothelial MPs which may contribute to acute occlusive events.

The major finding of our study is that inorganic phosphate concentrations similar to those observed in hyperphosphatemia in kidney patients trigger an acute release of pro-coagulant microparticles from human endothelial cells. This is of direct interest to nephrologists because it provides a molecular basis for the observed link between hyperphosphatemia and cardiovascular disease in kidney patients. It is also of interest to a wider audience because the proposed mechanism provides a widely applicable explanation for pathological effects of phosphate excess in mammalian cells. Our study provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk.