Hyperphosphatemia of chronic kidney disease

Abstract

Observational studies have determined hyperphosphatemia to be a cardiovascular risk factor in chronic kidney disease. Mechanistic studies have elucidated that hyperphosphatemia is a direct stimulus to vascular calcification, which is one cause of morbid cardiovascular events contributing to the excess mortality of chronic kidney disease. This review describes the pathobiology of hyperphosphatemia that develops as a consequence of positive phosphate balance in chronic kidney disease and the mechanisms by which hyperphosphatemia acts on neointimal vascular cells that are stimulated to mineralize in chronic kidney disease. The characterization of hyperphosphatemia of chronic kidney disease as a distinct syndrome in clinical medicine with unique disordered skeletal remodeling, heterotopic mineralization and cardiovascular morbidity is presented.

Fig. 1

Phosphorus balance in normal physiology. The kidney is the main regulator of human phosphate homeostasis. In adulthood, exit from the exchangeable phosphorus pool into the skeleton (bone formation) is roughly equal to entry into the exchangeable pool due to bone resorption. The skeleton is a storage depot for Pi and contains 85% of the total body phosphorus.

Fig. 2

Phosphorus homeostasis is lost in chronic kidney disease due to failure of excretion. Despite reductions in the fraction of filtered phosphorus that is reabsorbed, eventually the filtered load becomes insufficient to maintain homeostasis, and positive phosphorus balance ensues. Kidney disease decreases the exchangeable phosphorus pool size by inhibiting bone formation. The skeletal mineralization fronts at the sites of new bone formation are significant components of the exchangeable phosphorus pool. Positive phosphate balance is associated with establishment of heterotopic mineralization sites in soft tissue organs and the vasculature. Exit from the exchangeable phosphorus pool into the vasculature is portrayed as a bidirectional process because we have been able to demonstrate that stopping the exit into the vasculature results in diminishment of established vascular calcification levels.

Fig. 3

Regulation of phosphorus balance in chronic kidney disease. Regulation of phosphorus homeostasis is complex. In chronic kidney disease, a decrease in calcitriol production leads to a decrease in calcium absorption, hypocalcemia, and hyperparathyroidism. Hyperparathyroidism is one factor contributing to the decrease in the fraction of filtered phosphorus reabsorbed (decrease in the TRP). Additionally, high levels of FGF23 and hyperphosphatemia itself, contribute to reducing the TRP. However, when kidney failure becomes too severe, hyperphosphatemia ensues.

Fig. 4

Vascular calcification causes cardiac morbidity and mortality in chronic kidney disease. Vascular calcification increases arterial stiffness leading to an increase in pulse wave velocity and pulse pressure both of which contribute to development of cardiac ischemia, and left ventricular hypertrophy and cardiac failure.

Fig. 5

Control of hyperphosphatemia in translational studies results in reduction of established vascular calcium levels. LDLR−/− mice on high-fat diets with chronic kidney disease have established vascular calcification at 22 wks (baseline) which increases in vehicle treated animals sacrificed at 28 wks (veh). However, in animals treated with sevelamer carbonate (1% sev and 3% sev), aortic calcium levels were significantly reduced compared to baseline, as the hyperphosphatemia was controlled (28).

Fig. 6

Schematic of the experimental plan for in vitro studies demonstrating that high phosphorus causes vascular calcification and osteoblastic gene expression. Human vascular smooth muscle cells (hVSMC) derived from atherosclerotic aortas expressed increased levels of morphogens, specific transcription factors and biomarkers of the osteoblast and decreased levels of those corresponding to contractile hVSMC. Yet the cells did not mineralize until media Pi was increased from 1 to 2mM. High media Pi stimulated osterix expression, and when osterix expression was diminished in the presence of high media Pi there was no mineralization (38).

Fig. 7

Expression of osterix in the aortas of LDLR−/− high-fat fed mice. High fat feeding had a small effect to increase aortic osterix expression in sham operated animals (sham fat) compared to wild type mice. Induction of chronic kidney disease (CKD high fat) produced a several-fold increase in osterix expression which was eliminated by treatment with phosphate binders, in this case lanthanum carbonate 1% or 3% added to the diet (38).