Calcium, Phosphate, Renal Impairment and Coronary Artery Disease in the Cardio-renal Syndrome, The CAPRICORN-CRS Study

The interaction between cardiac and renal (dys)function has been a highly relevant, yet poorly understood phenomena to both clinicians and scientists. More than 50% of the heart failure patients suffers from renal impairment, defined as a creatinine clearance < 60 ml/min,while renal impairment is one of the most powerful predictors of outcome in heart failure.However, the complex mechanism why renal insufficiency is associated with a worse outcome, is still not fully elucidated.

It was presumed that in the setting of acute heart failure, cardiac output reduces, which is counteracted by systemic and other responses such as a decrease in renal blood flow, in order to retain circulating fluid and restore cardiac output.Yet, heart failure patients with deterioration in renal function are not necessarily those with the poorest ventricular function, lowest cardiac output or the lowest blood pressures.It is therefore hypothesized that renal impairment is not merely a marker of end-stage heart failure, but is associated with a myriad of pathophysiological processes which may influence prognosis.

One of the consequences of renal insufficiency that usually remains unnoticed by cardiologists, is a disregulation in the calcium and phosphate homeostasis. Yet, especially hyperphosphatemia is present in 50% of the pre-dialysis patients and is an important independent predictor of cardiovascular morbidity and mortality in this population.

The pathophysiological mechanisms behind this process are intensively studied. In vitro studies show that elevated phosphate concentrations induce differentiation of vascular smooth muscle cells (VSMC) via Cbfa1 to osteoblast-like cells. These osteoblast-like cells are capable of producing bone matrix proteins, which may subsequently regulate mineralization. Once mineralization is initiated, increased Ca x PO4 product from (ab)normal bone metabolism, secondary hyperparathyroidism, or excessive calcium intake may accelerate this process leading to vascular calcification.

Serum phosphate concentrations are regulated by fibroblast growth factor 23 (FGF-23), a circulating protein which may protect the transition of VSMC into osteoblast-like cells by lowering phosphate concentrations.Studies with FGF-23 null mice revealed extensive vascular calcification of the media layer in arteries.FGF-3 was also strongly related to vascular calcification in patients with end stage renal disease (ESRD), while there was no association found with atherosclerosis in subjects with normal renal function.