Elevated phosphate levels contribute to CV disease

Phosphate: a novel cardiovascular risk factor.

Literature - Ketteler M, Wolf M, Hahn K, Ritz E. - Eur Heart J. 2013 Apr;34(15):1099-101. doi: 10.1093/eurheartj/ehs247.

Ketteler M, Wolf M, Hahn K, Ritz E.
Eur Heart J. 2013 Apr;34(15):1099-101. doi: 10.1093/eurheartj/ehs247.


In chronic kidney disease (CKD), elevated serum phosphate has been recognised as an important risk factor for all-cause and cardiovascular (CV) mortality. Dietary phosphate restriction is associated with a survival benefit and is thus recommended in the CKD patient population. Evidence is now accumulating that high serum phosphate also predicts CV events in patients with CV disease and even in the normal population.  

New insights into the control of phosphate metabolism

Serum phosphate levels mainly depend on renal phosphate excretion. Previous focus was on parathyroid hormone as a key hormonal determinant of tubular phosphate reabsorbtion. More recently, attention has shifted to fibroblast growth factor (FGF23) as the master regulator of the complex renal phosphate handling (details on the regulatory pathways involving FGF23 are provided in the original article). FGF23 also acts on other organs, with the most relevant observation in a CV context being that it appears to trigger myocardial hypertrophy.

Mechanisms underlying the effects of phosphate on cardiovascular damage

Phosphate and cardiovascular calcification
Next to the passive precipitation of calcium and phosphate, an active mechanism is also at play of CV calcification. High phosphate triggers the differentiation of vascular smooth muscle cells into osteoblast-like cells. Inflammation is also thought to contribute to this process of osteogenic transdifferentiation.

Phosphate and endothelial dysfunction
Even transient increases of serum phosphate (e.g. after a meal) can promote endothelial dysfunction. Animal studies gave insight into the mechanism, but also in human volunteers a decrease in flow-mediated dilatation was observed after a meal containing 1200 mg of phosphate, as compared to a meal with 400 mg. Post-prandial endothelial cell dysfunction may contribute to cardiovascular morbidity.

FGF23 and myocardial hypertrophy/dysfunction
FGF23 not only acts via a complex interplay with cofactors, but also directly. It has been associated with left ventricular hypertrophy, an effect that appears to be independent of co-factors or blood pressure.
A remarkably strong correlation exists between serum phosphate levels and FGF23. Reducing dietary phosphate could therefore prevent the development of ventricular hypertrophy in renal patients, and possibly in a broader population.

Dietary phosphate

Natural phosphate sources in unprocessed food are slowly hydrolysed and only partly (30-60%) absorbed in the gastrointestinal tract. Inorganic phosphates that are often found in food additives, in processed foods, are readily absorbed to up to 80-100%.
This justifies the recommendation to measure fasting serum phosphate in patients with CKD or CV disease, as a risk predictor. Minimising food intake that contains inorganic phosphates could be valuable dietary advice for patients with CKD or CV disease.

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