Cardiovascular risk factors in chronic kidney disease: does phosphate qualify?

Abstract

Risk factors for disease states are rigorously defined. This analysis considers the definition of a risk factor as applied to the question of whether the serum phosphorus level is a risk factor for cardiovascular disease. Observational studies strongly suggest that phosphorus is associated with cardiovascular risk, and definitive prospective animal studies are supportive. A plausible mechanism of action has been discovered demonstrating that phosphorus stimulates osteoblastic transition of cells in the neointima of atherosclerotic plaques, which, if prevented, blocks vascular calcification. However, prospective studies demonstrating that modulation of the putative risk factor affects clinical outcomes are lacking, and phosphorus, as yet, does not qualify as a cardiovascular risk factor. This is a clarion call for additional research.

Figure 1

Observational studies from the general population, which suggest that phosphorus is a cardiovascular risk factor. The left panel assembles data from Dhingra et al. Cardiovascular disease (CVD) was scored as fatal/non-fatal MI, angina, cerebrovascular events, peripheral vascular disease, or heart failure. Hazard ratios are adjusted for age, sex, body mass index, diabetes, blood pressure, treatment of hypertension, smoking, alcohol consumption, total cholesterol/high-density cholesterol ratio, hemoglobin, serum albumin, estimated glomerular filtration rate, proteinuria, and high-sensitivity C-reactive protein. The right panel is adapted with permission from Tonelli et al. Hazard ratio values are adjusted for baseline age, sex, race, smoking status, diabetes, waist-to-hip circumference, fasting glucose, glomerular filtration rate, hemoglobin, serum albumin, aspirin use, and left ventricular ejection fraction. N=4127. CKD, chronic kidney disease; MI, myocardial infarction.

Figure 2

The two major types of large artery calcification stimulated by chronic kidney disease (CKD) are atherosclerotic neointimal calcification and medial calcification. Reproduced with permission from Dr Gerard London.

Figure 3

Hyperphosphatemia stimulates expression of osterix in the aortas of low-density lipoprotein receptor-deficient mouse (ldlr^–/–) with chronic kidney disease (CKD) fed high-fat diets. LaCO₃, a non-calcium-containing phosphate binder, reverses osterix expression. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

Figure 4

The phosphate balance diagram in chronic kidney disease (CKD) showing positive balance and a skeletal contribution to hyperphosphatemia, which blocks skeletal reservoir function. Reproduced with permission from Mathew et al.

Figure 5

Effects of serum phosphate and phosphate binder use on survival in the Accelerated Mortality in Renal Replacement study. Survival of treated and untreated patients in the overall propensity score-matched cohort (a) and according to quartiles of baseline serum phosphate (b–e). Reproduced by permission from Isakova et al.