Serum Phosphate : A Novel Cardiovascular Risk Factor Even in Nonrenal Patients Relation between Serum Phosphate Level and Cardiovascular Event Rate in People with Coronary Disease

I t has been known for decades that hyperphosphatemia is a feature of ESRD that may cause secondary hyperparathyroidism and soft tissue calcification (1), including vascular calcification (2). The latter comprises mainly calcification of intimal plaques (3) and of the media (4,5) of central arteries (Mönckeberg sclerosis), less frequently calcification of muscular arteries (the only type of vascular calcification that potentially disappears after reversal of hyperparathyroidism [6]) and calcific uremic arteriolopathy (calciphylaxis) (7,8). Because calcification of the intima and media seemed not to pose an immediate threat to the dialysis patient’s life, it was in the past treated to some extent with “benign neglect”, until in 1998 the renal community was rudely made aware of the clinical relevance of serum phosphate by the communication of Block et al. (9); he found that in dialysis patients, survival was 27% less when predialysis serum phosphate concentration exceeded 6.5 mg/dl. Remarkably, there was no indiscriminate increase of mortality from all different causes across the board; the increase mainly concerned death from coronary heart disease (10). This finding is not implausible, because in patients with ESRD and coronary heart disease, coronary plaque calcification is four times more frequent than in nonrenal patients with coronary heart disease (3). Obviously, vascular calcification is a much more complex process (11–14) than originally was thought (15). It certainly can not be explained fully by hyperphosphatemia alone, but phosphate, more specifically intracellular phosphate (12), plays a major role in the genesis of vascular calcification, particularly in the presence of ionized calcium (16). Myocardial infarction accounts only for a relatively small proportion of deaths in dialysis patients; the most frequent causes are sudden death and heart failure (www.usrds.org). For this and other reasons, I suspect that the role of hyperphosphatemia presumably extends beyond its role to promote calcification of coronary (3) and central (5) arteries. For instance, recently, more advanced thickening of the intima and media of the carotid artery was found in hyperphosphatemic hemodialysis patients (17). Furthermore, in an experimental study, we showed in subtotally nephrectomized rats that myocardial fibrosis and microvessel disease of the heart developed only in the presence of hyperphosphatemia (18), illustrating that in uremia phosphate also plays a more general role in the genesis of the excessive cardiovascular risk profile beyond causing vascular calcification. Phosphate has numerous roles in cellular metabolism and presumably also is an important intracellular signaling substance. Is the adverse role of high serum phosphate concentrations in renal patients restricted to end-stage renal failure? Kestenbaum et al. (19) recently reported that in patients with chronic kidney disease, serum phosphate concentrations 3.5 mg/dl were associated with higher mortality, and the risk increased stepwise with each 0.5-mg/dl higher serum phosphate concentration. Even the target of 5.5 mg/dl serum phosphate in dialysis patients, proposed by Block and Port (20) and the phosphate recommendations of current guidelines (21), which are extremely difficult to achieve to begin with, may not provide optimal cardiovascular protection. In the past, a paper by the Hammersmith hospital group (22), which failed to receive the attention that it deserved, had provided documentation in a small series of nonrenal patients with coronary heart disease that serum phosphate concentrations were positively and significantly (P 0.003) correlated with the severity of coronary artery disease and were correlated with the severity of stenoses and presence of occlusions (22). The above paper of Tonelli et al., a prespecified post hoc analysis of the Cardiac Arrhythmia Suppression Trial (CAST), extends this observation. In 4127 fasting patients, the authors documented that higher levels of serum phosphate within the normal range are associated with