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.: Circulation: 112: 2627-2633, 2005 : Journal of the American Society of Nephrology

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Nephrology beyond JASN

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. Circulation 112

2627-2633, 2005

Tonelli, M.; Sacks, F.; Pfeffer, M.; Gao, Z.H.; Curhan, G. for the Cholesterol and Recurrent Events (CARE) Trial Investigators

Journal of the American Society of Nephrology 17(8):p 2077-2085, August 2006. | DOI: 10.1681/ASN.2006060608
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It 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 (Mo[Combining Diaeresis]nckeberg 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 (1114) 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 ( 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 more adverse outcomes. In the CAST study, patients with a history of myocardial infarction had been randomly assigned to receive either Pravastatin 40 mg/d or placebo. They were followed for approximately 60 mo, during which time 375 patients died. The median serum phosphate concentration was 3.3 mg/dl, and only 5.8% had fasting serum phosphate concentrations outside the normal range (2.5 to 4.5 mg/dl).

There was a direct association between GFR and serum phosphate concentrations: The relation was inverse when GFR was <60 ml/min and positive when GFR was >60 ml/min. The observed relationship between serum phosphate and outcome was not an artifact of low GFR, however, because the GFR was similar in all quartiles of serum phosphate, and the relation between phosphate and outcome persisted when individuals with a GFR <60 ml/min were excluded.

The serum phosphate concentration at baseline was significantly associated with all-cause death even when adjusted for numerous confounders. The calcium × phosphate product was not independently associated with adverse outcome. If the serum phosphate concentration was higher by 1 mg/dl, then the hazard ratio was higher by 27% (hazard ratio 1.27; 95% confidence interval 1.02 to 1.58), comparable to the increase of risk that Block et al. (9) had found in dialyzed patients! Furthermore, a graded independent relation existed between serum phosphate and death across the entire spectrum of serum phosphate concentrations (P = 0.03 for trend). Apart from all-cause mortality, high serum phosphate concentrations (> 3.5 mg/dl) also were associated with a higher risk for de novo heart failure and myocardial infarction but not a higher risk for stroke. Residual confounding always is a concern in such post hoc analyses of patients who are not randomly assigned according to the question asked in the analysis, but the consistency of the results is remarkable. As a cautionary note, one must be aware that the results in this population with high cardiovascular risk cannot be extrapolated to the general population.

Fasting serum phosphate measurements are confounded easily by a number of factors, such as circadian rhythm, causing intraday differences of up to 30% (with a nadir in the late forenoon); habitual phosphate intake; phosphate leak from blood cells unless serum is separated within 2 h (I suspect that this also is the explanation for the highest serum phosphate value of 9.3 mg/dl in the CAST study); hemolysis; increase in P concentration in serum relative to plasma because of release from platelets; artifacts by clouding from hyperlipemia, and so forth. It well may be that the above relationship has been missed in past studies for such reasons. In the above study, blood was obtained under standardized conditions and measured in a central laboratory.

The finding raises the issue of the underlying mechanism. The authors speculate that because of the known role of phosphate in the control of vitamin D concentrations (23) and the effect of active vitamin D on renin activity (24) and cardiac function (25,26), changes in vitamin D metabolites well may explain the finding. This hypothesis is not unreasonable but is unproved in the absence of vitamin D measurements and does not exclude other explanations. For instance, as early as 1925, the effect of glucose on phosphate had been documented as well as the effect of insulin on phosphaturia and serum phosphate (27). In view of the roles of hyperinsulinemia and insulin resistance in the cardiovascular risk profile, this (and other) alternatives justify detailed pathomechanistic studies.

Finally, as a nephrologist, one is saddened by the reflection that even serum phosphate concentrations in the normal range are injurious to the nonrenal patient with coronary heart disease. How can we ever achieve “optimal” phosphate concentrations in the renal patient!

Eberhard Ritz:
Feature Editor

Address correspondence to: Prof. Eberhard Ritz, Department Internal Medicine, Division of Nephrology, Bergheimer Strasse 56a, D-69115 Heidelberg, Germany. Phone: 49-0-6221-601705 or 49-0-6221-189976; Fax: 49-0-6221-603302; E-mail: [email protected]


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