Lowering High-Normal Phosphate Levels Could Benefit Many, Studies Show

Knowledge of phosphate crystals such as those shown from a 19th century urological dictionary aided yesterday’s practitioners. Advanced understanding of phosphates’ role in health may change how today’s clinicians practice.

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Courtesy History and Special Collections for the Sciences, UCLA Louise M. Darling Biomedical Library.

Lowering serum phosphate levels may benefit three groups currently not often targeted for phosphate-lowering therapies, studies show. New dialysis patients, patients with early chronic kidney disease (CKD), and possibly even healthy individuals with no clinical evidence of cardiovascular or renal disease may all benefit from reducing their high-normal phosphate levels.

Taking phosphorus binders reduced the risk of death by 25 to 30 percent among dialysis patients in a study reported in the January 2009 Journal of the American Society of Nephrology. New dialysis patients with only modest or even no increase in their serum phosphate levels were among those who showed improved survival rates.

Two other reports suggest that high-normal phosphate levels may be tied to a marker of increased cardiovascular risk, not only in patients with moderate CKD but also in apparently healthy young adults.

Taken together, these studies suggest that phosphorus may be less of a bystander and more of an active player in kidney and cardiovascular health.

Phosphate Binders Lower Mortality in New Dialysis Patients

“A growing number of publications have suggested that abnormalities of phosphorus metabolism—specifically phosphorus overload—are risk factors for mortality,” said Myles Wolf, MD, of the University of Miami Miller School of Medicine in Miami, Fla. “As a result, many nephrologists believe that lowering serum phosphate levels can improve survival in patients with kidney disease, particularly those on dialysis. However, this therapeutic strategy has been largely based on opinion—no studies have been done to compare survival in dialysis patients receiving phosphate binders versus no treatment.”

To address this gap, Wolf and his colleagues compared mortality rates in two groups of new dialysis patients: 3555 patients who started on treatment with phosphorus binders during their first 90 days on dialysis and 5055 who did not. “This is the group we wanted to study, because if you wait until they’ve been on dialysis for a long time, just about everybody will develop a high serum phosphorus level leading most of them to be treated,” said Wolf. “With new dialysis patients, many will be treated and many will not—that’s because their serum phosphorus levels are not yet markedly elevated.”

During the first year on dialysis, patients treated with phosphate binders were at significantly lower risk of death—30 percent—than those not treated. When findings were adjusted for factors that would increase the likelihood of receiving phosphate binders, the protective effect was smaller but still significant at 25 percent.

“The survival benefit was independent of the baseline serum phosphorus level and extended even to patients who didn’t have high phosphorus levels at all,” said Wolf. “In other words, we found that there may be a beneficial effect in groups that currently are not routinely treated, suggesting that perhaps we should consider treating those patients as well.”

New Links to Vascular Calcification in CKD

Meanwhile, two studies in the February Journal of the American Society of Nephrology sought to determine whether the relationship between serum phosphate levels and cardiovascular risk might appear earlier in the course of kidney disease, or perhaps even in people with no evidence of renal or cardiovascular disease.

Both studies examined associations between serum phosphate levels and coronary artery calcification. Electron-beam or multidetector computed tomography was used to measure calcium in the coronary arteries. The coronary artery calcium (CAC) score, calculated using the Agatston method, provides an accurate indicator of atherosclerosis. The CAC score predicts the incidence of future cardiovascular events in dose-response fashion.

Researchers at the University of Washington measured serum phosphate levels and CAC in 439 patients with moderate CKD and no clinical cardiovascular disease, drawn from the Multi-Ethnic Study of Atherosclerosis. Serum phosphate concentrations were within the normal range—2.5 to 4.5 mg/dL—for 95 percent of patients. The goal was to assess the relationship between phosphate and CAC, focusing on high-normal phosphate levels.

“High serum phosphorus levels within the normal range have been associated with cardiovascular events and premature death in people with CKD,” said Bryan Kestenbaum, MD, a University of Washington nephrologist. “Experimental work suggests that phosphorus causes toxicity by promoting calcification of blood vessels.”

The group of patients with moderate CKD had high rates of vascular and valvular calcification. The overall prevalence of coronary artery calcification was 67 percent. Calcification was found in the descending thoracic aorta in 49 percent of patients, the aortic valve in 25 percent, and the mitral valve in 20 percent.

Coronary artery calcification was significantly related to serum phosphate level. For each 1 mg/dL increase in serum phosphate level, there was a 21 percent increase in coronary artery calcification, after adjusting for demographic factors and estimated kidney function. The same phosphate increment was linked to a 33 percent increase in thoracic aorta calcification, a 25 percent increase in aortic valve calcification, and a 62 percent increase in mitral valve calcification.

The association between high-normal phosphate level and CAC was unchanged after adjusting for cardiovascular risk factors or dietary intake. It was stronger among younger patients and among those with better kidney function.

The link between phosphate and CAC was also unaffected by adjustment for 1,25-dihydroxyvitamin D and serum parathyroid hormone levels, both of which could affect phosphate concentration.

Phosphates Also Linked to Coronary Artery Calcium in Healthy People

The link between high-normal phosphate levels and vascular calcification may extend to healthy people without kidney disease, according to Robert N. Foley, MB, of the United States Renal Data System and the University of Minnesota.

“Among apparently healthy young adults without kidney problems, there is an association between phosphate levels in the normal range and the occurrence of cardiovascular calcification 15 years later,” Foley said.

Foley and his colleagues analyzed the relationship between phosphate levels and atherosclerosis in 3015 healthy young adults, mean age 25 years, from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Almost all those studied were free of kidney and cardiovascular disease when they underwent measurement of serum phosphate level as part of their baseline evaluation.

When these individuals were re-evaluated 15 years later, coronary artery calcification was rated minimal in 3.2 percent of study participants, mild in 4.8 percent, moderate in 1.1 percent, and severe in 0.5 percent. When other risk factors were not taken into account, higher phosphate levels were associated with a lower rate of coronary artery calcification.

But when the findings were adjusted for other cardiovascular risk factors, the relationship between high-normal phosphate levels and CAC became significant. Higher phosphate levels were linked to African-American race, family history of myocardial infarction, and elevated triglycerides. For healthy adults with the highest phosphate levels (greater than 3.9 mg/dL), the risk of coronary artery calcification was increased by 52 percent, compared with those at the lowest level (3.3 mg/dL or less).

High-normal phosphate levels were also linked to some factors considered protective for cardiovascular disease, including younger age, female sex, lower body mass index, higher high-density lipoprotein cholesterol, and lower systolic blood pressure.

The relationship between phosphate and cardiovascular risk is complex. “It’s really a mixed bag of some good risk factors and some bad, and you have to take that into account when you look at the association between phosphate and CAC,” said Foley. “High phosphate seems to go with some of the risk factors that you might call metabolic syndrome or syndrome X, but then it goes against other ones as well.”

Such risk factor duality was also uncovered in a recent report from the Framingham Offspring Study. “In our community-based sample, serum phosphate was positively associated with age, female sex, high-sensitivity C-reactive protein, estimated glomerular filtration rate, and total/high-density lipoprotein cholesterol ratio, but it was inversely related to body mass index and systolic blood pressure,” said Vasan S. Ramachandran, MD, of Boston University and the Framingham Heart Study.

So far, it is unknown how these apparently diverse mechanisms work to increase cardiovascular risk in people with high-normal phosphate. “Multiple mechanisms might be operating, partly though metabolic syndrome, or partly through another mechanism tied to phosphate that we don’t really understand,” Foley said.

Lowering Phosphate Levels in CKD … and Before?

The newly discovered links between serum phosphate and CAC suggest a possible benefit of treatments to lower phosphate levels. While there are about 400,000 dialysis patients in the United States, there are estimated to be more than 15 million patients with less severe CKD.

“These patients are typically not considered for treatment with phosphorus binders, which are approved by the FDA only for use on dialysis,” Wolf said. “If further studies could demonstrate a similar survival benefit of binders in patients with pre-dialysis CKD, the results could have a significant impact on public health.”

Interventions to lower the cardiovascular risk associated with high phosphate levels already exist. Wolf said current dietary phosphate binders are “perfectly acceptable choices” for use in CKD patients.

Still, it is too early to infer that phosphorus is a cause of poor outcome in the CKD or the general population, said Kamyar Kalantar-Zadeh, MD, PhD, a nephrologist at UCLA David Geffen School of Medicine and Harbor-UCLA Medical Center.

“High-normal serum phosphorus, in addition to reflecting reduced kidney function, may be a surrogate of unhealthy lifestyle including unhealthy diet,” he said. “Similarly, the observation that intake of any phosphorus binder in dialysis patients is associated with greater survival compared to no binder could be due to confounding by unknown factors—for example, having received better care or being more compliant with medical care. The ultimate approach to remove unknown confounders is randomization in well designed controlled trials.”

Kestenbaum agreed: “It is premature to infer that phosphorus itself is the cause of cardiovascular events and especially premature to infer that lowering phosphorus will beneficially impact health.”

The findings in healthy adults also remain to be confirmed. However, even if the relationship isn’t a causal one, high-normal phosphate might become an important addition to cardiovascular risk screening.

Said Foley: “Even if you don’t have a single mechanism tying it all together, you certainly have a group of people at higher risk, after you take into account their other classic risk factors. At least you have another high-risk group that might benefit from intervention.”

Disclosures:

Prof. Adeney, principal investigator of the University of Washington research, has received consulting fees from Genzyme, Abbott, and Shire, Inc., and has received grant support from Amgen, Inc.

Dr. Wolf has received research support from Shire and Honoraria from Genzyme and Ineos.

Dr. Foley’s study was performed as a deliverable under a National Institutes of Health contract. Dr. Foley has received consulting fees from Amgen; other authors have also received consulting fees from Amgen or for work on Amgen-sponsored clinical trials.