Serum Phosphorus Levels Associate with Coronary Atherosclerosis in Young Adults
Robert N. Foley*,,
Allan J. Collins*,,
Charles A. Herzog,,
Areef Ishani and
Philip A. Kalra
Cardiovascular Special Studies Center, * United States Renal Data System, and University of Minnesota, Minneapolis, Minnesota; and Department of Renal Medicine, Salford Royal Hospital, Salford, United Kingdom
Correspondence: Dr. Robert N. Foley, US Renal Data System, 914 South 8th Street, Suite S-406, Minneapolis, MN 55404. Phone: 612-347-5979; Fax: 612-347-5980; E-mail: rfoley{at}usrds.org
Received for publication February 6, 2008.
Accepted for publication August 12, 2008.
Phosphorus levels correlate with atherosclerosis in both animalmodels and humans with advanced chronic kidney disease, butwhether this relationship exists among individuals with normalkidney function is unknown. This study aimed to determine whetheran association exists between phosphorus levels and coronaryartery calcium levels in a community-based cohort of 3015 healthyyoung adults in the prospective Coronary Artery Risk Developmentin Young Adults (CARDIA) study. Phosphorus levels were measuredat baseline, and presence of coronary artery calcium was assessedby computed tomography 15 yr later. Mean age at study inceptionwas 25.2 yr, and the mean levels of phosphorus and calcium were3.6 and 9.5 mg/dl, respectively. Only 0.2% of participants hadestimated GFR <60 ml/min per 1.73 m2. Phosphorus levels wereassociated with coronary artery calcium in unadjusted models.In multivariate models, however, phosphorus levels were significantlyassociated with the category of coronary artery calcium level.In conclusion, higher serum phosphorus levels, even within thenormal range, may be a risk factor for coronary artery atherosclerosisin healthy young adults.
Experimental studies have suggested that higher phosphorus levelscan cause vascular disease. For example, hyperphosphatemia,arteriosclerosis, and vascular calcification are cardinal featuresof fibroblast growth factor 23 gene 2 and Klotho gene 3 knockoutmodels, phenotypic characteristics that can be altered in Klothonull mice with a low-phosphorus diet.1–3 Current knowledgeremains incomplete, but, clearly, prevention of vascular calcificationis a dynamic, multifaceted process. Endogenous inhibitors ofcrystal formation and of osteogenic differentiation of vascularsmooth muscle cells have been identified, including matrix Glaprotein and fetuin-A; experimental studies have shown that exposureof experimental animals to high ambient phosphorus is followedby expression of an osteogenic phenotype in vascular smoothmuscle cells and by vascular calcification.4–8 Other potentialmechanisms linking rising phosphorus levels to vascular diseaseinclude inhibition of 1,25-dihydroxyvitamin D synthesis andincreased parathyroid hormone (PTH) production.9–11
Several observational studies of dialysis populations have shownthat high serum phosphorus levels are antecedent associationsof mortality and cardiovascular events, independent of calciumand PTH levels.12–15 If high phosphorus levels truly causevascular disease, then it seems natural to hypothesize thatthis relationship also applies within the normal range of phosphoruslevels, even in the presence of normal kidney function. Coronaryartery calcium levels are believed to reflect accurately theoverall burden of atherosclerosis and to exhibit dosage–responserelationships with the incidence of future cardiovascular events.16–26Studying phosphorous levels and coronary artery calcificationcan potentially reveal the mechanisms by which serum phosphorousmay lead to cardiovascular disease and, perhaps, suggest theexistence of novel mechanisms for developing atherosclerosis.The major objective of this study was to determine whether anassociation exists between phosphorus levels and coronary arterycalcium levels in community-dwelling young adults.
The Coronary Artery Risk Development in Young Adults (CARDIA)study is a prospective, multicenter, observational study ofcardiovascular disease in young adults.27 Initially, 5115 participants,aged 18 to 30 yr, were studied in 1985 and 1986 in Birmingham,AL; Chicago, IL; Minneapolis, MN; and Oakland, CA. Of these,3671 (71.8%) returned for the year 15 examination; 3042 (of3671) participants had coronary artery calcium estimated bycomputer tomography (CT), and serum phosphorus levels were availablefor 3015 (of 3042) participants. Table 1 shows the baselinecharacteristics of these 3015 participants at the first studyvisit. The mean age of the population was 25.2 yr, 54.4% werewomen, and 45.0% were black. Mean phosphorus level was 3.6 mg/dl,calcium level was 9.5 mg/dl, and calcium-phosphorus productwas 26.3 mg2/dl2. Mean estimated GFR (eGFR) was 116.6 ml/minper 1.73 m2, and values for 0.2% of participants were <60ml/min per 1.73 m2.
Table 1. Baseline characteristics at study inception (n = 3015)a
Multivariate associations of serum phosphorus, calcium, andcalcium-phosphorus product are shown in Table 2. The associationsof serum phosphorus included younger age, female gender, blackrace, family history of myocardial infarction (MI), lower bodymass index (BMI), HDL cholesterol, triglycerides, lower systolicBP (SBP), diastolic BP (DBP), exercise intensity score, lowercarbohydrate intake, and use of cardiac medications. Calciumlevels were associated with younger age, male gender, blackrace, <12 yr of education, self-reported hypertension, lowerBMI, LDL cholesterol, HDL cholesterol, triglycerides, glucose,DBP, and lower eGFR values. Calcium-phosphorus product levelswere associated with younger age, black race, lower SBP, andhigher DBP.
Table 2. Associations of phosphorus, calcium, and calcium-phosphorus product levels at study inceptiona
At year 15, 3.2% of the study population had minimal coronaryartery calcification, 4.8% had mild calcification, 1.1% hadmoderate calcification, and 0.5% had severe calcification (Figure 1).Table 3 summarizes associations between phosphorus levels atbaseline and coronary artery calcium categorized as 0, >0to <10, 10 to 100, 101 to 300, or >300 units. In unadjustedmodels, higher phosphorus levels, as a continuous variable,were associated with lower likelihood of coronary artery calcification(odds ratio [OR] 0.87 per 0.5 mg/dl; P = 0.0332). In multivariatemodels, higher phosphorus levels were associated with greaterlikelihood of higher calcium level categories (adjusted OR 1.17per 0.5 mg/dl; P = 0.0331); considered as quartiles, phosphorusvalues in the fourth quartile (>3.9 mg/dl) were associatedwith an adjusted OR of 1.52 (95% confidence interval 1.04 to2.22) compared with values in the first quartile (3.3 mg/dl).Table 3 shows that findings were broadly similar when coronaryartery calcium was analyzed as binary variables, defined bycalcium scores >0, 10, and 100 units.
Table 3. Associations between serum phosphorus at baseline and coronary artery calcium at year 15a
Multivariate P-spline plot analysis (Figure 2) suggested thatphosphorus levels >3.9 mg/dl were associated with greaterlikelihood of coronary artery calcium 100. As shown in Figure 3,serum calcium and calcium-phosphorus product levels had no associationwith coronary artery calcification. Figure 3 also shows thatassociations between coronary artery calcium and phosphorus,calcium, and calcium-phosphorus product were very similar whenindividual with eGFR <60 ml/min per 1.73 m2 were excluded.
Figure 3. Multivariate associations of coronary artery calcification severity and quartiles of phosphorus, calcium, and calcium-phosphorus product. (Top) Overall population. (Bottom) Population with eGFR 60 ml/min per 1.73 m2. Adjusted for age, gender, race, hypertension, diabetes, education, smoking, family history of MI, BMI, LDL cholesterol, HDL cholesterol, triglycerides, glucose, SBP, and eGFR.
We found that serum phosphorus levels in young adults showeda complex relationship with classic cardiovascular risk factors,including associations with younger age, female gender, blackrace, family history of MI, low BMI, HDL cholesterol, triglycerides,and lower SBP. Although phosphorus levels, especially levels>3.9 mg/dl, were associated with coronary artery calciumlevels, this association was evident only in multivariate models.
To date, most observational data examining the association betweenphosphorus levels and cardiovascular disease have come frompopulations with advanced chronic kidney disease (CKD). Thesestudies have shown consistent associations between abnormalphosphorus levels and cardiovascular outcomes; in contrast,associations with calcium levels and PTH levels have been inconsistentin the same studies.12–15 These findings have been extendedto phosphorus levels within the normal range by a retrospectiveanalysis of the Cholesterol and Recurrent Events (CARE) trialamong individuals with previous MI.28
Few studies have examined associations between phosphorus levelsand cardiovascular disease in community-dwelling adults withoutovert kidney disease. In this regard, a recent report from participantsin the Framingham Offspring Study was noteworthy. In this prospective,observational study, the average age of the study populationwas approximately 20 yr older than in the CARDIA study. Severalassociations of higher phosphorus levels mirrored the findingsin our study. For example, associations of higher phosphoruslevels included female gender, lower BP, and lower BMI. Duringa mean follow-up of 16.1 yr, 524 incident cardiovascular eventswere observed; when adjustment was made for classic cardiovascularrisk factors, GFR, hemoglobin, serum albumin, proteinuria, andC-reactive protein levels, serum phosphorus was associated withthese events in a continuous manner, and phosphorus levels 3.5mg/dl were associated with an adjusted hazard ratio 1.55 timeslevels <2.9 mg/dl.29
Because ours was a nonexperimental study, determining whetherthe association between phosphorus levels and coronary calcificationis a true phenomenon or the magnitude of residual confoundingis impossible. Similarly, the relative contributions of geneticand environmental factors to the associations remain speculative.The associations between phosphorus levels and other cardiovascularrisk factors were notable and seemed to be qualitatively differentfrom classical cardiovascular risk factors, in the sense thathigher phosphorus levels were associated with some seeminglyprotective factors (younger age, female gender, lower BMI, higherHDL cholesterol, and lower SBP) and other factors that mightbe considered to increase cardiovascular risk (black race, familyhistory of MI, and higher triglycerides). This duality may accountfor the observation that associations between phosphorus levelsand coronary artery calcification were more apparent in adjustedthan unadjusted analyses. Interestingly, a report from the FraminghamOffspring Study showed a similar pattern of risk factor duality;this unusual risk factor profile suggests novel mechanisms forcardiovascular disease that may be worth exploring using experimentalmethods.29
Our study has several strengths. The study population was relativelylarge, and the interval between putative risk factor and outcomeassessments was long. A population of young adults was studied,which should be useful for identifying earlier stage, subclinicalcoronary artery disease. The candidate risk factor seems tobe novel, has little overlap with classic treatable risk factors,and should be modifiable. Intervention trials targeting phosphorus,vitamin D metabolism, and PTH levels are already under way amongpatients with CKD.30
Unlike many cardiovascular risk factors uncovered in observationalstudies, potential interventions that can address some of thehypotheses suggested by this study may already exist. Our findingssuggest that extending these trials to high-risk individualswithout CKD in the general population has the potential to improvepublic health. Quite apart from the underlying determinants,the associations seen in this study suggest that high phosphoruslevels might help to identify young adults for whom modifiablerisk factors might be screened and managed more aggressively.
The limitations of our study include its nonexperimental design.In addition, PTH and vitamin D levels were not available, sothe hypothesis that our findings reflect phosphorus-inducedabnormalities of these axes cannot be refuted. Although inflammatorymarkers and urinary albumin-creatinine ratios were not availableat baseline, adjusting for C-reactive protein and urinary albumin-creatinineratios at year 15 had no effect on the associations betweenserum phosphorus and coronary calcium levels. Sample size issuesmay also be relevant. Approximately 10% of the study populationhad coronary calcification. To detect a 20% difference betweentwo groups with of 0.05 and power of 0.90, the total samplesize requirement would exceed 10,468. Finally, whereas the designof CARDIA enables enrollment of young adults representativeof the overall population, our study was somewhat self-selected,because it was limited to participants who attended the year15 examination.
Study Population
The CARDIA study used a random sampling scheme to ensure thatpopulation-based samples were balanced within centers by age,race, gender, and education level. The Chicago and Minneapoliscenters used census tract information to achieve the populationbalance mandated in the original request for proposals, whichrequired that the study should have approximately equal proportionsof men, women, and black and white Americans. The Oakland centerselected study participants from the Kaiser-Permanente healthplan membership, and the Birmingham center used telephone exchangesto sample the entire city population. One household member perhousehold was randomly selected and assessed for the study eligibilitycriteria: Aged between 18 and 30 yr with a permanent addressin the target area. Follow-up examinations were performed atyears 2, 5, 7, 10, and 15.
Measurements
Gender, race, education, cigarette smoking, previous hypertensionand diabetes, and parental history of MI were ascertained bystructured interviews and self-administered questionnaires.Participants were instructed to fast for 12 h and to avoid heavyphysical activity and smoking for 2 h before the examination.Sitting BP was measured in the right arm after 5 min of rest.First- and fifth-phase Korotkoff sounds were recorded threetimes at 1-min intervals with a random zero sphygmomanometer(WA Baum Company, Copiague, NY), and the average of the secondand third measurements was used in the analyses presented here.Phosphorus, calcium, albumin, and creatinine levels were measuredwith a SMAC 12 continuous-flow analyzer (Technicon InstrumentsCorp., Tarrytown, NY) at American BioScience Laboratories (nowSmithKline Beecham, King of Prussia, PA).
Data from the Third National Health and Nutrition ExaminationSurvey (1988 to 1992) were used to align creatinine levels fromthe first CARDIA examination to those expected on the basisof the age, gender, and racial characteristics of the CARDIAparticipants. Thus, 0.23 mg/dl was subtracted from creatininelevels for CARDIA participants, and the reexpressed Modificationof Diet in Renal Disease formula was used to estimate GFR. Calciumlevels were corrected for the presence of serum albumin levels<4 g/dl with the following formula: Corrected calcium (mg/dl)= observed calcium (mg/dl) + 0.8 (4 – serum albumin [mg/dl]).31Enzymatic methods were used to measure HDL cholesterol and triglycerides(University of Washington Northwest Lipid Research ClinicalLaboratory, Seattle, WA), and the Friedewald equation was usedto calculate LDL cholesterol levels. Glucose levels were measuredby the hexokinase-ultraviolet method at Linco (now Millipore,Billerica, MA).
The CARDIA diet history was an interviewer-administered instrumentbased on 24-h recall.32,33 The CARDIA activity instrument wasan interviewer-administered self-report that assessed frequencyof participation over the previous 12 mo in eight vigorous-intensityand five moderate-intensity leisure activities; a score of 200exercise units was equivalent to exercise performed at six metabolicequivalents for 2 h/wk for 11 mo of the year.34,35 Both instrumentshave been found to have good validity and reliability.
An Imatron (South San Francisco, CA) C-150 electron beam scanner,a GE (Fairfield, CT) Lightspeed multidetector scanner, or aSiemens (Berlin, Germany) VZ multidetector scanner was usedfor CT scanning. Two scans were performed on each participant,with a hydroxyapatite phantom used to standardize image brightness.Scans were electrocardiogram gated at 80% (Imatron) or 50% (GEand Siemens) of the R-R interval, with a slice thickness of3 mm (Imatron) or 2.5 mm (GE and Siemens), and completed within100 (Imatron), 520 (GE), or 360 ms (Siemens). Image processingsoftware was used to identify potential calcific foci with atleast two adjacent pixels of area 1.87 mm2 and density >130Hounsfield units (HU). Total coronary calcium scores were calculatedby multiplying focus area by a coefficient ranging between 1and 4, based on the peak density in the focus (1 = 131 to 200HU, 2 = 201 to 300 HU, 3 = 301 to 400 HU, and 4 = 401 HU).36Scan readers were blinded to participant characteristics andto image data from the other CT scan performed on each participant.Reproducibility rates within and between scan readers were high.37
Statistical Analysis
The analysis was restricted to individuals with CT scans atyear 15. Participants with CT scans were older than those withoutscans (25.2 versus 24.3 yr), more likely to be white (54.8 versus39.1%), and more likely to have completed a high school education(92.8 versus 86.1%). P < 0.05 was considered statisticallysignificant. Linear regression was used to quantify associationsof phosphorus, calcium, and calcium-phosphorus product levels.To address the hypothesis that serum phosphorus levels at baselinewere associated with coronary artery calcium burden 15 yr later,we treated coronary artery calcium level as an ordinal variabledefined by the categories 0 (no calcification), 1 to <10(minimal calcification), 10 to 100 (mild calcification), 101to 300 (moderate calcification), and >300 (severe calcification),17,38–40and we used ordinal logistic regression to quantify parameterestimates. We checked for statistical interactions between phosphorusand age, gender, and race in the multivariate analysis of coronarycalcification category and found none (P > 0.1 for all interactionstested). Binary logistic regression models were used to examineassociations between phosphorus levels and coronary artery calcium>0 (versus 0), 10 (versus <10), and 100 (versus <100).40Penalized smoothing splines (P-splines) were used for graphicaldepiction of the adjusted association between scores of 100and the range of phosphorus levels observed in this study.41,42We performed several sensitivity analyses. Thus, phosphorus-relatedfindings were similar when coronary artery calcium was treatedas a linear variable and when urinary albumin-creatinine ratiosmeasured at year 15 were included as covariates (C-reactiveprotein levels and urinary albumin-creatinine ratios were notmeasured at baseline).
SAS 9.1 (SAS Institute, Cary, NC) was used for all analyseswith the following exceptions: We adjusted national parameterestimates from the Third National Health and Nutrition ExaminationSurvey for the sampling weights implicit in complex survey designsusing SUDAAN software (Research Triangle Institute, ResearchTriangle Park, NC) for complex sample surveys, and we used S-PLUS6.1 (Insightful Corp., Seattle, WA) for P-spline analysis.
R.N.F. has received consulting fees from Amgen and Genzyme.A.J.C. has received consulting fees from Amgen. C.A.H. has receivedconsulting fees as a member of the Executive Committee of theEVOLVE trial, an Amgen-sponsored clinical trial of cinacalcetHCl therapy in dialysis patients.
Acknowledgments
This study was performed as a deliverable under contracts HHSN267200715002Cand HHSN267200715003C (National Institute of Diabetes and Digestiveand Kidney Diseases, National Institutes of Health, Bethesda,MD).
We thank United States Renal Data System colleagues Beth Forrestfor regulatory assistance, Shane Nygaard for manuscript preparation,and Nan Booth, MSW, MPH, for manuscript editing.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Top
Abstract
Introduction
3.3 mg/dl). Table 3 shows that findings were broadly similar when coronary artery calcium was analyzed as binary variables, defined by calcium scores >0, 10, and 100 units. 
100. As shown in Figure 3, serum calcium and calcium-phosphorus product levels had no association with coronary artery calcification. Figure 3 also shows that associations between coronary artery calcium and phosphorus, calcium, and calcium-phosphorus product were very similar when individual with eGFR <60 ml/min per 1.73 m2 were excluded. 
of 0.05 and power of 0.90, the total sample size requirement would exceed 10,468. Finally, whereas the design of CARDIA enables enrollment of young adults representative of the overall population, our study was somewhat self-selected, because it was limited to participants who attended the year 15 examination. 
