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Phosphorus Comes of Age as a Cardiovascular Risk Factor

Phosphorus Comes of Age as a Cardiovascular Risk Factor Phosphorus is an important biochemical entity.1 For example, Biochemistry 101 tells us that adenosine triphosphate is the molecular currency of intracellular energy transfer; cyclic adenosine monophosphate and cyclic guanosine monophosphate are second messengers regulating many biochemical processes; addition and removal of phosphorus moieties change the catalytic activity of many enzymes; the backbones of DNA and RNA are composed of phosphorus bound to sugars; 2,3-diphosphoglycerate is a critical regulator of oxygen dissociation from hemoglobin; phosphorus is a component of important coenzymes, like nicotinamide adenine dinucleotide; and phosphorus is an integral component of structural molecules like phosphoproteins and phospholipids. It would seem, therefore, that regulation of bodily phosphorus content should be an important homeostatic need, and the relatively narrow range of physiological serum phosphorus concentrations supports this contention. Phosphorus is ubiquitous in typical Western diets. In the short term, serum phosphorus concentrations are determined by dietary intake, gastrointestinal absorption, shifts between the intracellular and extracellular spaces, and urinary excretion rates. Long-term balance requires that urinary phosphorus excretion equals phosphorus absorption from the gastrointestinal tract. Phosphorus is freely filtered by the glomerulus, and a large proportion is then reabsorbed in the renal tubules, a process that is modulated by ambient parathyroid hormone (PTH) levels. In this simple model, isolated loss of tubular function or glomerular function should lead to hypophosphatemia in the first instance and hyperphosphatemia in the second. Although tubular gain-of-function mutations can lead to hyperphosphatemia, these are thought to be very rare. It is a widely held belief, then, that most instances of hyperphosphatemia are caused by inadequate glomerular function. Bone mineralization aside, phosphorus was a comparatively unexciting entity in the nephrology world until recently. For example, although extracellular calcium deposition typically occurs along with phosphorus deposition in end-stage renal disease, terms like phosphication are nonexistent. In contrast, the term calcification is used almost universally to describe the biological phenomenon of calcium-phosphorus deposition. A traditional scheme tying abnormal mineral balance to adverse events in late-stage kidney disease can be described as follows: glomerular disease leads to hyperphosphatemia, followed by precipitation of calcium and phosphorus from solution and hypocalcemia; this hypocalcemia (often exacerbated by failure to produce active 1,25-dihydroxyvitamin D3 by the failing kidneys) leads to hyperparathyroidism. In this simple scheme, where PTH level is the final mediator of adverse pathophysiological effects, one would predict that the magnitude of consequent clinical adversity would be as follows: abnormal PTH level first, abnormal calcium level second, and abnormal phosphorus level third. Several observational studies have been performed in populations of patients who are undergoing dialysis and have addressed the associations of these related entities with mortality and cardiovascular events. The findings have been relatively homogenous in one sense, with abnormal phosphorus levels consistently associated with adverse outcomes, in contrast with inconsistent or nonmonotonic observations for calcium and PTH values.2-5 These associations challenge the validity of the mechanism outlined herein, in which PTH level is the sole final arbiter of adverse outcomes. Although current understanding is just dawning, it is clear that the process of extracellular calcium-phosphorus deposition is biologically complex and dynamic. In particular, prevention of vascular calcification seems to be actively regulated by mechanisms that include endogenous inhibitors of osteogenic differentiation of vascular smooth muscle cells and crystal formation, like matrix Gla protein and fetuin-A; experimental studies suggest that abnormally high phosphorus levels tilt the balance of these processes toward an osteogenic phenotype and excessive mineralization of the vasculature.6-9 Although it remains to be determined how the latter phenotype leads to adverse events in humans, knockout models in experimental animals have provided insights. Matrix Gla protein knockout mice, for example, develop extensive aortic calcification and die prematurely of aortic rupture.10 A dose-dependent relationship between vascular disease and phosphorus levels residing in the abnormal range seen with late-stage kidney disease naturally leads one to speculate that this relationship also applies within the reference range of phosphorus levels, and by implication, in those with normal kidney function. In this regard, the study of Dhingra et al11 in this issue of the ARCHIVES should excite nephrologists (because it adds a nonnephrological context to a widely held but unproven belief) and to nonnephrologists (because it introduces a new cardiovascular risk factor that may be susceptible to intervention). This study followed Framingham Offspring participants for a mean duration of follow-up of 16.1 years and found substantial, dose-dependent associations between serum phosphorus levels and cardiovascular outcomes, even within the conventional reference range. Of note, subjects with creatinine-based glomerular filtration rates (GFRs) less than 60 mL/min per 1.73 m2 or preexisting cardiovascular disease were excluded in the main analysis. The study is noteworthy for several reasons, including the community setting, the standardization of exposure assessment, the ability to adjust for classic cardiovascular risk factors, and the precision of outcome ascertainment. Not even the most exemplary of epidemiological studies, however, can prove causation, and no such claims are made in this study.11 The association between phosphorus levels and cardiovascular events was quite clear-cut. Conventional wisdom suggests that inadequate renal function is a prerequisite for developing hyperphosphatemia. When this condition is satisfied, dietary phosphorus intake, 1,25-dihydroxyvitamin D3 levels, and PTH levels are considered to be important determinants of serum levels; although the unavailability of the last 3 parameters does not invalidate the findings of the study, it may add a degree of uncertainty. To appraise this study, perhaps the single most salient issue to consider is “How precise were the renal function measurements and could they have been biased?” The study used an estimate of GFR entirely dependent on serum creatinine level, age, sex, and race, derived from a population with overt kidney disease in whom mean GFRs were less than 40 mL/min per 1.73 m2,12,13 (a level seen in fewer than 1% of 100 US adults). Although the estimating formula may be accurate with GFR levels in this abnormally low range, it has never been validated in representative, community-dwelling individuals, and there is emerging concern that overestimation bias occurs as the GFR enters the reference range. In this regard, it is interesting that a previous study14 involving the parents of the current study participants (the Framingham Heart Study participants) showed that the formula used in the current study produced prevalence estimates of GFR less than 60 that were 50% higher in females, without apparent explanation. One cannot help wondering whether the limitations of this formula partly explain 2 unexpected findings in the study by Dhingra et al11: the observation that 67.6% of individuals with phosphorus levels in the fourth quartile were female and the highly unexpected association between rising quartiles of both GFR and phosphorus levels. In a related issue, the patients were observed from 1979 to 1982, and urinary protein estimates were semiquantitative. Although this and other issues may need clarification (including the independence of the findings from PTH levels, dietary phosphorus intake, and the relations between all these plus true GFR and urinary protein excretion rates), the study by Dhingra et al11 adds urgency to the need for future prospective research. If one assumes that high phosphorus levels truly cause cardiovascular disease, unraveling the underlying mechanisms will be an exciting challenge, as will the evaluation of interventions. Intervention trials addressing the hypothesis that normalizing calcium-phosphorus balance improves cardiovascular outcomes in late-stage chronic kidney disease have begun. The proximate targets for these trials include gastrointestinal tract phosphorus absorption, PTH levels, and abnormal vitamin D metabolism.15 Unlike many “novel” cardiovascular risk factors discovered in community-based studies, several potential interventions suitable for controlled trials may already exist. Correspondence: Dr Foley, US Renal Data System Coordinating Center, Minneapolis Medical Research Foundation, 914 S Eighth St, Suite D-253, Minneapolis, MN 55404 (RFoley@usrds.org). Financial Disclosure: None reported. References 1. Stryer L Biochemistry. 4th ed. New York, NY Lubert Stryer1995; 2. Block GAHulbert-Shearon TELevin NWPort FK Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998;31607- 617PubMedGoogle ScholarCrossref 3. Ganesh SKStack AGLevin NWHulbert-Shearon TPort FK Association of elevated serum PO4, Ca × PO4 product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;122131- 2138PubMedGoogle Scholar 4. Stevens LADjurdjev OCardew SCameron ECLevin A Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes. J Am Soc Nephrol 2004;15770- 779PubMedGoogle ScholarCrossref 5. Slinin YFoley RNCollins AJ Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol 2005;161788- 1793PubMedGoogle ScholarCrossref 6. Jono SMcKee MDMurry CE et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000;87E10- E17PubMedGoogle ScholarCrossref 7. Steitz SASpeer MYCuringa G et al. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 2001;891147- 1154PubMedGoogle ScholarCrossref 8. Wada TMcKee MDSteitz SGiachelli CM Calcification of vascular smooth muscle cell cultures: inhibition by osteopontin. Circ Res 1999;84166- 178PubMedGoogle ScholarCrossref 9. Chen NXO'Neill KDDuan DMoe SM Phosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells. Kidney Int 2002;621724- 1731PubMedGoogle ScholarCrossref 10. Luo GDucy PMcKee MD et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997;38678- 81PubMedGoogle ScholarCrossref 11. Dhingra RSullivan LMFox CS et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 2007;167879- 885Google ScholarCrossref 12. Klahr SLevey ASBeck GJ et al. Modification of Diet in Renal Disease Study Group, The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 1994;330877- 884PubMedGoogle ScholarCrossref 13. Levey ASBosch JPLewis JBGreene TRogers NRoth DModification of Diet in Renal Disease Study Group, A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130461- 470PubMedGoogle ScholarCrossref 14. Fox CSLarson MGLeip EPCulleton BWilson PWLevy D Predictors of new-onset kidney disease in a community-based population. JAMA 2004;291844- 850PubMedGoogle ScholarCrossref 15. Qunibi WY Reducing the burden of cardiovascular calcification in patients with chronic kidney disease. J Am Soc Nephrol 2005;16 ((suppl 2)) S95- S102PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Phosphorus Comes of Age as a Cardiovascular Risk Factor

Foley, Robert N.
Archives of Internal Medicine , Volume 167 (9) – May 14, 2007
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References (15)

Publisher
American Medical Association
Copyright
Copyright © 2007 American Medical Association. All Rights Reserved.
ISSN
0003-9926
DOI
10.1001/archinte.167.9.873
pmid
17502525
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Abstract

Phosphorus is an important biochemical entity.1 For example, Biochemistry 101 tells us that adenosine triphosphate is the molecular currency of intracellular energy transfer; cyclic adenosine monophosphate and cyclic guanosine monophosphate are second messengers regulating many biochemical processes; addition and removal of phosphorus moieties change the catalytic activity of many enzymes; the backbones of DNA and RNA are composed of phosphorus bound to sugars; 2,3-diphosphoglycerate is a critical regulator of oxygen dissociation from hemoglobin; phosphorus is a component of important coenzymes, like nicotinamide adenine dinucleotide; and phosphorus is an integral component of structural molecules like phosphoproteins and phospholipids. It would seem, therefore, that regulation of bodily phosphorus content should be an important homeostatic need, and the relatively narrow range of physiological serum phosphorus concentrations supports this contention. Phosphorus is ubiquitous in typical Western diets. In the short term, serum phosphorus concentrations are determined by dietary intake, gastrointestinal absorption, shifts between the intracellular and extracellular spaces, and urinary excretion rates. Long-term balance requires that urinary phosphorus excretion equals phosphorus absorption from the gastrointestinal tract. Phosphorus is freely filtered by the glomerulus, and a large proportion is then reabsorbed in the renal tubules, a process that is modulated by ambient parathyroid hormone (PTH) levels. In this simple model, isolated loss of tubular function or glomerular function should lead to hypophosphatemia in the first instance and hyperphosphatemia in the second. Although tubular gain-of-function mutations can lead to hyperphosphatemia, these are thought to be very rare. It is a widely held belief, then, that most instances of hyperphosphatemia are caused by inadequate glomerular function. Bone mineralization aside, phosphorus was a comparatively unexciting entity in the nephrology world until recently. For example, although extracellular calcium deposition typically occurs along with phosphorus deposition in end-stage renal disease, terms like phosphication are nonexistent. In contrast, the term calcification is used almost universally to describe the biological phenomenon of calcium-phosphorus deposition. A traditional scheme tying abnormal mineral balance to adverse events in late-stage kidney disease can be described as follows: glomerular disease leads to hyperphosphatemia, followed by precipitation of calcium and phosphorus from solution and hypocalcemia; this hypocalcemia (often exacerbated by failure to produce active 1,25-dihydroxyvitamin D3 by the failing kidneys) leads to hyperparathyroidism. In this simple scheme, where PTH level is the final mediator of adverse pathophysiological effects, one would predict that the magnitude of consequent clinical adversity would be as follows: abnormal PTH level first, abnormal calcium level second, and abnormal phosphorus level third. Several observational studies have been performed in populations of patients who are undergoing dialysis and have addressed the associations of these related entities with mortality and cardiovascular events. The findings have been relatively homogenous in one sense, with abnormal phosphorus levels consistently associated with adverse outcomes, in contrast with inconsistent or nonmonotonic observations for calcium and PTH values.2-5 These associations challenge the validity of the mechanism outlined herein, in which PTH level is the sole final arbiter of adverse outcomes. Although current understanding is just dawning, it is clear that the process of extracellular calcium-phosphorus deposition is biologically complex and dynamic. In particular, prevention of vascular calcification seems to be actively regulated by mechanisms that include endogenous inhibitors of osteogenic differentiation of vascular smooth muscle cells and crystal formation, like matrix Gla protein and fetuin-A; experimental studies suggest that abnormally high phosphorus levels tilt the balance of these processes toward an osteogenic phenotype and excessive mineralization of the vasculature.6-9 Although it remains to be determined how the latter phenotype leads to adverse events in humans, knockout models in experimental animals have provided insights. Matrix Gla protein knockout mice, for example, develop extensive aortic calcification and die prematurely of aortic rupture.10 A dose-dependent relationship between vascular disease and phosphorus levels residing in the abnormal range seen with late-stage kidney disease naturally leads one to speculate that this relationship also applies within the reference range of phosphorus levels, and by implication, in those with normal kidney function. In this regard, the study of Dhingra et al11 in this issue of the ARCHIVES should excite nephrologists (because it adds a nonnephrological context to a widely held but unproven belief) and to nonnephrologists (because it introduces a new cardiovascular risk factor that may be susceptible to intervention). This study followed Framingham Offspring participants for a mean duration of follow-up of 16.1 years and found substantial, dose-dependent associations between serum phosphorus levels and cardiovascular outcomes, even within the conventional reference range. Of note, subjects with creatinine-based glomerular filtration rates (GFRs) less than 60 mL/min per 1.73 m2 or preexisting cardiovascular disease were excluded in the main analysis. The study is noteworthy for several reasons, including the community setting, the standardization of exposure assessment, the ability to adjust for classic cardiovascular risk factors, and the precision of outcome ascertainment. Not even the most exemplary of epidemiological studies, however, can prove causation, and no such claims are made in this study.11 The association between phosphorus levels and cardiovascular events was quite clear-cut. Conventional wisdom suggests that inadequate renal function is a prerequisite for developing hyperphosphatemia. When this condition is satisfied, dietary phosphorus intake, 1,25-dihydroxyvitamin D3 levels, and PTH levels are considered to be important determinants of serum levels; although the unavailability of the last 3 parameters does not invalidate the findings of the study, it may add a degree of uncertainty. To appraise this study, perhaps the single most salient issue to consider is “How precise were the renal function measurements and could they have been biased?” The study used an estimate of GFR entirely dependent on serum creatinine level, age, sex, and race, derived from a population with overt kidney disease in whom mean GFRs were less than 40 mL/min per 1.73 m2,12,13 (a level seen in fewer than 1% of 100 US adults). Although the estimating formula may be accurate with GFR levels in this abnormally low range, it has never been validated in representative, community-dwelling individuals, and there is emerging concern that overestimation bias occurs as the GFR enters the reference range. In this regard, it is interesting that a previous study14 involving the parents of the current study participants (the Framingham Heart Study participants) showed that the formula used in the current study produced prevalence estimates of GFR less than 60 that were 50% higher in females, without apparent explanation. One cannot help wondering whether the limitations of this formula partly explain 2 unexpected findings in the study by Dhingra et al11: the observation that 67.6% of individuals with phosphorus levels in the fourth quartile were female and the highly unexpected association between rising quartiles of both GFR and phosphorus levels. In a related issue, the patients were observed from 1979 to 1982, and urinary protein estimates were semiquantitative. Although this and other issues may need clarification (including the independence of the findings from PTH levels, dietary phosphorus intake, and the relations between all these plus true GFR and urinary protein excretion rates), the study by Dhingra et al11 adds urgency to the need for future prospective research. If one assumes that high phosphorus levels truly cause cardiovascular disease, unraveling the underlying mechanisms will be an exciting challenge, as will the evaluation of interventions. Intervention trials addressing the hypothesis that normalizing calcium-phosphorus balance improves cardiovascular outcomes in late-stage chronic kidney disease have begun. The proximate targets for these trials include gastrointestinal tract phosphorus absorption, PTH levels, and abnormal vitamin D metabolism.15 Unlike many “novel” cardiovascular risk factors discovered in community-based studies, several potential interventions suitable for controlled trials may already exist. Correspondence: Dr Foley, US Renal Data System Coordinating Center, Minneapolis Medical Research Foundation, 914 S Eighth St, Suite D-253, Minneapolis, MN 55404 (RFoley@usrds.org). Financial Disclosure: None reported. References 1. Stryer L Biochemistry. 4th ed. New York, NY Lubert Stryer1995; 2. Block GAHulbert-Shearon TELevin NWPort FK Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998;31607- 617PubMedGoogle ScholarCrossref 3. Ganesh SKStack AGLevin NWHulbert-Shearon TPort FK Association of elevated serum PO4, Ca × PO4 product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;122131- 2138PubMedGoogle Scholar 4. Stevens LADjurdjev OCardew SCameron ECLevin A Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes. J Am Soc Nephrol 2004;15770- 779PubMedGoogle ScholarCrossref 5. Slinin YFoley RNCollins AJ Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol 2005;161788- 1793PubMedGoogle ScholarCrossref 6. Jono SMcKee MDMurry CE et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000;87E10- E17PubMedGoogle ScholarCrossref 7. Steitz SASpeer MYCuringa G et al. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 2001;891147- 1154PubMedGoogle ScholarCrossref 8. Wada TMcKee MDSteitz SGiachelli CM Calcification of vascular smooth muscle cell cultures: inhibition by osteopontin. Circ Res 1999;84166- 178PubMedGoogle ScholarCrossref 9. Chen NXO'Neill KDDuan DMoe SM Phosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells. Kidney Int 2002;621724- 1731PubMedGoogle ScholarCrossref 10. Luo GDucy PMcKee MD et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997;38678- 81PubMedGoogle ScholarCrossref 11. Dhingra RSullivan LMFox CS et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 2007;167879- 885Google ScholarCrossref 12. Klahr SLevey ASBeck GJ et al. Modification of Diet in Renal Disease Study Group, The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 1994;330877- 884PubMedGoogle ScholarCrossref 13. Levey ASBosch JPLewis JBGreene TRogers NRoth DModification of Diet in Renal Disease Study Group, A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130461- 470PubMedGoogle ScholarCrossref 14. Fox CSLarson MGLeip EPCulleton BWilson PWLevy D Predictors of new-onset kidney disease in a community-based population. JAMA 2004;291844- 850PubMedGoogle ScholarCrossref 15. Qunibi WY Reducing the burden of cardiovascular calcification in patients with chronic kidney disease. J Am Soc Nephrol 2005;16 ((suppl 2)) S95- S102PubMedGoogle ScholarCrossref

Journal

Archives of Internal Medicine – American Medical Association

Published: May 14, 2007

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