Renal Division, Department of Internal Medicine, Washington University of St. Louis, St. Louis, Missouri
Correspondence to Dr. Eduardo Slatopolsky, 660 South Euclid Avenue, Box 8126, St. Louis, MO 63110. Phone: 314-362-7208 or 8231; Fax: 314-362-7875; E-mail: eslatopo{at}imgate.wust1.edu
Patients with chronic renal failure have many associated medicalproblems, including a high propensity for cardiovascular disease(CVD). CVD and stroke are the leading causes of mortality inpatients with ESRD (chronic kidney disease stage 5), with a10- to 20-fold greater risk than in the general population (1,2).These data have generated greater awareness of cardiovascularrisk in the chronic renal failure patient, and the most recentNational Kidney Foundation guidelines for chronic kidney disease(CKD) state that patients with CKD and kidney transplant recipientsshould be considered in the highest risk group for CVD (3).Indeed, the significance of CVD in this patient population issuch that a separate guideline to address the issue of CVD inpatients with CKD is in development.
Hyperphosphatemia and Hyperparathyroidism of Renal Failure: A Vicious Cycle with Cardiovascular Consequences
It seems logical that an understanding of the basic pathologicmechanisms underlying the increased cardiovascular risk in CKDcould lead to the development of improved treatment paradigmsand better outcomes in patients with chronic renal failure.The consequences of progressive renal failure include an imbalanceof calcium and phosphorus, which are normally under the tighthomeostatic control of the kidneys. The loss of metabolic controlof calcium and phosphorus parallels the loss of renal function(4). In early renal failure, a reduction in serum calcitrioland moderate decreases in ionized calcium contribute to an increasedsynthesis and secretion of parathyroid hormone (PTH). In laterstages of renal failure, reduced expression of vitamin D andcalcium receptors contributes to glandular resistance to thealready decreased calcitriol and calcium, perpetuating the synthesisand secretion of PTH. Independent of these effects, renal failure–mediatedphosphate retention and dietary phosphorus lead to increasedserum phosphorus levels. Hyperphosphatemia promotes uremia-inducedparathyroid gland hyperplasia and PTH synthesis and secretion.
In the past decade, some of the molecular mechanisms of theeffects of phosphorus on the parathyroid gland have been determined.Data indicate that high levels of phosphorus can increase parathyroidglandular expression of transforming growth factor- and promotegrowth in the gland via activation of mitogen-activated proteinkinase cascades (5,6). Conversely, low phosphorus induces thecyclin-dependent kinase inhibitor p21, which inactivates cyclinor cyclin-dependent kinase complexes to specifically inducearrest of growth in the parathyroid gland (6). In sum, hyperphosphatemiaassociated with progressive renal failure can lead to secondaryhyperparathyroidism and accompanying elevated phosphorus andcalcium-phosphate product (Ca x P).
Hyperphosphatemia and secondary hyperparathyroidism are commoncomplications of ESRD (4,7). Importantly, a growing body ofevidence suggests that the clinical consequences of alteredphosphorus and calcium metabolism and hyperphosphatemia includean increased risk of mortality, CVD, cardiovascular mortality,bone disease, and extraskeletal calcification of soft tissues,including blood vessels, lungs, kidneys, and joints (8–12).Cardiac and vascular calcification is believed to be the underlyingcommon mechanism that mediates such increased risk of morbidityand mortality. Management of hyperphosphatemia thus is a criticalissue in the care of patients with renal failure and has thepotential to decrease risk for CVD, particularly when institutedwith appropriate measures to control other "traditional" cardiovascularrisk factors.
Although dietary phosphorus restriction and dialysis play importantroles in regard to the management of hyperphosphatemia, thereis a need for additional support from phosphate-binding therapies.Herein lies the challenge to the clinician. Oral or intravenousadministration of vitamin D metabolites can correct secondaryhyperparathyroidism (13) but may also lead to enhanced intestinalabsorption of calcium and phosphorus, indirectly contributingto vascular calcification.
Other available treatment options include phosphorus- sequesteringagents. These agents sometimes contain aluminum or, more typically,calcium, and their use is limited by toxicity in the case ofaluminum-containing agents (14,15) or by their potential forincreasing calcium load and soft tissue calcification, in thecase of calcium-containing phosphate binders (8,16,17). Thechallenge in the renal failure patient is to reduce effectivelyand safely serum phosphorus and Ca x P product without increasingserum calcium levels and the likelihood of vascular calcification.It is in this context that metal-free, calcium-free phosphatebinders may have an important role.
In this supplement, we discuss issues critical to the treatmentof the hyperphosphatemic renal failure patient. Advances inour understanding of the molecular biology of hyperphosphatemia-inducedcalcification and its clinical consequences are presented anddiscussed in the context of other well-known cardiovascularrisk factors, such as dyslipidemia and oxidative stress.
Molecular Biology and Clinical Correlates of Hyperphosphatemia in the Vasculature
Recent evidence indicates that vascular calcification can occurearly in a phosphate-rich environment. Furthermore, hyperphosphatemia-mediatedcalcification may not be a simple, passive process of depositionof calcium phosphate crystals in vascular walls. Rather, thework of Giachelli and others reviewed in this supplement suggeststhat calcification may be an active process under exquisitegenetic and molecular control. The unfolding in vitro data presentedby Giachelli paints an active process during which phosphateenters vascular smooth muscle cells via a sodium-dependent phosphateco-transporter–mediated mechanism, inducing the expressionof a "master gene"—the Cbfa-1 gene—and setting intoprocess the active deposition of calcium into vascular walls.The end result is a phenotypic cellular change, changing a vascularcell type to an osteogenic cell type (18,19). Calcificationis an inherent part of atherosclerosis and is the most frequentcause of CVD in patients with ESRD.
In an accompanying article, London discusses how vascular changesin ESRD not only are related to atherosclerosis and ischemicheart disease but also are associated with vascular stiffeningand "remodeling." These latter changes, collectively referredto as "arteriosclerosis," are more ubiquitous, involve calcificationof the intima and media of blood vessels, cause a stiffeningof the vessel wall (particularly of elastic vessels), and leadto hemodynamic changes, such as increased systolic BP and pulsepressure. These hemodynamic changes eventually lead to leftventricular hypertrophy (LVH), another major cause of cardiovascularmortality in patients with ESRD (20), further highlighting theheightened risk of CVD in patients with ESRD.
Management of Hyperphosphatemia and Reduction of Cardiovascular Risk
It is clear that hyperphosphatemia can facilitate calcificationof soft tissues such as blood vessels, with serious clinicalconsequences. The extent of calcification and the degree ofarterial stiffening are independent predictors of mortality.In his article, London also briefly reviews some studies inpatients with ESRD that show that attenuation of arterial stiffnesscan cause regression of LVH and have a favorable impact on patientsurvival. Although a direct impact of phosphate-binding therapyon LVH has not yet been documented, there is considerable evidenceindicating that the use of calcium-free, metal-free phosphatebinders can reduce coronary and aortic calcification scores,thereby decreasing some aspects of cardiovascular risk.
In another article, Chertow reviews the impact of phosphatebinder use on hyperphosphatemia and the progression of vascularcalcification. In a comparative study, Chertow and his colleagueshave shown similar phosphate control but lower calcium scoresin the aorta and coronary arteries of hemodialysis patientstreated with sevelamer (a non–aluminum-, non–calcium-containingbinder) compared with patients treated with calcium-containingphosphate binders (21).
It is interesting that a beneficial effect on the lipid profileseems to be a novel advantage of sevelamer treatment. This isexciting, considering the high cardiovascular risk of patientswith renal failure. Although the decrease in LDL cholesterol(LDL-C) and increase in HDL cholesterol with sevelamer werenot related to calcification scores in Chertow’s study,the implications of these data require further investigation.
In reviewing the impact of dyslipidemia in ESRD, Prichard presentsa thorough overview of the relative changes in lipids in patientswho receive hemodialysis versus peritoneal dialysis and showsthat dialysis in general can lead to atherogenic changes inlipids. Given this and given the well-established benefits oflipid-lowering treatment in the nondialysis population, Prichardadvocates aggressive treatment of dyslipidemia to an LDL-C goalless than 100 mg/dl in patients with renal failure, consistentwith the recommendations in the recently released Kidney DiseaseOutcomes Quality Initiative guidelines on managing dyslipidemiasin CKD (22). Whether the benefit on lipids conferred by sevelamerwill result in a replacement or reduction of lipid-loweringtherapies such as statins in patients with ESRD will need furtherinvestigation. The potential benefit in terms of reduction inthe number of medications that a patient must take and/or patientcompliance is certainly important.
For the future, investigation of the anti-inflammatory potentialof drugs such as sevelamer may also provide added insight andbenefit, because there is some evidence that calcium depositionin dialysis patients may be triggered by inflammation (23).If additional non–phosphate-related effects of sevelamerare confirmed in further studies, then the multiplicity of beneficialeffects of this phosphate binder will indeed be very advantageousin the treatment of patients with hyperphosphatemia. The evidencenow points to a relative superiority of sevelamer to calcium-containingphosphate binders in terms of a reduction in vascular calcificationand LDL-C levels, with comparable control of hyperphosphatemia,and that evidence indicates that calcium-containing phosphatebinders, given their propensity to increase vascular calcification,should be used judiciously.
Foley RN, Parfrey PS, Sarnak MI: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32 [Suppl 3]: S112–S119, 1998[Medline]
Cheung AK, Sarnak MJ, Yan G, Dwyer JT, Heyka RJ, Rocco MV, Teehan BP, Levey AS: Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int 58: 353–362, 2000[CrossRef][Medline]
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Slatopolsky E, Lopez-Hilker S, Delmez J, Dusso A, Brown A, Martin KJ: The parathyroid-calcitriol axis in health and chronic renal failure. Kidney Int Suppl 29: S41–S47, 1990[Medline]
Dusso AS, Pavlopoulos T, Naumovich L, Lu Y, Finch J, Brown AJ, Morrissey J, Slatopolsky E: p21(WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth. Kidney Int 59: 855–865, 2001[CrossRef][Medline]
Slatopolsky E, Brown A, Dusso A: Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 37 [Suppl 2]: S54–S57, 2001[Medline]
Block GA, Hulbert-Shearon TE, Levin NW, Port FK: Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Dis 31: 607–617, 1998[Medline]
Block GA, Port FK: Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management. Am J Kidney Dis 3596: 1226–1237, 2000
Drüeke TB, Touam M, Thornley-Brown D, Rostand SG: Extraskeletal calcification in patients with chronic kidney failure. Adv Nephrol Necker Hosp 30: 333–356, 2000[Medline]
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Introduction
Hyperphosphatemia and...
and promote growth in the gland via activation of mitogen-activated protein kinase cascades (5,6). Conversely, low phosphorus induces the cyclin-dependent kinase inhibitor p21, which inactivates cyclin or cyclin-dependent kinase complexes to specifically induce arrest of growth in the parathyroid gland (6). In sum, hyperphosphatemia associated with progressive renal failure can lead to secondary hyperparathyroidism and accompanying elevated phosphorus and calcium-phosphate product (Ca x P). 
