Slowing the Progression of Vascular Calcification in Hemodialysis
Glenn M. Chertow
Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California
Correspondence to Dr. Glenn M. Chertow, Department of Medicine Research, University of California at San Francisco, UCSF Laurel Heights Suite 430, 3333 California Street, San Francisco, CA 94118-1211. Phone: 415-476-2173; Fax: 415-476-9531;
ABSTRACT. Hyperphosphatemia and secondary hyperparathyroidismare common complications of ESRD (chronic kidney disease stage5) that, when untreated, may result in increased morbidity andmortality. Hyperphosphatemia and hypercalcemia have been associatedwith increased coronary artery calcification. Achieving controlof serum phosphorus without increasing serum calcium is an importantgoal for patients with ESRD. Although calcium-based phosphatebinders effectively reduce serum phosphorus and parathyroidhormone concentrations, these agents can lead to hypercalcemiaand have been associated with increased vascular calcification.The phosphorus binder sevelamer was developed to overcome thelimitations associated with the usual management of hyperphosphatemiaand secondary hyperparathyroidism (i.e., mineral salts). Sevelamer,a nonabsorbable hydrogel, is as efficacious as calcium-basedphosphate binders for reducing serum phosphorus but does notcause hypercalcemia or other adverse metabolic effects. Sevelameralso exhibits beneficial effects on lipids, consistently andsignificantly decreasing LDL cholesterol and increasing HDLcholesterol in most studies. In a head-to-head randomized clinicaltrial, sevelamer and calcium-based binders achieved similarlyexcellent phosphorus control, but the use of calcium-based bindersled to significantly higher serum calcium concentrations andan increased incidence of hypercalcemia and unintended suppressionof parathyroid hormone. Treatment with calcium-based bindersalso led to the progression of coronary artery and aortic calcification,whereas sevelamer attenuated or arrested progression. Strategiesthat use oral calcium and vitamin D in patients with ESRD shouldbe reexamined, and the potential advantages of sevelamer shouldbe considered when selecting a primary agent to reduce serumphosphorus in hemodialysis patients. E-mail: chertowg@medicine.ucsf.edu
Hyperphosphatemia and secondary hyperparathyroidism (HPT) arecommon complications of end-stage renal disease (ESRD) (1).Untreated secondary HPT can lead to significant morbidity asa result of pain, pruritus, bone loss, increased fracture risk,and anemia (2,3) and can contribute to heart disease and hypertension(4,5). Management of hyperphosphatemia and secondary HPT inpatients with ESRD is critical, because cardiovascular diseaseis the leading cause of death in this patient population (6).Annual cardiovascular mortality rates are several-fold higherin patients with ESRD than in the general population, even whenadjusted for age, gender, race, and the presence of diabetes.
In addition to traditional risk factors (age, gender, race,diabetes, hypertension, lifestyle factors, smoking, lipids,hyperhomocysteinemia), inflammation, oxidative stress as a resultof uremia and/or dialysis, and disorders of mineral metabolismmay contribute to cardiovascular disease in patients with ESRD(7,8). In particular, disorders of mineral metabolism may contributeto cardiac calcification, which may in turn increase the riskof cardiovascular disease and mortality. Individuals who areon dialysis are prone to severe calcification (9,10), and acorrelation has been demonstrated between the degree of coronarycalcification and the prevalence of overt atherosclerotic vasculardisease (11). These results are in agreement with those of Blacheret al. (12), who demonstrated that in hemodialysis patients,the probability of all-cause mortality increased with increasingcalcification score using B-mode ultrasound.
Hyperphosphatemia is associated with elevated cardiovascularrisk and mortality (13–16). Analysis of data from theUnited States Renal Data System demonstrated an associationbetween elevated phosphorus and calcium-phosphorus product andmortality (15), and a follow-up analysis indicated that hyperphosphatemiawas associated with cause-specific cardiovascular death (16).These adverse effects of hyperphosphatemia are thought to belinked to the ability of phosphate to enhance vascular calcification(14,16), although the exact mechanism(s) is unknown. Data fromGiachelli in this supplement (17) suggest that the mechanismis more complex than the traditional theory of passive crystallizationand tissue deposition.
Several treatment options, either alone or in combination, areavailable for the treatment of hyperphosphatemia and secondaryHPT in patients with ESRD (Table 1). The duration and frequencyof dialysis may be adjusted to normalize phosphorus levels;nocturnal hemodialysis with long treatment times seems to bemost effective (18). Dietary phosphorus restriction can be applied,although the need for adequate dietary protein limits this approach,and with conventional dialysis a phosphate binder is almostalways required. Oral or intravenous administration of vitaminD metabolites can correct secondary HPT (19) but leads to enhancedintestinal absorption of calcium and phosphorus and, in doingso, may indirectly contribute to vascular calcification. Aluminum,magnesium, and calcium salts have also been used to bind dietaryphosphorus. Aluminum salts can lead to osteomalacia, anemia,and, in rare cases, encephalopathy (20,21). Most physiciansadvise against the routine use of aluminum because of the sideeffects associated with its accumulation. Magnesium salts areinfrequently used, being dose limited by gastrointestinal sideeffects (22).
Table 1. Treatment options for hyperphosphatemia and hyperparathyroidism
Calcium salts tend to be well tolerated in most individualsand can effectively bind intestinal phosphorus. During the late1980s and the 1990s, calcium salts became the conventional strategyfor controlling hyperphosphatemia. However, a variable fractionof the calcium can be absorbed, depending in part on co-administrationof vitamin D and other gastrointestinal factors (e.g., gastricpH, timing of administration, meal content, other medications).Moreover, despite more intensive dialysis, dietary phosphorusrestriction, and treatment with calcium- and aluminum-basedphosphate binders, more than 60% of hemodialysis patients havesuboptimal control of calcium and phosphorus, and others experiencepersistent elevations of parathyroid hormone (PTH) or requireparathyroidectomy to achieve adequate phosphorus control (23).
The phosphate binder sevelamer (Renagel; Genzyme, Cambridge,MA) was developed and introduced in 1998 to overcome the limitationsassociated with traditional management of hyperphosphatemiaand secondary HPT. Sevelamer is a non–calcium-, non–aluminum-containinghydrogel that is resistant to digestive degradation and is notabsorbed from the gastrointestinal tract (23).
Short-Term Studies
Several short-term studies have shown sevelamer to be as efficaciousas calcium acetate or calcium carbonate in decreasing serumphosphorus concentrations (24–29). Moreover, results indicatethat sevelamer is well tolerated and provides adequate controlof HPT without increasing serum calcium, even when used in conjunctionwith vitamin D metabolites. In short-term studies, sevelamerconsistently reduced PTH (25,29). Furthermore, maintenance oftarget PTH concentrations in sevelamer-treated subjects wasaccomplished, often with the addition of vitamin D metabolites(30). Sevelamer also leads to significant decreases in the calcium-phosphorusproduct (23). Compared with calcium salts, sevelamer may leadto reductions in serum bicarbonate, on the order of 2 to 3 mEq/L,in part as a result of the withdrawal of acetate or carbonateanions from previous binder usage. In addition, sevelamer hasbeen shown to induce small but statistically significant reductionsin serum uric acid concentration (31). Unique among phosphatebinders, sevelamer has favorable effects on the lipid profile,consistently decreasing LDL cholesterol by more than 30% andincreasing HDL cholesterol by 5 to 15% in most studies (23–27,29).
Long-Term Studies
Recent long-term studies have evaluated the safety and efficacyof sevelamer in hemodialysis patients (23,32). The long-termefficacy of open-label sevelamer was evaluated over a 46-wkperiod in 192 adult hemodialysis patients (23). Sevelamer significantlydecreased serum phosphorus (mean decrease, 2.2 ± 2.4mg/dl) and calcium-phosphorus product (mean decrease, 18.1 ±22 mg2/dl2) and overall led to no significant changes in PTHat 1 yr. A small but statistically significant increase in serumcalcium was observed with sevelamer treatment that was independentof dose, although the average incidence of hypercalcemia (definedin this study as 11 mg/dl) was less than 2%.
A single long-term, randomized, clinical trial ("treat to goal")compared sevelamer with calcium-based phosphate binders in 200hemodialysis patients at 15 sites in the United States and Europe(32). The subjects were randomized to 1 yr of open-label treatmentwith sevelamer or calcium salts (acetate in the United Statesand carbonate in Europe). Patients were eligible for study participationwhen they were hyperphosphatemic (5.5 mg/dl) aftera 1- to 2-wk phosphate binder washout period. Target valuesfor serum phosphorus were more ambitious (3.0 to 5.0 mg/dl)than in other studies. Target values for serum calcium (adjustedfor albumin) were 8.5 to 10.5 mg/dl and for PTH were 150 to300 pg/ml. In addition to evaluating the comparative effectsof sevelamer and calcium salts on parameters of mineral metabolism,we tested the hypothesis that sevelamer and calcium salts wouldhave differential effects on vascular calcification. In evaluatingcoronary and aortic calcification, electron beam tomography(EBT) was performed at baseline, 6 mo, and 1 yr.
Subjects who were treated with sevelamer and calcium achievedexcellent phosphorus control (end of treatment serum phosphorusfor both groups, 5.1 mg/dl; Figure 1). The use of calcium-basedbinders led to significantly higher serum calcium concentrations(P = 0.002; Figure 2) and a higher incidence of hypercalcemia(P = 0.04; defined in this study as an adjusted serum calcium10.5 mg/dl; Figure 3). These changes were attenuatedduring the study by the reduction or discontinuation of vitaminD, reduction in dialysate calcium, and the use of "rescue" aluminumhydroxide in some calcium-treated subjects, all provided forby the study protocol for safety considerations. Subjects whowere treated with calcium-based binders experienced significantunintentional suppression of PTH with median values below 150pg/ml at all on-treatment time points compared with sevelamer-treatedsubjects, whose median PTH concentrations remained within thetarget range (Figure 4).
Figure 4. Serum intact parathyroid hormone response to calcium-containing versus non–calcium-containing (sevelamer) phosphate binders.
Even transient hypercalcemia with calcium-based phosphate bindersmay be undesirable. Guérin et al. (33) showed a significantrelation between vascular calcification by B-mode ultrasonographyand episodes of hypercalcemia (8%, 10%, 18%, 36%, and 42% inpatients with 0, 1, 2, 3, or 4 sites of calcification, respectively;P = 0.034). Several investigators have shown PTH concentrationsbelow 150 pg/ml to be associated with low bone turnover andan increased rate of fractures and extraskeletal calcification(34,35).
Atherosclerotic vascular disease is significantly associatedwith the coronary artery calcification score by EBT in the generalpopulation (36–38) and in people with uremia (11). Inhemodialysis patients, correlates of the extent of coronarycalcification were advanced age, male gender, white race, diabetes,and longer vintage; calcium and phosphorus were the only modifiablerisk factors. We found a 1.0-mg/dl higher serum phosphorus anda 0.5-mg/dl higher serum calcium to be associated with the samerelative increase in vascular calcification as 2.5 yr of dialysis.There were no associations between the extent of coronary arterycalcification and serum albumin, hemoglobin, and lipid parameters.Therefore, the favorable metabolic effects of sevelamer mightbe expected to reduce the extent of coronary artery calcificationand potentially reduce the risk of overt coronary heart disease.
In the treat-to-goal study, baseline EBT scores were extremelyhigh (93rd percentile for age- and gender-matched normal subjects)and were nominally higher in the subjects who were randomizedto sevelamer (although not significantly different) (32). However,the mean and median nominal change, mean and median percentagechange, and mean and median weekly trend scores were significantlyhigher in calcium-treated subjects. In other words, the differencein vascular calcification was evident regardless of the methodof data analysis. Given a median zero nominal change in coronaryand aortic calcification in sevelamer-treated subjects, an equalnumber of subjects experienced regression as progression overthe 1-yr study.
Non–Calcium-Based Versus Calcium-Based Phosphate Binders: A Comparative Overview
Evidence suggests that sevelamer would provide considerablebenefits over calcium salts as primary therapy for hyperphosphatemia.The treat-to-goal study demonstrated that in achieving satisfactoryphosphorus control using calcium salts, a high frequency ofunacceptable metabolic side effects can be anticipated. Indeed,the frequency of hypercalcemia and the more pronounced degreeof PTH lowering seen in calcium-treated subjects in the treat-to-goalstudy reflect the ambitious phosphorus targets. Therefore, evenin the absence of cardiovascular benefits, sevelamer would bepreferred for its metabolic effects on bone. The exact mechanism(s)for progressive vascular calcification in hemodialysis patientsis unknown. An increasing incidence of cardiovascular diseaseand other disorders of calcification (e.g., uremic calcificarteriolopathy) over the past decade has been attributed inpart to the widespread use of oral calcium and vitamin D metabolites.Possible reasons for a protective vascular effect of sevelamerinclude improved metabolic control; differences in calcium load;and differential effects on bone dynamics, lipids, and inflammation.
Calcium-based phosphate binders increase calcium load. Severalstudies have linked the dose of oral calcium with vascular calcification.Goodman et al. (10) showed that adolescents and young adultswho were on dialysis and had evidence of coronary artery calcificationwere prescribed nearly twice the dose of oral calcium carbonateas patients without calcification (mean, 6456 versus 3325 mg;P = 0.02). Guérin et al. (33) showed a direct correlationbetween prescribed oral calcium and the number of sites of vascularcalcification (1.35, 1.35, 1.50, 1.84, and 2.18 g elementalcalcium in patients with 0, 1, 2, 3, and 4 sites of calcification,respectively; P = 0.001).
We cannot determine whether the beneficial effects on lipidsinduced by sevelamer contributed to the benefit on vascularcalcification. In the treat-to-goal study, mean LDL cholesterol(71 versus 108 mg/dl; P < 0.001), mean apolipoprotein B (63versus 84 mg/dl; P < 0.0001), and median homocysteine (19.3versus 29.7 µmol/L; P = 0.04) concentrations were significantlylower in sevelamer-treated subjects than in subjects who receivedcalcium-based phosphate binders. Finally, differential effectsof sevelamer and calcium-based phosphate binders on inflammationmay contribute to differences in coronary calcification. Chronicinflammation is commonly observed in patients with ESRD (39),and markers of inflammation have been associated with coronarycalcification in these patients (33). It has been hypothesizedthat inflammation may trigger arterial calcium deposition indialysis patients, particularly at the end of the dialysis session,when back-filtration is most likely to occur and the plasmais maximally alkalinized (40). Further studies are needed toinvestigate the effects of sevelamer and calcium-based phosphatebinders on markers of inflammation, such as C-reactive proteinand fibrinogen, and to examine the relation between changesin these markers and changes in coronary calcification.
Hyperphosphatemia has been recognized as a key modifiable riskfactor in patients who are on hemodialysis. As target valuesfor serum phosphorus and the calcium–phosphorus producthave been reduced (e.g., Kidney Disease Outcomes Quality Initiativeguidelines of <5.5 mg/dl and <55 mg2/dl2, respectively[National Kidney Foundation, unpublished review, 2003]), theneed for improved phosphate binders has become even more pronounced.As the dose of calcium-based phosphate binders increases, sodoes the frequency of hypercalcemia, and excessive calcium intakecan lead to adynamic (low turnover) bone disease. In contrast,sevelamer can be titrated safely with no metal absorption. Changesin vascular calcification are provocative. Additional studiesare under way to examine the relative effects of sevelamer andcalcium-based phosphate binders on mortality and cardiovascularevents. For now, practitioners should use calcium-based phosphatebinders cautiously. With ongoing evidence, non–calcium-containingphosphate binders may soon evolve into first-line therapiesfor dialysis-related hyperphosphatemia.
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Abstract
Introduction
11 mg/dl) was less than 2%. 
