Current Controversies in Managing End-Stage Renal Disease Patients
Reducing the Burden of Cardiovascular Calcification in Patients with Chronic Kidney Disease
Wajeh Y. Qunibi
Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas
Address correspondence to: Dr. Wajeh Y. Qunibi, Department of Medicine, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Phone: 210-422-2692; Fax: 210-358-4710; E-mail: qunibi{at}uthscsa.edu
Patients with chronic kidney disease (CKD) have a higher burdenof atherosclerotic coronary artery disease compared with age-and gender-matched individuals with normal renal function. Cardiovascularcalcification (CVC), a marker of atherosclerosis, is also moreprevalent in these patients and is associated with serious clinicalconsequences. The pathogenesis of CVC is complex and includesfactors that promote calcification and others that inhibit calcification.Thus, multiple therapeutic interventions should be used simultaneouslyto reduce the burden of calcification in patients with CKD.Thus far, interventional attempts have focused on curtailingthe effects of factors that promote calcification such as managementof known traditional factors for atherosclerotic coronary arterydisease and on adopting specific approaches to normalize mineralmetabolism, deliver adequate dialysis, and control serum cholesterollevel. By contrast, interventions that may bolster the effectsof inhibitors of calcification have not yet been studied wellbut are beginning to attract attention. Ideally, the goal ofinterventions is not only to slow or halt progression of calcificationbut also to reverse pre-existing calcification. Whether thisgoal is achievable is not currently known. This review examinesthe potential of various therapeutic interventions in reducingthe CVC burden in patients with CKD. Moreover, the review isintended to stimulate more research in this area because theefficacy of these interventions has not been examined in controlledclinical trials.
Coronary artery calcification (CAC), which is absent in normalvessels, represents an integral part of the atheroscleroticplaque (1). Detection and quantification of arterial calcificationnow can be easily achieved by the use of newer imaging techniquessuch as electron-beam computed tomography (EBCT) and multislicecomputed tomography (2,3). In the general population, coronaryartery calcium (CAC) score as measured by EBCT was found tobe an independent predictor of subsequent cardiac events inboth symptomatic and asymptomatic individuals (3,4).
The pathogenesis of CVC is complex and includes factors thatpromote calcification and others that inhibit calcification(Tables 1 and 2). Several studies have clearly established thatthe prevalence and the extent of CVC are increased in patientswith ESRD (5–8). The mechanisms that are responsible forCVC in patients with ESRD are still being debated and have beenreviewed previously in detail (9). Briefly, cross-sectionalstudies in dialysis patients have shown a correlation betweenCAC and a number of uremia-related factors such as dialysisvintage, hyperphosphatemia, high calcium (Ca) x phosphorus (P)product, vitamin D therapy, and the prescribed daily dose ofCa-based phosphate binders (CBPB) (5–9).
Calcification of the aorta and other large vessels previouslyhas been considered a benign process without serious clinicalconsequences. However, several clinical studies have shown clearlythat calcification of various cardiovascular structures maybe associated with increased morbidity and mortality. Calcificationof the cardiac valves may lead to heart failure, coronary ischemia,arrhythmias, valve stenosis, increased risk for infective endocarditis,and thromboembolic events (10). Moreover, valve calcificationwas shown to be independently predictive of increased all-causemortality as well as cardiovascular death (10). Calciphylaxisor calcific uremic arteriolopathy, a form of medial calcification,is associated with very high risk for death (11). Moreover,medial arterial calcification often leads to stiffening anddecreased compliance of blood vessels, which in turn leads toincreased systolic BP, reduced diastolic BP, and increased pulsepressure (12). These hemodynamic changes may result in increasedafterload, left ventricular hypertrophy, decreased coronaryartery perfusion, and increased risk for death (13). Finally,CAC has been linked to increased risk for cardiovascular eventssuch as myocardial infarction, fatal arrhythmia, and congestiveheart failure (9,14,15). Given that CVC may lead to seriousclinical consequences, it is possible that interventions thatare designed to slow or even reverse the process of calcificationmay lead to improved patient outcomes.
Interventions Designed to Reduce CVC in Patients with CKD
Theoretically, for any intervention to reduce CVC, it shouldcurtail the influence of factors that promote calcificationand/or augment the effects of factors that inhibit calcification.Unfortunately, such interventions have not been investigatedin controlled clinical trials. Therefore, the potential beneficialrole of some of these interventions on CVC must be consideredspeculative at this time. Hopefully, future interventional clinicalstudies will be designed to examine more carefully the roleof these factors in reducing the burden of CVC in calcification-proneCKD patients (Table 3).
Control of Hyperphosphatemia, Hypercalcemia, and Ca x P Product
Disturbances in serum P, Ca, and Ca x P product are frequentlyseen in patients with CKD and have been implicated in promotingCVC as well as in increased risk for death (9,16). High P levelsstimulate osteoblastic differentiation of vascular smooth musclecells and directly enhance extracellular calcification by thesecells (17). Given that hyperphosphatemia is common in dialysispatients and that it plays a key role in the increased riskfor CVC, it is conceivable that control of serum P may resultin reduced burden of CVC in these patients and improve outcomes.
Because dietary restriction of P and intermittent dialysis arenot usually effective in controlling serum P, most dialysispatients require dietary phosphate binders (18). CBPB such asCa acetate and Ca carbonate have replaced aluminum hydroxideas the most widely prescribed phosphate binders. Although cost-effective,recent concern over the possible role of Ca loading from thesebinders in progression of CVC has led to more frequent use ofthe considerably more expensive noncalcium, nonaluminum phosphatebinder sevelamer hydrochloride (Renagel) (7–10). Thisconcern became more widespread after the publication of theTreat to Goal Study, which showed a 25% increase in the coronaryCa scores among the patients who were treated with Ca saltscompared with a 6% increment in the sevelamer group and a similardifference in aortic artery calcification scores. However, themechanism of the beneficial effect of sevelamer on progressionof calcification is unknown. One possible mechanism is reducedCa loading during treatment with sevelamer. However, reducedcardiovascular calcification may also result from dramatic reductionsin total and LDL cholesterol, which occur during treatment withthis bile acid sequestrant. Moreover, results of the CalciumAcetate Renagel Evaluation (CARE), a randomized, double-blindtrial, demonstrated that Ca acetate is significantly more effectivethan sevelamer in controlling serum P and Ca x P product tothe recommended goal levels (19). Thus, it is conceivable thatCa acetate might in fact reduce the risk for CVC and mortalityin dialysis patients as a result of better control of both serumP and Ca x P product. Clearly, more studies on the role of Caloading from CBPB in progression of CVC are needed before prematurelyabandoning these cost-effective binders.
Control of Hyperlipidemia
Hyperlipidemia, particularly increased LDL, has been implicatedin progression of CAC (20–23). In addition, the beneficialeffect of lowering LDL cholesterol levels on progression ofcalcification in the general population has been reported byseveral groups (21–23). Callister et al. (22) demonstratedthat treatment with 3-hydroxy-3-methylglutaryl CoA reductaseinhibitors can reduce the volume of calcified plaque in thecoronary arteries (Figure 1). At the follow-up EBCT scans, anet reduction in the Ca-volume score of 7% was observed onlyin treated patients whose final LDL cholesterol levels were<120 mg/dl (P < 0.01). Moreover, in the only prospectivestudy on the effect of lipid-lowering therapy on the progressionof CAC, Achenbach et al. (23) found that treatment with thecholesterol-synthesis enzyme inhibitor cerivastatin significantlyreduced coronary artery Ca progression in patients with LDLcholesterol levels >130 mg/dl (Figure 2). The median annualrelative increase in coronary Ca was 25% during the untreatedperiod versus 8.8% during the treatment period (P < 0.0001).
Figure 1. Reduction of LDL cholesterol to <120 mg/dl resulted in halting progression of coronary artery calcification (CAC). , Initial values; , final values for coronary artery Ca volume scores. As can be seen, patients in group 1 who were not treated with 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor had significant progression of CAC. Similarly, patients in group 2 who were also treated but their average LDL cholesterol levels remained >120 mg/dl had significant progression of calcification. Patients in group 3 who were treated with HMG-CoA reductase inhibitor and their average LDL cholesterol levels were successfully reduced to <120 mg/dl had no progression of calcification. Reprinted from reference (29), with permission.
Figure 2. (A) Reduction of progression of CAC during treatment with a cholesterol-synthesis enzyme inhibitor cerivastatin. The figure shows the annualized relative change of the calcium volume score during the untreated period (electron-beam tomography [EBT] 1 to EBT 2) and during the treatment period (EBT 2 to EBT 3) for all 66 patients. Despite interindividual variation, the median annualized relative change (bold line) was significantly lowered by cerivastatin (25 versus 8.8%; P < 0.0001). (B) Annualized relative change of the calcium volume score in 32 patients who achieved an LDL cholesterol level <100 mg/dl during treatment with cerivastatin. In these patients, the median annualized change (bold line) decreased from 27% to –3.4% (P = 0.0001). Reprinted from reference (64), with permission.
Results of the Treat to Goal Study (8) suggest that loweringthe LDL level in patients with ESRD may also result in ameliorationof progression of CVC. Patients who were treated with sevelamerhad a significant decrease in their plasma LDL cholesterol levelsfrom 102 to 65 mg/dl during the study period, whereas the LDLlevels did not change in patients who were treated with CBPB.Therefore, it is possible that the slower rate of progressionof cardiovascular calcification observed in the Treat to GoalStudy may have resulted from the significant lowering of theLDL level by sevelamer. Two other studies underscore the roleof dyslipidemia in the pathogenesis of CVC in patients withCKD. Nitta et al. (24) reported the results of their preliminarystudy from Japan, which showed that progression of aortic calcificationin patients with ESRD was significantly retarded during treatmentwith colistimide (a bile acid sequestrant similar to sevelamer)in combination with atorvastatin compared with the period beforetreatment was initiated. Tamashiro et al. (25) reported thatrapid progression of CAC in hemodialysis patients was associatedwith higher triglycerides and lower HDL cholesterol levels.
Control of Secondary Hyperparathyroidism: Vitamin D versus Calcimimetic Agents
The current treatment of secondary hyperparathyroidism (SHPT)in dialysis patients includes suppression of parathyroid hormonesecretion with supraphysiologic doses of vitamin D or its analogues.Unfortunately, vitamin D may predispose to vascular calcification.Rats that were treated with high-dose vitamin D developed calcificationin the aorta, carotid, hepatic, mesenteric, renal, and femoralarteries (26). Clinical studies have also reported an associationbetween vascular calcification and use of vitamin D therapyin hyperphosphatemic patients with renal failure (27,28). Vascularsmooth muscle cells (VSMC) have been shown to express vitaminD receptors (29). Although vitamin D inhibits VSMC proliferationby enhancing Ca flux into cells, it induces VSMC to exhibitan osteoblastic phenotype (29). Vitamin D has also been shownto increase calcification in VSMC in vitro (30). Moreover, vitaminD therapy enhances the intestinal absorption of Ca and P and,therefore, often results in hypercalcemia, worsening hyperphosphatemia,and increased Ca x P product. Thus, although effective in reducingthe severity of SHPT, vitamin D may increase the risk for CVC.
The new calcimimetic agents offer several advantages over vitaminD with respect to CVC. They prevent or treat SHPT without increasingserum Ca, P, or Ca x PO4 product (31). Moreover, they have noadverse effects on vascular calcification. Although no clinicalstudies have demonstrated such a beneficial effect, preliminaryin vitro and in vivo studies indicated that, compared with vitaminD, calcimimetic agents do not enhance aortic calcification (32–34).These effects, if confirmed in clinical studies, may resultin the preferential use of calcimimetic agents to slow or haltprogression of CVC in patients with CKD.
Treatment of Hypertension with Ca Channel Blockers
Several clinical trials in the general population have suggesteda therapeutic or prophylactic effect of Ca channel blockers(CCB) on the progression of the atherosclerotic process (35–37).In the PREVENT study, the CCB amlodipine was found to reduceintimal medial thickness in type 2 diabetes (37). More recently,Motro and Shamesh (38) compared the effect of nifedipine anddiuretics on progression of CAC in 201 hypertensive patientsover a 3-yr period. They showed that CAC score increased by40% in patients who were treated with nifedipine versus 78%on diuretics (P = 0.02). The effect was more pronounced in patientswho had higher CAC scores at baseline. No similar studies havebeen reported in patients with CKD. Clearly, the effect of CCBon progression of CVC deserves further study, particularly inpatients with CKD.
Role of Renal Transplantation
Cardiovascular mortality is clearly lower in renal transplantrecipients than in dialysis patients (39,40). Moreover, theprevalence of CVC is also lower in renal transplant recipientsthan in dialysis patients (41). A preliminary study by Moe etal. (42) showed that CAC can be slowed or arrested after renaltransplantation (Figure 3). A study by Stompor et al. (43) alsoshowed no progression of CAC in renal transplant recipientscompared with peritoneal dialysis patients. There are a numberof potential mechanisms by which renal transplantation reducesthe burden of CVC: First, renal transplantation restores renalfunction and therefore eliminates the role of uremic toxinsin promoting CVC. Second, because baseline CAC scores in renaltransplant recipients are dependent on the duration of dialysis(44), transplantation may reduce the burden of calcificationby shortening the duration of dialysis. Third, renal transplantationmay improve some disorders of mineral metabolism. Indeed, hypophosphatemia,rather than hyperphosphatemia, may develop in renal transplantrecipients with normal graft function. Further studies designedto examine the role of renal transplantation in amelioratingCVC are clearly needed.
Figure 3. Change in coronary artery calcium score over time. The changes in CAC in transplant recipients (A) and hemodialysis patients (B) are plotted for individual patients who had calcification at baseline. Reprinted from reference (53), with permission.
Augmenting Effects of Factors that Inhibit Vascular Calcification
Although CVC is very common in patients with CKD, it is conspicuouslyabsent in approximately 17% of patients despite similar exposureto factors that promote calcification (45). Moreover, patientswho do not have detectable vascular calcification rarely developcalcification on follow-up studies (46). Because the physiologicconcentrations of Ca and P in human serum, particularly in patientswith ESRD, are far above their solubility product and thereforeshould precipitate immediately, inhibitors of precipitationof these ions must be playing a major role in preventing extraosseouscalcification.
Several animal knockout models have shown that the Ca-regulatoryfactors matrix Gla protein (MGP), osteoprotegerin (OPG), andfetuin-A (2-Heremans-Schmid glycoprotein-Ahsg) may be protectivefrom vascular calcification (46–49). Mice deficient inMGP or OPG develop spontaneous vascular calcification (48).Similarly, mice deficient in fetuin-A also develop severe ectopiccalcification when fed a mineral- and vitamin D–rich dietor when fed a normal diet when combined with a DBA/2 geneticbackground (49). Unfortunately, the therapeutic potential ofthese inhibitors of calcification has not been explored in clinicaltrials. However, because MGP requires vitamin K for -carboxylation,acquired vitamin K deficiency, as with the use of warfarin,may predispose to vascular calcification (50). It is interestingthat calciphylaxis, or calcific uremic arteriolopathy, has beenreported with increasing frequency in patients who are treatedwith warfarin therapy (11). Thus, it is possible that by avoidingthe use of warfarin in patients with CKD, the risk for CVC maybe reduced by not interfering in the production of MGP.
Similarly, OPG knockout mice develop osteoporosis and severevascular calcification (48). This observation indicates thatOPG is an important inhibitor of calcification of blood vesselwalls. Paradoxically, serum OPG levels are associated with theextent of vascular calcification in hemodialysis patients (46,51).This may be a compensatory, protective response to the progressionof vascular calcification or due to the effect of OPG on decreasingbone turnover, thus impairing the ability of bone to bufferCa load (46). It is interesting that a study by Price et al.(52) showed that subcutaneous doses of OPG that inhibited boneresorption in rats were effective in inhibiting arterial calcificationinduced by warfarin or vitamin D.
Finally, fetuin-A has also been shown to be a potent systemicinhibitor of calcification, accounting for approximately 50%of the precipitation inhibitory capacity of serum (49,53). Hemodialysispatients have lower levels of fetuin-A compared with controlsubjects with normal renal function (53). The effect of restoringfetuin-A levels in dialysis patients on progression of CVC hasnot been reported but potentially could represent an attractivetherapeutic modality.
Inhibitors of Bone Resorption
Clinical and experimental studies have consistently establishedan association between arterial calcification and bone resorption(54–56). Consequently, it can be hypothesized that treatmentstrategies that reduce bone resorption and increase bone mineralizationmay simultaneously decrease the risk for vascular calcification.Indeed, several preliminary studies have shown a beneficialeffect of bisphosphonates and other inhibitors of bone resorptionon vascular calcification (54,57).
Etidronate was shown previously to inhibit vitamin D–inducedarterial calcification in rats (58,59). Other bisphosphonates,such as ibandronate and alendronate, also inhibited arterialand cardiac valve calcification after 2 and 4 wk in a warfarin-inducedectopic calcification model (50,54). The effect of intermittentetidronate therapy on progression of vascular calcificationwas recently reported in 35 hemodialysis patients (Figure 4)(59). In that study, three courses of etidronate, 200 mg/d for14 d every 3 mo, significantly suppressed CAC progression withno change in bone mineral density. This effect was associatedwith a decrease in both C-reactive protein and serum OPG levels.
Figure 4. Axial cross-section obtained by spiral computed tomography in a 73-yr-old patient at baseline (A) and after cyclic intermittent etidronate therapy (B). Reprinted from reference (59), with permission.
Aged garlic extracts (AGE), which have antioxidant properties,have the ability to reduce several cardiovascular risk factors,such as BP, serum cholesterol, and platelet aggregation andadhesion, while stimulating nitric oxide generation in endothelialcells (60). As a result, these may improve peripheral circulation.Thus, it has been claimed that AGE impart cardiovascular benefits.It is interesting that a recent small pilot study by Budoffet al. (60) showed that, compared with placebo, AGE may inhibitthe rate of progression of CAC in the general population. Themechanism is probably related to their ability to inhibit atherosclerosis(61).
Limited evidence suggests that CAC has strong genetic determinants(62). Possibly, some genes are procalcification genes, whereasothers are anticalcification (protective) genes. Little is knownabout these CAC susceptibility genes, and it is vitally importantto identify and characterize these genes by identifying thechromosomal regions that harbor them. The identification ofsusceptibility genes for CAC should increase the knowledge aboutCVD risk for a given patient and help to identify those forwhom intensive preventive or therapeutic measures may be mostbeneficial.
So far, the goal of most interventional studies has been toslow or halt progression of CVC. However, whether calcificationcan realistically be reversed, particularly in patients withCKD, is not known at the present time. It is interesting thatseveral studies have indicated that reversal of calcificationmay indeed be possible. Callister et al. (29) reported regressionof Ca volume score in 63% of 65 patients with LDL levels <120mg/dl. In another study of 102 symptomatic patients with CAC,Schmermund et al. (20) reported that standard therapy for coronaryartery disease resulted in regression of calcification in 15%of patients with suspected or known coronary artery diseaseon follow-up EBCT scans. Although it is possible that regressionof calcification may be due to interscan variability, theseauthors speculated that reduction of calcification may be theresult of shrinkage and increased density of the calcified lesions.Given that CAC may be predictive of cardiovascular events anddeath from CVD, interventions designed to induce regressionof calcification may help to reduce the risk for death in patientswith CKD and coronary artery disease.
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Top
Abstract
Introduction
2-Heremans-Schmid glycoprotein-Ahsg) may be protective from vascular calcification (46–49). Mice deficient in MGP or OPG develop spontaneous vascular calcification (48). Similarly, mice deficient in fetuin-A also develop severe ectopic calcification when fed a mineral- and vitamin D–rich diet or when fed a normal diet when combined with a DBA/2 genetic background (49). Unfortunately, the therapeutic potential of these inhibitors of calcification has not been explored in clinical trials. However, because MGP requires vitamin K for 
-carboxylation, acquired vitamin K deficiency, as with the use of warfarin, may predispose to vascular calcification (50). It is interesting that calciphylaxis, or calcific uremic arteriolopathy, has been reported with increasing frequency in patients who are treated with warfarin therapy (11). Thus, it is possible that by avoiding the use of warfarin in patients with CKD, the risk for CVC may be reduced by not interfering in the production of MGP. 
, Initial values; 
, final values for coronary artery Ca volume scores. As can be seen, patients in group 1 who were not treated with 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor had significant progression of CAC. Similarly, patients in group 2 who were also treated but their average LDL cholesterol levels remained >120 mg/dl had significant progression of calcification. Patients in group 3 who were treated with HMG-CoA reductase inhibitor and their average LDL cholesterol levels were successfully reduced to <120 mg/dl had no progression of calcification. Reprinted from reference (
