Soft tissue calcification that involves primarily the medialportion of the arterial vasculature is a widely recognized andcommon complication of chronic kidney disease Vascular calcification(VC) causes increased arterial stiffness and contributes tothe high cardiovascular mortality and morbidity in dialysispatients. The pathogenesis of VC is complex and includes factorsthat promote calcification and others that inhibit calcification.Studies in dialysis patients have shown a correlation betweenVC and a number of uremia-related factors. Overall, abnormalitiesin calcium and phosphate metabolism, such as hyperphosphatemiaand a raised serum calcium-phosphorus product traditionallyhave been thought of as important determinants in patients withchronic renal failure. Common therapeutic interventions in secondaryhyperparathyroidism have come under scrutiny for associationswith the development of VC. Calcimimetics provide a means ofcontrolling serum levels of parathyroid hormone in secondaryhyperparathyroidism without increasing the calcium-phosphorusproduct and, more important, may lower the risk for VC in thesepatients.
Secondary hyperparathyroidism (SHPT) generally develops earlyin chronic kidney disease (CKD), before dialysis is needed;consequently, most patients who have ESRD and are undergoingdialysis will have elevated parathyroid hormone (PTH) and SHPTof variable severity (1–3). Cardiovascular disease accountsfor almost half of all deaths in patients with ESRD, with riskbeing particularly elevated in younger individuals (4). Patientswith CKD may develop soft tissue calcification of various typesand locations, including vascular calcification (VC). This processstarts long before reaching ESRD (5).
Intima calcification: Depositsof calcium and phosphate in atheromatousplaques. It is associatedwith lipid-laden macrophages and intimalhyperplasia.
Mediacalcification: Characterized by diffuse deposits in themedialayer of the arterial tree. Occurs in the media of thevesselin conjunction with a phenotypic transformation of smoothmusclecells into osteoblast-like cells (6).
Calciphylaxis: Alsocalled calcific uremic arteriolopathy, amuch more infrequent,rapidly progressive form of VC.
Medial arterial calcificationoften leads to stiffening and decreased compliance of bloodvessels, which in turn leads to increased systolic BP, reduceddiastolic BP, and increased pulse pressure (7). These hemodynamicchanges may result in increased afterload, left ventricularhypertrophy, decreased coronary artery perfusion, and increasedrisk for death (8). Coronary artery calcification has been linkedto increased risk for cardiovascular events such as myocardialinfarction, fatal arrhythmia, and congestive heart failure (9,10).Therefore, given that cardiovascular calcification may leadto serious clinical consequences, it is possible that interventionsthat are designed to slow or even reverse the process of calcificationmay lead to improved patient outcomes.
The causes of calcification in CKD remain to be to elucidatedAssociated risk factors include age, hypertension, diabetes,male gender, white race, and time on dialysis. Many local factorsare involved in the regulation of the calcification process,by either inhibiting or stimulating VC and the associated phenotypictransformation of local vascular smooth muscle cells (VSMC)toward osteoblast-like calcifying cells (11). SHPT is associatedwith elevated serum calcium and phosphorus, and calcium-phosphorusproduct (Ca x P), and these elevations have been associatedwith an increased risk for VC (10,12–14).
If the serious consequences of SHPT are to be avoided in patientswho are on dialysis, then PTH, phosphorus, and calcium all mustbe managed effectively. However, common therapeutic interventionsin SHPT have come under discussion for associations with thedevelopment of VC (15,16). The National Kidney Foundation recentlypublished revised targets for PTH, calcium, phosphorus, andCa x P levels as part of its Kidney Disease Outcomes QualityInitiative (K/DOQI) program (17). It is hoped that these guidelineswill help physicians to improve control of SHPT and clinicaloutcomes, because published observational studies suggest thatphysicians find it difficult to achieve optimal control of PTHand mineral levels in their patients (18,19). Given that fewpatients have optimally controlled PTH and mineral levels, itis cause for concern that even these patients do not seem toremain within treatment targets over the long term (20,21,22).
Traditional SHPT therapies, particularly vitamin D sterols andcalcium-based phosphate binders, have failed to assist the majorityof patients to achieve K/DOQI goals In addition, they can exacerbatemineral imbalances, resulting in hypercalcemia and further hyperphosphatemiaand consequently an increase in the risk for VC.
The severe outcomes that are associated with poorly controlledSHPT emphasize the need for improved pharmacologic management.Several treatment options are available, but many data suggestthat these agents do not allow physicians to achieve and sustainnew therapeutic targets in the majority of their patients.
Calcium supplementation has several limitations, and concernsabout calcium overload have led to the revision of dosing recommendationswith an earlier limit of 6 g of elemental calcium per day beingreduced to a new maximum of 1 to 2 g/d (23,24).
Vitamin D and analogue supplementation and, eventually, activevitamin D therapy are the mainstay of treatment for SHPT. Unfortunately,a substantial proportion of patients do not respond to vitaminD therapy (25–27), most likely those with advanced SHPT,in whom nodular hyperplasia has reduced expression of vitaminD receptors and calcium-sensing receptors (CaR). In additionto its effects on PTH synthesis, vitamin D has an indirect effecton PTH through facilitating the intestinal absorption of calcium,and it may induce episodes of hyperphosphatemia and/or hypercalcemia(25,26). Accordingly, vitamin D therapy may add to the riskfor extraskeletal calcification (28). It has been suggestedthat newer vitamin D analogues are less calcemic than calcitriol,although hypercalcemic episodes also have been. As such, vitaminD and its analogues are contraindicated in patients with highcalcium or phosphorus levels, and episodes of hypercalcemiaand/or hyperphosphatemia may necessitate dosing adjustmentsor temporary withdrawal of therapy (29–31).
Finally, it has become apparent that sustained treatment withhigh-dosage vitamin D can cause oversuppression of PTH, leadingto the onset of adynamic bone disease. Further administrationof vitamin D may induce hypercalcemia, thereby increasing therisk for VC in affected patients (23). A second mechanism forinducing VC is that the active vitamin D sterol calcitriol mayact on specific vitamin D receptors that are constitutivelyexpressed by VSMC (32). Calcitriol has been shown to increaseexpression of several proteins that are involved in calcification(e.g., alkaline phosphatase) and to decrease expression of proteinsthat inhibit calcification (e.g., PTH-related peptide [28,33]).
Among other treatment options that are available as SHPT therapiesfor those in whom dietary restriction is not sufficient to controlserum phosphorus levels, phosphate-binding agents must be prescribed.Of the currently available phosphate-binding agents, the majorityof patients with hyperphosphatemia now receive either calcium-basedphosphate binders or the noncalcium, nonaluminum agent sevelamerHCl, which have been shown to be similarly effective in clinicaltrials (34). Calcium-based agents unfortunately can add to systemiccalcium load and have been associated with increased risk forcardiovascular calcification by a number of authors (14,35).
The most recently approved phosphate binder is lanthanum carbonate.Lanthanum carbonate has been shown to reduce serum phosphoruslevels. However, because of similarities to aluminum, concernsabout long-term safety with lanthanum have been voiced (36).Although recently presented preliminary evidence suggests thatthere are no aluminum-like effects on bone in the clinic (37),the long-term effects remain to be elucidated. The efficacyof these agents also is compromised in that they are able tobind only dietary phosphate and not phosphorus that is releasedfrom skeletal stores.
Calcimimetics are small, orally active organic compounds thatincrease CaR sensitivity to extracellular calcium, thus maximizingthe suppressive effect of calcium on PTH secretion and production(38). In SHPT, the CaR-mediated balance between PTH and calciumoften is skewed in that inappropriately low levels of PTH arereleased on the basis of serum calcium levels. This suggeststhat increasing the sensitivity of the parathyroid gland toextracellular calcium through the modulation of the CaR mayhave therapeutic potential.
The utility of cinacalcet in the treatment of SHPT has beendemonstrated in several clinical trials (39–42). In anearly study, patients who had SHPT and were on hemodialysiswere administered cinacalcet that ranged from 10 to 50 mg/dor placebo for 8 d. Treatment with the higher dosages of cinacalcetresulted in reductions in plasma PTH, Ca x P, calcium, and phosphorus(39).
Two additional 18-wk studies explored the efficacy and the safetyof cinacalcet in dialysis populations with uncontrolled SHPT.Patients who were enrolled in these studies were required tohave a minimum PTH of 300 pg/ml, but no upper limit was established.These trials consisted of two phases: A 12-wk dosage-titrationphase to establish an efficacious dosage of cinacalcet and a6-wk maintenance phase to explore the sustainability of thetherapeutic effect. Patients were treated with a range of dosages(20 to 50 mg/d [41] or 25 to 100 mg/d [40]). During the maintenancephase, the mean PTH, Ca x P, calcium, and phosphorus were reducedafter treatment with cinacalcet.
These positive data were supported and reinforced by a reportthat combined two major Australian, European, and United Statesphase 3 trials (42). Patients who had SHPT and were undergoingdialysis were treated with standard-of-care therapy (vitaminD analogues and/or phosphate binders) or standard-of-care therapyplus cinacalcet (30 to 180 mg/d) for a total of 26 wk (12-wktitration phase and 14-wk efficacy assessment phase). Patientsresponded well to cinacalcet treatment, with significant reductionsin the four key K/DOQI laboratory target guidelines during theefficacy assessment phase. Significant differences in PTH andCa x P between groups occurred by 2 wk after the start of treatment.In addition to the reduction in PTH overall, a significant portion(43%; P < 0.001) of cinacalcet-treated patients achievedmean PTH levels 250 pg/ml, the primary study end point. An evenmore substantial proportion (64%) achieved a 30% reduction inPTH. Similar achievement of the iPTH 30% reduction occurredregardless of baseline PTH level (300 to 500 pg/ml, 501 to 800pg/ml, and >800 pg/ml). Changes in vitamin D dosage seemedto have no significant effect on the cinacalcet-induced reductionsin PTH and Ca x P. Of note, the significant improvement in Cax P (–14.6%; P < 0.001) resulted from significant improvementsin both serum calcium (–6.8%) and phosphorus (–8.4%)levels (both P < 0.001) after treatment with cinacalcet inrelation to placebo (0.5, 0.4, and 0.2%, respectively). Thesedata suggest that cinacalcet treatment could be an effectivetherapeutic option in patients regardless of disease severityof SHPT or vitamin D analogue status.
Several preliminary reports have described the long-term efficacyof cinacalcet in patients who had SHPT and entered extensiontrials after the successful completion of one of a number ofcinacalcet trials. Briefly, these studies suggested that cinacalcetcan assist patients to reduce their PTH and Ca x P with thesereductions sustained for up to 1 yr after the initiation oftherapy (43), control their PTH and Ca x P levels for >3yr (44), and assist a substantial proportion of patients toachieve the K/DOQI targets for PTH and Ca x P (45). Cinacalcetwas reported to be well tolerated in all of these studies. Itshould be borne in mind that the patients who entered thesetrials previously had completed successfully another cinacalcettrial, although they could have received placebo in this earliertrial. These data are encouraging for the long-term efficacyand safety of cinacalcet in patients with SHPT.
Interim data from two ongoing studies, Treatment Strategiesto Achieve Recommended K/DOQI Goals in ESRD Subjects on Cinacalcet(TARGET) and Cinacalcet Open Label Study To Reach K/DOQI Levels(CONTROL), support the ability of cinacalcet to maintain orimprove K/DOQI variables within target ranges with reduced dosagesof vitamin D analogues. In TARGET, cinacalcet assisted patientsto achieve target PTH while lowering Ca x P (46). Similarly,in CONTROL, patients with PTH within the target range but withelevated Ca x P exhibited maintenance of PTH and achievementof Ca x P goal (47).
Because calcimimetics reduce PTH levels without the inductionof hypercalcemia, it is likely that patients who have advancedCKD and are treated with a calcimimetic may show less risk forVC than patients who are treated with vitamin D sterols. Toexplore this concept better, Henley et al. (48) in a rat modelof SHPT (five-sixths nephrectomy) studied the administrationof cinacalcet HCl, 1,25-dihydroxyvitamin D3, or the combination.Calcitriol-treated rats had moderate to marked aortic calcification,whereas no significant calcification was observed in vehicle-or cinacalcet HCl only–treated groups. Cinacalcet HCland calcitriol both effectively reduce PTH, albeit via differentmechanisms, but unlike calcitriol, cinacalcet HCl did not producehypercalcemia, an increased Ca x P, or VC. However, calcitriol-producedaortic VC was unaffected by concomitant treatment with cinacalcetHCl.
Lopez et al. (49) studied the effect of the calcimimetic R-568alone or in combination with calcitriol on the development ofVC and other soft tissue calcifications in a rat model of uremia-associatedSHPT. They studied both calcitriol and R-568. Treatment withcalcitriol induced significant VC (aortic Ca increased) andwith R-568 did not induce VC. Concurrent administration of R-568with calcitriol reduced the aortic Ca in relation to calcitriolalone. Soft tissue calcifications mirrored aortic mineralizations.They concluded that in uremic rats, R-568 reduces elevated PTHlevels without inducing VC and prevents calcitriol-induced VC.
The calcitriol-induced VC was localized consistently in themedia of the aorta of uremic rats. The mineralizing effect ofcalcitriol can be explained by the increase in the serum Caand P observed after its administration, although other smoothmuscle–based mechanisms also may play a role (28). Thiskind of calcification is independent of lipids and seems tobe related to phenotypic transformation of smooth muscle cellsinto bone-producing cells (6).
How can the anticalcification effect of the calcimimetic beexplained? The most valuable explanation is related to the controlof PTH levels without increasing the Ca x P. Lopez et al. (49),in addition, pointed to a direct action of calcimimetic at thecellular level on the arterial wall. Vessels express CaR (50),and some investigators have demonstrated the presence of CaRusing a polyclonal antibody to the CaR (51), whereas other preliminarystudies have failed to detect CaR in bovine and human VSMC usingRNase protection assays (52). Calcium modulates the functionof vessels, and it is of considerable importance the findingsthat calcimimetics influence BP profile.
VC contributes to the high cardiovascular mortality and morbidityin dialysis patients. SHPT often is associated with elevatedserum calcium and phosphorus and Ca x P, and common therapeuticinterventions in SHPT have come under scrutiny for associationswith the development of VC. Calcimimetics provide a means ofcontrolling serum levels of PTH in SHPT without increasing theCa x P and, more important, may lower the risk for VC in thesepatients.
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Top
Abstract
Introduction
250 pg/ml, the primary study end point. An even more substantial proportion (64%) achieved a 
30% reduction in PTH. Similar achievement of the iPTH 
