Calcemia is a risk factor for cardiovascular (CV) events indialyzed patients. The relation between serum calcium and cardiovascularevents is continuous and linear. Calcium plays a potent rolein the genesis of cardiovascular dysfunction, particularly bypromoting vascular calcification. Parathyroid hormone (PTH)also is associated with increased CV risk in both primary andsecondary hyperparathyroidism. There is a nonlinear relationshipbetween PTH and CV risk; both high and low PTH concentrationsincrease CV risk. The CV risk profile (BP, dyslipidemia) isstrikingly ameliorated by the administration of calcimimetics.Apart from lowering PTH, whether calcimimetics have intrinsiceffects on CV risk profile is unknown.
Correlations between Survival on Dialysis and Calcemia or Calcium Regulatory Hormones
It has been known for some time that cardiovascular (CV) morbidityand mortality are increased dramatically in patients who areon maintenance hemodialysis (1,2). For a long time, it has notbeen appreciated that concentrations of parathyroid hormone(PTH) as well as of calcium and phosphate have an impact onpatient survival. In 1998, Block et al. (3) reported a progressiveincrease in mortality when the predialytic phosphate concentrationexceeded 6.5 mg/dl. Subsequent analyses showed that this wasdue to an increase in coronary mortality (4). More recently,it has been documented that high phosphate concentrations promotevascular calcification (5–7) but also other cardiovascularabnormalities (8).
The impact of calcium on survival has been less obvious. Thisis because interactions between calcium phosphate and PTH arecomplex (9,10). Block et al. (10) observed a continuous linearincrease of CV mortality with increasing predialytic concentrationsof calcium (corrected for protein). One potential explanationfor the strikingly adverse effect of calcemia is potentiallythe observation of Ghiacelli and colleagues (11,12) that calciumpotentiates the ability of phosphate to promote vascular calcification.This observation is particularly important because, with theexception of calcimimetics, all interventions to reduce PTHconcentration are associated with an increase of calcemia andthe Ca x P product, e.g., active vitamin D- or calcium-containingphosphate binders.
It is widely known that in primary hyperparathyroidism, CV morbidityand mortality are increased (13,14). This is associated withan adverse CV risk profile, particularly hyperlipidemia (15).
Against this background, it was surprising that numerous studiesfailed to find a clear-cut relationship in hemodialysis patientsbetween intact PTH concentration and CV events or survival.This is explained by the recent observation of Stevens et al.(9) that the relation between PTH and mortality is nonlinear,mortality being higher for both high and low PTH concentrations.Low PTH concentrations are presumably a surrogate marker forand associated with low bone turnover, which is known to increasethe risk for vascular calcification (5).
The adverse CV outcome in patients with high PTH concentrationsis presumably not only explained by the association betweenPTH and high serum calcium and phosphate concentrations. Itpresumably also reflects direct adverse effects of PTH on cardiacfunction (16–18) and cardiac morphology. We could showthat PTH is a permissive factor for the development of cardiacfibrosis or microvessel disease (19,20). It was among othersbecause of the impact on cardiac dysfunction that PTH had beendesignated a "uraemic toxin" (21). Two recent retrospectiveanalyses documented higher perioperative mortality but superiorlong-term survival in hemodialysis patients after parathyroidectomy(22,23), suggesting that high PTH concentrations have an adverseeffect on survival of hemodialyzed patients.
A major breakthrough in the management of the deranged calciumphosphate metabolism of dialysis patients was achieved recentlywith the introduction of calcimimetics (24). These are the firstagents that lower PTH without increasing the concentrationsof serum calcium and phosphate. Calcimimetics act as allostericmodulators of the calcium-sensing receptor (25,26). This receptoris ubiquitously expressed in almost all cells. The questionarose whether administration of calcimimetics has (potentiallyadverse) effects beyond lowering of PTH. To address this issue,Ogata et al. (27) performed in subtotally nephrectomized ratsan experiment that proved that the calcimimetic NPS-R 568 loweredBP, reversed dyslipidemia, attenuated progression (reductionof albuminuria, less glomerulosclerosis), and improved cardiacmorphology (capillary density, fibrosis). The magnitude of theseeffects was comparable to that seen with parathyroidectomy,illustrating the concept of Massry that PTH is a uremic toxin(21)
It is currently unsettled whether all of these effects of calcimimeticson the CV risk profile are due to lowering PTH or calcimimeticshave direct effects on target structures such as vessels oradipocytes. Vessels (28) as well as adipocytes (29) expresscalcium-sensing receptors. Calcium modulates the function ofvessels, i.e., reduces luminal width followed by vasodilation(28), and the function of preadipocytes, i.e., suppresses expressionof differentiation markers such as peroxisome proliferator-activatedreceptor , diminishes fat storage, etc. (29). In this context,our recent finding that calcimimetics influence the BP profile,as measured by telemetry, is of considerable interest (30)
An unknown factor is the action of vitamin D on CV risk. Theissue is of clinical relevance, because it is likely that despitenew approaches to patient management, including calcimimetics,the need for administration of vitamin D or its analogues, presumablyin lower doses, will persist. The issue is very complex (31).On the one hand, adequate vitamin D is essential for optimalvascular function (32). Absence of vitamin D as in vitamin Dreceptor knockout mice causes hypertension and high renin expression(33), and, conversely, 1,25(OH)2D3 amplifies expression of ANPtype A receptors, which should be beneficial for CV risk (34).On the other hand, vitamin D, admittedly at toxic and hypercalcemicdoses, was proatherogenic in animal models (35); more convincingly,it also exacerbated intimal hyperplasia after carotid ballooninjury (36). Furthermore, it stimulated processes that are involvedin atherogenesis, such as proliferation and migration of vascularsmooth muscle cells (37). It is interesting that a retrospectiveobservational study suggested recently that mortality, includingCV mortality, was less in hemodialyzed patients who were treatedwith paricalcitol as compared with calcitriol (38). It has beensuggested that paricalcitol does not act as a classical agonistbut rather as a vitamin D receptor modulator. Definite prooffor this concept and replication of the finding in a controlledprospective study are not yet available, however. This wholearea is in dire need of further investigation.
It follows from the above that calcium and calcium regulatoryhormones are important CV risk factors and contribute to thediminished survival of uremic patients who are on maintenancehemodialysis. It remains to be seen whether calcimimetics bycontrolling hyperparathyroidism without provoking an increasein calcemia and phosphatemia will improve survival of dialyzedpatients.
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Abstract
Correlations between Survival on...
, diminishes fat storage, etc. (29). In this context, our recent finding that calcimimetics influence the BP profile, as measured by telemetry, is of considerable interest (30) 
