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Perit Dial Int 27(Supplement_2): 215-222
2007
© 2007 International Society for Peritoneal Dialysis
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Part 6: Cardiovascular Complications in PD

AN OVERVIEW OF THE PATHOPHYSIOLOGY OF VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE

Tomasz Stompór

Chair and Department of Nephrology, Medical Faculty, Jagiellonian University, Cracow, Poland

Correspondence to: T. Stompór, Chair and Department of Nephrology, Medical Faculty, Jagiellonian University, 15c Kopernika Str., Cracow 31-501 Poland. stompin{at}mp.pl


   ABSTRACT
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Abnormalities of calcium–phosphate balance, with subsequent bone metabolism disorders, are among the key and earliest features of chronic kidney disease (CKD). Recently, another consequence of these abnormalities was brought to light—namely, vascular calcification. Most studies performed in patients on dialysis suggest that their vascular calcification is more advanced than that seen in the general population. Furthermore, the progression of vessel wall mineralization is much more dynamic in patients with CKD.

Apart from the commonly assessed factors that promote vascular calcification, such as age, duration of dialysis, or poor control of calcium–phosphate status, several other factors have recently been identified. In the spectrum of substances involved in the regulation of the process of soft-tissue calcification, the most extensively studied in the nephrology literature are bone morphogenetic protein 7, osteoprotegerin, matrix Gla protein, fetuin-A, and the phosphatonins. Better understanding of the mechanisms underlying excess vascular mineralization have led to the development of promising new therapies.

KEY WORDS: Chronic kidney disease; vascular calcification; calcification score; fetuin-A; osteoprotegerin; bone morphogenetic protein 7; phosphatonins; sevelamer; calcimimetics.

Abnormalities in calcium–phosphate balance develop early in the course of chronic kidney disease (CKD). For many years, the approach to abnormalities in calcium–phosphate balance considered mostly the bone consequences. Currently, the real effects of these abnormalities are known to go far beyond osteodystrophy.

In several observational studies, a tight association has been observed between elevated serum phosphate, intact parathyroid hormone, CaxP product, and mortality (1). These associations cannot be explained simply by osteodystrophy and its complications. It seems likely that the relationship between calcium–phosphate balance and outcome of patients on dialysis can be explained to a large extent by the effect of the observed abnormalities on the cardiovascular system.

Several recently introduced imaging techniques have enabled a quantitative approach to the content of mineral deposition within the vascular wall, predominantly in the aorta and coronary arteries. The most popular of these techniques are currently electron-beam computed tomography and multislice spiral computed tomography. Several cross-sectional and follow-up studies revealed that, in patients with advanced kidney failure, the initial advancement of the calcification score (CaS, the quantitative measure of mineral burden within the vessel wall) and its progression over time are much more pronounced than in the general population—that is, in subjects with normal kidney function. Table 1 summarizes some of the relevant studies.


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  		TABLE 1 Selected Studies on Coronary Artery Calcification in Patients with Chronic Kidney Disease

 


   FACTORS DETERMINING THE DEVELOPMENT AND PROGRESSION OF VASCULAR CALCIFICATION IN END-STAGE RENAL DISEASE PATIENTS
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Several classical factors that determine the value of the CaS have been identified: age, presence of coronary artery disease, dialysis duration, duration of the entire period of CKD, body mass index, and lipid profile abnormalities (2,3,10,15). Interestingly, in other studies, no association could be demonstrated between advancement of calcification and variables such as dialysis duration, lipid profile, presence of diabetes, or hypertension (2).

Many reports observed associations between the initial advancement of calcification (and its further progression) and serum calcium, phosphate, CaxP product, number of hypercalcemic episodes, and the dose of calcium given to bind dietary phosphate (3,4,11,13,15,16). Interestingly, these data are not fully consistent, given that some authors failed to demonstrate such associations (2,10).

In the first milestone study in the field, Braun et al. (2) failed to find any relationship between various parameters of calcium–phosphate balance, but they noticed that the CaS correlated inversely with bone mineral density in the lumbar spine. Those findings suggest that bone metabolism and turnover may affect the degree of mineral content deposition within the vascular wall. The results obtained by many other authors, and data from our own group, point to a possible relationship between vascular calcification and bone turnover. For example, studies by our group found that, in patients on peritoneal dialysis (PD) who are characterized by low levels of serum intact parathyroid hormone (iPTH), the CaS progresses significantly faster than in those with higher levels of iPTH (13). Also, in other reports, low iPTH or low serum alkaline phosphatase (ALP) activity were found to be associated with more pronounced calcification (3,16). A similar association between calcification and PTH was previously observed in heart valves (17).

Because low PTH and ALP may be considered indirect measures of low-turnover bone disease, these findings accord with the general concept that metabolically "silent" bones in adynamic bone disease, which are not able to incorporate the mineral substances absorbed from the gut, leave the substrate "ready-for-use" for vascular calcification (18). An inverse correlation between the advancement of calcification measured semi-quantitatively and "real" bone turnover as assessed by histomorphometry has also been shown in ESRD patients (19).

The chronic "nonspecific" inflammatory state of uremia, a well-defined factor promoting and accelerating atherosclerosis, has also been studied in the context of vascular calcification. Many studies performed in ESRD patients (7,13,16,20) have demonstrated that advancement of vascular or valvular calcification is associated with serum levels of inflammatory markers such as C-reactive protein (CRP), interleukin-6, and tumor necrosis factor {alpha} (TNF-{alpha}). Correlations between coronary artery CaS and leptin were also observed by our group (7). And recently, Wang and colleagues confirmed the link between malnutrition, markers of inflammation, atherosclerotic vascular disease, and cardiac calcification in PD patients—rightly extending the previously-known term "malnutrition–inflammation–atherosclerosis syndrome" to "malnutrition–inflammation–atherosclerosis–calcification syndrome" (20).


   PATHOPHYSIOLOGY OF VASCULAR CALCIFICATION: ROLE OF PROTEINS REGULATING PHYSIOLOGIC AND ABNORMAL MINERALIZATION
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Data from clinical studies do not completely explain the pathophysiology of pathologic mineralization. Large discrepancies are seen regarding the associations between several variables and the advancement and progression of vessel wall mineralization. In the case of calcium–phosphate balance parameters especially, some studies do not report the relationship between these parameters and calcification at all. The suggestion, therefore, is that vascular calcification is not just a "passive," concentration-dependent deposition of substrate dissolved in uremic serum, but a precisely regulated—or perhaps "precisely deregulated"—controlled process. More importantly, the nature of the mineral content and the tridimensional organization of the vascular deposits resemble those of "regular" bone (21).

The key cellular effectors of mineralization within the vascular wall are the osteoblast-like cells derived from vascular smooth muscle cell (VSMC) differentiation. In transformed VSMCs, several osteoblast-specific genes become activated, and the cells acquire the ability to synthesize bone-specific extracellular matrix, to accumulate bone-specific minerals, and to form bone-specific tridimensional structures.

One of the key activators of this phenotype change is serum phosphate, which can stimulate certain transcription factors after using sodium-dependent Pit-1 transport to enter a VSMC (22,23). The VSMC may undergo apoptosis, releasing small, membrane-infested fragments called matrix vesicles. These structures are highly homogenous with those released by osteoblasts, chondroblasts, and odontoblasts during physiologic mineralization. The matrix vesicles may serve as nuclei of mineralization: they become surrounded by extracellular matrix, and mineralization follows (22). Again, serum phosphates may also stimulate the release of matrix vesicles.

One prediction that can be made is that all circumstances that stimulate and sustain inflammation within the vascular wall, and all substances that promote VSMC apoptosis, will promote vascular calcification. Indeed, the clinical notion concerning an association between inflammation and calcification may be explained by experimental data. Activated macrophages within the vascular wall and their key proinflammatory product, TNF-{alpha}, can stimulate VSMC–to–osteoblast-like cell transformation (24). Interestingly, TNF-{alpha} stimulates osteoblast-like cells into pro-mineralizing activity, but it acts in an exactly contrary manner on "true" osteoblasts in bone, inhibiting bone formation.

The foregoing mechanism provides a very good explanation for the postulated mineralization link between bone and vascular wall: the same agent promotes the release of minerals from bone and helps to incorporate them into the vessel wall. The adipose tissue–derived hormone leptin can also stimulate osteoblasts and osteoblast-like cell activity (25,26).

In recent years, several new proteins have been identified that may play roles in the regulation of vascular mineralization. Some of them have been well known for many years from other physiologic processes and were only recently identified as either pro- or anti-mineralizing agents.

The first worth mentioning is the interaction between bone morphogenetic proteins 2a (BMP-2a) and 7 (BMP-7). The beneficial effect of slowing and even reversing renal scarring and progression of CKD are what attracted the attention of nephrologists to BMP-7 (27). The BMP-7 protein was demonstrated to block the differentiation of VSMCs into osteoblast-like cells (28–30). The BMP-2 protein antagonizes BMP-7, promoting differentiation of VSMCs into the osteoblast-like phenotype. (Remember that expression of BMP-2 is stimulated by hyperphosphatemia.)

Interestingly, BMP-7 in bone promotes mineralization. Exogenous BMP-7 given to uremic animals significantly reduced their serum phosphate level, even without phosphate-binding agents. In these experiments, treatment with BMP-7 normalized serum phosphate and CaxP product, improved bone turnover, and at the same time, reduced the calcification burden in the aorta (29). This finding demonstrated that BMP-7 may be another substance that links bone turnover and vascular calcification, being beneficial in both sites.

Osteoprotegerin (OPG) emerged as another protein potentially involved in the process of pathologic calcification. This circulating decoy receptor from the TNF-receptor family binds receptor activator of nuclear factor {kappa}B ligand (RANKL) and thereby blocks the activation, maturation, migration, and viability of osteoclasts (31). Animals lacking the OPG gene TBFRSF11B develop severe osteoporosis and disseminated vascular system calcification, an observation that stimulated investigations to find the role of OPG in regulating vascular calcification (32).

In animal models, treatment with OPG completely abolished vascular mineralization caused by large doses of vitamin D or warfarin (33). Hence arose the concept of OPG as an agent preventing pathologic calcification, probably by binding several proinflammatory and promineralizing agents in circulation. However, clinical observations in both the general population and ESRD patients demonstrated an increase in cardiovascular disease severity and vascular calcification with increasing serum levels of OPG (34,35). An explanation for this phenomenon might be that OPG increases to prevent cardiovascular pathology, but that the increase is insufficient to counterbalance the complex action of harmful agents (36). An alternative explanation arises from the notion that high serum levels of OPG parallel low bone turnover in ESRD as assessed with bone histomorphometry (37,38). Hence, OPG may be the marker of low bone turnover—a well-known risk factor for calcification.

Recent experiments performed in mice lacking the OPG gene demonstrated that simultaneous feeding of a calcium- and phosphate-rich diet and treatment with incadronate abolishes vascular system mineralization. The ability to block vascular calcification by blocking bone resorption, even in the absence of OPG, suggests a lack of active protective properties of this substance (39).

The next protein in the list of vascular calcification regulators is matrix Gla protein (MGP). This member of the Gla protein family is activated via vitamin K–dependent {gamma}-carboxylation. As in the case of OPG mice, mice lacking the MGP gene and protein exhibit severe, disseminated calcification of the vascular wall and cartilages, and premature death. Interestingly, inactivating mutations of the MGP gene in humans results in cartilage calcification, shortened terminal phalanges, and mid-facial hypoplasia (Keutel syndrome), but not in vascular calcification nor in impacts on lifespan (40). Despite such a strong background from genetics and basic science, to date no association can be demonstrated between serum level of MGP and calcium–phosphate balance, serum fetuin-A, OPG, or vascular calcification in CKD patients (36).

Probably the most revolutionary and fascinating findings in the field of vascular calcification regulation are associated with fetuin-A (the {alpha}2–Heremans–Schmid protein). This protein has been well known for decades as a negative acute-phase reactant, strongly downregulated in the course of sepsis. Recently, novel properties of this substance were discovered: Fetuin-A–deficient mice develop severe and disseminated soft-tissue calcification, even when their calcium–phosphate balance is normal. Mice with normal fetuin-A expression do not develop calcification even when exposed to a calcium- and phosphate-rich diet after subtotal nephrectomy (41).

Fetuin-A possesses several properties that can explain its anti-mineralizing action in the vessel wall. Its structure resembles the transforming growth factor β receptor, and thus, it can antagonize the action of that growth factor. It decreases macrophage activation and release of proinflammatory cytokines. This latter property may be explained by fetuin-A's promotion of the uptake of endogenous and exogenous inhibitors of TNF synthesis and release by macrophages (42,43). Fetuin-A can also opsonize apoptotic bodies and promote their phagocytosis (44).

In CKD patients, serum levels of fetuin-A are significantly lower than in healthy control subjects and in patients with a functioning renal graft. In addition, in CKD patients, serum levels of fetuin-A are lower among those with diabetes, with higher serum levels of CRP, and with malnutrition and cardiovascular disease (45). Wang and colleagues from Hong-Kong found that fetuin-A levels decrease composites that are increased by the malnutrition–inflammation–atherosclerosis–calcification syndrome (20).

The most important finding concerning fetuin-A is that it is the first substance among the pathologic calcification regulatory proteins that reveals significant and independent associations with morbidity and mortality in ESRD patients. Low serum fetuin-A has been demonstrated to be an independent predictor of all-cause and cardiovascular mortality in patients on hemodialysis. This effect was the opposite of that with CRP: fetuin-A mortality curves are mirror images of those for CRP (46).

Stenvinkel et al. showed similar associations in patients treated with PD or HD. In a multiple regression analysis model that included such "strong" predictors of outcome as diabetes, serum albumin, and CRP, only fetuin-A was independently associated with all-cause and cardiovascular mortality after its inclusion in the model. The same authors indicated that certain polymorphisms in the fetuin-A gene have a strong negative impact on mortality, especially when coupled with a high inflammatory status (47). In the Hong Kong study in this field, exclusively conducted in patients on PD, survival and time to first cardiovascular episode were longer in patients with higher serum levels of fetuin-A (20).

Results of the foregoing studies permit consideration of fetuin-A as the "missing link" between inflammation, atherosclerosis, and calcification in patients with CKD.

In studies of the physiologic regulation of calcium–phosphate balance, a group of new substances has recently emerged—namely, the phosphatonins. The best-examined agent in this group is fibroblast growth factor 23 (FGF23). This hormone possesses a strong phosphaturic action and inhibits 1{alpha}-hydroksylase, the enzyme that activates 25-hydroxyvitamin D to calcitriol in renal tissue (47). As a result, FGF23 has attracted much attention from nephrologists: a high serum level has been found to predict poor response to treatment with calcitriol in secondary hyperparathyroidism and progression of moderate-to-severe and treatment-resistant secondary hyperparathyroidism (48,49).

Transgenic animals lacking the FGF23 gene and protein develop severe and disseminated calcification of soft tissues (including vessel walls), whereas double knock-out (FGF23 and the 1{alpha}-hydroxylase gene) completely protects animals from pathologic calcification (50). These results suggest that FGF23 may protect against excess mineralization, most likely by acting on the 1{alpha}-hydroxylase activity regulation.


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The introduction of quantitative methods that permit assessment of vascular calcification has allowed the renal community to understand the importance of this problem in CKD. During the last few years, the paradigm of diagnosis and treatment of renal osteodystrophy has noticeably changed from being "bone-oriented" to using an integrated approach encompassing bone and the cardiovascular system, which are tightly associated. Because cardiovascular disease remains the leading comorbidity and the most important cause of death in CKD, therapeutically addressing both of these aspects of uremia has become crucial.

First, from large studies such as DOPPS, it can be concluded that much remains to be done to optimize treatment of calcium–phosphate balance abnormalities (18). New drugs are already available that may help to more effectively treat hyperphosphatemia and secondary hyperparathyroidism without concomitant hypercalcemia and exaggerated depression of the parathyroid glands.

Current experience with sevelamer demonstrates that this new phosphate-binding compound may not only effectively control hyperphosphatemia, but also slow down the rate of progression of coronary and aortic calcification (11). More importantly, prolonged treatment with sevelamer, especially in elderly patients, may have beneficial effects, lowering mortality and hospitalization rates (51). Indeed, this drug seems to simultaneously address several mechanisms of vascular calcification: it lowers the serum phosphate level and CaxP product without hypercalcemia and excess depression of parathyroid function, it significantly improves lipid profile, and it reduces the degree of systemic inflammation, most likely by absorption of certain toxins within the bowel lumen (52).

It is probably too early to judge the true value of another drug in this field, cinacalcet, in terms of its impact on vascular calcification; however, in a large cohort of patients treated with cinacalcet, a significant reduction in hospitalization attributable to cardiovascular disease was observed as compared with hospitalization seen in control subjects. In addition, a nonsignificant 19% reduction in all-cause mortality was observed in the active treatment arms of cinacalcet studies (53). The exact mechanism of this difference cannot be clearly explained at this point, but speculation about the beneficial effects of this calcimimetic agent on vascular calcification is tempting. Last but not least, the data concerning survival benefit in patients treated with a non-hypercalcemizing analogue of vitamin D accord with the foregoing observations (54).

No clear statement can be made with regard to statins. Some studies performed in the general population suggested a benefit associated with the use of these drugs in lowering the rate of progression of calcification (55,56). Unfortunately, prospective and randomized trials failed to confirm such a benefit (57,58). In recent months, the renal community has been largely unimpressed (and probably disappointed) by the results of Die Deutsche Diabetes Dialyse study, which has shown no clear benefit from statin treatment in the high-risk ESRD population (59). Several other studies exploring this issue are still ongoing and may clarify the effect of statins on various endpoints in CKD patients. Recently, Quinibi undertook to analyze the effect of atorvastatin combined with "traditional" calcium-containing phosphate binder on vascular calcification (60).


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Currently, we are witnessing the emergence of new, revolutionary therapies for many diseases. The very best examples in the field of calcium–phosphate balance abnormalities are the calcimimetics, treatments developed based on identifying and understanding the biology of calcium-sensing receptors. Recently, new compounds that interfere with the RANK–RANKL–OPG axis—for example, human recombinant anti-RANKL monoclonal antibody—were introduced into the treatment of postmenopausal osteoporosis and osteolytic metastases to bone (61,62).

Based on these examples, it cannot be excluded that, sometime in the future, new-generation agents such as recombinant BMP-7 or fetuin-A will be used in ESRD patients at risk of vascular calcification. And if that idea seems fantastic today, who could have predicted 25 years ago that recombinant human erythropoietin would be readily available in every renal ward for routine treatment of anemia? Furthermore, it should be remembered that kidney transplantation remains the most important and successful therapy for ESRD, including from the view-point of vessel wall mineralization.


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