Bone and vascular health and the kidney




Jorge B. CANNATA-ANDÍA MD, PhD
Pablo ROMÁN GARCÍA, BSc
Ivan CABEZAS-RODRIGUEZ, MD
Minerva RODRIGUEZ-GARCÍA MD, PhD
Bone and Mineral Research Unit
Hospital Universitario Central
de Asturias, Instituto Reina Sofía
de Investigación, REDinREN del
ISCIII, Universidad de Oviedo
Oviedo, Asturias, SPAIN

Bone and vascular health and the kidney

by J . B. Cannata-Andía, P. Román García, I . Cabezas -Rodr iguez, and M. Rodriguez-García,Spain

In patients with progressive chronic kidney disease (CKD), the homeostatic mechanisms regulating calcium and phosphate metabolism suffer important changes, resulting in low serum levels of calcitriol and calcium and phosphorous retention. The regulatory mechanisms fail and several chronic kidney disease mineral bone disorders (CKD-MBD) occur, including bone disease, vascular calcifications, cardiovascular disorders, bone fragility fractures, and reduced survival. Vascular calcification, bone loss, and increased fracture risk are severe disorders associated with aging in chronic CKD, but also generally speaking. Several epidemiological studies have shown the relationship between impaired bonemetabolism, vascular calcification, and increasedmortality. Recent data suggest this association may be not just a consequence of aging. The frequent occurrence of severe cases of vascular calcification together with low bone activity and osteoporosis suggests direct biological links may exist between bone and the vascular system. New challenging experimental data suggest that once severe vascular calcifications set in, vessels may develop amechanismto diminish vascularmineralization in the arterial wall, and that this defensive mechanism may have a negative impact that favors the reduction of bone mass.

Medicographia. 2010;32:370-376 (see French abstract on page 376)

In healthy individuals, the kidneys regulate calcium and phosphorus homeostasis through active tubular mechanisms. Hormones and factors that contribute to kidney regulation of calcium and phosphorus include 1,25-dihydroxyvitamin D (1,25 [OH]2D or calcitriol), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF- 23). In patients with progressive chronic kidney disease (CKD), the normal homeostaticmechanisms are challenged, leading to important compensatory changes in serum levels of calcium, phosphorus, calcitriol, FGF-23, and PTH. All these changes lead in part to several manifestations that for almost 60 years have been known as “renal osteodystrophy.”1 In addition, clinical, epidemiological, and experimental data have identified a clear association between the aforementioned changes in biochemical markers and some relevant outcomes such as vascular calcification, myocardial dysfunction, and mortality. As a result, a new term—chronic kidney disease–mineral bone disorder (CKD-MBD)—has been recently coined to encompass all these disorders.2

Clinical impact and pathogenesis of mineral and bone disorders

The calcium, phosphorus, vitamin D, PTH, and FGF23 axis is closely regulated and interrelated. Several of the compensatory variations in the aforementioned factors take place at the same time under the control of complex feedback mechanisms.3-5 The progression of CKD leads to a decrease in active renal mass and then to a reduction in 1-alpha hydroxylase in the kidney, which in turn results in low levels of calcitriol, the physiological active form of vitamin D, impairing calcium absorption in the intestine and favoring the reduction in serum calcium. As a result, the decreases in serum calcium stimulate parathyroid hormone (PTH) synthesis and release, increasing bone turnover, bone resorption, and the stimulation of 1-alpha hydroxylase. All these mechanisms lead to compensatory increases in serum calcium.

In addition, the progressive reduction in renal function impairs phosphorus excretion, leading to increases in serum phosphorus, which stimulates the synthesis of both FGF23 and PTH. Thee two factors work in the same direction, increasing urinary phosphorus excretion. However, it is important to stress that, regarding vitamin D metabolism, the response is more complex, and FGF23 and PTH work in opposite directions: regarding calcitriol synthesis, FGF23 inhibits 1-alpha hydroxylase, reducing calcitriol synthesis, whereas PTH stimulates it.6-8 As renal function decreases, all these complex and tightly interrelated mechanisms of parathyroid gland regulation become insufficient and fail to adequately control parathyroid gland function and calcium and phosphorus homeostasis.

As a result, low serum levels of calcitriol and calcium, coupled with a trend toward phosphorus retention, prevail in the more advanced stages of CKD.3-5 Furthermore, in CKD stage 5D, severe forms of secondary hyperparathyroidism are frequently found, with diffuse and nodular parathyroid hyperplasia, as well as clinically relevant monoclonal growth with reduction in the expression of the vitamin D and calcium-sensing receptors (VDR and CaSR).9-11 These changes are the main culprits for the poor response of the parathyroid glands to the increments in serum calcium and active vitamin D therapy. Finally, due to the lack of adequate parathyroid gland control, there is a clear trend toward autonomous parathyroid gland behavior (tertiary hyperparathyroidism), which frequently requires surgical removal of the glands.

Many of the aforementioned abnormalities and others beyond the scope of this review end up not only inducing several varieties of bone disease, but also vascular calcifications, cardiovascular disorders, bone fragility fractures, and a higher mortality risk. The recently coined term CKD-MBD encompasses all these mineral and bone metabolism disorders.2-12 As CKD is subdivided according to the degree of renal function into five stages, it is important to stress that marked differences exist between the initial and final periods of CKD.

Clinical impact and pathogenesis of vascular calcification

The predisposition of CKD patients toward the development of vascular calcification was mentioned for the first time in the 19th century; since then, many studies have looked into this issue. Vascular calcification can be classified into three types according to the size and structure of the arteries: elastic or large-caliber arteries, muscular or medium-caliber arteries, and small-caliber arteries.13

Elastic or large-caliber arteries show a relatively thin wall in proportion to their diameter, and the tunica media contains more elastic fibers than smooth muscle fibers. Muscular or medium-caliber arteries contain a greater proportion of smooth muscle fibers than elastic fibers in the tunica media; finally, small-caliber arteries contain only smooth muscle fibers in the tunica media. The classic description of arterial calcification specifies that it may occur in two locations: the intima and the media layers.14 Nevertheless, this classic concept is not fully accepted by all authors.15,16

Intimal calcification begins and progresses under the influence of both genetic and lifestyle-related circumstances. It is associated with a sequence of atherosclerotic events such as endothelial dysfunction, intimal edema, lipid cell formation, plaque rupture, and formation of the thrombus.17 They have a patchy distribution along the length of the artery and cause local stenoses and occlusions. They are associated with several risk factors such as inflammation, alterations in lipid metabolism, obesity, hypertension, diabetes, smoking, and a family history of heart disease.

Media calcification occurs in the elastic lamina of large-caliber and medium-to-small-sized arteries; it is either independent of atherosclerosis or associated with it.X-ray imaging shows them as railway tracks. They are commonly found in the aorta, but also appear in arteries that are less likely to develop atherosclerosis, such as the visceral, abdominal, limb, and femoral arteries.18 Calcification of the media increases linearly with age and is frequently found in CKD, vitamin D metabolism disturbances, and diabetes, among other situations.19-22

Table I (page 372) summarizes the most prevalent traditional, uremia-related, and nontraditional risk factors for vascular calcification in CKD patients. Like in the general population, the traditional cardiovascular risk factors, present in a large proportion of patients with CKD, are responsible to a great extent for the progression of vascular calcification. Among these, nontraditional cardiovascular risk factors, including uremiarelated risk factors, time on dialysis, and hyperphosphatemia, are the risk factors more strongly associated with increased vascular calcification and mortality. Elevated C-reactive protein (CRP) and interleukin (IL)-6, as expressions of chronic inflammation, have been also frequently associated with vascular calcification.17

Table I
Table I. Risk factors associated with vascular calcification in chronic
kidney disease patients.

Abbreviations: CRP, C reactive protein; IL-1, interleukin 1 ; IL-6, interleukin 6; TNFα, tumoral necrosis factor–α.
Modified from reference 13: Román-García et al. Med Prin Pract. 2010. In press. © 2010, S. Karger AG, Basel.

CKD is associated with a high prevalence of vascular calcifications,18,22-25 which leads to a high prevalence of cardiovascular disease and reduced life expectancy.26 A high prevalence of vascular calcifications has been also reported in the early stages of CKD, where it has been shown that 40% of patients (CKD stages 2 to 4, mean glomerular filtration rate [GFR] 33 mL/min) have calcification of the coronary arteries, compared with 13%of control subjects (similar age, with normal renal function).24 However, vascular calcification is not only seen in CKD patients; a subgroup of randomly selected European subjects older than 50 years (European Vertebral Osteoporosis Study [EVOS]) showed aortic calcification in 54.2% of men and 43.1% of women.20

In a recent study, the prevalence of aortic calcification was higher in hemodialysis patients (79%) than in a random-based and age-matched general population (37.5%).22 Time on renal replacement therapy has been also positively associated with vascular calcification, mainly in medium-caliber arteries; in fact, each year on renal replacement therapy increased the risk of vascular calcifications by 15%.27 In addition, the number and severity of vascular calcifications have been positively associated with mortality, both in the general population and in CKD patients.20,22,26 In CKD, an up to 10 to 30 times higher mortality than in the general population has been reported.28 Women on hemodialysis showed an increased risk of severe aortic calcifications compared with women from the general population, probably due to a combination of atherosclerosis and arteriosclerosis.22

Until recently, vascular calcification was considered the result of a simple precipitation of circulating calcium and phosphate. However, the mechanism by which the process of vascular calcification is produced is complex; it does not consist in a simple precipitation of calcium and phosphate; on the contrary, it is an active and regulated process in which, step by step, vascular smooth cells undergo apoptosis and vesicle formation, changing the phenotype of smooth vascular cells into osteoblast-like cells. Vascular calcification can be considered as the result of the lack of the physiological equilibriumbetween the promoters and inhibitors of the calcification process, in which several uremic factors—phosphorus topping the list—play a key role.

In humans and mammals, serum concentrations of calcium and phosphate exceed the calcium_phosphate solubility product; however, no intravessel precipitation takes place. This fact stresses the important role played by physiological inhibitors of calcification, which counterbalance the well-known effect of calcification promoters. The list of promoters and inhibitors of the calcification process has increased in recent years.29-32 The main interest has focused on the “modifiable promoters of calcification” with the aim of developing strategies to minimize them. Some have been associated with the risk of mortality, such as phosphorus, calcium, vitamin D, PTH, dyslipidemia, inflammation, nutrition, CRP, homocysteine, fibrinogen, and albumin. Among these, serum phosphorus needs to be highlighted as one of the more important risk factors, which is strongly associated with increased vascular calcifications and mortality.29-34

Today, the fact that elevated phosphorus is a key factor in the differentiation of smooth vascular cells into osteoblast-like cells, triggering signals that will stop the promotion of mineralization, is well accepted.30,32,35 In vitro experiments have demonstrated that elevated phosphorus levels act directly on the transcription of bone-related genes, such as Cbfa-1 and osteocalcin, resulting in the activation of several osteogenic pathways.35,36 In addition, phosphorus is able to act as a secondary intracellular messenger activating several molecular pathways involved in bone formation. Other important factors from this list include the following most studied mineral- ization promoters and inhibitors: BMPs (bone morphogenic proteins), an important family of proteins involved in bone formation and vascular calcifications; Cbfa-1; the Msx-Wnt axis; vitamin D; calcium; phosphorus; tumor necrosis factor–α (TNFα); oxidative stress; matrix GLA protein (MGP); osteoprotegerin (OPG); fetuin A; pyrophosphates; and bisphosphonates.13,29-31,36,37

Links between bone metabolism and vascular calcification

Bone loss, increased fracture risk, and vascular calcification are severe disorders associated with aging in CKD patients and the general population.19,20,22,38 Furthermore, several epidemiological studies suggest a relationship between impaired bone metabolism, vascular calcification, and increased mortality.

The pathogenetic factors linking bone fragility with vascular calcification are not fully understood, but this relationship has been known for almost 20 years, when for the first time a significant inverse correlation between osteoporosis and aortic calcification was reported.39 However, during the following years, this association was probably underestimated because osteoporosis and vascular calcification were considered nonmodifiable age-dependent disorders. Nevertheless, recent data suggest this association may not be just a consequence of aging.20,22 The role of aging cannot be completely dismissed, but the clinical coincidence of vascular calcifications with low bone activity and osteoporosis suggests there might be direct biological links between arteriosclerosis and osteoporosis. In fact, osteoporosis and vascular calcifications are influenced by several common risk factors such as inflammation, dyslipidemia, oxidative stress, as well as estrogen, vitamin D, and K deficiencies. Some population-based longitudinal studies have demonstrated an association between osteoporosis and vascular calcification or arterial stiffness.25 A largecohort study published in 2004 showed that the degree of vascular calcification inversely correlated with bone mineral density. Furthermore, in part of the same cohort followed up for 2 years, the progression of vascular calcification inversely correlated with the rate of bone loss.40

In agreement with previous results, a recent study showed that after 4 years of follow-up, individuals who showed the most severe vascular calcification or the greatest progression of vascular calcification were those who showed not only the lowest bone mass, but also the highest incidence of new osteoporotic fractures.20 In addition, as expected, bone mass decreased and nontraumatic vertebral fractures increased in both sexes, as age increased. Also, serum levels of 25(OH)D3 inversely correlated with vascular calcification and bone mass, and positively correlated with the prevalence of secondary hyperparathyroidism and nontraumatic vertebral fractures. The progression of aortic vascular calcifications (new calcifications or increase in the size of preexisting calcifications) was significantly higher in patients who had a previous aortic calcification regardless of severity (mild, moderate, severe; P<0.001, age-adjusted). Interestingly, after 4 years of followup, mortality was also significantly and positively associated with the rate of severe vascular calcifications in men and with the rate of nontraumatic bone fractures in women.20

Similar results have also been published about patients on hemodialysis, which showed that vascular calcification in some areas (eg, the large and medium-caliber arteries [utero-sperm], femoral, iliac; hands [digital, palm arch, radial]), was associated with an increased risk of vertebral fractures.22 In addition, comparing findings from hemodialysis patients with those of the EVOS study (age- and sex-matched population), the risk of aortic calcification was significantly higher in hemodialysis patients (men: odds ratio [OR], 7.7; women: OR, 9.0). In addition, women on hemodialysis with severe vascular calcifications (any localization), as well as women with vertebral fractures, showed a high mortality risk after all adjustments including age (Figure 1). Similarly, women who died during the 2-year follow-up period had a prevalence of vertebral fractures 3 times higher (58.8% vs 19.3%) than those women who were alive at the end of the observation period (adjusted for the same variables) (Figure 2).

Figure 1
Figure 1.
Kaplan-Meyer analysis in women (A) with prevalent severe vascular calcifications at any vascular site, (B) with prevalent vertebral fractures.

Modified from reference 22: Rodriguez-Garcia et al. Nephrol Dial Transplant. 2009; 24(1):239-246. © 2009, European Renal Association/European Dialysis and Transplant Association.

Age and diabetes were strongly associated with vascular calcifications, but other well-know modifiable risk factors such as serum PTH, Ca, and P levels, vitamin D, calcium-based phosphate binders intake, dyslipidemia, hypertension, and smoking were not associated with the prevalence, severity, or progression of vascular calcification. If we combine the clinic and epidemiologic data, the association between serum 25(OH)D3 levels, vascular calcification, bone mass, and nontraumatic bone fractures, we may speculate that all of these could be linked by causes other than aging.20,25,26,41

Figure 2
Figure 2. Effect of vertebral fractures on the risk for mortality in men and women who were on hemodialysis after a 2-year followup period.

Modified from reference 19: Cannata-Andia et al. J Am Soc Nephrol. 2006;17 (12 suppl 3):S267-S273. © 2006, American Society of Nephrology.

The relationship between vascular calcification and low bone turnover has also been assessed by histomorphometry in hemodialysis patients.25 A negative relationship between low bone turnover and the degree of vascular calcification has been found.41-43 An inverse relationship between coronary calcification and vascular stiffness with mineralized bone volume has been recently published.42 Nevertheless, despite the weight of the evidence, the relationship between low bone turnover and vascular calcification is still a matter of debate. A recent publication found that vascular calcification was not influenced by bone turnover when a multivariate analysis was performed,43 even though a high percentage of patients with high bone turnover were included in this study. It is known that high PTH levels are another important pathogenetic factor positively associated with vascular calcification. In fact, it has been reported that correction of the balance in bone turnover, whether the latter was high or low, protects against the progression of vascular calcification.44 In any event, overall, the sum of epidemiological and clinical studies strongly suggests that the prevalence and progression of vascular calcification are related to bone mass, bone turnover and mineralization, bone loss, and osteoporotic fragility fractures.

Likely negative effect of vascular calcification on bone health: a challenging hypothesis for further research

An intriguing question is whether the presence of vascular calcification can have a further negative impact on bone metabolism. In a recent study, rats developing severe vascular calcification after a phosphorus load showed no increase in bone mass at any of the sites studied after 20 weeks.34 In contrast, rats with no phosphorus load develop no vascular calcification. Furthermore, bone mass increased during the study period as expected.Microarray analysis of the aortas with severe vascular calcification evidenced overexpression of secreted frizzled-related proteins (SFRPs). It is well-known that SFRPs are inhibitors of the canonical Wnt signaling pathway, which is actively involved in bone formation and vascular calcification.34,45,46

The increase in SFRPs in areas of severe vascular calcification may be indicative of a wall artery–defensive mechanism triggered to block the activation of the Wnt pathway, aimed at attenuating mineralization in the calcified aortic wall. Since SFRPs are secreted proteins, they can act not only locally on the artery wall to reduce the mineralization, but may be able to reach the bone, where they could act as they do in the vessels to decrease mineralization, resulting in reduction of bone mass. This is a challenging feedback hypothesis that could help explain the findings reported in the clinical and epidemiological studies discussed above, in which the most severe cases of progressive vascular calcification were associated with low bone mass and a greater percentage of bone fractures.

In summary, in both the general and CKD populations, vascular calcification and its severity seems to correlate inversely related with bone mass, with a resultant increase in bone fractures. In addition, the increase in vascular calcification and bone fractures is associated with reduced survival. Interestingly, once vascular calcifications appear and progress, arteries may develop a defensive mechanism aimed at attenuating or regressing vascular mineralization of the arterial wall, and this in turn may exert a negative impact on bone health. _

Part of the work presented in this review was supported by Fondo de Investigaciones Sanitarias (FIS 04/1567, 07/0893 and 08/90136), Fundación para el Fomento en Asturias de la Investigación Científica aplicada Y Técnica (FICYT I30P06P and IB 05-060), Instituto de Salud Carlos III (Retic-RD06), Red Investigación Renal (16/06), Fondo de Desarrollo Regional (FEDER), Instituto Reina Sofía de Investigación and Fundación Renal Íñigo Álvarez de Toledo. We also thank Marino Santirso for the lenguaje review. Pablo Román-García is supported by Fundación para el Fomento en Asturias de la Investigación Científica aplicada Y Técnica (FICYT), Spain. Iván Cabezas-Rodriguez is supported by the Rio Hortega program, Instituto de Salud Carlos III, Spain.

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Keywords: bone; vascular calcification; osteoporosis; bone density; bone fracture; low bone mass; bone disease; chronic kidney disease; mineral bone disorder