Calcium phosphate metabolism and cardiovascular disease in patients with chronic kidney disease

Traditional risk factors for atherosclerotic cardiovascular disease (CVD) do not adequately explain the considerable increase in cardiovascular mortality observed among patients with end-stage renal disease (ESRD): these patients experience mortality rates 10-100 times those without ESRD. Disorders of mineral metabolism, including abnormalities in calcium, phosphorus, parathyroid hormone, and vitamin D, represent cardiovascular risk factors unique to the ESRD population. These disturbances manifest clinically through the promotion of extraskeletal calcification and disorders of bone remodeling, two processes which appear to share a common pathogenesis. This article presents evidence describing the impact of calcification-induced arterial stiffness on cardiovascular outcomes of patients with ESRD, along with data relating altered mineral metabolism to all-cause and cardiovascular mortality. Specific management recommendations include 1) early intervention to prevent the development of overt secondary hyperparathyroidism, 2) a more judicious strategy for vitamin D therapy, and 3) a thoughtful approach to the use of calcium-containing phosphate binders, taking into account the underlying bone remodeling disorder and the presence or absence of extraskeletal calcium accumulation.     

Gene polymorphism association studies in dialysis: bone and mineral metabolism

Abnormalities in bone and mineral metabolism have a significant impact on morbidity and mortality among patients with end-stage renal disease (ESRD). In addition to confounding environmental factors, genetic susceptibility factors may also influence the occurrence and severity of these abnormalities and account for interindividual variability among patients. Indeed, polymorphisms involving genes of the calcium/parathyroid hormone/calcitriol axis have been associated with bone and mineral metabolism abnormalities. This review summarizes studies involving polymorphisms of candidate genes and their effects on the development of complications related to bone and mineral metabolism abnormalities among patients with ESRD.     

Detection and quantification of cardiovascular calcifications with electron beam tomography to estimate risk in hemodialysis patients

Cardiovascular disease is the leading cause of death in dialysis patients, accounting for nearly half of all deaths among end-stage renal disease (ESRD) patients. Even young dialysis patients are at risk. Cardiovascular disease in chronic renal failure patients has been associated with elevated serum phosphorus levels and elevated calcium-phosphorus (Ca x P) product, and mismanagement of calcium and phosphorus metabolism has been implicated as a major factor in the development of soft tissue calcification and cardiovascular disease. ESRD patients frequently face hyperphosphatemia as well as excess calcium load, which elevate the Ca x P product, thereby contributing to the development of calcific complications. Electron beam computed tomography (EBCT) can be used to detect different calcification stages in a variety of tissues, and is a sensitive tool for detecting calcified coronary artery plaques as well as cardiac and valvular calcifications. Hemodialysis patients have high calcium scores on EBCT imaging, and these are associated with elevations in Ca x P product. In a recent study, patients with calcification were found to have had twice the daily calcium intake from calcium-based phosphate binders than patients without calcification. Strategies to reduce cardiac risk in hemodialysis patients include use of a dialysate low in calcium, use of vitamin D analogs that are less calcemic, and use of calcium-free phosphate binders. EBCT can be a useful adjunct to these therapies, since it permits sensitive and quantitative initial assessment, as well as ongoing monitoring of disease progression.     

Novel Therapeutic Options for the Treatment of Mineral Metabolism Abnormalities in End Stage Renal Disease

Abnormalities in mineral metabolism are a universal complication in dialysis patients and are associated with an increased risk of cardiovascular disease and mortality. Hyperphosphatemia, increased fibroblast growth factor 23 levels and secondary hyperparathyroidism are all strongly associated with adverse outcomes in end stage renal disease (ESRD) and most treatment strategies target these parameters. Over the past few years, new therapies have emerged for the treatment of abnormalities of mineral metabolism in ESRD and many are promising. This article will review these new therapeutic options including the potential advantages and disadvantages compared to existing therapies.     

The clinical significance of vascular calcification in young patients with end-stage renal disease

Mortality statistics of young adults with childhood-onset end-stage renal disease (ESRD) show that cardiovascular disease (CVD) is responsible for most deaths on dialysis and after transplantation. This is most likely explained by the presence of a multitude of traditional and non-traditional risk factors in uremia, promoting the combination of classical atherosclerosis, uremic vasculopathy, and uremic cardiomyopathy. Vascular (arterial) calcifications occur with a high prevalence in young adults and their presence correlates with non-traditional risk factors, markers of inflammation, intake of calcium-containing phosphate binders, and the calcium-phosphorus product in serum. This might be explained by a high positive calcium and phosphorus balance in ESRD patients, which may be comparatively higher in the young. In addition, treatment with active vitamin D preparations may enhance the positive calcium and phosphorus balance and have a direct calcifying effect on the arterial wall. The biological process of vascular calcification resembles osteogenesis. These data indicate that vascular calcifications are related to non-traditional risk factors, inflammatory mechanisms, and disturbances in calcium and phosphorus metabolism in uremia. They provide strong evidence for a change in the current management of renal osteodystrophy in children and adolescents with ESRD.     

Fetuin-A: A Novel Cardiovascular Risk Factor

Fetuin-A, or α₂-Heremans–Schimd glycoprotein, is a potent inhibitor of calcium-phosphate precipitation. In end-stage renal disease (ESRD) patients, its serum levels are significantly reduced favouring ectopic calcifications, such as vascular and valvular calcifications for hyperphosphatemia and increased Ca × P product. Numerous evidences indicate that in low fetuin-A levels patients, mitral and/or aortic calcifications are often present. Coronary, carotid calcifications and/or other vascular phatological findings connected with increased calcium deposition in the lamina media of the arterial wall (Monkeberg’s calcinosis or arteriosclerosis), acute inflammation and/or endothelial dysfunction can be also found. Thus, low levels of fetuin-A in ESRD act as “non-traditional” risk factor for cardiovascular disease. Other “non-traditional” cardiovascular risk factors in dialyzed patients are: extracellular volume overload; insulin resistance; anaemia, and oxidative stress, many cross-sectional studies showed a direct associations of high fetuin-A levels with impaired glucose and lipid metabolism inducing metabolic syndrome in non-dialyzed patients. In these, high fetuin-A levels induce atherosclerotic lesions by insulin resistance. In conclusion, fetuin-A is able to induce both arteriosclerosis and atherosclerosis. Its serum levels seems to act (both in dialyzed and non-dialyzed patients) such as “non-traditional” cardiovascular risk factor, even if its action mechanism was not completely elucidated and further studies performed in wide range are requested. Therapeutically, some compounds such as Sevelamer, etidronate, calcium channel blockers and others interventions, are promising in to reduce calcium deposition in the vessel walls and acute inflammation induced by the low α₂-Heremans–Schmid glycoprotein serum levels in dialyzed patients. On the contrary, extended-release niacin seems to be able to reduce cardiovascular, metabolic and inflammatory complicances dependent on high fetuin-A serum levels.     

Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease

Renal function impairment goes along with a disturbed calcium, phosphate, and vitamin D metabolism, resulting in secondary hyperparathyroidism (sHPT). These mineral metabolism disturbances are associated with soft tissue calcifications, particularly arteries, cardiac valves, and myocardium, ultimately associated with increased risk of mortality in patients with chronic kidney disease (CKD). sHPT may lead to cardiovascular calcifications by other mechanisms including an impaired effect of parathyroid hormone (PTH), and a decreased calcium-sensing receptor (CaR) expression on cardiovascular structures. PTH may play a direct role on vascular calcifications through activation of a receptor, the type-1 PTH/PTHrP receptor, normally attributed to PTH-related peptide (PTHrP). The CaR in vascular cells may also play a role on vascular mineralization as suggested by its extremely reduced expression in atherosclerotic calcified human arteries. Calcimimetic compounds increasing the CaR sensitivity to extracellular calcium efficiently reduce serum PTH, calcium, and phosphate in dialysis patients with sHPT. They upregulate the CaR in vascular cells and attenuate vascular mineralization in uremic states. In this article, the pathophysiological mechanisms associated with cardiovascular calcifications in case of sHPT, the impact of medical and surgical correction of sHPT, the biology of the CaR in vascular structures and its function in CKD state, and finally the role played by the CaR and its modulation by the calcimimetics on uremic-related cardiovascular calcifications are reviewed.     

Arterial calcifications and bone histomorphometry in end-stage renal disease

Arterial calcification (AC) is a common complication of end-stage renal disease (ESRD). The mechanisms responsible are complex, including disturbances of mineral metabolism and active expression of various mineral-regulating proteins. An inverse relationship between AC and bone density has been documented in uremic patients. In the study presented here, which included 58 patients with ESRD on hemodialysis (HD), bone-histomorphometry characteristics were compared with the AC scores (0 to 4) determined according to the number of arterial sites with calcifications. Patients with AC scores of 0 (no calcifications), or 1 or 2 (mild calcifications) had similar serum parathyroid hormone levels and bone histomorphometry, with larger osteoclast resorption, higher osteoclast numbers, and larger osteoblastic and double tertracycline-labeled surfaces. In contrast, patients with high AC scores (3 and 4) were characterized by lower serum parathyroid hormone, low osteoclast numbers and osteoblastic surfaces, smaller or absent double tetracycline-labeled surfaces, and high percentages of aluminum-stained surfaces. According to multivariate analysis, AC score was positively associated with age (P < 0.0001), daily dose of calcium-containing phosphate binders (P = 0.009), and bone aluminum-stained surfaces (P = 0.037), and an inverse correlation was observed with osteoblastic surfaces (P = 0.001). A high AC score is associated with bone histomorphometry suggestive of low bone activity and adynamic bone disease. These findings suggest that therapeutic interventions associated with excessive lowering of parathyroid activity (parathyroidectomy, excessive calcium or aluminum load) favor lower bone turnover and adynamic bone disease, which could influence the development and progression of AC.     

Mineral metabolism, mortality, and morbidity in maintenance hemodialysis

Mortality rates in ESRD are unacceptably high. Disorders of mineral metabolism (hyperphosphatemia, hypercalcemia, and secondary hyperparathyroidism) are potentially modifiable. For determining associations among disorders of mineral metabolism, mortality, and morbidity in hemodialysis patients, data on 40,538 hemodialysis patients with at least one determination of serum phosphorus and calcium during the last 3 mo of 1997 were analyzed. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum phosphorus, calcium, calcium x phosphorus product, and intact parathyroid hormone (PTH) using proportional hazards regression. Also determined was whether disorders of mineral metabolism were associated with all-cause, cardiovascular, infection-related, fracture-related, and vascular access-related hospitalization. After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and >/=9.0 mg/dl). Higher adjusted serum calcium concentrations were also associated with an increased risk of death, even when examined within narrow ranges of serum phosphorus. Moderate to severe hyperparathyroidism (PTH concentrations >/=600 pg/ml) was associated with an increase in the relative risk of death, whereas more modest increases in PTH were not. When examined collectively, the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperphosphatemia. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization. Disorders of mineral metabolism are independently associated with mortality and morbidity associated with cardiovascular disease and fracture in hemodialysis patients.     

Peritoneal dialysis and cardiovascular disease

Cardiovascular (CV) death is the most frequent cause of dying in peritoneal dialysis (PD) patients. Risk factors include not only those that can be present in the general population, but also those related to the presence of end-stage renal disease (ESRD) and factors that are specific for PD modality. Hypertension is the most important general risk factor in PD patients, while obesity remains controversial. Inflammation, malnutrition, calcifications and probably endothelial dysfunction and oxidative stress are all CV risk factors present in ESRD that contribute to mortality in PD patients. Additional CV risk factors in PD are related to the glucose load, leading to increasing insulin resistance and a more atherogenic lipid profile. The presence of glucose degradation products in conventional dialysis solutions is mainly related to the development of peritoneal abnormalities, but not directly to cardiovascular disease. Loss of residual renal function and ultrafiltration failure promote overhydration, which is the most important PD-related risk factor for CV disease.     

Soft bone - hard arteries: a link?

Chronic kidney disease is characterized by mineral and various bone disorders associated with extraosseous and cardiovascular calcifications. Experimental studies and clinical observations in the general population and in chronic kidney disease patients show an inverse relationship between the extent of cardiovascular calcifications and bone mineral density or bone metabolic activity. Arterial calcification and osteoporosis are frequently observed in the same subjects and progress in parallel in postmenopausal women, and associations between histomorphometric indices of bone activity and vascular calcifications were also observed in patients with chronic and end-stage kidney diseases. The biological linkage between vascular calcifications and bone changes is certainly a part of the aging process, but in many studies these bone-vascular associations remained significant after adjustment for age, which suggests an age-independent causal relationship. Based on clinical and experimental evidence showing an association between bone disorders and functional and structural changes of the arterial system the concept of a bone-vascular axis was established complementary to the classical kidney-bone axis. Nevertheless, the factors or mechanisms accounting for these associations are not well understood, and could result from (1) arterial disease responsible for bone abnormalities; (2) action of common dysmetabolic or 'toxic' factors and mechanisms acting on bones and vessels, or (3) direct or indirect influence of bone cells and metabolism on the arterial system. This short review aims to illustrate these possible mechanisms.     

Cardiovascular calcification in nondialyzed patients with chronic kidney disease

Chronic kidney disease (CKD) has become a major health-care problem of global proportions. Progression to end-stage renal disease (ESRD), the need for renal replacement therapy, and the high annual death rate of dialysis patients are the most noticeable outcomes of CKD. Less appreciated, however, is the fact that most patients with CKD actually die mainly from cardiovascular disease, rather than progress to ESRD. Coronary artery calcification (CAC), a surrogate marker of atherosclerosis, is common in dialysis and CKD patients. Coronary artery calcium scores, as measured by ultrafast computed tomography, is an independent predictor of future cardiac events. Using this technique, several studies have documented extensive calcification in dialysis patients, a subject of several exhaustive reviews. Unfortunately, much less attention has been paid to calcification in nondialyzed patients with CKD. In this review, I will emphasize the fact that CVC is common in patients with CKD not yet on dialysis, develops early in the course of CKD, and worsens with the decline in renal function particularly among diabetics who progressed to ESRD. I will also discuss the pathogenesis of CVC in CKD patients and highlight the lack of a major role for abnormalities of mineral metabolism in the pathogenesis of calcification in CKD patients. In addition to the high prevalence of traditional risk factors for CAD, the presence of proteinuria, reduced renal function, diabetic nephropathy, and the rate of progression to ESRD may represent the main uremia-related factors that increase the risk for calcification in CKD. Finally, I will review the protective role of inhibitors of calcification in CKD.     

Vascular calcification and disordered mineral metabolism in dialysis patients

Vascular calcification is an active, cell-mediated process that can involve either the intima or media of the blood vessels. The current methods used to clinically measure vascular calcification cannot distinguish between intimal (invariably atherosclerotic) and medial calcification. The high calcification scores seen in patients with end-stage renal disease likely represent a composite of high calcification burden in both sites. The severity of vascular calcification has been associated with a variety of findings including left ventricular hypertrophy and angiographic vascular stenosis as well as with all-cause and cardiovascular mortality. There is increasing evidence that disordered mineral metabolism participates in the process of vascular calcification and is one of the mechanisms whereby hyperphosphatemia, hypercalcemia, and hyperparathyroidism enhance cardiovascular and all-cause mortality of end-stage renal disease patients. There are no studies showing improved outcomes of ESRD patients with aggressive control of disordered mineral metabolism. However, the preponderance of evidence argues strongly in favor of aggressive management of these abnormalities from starting early in the course of chronic kidney disease in the hope of improving patient outcomes.     

Pathogenesis of vascular calcification in dialysis patients

Soft-tissue and vascular calcification are highly prevalent in end-stage renal disease (ESRD). Vascular calcifications manifest as both medial and intimal calcification of arteries and are a hallmark of the accelerated atherosclerosis observed in uremia. The nature of vascular calcification is progressive, and is associated with arterial stiffness and increased cardiovascular mortality. Age, duration of dialysis, and diabetes mellitus are clear determinants of the severity of vascular calcification; however, more recently novel insights into the pathomechanisms of unwanted calcification processes have been gained. Disturbances of mineral metabolism such as hyperphosphatemia and hypercalcemia appear to contribute to progressive calcification, not only by passive precipitation but by actively inducing changes in vascular smooth muscle cell behavior toward an osteoblast-like phenotype. Specific calcium-regulatory proteins may act locally or systemically as calcification inhibitors. Dysregulations of calcification inhibitors, including fetuin-A, matrix Gla protein, osteoprotegerin, and pyrophosphates may also be pathophysiologically relevant factors in the context of uremic extraosseous calcification. In this context, low serum fetuin-A levels were recently found to be associated with increased mortality in cohorts of dialysis patients. This overview intends to summarize current knowledge of the scientific concepts involved in the pathogenesis of extraosseous calcification in ESRD.     

Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population.

BACKGROUND: Renal failure results in deficiency of active vitamin D3 that has diverse effects on metabolism and organ functions. Treatment with active forms of vitamin D(3) ameliorates abnormalities in bone and mineral metabolism, cardiac function, immune response and others. We hypothesized that treatment with vitamin D(3) may be beneficial for survival in patients with end-stage renal disease (ESRD). METHODS: We compared the risk of death between regular users (n = 162) and non-users (n = 80) of oral 1alpha-hydroxyvitamin D3 (alfacalcidol) in a cohort of ESRD patients undergoing haemodialysis for a follow-up of 61 +/- 23 months. The daily dose of alfacalcidol ranged from 0.25 to 1.5 microg, with a median of 0.5 microg. RESULTS: The alfacalcidol users showed a lower risk of death from cardiovascular disease than the non-users in a univariate Cox model [hazards ratio (HR) 0.287, 95% confidence interval (CI) 0.127-0.649, P = 0.003], whereas the risk for death from non-cardiovascular disease was not different between the two groups. Stepwise multivariate Cox analysis showed that cardiovascular mortality was significantly associated with age, presence of diabetes mellitus and treatment with alfacalcidol (HR 0.377, 95% CI 0.246-0.578, P = 0.022). CONCLUSIONS: These results indicate that use of oral alfacalcidol was associated with reduced risk for cardiovascular death in this cohort of ESRD patients. The result of this observational study warrants further randomized controlled trials with 1alpha-hydroxy vitamin D3 to confirm the possibility that such medication improves survival of ESRD patients.     

Novel cardiovascular risk factors in end-stage renal disease

Traditional risk factors only in part explain the risk differential between the general population and the population of patients with chronic nephropathies. Uncontrolled hyperphosphatemia and high calcium phosphate product constitute risk factors for cardiovascular calcifications, cardiac ischemia, and adverse cardiovascular outcomes, yet inflammation may be an even more important trigger of vascular calcification than these metabolic derangements. Homocysteine predicts cardiovascular events in ESRD, but evidence that this sulfur amino acid is directly implicated in the high cardiovascular mortality of uremic patients is still lacking. It seems unlikely that Chlamydia pneumoniae is a major risk factor in dialysis patients because the association between anti-Chlamydia antibodies and incident cardiovascular events seems to depend largely on the confounding effect of some traditional risk factors. Oxidative stress and raised plasma concentration of asymmetric dimethylarginine (ADMA) are pervasive in ESRD, and high ADMA in these patients may be at least in part the expression of the high rate of generation of oxidants. ADMA per se seems responsible for a 52% increase in the risk of death and for a 34% increase in the risk of cardiovascular events in dialysis patients.     

Arterial stiffening and vascular calcifications in end-stage renal disease.

BACKGROUND: Epidemiological studies have identified aortic stiffness as an independent predictor of cardiovascular mortality in end-stage renal disease (ESRD) patients. In these patients, aortic pulse wave velocity (PWV) was associated with mediacalcosis, but the influence of arterial calcifications on the viscoelastic properties of large arteries was not well characterized. The purpose of the present study was to analyse the influence of arterial calcifications on arterial stiffness in stable haemodialysed patients. METHODS: We studied 120 stable ESRD patients on haemodialysis. All patients underwent B-mode ultrasonography of common carotid artery (CCA), aorta, and femoral arteries to determine CCA distensibility, the elastic incremental modulus (Einc), and the presence of vascular calcifications. All patients underwent measurement of aortic PWV and echocardiogram. The presence of calcifications was analysed semiquantitatively as a score (0 to 4) according to the number of arterial sites with calcifications. RESULTS: Our observations indicate that arterial and aortic stiffness is significantly influenced by the presence and extent of arterial calcifications. The extent of arterial calcifications is in part responsible for increased left ventricular afterload, and is inversely correlated with stroke volume. The influence of calcifications is independent of the role of ageing and blood pressure. Arterial calcifications density increases with age, duration of haemodialysis, the fibrinogen level, and the prescribed dose of calcium-based phosphate binders. CONCLUSIONS: The results of this study showed that the presence of vascular calcifications in ESRD patients was associated with increased stiffness of large capacity, elastic-type arteries, like the aorta and CCA. The extent of arterial calcifications increased with the use of calcium-based phosphate-binders.     

Association of bone activity, calcium load, aortic stiffness, and calcifications in ESRD

An inverse relationship between arterial calcifications and bone activity has been documented in patients with ESRD. Calcium overload is associated with arterial calcification, which is associated with arterial stiffening. Whether bone activity interacts with calcium load, aortic stiffness, or arterial calcification is unknown. This study assessed the impact of bone activity on the relationships between the dosage of calcium-containing phosphate binders and aortic stiffness (measured by pulse wave velocity) or abdominal aorta calcification score. Aortic stiffness and calcification were both positively associated with calcium load and negatively associated with bone activity. A significant interaction was found between dosage of calcium-containing phosphate binders and bone activity such that calcium load had a significantly greater influence on aortic calcifications and stiffening in the presence of adynamic bone disease. Independent of any other factor, including dosage of calcium-containing phosphate binders, adynamic bone was associated with greater aortic stiffening, suggesting cross-talk between the bone and arterial walls.     

Vascular calcifications in uremia: old concepts and new insights

The annual mortality rate in uremic patients, corrected for age, sex, and race, is significantly higher than in the general population. This is primarily due to cardiovascular events. Vascular calcifications play a vital role in the development of cardiovascular morbidity and subsequent increased mortality. Vascular calcification affects both vascular intima and media layers and its mechanism remains poorly understood. Over the last few years it has been shown that, in addition to traditional cardiovascular risk factors, disturbances in mineral metabolism in the uremic milieu, calcium-containing phosphate binders, and vitamin D treatment of secondary hyperparathyroidism may contribute to the pathogenesis of vascular calcifications. Other uremia-related risk factors (e.g.increased oxidized low-density lipoprotein cholesterol, uremic toxins, increased oxidative stress, dialysis and dialysate-related factors, hemodynamic overload, hyperhomocysteinemia) may also play a role. In uremic patients, apart from these facilitating factors, decreased levels of endogenous calcification inhibitors such as fetuin-Amatrix Gla protein, osteoprotegerin, and osteopontin have also been associated with increased calcium-phosphate precipitation in extraskeletal tissues. Finally, vascular calcification is the outcome of the active and dynamic balance of procalcifying and anticalcifying influences. For the prevention and treatment of vascular calcifications, it is essential to avoid treatment modalities that lead to calcium overload, achieve good metabolic control, and optimize dialysis.