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PubMed2005

Low bone density and low serum levels of soluble RANK ligand are associated with severe arterial calcification in patients with Takayasu arteritis.

OBJECTIVE: Takayasu arteritis (TA) is a chronic inflammatory disorder affecting the aorta and its branches. Vascular calcification has been described in 29-54% of cases of TA, although its aetiology remains unknown. Recently the osteoprotegerin/RANKL/RANK system has emerged as an important contributing factor to atherogenesis and osteogenesis. Our aim is to investigate the association between vascular calcification, bone mineral density (BMD) and the osteoprotegerin/RANK/RANKL system in TA. METHODS: Thirty pre-menopausal female TA patients and 30 age- and sex-matched controls were studied. BMD was measured by dual X-ray absorptiometry. Arterial calcification in TA patients was analysed by computed tomography in thoracic and abdominal sites. Serum levels of osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand (sRANKL) were quantified by enzyme-linked immunosorbent assay. RESULTS: Patients with severe arterial calcification showed lower BMD values than controls in lumbar spine (0.965 +/- 0.055 vs 1.126 +/- 0.153 g/cm2, P = 0.009) and total body (0.993 +/- 0.065 vs 1.085 +/- 0.082 g/cm2, P = 0.019). In contrast, TA patients without calcification presented BMD values similar to controls (P > 0.05). Interestingly, lower serum levels of sRANKL (1.89 +/- 2.35 vs 2.80 +/- 2.23 pg/ml, P = 0.031) and a longer disease duration (12.20 +/- 6.61 vs 3.56 +/- 5.33 yr, P = 0.004) were observed in TA patients with severe calcification compared with patients without calcification. CONCLUSIONS: Severe arterial calcification in TA is associated with low values of BMD and sRANKL, reinforcing the possible link between bone and vascular disease.

Adult↗
PubMed1987

Blood flow in the foot, polyneuropathy and foot ulceration in diabetes mellitus.

Comparable groups of diabetic patients asymptomatic of neuropathy (Group A), with chronic painful polyneuropathy (Group B) and painless polyneuropathy causing recurrent foot ulceration (Group C) were studied for differences in pedal blood flow, peripheral somatic and autonomic neuropathy and vascular calcification. Blood flow abnormalities detected by doppler waveform analysis, and consistent with reduced peripheral vascular resistance, were found in all three diabetic patient groups. The abnormalities were of similar severity in Group A and B but generally more marked in Group C. Tests of peripheral somatic nerve function became progressively more abnormal from Group A to Group C. Autonomic neuropathy was equally severe in Groups B and C, although mild abnormalities were recorded in diabetic patients asymptomatic of neuropathy. A similar pattern was seen for vascular calcification in the tarsal and metatarsal arteries: marked in both neuropathic groups (B and C) but mild in Group A. It was concluded that abnormal blood flow consistent with reduced peripheral vascular resistance is very common in the feet of diabetic patients whether or not they are symptomatic of neuropathy, and is most severe in those with chronic painless polyneuropathy and recurrent foot ulceration. No clear relationship was found between autonomic nerve dysfunction and the degree of abnormality of blood flow.

Adult↗
PubMed2004

Uremic vasculopathy.

Recent evidence suggests that uremic vascular calcification is an active cell-mediated process resembling osteogenesis in bone rather than passive precipitation. We have identified increased expression of bone-associated proteins (osteopontin, bone sialoprotein, alkaline phosphatase, type I collagen), and the bone-specific transcription factor core-binding factor alpha-1 (Cbfa1) in histologic sections of inferior epigastric arteries obtained from patients with end-stage renal disease (ESRD) or calcific uremic arteriolopathy. In in vitro experiments, the addition of uremic serum to cultured vascular smooth muscle cells up-regulated osteopontin and Cbfa1 expression and accelerated mineralization. This implies that the uremic milieu may lead to dedifferentiation of vascular smooth muscle cells with subsequent mineralization. Further understanding of the pathophysiology of uremic vascular calcification is needed to design effective therapeutic strategies to intervene with this devastating condition in ESRD patients.

Calcinosis↗
PubMed2005

Reduced plasma pyrophosphate levels in hemodialysis patients.

Pyrophosphate (PPi) is a known inhibitor of hydroxyapatite formation and has been shown to inhibit medial vascular calcification in vitamin D-toxic rats. It was demonstrated recently that endogenous production of PPi prevents calcification of rat aorta that are cultured in high concentrations of calcium and phosphate. For determining whether PPi metabolism is altered in hemodialysis patients, plasma levels and dialytic clearance of PPi were measured in stable hemodialysis patients. Predialysis plasma [PPi] was 2.26 +/- 0.19 microM in 38 clinically stable hemodialysis patients compared with 3.26 +/- 0.17 in 36 normal subjects (P < 0.01). Approximately 30% of plasma PPi was protein bound, and this was not altered in dialysis patients. There was a weak inverse correlation with age in normal individuals but not in dialysis patients. Plasma [PPi] in dialysis patients was correlated with plasma [PO4(3-)] (r = 0.56) but not with [Ca2+], parathyroid hormone, or the dose of dialysis, and levels did not vary between interdialytic periods of 2 and 3 d. Plasma [PPi] decreased 32 +/- 5% after standard hemodialysis in 17 patients. In vitro clearance of PPi by a 2.1-m2 cellulose acetate dialyzer was 36%, and the mean PPi removal in five patients was 43 +/- 5 micromol, consistent with a similar in vivo clearance. Cleared PPi was greater than the plasma pool but less than the estimated extracellular fluid pool. Erythrocyte PPi content decreased 24 +/- 4%, indicating that intracellular PPi is removed as well. It is concluded that plasma [PPi] is reduced in hemodialysis patients and that PPi is cleared by dialysis. Plasma levels in some patients were below those that have previously been shown to prevent calcification of vessels in culture, suggesting that altered PPi metabolism could contribute to vascular calcification in hemodialysis patients.

Adult↗
PubMed2006

Plasma leptin levels and coronary artery calcification in older adults.

CONTEXT: Leptin is associated with adiposity and insulin resistance and may play a direct role in vascular calcification. It is unclear, however, whether leptin is an independent predictor of atherosclerotic burden. OBJECTIVE: The aim of this study was to examine the association between plasma leptin and coronary artery calcification (CAC) in an ethnically diverse cohort of older adult men and women free of clinical cardiovascular disease. DESIGN: This was a cross-sectional study with data collection between January 2002 and February 2004 as part of the ADVANCE Study. SETTING: The study was conducted at an integrated health care delivery system in Northern California. PARTICIPANTS: Participants included 949 men and women aged 60-69 yr old. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: The main outcome measure was CAC by multidetector row computed tomography. RESULTS: In ordinal logistic regression, plasma leptin levels were positively associated with extent of CAC independently of age, race/ethnicity, and smoking status in women (odds ratio of higher CAC for the sex-specific upper tertile vs. lower tertile = 1.81; 95% confidence interval, 1.10-3.00) but not in men (odds ratio = 1.29; 95% confidence interval = 0.89-1.86). However, this association was explained by metabolic risk factors and adiposity measures. CONCLUSIONS: Our findings support a role of leptin on vascular calcification in women but, in our sample of older adults, the association between leptin and CAC was not independent of other cardiac risk factors.

Aged↗
PubMed2004

Effective doses of ibandronate do not influence the 3-year progression of aortic calcification in elderly osteoporotic women.

Animal experiments revealed conflicting results as to the impact of bisphosphonate treatment on atherosclerosis and related vascular calcification. The effect of long-term treatment with clinical doses of bisphosphonates on aortic calcification (AC) in an "at-risk" population of osteoporotic elderly women has not been assessed systematically. In the present analysis including 474 women (55-80 years) participating in two 3-year randomized, placebo-controlled clinical trials, we assessed the simultaneous impact of ibandronate given either orally (2.5 mg daily or 20 mg intermittently) or intravenously (0.5 mg or 1.0 mg IV every 3 months) on bone mass and AC. All women received calcium and vitamin D supplements. Bone mineral density (BMD) was measured at the lumbar spine and the total hip using dual-energy X-ray absorptiometry (DXA). Calcified deposits of the lumbar aorta (L1-L4) were visualized on lateral radiographs and severity was graded by a validated scoring system. Measurements were performed at baseline and at years 1, 2, and 3. At baseline, there was a significant inverse correlation between the severity of AC and BMD at the hip (r=-0.151, P=0.003), but not at the lumbar spine. The two oral doses and the 1.0 mg IV dose evoked statistically significant increases in both hip and spine BMD compared with placebo, whereas the effect of 0.5 mg was significant only at the hip (P<0.05). No differences in the yearly rate of progression or the 3-year change in AC was observed between the different intervention groups. Furthermore, there were no statistically significant correlations between the 3-year change in BMD and the simultaneous change in AC. These findings thus suggest that 3-year treatment with effective doses of ibandronate does not pose any cardiovascular risk in terms of altering vascular calcification.

Administration, Oral↗
PubMed2002

Hyperphosphataemia as a cardiovascular risk factor -- how to manage the problem.

Hyperphosphataemia is a frequent and important cardiovascular risk factor in patients with chronic kidney disease (CKD). High phosphate levels may influence vascular calcifications by two separate mechanisms: by worsening secondary hyperparathyroidism, which in turn facilitates calcification, and by promoting calcium phosphate deposition in pre-formed endothelial plaques and in the arterial wall. Recent studies have shown that hyperphosphataemia induces the proliferation and differentiation of endothelial vascular cells into osteoblast-like cells, promoting vascular calcification. High phosphate levels also increase the risk of mortality in patients with CKD. To reduce the negative impact of high phosphate, serum phosphate levels should be <5 mg/dl and serum calcium <10 mg/dl. This allows the calcium x phosphate product to be maintained at < or =50 mg(2)/dl(2), reducing the risk of vascular, valvular, and extraskeletal calcification. A multiple-factor approach can be used to reduce serum phosphate: (i). decrease bone resorption by maintaining adequate serum parathyroid hormone levels; (ii). reduce phosphorous intake in the diet, (iii). use phosphate binders efficiently; and (iv). avoid under-dialysis. The patient's diet should be high in nutrition but with the lowest possible phosphorous content. Doses of phosphate binders should be tailored to individual dietary habits and must be taken during meals in a dose proportional to the phosphorous content of the meal. Because of the risk of increased extraskeletal calcification, calcium-containing phosphate-binder intake should not exceed 2-3 g/day. Sevelamer hydrochloride, a non-calcium and non-aluminium phosphate binder with a potency similar to that of calcium salts has shown beneficial effects on lipid profiles. Better control of serum phosphate is achieved in patients on continuous ambulatory peritoneal dialysis than in those on haemodialysis. Removal of phosphate is directly correlated with duration and frequency of dialysis sessions. Thus, it is advisable not to reduce the duration of dialysis sessions to <4 h three times per week.

Calcinosis↗
PubMed2001

[Clinical significance of close relationship between bone and vasculature].

Recently, evidences are accumulating that there is a close relationship between bone and vasculature and both organs are regulated by common factors. Thus, matrix Gla protein (MGP) , which is a non-collagen bone matrix protein was shown to be an important regulator of calcification both in the cartilage and blood vessel. We have recently shown that natriuretic peptides are very potent regulator of endochondral bone formation. Vascular "calcification" resembles the process of bone formation in many aspects. These observations suggest the possibility that osteoporosis and vascular lesions such as atherosclerosis and vascular calcification, are based on common factors, as in the case of multiple risk factor syndrome. Some drugs, currently used for the treatment of osteoporosis, has potential benefits for vascular lesions also.

English Abstract↗
PubMed2003

Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels.

Patients with vascular calcifications often have low bone mineral density (BMD), but it is still uncertain if osteoporosis and peripheral vascular disease (VD) are interrelated and linked by a common pathomechanism. Moreover, data on bone turnover in patients with advanced atherosclerosis are lacking. We measured BMD by dual-energy X-ray absorptiometry (DXA) and quantitative bone ultrasound (QUS), as well as the serum levels of osteocalcin (OC), bone-specific alkaline phosphatase (BAP), osteoprotegerin (OPG) and its ligand RANKL, and the urinary concentration of the C-terminal telopeptides of type I collagen (CrossLaps), in 36 patient (20 male and 16 female) with serious atherosclerotic involvement of the carotid and/or femoral artery to investigate the underlying mechanism of vascular and osseous disorders. Thirty age-matched and gender matched healthy individuals served as controls. After adjustment for age, BMD was significantly reduced at the lumbar spine in 23/36 (63%) patients (mean T score -1.71+/-1.42) and at the proximal femur in 34/36 (93%) patients (neck mean T score -2.5+/-0.88). Ten patients (27%) had abnormal QUS parameters. Gender and diabetes had no effect on the relationship between vascular calcification and bone density at any site measured. VD subjects had OC and BAP serum levels lower than controls (13.3+/-3.1 vs 27.7+/-3.3 ng/ml, P<0.01, and 8.4+/-2.3 vs 12.5+/-1.4 microg/l, P<0.01, respectively). Urinary CrossLaps excretion was not significantly different in patients with VD and in controls (257.9+/-138.9 vs 272.2+/-79.4 micro g/mmol Cr, respectively). Serum OPG and RANKL levels were similar in patients and in controls (3.5+/-1.07 vs 3.4+/-1.05 pmol/l, and 0.37+/-0.07 vs 0.36+/-0.06 pmol/l, respectively). We proved high occurrence of osteoporosis in VD, with evidence of age and gender independence. Negative bone remodelling balance would be a consequence of reduced bone formation, with no apparent increased activation of the OPG-RANKL system.

Absorptiometry, Photon↗
PubMed1998

Noncollagenous matrix proteins controlling mineralization; possible role in pathologic calcification of vascular tissue.

Biomineralization is a highly controlled process that is believed to be regulated by noncollagenous proteins found in the organic matrix of bone. Dystrophic calcification possesses several features of bone, including the presence of noncollagenous proteins, which are also thought to regulate pathologic calcification. Noncollagenous proteins have been demonstrated to be present in a wide variety of tissues. They are also believed to play a role in the pathogenesis of a number of disease processes, including atherosclerosis, restenosis, valvular stenosis, nephrolithiasis, glomerulonephritis, malignant transformation, and metastasis. This review discusses the structure, function, and possible roles of noncollagenous proteins in physiologic and pathologic processes.

Journal Article↗
PubMedDate not supplied

[Prevention of extraskeletal calcifications in uremia].

Secondary hyperparathyroidism (HPTH) is a common feature in end-stage renal disease (ESRD) patients. The three main factors involved in secondary HPTH pathogenesis are high phosphate levels, hypocalcemia and vitamin D deficiency. Recently, many studies demonstrated a strong association between bone disease and cardiovascular events in chronic kidney disease patients. In addition, cardiovascular events are the most frequent cause of death in patients with chronic renal failure. Increased levels of serum phosphorus and calcium-phosphate product are directly involved in the pathogenesis of extraskeletal calcifications (blood vessels, soft tissues, etc) in dialyzed patients compared to the non-uremic population. Recent studies suggested that vascular calcification is due not only to a passive calcium-phosphate deposition on atherosclerotic arteries, but also to active mechanisms regulated by bone-associated genes. In particular, fetuin and matrix Gla-protein are two 'protective' proteins associated with reduced vascular calcification and could be the regulatory keys in preventing this process in renal failure. The limitations of calcium salts as phosphate-binders in patients with advanced renal failure have been thoroughly evaluated in the last 5 yrs. New phosphate binders, which do not contain aluminum or calcium, have been developed to reduce the risk of extraskeletal calcifications in ESRD.

Animals↗
PubMed2004

Statins inhibit in vitro calcification of human vascular smooth muscle cells induced by inflammatory mediators.

Although lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decreases the progression of coronary artery and aortic valve calcification, the mechanism of action of these drugs to inhibit the calcification process remains unclear. In this study, we investigated the effect of statins such as cerivastatin and atorvastatin on vascular calcification by utilizing an in vitro model of inflammatory vascular calcification. Cerivastatin and atorvastatin dose-dependently inhibited in vitro calcification of human vascular smooth muscle cells (HVSMCs) induced by the following inflammatory mediators (IM): interferon-gamma, 1alpha,25-dihydroxyvitamin D3, tumor necrosis factor-alpha, and oncostatin M. These statins also depressed expression of alkaline phosphatase (ALP) in HVSMCs induced by these factors. Mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effect of cerivastatin on ALP expression in HVSMCs, while farnesylpyrophosphate showed no effect on the ALP activities inhibited by this drug, suggesting that inhibition of Rho and its downstream target, Rho kinase may mediate the inhibitory effect of cerivastatin. Cerivastatin prevented RhoA activation in HVSMCs induced by the IM. A specific inhibitor of Rho kinase (Y-27632) inhibited in vitro calcification and induction of ALP in HVSMCs. These findings provide a possible mechanism of statins to prevent the progression of calcification in inflammatory vascular diseases such as atherosclerosis and cardiac valvular calcification.

Alkaline Phosphatase↗
PubMed2004

Aortic calcification and the risk of osteoporosis and fractures.

We investigated the relation between computed tomography measures of aortic calcification and values for bone density and the number of fragility fractures in 2348 healthy, postmenopausal women. To determine whether increases in vascular calcification and bone loss progress in parallel, baseline values were compared with measurements obtained 9 months to 8 yr later in a subgroup of 228 women. Of the 2348 subjects studied, 70% had osteoporosis, 30% had at least one vertebral fracture, and 9% had at least one hip fracture. Aortic calcifications were inversely related to bone density and directly related to fractures. After adjusting for age and potential confounders, measures for aortic calcification predicted 26.1% of the variance in bone density (P < 0.001). Compared with women without calcification, the odds ratios for vertebral and hip fractures in those with calcification were estimated to be 4.8 (95% confidence interval, 3.6-6.5) and 2.9 (95% confidence interval, 1.8-4.8), respectively. The subgroup analysis of 228 women longitudinally studied showed that the percentage of yearly increase in aortic calcification accounted for 47% of the variance in the percentage rate of bone loss (P < 0.001). Moreover, a strong graded association was observed between the progression of vascular calcification and bone loss for each quartile. Women in the highest quartile for gains in aortic calcification had four times greater yearly bone loss (5.3 vs.1.3% yearly; P < 0.001) than women of similar age in the lowest quartile. Smaller, but highly significant differences were also found between all other quartiles. We conclude that aortic calcifications are a strong predictor for low bone density and fragility fractures.

Aged↗
PubMed2001

Current issues in the management of secondary hyperparathyroidism and bone disease.

Recent research has demonstrated active bone-like remodelling of vascular tissue in dialysis and non dialysis patients. Cross-sectional studies indicate that the presence of vascular calcification is inversely related to bone mass. Theoretically, the relationship implies that maintaining normal bone turnover and mass may help to decrease vascular calcification. In addition, it is now apparent that phosphorus and the Ca x P product need to be kept as close to normal as possible. Thus, the present goal should be a serum phosphorus of 3.5-5.5 mg/dL, a Ca x P product of <55 mg/dL, and a PTH of around 150-200 pg/mL with the intact assay. Ten years ago, those goals would have been impossible. However, new pharmacologic agents will make their achievement much more realistic.

Bone Remodeling↗
PubMed2005

Cardiovascular calcification in patients with end-stage renal disease.

Vascular calcifications are very frequent extraosseous calcifications in patients with chronic renal disease. They occur in the intima and in the media. They are associated with decreased arterial elasticity and increased mortality. The risk factors are: advanced age, duration of dialysis treatment, diabetes, increased phosphate concentration, the dose of Ca-containing phosphate binders and inflammation. It is now well established that vascular smooth muscle cells actively take up phosphate to form bioapatite. This process is associated with a phenotypic transformation of vascular smooth muscle cells during which they express osteoblast markers. Lipids and inflammatory cytokines also increase bioapatite formation. Calcification inhibitors are matrix Gla protein and fetuin-A. Decreased serum fetuin-A concentration is associated with a higher mortality rate in dialysis patients. An important preventive measure for vascular calcification is the substitution of Ca-containing by non-Ca-containing phosphate binders.

Calcinosis↗
PubMed2006

Calcification inhibitors and Wnt signaling proteins are implicated in bovine artery smooth muscle cell calcification in the presence of phosphate and vitamin D sterols.

Administration of active vitamin D sterols to treat secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis has been associated with elevated serum calcium and phosphorus levels, which may lead to increased risk of vascular calcification. However, calcimimetics, by binding to the parathyroid gland calcium-sensing receptors, reduce serum parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Using cultured bovine aorta vascular smooth muscle cells (BASMCs), an in vitro model of vascular calcification, we compared calcification levels and gene expression profiles after exposure to the phosphate source ss-glycerolphosphate (BGP), the active vitamin D sterols calcitriol and paricalcitol, the calcimimetic R-568, or BGP with the active vitamin D sterols or R-568. Cells exposed to BGP (10 mM) alone or with calcitriol or paricalcitol showed dose-dependent BASMC calcification. No change in calcification was observed in cultures exposed to BGP with R-568, consistent with the observed lack of calcium-sensing receptor expression. Microarray analysis using total cellular RNA from cultures exposed to vehicle or BGP in the absence and presence of 10(-8) M calcitriol or paricalcitol for 7 days showed that cells exposed to BGP with calcitriol or BGP with paricalcitol had virtually identical gene expression profiles, which differed from those of cells treated with BGP or vehicle alone. Several osteoblast- and chondrocyte-associated genes were modulated by BGP and vitamin D exposure. In this study, exposure of BASMCs to phosphate and active vitamin D sterols induced calcification and changes in expression of genes associated with mineralized tissue.

Alkaline Phosphatase↗
PubMed2005

Insulin-like growth factor-I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways.

Vascular calcification develops within atherosclerotic lesions and results from a process similar to osteogenesis. One of the paracrine regulators of bone-derived osteoblasts, insulin-like growth factor-I (IGF-I), is also present in atherosclerotic lesions. To evaluate its possible role in vascular calcification, we assessed its in vitro effects on proliferation and differentiation in calcifying vascular cells (CVCs), a subpopulation of bovine aortic medial cells. Results showed that IGF-I inhibited spontaneous CVC differentiation and mineralization as evidenced by decreased alkaline phosphatase (AP) activity and decreased matrix calcium incorporation, respectively. Furthermore, IGF-I inhibited the AP activity induced by bacterial lipopolysaccharide, TNF-alpha, or H2O2. It also induced CVC proliferation based on 3H-thymidine incorporation. Results from Northern analysis and tests using IGF-I analogs suggest that IGF-I effects are mediated through the IGF-I receptor. IGF-I also activated both the extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibition of either the ERK or PI3K pathway reversed IGF-I effects on CVC proliferation and AP activity, suggesting a common downstream target. Overexpression of ERK activator also mimicked IGF-I inhibition of lipopolysaccharide-induced AP activity. These results suggest that IGF-I promotes proliferation and inhibits osteoblastic differentiation and mineralization of vascular cells via both ERK and PI3K pathways.

Alkaline Phosphatase↗
PubMed2004

Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function, and bone in rats with renal failure.

BACKGROUND: Hyperphosphatemia and disturbances in calcium or parathyroid hormone (PTH) metabolism contribute to the high incidence of cardiovascular disease and renal osteodystrophy in chronic renal failure (CRF). We evaluated the effect of hyperphosphatemia on the cardiovascular system, on renal function, and on bone in experimental uremia. METHODS: Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx) with minipump implantation, delivering 1-34 rat PTH (physiologic rate), or were sham-operated and received vehicle. Only phosphorus content (low-phosphorus (LP) 0.2%; high-phosphorus (HP) 1.2%) differentiated diets. We divided the groups as follows: PTx +Nx +LP; sham + LP; PTx + Nx + HP; and sham + HP. Tail-cuff pressure and weight were measured weekly. After 2 months, biochemical, arterial, and myocardial histology and bone histomorphometry were analyzed. RESULTS: Heart weight normalized to body weight (heart weight/100 g body weight) was higher in PTx + Nx + HP rats (PTx + Nx + HP = 0.36 +/- 0.01 vs. sham + HP = 0.29 +/- 0.01, PTx + Nx + LP = 0.32 +/- 0.01, sham + LP = 0.28 +/- 0.01) (P < 0.05). Serum creatinine levels were higher in PTx + Nx + HP rats than in PTx + Nx + LP rats (1.09 +/- 0.13 vs. 0.59 +/- 0.03 mg/dL) (P < 0.05). Levels of PTH did not differ significantly between the groups. Myocardial and arterial histology detected no vascular calcification or fibrosis. Bone histomorphometry revealed an association, unrelated to uremia, between HP diets and decreased trabecular connectivity. CONCLUSION: Myocardial hypertrophy, impaired renal function, and adverse effects on bone remodeling were associated with hyperphosphatemia and were not corrected by PTH replacement. Although no vascular calcification was observed in this model, we cannot rule out an adverse effect of hyperphosphatemia on the vascular bed. Our finding underscores the importance of phosphorus control in reducing morbidity and mortality in CRF patients.

Animals↗