Differential effects of paricalcitol and calcitriol on intestinal calcium absorption in hemodialysis patients.

BACKGROUND/AIMS: Increased parathyroid activity associated with chronic kidney disease is often managed with calcitriol, which can elevate serum calcium (Ca) by increasing bone resorption and intestinal absorption, whereas paricalcitol promotes less bone resorption. This study compared intestinal Ca absorption in hemodialysis patients treated with calcitriol versus paricalcitol (dose ratio 1:3). METHODS: Patients (n = 22) aged > or =20 years, on maintenance hemodialysis for > or =2 months with intact parathyroid hormone (iPTH) levels of >200 pg/ml were enrolled in a single-center, double-blind, active-controlled, randomized, crossover trial. Mean fractional intestinal Ca absorption (+/-SE) was measured by the single-tracer method ((42)Ca) and evaluated with an analysis of variance crossover model. RESULTS: Mean fractional intestinal Ca absorption was significantly lower after paricalcitol (0.135 +/- 0.006) versus calcitriol treatment (0.158 +/- 0.006, p = 0.022), a 0.023 difference in absolute Ca absorption fraction. Overall Ca absorption was low in the study population, indicating that regulation of Ca absorption may be dysfunctional. There were no significant differences in serum PTH, Ca, phosphorus (P), or Ca x P. CONCLUSION: Overall, paricalcitol-treated patients absorbed approximately 14% less Ca compared with calcitriol-treated patients with similar effects on PTH. In hemodialysis patients, paricalcitol may provide a benefit by lowering the Ca available for removal by dialysis and/or for deposit in bone or soft tissues.

The pathogenesis of vascular calcification in the chronic kidney disease mineral bone disorder: the links between bone and the vasculature.

Considerable scientific progress in the pathogenesis of vascular calcification that has accrued in recent years is reviewed in this article. Factors regulating mesenchymal cell differentiation and their role in the neointimal calcification of atherosclerosis and the vascular media calcification observed in chronic kidney disease and diabetes are discussed, as is the role of bone regulatory proteins in bone mineralization and vascular calcification. This includes recent studies related to fetuin-A, and the discovery of a new circulating hormone involved in regulating phosphate homeostasis and sensing skeletal hydroxyapatite precipitation. Finally, the relationship between skeletal mineralization and vascular mineralization is discussed in terms of their links, especially through serum phosphate concentrations.

Vitamin D receptor activators can protect against vascular calcification.

An apparent conflict exists between observational studies that suggest that vitamin D receptor (VDR) activators provide a survival advantage for patients with ESRD and other studies that suggest that they cause vascular calcification. In an effort to explain this discrepancy, we studied the effects of the VDR activators calcitriol and paricalcitol on aortic calcification in a mouse model of chronic kidney disease (CKD)-stimulated atherosclerotic cardiovascular mineralization. At dosages sufficient to correct secondary hyperparathyroidism, calcitriol and paricalcitol were protective against aortic calcification, but higher dosages stimulated aortic calcification. At protective dosages, the VDR activators reduced osteoblastic gene expression in the aorta, which is normally increased in CKD, perhaps explaining this inhibition of aortic calcification. Interpreting the results obtained using this model, however, is complicated by the adynamic bone disorder; both calcitriol and paricalcitol stimulated osteoblast surfaces and rates of bone formation. Therefore, the skeletal actions of the VDR activators may have contributed to their protection against aortic calcification. We conclude that low, clinically relevant dosages of calcitriol and paricalcitol may protect against CKD-stimulated vascular calcification.

Prevalence of the metabolic syndrome in an incident dialysis population.

The National Heart, Lung, and Blood Institute's National Cholesterol Education Program 2001 Adult Treatment Panel III report defined the metabolic syndrome as having at least 3 of the following 5 criteria: abdominal obesity, elevated triglyceride levels, low high-density lipoprotein cholesterol levels, an elevated blood pressure, and an elevated fasting glucose. Evidence is accumulating to suggest that the metabolic syndrome predisposes to cardiovascular disease (CVD). End-stage kidney disease (ESKD) patients requiring dialysis have a substantially elevated risk of CVD morbidity and mortality. Dialysis patients' increased risk can be partially explained by traditional and nontraditional risk factors. The prevalence of the metabolic syndrome in dialysis patients is unknown. This retrospective, cross-sectional study of 202 incident dialysis patients examined the prevalence of the metabolic syndrome at the time of renal replacement therapy initiation. The study group was compared with all incident dialysis patients in 2002 on file with the U.S. Renal Data System. Females represented 39.1% of the study population. Blacks composed 34.7% of the study group. Diabetes was the etiology of ESKD in 44.6% of our patients. Surrogate criteria were used for the Adult Treatment Panel III risk factors of abdominal obesity and elevated fasting glucose levels. Overall, the prevalence of the metabolic syndrome was 69.3% in our population and was especially prevalent among diabetic, female, and white ESKD patients. Study limitations included the use of surrogate markers for 2 criteria of the metabolic syndrome and dependence on the Medical Evidence Report (Form 2728) for baseline characteristics. In summary, the metabolic syndrome is highly prevalent in incident dialysis patients.

Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy.

A model of chronic kidney disease (CKD)-induced vascular calcification (VC) that complicates the metabolic syndrome was produced. In this model, the metabolic syndrome is characterized by severe atherosclerotic plaque formation, hypertension, type 2 diabetes, obesity, and hypercholesterolemia, and CKD stimulates calcification of the neointima and tunica media of the aorta. The CKD in this model is associated the adynamic bone disorder form of renal osteodystrophy. The VC of the model is associated with hyperphosphatemia, and control of the serum phosphorus both in this animal model and in humans has been preventive in the development of VC. This article reports studies that demonstrate reduction of established VC by the addition of sevelamer carbonate to the diets of this murine metabolic syndrome model with CKD. Sevelamer, besides normalizing the serum phosphorus, surprisingly, reversed the CKD-induced trabecular osteopenia. Sevelamer therapy increased osteoblast surfaces in the metaphyseal trabeculae of the tibia and femur. It also increased osteoid surfaces and, importantly, bone formation rates. In addition, sevelamer was found to be effective in decreasing serum cholesterol levels. These results suggest that sevelamer may have important actions in decreasing diabetic and uremic vasculopathy and that sevelamer carbonate may be capable of increasing bone formation rates that are suppressed by diabetic nephropathy.

Connections between vascular calcification and progression of chronic kidney disease: therapeutic alternatives.

We have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreases the serum phosphate. Most recently, these observations were rediscovered in low-density lipoprotein receptor null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia, and insulin resistance). We had demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial type. We have shown that VC is worsened by CKD and ameliorated by bone morphogenetic protein -7 (BMP-7). The finding that high-fat-fed low-density lipoprotein receptor null animals without CKD have hyperphosphatemia led us to examine the skeletons of these mice. We found significant reductions in bone formation rates, associated with increased VC and superimposing CKD results in the adynamic bone disorder (ABD), while VC was worsened and hyperphosphatemia persisted. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. BMP-7 treatment corrected the ABD and corrected hyperphosphatemia, compatible with BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. Thus, in the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to ABD producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through increased bone formation and skeletal deposition of phosphate, and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury before demonstrable hyperphosphatemia, and they are preventable and treatable. Therefore, early intervention in CKD is warranted and may affect mortality of the disease.

Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome.

LDL receptor (LDLR)-null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome, have vascular calcification (VC) worsened by chronic kidney disease (CKD) and ameliorated by bone morphogenetic protein-7 (BMP-7), an efficacious agent in treating animal models of renal osteodystrophy. Here, LDLR-/- high-fat-fed mice without CKD were shown to have significant reductions in bone formation rates, associated with increased VC and hyperphosphatemia. Superimposing CKD resulted in a low turnover osteodystrophy, whereas VC worsened and hyperphosphatemia persisted. BMP-7 treatment corrected the hyperphosphatemia, corrected the osteodystrophy, and prevented VC, compatible with skeletal phosphate deposition leading to reduced plasma phosphate and removal of a major stimulus to VC. A pathologic link between abnormal bone mineralization and VC through the serum phosphorus was supported by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in this model of the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to low bone turnover rates, producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through deposition of phosphate and increased bone formation.

Successful treatment of an adynamic bone disorder with bone morphogenetic protein-7 in a renal ablation model.

An adynamic bone disorder (ABD) is an important complication of chronic kidney disease (CKD) of unknown etiology for which there is no adequate treatment. Reported is an animal model of ablative CKD complicated by an ABD characterized by the absence of secondary hyperparathyroidism and its successful treatment with a skeletal anabolic factor, bone morphogenetic protein-7 (BMP-7). Adult mice were subjected to electrocautery of the right kidney followed by left nephrectomy. Animals were randomized into groups fed normal chow or fed low-phosphate chow supplemented with calcitriol to maintain normophosphatemia in CKD. All groups were maintained on the regimens for 12 wk. Hyperphosphatemia, secondary hyperparathyroidism, and a mild osteodystrophy developed in the CKD/chow-fed group, as expected. When dietary phosphorus was restricted and calcitriol was administered in the CKD low-phosphate/calcitriol group (ABD), Ca, PO(4), and parathyroid hormone levels were maintained normal. A significant ABD developed in the ABD group characterized by significant depressions in osteoblast number, perimeters, bone formation rates, and mineral apposition rates when compared with the sham-operated, chow-fed group. The abnormal skeletal histomorphometry was reversed by BMP-7 therapy to normal values and significantly improved from the ABD group (P < 0.05). The sham-operated low-phosphate/calcitriol-fed control group and the CKD low-phosphate/calcitriol/BMP-7 groups had reduced phosphate levels compared with the other groups (P < 0.05). ABD produced in mice with CKD in the absence of hyperparathyroidism was successfully reversed with a bone anabolic, BMP-7, associated with a reduction in plasma phosphorus.

Kidney-bone, bone-kidney, and cell-cell communications in renal osteodystrophy.

The relationship between bone and the kidney in renal osteodystrophy is a complex interplay of kidney to bone connections, bone to kidney connections, and cell to cell connections. In addition, such interactions have a profound effect on the vasculature. In this review, we discuss the role of the bone morphogenetic proteins (BMPs) in the skeleton, kidney, and vasculature. In addition, we propose that deficiencies of these BMPs seen in chronic kidney disease (CKD) result in decreased bone remodeling and a compensatory secondary hyperparathyroidism (high turnover state). Treatment of the hyperparathyroidism blocks this compensatory arm and thus decreased bone remodeling occurs (low turnover). We review animal models of CKD in which treatment with BMP-7 resulted in normalization of both high and low turnover states. Finally, we discuss vascular calcification as it relates to bone metabolism. We discuss the roles of BMP-7 and 2 other bone regulatory proteins, osteoprotegerin (OPG) and alpha2-HS glycoprotein (AHSG, human fetuin), in the human vasculature and their implications for vascular calcification.

BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure.

Chronic renal failure is complicated by high cardiovascular mortality. One key contributor to this mortality is vascular calcification, for which no therapy currently exists. Bone morphogenetic protein 7 is an essential renal morphogen that maintains renal tubular differentiation in the adult and is downregulated in renal failure. Several studies have demonstrated its efficacy in treating various renal diseases in rodents, and it was hypothesized that it would also be an effective treatment of vascular calcification in this setting. Uremia was imposed on LDL receptor null mice (a model of atherosclerosis), which were then treated with bone morphogenetic protein 7 for 15 wk. Uremic animals had increased vascular calcification by histology and chemical analysis. Calcification in treated animals was similar to or less than non-uremic control animals. Cells exhibiting an osteoblast-like phenotype in the vessel wall may be important in the etiology of vascular calcification. Expression of osteocalcin was assessed as a marker of osteoblastic function, and it is shown that it is increased in untreated uremic animals but downregulated to levels similar to non-uremic control animals with treatment. The data are compatible with bone morphogenetic protein 7 deficiency as a pathophysiologic factor in chronic renal failure, and they demonstrate its efficacy as a potential treatment of vascular calcification.

Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7.

BACKGROUND: The secondary hyperparathyroidism of chronic kidney disease (CKD) produces a high turnover osteodystrophy that is associated with peritrabecular fibrosis. The nature of the cells involved in the development of peritrabecular fibrosis may represent osteoprogenitors expressing a fibroblastic phenotype that are retarded from progressing through osteoblast differentiation. METHODS: To test the hypothesis that osteoblast differentiation is retarded in secondary hyperparathyroidism due to CKD producing bone marrow fibrosis, we administered bone morphogenetic protein 7 (BMP-7), a physiologic regulator of osteoblast regulation, to C57BL6 mice that had CKD produced by electrocautery of one kidney followed by contralateral nephrectomy two weeks later. Following the second surgical procedure, a subgroup of mice received daily intraperitoneal injections of BMP-7 (10 microg/kg). Three to six weeks later, the animals were sacrificed, blood was obtained for measurements of blood urea nitrogen (BUN) and parathyroid hormone (PTH) levels, and the femora and tibiae were processed for histomorphometric analysis. RESULTS: The animals had significant renal insufficiency with BUN values of 77.79 +/- 22.68 mg/dL, and the level of renal impairment between the CKD untreated mice and the CKD mice treated with BMP-7 was the same in the two groups. PTH levels averaged 81.13 +/- 51.36 and 75.4 +/- 43.61 pg/mL in the CKD and BMP-7 treated groups, respectively. The animals with CKD developed significant peritrabecular fibrosis. In addition, there was an increase in osteoblast surface and osteoid accumulation as well as increased activation frequency and increased osteoclast surface consistent with high turnover renal osteodystrophy. Treatment with BMP-7 eliminated peritrabecular fibrosis, increased osteoblast number, osteoblast surface, mineralizing surface and single labeled surface. There was also a significant decrease in the eroded surface induced by treatment with BMP-7. CONCLUSIONS: These findings indicate that BMP-7 treatment in the setting of high turnover renal osteodystrophy prevents the development of peritrabecular fibrosis, affects the osteoblast phenotype and mineralizing surfaces, and decreases bone resorption. This is compatible with a role of osteoblast differentiation in the pathophysiology of osteitis fibrosa.

Bone morphogenetic protein-7: an anti-fibrotic morphogenetic protein with therapeutic importance in renal disease.

Bone morphogenetic proteins are members of the transforming growth factor-beta superfamily of cytokines and consist of a group of at least 15 morphogens involved in intracellular messaging through complex bone morphogenetic protein receptor mediated Smad signaling. Bone morphogenetic protein-7 knockout mice die shortly after birth due to uremia, demonstrating that this morphogenetic protein is essential for renal development. Recent investigations have characterized renal bone morphogenetic protein-7 receptors, shown exogenous bone morphogenetic protein-7 to prevent fibrogenesis associated with ureteral obstruction, indicated a loss of renal bone morphogenetic protein-7 associated with diabetic nephropathy, and an improvement in glomerular pathology in rodent streptozocin-induced diabetes with bone morphogenetic protein-7 treatment. In addition, this morphogenetic protein has been shown to reduce glomerulonephritis and tubulointerstitial fibrosis in a murine model of lupus nephritis as well as decrease the peritrabecular fibrosis associated with murine high turnover renal osteodystrophy. Finally, we review the effects of bone morphogenetic protein-7 on vascular calcification in an animal model, a potential complication of this therapy given its osseous morphogenetic effect.