Parathyroid suppression therapy normalizes chronic kidney disease-induced elevations in cortical bone vascular perfusion: a pilot study.

Interventions that alter PTH levels in an animal model of chronic kidney disease have effects on the perfusion of bone and bone marrow. INTRODUCTION: Patients with chronic kidney disease (CKD) have accelerated bone loss, vascular calcification, and abnormal biochemistries, together contributing to an increased risk of cardiovascular disease and fracture-associated mortality. Despite evidence of vascular pathologies and dysfunction in CKD, our group has shown that cortical bone tissue perfusion is higher in a rat model of high-turnover CKD. The goal of the present study was to test the hypothesis that parathyroid hormone (PTH) suppressive interventions would normalize cortical bone vascular perfusion in the setting of CKD. METHODS: In two separate experiments, 35-week-old CKD animals and their normal littermates underwent intra-cardiac fluorescent microsphere injection to assess the effect of 10 weeks of PTH suppression (Experiment 1: calcium supplementation, Experiment 2: calcimimetic treatment) on alterations in bone tissue perfusion. RESULTS: In Experiment 1, CKD animals had serum blood urea nitrogen (BUN) and PTH levels significantly higher than NL (+ 182% and + 958%; p < 0.05). CKD+Ca animals had BUN levels that were similar to CKD, while PTH levels were significantly lower and comparable to NL. Both femoral cortex (+ 220%, p = 0.003) and tibial cortex (+ 336, p = 0.005) tissue perfusion were significantly higher in CKD animals when compared to NL; perfusion was normalized to those of NL in CKD+Ca animals. MicroCT analysis of the proximal tibia cortical porosity showed a trend toward higher values in CKD (+ 401%; p = 0.017) but not CKD+Ca (+ 111%; p = 0.38) compared to NL. Experiment 2, using an alternative method of PTH suppression, showed similar results as those of Experiment 1. CONCLUSIONS: These data demonstrate that PTH suppression-based interventions normalize cortical bone perfusion in the setting of CKD.

Skeletal effects of zoledronic acid in an animal model of chronic kidney disease.

UNLABELLED: Bisphosphonates reduce skeletal loss and fracture risk, but their use has been limited in patients with chronic kidney disease. This study shows skeletal benefits of zoledronic acid in an animal model of chronic kidney disease. INTRODUCTION: Bisphosphonates are routinely used to reduce fractures but limited data exists concerning their efficacy in non-dialysis chronic kidney disease. The goal of this study was to test the hypothesis that zoledronic acid produces similar skeletal effects in normal animals and those with kidney disease. METHODS: At 25 weeks of age, normal rats were treated with a single dose of saline vehicle or 100 µg/kg of zoledronic acid while animals with kidney disease (approximately 30% of normal kidney function) were treated with vehicle, low dose (20 µg/kg), or high dose (100 µg/kg) zoledronic acid, or calcium gluconate (3% in the drinking water). Skeletal properties were assessed 5 weeks later using micro-computed tomography, dynamic histomorphometry, and mechanical testing. RESULTS: Animals with kidney disease had significantly higher trabecular bone remodeling compared to normal animals. Zoledronic acid significantly suppressed remodeling in both normal and diseased animals yet the remodeling response to zoledronic acid was no different in normal and animals with kidney disease. Animals with kidney disease had significantly lower cortical bone biomechanical properties; these were partially normalized by treatment. CONCLUSIONS: Based on these results, we conclude that zoledronic acid produces similar amounts of remodeling suppression in animals with high turnover kidney disease as it does in normal animals, and has positive effects on select biomechanical properties that are similar in normal animals and those with chronic kidney disease.

Vascular calcification and renal osteodystrophy relationship in chronic kidney disease.

Cardiovascular disease and stroke account for 60-70% of all deaths in patients with end-stage renal disease (ESRD), at a risk that is 10-20-fold the age- and sex-matched general population. There is also increased coronary artery calcification and increased cardiovascular mortality in chronic kidney disease (CKD) and dialysis patients compared with the general population. Bone is similarly abnormal in CKD. There is an increased incidence of low bone mass and fractures in dialysis patients compared with the general population. Furthermore, a hip fracture in a dialysis patient is associated with a doubling of the mortality observed in nondialysis patients with a hip fracture. These two problems may be linked, as cross-sectional studies have demonstrated an inverse relationship between osteoporosis and coronary artery calcification in the general population and in ESRD patients. In vitro and ex vivo, there is clear evidence that vascular calcification is an active cell-mediated process, made worse by disorders of mineral metabolism. Many factors known to be associated with cardiovascular disease in CKD patients can directly increase calcification in vitro. In addition, in CKD, there are many mechanisms by which bone may adversely affect vascular calcification including disorders of bone remodelling, altered secretion of parathyroid hormone (PTH), hyperphosphatemia, hypercalcaemia, use of calcium based binders, and excessive vitamin D therapy. The coexistence of vascular risk factors and abnormal bone represent a double threat to the well being of patients with CKD.

Distal calcific uremic arteriolopathy in a hemodialysis patient responds to lowering of Ca x P product and aggressive wound care.

Calcific uremic arteriolopathy (CUA; calciphylaxis), is reported in approximately 4% of patients receiving hemodialysis, and is characterized by skin lesions that may include firm plaques or subcutaneous nodules. The syndrome has been associated with the use of calcium-containing phosphate binders, high serum phosphorus levels, and elevated calcium x phosphorus (Ca x P) product. This report describes a 73-year-old white male with chronic renal failure due to diabetes mellitus and hypertension, who had been on home hemodialysis for 3 years. He developed CUA after an acute elevation in serum phosphorus (8.1 mg/dl) and Ca x P product (84.2), with painful skin lesions that rapidly progressed to become circumferentially located around the entire lower left extremity. The patient declined amputation, opting for a treatment approach that included aggressive management of phosphorus and calcium, more frequent dialysis, and rigorous wound care. All calcium-containing phosphate binders were discontinued. The patient was switched from calcitriol to paricalcitol, a less calcemic form ofvitamin D replacement therapy, from which he was slowly weaned. Dialysis dose and frequency was also increased to 4 hours, 6 times weekly. The patient was given sevelamer hydrochloride (Renagel)--a calcium-free phosphate binder--with meals at an initial dose of 6.4 g/day. After 5 months, the dose was increased to 8 g/day, with additional dietary counseling to restrict phosphorus intake. At this point, serum phosphorus decreased to 4.9 mg/dl and calcium levels had fallen to 8.5 mg/dl, compared to 9.5 - 10.4 mg/dl prior to diagnosis of CUA with an overall decline in the Ca x P product. Significant healing of the lesions was noted at 8 months following diagnosis, with near-total healing by 12 months. Our studies support that lowering of elevated serum phosphorus, calcium, and Ca x P product, together with aggressive wound care may contribute to the successful outcome of patients with CUA.

Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells.

Calciphylaxis or calcific uremic arteriolopathy (CUA) is a fatal disease in dialysis patients due to calcification of cutaneous blood vessels. The pathogenesis has been attributed to elevated parathyroid hormone (PTH). However, recent studies evaluating vascular calcification in nondialysis patients have found that the smooth muscle cells play an active role, including production of the bone matrix protein osteopontin. To examine the involvement of various clinical parameters and smooth muscle cells of CUA, we performed a case-control analysis comparing 10 CUA patients with our current dialysis patients. Available histologic sections were immunostained for osteopontin, markers of smooth muscle cells, endothelial cells, and macrophages. Compared with our current dialysis population, patients with CUA were more likely to be obese, white, and female (P < 0.02). Comparison of laboratory values found CUA patients with lower serum albumin, greater serum phosphorus, and greater calcium X phosphorus product (P < 0.01). In contrast, there was no difference in the concentration of PTH or calcium between the 2 groups. Immunostaining of calcified blood vessels showed that all calcified vessels stained positive for osteopontin, whereas all the noncalcifed vessels showed no osteopontin localization. Staining for smooth muscle alpha-actin decreased in the medial layer with calcification, with cells appearing to be sloughed off, leading to near occlusion of the vessel lumen. Our case-control study demonstrates that hyperphosphatemia and an elevated calcium X phosphorus product is associated with CUA. Histologic examination suggests that the calcification is associated with increased expression of osteopontin by smooth muscle cells.

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.

Role of IL-1 beta and prostaglandins in beta 2-microglobulin-induced bone mineral dissolution.

beta 2-microglobulin (beta 2m) induces an osteoclast-mediated net calcium efflux from neonatal mouse calvariae which occurs only after 48 hours of incubation, suggesting that beta 2m acts via other growth factors. To further test this hypothesis, calvariae were incubated with and without beta 2m in the presence of the prostaglandin inhibitor indomethacin, anti-interleukin-1 beta antibody (anti-IL-1 beta), or interleukin-1 beta receptor antagonist (IL-1 beta RA). The addition of beta 2m to the culture medium stimulated, whereas indomethacin inhibited basal calcium efflux following 48 hours. However, the difference (delta) between the calcium efflux induced in calvariae incubated with and without beta 2m in basal medium and that in calvariae incubated with and without beta 2m in indomethacin supplemented medium was similar, suggesting a prostaglandin independent mechanism. There was a time dependent increase in PGE2 in basal medium which was unaffected by beta 2m. In contrast, pre-incubating calvariae with either anti-IL-1 beta or IL-1 beta RA did not alter basal calcium efflux but completely blocked the beta 2m induced calcium efflux. Anti-IL-1 beta had no effect on the basal release of beta-glucuronidase but partially blocked the beta 2m induced release of beta-glucuronidase. Thus, the beta 2m-induced calcium efflux observed in neonatal mouse calvariae is dependent on interleukin-1 beta but not prostaglandins.