Lanthanum carbonate vs. sevelamer hydrochloride for the reduction of serum phosphorus in hemodialysis patients: a crossover study.

AIMS: The aim of this crossover study was to compare the reduction of serum phosphorus (SP) with fixed doses of the non-calcium-containing phosphate binders lanthanum carbonate (LC) and sevelamer hydrochloride (SH) in hemodialysis patients. METHODS: Following washout (2 - 3 weeks), 182 patients with SP >or= 6.0 mg/dl and calcium >or= 8.4 mg/dl were randomized (1:1) to receive LC (2,250 to 3,000 mg/day) or SH (4,800 to 6,400 mg/day) for 4 weeks. Patients underwent a second washout (2 weeks) and switched to the alternative binder for 4 weeks. RESULTS: At the end of treatment, LC had reduced SP by 1.7 +/- 0.1 mg/dl, compared with 1.4 +/- 0.1 mg/dl for SH; the difference was not statistically significant in the primary analysis (LOCF, p = 0.133). However, the reduction with LC was significantly greater than with SH in a prespecified key secondary analysis of patients who completed 4 weeks of treatment with each binder (0.5 mg/dl difference, p = 0.007). The reduction of SP was also greater with LC than SH after 1 week of treatment (p = 0.024). CONCLUSIONS: Although the primary analysis found no difference between LC and SH in the reduction of SP, a significant difference in favor of LC was observed in patients who completed treatment. The results of this study show interesting trends with respect to onset and duration of action that warrant further investigation in longer-term studies.

Beta2-microglobulin stimulates osteoclast formation.

Dialysis-related amyloidosis is a complication of long-term chronic kidney disease (CKD) resulting in deposition of beta(2)-microglobulin (beta(2)M) amyloid in osteoarticular tissue. Clinical manifestations include destructive arthropathy, bone cysts, and fractures. Since osteolytic lesions are prominent findings around the beta(2)M deposits, we sought evidence whether beta(2)M causes bone destruction by directly stimulating osteoclast activity and if this was mediated by local cytokine production. A dose-dependent increase in the number of tartrate-resistant alkaline phosphatase-positive multinucleated cells was found in cultured mouse marrow cells treated with beta(2)M. Osteoprotegerin was unable to block this osteoclastogenic effect of beta(2)M. Osteoblasts or stromal cells were not necessary to induce this osteoclastogenesis, as formation was induced by incubating beta(2)M with colony-forming unit granulocyte macrophages (the earliest identified precursor of osteoclasts) or the murine RAW 264.7 monocytic cell line. beta(2)M Upregulated tumor necrosis factor-alpha (TNF-alpha) and IL-1 expression in a dose-dependent manner; however, a TNF-alpha-neutralizing antibody blocked beta(2)M-induced osteoclast formation. These results show that beta(2)M stimulates osteoclastogenesis, supporting its direct role in causing bone destruction in patients with CKD.

Clinical and economic burden of fractures in patients with renal osteodystrophy.

UNLABELLED: Renal osteodystrophy is a key cause of fractures in patients with chronic kidney disease (CKD). AIMS: This article reviews the clinical and economic burden of fractures and explores the types of studies that need to be conducted in order to fully understand the impact of fractures in renal osteodystrophy. We also discuss the role that active vitamin D compounds and calcimimetics play in treating secondary hyperparathyroidism. MATERIALS AND METHODS: Medline was searched for relevant articles on renal osteodystrophy and fractures. RESULTS: CKD-related fractures are the source of significant morbidity and costs. Extensive osteoporosis research has been utilized to guide fracture prevention and improve disease management, but further costs and outcomes analyses are needed for renal osteodystrophy. Recent research regarding newer, present-day treatment paradigms has suggested that distinct cost savings and improved patient outcomes are possible. CONCLUSIONS: In order to realize such economic and human benefits, the medical community must first have sufficient pathologic, pharmacoeconomic and epidemiologic data to properly understand, manage and prevent renal osteodystrophy and fractures.

Encephalopathy in chronic renal failure responsive to deferoxamine therapy. Another manifestation of aluminum neurotoxicity.

We describe a patient undergoing chronic hemodialysis who developed a neurologic syndrome consisting of seizures, progressive myoclonus, and mild dementia and who responded to chelation therapy with deferoxamine mesylate. Neither her serum nor bone aluminum concentrations indicated aluminum toxicity. However, the presence of a positive deferoxamine-infusion test was suggestive of an elevated body burden of aluminum. Treatment with deferoxamine resulted in marked clinical improvement in her neurologic status within two months. The utility of using the deferoxamine-infusion test rather than serum aluminum levels in evaluating aluminum toxicity in chronic renal failure is suggested.

Relationship of aluminum to neurocognitive dysfunction in chronic dialysis patients.

Aluminum has been proposed as the causative agent in dialysis encephalopathy syndrome. We prospectively assessed whether other, less severe, neuropsychologic abnormalities were also associated with aluminum. A total of 16 patients receiving chronic dialytic therapy were studied. The deferoxamine infusion test (DIT) was used to assess total body aluminum burden. Neurologic function was evaluated by quantitative measures of asterixis, myoclonus, motor strength, and sensation. Cognitive function was assessed by measures of dementia, memory, language, and depression. There were four patients with a positive DIT (greater than 125 micrograms/L increment in serum aluminum) that was associated with an increase in the number of neurologic abnormalities observed, as well as an increase in severity of myoclonus, asterixis, and lower extremity weakness. Patients with a positive DIT also showed significant impairment in memory; however, no differences were noted on tests of dementia, depression, or language. There was no significant correlation between sex, age, presence of diabetes, mode of dialysis, years of chronic renal failure, years of dialysis or years of aluminum ingestion and any neurologic or neurobehavioral measurement, serum aluminum level, or DIT. These changes may represent early aluminum-associated neurologic dysfunction.

1,25-Dihydroxyvitamin D3-induced calcium efflux from calvaria is mediated by protein kinase C.

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is an important regulator of bone metabolism involved in both formation and resorption. Traditionally it was assumed that vitamin D receptors are intracellular. Recent data indicate that vitamin D may also act through a membrane receptor, specifically raising intracellular calcium and inositol 1,4,5 triphosphate. The present study was undertaken to explore further the mechanism(s) of vitamin D-induced bone resorption in cultured bone. 1,25(OH)2D3 induced a dose-dependent increase of calcium efflux from cultured bone. This increase was completely obliterated by inhibition of protein kinase C (PKC) with either staurosporine or calphostin C. In cultured rat calvariae, 1,25(OH)2D3 also induced a dose-dependent translocation of PKC from cytosol to membrane. The activation of PKC by 1, 25(OH)2D3 occurred following a 30-s incubation, peaked at 1 minute, and disappeared by 5 minutes. 1,25(OH)2D3 did not increase cAMP production in similarly cultured calvaria. These results suggest that the action of 1,25(OH)2D3 on calcium flux from cultured bone is mediated, in part, via activation of PKC.

Effects of aluminum on bone surface ion composition.

Aluminum induces net calcium efflux from cultured bone. To determine whether aluminum alters the bone surface ion composition in a manner consistent with predominantly cell-mediated resorption, a combination of cell-mediated resorption and physicochemical dissolution or physicochemical dissolution alone, we utilized an analytic high-resolution scanning ion microprobe with secondary ion mass spectroscopy to determine the effects of aluminum on bone surface ion composition. We cultured neonatal mouse calvariae with or without aluminum (10(-7) M) for 24 h and determined the relative ion concentrations of 23Na, 27Al, 39K, and 40Ca on the bone surface and eroded subsurface. Control calvariae have a surface (depth approximately 6 nm) that is rich in Na and K compared with Ca(Na/Ca) = 24.4 + 1.4, mean + 95% confidence limit of counts per second of detected secondary ions, K+Ca = 13.2 + 0.9). Aluminum is incorporated into the bone and causes a depletion of surface Na and K relative to Ca (Na/Ca = 9.6 + 0.7, K/Ca = 4.9 + 0.4; each p < 0.001 versus control). After erosion (depth approximately 50 nm), control calvariae have more Na and K than Ca (Na/Ca = 16.0 + 0.1, K/Ca = 7.5 + 0.1); aluminum again depleted Na and K relative to Ca (Na/Ca = 4.1 + 0.1 K/Ca = 1.9 + 0.1; each p < 0.001 versus control). Aluminum produced a greater net efflux of Ca (362 +/- 53, mean +/- SE, nmol/bone/24 h) than control (60 +/- 30, p < 0.001). With aluminum, the fall in the ratios of both Na/Ca and K/Ca coupled with net Ca release from bone indicates that aluminium induces a greater efflux of Na and K than Ca from the bone surface and is consistent with an aluminum-induced removal of the bone surface. This alteration in surface ion concentration and calcium efflux is consistent with that observed when calcium is lost from bone through a combination of cell-mediated resorption and physicochemical dissolution.

Increased risk of fracture in patients receiving solid organ transplants.

The success of organ transplantation is related to advances in immunosuppressive therapy. These medications are associated with medical complications including bone damage. The objective of this study was to estimate and compare age, gender-specific fracture incidence between transplant recipients, and a large sample representative of the civilian noninstitutionalized United States population using the 1994 National Health Interview Survey (NHIS). This was a cohort study set in tertiary care centers. Five hundred and thirty-nine individuals who received abdominal organ and 61 heart transplants surviving at least 30 days at our institution from 1986 to 1996 were included in the study. Incident fractures were ascertained by mail, in-person interview, telephone survey, or medical record review. All fractures were verified. Organ-, age-, and gender-specific fracture numbers and rates and person-years of observation, were calculated for the transplant patients. Weighted age- and gender-specific fracture rates from the 1994 NHIS were applied to the number of person-years of observation for each organ-specific age and gender category of transplant patients to generate an expected number of fractures. The ratio of observed to expected number of fractures was used to compare fracture experience of transplant patients to that of the national sample from the 1994 NHIS. Fifty-six of 600 (9.3%) patients had at least one fracture following 1221 person-years of observation. The sites of initial symptomatic fracture were as follows: foot (n = 22), arm (n = 8), leg (n = 7), ribs (n = 6), hip (n = 4), spine (n = 3), fingers (n = 3), pelvis (n = 2), and wrist (n = 1). Fracture incidence was 13 times higher than expected in male heart recipients age 45-64 years; nearly 5 times higher in male kidney recipients age 25-44 and age 45-64 years; and 18 times and 34 times higher in female kidney recipients age 25-44 years and 45-64 years compared with NHIS data. We have shown an increased incidence of fractures and estimated the magnitude of this problem in patients undergoing solid organ transplantation. Our work defines the need for a long-term prospective study of fracture risk in these patients.

Glucose-induced inhibition of in vitro bone mineralization.

Patients with diabetes tend to have an increased incidence of osteopenia that may be related to hyperglycemia. However, little is known about how glucose may alter bone formation and osteoblast maturation. To determine whether glucose affects osteoblastic calcium deposition, MC3T3-E1 cells were incubated in media containing either a normal (5.5 mmol/L) or high glucose concentration (15 mmol/L) or mannitol (15 mmol/L), and bone nodule formation was examined. Net calcium flux was measured thrice weekly and cumulative calcium uptake was determined. Compared with control incubations, glucose significantly inhibited daily and cumulative calcium uptake into the nodules. At the time of matrix maturation, cultures undergo a rapid phase of increased calcium deposition; this was significantly inhibited by the presence of glucose. Total calcium uptake, determined by acid digestion, was also significantly inhibited by glucose. Area and number of nodules were quantitated at the end of the incubation period (day 30) by staining with Alizarin Red S calcium stain. Compared with both control and mannitol-treated cultures, the number of nodules was increased by incubation with glucose. Furthermore, both the average total nodular area and calcified nodular area of large nodules were increased by glucose. Cellular proliferation as well as the release of markers of osteoblast activity (osteocalcin and alkaline phosphatase) were determined at the end of the experimental period (day 30). Cellular proliferation and alkaline phosphatase activity was significantly increased in the presence of glucose, however, the release of osteocalcin into culture media was similar in all three groups. In conclusion, the present study shows that elevated glucose concentration present throughout the development of murine osteoblasts stimulates cellular proliferation while inhibiting calcium uptake. The result of glucose inhibition of calcium uptake suggests that bone could be structurally altered in diabetes.

Posttransplant bone disease: a case illustrating dramatic improvements in bone density with vitamin D replacement therapy.

Although bisphosponates are proposed as first-line treatment for posttransplant bone disease they are not optimal in all situations. A kidney transplant recipient developed hypercalcemia from mobilization of extraskeletal calcium. He had low serum parathyroid hormone and vitamin D; high calcium excretion; and normal calcium intake. Bone biopsy revealed severe osteomalacia. Bisphosphonates, used in the early treatment of acute hypercalcemia, were not indicated to treat osteomalacia. However, over several months serum calcium declined sufficiently to allow treatment of the bone disease with oral calcitriol. Dual-energy radiographic absorptiometry over the next 2 years documented dramatic improvements in bone density (percent of young-normal controls) : from 63 to 85%, at the lumbar spine; from 38 to 67%, at the femoral neck. This response to treatment could not have been achieved with an antiresorptive strategy. Optimal management of posttransplant bone disease requires a diagnostic approach, which considers all plausible contributing factors.

Effect of the vitamin D analogues paricalcitol and calcitriol on bone mineral in vitro.

Paricalcitol (19-nor-1,25-dihydroxyvitamin D(2)), a new vitamin D analogue, recently became available for the treatment of hyperparathyroidism in patients with end-stage renal disease. It is safe and effective in suppressing parathyroid hormone, with apparently less propensity for hypercalcemia than calcitriol (1, 25-dihydroxyvitamin D(3)). However, the mechanism of action on bone has not been fully elucidated. This study compares the effects of paricalcitol and calcitriol on the bone mineral. Neonatal (5- to 7-day-old) mouse calvariae were incubated in the absence or presence of either paricalcitol or calcitriol for 48 hours, and calcium flux, osteocalcin and acid and alkaline phosphatase activity, and interleukin-6 (IL-6) release were determined. Increasing concentrations of both calcitriol and paricalcitol increased calcium efflux. At lower concentrations, paricalcitol had no effect on acid phosphatase activity; however, at 10(-8) mol/L, paricalcitol caused a significant increase similar to that of calcitriol at 10(-9) mol/L. Increasing concentrations of paricalcitol had no effect on alkaline phosphatase activity, whereas calcitriol (10(-8) mol/L) caused significant inhibition. At low concentrations, paricalcitol had no effect on osteocalcin release; however, at 10(-8) mol/L, both compounds significantly increased osteocalcin production. Neither compound had an effect on IL-6 release. These data show that: (1) at low concentrations, both compounds induce a similar calcium efflux from cultured bone; (2) at low concentrations, paricalcitol has no effect on osteocalcin or acid and alkaline phosphatase activity; (3) at greater concentrations, paricalcitol and calcitriol have similar effects on acid phosphatase and osteocalcin activity; (4) calcitriol, but not paricalcitol, inhibits alkaline phosphatase release; and (5) the bone-resorbing effect of both compounds is independent of IL-6 release. Thus, although both compounds have similar effects on calcium efflux from bone, at therapeutic concentrations, paricalcitol does not seem to inhibit osteoblast activity. This may explain, in part, the lower calcemic effect of paricalcitol.

Suppression of parathyroid hormone secretion in hemodialysis patients: comparison of paricalcitol with calcitriol.

Paricalcitol was introduced recently as an effective alternative to calcitriol for the suppression of parathyroid hormone (PTH) in patients with end-stage renal disease. An international, multicenter, double-blinded, randomized, comparative study of intravenous paricalcitol and calcitriol was performed. Results from 38 patients at dialysis units affiliated with the Northwestern University Medical School (Chicago and Evanston, IL) are reported here while a report of the full clinical trial is being completed. Results were evaluated in terms of obtaining the following end points: decrease of at least 50% in baseline PTH concentration and the occurrence of hypercalcemia and hyperphosphatemia. Paricalcitol therapy was started at a dose of 0.04 microgram/kg and increased by 0.04 microgram/kg increments every 4 weeks to a maximum allowable dose of 0.24 microgram/kg or until there was at least a 50% decrease in serum PTH concentration. Calcitriol therapy was started at a dose of 0.01 microgram/kg and increased by 0.01 microgram/kg increments every 4 weeks to a maximum allowable dose of 0.06 microgram/kg or until there was at least a 50% decrease in serum PTH concentration. Mean baseline serum PTH, calcium, and phosphorus concentrations were similar. Reductions in PTH occurred more rapidly in subjects administered paricalcitol compared with calcitriol, with no difference in serum calcium levels throughout the study between groups. The percentage of subjects experiencing severe hyperphosphatemia (serum phosphorus >8.0 mg/dL) was greater in those administered calcitriol compared with paricalcitol. In conclusion, our data suggest that paricalcitol reduces PTH levels more rapidly, with fewer episodes of hyperphosphatemia, than intravenous calcitriol.

Acute renal failure associated with cardiac operations. A case-control study.

We performed a case-control study to identify risk factors for the development of acute renal failure after cardiac operations. Forty-two cases of acute renal failure were identified in a total of 572 patients who underwent cardiac operations. They were matched with a control population of patients having cardiac operations without acute renal failure. Discriminant analysis performed with preoperative variables revealed preoperative serum creatinine values, concurrent valve and bypass surgery, and age to be significant variables for identifying patients at risk for acute renal failure. The use of these three variables in a discriminant model correctly classified 77% of patients. The addition of intraoperative variables did not significantly improve the ability of the model to correctly classify patients. Acute renal failure was associated with a significant increase in the number of postoperative complications, mortality, and length of hospitalization and intensive care unit stay.

Engineering bone regeneration with bioabsorbable scaffolds with novel microarchitecture.

Critical-sized defects (CSDs) were introduced into rat calvaria to test the hypothesis that absorption of surrounding blood, marrow, and fluid from the osseous wound into a bioabsorbable polymer matrix with unique microarchitecture can induce bone formation via hematoma stabilization. Scaffolds with 90% porosity, specific surface areas of approximately 10 m2/g, and median pore sizes of 16 and 32 microm, respectively, were fabricated using an emulsion freeze-drying process. Contact radiography and radiomorphometry revealed the size of the initial defects (50 mm2) were reduced to 27 +/- 11 mm2 and 34 +/- 17 mm2 for CSDs treated with poly(D,L-lactide-co-glycolide). Histology and histomorphometry revealed scaffolds filled with significantly more de novo bone than negative controls (p < 0. 007), more osteoid than both the negative and autograft controls (p < 0.002), and small masses of mineralized tissue (< 15 mm in diameter) observed within the scaffolds. Based on these findings, we propose a change in the current paradigm regarding the microarchitecture of scaffolds for in vivo bone regeneration to include mechanisms based on hematoma stabilization.

Uremic encephalopathy.

The neurologic manifestations of renal failure are variable, nonspecific and most likely result from multiple metabolic derangements. Commonly used neurodiagnostic tests may be abnormal but are generally nondiagnostic. The EEG, although nonspecific, correlates with clinical symptoms and may be of diagnostic value if serial studies are performed. The pathophysiology of uremic encephalopathy is not well understood and multiple potential "uremic toxins" have been evaluated. Of these, parathyroid hormone is the only substance to be clearly linked to clinical findings. It is likely that other, even unidentified toxins, may play a role in the complex pathogenesis of neurologic disease associated with renal failure.

Oral doxercalciferol therapy for secondary hyperparathyroidism in a peritoneal dialysis patient.

Control of hyperphosphatemia and the administration of vitamin D are the primary treatment modalities for the prevention and management of secondary hyperparathyroidism. Vitamin D therapy for secondary hyperparathyroidism has been limited by the development of hypercalcemia and/or hyperphosphatemia due to increased intestinal absorption of these minerals. Recently, selective vitamin D analogs specifically designed to suppress parathyroid hormone (PTH) without causing hypercalcemia or hyperphosphatemia have shown promise for the treatment of secondary hyperparathyroidism in uremia. This case report describes the successful use of doxercalciferol to treat severe secondary hyperparathyroidism in an adult male patient undergoing chronic peritoneal dialysis, with a follow-up period of 9 months. During this period, the patient's hyperparathyroidism was rapidly and easily controlled. Treatment was complicated by a single incident of over suppression of PTH, with concomitant hypercalcemia. This quickly resolved upon temporary discontinuation of doxercalciferol therapy, after which therapy was resumed without further incident.

Dialysis-related amyloidosis.

Dialysis-related amyloidosis (DRA) is a complication of long-term dialysis and can also be seen in patients with chronical renal failure and on continuous ambulatory peritoneal dyalisis. This review focuses on the chemical modifications of beta(2)-microglobulin that lead to the formation and deposition of beta(2)-amyloid fibrils in periarticular and articular sites which ultimately results in the clinical and radiographic characteristics of this devastating disease. Its most common manifestations are carpal tunnel syndrome, shoulder pain and destructive arthropathy. Treatment of DRA has been directed towards achieving normal serum levels of beta(2)M in end stage renal disease (ESRD) patients which usually results in clinical improvement and delay in disease progression. Medical treatment consists of the use of corticosteroids and nonsteroidal anti-inflammatory drugs. Surgical intervention for carpal tunnel syndrome or spinal cord compression can greatly improve quality of life.

Evaluation of cinacalcet HCl treatment after kidney transplantation.

BACKGROUND: Hyperparathyroidism often remains or develops after kidney transplantation. Vitamin D sterol used as treatment for an elevated parathyroid hormone (PTH) level and associated bone disease may be contraindicated due to hypercalcemia. The calcimimetic cinacalcet HCl (cinacalcet), which lowers PTH and calcium (Ca) in chronic kidney disease patients, may represent an alternate therapeutic modality. METHODS: This multicenter, retrospective, observational study examined 41 kidney transplant patients receiving cinacalcet for ≥3 months starting ≥3 months posttransplantation. Levels of intact PTH, Ca, and phosphorus (P) were examined during the assessment phase (3-6 months after initiation). RESULTS: Median PTH decreased 21.8% during the assessment phase (P < .001), with 32.5% of patients exhibiting a ≥30% decrease in PTH from baseline. Median Ca decreased 6.8% (P < .0001). Median serum P rose 10.0% (P = .0124), but remained within normal limits. The estimated glomerular filtration rate was stable throughout the study. CONCLUSIONS: Cinacalcet may be useful for the treatment of hyperparathyroidism after kidney transplantation. Randomized, prospectively designed clinical trials are required to confirm these results.