To determine the effects of renal osteodystrophy (ROD) on bone microarchitecture in growing rats.
A total of 24 rats underwent 5/6 nephrectomy (NX) and were fed a high-phosphorus diet to induce ROD; ...another 6 underwent sham NX. In vitro microcomputed tomography images (GEMS, London, Ontario, Canada) were obtained in the femoral metaphysis and midshaft.
Trabecular and cortical bone volume/total volume (BV/TV) were significantly lower in NX specimens because of pores within the trabeculae and along the endosteal surface. Topological analysis using component labeling in 3-dimensions verified that trabecular pores connected to the marrow space. After the trabecular pores were filled using a morphological filter, trabecular thickness was significantly increased in NX. In contrast, cortical thickness was significantly decreased in NX compared with controls; however, after filling the endocortical pores, thickness did not differ.
The ROD resulted in decreased cortical and trabecular BV/TV, increased porosity, and increased trabecular thickness. Advanced image processing algorithms demonstrated the effects of cortical and trabecular porosity on BV/TV and structure in ROD.
Background. We recently reported that administration of high doses of lanthanum carbonate (1000 mg/kg/day) to chronic renal failure (CRF) rats can result in a mineralization defect. Our results ...suggested, however, that the impaired mineralization was not due to a direct toxic action of lanthanum on the bone, but rather was an indirect consequence of a phosphate depletion resulting from the compound's high phosphate-binding capacity. To further substantiate these results, in the present study, the effects of lanthanum carbonate on bone were compared to the effects of sevelamer, a nonabsorbed, non-metal-containing polymeric phosphate-binding agent. Methods. Male Wistar rats underwent a 5/6th nephrectomy to induce chronic renal failure, after which they were treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) by oral gavage for 12 weeks. Results. CRF animals treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) developed a phosphate depletion after 4 weeks of treatment, as evidenced by a marked reduction in phosphaturia. At sacrifice after 12 weeks of treatment, bone histomorphometry showed that a mineralization defect had developed in two out of six animals in the lanthanum-carbonate-treated group, in four out of seven animals in the 1000 mg/kg/day sevelamer group, and in one out of nine animals in the 500 mg/kg/day sevelamer group. Conclusions. These results corroborate our previous findings that the administration of a powerful phosphate-binding agent to CRF rats can induce phosphate depletion, resulting in a mineralization defect.
Brown tumors, or osteoclastomas, are erosive bony lesions arising as a complication of hyperparathyroidism (HPT). In patients with end-stage renal disease (ESRD), brown tumors are classic skeletal ...manifestations usually seen in severe forms of secondary HPT. However, involvement of the spine is considered extremely rare. We report a long-term hemodialysis case, in which cauda equina compression developed due to a sacral brown tumor. A decompressive surgery and subtotal parathyroidectomy were indicated to preserve neurologic function, and to ensure remineralization of the lesion. This case illustrates that, though rare, brown tumors should be considered in uremic patients with neurological symptoms. Emergent decompressive surgery is required to remove pressure on neurological structures and to stabilize the spine.
Aluminum posttranscriptional regulation of parathyroid hormone synthesis: A role for the calcium-sensing receptor.
Calcium regulates parathyroid hormone (PTH) gene expression by a posttranscriptional ...mechanism, as well as parathyroid gland growth through the activation of the calcium-sensing receptor. Aluminum decreases both parathyroid cell proliferation and PTH levels by an unknown mechanism.
To investigate the possible role of calcium-sensing receptor in the aluminum-induced PTH inhibition we used human embryonic kidney (HEK-293) cells transiently transfected with the human calcium-sensing receptor. We used a parathyroid gland tissue culture model to investigate whether the effect of aluminum in PTH mRNA was a transcriptional mechanism and also its possible role in calcium-sensing receptor expression.
We found that Al activated the calcium-sensing receptor with higher efficiency than calcium, its biologic ligand. Aluminum inhibited PTH gene expression by a posttranscriptional mechanism, but only when low calcium is present in the medium. Finally, we found that aluminum is also able to decrease calcium-sensing receptor mRNA levels by a posttranscriptional mechanism; however, no effect was observed on calcium-sensing receptor protein.
These findings indicate that aluminum impairs parathyroid function through a calcium-like mechanism due to the lack of specificity of the calcium-sensing receptor. Additionally, aluminum decreases parathyroid calcium-sensing receptor mRNA levels, and the regulatory mechanism was posttranscriptional. These findings demonstrate for the first time a regulatory effect in the calcium-sensing receptor by one of its ligands.
Low bone turnover in patients with renal failure Couttenye, Marie Madeleine; D'haese, Patrick C.; Verschoren, Wim J. ...
Kidney international,
12/1999, Letnik:
56, Številka:
S73
Journal Article
Recenzirano
Odprti dostop
Low bone turnover in patients with renal failure. Renal failure inevitably leads to metabolic bone disease. Low turnover disease or adynamic bone disease (ABD) is characterized by a low number of ...osteoblasts with normal or reduced numbers of osteoclasts. Mineralization proceeds at a normal rate, resulting in normal or decreased osteoid thickness. Recently, it became clear that the relative contribution of the various types of renal osteodystrophy (ROD) to the spectrum of the histologic picture in renal failure patients underwent profound changes during the last 25 years. At the moment, the exact physiopathological mechanisms behind ABD are not yet elucidated, and thus the reason(s) for its increasing prevalence remains poorly understood. A number of epidemiological and experimental data suggest a multifactorial pathophysiologic process, in which hypoparathyroidism and suppression of the osteoblast are the main actors. Compared to adynamic bone disease, osteomalacia has now become a much rarer disease (around 4%), at least in Western countries. On the other hand, recent studies indicate that this particular bone disease entity might still regularly occur in less developed countries. Osteomalacia originates from a direct effect on the mineralization process. With this type of renal bone disease, the effects of secondary hyperparathyroidism on bone are overridden by a number of metabolic abnormalities that finally result in a defective bone mineralization, as occurs, for instance, when the lag time between osteoid deposition and its mineralization is increased. The relationship between exogenous and endogenous vitamin D deficiency (mainly calcitriol) and the histologic finding of osteomalacia in uremic patients is well known. Recent data showed distinctly lowered 25-(OH) vitamin D3 levels in the presence of unaffected calcitriol concentrations in patients with osteomalacic lesions, as assessed radiologically by the presence of Looser's zones. Recently, we found that bone strontium levels were increased in patients with osteomalacia as compared to all other types of ROD. Strontium accumulation appeared to originate mainly from the use of strontium-contaminated dialysate, which resulted from the addition of strontium-containing acetate-based concentrates. Evidence for a causal role of the element in the development of a mineralization defect could be tested experimentally by adding strontium to drinking water in a chronic renal failure rat model.
Abnormalities in mineral metabolism and changes in skeletal histology may contribute to growth impairment in children with chronic renal failure. Hyperphosphatemia, hypocalcemia, metabolic acidosis, ...alterations in vitamin D and IGF synthesis and parathyroid gland dysfunction play significant roles in the development of secondary hyperparathyroidism and subsequently, bone disease in renal failure. The recent KDIGO conference has made recommendations to consider this as a systemic disorder (chronic kidney disease-mineral bone disorder) and to standardize bone histomorphometry to include bone turnover, mineralization and volume (TMV). The use of DXA to assess bone mass is controversial in children with chronic renal failure. Questions arise regarding the accuracy of bone measurements and difficulty in data interpretation especially in children with renal failure who are not only growth retarded but often have pubertal delay and osteosclerosis. The validity and feasibility of new modalities of skeletal imaging which can detect changes in both trabecular and cortical bone are currently being investigated in children. The management of mineral abnormalities and bone disease in chronic renal failure is multifactorial. To manage hyperphosphatemia, dietary phosphate restriction accompanied by intake of calcium-free and metal-free phosphate binding agents are widely utilized. Vitamin D analogs remain the primary therapy for secondary hyperparathyroidism, although the use of the less hypercalcemic agents is preferred due to concerns of calciphylaxis and vascular calcification. Future clinical studies are needed to evaluate the long-term effects of calcimimetic agents and bisphosphonate therapy in children with chronic renal failure.
Chronic kidney disease (CKD) is accompanied by disturbances in calcium, phosphate, vitamin D, and parathyroid hormone (PTH) homeostasis that play an important role in the pathophysiology of renal ...bone disease. The increased cardiovascular morbidity and mortality observed among patients with CKD has recently been recognized to be associated with these disturbances in mineral metabolism. Thus, disturbances in mineral metabolism observed in renal failure results in a multisystem disorder, making the development of a standardized definition of these disorders a top priority. Therefore, the Board of Directors of Kidney Disease: Improving Global Outcomes proposed to define the broader category of mineral disorders associated with CKD as CKD-mineral and bone disorder (CKD-MBD). This newly proposed definition will include the disorders of mineral metabolism, bone histology (renal osteodystrophy), and the extraskeletal manifestations such as vascular calcification. This new definition and stratification of disease should result in improvement not only in the clinical management of patients but also will facilitate the interpretation and translation of clinical research. Renal osteodystrophy is now considered as 1 component of this disorder and will be defined as a morphologic alteration only, based on unification of the histomorphometric definitions that will include parameters of turnover, mineralization, and volume. An internationally accepted classification system will enable the consensus for bone biopsy evaluation as well as for the role of biomarkers. This article will focus on the newly proposed definitions of bone disease as part of CKD-MBD, based on the complex pathophysiologic process underlying bone disease in CKD stages 2 to 5.
Abstract Background The validity of serum parathyroid hormone (PTH) as a surrogate marker of bone turnover in chronic kidney disease (CKD) is limited by several factors such as relative resistance of ...bone to PTH, hyperphosphatemia, diabetes, gender, age, race and vitamin D analog action on the PTH-bone axis. Urinary collagen N-terminal telopeptide X (NTx), a bone collagen degradation product, expressed as bone collagen equivalents (BCE) per mM of creatinine (NTx/Cr ratio), is routinely used to estimate bone turnover in osteoporosis. The purpose of this study is to evaluate NTx as a marker of bone turnover in CKD. Methods We studied the relationship between bone-specific alkaline phosphatase (BSAP), PTH and urine NTx/Cr in 37 CKD out-patients. Results In a multivariate model, PTH had a positive correlation with BSAP ( r = 0.44, P < 0.19) and U-NTx/Cr ( r = 0.55, P < 0.30), after adjusting for age, gender, estimated glomerular filtration rate (GFR), serum phosphorus, corrected calcium, and race. However, the strongest correlation was found between the two direct markers of bone resorption and formation (U-NTx vs. BSAP; r = 0.80; P < 0.0001), suggesting a tight coupling of bone resorption and formation in CKD. The effect of gender on U-NTx/Cr was studied in a multivariate model after adjusting for age, race, GFR, serum calcium, phosphorus and PTH. Females had a higher U-NTx/Cr than males. Conclusion Our findings indicate that urinary NTx, a promising marker of bone resorption in CKD patients, exhibits a strong positive correlation with other markers used to assess renal osteodystrophy i.e. PTH and BSAP. Unlike PTH and BSAP, urine NTx also measures bone loss secondary to osteoporosis.
Calcium absorption from the bowel is known to depend upon gastric acidity. We chose to investigate whether the use of omeprazole could reduce the incidence of hypercalcemia in dialysis patients who ...could not afford expensive non-calciumbased phosphate binders.
26 hemodialysis patients at the Hypertension, Nephrology, Dialysis, and Transplantation Clinic in Opelika, Alabama (USA) with refractory hypercalcemia for at least 3 months prior to the study who were unable to afford non-calcium-based binders were treated with 20 mg of omeprazole a day for three months and then compared to 27 similar patients who were taking non-calcium-based binders.
While there was a trend towards lower serum calcium levels and phosphate binder dosages in the omeprazole group (particularly with the calcium carbonate binders as opposed to the calcium acetate binders), there was no statistical difference in any variable in either controls or the omeprazole group from pre-study period.
While theoretically advantageous, we found that omeprazole had little clinical benefit in reducing hypercalcemia in a population who are unable to afford non-calcium-based binders; however, further studies may be warranted.
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