Cheryl P. Sanchez

Impaired growth, delayed ossification, and reduced osteoclastic activity in the growth plate of calcium-supplemented rats with renal failure.

Linear growth is reduced in prepubertal children with adynamic renal osteodystrophy, suggesting that the proliferation and/or differentiation of epiphyseal growth plate chondrocytes is abnormal in this disorder. To examine this issue, in situ hybridization and histochemistry were used to measure selected markers of endochondral bone formation and bone resorption in the proximal tibia of subtotally nephrectomized rats fed a high calcium diet to induce biochemical changes consistent with adynamic osteodystrophy. Blood ionized calcium concentrations were higher and serum PTH levels were lower in nephrectomized, calcium-supplemented rats than in either intact or nephrectomized control animals. Linear growth and tibial length were reduced, but messenger RNA levels for type II collagen, type X collagen, and the PTH/PTHrP receptor did not differ from control values in nephrectomized rats given supplemental calcium. In contrast, both the width of epiphyseal cartilage and the height of the zone of hypertrophic cho...

Bone growth during rapamycin therapy in young rats

BackgroundRapamycin is an effective immunosuppressant widely used to maintain the renal allograft in pediatric patients. Linear growth may be adversely affected in young children since rapamycin has potent anti-proliferative and anti-angiogenic properties.MethodsWeanling three week old rats were given rapamycin at 2.5 mg/kg daily by gavage for 2 or 4 weeks and compared to a Control group given equivalent amount of saline. Morphometric measurements and biochemical determinations for serum calcium, phosphate, iPTH, urea nitrogen, creatinine and insulin-growth factor I (IGF-I) were obtained. Histomorphometric analysis of the growth plate cartilage, in-situ hybridization experiments and immunohistochemical studies for various proteins were performed to evaluate for chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption.ResultsAt the end of the 2 weeks, body and tibia length measurements were shorter after rapamycin therapy associated with an enlargement of the hypertrophic zone in the growth plate cartilage. There was a decrease in chondrocyte proliferation assessed by histone-4 and mammalian target of rapamycin (mTOR) expression. A reduction in parathyroid hormone/parathyroid hormone related peptide (PTH/PTHrP) and an increase in Indian hedgehog (Ihh) expression may explain in part, the increase number of hypertrophic chondrocytes. The number of TRAP positive multinucleated chondro/osteoclasts declined in the chondro-osseous junction with a decrease in the receptor activator of nuclear factor kappa β ligand (RANKL) and vascular endothelial growth factor (VEGF) expression. Although body and tibial length remained short after 4 weeks of rapamycin, changes in the expression of chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption which were significant after 2 weeks of rapamycin improved at the end of 4 weeks.ConclusionWhen given to young rats, 2 weeks of rapamycin significantly decreased endochondral bone growth. No catch-up growth was demonstrated at the end of 4 weeks, although markers of chondrocyte proliferation and differentiation improved. Clinical studies need to be done to evaluate these changes in growing children.

Growth hormone and the skeleton in pediatric renal allograft recipients

Abstract Recombinant human growth hormone has been utilized to augment linear growth in pediatric renal allograft recipients. The skeletal changes that accompany growth hormone therapy have not been described in children. Thus, 23 stable prepubertal pediatric kidney recipients, aged 10±3 years, with a mean transplant time of 3.4±2.5 years and histological findings of normal bone formation and adynamic bone on bone biopsies were prospectively randomized into two groups. These comprised a treated group that received 12 months of growth hormone and a control group that did not receive any treatment. Anthropometric measurements and blood for serum calcium, phosphorus, parathyroid hormone (PTH), osteocalcin, and insulin-like growth factor-I (IGF-I) were obtained every 3 months. Measurements of bone mass by dual-energy X-ray absorptiometry were performed at the beginning and end of the study period. All patients underwent an initial and final bone biopsy procedure after double tetracycline labeling. Annual growth velocity increased and standard deviation scores for height improved in the treated group. Serum IGF-I levels increased in the treated group and the increase was evident in patients with normal bone formation who received growth hormone but not in patients with adynamic bone. Serum calcium, phosphorus, osteocalcin, and PTH levels did not differ between the treated and control groups. Bone mass did not change in the treated group, but declined after 12 months in the control group. Bone formation rates did not increase with growth hormone treatment. Thus, growth hormone therapy improves linear growth and maintains bone mass, but does not favorably affect bone formation rates in stable pediatric renal allograft recipients.

Quantitative microcomputed tomography assessment of intratrabecular, intertrabecular, and cortical bone architecture in a rat model of severe renal osteodystrophy.

Objective: To determine the effects of renal osteodystrophy (ROD) on bone microarchitecture in growing rats. Methods: 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. Results: 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. Conclusions: 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.

Mineral metabolism and bone abnormalities in children with chronic renal failure

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.

Secondary Hyperparathyroidism in Children with Chronic Renal Failure

Despite advances in the management of patients with chronic renal failure, histologic features associated with secondary hyperparathyroidism remain the predominant skeletal findings; however, over the last decade the prevalence of adynamic bone has increased in both adult and pediatric patients with chronic renal failure.The management of children with secondary hyperparathyroidism and mild to moderate chronic renal failure should be started early, and should include correction of hypocalcemia and metabolic acidosis, maintenance of age-appropriate serum phosphorus levels, and institution of vitamin D therapy when serum intact parathyroid hormone (PTH) measurements are elevated to maintain the blood levels within normal limits; however, in children undergoing chronic dialysis therapy, the current recommendation is to maintain the serum intact PTH levels at least 2–4 times the upper limits of normal to prevent the development of low bone turnover disease. Serum calcium, phosphorus, alkaline phosphatase, and PTH levels should be monitored frequently, especially in infants and very young children. Discontinuation or reduction of vitamin D should be considered when there is a rapid decline in PTH levels, persistent elevation in serum calcium and serum phosphorus levels, and a significant diminution in alkaline phosphatase levels. In addition, a reduction in the calcium concentration of the dialysis fluid, and judicious use of calcium-containing salts as phosphate binding agents should also be performed in these patients. Although not yet extensively used in pediatric patients with secondary hyperparathyroidism, several therapeutic alternatives, such as the less calcemic vitamin D analogs, including paricalcitol [19-nor-1,25-(OH)2D2] and doxercalciferol [1-α-(OH)2D2], calcimimetics, and the availability of a calcium-free, aluminum-free phosphate binder such as sevelamer hydrochloride and lanthanum carbonate, may play significant roles in the future management of children with secondary hyperparathyroidism to promote linear growth, prevent parathyroid gland hyperplasia, avoid calciphylaxis and, in the long run, avert vascular calcifications.

Prevention of Renal Osteodystrophy in Predialysis Patients

Impaired calcitriol synthesis is one of the major factors contributing to the development of secondary hyperparathyroidism in patients with chronic renal failure. Vitamin D therapy, particularly 1alpha-hydroxyvitamin D3, even in low doses, has been shown to be effective in the treatment of secondary hyperparathyroidism in patients with mild-to-moderate chronic renal failure. Complications associated with calcitriol and alfacalcidol therapy, which include hypercalcemia and progressive deterioration of renal function, have been reported in some patients. The majority of the studies reviewed, however, demonstrated that daily calcitriol and alfacalcidol doses below 0.25 microg are rarely associated with hypercalcemia, hyperphosphatemia, or progressive decline in renal function. In addition, these complications usually resolve with the reduction in dose or discontinuation of the medication. Thus, vitamin D therapy may be valuable in the treatment of patients with mild-to-moderate chronic renal failure who may be at high risk of developing secondary hyperparathyroidism.

The Renal Bone Diseases in Children Treated With Dialysis

Renal osteodystrophy represents a spectrum from high- to low-turnover bone lesions. The specific pattern, however, may change during selected therapeutic interventions. As in the past, osteitis fibrosa remains the most frequent histologic lesion in pediatric patients on dialysis, although recently the prevalence of low-turnover bone lesions without aluminum toxicity has been increasing in the pediatric population. This may be a consequence of aggressive calcitriol and calcium therapy. The different factors involved in the development of secondary hyperparathyroidism include hyperphosphatemia, hypocalcemia, altered vitamin D synthesis, impairments in parathyroid hormone (PTH) secretion and metabolism, and, recently, possible downregulation of renal PTH/PTH-rP messenger RNA receptor. New developments in molecular biology have demonstrated the relationship between vitamin D and PTH. The use of high-dose pulse intravenous, intraperitoneal, and oral calcitriol therapy has significantly decreased serum PTH levels and retarded the progression of osteitis fibrosa. These therapeutic interventions, however, may have led to the development of adynamic bone lesions. The impact of adynamic bone lesions in the young and growing skeleton remains to be determined.

Modulation of endochondral bone formation: roles of growth hormone, 1,25-dihydroxyvitamin D and hyperparathyroidism

Abstract Impairment of linear growth occurs invariably in children with chronic renal failure. Recombinant human growth hormone and 1,25-dihydroxyvitamin D (calcitriol) are widely utilized to improve linear growth in children. Large doses of calcitriol, however, have been shown to suppress chondrocyte proliferation and may lead to the development of adynamic bone. Substantial reductions of growth have been shown in children with chronic renal failure treated with intermittent calcitriol therapy. These findings suggest that calcitriol can modify chondrocyte proliferation and/or differentiation in epiphyseal growth plate cartilage and may counteract the effects of growth hormone therapy in increasing linear growth in children with chronic renal failure. Parathyroid hormone related peptide (PTHrP) and its receptor (PTH/PTHrP receptor) play critical roles in regulating chondrocyte differentiation in the growth plate. The expression of PTH/PTHrP receptor mRNA is downregulated in animals with chronic renal failure and advanced secondary hyperparathyroidism; calcitriol and growth hormone therapy may modify the expression of PTH/PTHrP receptor. This article summarizes the separate and combined effects of growth hormone and calcitriol on endochondral bone formation in chronic renal failure and secondary hyperparathyroidism.

Pediatric renal transplantation

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