Little is known about the extent and severity of bone disease in children undergoing successful renal transplantation. To address this issue, 47 patients with stable renal function 3.2 +/- 1.7 years after transplantation (Tx) underwent iliac crest bone biopsy. The mean age of patients was 12 +/- 2.0 years; 36 had received cadaveric renal grafts, whereas 11 had undergone living-related Tx. Immunosuppressive drugs included cyclosporine 0.17 +/- 0.4 mg/kg/day, prednisone 7.5 +/- 2.1 mg/kg/day, and either azathioprine 1.6 +/- 0.9 mg/kg/day or mycophenolate mofetil 30 +/- 3 mg/kg/day. In addition to quantitative bone histomorphometry, the bone mineral content (BMC) of the lumbar spine was measured by dual energy X-ray absorptiometry (DXA) in 24/47 patients. Thirty-one transplant recipients had normal bone formation (N-Bfr), 11 had mild hyperparathyroidism (HPT) and 5 had adynamic skeletal lesions (AD). The interval since Tx, duration of dialysis before Tx and cumulative prednisone dose did not differ among groups. Trabecular bone area was highest in subjects with HPT. Unexpectedly, eroded bone perimeter exceeded normal reference values both in patients with AD and in those with N-Bfr; the osteoid area and osteoid perimeter were also elevated in these two groups. Hyperparathyroidism improved or resolved after Tx in all 14 subjects with this skeletal lesion prior to Tx, but one patient developed AD after Tx. Bone histology did not change after Tx in those with N-Bfr during regular dialysis, but bone formation increased after Tx in two of three patients with AD during regular dialysis. Z-scores for height in pre-pubertal patients after Tx were below age-appropriate values in each histologic subgroup, but values did not differ among groups. Z-scores for bone mineral content at the lumbar spine were also less than age-predicted values, -0.67 +/- 1.2. After adjusting for the degree of growth retardation, height-adjusted z-scores for lumbar spine BMC after Tx were above normal in all three histologic groups (0.68 +/- 1.0). The results suggest that reductions in bone mass and post-transplant osteoporosis are not prominent findings in pediatric renal transplant recipients when the influence of growth retardation on bone mass measurements by DXA is carefully considered.

Calcitriol counteracts the trophic actions of growth hormone on epiphyseal growth plate cartilage and modifies chondrocyte differentiation in vivo, and these mechanisms may contribute to disturbances in longitudinal bone growth in renal failure.

Background: Rapamycin 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.

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 chondrocytes were greater in calcium-supplemented nephrectomized rats. These morphological changes were associated with decreases in histochemical staining for tartrate-resistant acid phosphatase and lower levels of messenger RNA expression for the matrix metalloproteinase MMP-9/gelatinase B immediately adjacent to the epiphyseal growth plate. Diminished chondroclastic/osteoclastic activity alters growth plate morphology and adversely affects linear bone growth in calcium-supplemented, nephrectomized rats.

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Hypercalcemia and low serum parathyroid hormone (PTH) levels are features of the adynamic lesion (AD) of renal osteodystrophy, but there is little information about parathyroid gland function in this disorder. Therefore, the four parameter model was used to evaluate calcium-regulated PTH release in patients with either adynamic bone or secondary hyperparathyroidism (OF) as documented by bone biopsy and in normal volunteers (NL). Patients had undergone CCPD for 20 +/- 4.2 months, and all received calcium carbonate as the sole phosphate-binding agent. During two hours infusions of sodium citrate, the rate of decline in serum ionized calcium levels did not differ among groups; serum PTH levels rose from 136 +/- 38 to 342 +/- 140 pg/ml in AD and from 691 +/- 99 to 869 +/- 121 pg/ml in OF. Maximum PTH levels were 322 +/- 42% of baseline values in AD but only 146 +/- 9.7% of baseline in OF (P < 0.001), and the increase above baseline levels in AD did not differ from that in NL (300 +/- 25%, NS). During calcium infusions, serum PTH levels fell from 164 +/- 75 to 39 +/- 11 pg/ml in AD and from 622 +/- 76 to 171 +/- 29 pg/ml in OF; minimum serum PTH levels, expressed as a percentage of pre-infusion values, were 25 +/- 2% in AD and 26 +/- 5% in OF (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitriol is a standard therapy for secondary hyperparathyroidism in chronic renal failure. We evaluated whether the effect of daily or intermittent calcitriol administration is more efficient in enhancing bone growth in renal failure with advanced secondary hyperparathyroidism in weanling 5/6 nephrectomized rats loaded with phosphorus to induce severe secondary hyperparathyroidism. The animals were treated daily or three times weekly with calcitriol for 4 weeks but the total weekly dose of calcitriol was the same. Although calcitriol increased the serum calcium, it did not lower parathyroid hormone (PTH) or improve tibia and body length. Animals with renal failure and advanced secondary hyperparathyroidism had decreased PTH/PTHrP, which was accompanied by an increase in the cyclin kinase inhibitor p57(Kip2). Calcitriol treatment upregulated the PTH/PTHrP receptor but also increased inhibitors of cell proliferation such as p21(Waf1/Cip1), IGFBP3, and FGFR3. Calcitriol also enhanced markers of chondrocyte differentiation, such as IGF1, Vitamin D receptor, FGF23, and bone morphogenetic protein-7. Receptor activator of nuclear factor-kappabeta ligand levels improved with calcitriol treatment but without changes in osteoprotegerin suggesting an enhancement of osteo/chondroclastogenesis and mineralization. Overall, both daily and intermittent calcitriol had similar effects on endochondral bone growth in phosphorus-loaded rats with 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)(2)D(2)] and doxercalciferol [1-alpha-(OH)(2)D(2)], 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.