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The endocrine response of porcine parathyroid gland tissue slices in vitro to aluminum was studied by electron microscopy and radioimmunoassay of PTH. Medium aluminum concentrations were 20 to 500 ng/ml covering the range corresponding to concentrations reported in the plasma of aluminum-intoxicated hemodialyzed patients. Aluminum inhibited iPTH-release and caused severe cell alterations. This inhibition was incomplete and there was an aluminum-insensitive iPTH-release capacity. This phenomenon seemed to be due to heterogeneous parathyroid cell population as regards aluminum sensitivity, perhaps linked to the spontaneous asynchronous cyclic parathyroid cell changes. Sensitivity to aluminum was modulated by the extra-cellular calcium concentration. Sensitivity to extra-cellular calcium concentration variations persisted in aluminum intoxicated tissues. The severity of the observed cell lesions induced by high concentrations of aluminum suggested that the recovery of an iPTH-release capacity when parathyroid tissue was withdrawn from a toxic environment and switched to aluminum-free media is more likely to be due to activation of a "less-sensitive to aluminum" cell pool than to a true reversibility of the toxic effect.

Quantitative histology was performed on serial iliac crest biopsies obtained from 14 children with terminal renal failure. A long-term study on the comparative effects of vitamin D2 and 25-hydroxycholecalciferol [25-(OH)D3], in five patients with severe lesions of osteomalacia and/or osteitis fibrosa, demonstrated the efficiency of 25 to 200 mug/day of 25-(OH)D3 and the lack of therapeutic action of 345 to 685 mug/day of vitamin D2. In nine subjects with normal roentgenograms or minimal skeletal alterations, the first biopsy taken at the beginning of intermittent hemodialysis showed evidence of defective mineralization and/or lesions of resorption. Four of these children were treated with 25-(OH)D3 (25 to 50 mug/day) and calcium supplementation orally (0.5 to 1.5 g/day); five children received calcium orally (0.5 to 0.75 g/day) alone. Aggravation of bone lesions during intermittent hemodialysis was observed in patients treated with calcium supplements alone. In subjects who were given 25-(OH)D3, mineralization improved and marrow fibrosis disappeared. However, as the two groups of patients were different in composition and in the manner in which they were treated, it is difficult to state whether the beneficial effects observed were solely attributable to 25-(OH)D3 administration. 25-(OH)D3 therapy induced severe intoxication in two patients. A rise in plasma calcium concentration to 11.0 to 11.5 mg/100 ml was observed in two other patients. It is concluded that: a) pharmacologic doses of 25-(OH)D3 are highly effective in healing bone lesions of children with terminal renal failure; b) such treatment requires strict clinical surveillance as 25-(OH)D3 intoxication may occur even in anephric patients.

In hemodialyzed patients aluminum (Al) intoxication may induce osteomalacic lesions which are mainly observed when plasma immunoreactive parathyroid hormone (iPTH) concentrations are low, and osteitis fibrosa absent. In this study, the bone tissue of eight hemodialyzed patients with elevated plasma and bone Al concentrations was examined by histomorphometry, electron microscopy, and x-ray microanalysis. Five patients (group 1) had osteomalacia and minimal osteitis fibrosa, three patients (group 2) had severe osteitis fibrosa. In group 1, Al was concentrated at the mineralizing front, in hexagonal structures measuring 200 to 1,000 A which also contained phosphorus, but not calcium. Hydroxyapatite needles had a normal aspect. Osteoblasts appeared inactive. In group 2, Al was also present at the mineralizing layer of osteoid, but, in these cases, in small clusters next to abnormal calcium deposits. Osteoblasts appeared very active. Their mitochondria contained calcium and phosphorus granules, or amorphous material, measuring 1,500 to 2,000 A, emitting x-rays characteristic for Al and phosphorus. These results suggest that secondary hyperparathyroidism, by stimulating the cellular activity, may increase the uptake and release of Al by the osteoblasts. The presence of Al within the mitochondria of these cells may be one of the factors inducing the mineralization defect.

The purpose of this investigation is to analyze changes in plasma 1,25-(OH)2D and 24,25-(OH)2D after successful renal transplantation in 20 children and young adults. Studies were performed on 8 subjects between the 1st and 10th month and on 12 others between the 20th and 30th to 36th month. Samples were assayed for plasma and urinary calcium, inorganic phosphate, creatinine, plasma bicarbonate, immunoreactive parathyroid hormone, 25-(OH)D, 24,25-(OH)2D, and 1,25-(OH)2D concentrations. Results showed the following: (1) All subjects had normal or high plasma levels of dihydroxyvitamin D metabolites. (2) In subjects with normal GFR's there was a significant inverse correlation between plasma 1,25-(OH)2D concentrations and tubular reabsorption of phosphorus. (3) These correlations were not found in subjects with subnormal creatinine clearances (50 to 100 ml/min/1.73 m2) even though plasma 1,25-(OH)2D concentrations in these subjects were similar to those with normal creatinine clearances. (4) In subjects with subnormal creatinine clearances, an increase in plasma 1,25-(OH)2D concentrations to very high levels was observed during the first months following renal transplantation.

It has been suggested that in uremic bone, aluminum interferes with normal mineralization. Aluminum content and aluminum localization were studied in iliac crest biopsies of two groups of patients on regular hemodialysis; one group had histologic osteomalacia, and little or no bone resorption (group 1); the other, osteitis fibrosa and no mineralization defect (group 2). Group 1 patients had significantly higher plasma aluminum concentrations than those of group 2. No difference was found in bone aluminum content, which was above normal in both groups. In the bone samples of the osteomalacic subjects, aluminum was mainly localized at the limit between osteoid and calcified tissue, the site where the bone mineral is normally first deposited. Osteomalacia could not be related to hypocalcemia or to phosphate depletion. Active vitamin D derivatives (25-hydroxycholecalciferol and 1alpha-hydroxycholecalciferol) failed to prevent or to improve the bone disease. In the bone samples of group 2 subjects, aluminum could not be localized by the methods used, except in the two cases with greatly elevated bone aluminum, where it was mainly localized on cement lines. In group 2 subjects, immunoreactive parathyroid hormone plasma concentration, osteoclast surface, and marrow fibrosis were significantly higher than they were in group 1 subjects. It is concluded that in bone from uremic patients on regular dialysis, aluminum can induce a particular form of osteomalacia, resistant to the vitamin D active derivatives. The bone disease is only observed in the absence of severe secondary hyperparathyroidism. This suggests that parathyroid hormone may be involved in the development of the aluminum-induced mineralization defect.