Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

The factors involved in abnormal parathyroid cell secretory function and growth in patients with primary (I degree) and secondary (II degree) hyperparathyroidism are still incompletely understood. We compared the expression of the calcium-sensing receptor (CaR) at the gene message and the protein level in parathyroid tissue obtained from patients with I degree non-uremic or II degree uremic hyperparathyroidism with that in normal parathyroid tissue, using in situ hybridization and immunohistochemistry techniques. The expression of the CaR mRNA and protein was reduced in most cases of I degree adenoma and II degree hyperplasia, compared with strong expression normal parathyroid tissue. In II degree hyperparathyroidism, expression of both receptor mRNA message and protein was often particularly depressed in nodular areas, compared with adjacent non-nodular hyperplasia. Decreased Ca-R expression in adenomatous and hyperplastic parathyroid glands would be compatible with a less efficient control of PTH synthesis and secretion by plasma calcium than in normal parathyroid tissue.

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ABSTRACT

In athymic mice we have developed a model of long-term human PTH hypersecretion, using xenotransplantation of respectively parathyroid gland fragments obtained from patients with primary (primary) or secondary (secondary) uremic hyperparathyroidism (HPT), and parathyroid cells maintained in culture from patients with secondary uremic HPT. Both grafted parathyroid tissue fragments and cultured cells induced prolonged and marked secretion of human intact PTH (iPTH) in nude mice. Despite extremely high plasma iPTH levels, hypercalcemia or hypophosphatemia was not observed. Moreover, PTH secretion was not significantly modified by low-calcium, high-phosphate diet for 3 weeks. Four mice which had a mean plasma human iPTH level of 237+/-152 pg/ml for more than 9 months and 4 age-matched, sham-grafted control mice with undetectable human iPTH levels underwent bone histomorphometry examination. No difference was found between the two groups with respect to active bone resorption surface or number of osteoclasts/mm2. We hypothesize that the characteristic deficit of T cell function and of cytokine and growth factor production may protect nude mice with chronic hypersecretion of human PTH from hypercalcemia and bone lesions. We suggest that this strain of mice could be used for better understanding the relationship between cytokines and bone turnover.

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Nephrolithiasis is uncommon after kidney transplantation. However, calcium (Ca) supplementation, which has been proposed as a treatment of post-transplant osteopenia, might increase calciuria and bolster Ca stone formation. Therefore, in 24-hour urine of 82 normocalcemic long-term renal transplant recipients (RT) and in 82 healthy subjects (HS), we assessed some Ca nephrolithiasis risk factors and the Ca-salt saturation estimated by the ion-activity product index (AP) and relative supersaturation (RS). In RT, calciuria was lower (mean +/- SD, 3.20 +/- 2.25 vs. 4.61 +/- 1.71 mmol/day; P < 0.001), urinary volume higher (2.41 +/- 0.83 vs. 1.39 +/- 0.53 liter/day; P < 0.001), oxaluria higher (419 +/- 191 vs. 311 +/- 79 mumol/day; P < 0.001) and citraturia lower (1.40 +/- 1.36 vs. 3.77 +/- 1.36 mmol/day; P < 0.001) than in HS. As a result, Ca-oxalate supersaturation was lower in RT than HS (AP, 1.07 +/- 0.69 vs. 2.07 +/- 1.13, P < 0.001; and RS, 0.62 +/- 0.26 vs. 0.94 +/- 0.21, P < 0.001), and was similar in subgroups of RT (N = 37) and HS (N = 37) matched for urinary volume, demonstrating that even without any larger urinary volume, Ca-oxalate saturation was not higher in RT than HS, and suggesting that opposite changes in Ca and oxalate in RT likely canceled their effects on lithogenic risk. In RT which had similar urinary pH and phosphate (P) than HS, Ca-P supersaturation was lower than in HS for brushite (AP, 3.25 +/- 6.67 vs. 6.01 +/- 4.85, P < 0.001; RS, -0.33 +/- 0.76 vs. 0.48 +/- 0.53, P < 0.001) and octacalcium phosphate (RS, -0.95 +/- 0.72 vs. 0.21 +/- 0.85, P < 0.001), and similar for apatite. Finally, fasting calciuria and calciuric response to a single oral Ca load were similar in RT (N = 19) and HS (N = 8). Together, these results argue strongly against a higher risk of Ca stone formation in RT than HS, even in case of Ca supplementation.