Direct effect of phosphate on parathyroid function.

Patients with chronic renal failure develop secondary [18,19]. These findings are further evidence of the hyperparathyroidism (HPT-2). Decreased calcitriol important role of phosphorus in HPT-2 which, in endproduction, hypocalcaemia and phosphate retention stage renal disease, may not be overcome by the are the main pathogenic factors involved in the develadministration of calcitriol. opment of HPT-2 in these patients. Hernandez et al. [20] have analysed the changes in The accumulation of phosphate favours HPT-2 serum PTH and PTH mRNA in rats after a meal with through indirect and direct mechanisms [1]. High a high phosphorus content. The serum PTH increased phosphate inhibits calcitriol production [2–5] which in after the high phosphorus meal with a peak at 8 h and turn causes hypocalcaemia; furthermore uraemia may serum calcium and calcitriol remained unchanged. The directly affect the function of calcitriol and parathyroid increase in serum PTH was associated with an increase (PTH ) receptors [6,7]. High phosphate also impairs in the PTH mRNA. In a different study the same the calcaemic action of PTH [8,9] which is another authors showed that the high phosphate meal did not cause of hypocalcaemia in renal patients. change the parathyroid cell calcium receptor mRNA Recent studies in animals and patients have con[21]. These results demonstrate that an oral phosfirmed the beneficial effect of dietary phosphorus phorus load can directly stimulate the synthesis of restriction for the control of HPT-2. Furthermore PTH. animal experiments and clinical observations have sugRecent in vitro studies at this hospital and by others gested that high phosphate may have a direct effect on have demonstrated that high phosphate in the medium parathyroid glands. These studies demonstrate that stimulates PTH secretion and synthesis [22–24]. dietary phosphorus modulates serum PTH independent Interestingly, the in vitro effect of phosphate on PTH of the severity of renal failure and this effect is observed secretion is observed in parathyroid tissue preparations even with no changes in serum calcitriol. In rats with and not in dispersed parathyroid cells. This suggests surgically induced renal failure, a high phosphorus diet that in order to prove the effect of phosphate, cell to induces severe HPT-2 compared with a moderate phoscell contact or cell to cell communication may be phorus diet [10]. Lopez-Hilker et al. [11] showed that required. Another possibility is that in isolated parareduction of dietary phosphorus reduced PTH indethyroid cells, the phosphate sensing mechanism is pendently of calcium and calcitriol, suggesting that damaged. control of HPT-2 was a direct effect of the decrease in Using intact rat parathyroid glands incubated with serum phosphorus. In different studies by Bover et al. 1.25 mM calcium and 1, 2, 3, and 4 mM phosphate, [12] and by Yi et al. [13] restriction of dietary phoswe observed that with phosphate concentrations of 3 phorus prevented HPT-2. In patients with moderate and 4 mM, the PTH concentration in the medium was renal failure, the serum PTH directly correlated with increased twoand threefold respectively when comserum phosphorus in patients with mild renal failure pared with 1 or 2 mM phosphate (Figure 1); the suggesting a predominant effect of phosphorus on stimulatory effect of phosphate on PTH secretion was HPT-2 [14]. Furthermore, reduction of dietary phosmaintained despite high calcium in the medium; similar phorus has been shown to be highly effective in reduresults were obtained in bovine parathyroid tissue [24]. cing PTH [15–17]. Although reduction of dietary The effect of phosphate was also tested in human phosphorus is effective in the control of HPT-2, poor parathyroid tissue in vitro [25]. The study includes nutrition as a consequence of protein restriction must parathyroid glands obtained from patients with primnot be allowed. ary adenomas and from haemodialysis and kidney Past and recent reports on calcitriol treatment of transplant patients with diffuse and nodular secondary HPT-2 have shown that the PTH response to calcitriol hyperplasia. The decrease in PTH secretion induced treatment is poor when serum phosphorus is high by high extracellular calcium was less in adenomas than in secondary hyperplasia and nodular hyperplasia Correspondence and offprint requests to: M. Rodriguez, Servicio de was less responsive than diffuse hyperplasia. In diffuse Nefrologiá, Unidad de Investigacion, Hospital Reina Sofia, Cordoba, Spain. hyperplasia, high extracellular phosphate (3 and