Molecular pathogenesis of secondary hyperparathyroidism in renal failure: basic and clinical aspects.

the calcitriol–receptor complex with target genes [8] Introduction and a recently revealed decrease of retinoid-X receptor density [9]. As renal failure progresses, this disturbance High turnover bone disease remains one of the central may form a vicious cycle of further reducing calcitriol features of renal osteodystrophy seen in chronic dialysis receptor density leading to progressive resistance to patients [1]. This type of bone disease is caused by calcitriol. excess parathyroid hormone (PTH) secreted from markedly enlarged parathyroid glands [2]. Based on significParathyroid hyperplasia and resistance to calcitriol ant clinical and experimental observations, several models for the pathogenesis of secondary hyperparathyroidism in chronic renal failure have been proposed and Marked hyperplasia of parathyroid glands is a unique new options of therapeutic modalities have recently feature of hyperparathyroidism in chronic dialysis patients [10]. Long-term observation of patients become practical based on such models [3]. treated by calcitriol pulse therapy revealed that the initial size of the parathyroid glands is the critical marker for the long-term prognosis of vitamin D Resistance to calcitriol as a major mechanism of therapy [11]. If at least one gland is larger than 1 cm hyperparathyroidism in uraemia in diameter or, more precisely, larger than 0.5 cm3 in volume, it is usually difficult to control PTH secretion Since decreased concentrations of ionized calcium and in the long term. In such patients, hyperparathyroidism calcitriol stimulate PTH secretion, the treatment of always relapses even if it initially responds to calcitriol hyperparathyroidism in chronic dialysis patients has pulse therapy. By contrast, patients with glands smaller been aimed mainly at ameliorating hypocalcaemia and than 0.5 cm3 respond to calcitriol pulse therapy well at maintaining the physiological concentration of calciand can be controlled with active vitamin D sterols in triol [2,3]. Despite routine use of phosphate binders the long term. and oral active vitamin D sterols, it is still difficult to How can such differences in the response to calcitriol control PTH secretion in some patients. It has been be explained? In patients with severe parathyroid hypreported that some of such patients may respond erfunction, large parathyroid glands are usually comto supraphysiological concentrations of calcitriol posed of nodular hyperplasia, a more advanced type achieved by calcitriol pulse therapy [4]. These observathan the diffuse hyperplasia seen in small glands. Our tions suggest that the resistance of parathyroid cells to data clearly show that the number of calcitriol recepcalcitriol may serve as another stimulus for PTH tors is decreased in nodular hyperplasia compared to secretion in chronic renal failure [5]. diffuse hyperplasia [12]. Recently, we have demonReduction of calcitriol receptor density in the parastrated more direct evidence of parathyroid cell prolifthyroid glands is currently considered to be the mecheration and the decrease of calcitriol receptor density [13]. Since nodular hyperplasia is demonstrated in anism responsible for the resistance in chronic renal more than 90% of glands heavier than 0.5 g [14], the failure [6 ]. Although the precise mechanism is still difference in the response to calcitriol dependent upon controversial, disturbance in the upregulation of the gland size can be explained by these data. calcitriol receptors by calcitriol itself [7] is considered to be the main mechanism leading to the decrease of calcitriol receptor density. Other mechanisms for the Management of hyperparathyroidism in patients resistance to calcitriol include inhibited interaction of with parathyroid hyperplasia