Masafumi Fukagawa, M.D., Ph.D.

1. Pathogenesis of Secondary Hyperparathyroidism

Since decreased concentrations of ionized calcium and calcitriol stimulate parathyroid hormone (PTH) secretion, the treatment of hyperparathyroidism in chronic dialysis patients has been mainly aimed at ameliorating hypocalcemia and at maintaining physiological concentration of 1,25-dihydroxyvitamin D (calcitriol). Despite routine use of phosphate binders and oral active vitamin D sterols, it is still difficult to control PTH secretion in some patients. Such patients may respond to supraphysiological concentration of calcitriol achieved by calcitriol pulse therapy (2).

These observations suggest that the resistance of parathyroid cells to calcitriol may serve as another stimulus for PTH secretion in chronic renal failure (3). Such resistance of parathyroid to calcitriol may be also present even from the early phase of chronic renal failure as shown in model rats. In support of such a model, it was shown in dialysis patients and in experimental animals that the peak concentration of calcitriol is more important for the suppression of parathyroid hyperfunction than the total dose of calcitriol.

Reduction of calcitriol receptor density in parathyroid glands is currently considered the mechanism responsible for the resistance in chronic renal failure (4). Similar reduction of calcium-sensing receptor and RXR in parathyroid cells has also been also reported. Although the precise mechanism is still controversial, disturbance in the up-regulation of calcitriol receptor by calcitriol itself is considered the main mechanism leading to the decrease of calcitriol receptor density. As renal failure progresses, this disturbance may form a vicious cycle of further reducing calcitriol receptor density leading to progressive resistance to calcitriol. In addition to this mechanism, the disturbance of the interaction between calcitriol receptor and target genes by uremic toxins has been also implicated.

Role of phosphate in the pathogenesis of secondary hyperparathyroidism has long been recognized as indirect mechanisms through the modulation of serum calcium and calcitriol production. In addition to such mechanisms, direct effect of phosphate on parathyroid has been suggested by several groups. Recent data with organ culture of parathyroid further support this hypothesis on direct effect of phosphate (5). Existence of phosphate sensor of parathyroid cells remains to be proved in future.

2. New Principles of Treatment

Recently, several new agents including calcimimetics (6), new phosphate binders(7) and less-calcemic vitamin D analogues (8, 9), have been added to the list of therapeutic modalities in the management of secondary hyperparathyroidism. To select the optimal treatment among these options, it is mandatory to evaluate the stage of secondary hyperparathyroidism.

First of all, it should be noted that size of parathyroid glands, in addition to the degree of PTH hypersecretion, is an important parameter. Patients with at least one enlarged gland larger than 0.5 cm3 (1 cm in diameter) are usually resistant to medical therapy including calcitriol pulse therapy (10), because most of the glands of this size are composed of nodular hyperplasia with lower density of calcitriol receptor (11).

Thus, prevention of parathyroid hyperplasia should be given priority. For this purpose, control of hyperphosphatemia from the early stage, by diet therapy and by new phosphate binders, has become more important than ever, because direct stimulation of PTH secretion by phosphate is more evident in diffuse hyperplasia than in nodular hyperplasia (12).

For the management of patients with enlarged parathyroid glands, we have established selective Percutaneous Ethanol Injection Therapy (PEIT) (13) in addition to surgical parathyroidectomy. In this therapy, all enlarged parathyroid glands larger than 0.5 cm3 were destroyed by ethanol injections under ultrasonographic guidance, leaving smaller glands which should be responsive to medical therapy. By the help of Doppler color flow mapping, we could optimize the site of ethanol injection and minimize the amount of ethanol injected. Most patients became responsive to calcitriol pulse the rapy after selective PEIT with fewer complications (14).

We also established Direct Calcitriol Injection Therapy (15). In this therapy, to achieve extremely high concentration of calcitriol only within parathyroid, we directly injected calcitriol solution (1 mcg/ml) into enlarged parathyroid glands for more than three times. After direct injection, PTH levels were suppressed to less than 200 pg/ml and became controllable by medical therapy without any episode of hypercalcemia. Thus, very high local concentration of calcitriol not only suppressed the function of the parathyroid cells with lower density of calcitriol receptor, but may also have up-regulated the calcitriol receptor. This route can be used also for the direct injection of calcimimetics as recently tried in uremic animals.

Furthermore, modulation and correction of abnormal parathyroid cell function has become possible by recently developed gene transfer techniques. For this purpose, we adopted to use replication-deficient adenovirus vector because adenovirus vector can transfer foreign genes very efficiently, irrespective of cell proliferation, and also in vitro and in vivo. By transferring calcitriol receptor gene into dispersed human parathyroid cells, PTH secretion became suppressed in response to very low concentration of calcitriol. Since we have also succeeded in transferring lacZ gene into rat parathyroid glands by direct injection of virus solution, it will soon become possible to modulate parathyroid function in vivo by this direct gene transfer by adenovirus vector.

3. Optimal PTH level for Bone and Parathyroid

As discussed so far, we have now various options for suppressing PTH secretion in chronic renal failure. Then, how low should we set the target PTH level?

Available data suggest that two to three times high PTH i s needed to maintain bone turnover normal in chronic renal failure (16). Accordingly, consensus of target PTH level has been set around 200 pg/ml.

Even though this level of PTH is optimal for bone, parathyroid secretes much more PTH than normal. Thus, maintenance of this level of PTH leads to the development parathyroid hyperplasia in the long-term, which will eventually become uncontrollable by medical therapy.

Without doubt, the next important issue to be solved for better management of secondary hyperparathyroidism is the skeletal resistance to PTH in renal failure. Since mechanism of bone turnover has recently been clarified at molecular level, it may not take so long time for the elucidation of this abnormality. For an example, overestimation of full\length (1-84) PTH by intact PTH assay and inhibition of PTH action by 7-84 fragment have been recently suggested (17, 18). In addition, our preliminary data suggest that osteoclastgenesis inhibitory factor (OCIF)/osteoprotegerin (OPG) accumulated in the serum of uremic patients may block the action of osteoclast differentiating factor (ODF) produced by osteoblasts in response to PTH (19).

Conclusion

As shown in this presentation, stage of parathyroid hyper plasia can serve as a useful marker for the selection of therapeutic modality for hyperparathyroidism in chronic dialysis patients. Cellular and molecular analyses of parathyroid hyperplasia have not only revealed new mechanisms underlying hyperparathyroidism, but also contributed to the development of new medical therapies. As a concluding remark, I would like to emphasize again the importance of the prevention of parathyroid hyperplasia for the appropriate management of hyperparathyroidism.

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14. Kakuta T, Fukagawa M, Fujisaki T, Hida M, Suzuki H, Sakai H, Kurokawa K, Saito A: Prognosis of parathyroid function after successful percutaneous ethanol injection therapy (PEIT) guided by color Doppler flow mapping in chronic dialysis patients, Am J Kidney Dis 1999; 33: 1091-1099.

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19. Kazama JJ, Shigematsu T, Tsuda E, Yano K, Gejyo F, Kawaguchi Y, Kurokawa K, Fukagawa M: Increased circulating osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF) in patients with chronic renal failure (abstract), J Am Soc Nephrol 1999; 10: 599A.