Basic and clinical aspects of parathyroid hyperplasia in chronic kidney disease

Transcription

1 & 2006 International Society of Nephrology Basic and clinical aspects of parathyroid hyperplasia in chronic kidney disease M Fukagawa 1, S Nakanishi 1 and JJ Kazama 2 1 Division of Nephrology and Dialysis Center, Kobe University School of Medicine, Kobe, Japan and 2 Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan Marked parathyroid hyperplasia develops in patients with chronic kidney disease, especially those with long dialysis vintage. Although progression of hyperplasia is associated with downregulation of vitamin D receptor and calcium-sensing receptor, initial abnormality that triggers and maintains parathyroid cell proliferation, as well the critical abnormality for the progression of diffuse hyperplasia to nodular hyperplasia, still remains to be elucidated. It is quite important for the optimal management of renal osteodystrophy to recognize the development of nodular hyperplasia, because the cells in nodular hyperplasia are usually resistant to medical therapy and further treatment of such patients often leads to vascular calcification. For this purpose, size and blood supply of enlarged parathyroid glands have been used as good clinical markers. Furthermore, we have recently shown that the serum fibroblast growth factor 23 level can be used for predicting refractory hyperparathyroidism. Once nodular hyperplasia develops in any of the enlarged parathyroid glands, such patients need to be treated by parathyroid intervention including percutaneous ethanol injection therapy. In addition, as direct vitamin D injection therapy has been shown to induce regression of hyperplasia, it may become possible to reverse or normalize established nodular hyperplasia if we can develop new agents with such effects in the near future.. doi: /sj.ki KEYWORDS: parathyroid; PTH; nodular hyperplasia; CKD; ultrasonography; FGF23; vitamin D Correspondence: M Fukagawa, Division of Nephrology and Dialysis Center, Kobe University School of Medicine, Kusunoki-cho, Chuo-ku, Kobe , Japan. fukagawa@med.kobe-u-ac.jp DEVELOPMENT OF PARATHYROID HYPERPLASIA IN CHRONIC KIDNEY DISEASE Secondary hyperparathyroidism is one of the most popular and important abnormalities of mineral metabolism in patients with chronic kidney disease (CKD). 1 Persistent hyperparathyroidism often leads to the development of parathyroid hyperplasia in dialysis patients, 2 especially those with long dialysis vintage. 3 One of the most interesting features of parathyroid hyperplasia in these patients is that the size of the glands varies markedly even in one patient. In sharp contrast to primary hyperparathyroidism, any acceptable common gene mutation has not been identified yet in secondary hyperparathyroidism in CKD. 4,5,6 Nevertheless, the different characteristics of the component cells between small and large glands have recently become revealed. Parathyroid hyperplasia in the advanced stage of CKD is classified into two types, diffuse hyperplasia and nodular hyperplasia. 7 Nodular hyperplasia has been considered to be the advanced type seen in patients with more severe hyperparathyroidism. Development of hyperplasia not only leads to the increased volume of parathyroid mass, but also altered qualities, such as abnormal control of parathyroid hormone (PTH) secretion. 8 Thus, PTH secretion may not be suppressed even in the presence of hypercalcemia in severe cases, which can be usually normalized by medical therapy in patients with less severe type of hyperplasia, that is, diffuse hyperplasia. 9 In CKD, several factors, such as phosphorus load, hypocalcemia, and reduced production of active vitamin D (1,25D), stimulate PTH secretion, then induce hypertrophy and proliferation of parathyroid cells, initially leading to diffuse hyperplasia. 10,11 Some cells proliferate more vigorously than others, forming small nodules each of which is monoclonal in origin. 12 When these nodules grow bigger and become encapsulated, they are called nodular hyperplasia. In the most severe cases, one of these nodules occupies the whole gland (single nodular gland) (Figure 1). Although it is now well accepted that the development of nodular hyperplasia is associated with the downregulation of vitamin D receptor 13 and calcium-sensing receptor 14 through several mechanisms, the initial event that triggers and maintains abnormal parathyroid cell proliferation still remains to be elucidated. 15,16 It has not been fully clarified S3

2 Hypertrophy Diffuse hyperplasia Early nodularity in diffuse hyperplasia Nodular hyperplasia Single nodular gland Monoclonal proliferation of nodules Genetic abnormality? Figure 1 Progression of parathyroid hyperplasia in CKD. either what is the critical event in the progression from diffuse to nodular hyperplasia. 17,18 REFRACTORY HYPERPARATHYROIDISM AND PARATHYROID HYPERPLASIA Current clinical guidelines on renal osteodystrophy, such as K/DOQI guideline, recommend that serum levels of calcium and phosphorus should be maintained within the target ranges in order to avoid the development of vascular calcification. 19 As serum calcium and phosphorus levels can be also extensively modified by medical therapy including vitamin D analogues, it is quite important to identify the refractory cases as early as possible during the course of medical management. 20 Dialysis patients with severe hyperparathyroidism are usually associated with marked parathyroid hyperplasia. In a recent study from a Japanese group, 21 effect of a single oral dose of calcitriol on PTH level was examined together with the evaluation of parathyroid hyperplasia by ultrasonography. PTH levels were significantly suppressed in patients without any detectable glands, but not in those with one or more detectable glands. Thus, the response to medical therapy may be dependent on the development of parathyroid hyperplasia. Several clinical observations also support the notion that the size of parathyroid gland can be an indicator for the controllability of parathyroid function in CKD patients. For measurement of the gland size, ultrasonography has been most widely used. As we reported in the early 1990s, patient with one or more enlarged glands larger than 0.5 cm 3 or 1 cm in diameter became refractory to medical therapy in the long-term. 22 In patients treated by total parathyroidectomy with autotransplantation, relapse of transplanted glands often developed if the fragments were taken from a gland heavier than 0.5 g. 7 Furthermore, another group recently reported that patients with enlarged parathyroid glands larger than 11 mm in diameter were less responsive to intravenous maxacalcitol therapy than those with smaller glands. 23 Thus, this size, around 10 mm in the longest axis or 0.5 g, seems to be the critical size. According to the histological analysis of surgically removed specimens, glands heavier than 0.5 g were composed of nodular hyperplasia in most of the cases. 7 It has also been reported that positive blood flow inside the gland by Doppler color flow mapping was highly suggestive of nodular hyperplasia, 24 even in case of smaller glands. Recently, production of a new form of PTH has been implicated in the most severe cases of primary and secondary hyperparathyroidism with single nodule. 25,26 Clinical significance of such parameters remains to be determined in the near future. REFRACTORY HYPERPARATHYROIDISM AND FIBROBLAST GROWTH FACTOR 23 Fibroblast growth factor 23 (FGF23) is a newly identified phosphaturic factor. 27 We have recently reported that serum FGF23 level can be another useful marker for the resistance to medical therapy. It has been shown that FGF23 is responsible for several hypophosphatemic diseases, such as tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal-dominant hypophosphatemic rickets. 28 In these diseases, excessive FGF23 activity leads to hypophosphatemia and also to low 1,25D level, resulting in osteomalacia or rickets. 29 Recent data suggest that FGF23 plays an important role in the homeostasis of phosphate both in normal and in CKD. 30 With sufficient renal function, FGF23, secreted in response to dietary phosphorus load, acts on the kidney to excrete phosphorus in the urine and it also suppresses 1,25D production to prevent further phosphorus absorption from the intestine. 31,32 The number of viable nephrons decreases in patients with advanced stages of CKD, the amount of net phosphate excretion does not increase sufficiently, and serum phosphate level remains high despite high FGF23 level. Decreased level of 1,25D as well as hyperphosphatemia stimulates PTH secretion Thus, FGF23 is a new player in the classic trade-off theory on the pathogenesis of secondary hyperparathyroidism in CKD. 30,36 In the majority of dialysis patients, serum intact FGF23 level was extremely high. 37,38 FGF23 and intact PTH levels showed a weak but significant positive correlation; however, FGF23 level showed even better correlation with intact PTH level 2 years after the measurement of FGF23. We have recently shown that the measurement of initial serum FGF23 level was the better screening test than intact PTH or calcium level to discriminate patients in whom secondary hyperparathyroidism would develop within 2 years. 38 In another study, we also demonstrated that serum FGF23 level was useful in predicting the responsiveness to intravenous calcitriol therapy in patients with established secondary hyperparathyroidism. 39 We further examined the role and the origin of high level of FGF23 in dialysis patients. First possibility is that they S4

3 Parathyroid PTH Pi Bone? FGF-23 Active Vitamin D Figure 2 Role of FGF23 in the development of severe hyperparathyroidism. PTH, high phosphorus level, and vitamin D treatment increase FGF23 production in the bone. Very high level of FGF23 may directly stimulate parathyroid cell proliferation. came from enlarged parathyroid glands, because parathyroid hyperplasia developed in transgenic mice overexpressing FGF23 in a recent study. 40 After surgical parathyroidectomy, serum FGF23 level decreased slowly, but did not return to the normal range. 41,42 By reverse transcription-polymerase chain reaction, no expression of fgf23 mrna was found in enlarged parathyroid glands, but was found in the bone. 38 Thus, parathyroid does not seem to be the origin of FGF On the contrary, PTH may induce FGF23 production in other organs such as in the bone. 43 In another clinical study, intravenous calcitriol therapy not only suppressed PTH level, but also further increased serum FGF23 level. 44 Serum FGF23 level at 6 months significantly correlated with the cumulative dose of calcitriol during the 6 months. Delta increase of serum FGF23 level during 6 months also showed significant positive correlation with the cumulative doses of calcitriol. Thus, treatment with vitamin D analogues may increase FGF23 production, possibly in the bone. Such a mechanism has been recently supported by several in vivo and in vitro studies Current understanding of the role of very high level of serum FGF23 in severe hyperparathyroidism can be summarized as in Figure 2. In advanced stages of CKD, high level of PTH as well as that of phosphate stimulates FGF23 production in the bone. In addition, 1,25D, including exogenous active vitamin D analogues, increases FGF23 level. Recently, the mechanism of FGF23 action has been extensively studied. 49 Although it has recently been shown that parathyroid cells are equipped with two key molecules for FGF23 action, that is, klotho protein and FGFR1 (IIIc), it remains to be elucidated whether high levels of FGF23 directly stimulate parathyroid growth. MANAGEMENT OF REFRACTORY HYPERPARATHYROIDISM WITH NODULAR HYPERPLASIA How can we manage refractory patients with nodular hyperplasia? 20 At the moment, such patients are good indications for surgical parathyroidectomy. 50 In patients with one or two glands with nodular hyperplasia, parathyroid function can be controlled by percutaneous ethanol injection therapy under ultrasonographic guidance It has been shown that glands with diffuse hyperplasia regressed by oral vitamin D pulse therapy. 22,54 By contrast, regression of nodular hyperplasia may not occur except for the rare cases with necrosis due to spontaneous bleeding. 55,56 Despite such a consensus, we and another group have shown that direct vitamin D injection therapy induced the regression of nodular hyperplasia In these patients, responsiveness to oral or intravenous vitamin D therapy was also restored. Induction of apoptosis of parathyroid cells by vitamin D therapy was controversial until recently; 60 however, recent studies with parathyroid biopsy and animal model have clearly shown that direct vitamin D injection did induce apoptosis of parathyroid cells. 59,61 Direct injection therapy also upregulated vitamin D receptor and calciumsensing receptor, resulting in the normalization of the shifted sigmoidal curve between calcium and PTH. Furthermore, Taniguchi et al. 62 have recently shown the same results by intraperitoneal administration of 1,25D for established parathyroid hyperplasia in uremic rats. Calcimimetic agents suppress parathyroid function through calcium-sensing receptor. 63 Calcimimetics has been shown to prevent parathyroid hyperplasia in uremic animals; 64 however, it has not been fully elucidated yet whether the patients with established nodular hyperplasia can be controlled by calcimimetics. 65 CONCLUDING REMARKS Despite the recent progresses in therapeutic modalities, prevention still remains to be the best strategy against the development of parathyroid hyperplasia in CKD. Once nodular hyperplasia develops, hyperparathyroidism will usually become refractory to medical therapy. Such patients need to be treated by parathyroid intervention therapy including surgical parathyroidectomy at the earliest occasion to prevent vascular calcification by further medical therapy as well as by hyperparathyroidism itself. Nevertheless, if we can develop new agents that induce apoptosis of parathyroid cells, it may become possible to reverse and normalize the established nodular hyperplasia in the near future. ACKNOWLEDGMENTS This work was supported in part by a grant-in-aid from the Japanese Society for the Promotion of Science ( to MF). We are grateful to the members of Kobe Parathyroid and Bone Forum (KPBF) and those of ROD21 Clinical Study Group for thoughtful and inspiring discussions. REFERENCES 1. Kurokawa K, Fukagawa M. Uremic bone diseases: advances over the last 30 years. J Nephrol 1999; 12(Suppl 2): S63 S Drueke TB. Cell biology of parathyroid gland hyperplasia in chronic renal failure. J Am Soc Nephrol 2000; 11: Patient Registration Committee, Japanese Society for Dialysis Therapy. An overview of regular dialysis treatment in Japan as of 31 December Ther Apher Dial 2005; 9: Tominaga Y, Tsuzuki U, Uchida K et al. 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