钙敏感受体在甲状旁腺功能亢进中的作用

钙敏感受体(CaSR)主要表达于甲状旁腺细胞和肾小管七皮细胞,它可通过细胞内信号传导通路改变甲状旁腺激素(PTH)的分泌和肾小管对电解质和水的处理,调节体内钙平衡,同时CaSR也参与了骨重塑的过程.其遗传性的基因异常可引起各种不同的疾病,包括CaSR失活突变引起的良性家族性低尿钙高钙血症和新生儿期重度甲状旁腺功能亢进,...     

肾性甲状旁腺功能亢进患者甲状旁腺素钙敏感受体的表达

目的研究肾性甲状旁腺功能亢进(甲旁亢)患者甲状旁腺组织钙敏感受体(CaR)的表达,探讨CaR在肾性甲旁亢发病机制中的作用。方法用免疫组织化学的方法,比较正常对照组和继发性甲旁亢(SHPT)组甲状旁腺CaR蛋白质的表达。结果CaR在正常甲状旁腺组织的细胞膜和细胞浆均有表达,细胞阳性率为(75．20±2．31)％,而SHPT组为(27．88±4．90)％,明显减少(P＜0．01)。弥漫性增生和结节性增生之间差异也有显著性[分别为(40．00±3．34)％和(15．75±1．75)％,P＜0．01]。CaR表达阳性率与腺体重量呈负相关(r＝0．86,P＜0．01)。结论严重肾性甲旁亢患者甲状旁腺CaR表达明显下降,结节性增生比弥漫性增生下降更显著,是引起PTH过度分泌的重要原因。上调CaR的表达或激活CaR的功能将成为肾性甲旁亢新的治疗目标。     

钙敏感受体激动剂治疗继发性甲状旁腺功能亢进研究进展

继发性甲状旁腺功能亢进(SHPT)是慢性肾衰竭的常见并发症,现有的治疗药物包括钙剂、磷结合剂和活性维生素D3等,但疗效不理想.近年研究发现,钙敏感受体激动剂可有效降低SHPT患者血清甲状旁腺激素(PTH)、钙、磷及钙磷乘积水平,抑制甲状旁腺组织增生,改善骨代谢紊乱,抑制心血管钙化,是治疗SHPT的新选择.     

钙受体激动剂在继发性甲旁亢治疗中的研究进展

胞外Ca2 通过激活甲状旁腺细胞表面的钙敏感受体 (CaR) ,可独立、快速地调节甲状旁腺激素 (PTH)的释放 ,慢性肾衰继发甲旁亢 (SHPT)时 ,甲状旁腺CaR的表达减少 ,是引起甲状旁腺细胞过度分泌PTH的直接原因之一。新问世的CaR激动剂 ,可模仿甚至增强胞外Ca2 对CaR的作用 ,初步研究证实 ,它能降低SHPT患者血PTH水平 ,动物实验还发现它有改善骨骼病变的作用 ,因此具有良好的应用前景。     

钙受体激动剂治疗慢性肾衰竭继发性甲状旁腺功能亢进的应用进展

继发性甲状旁腺功能亢进症（SHVF）是慢性肾衰竭（CRF）常见的并发症，多发生于肾小球滤过率（GFR）低于80ml·min^-1·1．73m^-23个月以上，是机体对钙、磷、活性维生素D代谢紊乱的一种适应性反应。     

维持性血液透析继发性甲状旁腺功能亢进患者甲状旁腺切除术后低钙血症的危险因素分析

目的:探讨继发性甲状旁腺功能亢进（secondary hyperparathyroidism,SHPT）维持性血液透析患者接受甲状旁腺切除术（parathyroidectomy,PTX）后补钙量与临床指标的相关性、术后发生低钙血症的危险因素以及PTX术后补钙量对患者远期预后的影响。方法:本研究为单中心回顾性研究,入选2...     

原发性甲状旁腺功能亢进的诊治

目的：总结原发性甲状旁腺功能亢进(PHPT)的诊治经验。方法：回顾性分析2001～2005年上海一家三级 医院外科手术经病理证实的原发性甲状旁腺功能亢进的诊治经验。结果：经手术病理证实的原发性甲状旁腺功能亢 进共20例。其中颈部单发腺瘤13例，异位(胸腔纵隔)单发腺瘤2例，复发1例(因为单发腺瘤切除不彻底)，多发腺 瘤和增生各1例，恶性2例。骨病型12例，骨肾混合型7例，肾型1例。AKP 升高17例，PTH 升高20例，高钙血症 18例(其中高钙危象2例)，低磷血症10例。三项辅助检查(B 超、CT 和~(99m)Tc-MIBI 扫描)两项阳性90%。双侧甲状旁 腺探查3例，异位甲状旁腺经胸或经颈各1例，腔镜辅助甲状旁腺手术2例，其余均为一侧开放手术。术后3例严重 低钙血症，需要2～3个月的补钙调理。19例得到随访，术后半年血钙和 PTH 均正常。结论：遇骨质疏松、纤维囊性骨 瘤、不明原因骨折或变矮、反复肾结石、不明原因的 AKP 升高，需考虑 PHPT，需测定血钙与 PTH 作定性诊断。联合 B 超、CT 和核素扫描能协助定位。PHPT 手术是有效的治疗手段，微创化是趋势。要注重术前高钙危象和术后低钙血症 的处理。     

Paricalcitol治疗尿毒症继发性甲状旁腺功能亢进

继发性甲状旁腺功能亢进是尿毒症的常见并发症。可致骨骼、心血管和神经系统病变,日益受到临床的重视。目前对于继发性甲状旁腺功能亢进的治疗主要有限制磷的摄入、补充活性维生素D制剂以及必要时采取甲状旁腺切除术。动物实验及临床研究显示新型活性维生素D衍生物padcalcitol具有相对选择性的药理作用,能安全有效地抑制甲状旁腺激素的分泌及甲状旁腺的增生而很少引起高钙血症和高磷血症,可替代骨化三醇用于尿毒症特别是长期血液透析病人继发性甲状旁腺功能亢进的治疗。     

慢性肾衰竭继发性甲状旁腺功能亢进的治疗进展

继发性甲状旁腺功能亢进（SHPT）是慢性肾衰竭的常见并发症，可引起心血管、骨等全身各系统损害，严重影响患者的生活质量。近些年，对与SHPT有关因素如低钙血症、钙敏感受体、高磷血症、活性维生素D等的研究有了进一步的认识，治疗有了明显进步。     

Persistent hyperparathyroidism in renal allograft recipients: vitamin D receptor, calcium-sensing receptor, and apoptosis

The phenotypic changes in parathyroid cells after successful renal transplantation remain to be elucidated. We compared 10 diffuse and 11 nodular hyperplastic parathyroid glands from five renal allograft recipients with persistent hyperparathyroidism, with five diffuse and 13 nodular hyperplasia from seven uremic patients on hemodialysis, and 13 normal glands. Comparisons included expressions of both vitamin D receptor (VDR) and calcium-sensing receptor (CaSR), proliferative activity (Ki67), and apoptosis (TUNEL). Immunoreactivity was assessed semiquantitatively and expressed as labeling index. The area/cell was also measured to assess cellular hypertrophy. The labeling indexes of VDR (587+/-71; mean+/-s.e.m.) and CaSR (45.0+/-2.8) in recipients' diffuse hyperplasia were significantly higher than those in uremic diffuse hyperplasia (224+/-44, 29.3+/-2.3, respectively) (P<0.01, each). However, these expressions remained low in recipients' nodular hyperplasia (42+/-8, 11.8+/-1.4, respectively). Ki67 labeling index in recipients' nodular hyperplasia (7+/-1) was significantly smaller than in uremic patients (24+/-6, P<0.01). TUNEL labeling index in recipients' diffuse hyperplasia (30+/-5) was the highest among the groups. The cell volume tended to be smaller in both patterns of hyperplasia in allograft recipients compared with uremic patients. Our results suggest that the phenotypic change in parathyroid cells after renal transplantation depends on the pattern of hyperplasia, where it is normalized only in diffuse hyperplastic glands in which the number of cells also regresses with significant induction of apoptosis.     

Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism

BACKGROUND: The down-regulation of both calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) in parathyroid (PT) glands of secondary hyperparathyroidism (HPT) caused by chronic renal failure has been associated with PT hormone hypersecretion as well as PT hypergrowth. To clarify the predominance of decreased expression of CaSR and VDR in the high proliferative activity of PT glands, we examined the relationship between the expression of both receptors and proliferative activity in human PT glands. METHODS: Serial sections of 56 PT glands, including 52 glands from secondary HPT and 4 normal PT glands resected together with thyroid carcinoma, were examined immunohistochemically with specific antibodies against CaSR, VDR, and Ki67. The Ki67-positive cell number was counted and expressed as the Ki67 score. The CaSR and VDR expressions were semiquantitatively analyzed. RESULTS: The expressions of both CaSR and VDR were markedly decreased in PT glands of secondary HPT, while the Ki67 score was significantly higher than it was in normal controls. When hyperplastic glands were classified into two subgroups, with [N(+)] or without [N(-)] nodular formation, CaSR expression was significantly decreased in N(+), while VDR expression was not different. Multiple regression analyses revealed that the decreased expression of CaSR could contribute significantly to the high proliferative activity, even if VDR expression was taken into account. CONCLUSION: The decrease in CaSR expression is associated with the high proliferative activity of PT glands in secondary HPT, independently of the decreased VDR expression. These findings provide a new insight into the pathogenesis of PT hyperplasia, which is refractory to vitamin D therapy in patients with severe secondary HPT.     

Reversal of secondary hyperparathyroidism by phosphate restriction restores parathyroid calcium-sensing receptor expression and function.

Secondary hyperparathyroidism (secondary HPT), a common disorder in chronic renal failure (CRF) patients, is characterized by hypersecretion of parathyroid hormone (PTH), parathyroid hyperplasia, and decreased expression of the calcium-sensing receptor (CaR). Dietary phosphate loading promotes secondary HPT, and phosphate restriction prevents and arrests secondary HPT in CRF. This study examined the ability of phosphate restriction to restore parathyroid CaR expression and function. Uremic rats fed a 1.2% P diet for 2 weeks developed secondary HPT with down-regulated CaR expression. Continuation on the 1.2% P diet for 2 more weeks worsened the secondary HPT and further decreased CaR, but switching the rats to a 0.2% P diet for 2 weeks normalized PTH, arrested parathyroid hyperplasia, and restored CaR expression to normal. The calcium-PTH relationship was abnormal in uremic rats fed a high phosphate (HP) diet with a right-shifted calcium set point but was corrected by 2 weeks of phosphate restriction. A time course revealed that following the switch to a low phosphate diet, PTH levels were normalized by day 1, and growth was arrested by day 2, but CaR expression was restored between days 7 and 14. We conclude that although phosphate restriction restores CaR expression and function in parathyroid glands of uremic rats, it is a late event and not involved in the arrest of secondary HPT.     

Calcimimetic agents and the calcium-sensing receptor

Blood ionized extracellular calcium is closely regulated. To accomplish this, a hormone-like receptor that is responsive to extracellular ionized calcium regulates both the secretion of parathyroid hormone and the excretion of urinary calcium (as well as other cellular processes). Several hereditary disorders have mutations that cause either loss or gain of function of the calcium-sensing receptor, and alterations of the calcium-sensing receptor may play a role in both primary and secondary hyperparathyroidism. Calcimimetics are agents that act to make the calcium-sensing receptor more sensitive to extracellular ionized calcium; thereby they suppress the secretion of parathyroid hormone. Early trials in animal models of secondary hyperparathyroidism and in patients with primary hyperparathyroidism or with uremic secondary hyperparathyroidism have shown that the first generation calcimimetic, R-568, effectively lowers parathyroid hormone levels and is well tolerated.     

Primary hyperparathyroidism in a patient with familial hypocalciuric hypercalcaemia due to a novel mutation in the calcium-sensing receptor gene

We describe the clinical and genetic findings in pedigree with a novel mutation in the calcium sensing receptor (CaSR) gene and the unusual coexistence of primary hyperparathyroidism (HPT) and familial hypocalciuric hypercalcaemia (FHH) and its clinical management. The occurrence of both FHH and primary HPT in the same patient has been described rarely. Our pedigree has a novel mutation in the CaSR gene. Parathyroidectomy led to a reduction, but not normalization of the calcium levels in the patient identified as having HPT. The coexistence of HPT and FHH was considered in this patient as her calcium and PTH levels were rising with time. Surgical resection of her parathyroid adenoma resulted in reduction of her calcium levels to above normal and significant reduction in her symptoms of fatigue and low mood.     

Persistent downregulation of calcium-sensing receptor mRNA in rat parathyroids when severe secondary hyperparathyroidism is reversed by an isogenic kidney transplantation

Experimental severe secondary hyperparathyroidism (HPT) is reversed within 1 wk after reversal of uremia by an isogenic kidney transplantation (KT) in the uremic rats. Abnormal parathyroid hormone (PTH) secretion in uremia is related to downregulation of CaR and vitamin D receptor (VDR) in the parathyroid glands (PG). The aim of this investigation was to examine the expression of CaR and VDR genes after reversal of uremia and HPT in KT rats. 5/6 nephrectomized rats were kept on a normal or high-phosphorus (hP) diet for 8 wk to induce severe HPT (n = 8 in each group). In another group of seven uremic hP rats, uremia was reversed by an isogenic KT and PG were harvested within 1 wk posttransplant. Plasma urea, creatinine, total calcium, phosphorus, and PTH levels were measured. Parathyroid CaR and VDR mRNA were measured by quantitative PCR. Uremic hP rats had significantly elevated levels of creatinine, urea, and phosphorus (P < 0.001) and developed significant hypocalcemia (plasma calcium 1.83 +/- 0.2 mmol/L; P < 0.001) compared with normal control rats. After KT, the levels were normalized from day 3 to 7: creatinine from 0.117 +/- 0.016 to 0.050 +/- 0.002 mmol/L; urea from 23 +/- 4 to 7 +/- 0.3 mmol/L; phosphorus from 3.9 +/- 0.6 to 1.5 +/- 0.06 mmol/L; calcium from 1.8 +/- 0.2 to 2.5 +/- 0.02 mmol/L. Plasma PTH levels fell from 849 +/- 224 to a normal level of 38 +/- 9 pg/ml (P < 0.01). In uremic rats on a standard diet, CaR mRNA was similar to that of normal control rats, whereas VDR mRNA was significantly decreased. In uremic rats kept on hP diet, CaR mRNA was significantly decreased to 26 +/- 7% of control rats (P = 0.01) and VDR mRNA reduced to 36 +/- 11% (P < 0.01). In KT, previously hP uremic rats, both CaR mRNA and VDR mRNA remained severely reduced (CaR, 39 +/- 7%; VDR, 9 +/- 3%; P < 0.01) compared with normal rats. In conclusion, circulating plasma PTH levels normalized rapidly after KT, despite persisting downregulation of CaR and VDR gene expression. This indicates that upregulation of CaR mRNA and VDR mRNA is not necessary to induce the rapid normalization of PTH secretion from hyperplastic parathyroid glands.