甲状旁腺激素的功能及其在肾性骨病发病中的作用

甲状旁腺素（parathyroid hormone，PTH）是甲状旁腺分泌的一种激素，主要调节机体的钙磷代谢及骨代谢。终末期肾病（end stage renal disease，ESRD）患者中PTH作为一种尿毒症毒素，可引起多种器官损伤，如肾性骨病（renal ostecdystrophy，ROD）、心脏肥大、软组织钙化等。血PTH水平与ROD不同病理类型之间的关系长期以来受到人们的广泛关注。血清或血浆中PTH浓度准确的测定，对于各种骨或矿物质代谢紊乱性疾病的诊断有着重要的意义，以往各种PTH检测方法检测的并不都是所谓的“整分子PTH”（whote PTH），即PTH（1—84），往往高于实际值。本文旨在对PTH的生物学特性、检测方法及其与ROD的研究进展作一综述。     

肾性骨病的诊疗进展

本文对肾性骨病的发病机制 ,诊断依据及内外科治疗等方面的进展作了综述。     

血清高水平甲状旁腺激素-非透析慢性肾脏疾病患者的隐形杀手

维持性血液透析患者血清甲状旁腺激素(Parathyroid hormone,PTH)水平显著增高,PTH与患者心功能下降、营养状态恶化以及死亡率的增加密切相关.然而,临床实践发现,部分慢性肾脏疾病(Chronic kidney disease,CKD)3-4期、甚至CKD1期的患者血清PTH水平也增高,PTH对此类患者的影响如何,目前报道较为少见.本文结合文献就FTH对非透析CKD患者的心血管系统、骨代谢、营养状况及预后的影响作一综述.     

尿毒症肾性骨病继发甲状旁腺腺瘤的诊治探讨

目的探讨尿毒症肾性骨病继发甲状旁腺腺瘤的诊治方法、疗效及预后。方法比较罗钙全冲击治疗、甲状旁腺腺瘤切除术两种治疗方式的疗效及预后。结果罗钙全冲击治疗后，患者病情反而加重：未行正规治疗．疾病进展至晚期或钙化防御者．不可逆转；行甲状旁腺腺瘤切除术者，短期效果良好。结论甲状旁腺功能亢进应强调早期诊断，治疗方案要个体化、正规化。治疗上，罗钙全等活性维生素D3冲击治疗效果不佳．甲状旁腺腺瘤切除术短期效果明显．且理论上不会导致甲状旁腺功能低下，是一种有选择价值的治疗方法。     

甲状旁腺激素的不同检测方法及其在肾性骨病诊断中的价值

甲状旁腺激素（PTH）作为一种尿毒症毒素。日益引起人们关注。它可以引起多种器官损伤。如肾性骨病、心脏肥大、软组织钙化等。一直以来，PTH检测是临床上诊断、监测肾性骨病的主要手段。但近来有研究报道，维持性血透患者的PTH值不能正确判断骨转运状态。甚至iPTH〉500pg／ml的患者骨活检也有显示低转运性骨病的可能。那么。PTH水平是否能够反映骨病状态呢？还是PTH检测方法不能反映真实的PTH值呢？为此我们回顾一下目前的进展。     

血清高水平甲状旁腺激素-非透析慢性肾脏疾病患者的隐形杀手

维持性血液透析患者血清甲状旁腺激素(Parathyroid hormone,PTH)水平显著增高,PTH与患者心功能下降、营养状态恶化以及死亡率的增加密切相关.然而,临床实践发现,部分慢性肾脏疾病(Chronic kidney disease,CKD)3-4期、甚至CKD1期的患者血清PTH水平也增高,PTH对此类患者的影响如何,目前报道较为少见.本文结合文献就FTH对非透析CKD患者的心血管系统、骨代谢、营养状况及预后的影响作一综述.     

血清高水平甲状旁腺激素-非透析慢性肾脏疾病患者的隐形杀手

维持性血液透析患者血清甲状旁腺激素(Parathyroid hormone,PTH)水平显著增高,PTH与患者心功能下降、营养状态恶化以及死亡率的增加密切相关.然而,临床实践发现,部分慢性肾脏疾病(Chronic kidney disease,CKD)3-4期、甚至CKD1期的患者血清PTH水平也增高,PTH对此类患者的影响如何,目前报道较为少见.本文结合文献就FTH对非透析CKD患者的心血管系统、骨代谢、营养状况及预后的影响作一综述.     

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。     

肾性骨病的诊疗进展

本文对肾性骨病的发病机制，诊断依据及内外科治疗等方面的进展作了综述。     

Parathyroid hormone changes during phosphorus load in patients with chronic renal insufficiency with low serum parathyroid hormone or adynamic bone disease

Adynamic bone disease (ABD) is frequently associated with low serum parathyroid hormone (PTH) concentrations. Many clinical and therapeutic conditions have been associated with ABD, and recently, a low phosphorus intake accompanied by low serum concentration of phosphorus and PTH has been described. AIM: To evaluate the parathyroid gland response of chronic renal insufficiency patients (CRI) with low serum PTH or ABD to a phosphorus load. METHODS: We examined the effects of 0.5 and 1.0 g/d of phosphorus load over a period of 60 days in 18 patients with mild CRI with a bone biopsy showing ABD (n = 7) or with low serum PTH (serum intact PTH < or = 40 ng/l) and serum phosphorus < 4.5 mg/dl (n = 11). RESULTS: Serum intact PTH increased significantly only after 1 g of phosphorus (58.5 to 83 ng/l) with a median percent increase of 72%. PTH secretion increased more in patients with lower basal PTH levels (81%). Serum phosphorus did not change significantly and urinary phosphorus increased from 487 to 1,062 mg/dl (p < 0.05). Significant decreases in serum ionized calcium (from 1.26 to 1.19 mmol/l) and calcitriol (from 34.5 to 24.9 pg/ml) were observed. Changes in PTH were inversely correlated with changes in serum ionized calcium (r = -0.54, p < 0.05) and the final PTH concentrations were positively correlated with changes in serum phosphorus (r= 0.52, p < 0.05). CONCLUSIONS: The parathyroid glands of chronic renal insufficiency patients with "relative hypoparathyroidism" or ABD responded to a phosphorus load with an increase in serum PTH levels. The decrease in serum ionized calcium and calcitriol as well as minimal changes in serum phosphorus appeared to be involved in this response.     

重组人甲状旁腺素促骨合成研究进展

人甲状旁腺素(hPTH)的主要生理功能是调节钙磷代谢、促进维生素D代谢、激活骨细胞,是调节钙、磷代谢及骨转换的重要肽类激素之一,能精确调节骨的合成及分解代谢过程.hPTH片段目前已成为重要的骨形成促进剂,与受体结合后通过活化cAMP依赖的蛋白激酶A及钙离子依赖的蛋白激酶C信号传导途径发挥生物学作用.hPTH可使血清磷降低,间接影响骨的生长.大剂量hPTH可同时刺激和抑制骨胶原的合成,促进骨吸收,抑制骨形成;小剂量,特别是hPTH1～34片段可刺激骨胶原合成而促进骨形成.近年随着对成骨细胞与破骨细胞生物学的更深入了解,hPTH对骨的作用,尤其在骨质疏松症治疗上的研究有了很大进展,开发出特立帕肽(teriparatide)等新药用于预防和治疗原发性和继发性骨质疏松症.该文就hPTH的结构、作用机制及其促进骨形成、预防骨质疏松性骨折的研究进展作一综述.     

Phosphorus reduces renal receptivity for parathyroid hormone in rats

Changes in kidney calcium concentration and secreted parathyroid hormone were studied in weanling male rats (n = 12) fed diets containing either 0.5% (n = 6) or 1.5% (n = 6) total phosphorus. Calcium and phosphorus concentrations in the kidney of rats fed a high-phosphorus diet were markedly greater than those in rats fed a control diet. In addition, urinary excretion of phosphorus increased gradually after administration of a high-phosphorus diet, but there was no similar tendency of phosphorus/creatinine excretion, which decreased gradually from the starting day of feeding to the end of the feeding period. The high-phosphorus diet also produced greater serum parathyroid hormone (PTH) without urinary cyclic adenosine monophosphate (cAMP) excretion stimulated by PTH. The mean values of serum 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃) concentrations were significantly increased 1 h after injection of 2.77 g rat PTH(1–34) in all rats. However, in rats fed a high-phosphorus diet, the rise of serum 1,25(OH)₂D stimulated by exogenous PTH was lower than that in rats fed a control diet.     

Interspecies comparison of renal cortical receptors for parathyroid hormone and parathyroid hormone-related protein.

Parathyroid hormone (PTH) and PTH-related proteins (PTHrP) interact with a common receptor in rat bone cells and in canine renal membranes with similar affinity, but PTHrP are substantially less potent than PTH in stimulating adenylate cyclase in canine renal membranes; in contrast, PTH and PTHrP are equipotent in stimulating adenylate cyclase in rat bone cells. This discrepancy has been largely viewed as reflecting differences in the relative efficiency of signal transduction of PTHrP between bone and kidney assay systems. To test the alternative (but not mutually exclusive) hypothesis that these differences could reflect interspecies differences in PTH receptors, we have characterized the bioactivity of amino-terminal PTHrP and PTH in rat and human renal cortical membranes (RCM) and compared them to results we previously reported in canine RCM. The stability of PTH and PTHrP peptides under binding and adenylate cyclase assay conditions was greater than 80% for each species. Competitive inhibition of [125I](Tyr36)hPTHrP-(1-36)NH2 binding to rat RCM by bPTH-(1-34) and (Tyr36)hPTHrP-(1-36)NH2 yielded nearly identical binding dissociation constants (3.7 and 3.6 nM, respectively), and binding to human RCM demonstrated slightly greater potency for PTHrP (0.5 nM) than for PTH (0.9 nM). Similarly, adenylate cyclase stimulating activity was equivalent for the two peptides in rat RCM, but PTHrP was twofold more potent than PTH in human RCM. Covalent photoaffinity labeling of protease-protected rat RCM yielded an apparent 80 kD receptor protein, and cross-linking of human RCM labeled an 85 kD receptor, indistinguishable in size from the canine renal PTH receptor. We conclude that rat, canine, and human renal cortical PTH receptors exhibit species specificity. The previously observed differences between rat bone cells and canine renal membranes in the efficiency of signal transduction by PTHrP may be explained, at least in part, by these species differences.     

慢性肾脏病患者甲状旁腺激素水平对肾性贫血的影响

目的 探讨慢性肾脏病（CKD）患者甲状旁腺激素（PTH）升高致红细胞寿命缩短的机制。 方法 以住院初治的CKD患者75例（按eGFR分为1～2期、3～4期和5期）和健康对照组30例为对象。免疫发光法测全段甲状旁腺激素（iPTH）;流式细胞术测红细胞表面磷脂酰丝氨酸（PS）外翻水平及红细胞内钙离子浓度（[Ca2+]i）。 结果 （1）随着肾功能的减退,CKD3～4期及5期患者 iPTH、[Ca2+]i及红细胞表面PS外翻水平逐渐升高、贫血逐渐加重,明显高于CKD1～2期和对照组（均P < 0.05）。（2）CKD3～4期或5期患者Hb与iPTH和红细胞表面PS外翻水平呈负相关（r = -0.830和-0.791,均P < 0.01）;iPTH与 [Ca2+]i和红细胞表面PS外翻水平呈正相关（r = 0.882和0.924,均P < 0.01）,与血钙浓度呈负相关（r = -0.544, P < 0.01）;红细胞表面PS外翻水平与 [Ca2+]i呈正相关（r = 0.923,P < 0.01）,与血钙浓度无相关（r = -0.138,P = 0.365）。（3）[Ca2+]i（Y）对iPTH（X）的直线回归方程：Y=3.327+0.213X（F=21.529,P < 0.05）;红细胞表面PS外翻水平（Y）对iPTH（X1）及[Ca2+]i（X2）的多元线性回归方程：Y=-0.303+0.283X2+0.139X1（F = 6.59,P < 0.01）。 结论 iPTH增加红细胞内钙离子浓度,引起红细胞表面PS外翻增多,致红细胞寿命缩短而加重肾性贫血。     

Intact parathyroid hormone levels in renal insufficiency

To define the onset of the rise in intact parathyroid hormone (PTH) levels in renal insufficiency, we conducted a cross-sectional study of parameters of mineral metabolism in patients with varying degrees of renal impairment. Using an immunoradiometric assay to measure intact PTH levels, we found elevations in intact PTH levels as creatinine clearance approaches 60 ml/minute (serum creatinine near 1.8) and a significant inverse relationship between indices of renal function and intact PTH levels (r=-0.60, P<0.001 for intact PTH and creatinine clearance). Calcium and phosphate levels correlate less strongly with the degree of hyperparathyroidism (r=-0.39, P<0.001 for total calcium; r=0.31, P<0.05 for phosphate). As a group, only patients with severe renal failure (creatinine clearance <20 ml/minute) had 1,25-dihydroxyvitamin D levels below normal (11±4 [SEM] pg/dl, normal range 15–60). Intact and n-terminal PTH measurements correlate well in this patient population with varying degrees of renal insufficiency (r=0.9, P<0.001). Intact PTH can be elevated in patients with mild to moderate renal insufficiency, thus efforts to prevent the development of secondary hyperparathyroidism in renal failure should be undertaken early in the course of renal insufficiency.     

甲状旁腺素与骨质代谢相关研究进展

目前全球骨质疏松发病率位于第6位,因此骨质疏松症发病机制一直是重点研究的课题之一,但是骨质疏松的发生、发展、机制至今尚未完全明了.自20世纪20年代发现骨形成和吸收与血液中甲状旁腺素密切相关开始,经过多年探索、研究,甲状旁腺素与骨的形成、吸收的部分机制已经阐明.该文回顾近几年来关于甲状旁腺素与骨质代谢的相关文献,并作一综述.     

Effect of aluminum and parathyroid hormone on osteoblasts and bone mineralization in chronic renal failure

Summary Bone aluminum, quantitative bone histology, and plasma parathyroid hormone (PTH) were compared in 29 patients undergoing chronic hemodialysis. Histologic techniques included double tetracycline labeling and histochemical identification of osteoclasts and osteoblasts. Bone aluminum was measured chemically by flameless atomic absorption spectrophotometry, and histochemically. When measured chemically, the bone aluminum was 67±46 (SD) mg/kg dry weight (normal 2.4±1.2 mg/kg); histochemically, aluminum was present at 2.9±4.4% of trabecular surface. The biochemical and histochemical results agreed well (r=0.80,P<0.001). No double tetracycline labels were seen at the mineralization front where aluminum was deposited, indicating cessation of mineralization at these sites. The osteoblast surface correlated positively with plasma PTH (r=0.67,P<0.001) and negatively with bone aluminum level (r=−0.42,P<0.05). Multiple linear regression showed a correlation of aluminum with osteoblasts additional to that of PTH, consistent with a direct effect of aluminum in depressing osteoblast numbers. Though a relationship between PTH and chemically determined bone aluminum level could not be demonstrated, there was a negative correlation between osteoclast count and aluminum, and the nine patients with severe hyperparathyroid bone disease had lower chemically determined aluminum levels than the other patients. These results suggest that aluminum (a) directly inhibits mineralization, (b) is associated with decreased PTH activity and hence osteoblast numbers, and (c) directly reduces osteoblast numbers. In addition to inducing severe, resistant osteomalacia, aluminum appears to contribute to the mild osteomalacia commonly seen in renal failure, characterized by extensive thin osteoid and low tetracycline and osteoblast surfaces.     

Effect of aluminum and parathyroid hormone on osteoblasts and bone mineralization in chronic renal failure

Bone aluminum, quantitative bone histology, and plasma parathyroid hormone (PTH) were compared in 29 patients undergoing chronic hemodialysis. Histologic techniques included double tetracycline labeling and histochemical identification of osteoclasts and osteoblasts. Bone aluminum was measured chemically by flameless atomic absorption spectrophotometry, and histochemically. When measured chemically, the bone aluminum was 67 +/- 46 (SD) mg/kg dry weight (normal 2.4 +/- 1.2 mg/kg); histochemically, aluminum was present at 2.9 +/- 4.4% of trabecular surface. The biochemical and histochemical results agreed well (r = 0.80, P less than 0.001). No double tetracycline labels were seen at the mineralization front where aluminum was deposited, indicating cessation of mineralization at these sites. The osteoblast surface correlated positively with plasma PTH (r = 0.67, P less than 0.001) and negatively with bone aluminum level (r = -0.42, P less than 0.05). Multiple linear regression showed a correlation of aluminum with osteoblasts additional to that of PTH, consistent with a direct effect of aluminum in depressing osteoblast numbers. Though a relationship between PTH and chemically determined bone aluminum level could not be demonstrated, there was a negative correlation between osteoclast count and aluminum, and the nine patients with severe hyperparathyroid bone disease had lower chemically determined aluminum levels than the other patients. These results suggest that aluminum (a) directly inhibits mineralization, (b) is associated with decreased PTH activity and hence osteoblast numbers, and (c) directly reduces osteoblast numbers. In addition to inducing severe, resistant osteomalacia, aluminum appears to contribute to the mild osteomalacia commonly seen in renal failure, characterized by extensive thin osteoid and low tetracycline and osteoblast surfaces.