Abnormal skeletal response to parathyroid hormone in dogs with chronic uremia

Summary The release of cyclic AMP from bone in response to stimulation with PTH 1–34 was examined in 20 dogs with long-term chronic renal failure (CRF) produced by unilateral nephrectomy and contralateral partial renal artery ligation. After 9 to 15 months of uremia, the tibiae were removed and perfused in vitro. Seven dogs with CRF served as controls, 7 dogs with CRF were treated with 24,25(OH)₂D₃ — 2.5 μg per day, and 6 CRF dogs underwent thyroparathyroidectomy (TPTX) 42 h before they were sacrificed. The release of cyclic AMP from bone in response to PTH 1–34 in the CRF dogs was severely reduced compared to the response observed in 7 dogs with normal renal function (net accumulation of cyclic AMP release 86±8.5 versus 426±59.0 pmol/30 min). Long-term treatment of uremic dogs with 24,25(OH)₂D₃ had no effect on the release of cyclic AMP by bone. However, the release of cyclic AMP was restored to normal levels in the CRF dogs that underwent thyroparathyroidectomy. All CRF dogs had secondary hyperparathyroidism and the fact that TPTX returned the cyclic AMP response to normal values suggests that desensitization to PTH of the adenylate cyclase system of bone exists in chronic uremia.     

Frusemide therapy and intact parathyroid hormone plasma concentrations in chronic renal insufficiency.

It has been suggested that frusemide affects plasma parathyroid hormone (PTH) concentrations. To further investigate this issue we analysed plasma intact PTH in 77 patients with chronic renal failure (CCr 8.0-89.8 ml/min per 1.73 m2) as a function of frusemide therapy. The rate of increase of plasma PTH observed with progression of renal failure was faster in patients who received frusemide as compared to patients who did not receive the drug. The slope of the regression line of PTH on CCr was steeper (P less than 0.02) for patients with frusemide (n = 40, slope -0.34) than without frusemide (n = 37, slope -0.20). This effect was specific for frusemide therapy since therapy with other antihypertensive drugs (including thiazides and beta-blockers) was not correlated with PTH plasma concentrations. Frusemide therapy was also associated with a significantly greater urinary calcium excretion in uraemic patients but did not influence other parameters of calcium metabolism. To clarify mechanisms involved in the effect of frusemide on plasma PTH values, seven normal subjects were studied for 24 h before and for 24 h after oral administration of 80 mg frusemide. The main findings were: (1) Median PTH values were higher than on a control day (P less than 0.05) 3 h after frusemide (3.9 pmol/l vs 1.8) and 6 h after frusemide (4.0 vs 2.6); (2) ionised plasma calcium did not change significantly, whereas mean calcium/creatinine ratio increased from 0.20 to 0.46 after frusemide treatment through an increase in absolute calcium excretion; (3) plasma 1 alpha,25-dihydroxyvitamin D3, catecholamines, and magnesium concentrations did not change significantly after frusemide.(ABSTRACT TRUNCATED AT 250 WORDS)     

PHEX expression in parathyroid gland and parathyroid hormone dysregulation in X-linked hypophosphatemia

X-linked hypophosphatemia (XLH), a renal phosphate (Pi) wasting disorder with defective bone mineralization, is caused by mutations in the PHEX gene (a Pi-regulating gene with homology to endopeptidases on the X chromosome). Parathyroid hormone (PTH) status in XLH has been controversial, with the prevailing belief that hyperparathyroidism develops in response to Pi therapy. We report a 5-year-old girl with XLH (patient 1) who had significant hyperparathyroidism at presentation, prior to initiation of therapy. We examined her response to a single oral Pi dose, in combination with calcitriol, and demonstrated a rise in serum concentration of intact PTH, which peaked at 4 h and paralleled the rise in serum Pi concentration. We also present two other patients whose parathyroid glands were analyzed for PHEX mRNA expression following parathyroidectomy. Patient 2 had autonomous hyperparathyroidism associated with chronic renal insufficiency, and patient 3, with XLH, developed autonomous hyperparathyroidism after 8 years of therapy with Pi and calcitriol. Following parathyroidectomy, patient 3 exhibited an increase in both serum Pi concentration and renal Pi reabsorption. The abundance of PHEX mRNA, relative to β-actin mRNA, in parathyroid glands from patients 2 and 3 was several-fold greater than that in human fetal calvaria, as estimated by ribonuclease protection assay. In summary, we have shown that hyperparathyroidism can be a primary manifestation of XLH and that PHEX is abundantly expressed in the parathyroid gland. Given that PHEX has homology to endopeptidases, we propose that PHEX may have a role in the normal regulation of PTH. Received: 27 May 1999 / Revised: 11 June 1999 / Accepted: 11 June 1999     

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.     

Inhibition of erythropoiesis in chronic renal failure: the role of parathyroid hormone

Sera from 20 anemic patients with chronic renal failure (CFR) were studied for their effect on bone marrow in vitro erythroid colony formation (CFUE) and the observations correlated with parathyroid hormone (PTH) and ionized calcium levels in the patients' sera. Results demonstrated that 17 out of 20 patients' sera significantly inhibited in vitro erythropoiesis by 47% to 97%. No significant elevation in ionized calcium was found in 16 of the patients tested. Furthermore, assay of PTH levels in these patients revealed that 9 out of 20 had elevated levels of PTH. No correlation was found between PTH serum levels and the degree of in vitro inhibition of erythropoiesis (CFUE) by the patients' sera. Addition of up to 2,000 pg/mL (far above the patients' levels) of exogenous N-terminal or C-terminal PTH with in vitro bone marrow cultures resulted in no inhibitory effect on CFUE. It is concluded that the circulating inhibitor of erythropoiesis which has been shown to exist in the sera of this particular group of patients with CRF, is not PTH.     

Parathyroid hormone and its fragments in children with chronic renal failure

Parathyroid hormone (PTH) immunoradiometric assays (IRMA) exhibit cross-reactivity between 1-84 PTH and long carboxyl-terminal-PTH (C-PTH) molecules. C-PTH antagonizes the biological actions of 1-84 PTH and circulates in excess in chronic renal failure (CRF), partially explaining why supra-physiological PTH levels are recommended to maintain bone turnover. Furthermore, the ratio 1-84 PTH/C-PTH may be related to bone turnover. This study characterizes the 1-84 PTH/C-PTH ratio in children with varying severity of CRF and levels of PTH. Two hundred and forty-one children with CRF, managed with the aim of preventing the development of hyperparathyroidism, had PTH measured by intact IRMA and a new more specific Cyclase-Activating-PTH (CAP) IRMA. C-PTH levels were calculated by subtracting CAP-IRMA from intact IRMA. Fifty-three controls with normal renal function were also recruited. Mean intact IRMA correlated with CAP-IRMA (r=0.98), but was higher (P<0.001). The mean 1-84 PTH/C-PTH ratio was lower than controls in dialysis patients (P=0.022) and those with a glomerular filtration rate <30 ml/min per m² (P=0.033). This ratio was comparable to controls when the PTH level was normal, but was lower with PTH levels outside the normal range (P<0.01). These data suggest that CAP-IRMA gives a more accurate assessment of actual PTH levels than intact IRMA in CRF. Maintenance of normal PTH levels throughout the course of CRF permits the maintenance of a normal 1-84 PTH/C-PTH ratio, the clinical significance of which requires further investigation in children.     

血液灌流联合血液透析对血液透析患者甲状旁腺素的清除效果观察

目的观察血液灌流联合血液透析对血液透析患者甲状旁腺素的清除效果观察。方法将50例尿毒症合并顽固性皮肤瘙痒患者,随机分为两组。串联组22例,采用血液灌流联合血液透析治疗,每周3次。对照组28例,采用常规血液透析治疗,每周3次,共治疗4周。治疗前、后测定血清甲状旁腺素的水平。结果串联组治疗前血清甲状旁腺素为（325．85±218．65）ng／L,治疗后降至（153．80±248．65）ng／L,皮肤瘙痒症状改善率77．78％,治疗前、后比较差异显著（P〈0．05）。对照组治疗前血清甲状旁腺素为（392．85±248．65）ng／L,治疗后降至（348．79±231．65）ng／L,皮肤瘙痒症状改善率29．41％,治疗前、后比较差异无显著性（P〉0．05）。结论血液灌流联合血液透析能有效地清除血清甲状旁腺素,改善患者的皮肤瘙痒症状。     

Hetereogeneity in skeletal response to full-length parathyroid hormone in the treatment of osteoporosis

Summary In the PaTH trial, among the 119 women randomized to parathyroid hormone PTH(1–84) and 60 to alendronate, we found much greater variation in BMD and markers in response to PTH(1–84) compared to alendronate. No baseline participant characteristic consistently predicted increased bone density response to PTH(1–84), although women with larger changes in 1,25 dihydroxyvitamin D during therapy had larger increases in BMD. Introduction We examined variability in BMD and markers of bone turnover in response to treatment with PTH(1–84) or alendronate in the PaTH trial. Methods Differences in SD were examined using Levine’s test for homogeneity of variance. Change in BMD across quartiles of participant characteristics was examined using ANOVA. Results We found much greater variation in response to PTH(1–84) compared to alendronate. The SD for change in cancellous spine BMD (by QCT) was 32% on PTH(1–84) compared to 13% on alendronate (p < 0.0001). The higher variability in the PTH(1–84) group was due to substantial numbers of women with large increases in BMD on PTH(1–84). Similarly, the SD of changes in markers of formation and resorption were significantly higher on PTH(1–84) than on ALN. No baseline participant characteristics predicted increased bone density response to PTH(1–84) therapy. However, change in 1,25-OH₂D explained 16% of the variance in BMD response to PTH(1–84). Conclusion There is significant variability in the skeletal response to PTH(1–84), which exceeds that observed with alendronate. Changes in 1,25-OH₂D were related to larger gains in BMD. This finding may have implications for elucidating either the pathway by which PTH affects the skeleton or traits that result in particular responsiveness to PTH therapy.     

甲状旁腺激素及其受体与骨关节炎的关系研究进展

骨关节炎是一种以关节软骨破坏、软骨下骨的硬化和滑膜反应为特征的慢性疾病.目前发现甲状旁腺激素(Parathyroid hormone,PTH)能够抑制骨关节炎患者软骨细胞终末期成熟分化,有明显软骨保护、延缓骨关节炎进展的作用.通过研究PTH、PTHR与骨关节炎的关系,对骨关节炎治疗及预后将起到重要的指导作用.     

肾脏病患者甲状旁腺素受体基因表达的研究

目的 探讨肾脏疾病不同阶段中甲状旁腺素(PTH)受体基因表达的变化及可能机制。方法 应用半定量RT/PCR方法观察各组患者肾穿刺或手术标本中PTH受体mRNA表达。结果 慢性肾炎肾功能正常、中度肾功能减退、尿毒症及急性肾衰患者均有不同程度PTH受体基因表达减少,且和肾脏损害密切相关。结论 在肾脏疾病进程中PTH受体下调明显早于肾功能、血PTH和钙磷的变化。     

肾脏病患者外周血淋巴细胞上甲状旁腺素受体的表达

目的　探讨人外周血淋巴细胞上有无甲状旁腺素（PTH）受体表达及其在肾脏疾病不同阶段的改变。方法应用RT-PCR方法观察各组患者淋巴细胞和肾脏组织中PTH受体mRNA表达。结果人淋巴细胞上可检出PTH受体基因表达；在慢性肾炎肾功能代偿期和尿毒症患者中均有不同程度下调，与肾功能损害密切相关，且与同组患者肾脏组织中PTH受体的改变相一致。结论肾功能减退时，患者淋巴细胞上PTH受体显著下调。     

Serum intact parathyroid hormone and ionised calcium concentration in children with renal insufficiency

We report our experience of the use of an immunoradiometric assay for intact parathyroid hormone (i-PTH) and the measurement of plasma ionised calcium concentration (PCa²⁺) in 73 children with chronic renal insufficiency (CRI); plasma creatinine concentration (PCr) 52–856 mol/l.There was a poor correlation between i-PTH and PCr (r=0.10,n=552) compared with that for C-terminal PTH and PCr (r=0.60,n=248), suggesting that the i-PTH assay is independent of renal function in this group of treated children. A clear response of i-PTH to a low total plasma Ca (tPCa) and PCa²⁺ was observed. There was a significant positive correlation between both tPCa and PCa²⁺ (r=0.50,n=389) and the fraction of Ca²⁺ (the fraction of tCa which was ionised) and PCa²⁺ (r=0.50,n=389). The finding of a low or normal PCa²⁺ with a low calculated fraction of Ca²⁺ was frequently observed, i. e. the measured tPCa was unexpectedly high, suggesting complexing of Ca²⁺ by accumulated anions in CRI. There was a poor relationship between the plasma albumin concentration and both bound plus complexed Ca (tPCa minus PCa²⁺) and the fraction of Ca²⁺ (r=0.15 and –0.17, respectively). The positive predictive value for a raised i-PTH of a tubular reabsorbtion of phosphate of less than 80% was 0.87, and of an alkaline phosphatase greater than 800 U/l was 0.37. We conclude that the immunoradiometric assay for i-PTH should replace indirect assessments of secondary hyperparathyroidism, and that measurement of the Ca²⁺ concentration is necessary to evaluate the true Ca status in children with CRI.     

Expression of parathyroid hormone/parathyroid hormone-related peptide receptor 1 in normal and diseased bladder detrusor muscles: a clinico-pathological study

Background

To investigate the expression of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor 1 (PTH1R) in clinical specimens of normal and diseased bladders. PTHrP is a unique stretch-induced endogenous detrusor relaxant that functions via PTH1R. We hypothesized that suppression of this axis could be involved in the pathogenesis of bladder disease.

Methods

PTH1R expression in clinical samples was examined by immunohistochemistry. Normal kidney tissue from a patient with renal cancer and bladder specimens from patients undergoing ureteral reimplantation for vesicoureteral reflux or partial cystectomy for urachal cyst were examined as normal control organs. These were compared with 13 diseased bladder specimens from patients undergoing bladder augmentation. The augmentation patients ranged from 8 to 31 years old (median 15 years), including 9 males and 4 females. Seven patients had spinal disorders, 3 had posterior urethral valves and 3 non-neurogenic neurogenic bladders (Hinman syndrome).

Results

Renal tubules, detrusor muscle and blood vessels in normal control bladders stained positive for PTH1R. According to preoperative urodynamic studies of augmentation patients, the median percent bladder capacity compared with the age-standard was 43.6% (range 1.5–86.6%), median intravesical pressure at maximal capacity was 30 cmH₂O (range 10–107 cmH₂O), and median compliance was 3.93 ml/cmH₂O (range 0.05–30.3 ml/cmH₂O). Detrusor overactivity was observed in five cases (38.5%). All augmented bladders showed negative stainings in PTH1R expression in the detrusor tissue, but positive staining of blood vessels in majority of the cases.

Conclusions

Downregulation of PTH1R may be involved in the pathogenesis of human end-stage bladder disease requiring augmentation.     

不同血液净化方法对尿毒症患者甲状旁腺素水平的影响

目的比较联机血液透析滤过（HDF）和常规血液透析（HD）对尿毒症患者甲状旁腺素（iPTH）水平的影响。方法选择我院血液净化中心2004年6月至2006年12月期间透析龄超过9个月且iPTH明显升高的尿毒症患者60例,其中男38例、女22例,平均年龄43．5岁,平均透析龄（18．6±9．3）月。将患者随机分为HDF组和HD组,每组30例。两组患者每周均透析三次,HDF组为1次HDF、2次HD,每次透析4h。HDF组使用F60滤过器;HD组使用F6HPS透析器,统一低分子肝素抗凝。检测透析前后患者血液血肌酐（SCr）、血尿素氮（BUN）及iPTH水平并计算其清除百分率。结果SCr与BUN清除率在HD组分别为（70.6％±3．2％）和（74．2%±4．0％）,在HDF组分别为（71．8％±2．3％）和（76．2%±3．8％）,两组之间差异无统计学意义。HD组血iPTH值透析前后无显著差异,清除率仅为（1．7%±0．9%）,而HDF组iPTH的清除率为（32．8％±7．8％）,该组透析前后溶质浓度及清除率的差异均有统计学意义。结论两种血液净化治疗方式对小分子物质的清除效果无差异,但HDF对中分子物质（iPTH）的清除效果明显优于HD。定期HDF有利于iPTH的清除、防止iPTH异常导致的钙磷代谢紊乱、降低代谢性骨病等并发症的发生率。     

Growth hormone resistance in uremia

Growth retardation is a major complication in children with uremia. Protein restriction, calorie deficit, metabolic acidosis, renal osteodystrophy, and endocrinologic disturbances contribute to the growth failure. The effect of these factors on growth retardation can be attenuated in part by therapy with vitamin D metabolites, adequate nutrition, alkalization, and dialysis. Linear growth in children with uremia is markedly retarded despite normal or increased levels of circulating serum growth hormone. An increased growth hormone level in children with uremia is due to normal growth hormone secretion from the pituitary gland and impaired growth hormone clearance in the kidney. However, the elevated growth hormone level does not lead to a commensurate rise in serum insulin-like growth factor I (IGF-I); the serum IGF-I level is decreased or normal in relation to the degree of renal failure. This discrepancy suggests growth hormone resistance in the liver in uremia. Recent molecular techniques open a new era in studying the gene expression for growth hormone or IGF-I. There is no doubt today that growth hormone treatment has the beneficial effect of growth promotion in children with uremia, which also suggests endogenous growth hormone resistance in target organs or target cells in uremia.     

Osteoporotic fracture and parathyroid hormone

Osteoporosis and age-related bone loss is associated with changes in bone remodeling characterized by decreased bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis. Recombinant parathyroid hormone (PTH), PTH(1-34), is an anabolic agent with proven benefits to bone strength and has been characterized as a potential therapy for skeletal repair. In spite of PTH's clinical use, safety is a major consideration for long-term treatment. Studies have demonstrated that intermittent PTH treatment enhances and accelerates the skeletal repair process via a number of mechanisms. Recent research into the molecular mechanism of PTH action on bone tissue has led to the development of PTH analogs to control osteoporotic fractures. This review summarizes a number of advances made in the field of PTH and bone fracture to combat these injuries in humans and in animal models. The ultimate goal of providing an alternative to PTH, currently the sole anabolic therapy in clinical use, to promote bone formation and improve bone strength in the aging population is yet to be achieved.     

重症急性胰腺炎大鼠骨组织甲状旁腺素受体mRNA的表达

目的探讨重症急性胰腺炎(SAP)低钙血症的发生机制。方法逆行性胰管注射牛磺胆酸制作重症急性胰腺炎大鼠动物模型。SD大鼠分为假手术组28只,SAP组28只,SAP治疗组18只,假手术治疗组16只。治疗组采用大鼠甲状旁腺素（ratPTH)和人甲状旁腺素相关肽(hPTHrP)。逆转录-聚合酶链反应(RT-PCR)动态观察骨组织甲状旁腺素受体mRNA的表达。检测血钙变化。结果SAP大鼠起病后12、48h血清钙为(1.98±0.23)mmol/L、(1.76±0.16)mmol/L,游离钙为(0.93±0.16)?mmol/L、(0.75±0.14)mmol/L,与假手术组对比各时相血清钙和游离钙显著下降（P＜0.01）。SAP大鼠骨组织甲状旁腺素受体（PTHR）mRNA表达与假手术组对比各时相均显著下降（P<0.01）。经ratPTH和hPTHrP治疗后,SAP大鼠血钙无显著变化。结论重症急性胰腺炎低血钙可能与PTHR受损其mRNA低表达有关。     

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。