甲状旁腺素测定方法及其在肾性骨病诊断上的应用

肾性骨病是慢性肾功能不全患者的常见并发症,目前多应用甲状旁腺素（PTH）的测定来诊断肾性骨病。本文简要介绍了PTH的测定方法,并对其在肾性骨病诊断上的应用进行分析。     

Image diagnosis of parathyroid glands in chronic renal failure.

Twenty-two out of 31 patients with chronic renal failure and secondary hyperparathyroidism who underwent parathyroidectomy before operation underwent non-invasive image diagnosis of parathyroid glands by computed tomography (CT), scintigraphy with 201TlCl and 99mTcO4+, and/or ultrasonography. CT visualized 39 of 45 parathyroid glands (86.7%), weighing more than 500 mg. Scintigraphy with a subtraction method using a computer performed the diagnosis in 19 of 27 glands (70.4%). Ultrasonography detected 21 of 27 glands (77.8%). Image diagnosis was also useful in the postoperative follow-up study. The non-invasive image diagnosis of parathyroid glands in patients with chronic renal failure is thus valuable for 1) definite diagnosis of secondary hyperparathyroidism, 2) localization, and 3) diagnosis for effectiveness of conservative treatment.     

Pathogenesis of parathyroid hyperplasia in renal failure

In chronic kidney disease, secondary hyperparathyroidism (HPTH) is characterized by parathyroid hyperplasia and enhanced synthesis and secretion of parathyroid hormone (PTH). Elevated PTH levels cause renal osteodistrophy and cardiovascular complications, with significantly increased morbidity and mortality in renal failure. The three main direct causes of renal HPTH are hypocalcemia, hyperphosphatemia and vitamin D deficiency. A link between the mechanisms controlling proliferation and hormonal production also exists in normal parathyroid cells which respond to the stimulus of chronic hypocalcemia, not only by an increase in PTH release but also with a consequent parathyroid cell proliferation. The mechanisms responsible for this link, however, remain poorly understood. In this review, we analyze the current understanding concerning the new insights into the molecular mechanisms of parathyroid hyperplasia and PTH secretion in renal failure regulated by calcium, phosphate and vitamin D.     

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。     

Spectrum of renal bone disease in end-stage renal failure patients not yet on dialysis.

BACKGROUND: During the last few years the spectrum of renal osteodystrophy (ROD) in dialysis patients has been studied thoroughly and the prevalence of the various types of ROD has changed considerably. Whereas until a decade ago most patients presented with secondary hyperparathyroidism (HPTH), adynamic bone (ABD) has become the most common lesion within the dialysis population over the last few years. Much less is known about the spectrum of ROD in end-stage renal failure (ESRF) patients not yet on dialysis. METHODS: Transiliac bone biopsies were taken in an unselected group of 84 ESRF patients (44 male, age 54+/-12 years) before enrolment in a dialysis programme. All patients were recruited within a time period of 10 months from various centres (n=18) in Macedonia. Calcium carbonate was the only prescribed medication in patients followed up by the outpatient clinic. RESULTS: HPTH was found in only 9% of the patients, whilst ABD appeared to be the most frequent renal bone disease as it was observed in 23% of the cases next to normal bone (38%). A relatively high number of patients (n=10; 12%) fulfilled the criteria of osteomalacia (OM). Mixed osteodystrophy (MX) was diagnosed in 18% of the subjects. There was no significant difference between groups in age, creatinine, or serum and bone strontium and aluminium levels. Patient characteristics associated with ABD included male gender and diabetes, whilst OM was associated with older age (>58 years). CONCLUSIONS: In an unselected population of ESRF patients already, 62% of them have an abnormal bone histology. ABD is the most prevalent type of ROD in this population. In the absence of aluminium or strontium accumulation the relatively high prevalence of a low bone turnover as expressed by either normal bone or ABD and OM is striking.     

Vascular calcification: contribution of parathyroid hormone in renal failure

Hyperphosphatemia is a driving force in the pathogenesis of vascular calcification (VC) and secondary hyperparathyroidism associated with renal failure. To test for the possible contribution of parathyroid hormone (PTH) to cardiovascular calcification, we removed the parathyroid glands from rats but infused synthetic hormone at a supraphysiologic rate. All rats were pair-fed low, normal, or high phosphorus diets and subjected to a sham or 5/6 nephrectomy (remnant kidney). Control rats were given a normal diet and underwent both sham parathyroidectomy and 5/6 nephrectomy. Heart weight/body weight ratios and serum creatinine levels were higher in remnant kidney rats than in the sham-operated rats. Remnant kidney rats on the high phosphorus diet and PTH replacement developed hyperphosphatemia and hypocalcemia along with low bone trabecular volume. Remnant kidney rats on the low phosphorus diet or intact kidney rats on a normal phosphorus diet, each with hormone replacement, developed hypercalcemia. All rats on PTH replacement developed intense aortic medial calcification, and some animals presented coronary calcification. We suggest that high PTH levels induce high bone turnover and medial calcification resembling M?mckeberg's sclerosis independent of uremia. This model may be useful in defining mechanisms underlying VC.     

Effect of fluoride on aluminum-induced bone disease in rats with renal failure.

Aluminum (Al) accumulation in renal failure is an etiological factor in the pathogenesis of low turnover bone disease. Aluminum-induced impairment of mineralization has been related to a reduced extent of active bone-forming surface. The present study investigated the effect of fluoride, a potent stimulator of osteoblast number, on the toxicity of aluminum in rats with renal failure (Nx). Following a large parenteral aluminum load (3.2 mg/kg x day) over a period of nine weeks, bone histomorphometry of vertebral cancellous bone revealed a severe low-turnover osteodystrophy as evidenced by a fall in osteoblastic osteoid surfaces and mineral apposition rates. Concurrent administration of fluoride [20 mg/liter (F20) or 40 mg/liter (F40) supplied with the drinking water] resulted in a significant increase in the number of osteoblasts (Nx+Al+F40 vs. Nx+Al, 33.75 +/- 2.83 vs. 1.81 +/- 0.43 mm-1, P less than 0.001) together with an overall reduced deposition of aluminum in bone (469.3 +/- 24.6 vs. 592.2 +/- 28.3 micrograms/g, P less than 0.01). However, there was an increase in the fraction of osteoid surface exhibiting stainable aluminum at the bone-osteoid interface (70.7 +/- 7.1 vs. 44.3 +/- 6.0%, P less than 0.005). Fluoride-exposed rats accumulated a significantly larger osteoid volume, suggesting an exacerbation of the osteomalacic lesion, and furthermore, dynamic histomorphometric parameters remained depressed. These results indicate that fluoride has a distinct effect on the pattern of aluminum deposition in bone. In addition, fluoride antagonizes the aluminum-induced reduction in osteoblast number but provides no amelioration of the impaired mineralization in aluminum-intoxicated rats. Thus, in this model a decrease in the extent of osteoblast surface does not account for the development of aluminum-related bone disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

The use of drugs in renal failure

We have tried to emphasize specific variables that impact upon the use of drugs in the patient with renal disease. These variables are complex, often interrelated, and if neglected by the physician will surely lead to unwarranted drug reactions and serious harm to the patient. We have purposely limited the tables of "Selected Pharmacologic Agents" to a few prototypic drugs from each class, emphasizing the newer agents recently introduced in clinical medicine. We strongly recommend that as new drugs are used, the original literature be consulted for verification.     

The role of mast cells in parathyroid bone disease

Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT. In rats, mature mast cells were preferentially located at sites undergoing bone turnover, and the number of mast cells at the bone–bone marrow interface was greatly increased following treatment with PTH. Time‐course studies and studies employing parathyroid hormone–related peptide (PTHrP), as well as inhibitors of platelet‐derived growth factor‐A (PDGF‐A, trapidil), kit (gleevec), and PI3K (wortmannin) signaling revealed that mature mast cell redistribution from bone marrow to bone surfaces precedes and is associated with osteitis fibrosa, a hallmark of parathyroid bone disease. Importantly, mature mast cells were not observed in the bone marrow of mice. Mice, in turn, were resistant to the development of PTH‐induced bone marrow fibrosis. These findings suggest that the mast cell may be a novel target for treatment of metabolic bone disease. © 2010 American Society for Bone and Mineral Research     

Preoperative parathyroid localization: a prospective evaluation of ultrasonography and thallium-technetium scintigraphy in hyperparathyroidism

To assess the ability of ultrasonography (US) and dual tracer thallium-technetium subtraction scanning (NS) to localize abnormal parathyroid glands, these two investigations were carried out preoperatively in 27 consecutive patients who underwent surgery for hyperparathyroidism. Nineteen patients had adenomas and 8 hyperplasia. Of 23 US procedures 2 were inadequate, and of 26 NS procedures 1 was inadequate. Ultrasonography was found to be superior to NS for preoperative localization of abnormal parathyroid glands (sensitivity per gland 53% versus 36%); detection rates for hyperplasia were poor for both techniques (sensitivity per gland 36% and 25%). However, when positive, both techniques were extremely accurate (positive predictive value of 100% for both). There was no correlation between the weight of the gland or degree of physiological hyperfunction (parathyroid hormone level) and detection rates for the two techniques. False-positive results were rare for both, so a positive result was highly predictive of an abnormality at that location. Ultrasonography had sufficient accuracy to suggest its routine use when adenoma is suspected, particularly to detect the side of the lesion (sensitivity 78% and positive predictive value 100%). The addition of subtraction scintigraphy does not appear to be warranted.     

Regulation of parathyroid function in chronic renal failure

This review summarizes the factors involved in the development of hyperparathyroidism secondary (2nd-HPTH) to chronic kidney disease (CKD). Calcium and calcitriol act on their respective specific parathyroid cell receptors to inhibit parathyroid function. As well as the well-known effect of calcium and calcitriol on parathyroid cell function, there is experimental work that demonstrates that phosphate, changes in pH, PTHrP, estrogens, and some cytokines also have an effect on PTH secretion. These factors are relevant in patients with chronic kidney disease. However, low calcium, vitamin D deficiency, and an accumulation of phosphate due to the decrease in renal function are the main pathogenic factors involved in the pathogenesis of 2nd-HPTH in CKD patients.     

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.     

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.     

Role of parathyroid hormone in the downregulation of liver cytochrome P450 in chronic renal failure

Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes were determined. The depletion of PTH from CRF serum completely reversed the downregulating effect of CRF serum on P450 in hepatocytes. Addition of PTH (10(-9) M) to depleted CRF serum induced a decrease in P450 similar to nondepleted CRF serum. The serum of CRF-PTX rats had no effect on P450 in hepatocytes compared with CRF serum. Adding PTH to CRF-PTX serum induced a similar decrease in P450 as obtained with CRF serum. Finally, PTX prevented the decrease of liver P450 in rats with CRF. In summary, PTH is the major mediator implicated in the downregulation of liver P450 in rats with CRF.     

Calcium, phosphate and parathyroid disturbances in acute renal failure.

Thirteen of sixteen patients with acute renal failure and requiring respiratory and other supportive treatment in an intensive care area became hypercalcaemic whilst still receiving haemodialysis. Results of calcium, phosphate and parathyroid hormone estimations are presented and their disturbances in acute renal failure are discussed.