Parathyroid hormone desensitization in renal membranes of vitamin D-deficient rats is associated with a postreceptor defect

We examined the characteristics of PTH resistance in vitamin D-deficient rats employing renal membranes in vitro. Homologous desensitization was characterized by diminished PTH-stimulated adenylate cyclase activity and was associated with a reduction in PTH-binding capacity, but not affinity. Heterologous desensitization was also seen, as manifested by decreased calcitonin (CT)-stimulated adenylate cyclase activity with normal CT receptor binding. The reduced capacity of the nonhormonal effectors NaF and guanylylimidodiphosphate to stimulate adenylate cyclase indicated a postreceptor defect at the level of the guanyl nucleotide-binding protein (G protein), whereas a normal forskolin response was consistent with a fully functional catalytic component. The G protein deficiency was confirmed by demonstrating that the addition of extracts of vitamin D-sufficient membranes to preparations of vitamin D-deficient membranes restored the normal responses to NaF and guanylylimidodiphosphate. In addition, cholera toxin- and pertussis toxin-catalyzed labeling of vitamin D-deficient renal membranes with [32P]NAD revealed a decrease in both the stimulatory and inhibitory binding proteins. Experiments with testicular membranes in vitro indicated that the adenylate cyclase abnormality was absent in tissue lacking PTH receptors. The results suggest that a major contribution to PTH resistance in vitamin D-deficient animals is a postreceptor defect at the level of the G proteins and that this defect is manifest only in tissue expressing the PTH receptor.     

Recovery of rats from vitamin D-deficient mothers.

Two separate studies were conducted using weanling rats from either an unsupplemented, low vitamin D colony or a supplemented, adequate vitamin D colony. Severe hypocalcemia, slower increases in body weight gain, and lower apparent calcium, magnesium, and phosphorus balance values occurred in the rats from the low vitamin D colony fed a purified AIN-76A, vitamin D-devoid diet compared to rats from the vitamin D-adequate colony fed the same diet. Apparent calcium, magnesium, and phosphorus balance values, as well as most other measurements, in rats from the low vitamin D colony fed a purified AIN-76a, vitamin D-adequate diet were greater than or equal to those of rats never subjected to low vitamin D. This was suggestive of overcompensation in recovery from low maternal vitamin D. However, rats from the low vitamin D colony fed an unrefined (chow), vitamin D-adequate diet had lower apparent balance and bone values compared with rats from the vitamin D-supplemented colony fed the same diet. Presumably high levels of calcium, magnesium, and phosphorous in the unrefined diet prevented any overcompensation during recovery, as occurred with purified diets, from the earlier vitamin D deficiency. Overall, results indicated weanling rats from a low vitamin D colony had low vitamin D stores and were marginally vitamin D-deficient. In addition, recovery from the marginal deficiency had occurred to a large extent after feeding a purified, vitamin D-adequate diet. The results suggest the use of low vitamin D colony rats as a model for human, marginal vitamin D deficiency.     

Early treatment of secondary hyperparathyroidism in moderate renal insufficiency: low-phosphorus diet versus calcium carbonate

Calcitriol deficiency and phosphorus retention are mechanisms involved in the pathogenesis of renal hyperparathyroidism. The aim of this study was to evaluate the effect of dietary phosphorus restriction versus calcium carbonate treatment for one month on PTH and calcitriol levels in patients with mild renal failure. We studied two groups of patients: Group I: 21 patients (14M/7F); mean age 61 years old; mean glomerular filtration rate 51 ml/min. Their diet contained phosphorus 700 mg/day. Group II: 30 patients (21M/9F); mean age 58; mean glomerular rate 56 ml/min. They were divided in two subgroups: 18 patients treated with calcium carbonate 2.5 g/day and 12 patients with 5 g/day. Serum PTH, calcitriol, 25(OH)D3, calcium, phosphorus and urinary excretion of calcium and phosphorus were measured before and after a 30 day period. The low phosphorus diet (Group I) resulted in a significant decrease in PTH levels (81.3 +/- 35 vs 71 +/- 39 pg/ml, p < 0.05) and significant increase in calcitriol levels (22.4 +/- 4.4 vs 33.4 +/- 7.5 pg/ml, p < 0.05). In our study calcium carbonate treatment (Group II) had no effect on PTH and calcitriol levels.     

Complex carbohydrate diets are not capable of maintaining normal plasma calcium and phosphorus levels in vitamin D-deficient rats.

Substitution of Cerelose (glucose monohydrate) for complex carbohydrate (whole wheat flour) does not alter plasma calcium levels in vitamin D-deficient rats, contrary to a previous report. It is suspected that whole wheat flour may contain traces of vitamin D that result in a slower rate of depletion than found with Cerelose diets. Vitamin D-deficient rats showing low plasma 1,25-dihydroxyvitamin D3 levels and no detectable 25-hydroxyvitamin D3 levels in their blood show a hypocalcemia (5.6 mg/dl) and normal phosphatemia whether fed whole wheat or Cerelose diets.     

慢性肾功能衰竭患者继发性甲状旁腺功能亢进的外科治疗

目的:探讨甲状旁腺全切加自体胸锁乳突肌移植术治疗慢性肾功能衰竭患者继发性甲状旁腺功能亢进的临床疗效。方法:回顾性分析民航总医院耳鼻咽喉头颈外科2009年9月至2013年3月收治的32例继发性甲状旁腺功能亢进症患者的临床资料,患者均行中央区加前上纵隔清扫切除全部甲状旁腺加自体胸锁乳突肌移植术。比较手术前后症状缓解程度,血清全段甲状旁腺激素(i PTH)、血钙、血磷和血红蛋白变化评价手术效果。结果:手术成功率100%。术后半年内所有患者骨痛、皮肤瘙痒均缓解。肌无力、不宁腿及睡眠质量均明显改善。术后半年血清i PTH[(80.62±81.28)pg/ml vs(1 492.9±1 170.70)pg/ml]、血钙[(2.15±0.33)mmol/L vs(2.39±0.22)mmol/L]、血磷[(1.09±0.38)mmol/L vs(2.25±0.60)mmol/L]和血钙磷乘积[(28.63±10.19)mg/d L vs(67.12±20.35)mg/dl]均较术前明显下降,且统计学差异显著(P0.01)。术后半年血红蛋白[(118.45±11.88)g/L vs(109.60±16.17)g/L]和红细胞压积[(37.16%±3.42%)vs(34.01%±5.25%)]均较术前明显升高(P0.05)。经病理证实,32例患者共切除甲状旁腺121枚,其中108枚位于气管食管沟,9枚位于前上纵隔,4枚位于甲状腺内。结论:中央区加前上纵隔清扫切除全部甲状旁腺加自体胸锁乳突肌移植术治疗继发性甲状旁腺功能亢进症安全可靠,初次手术的成功率高。     

Effect of calcium supplementation on blood pressure in patients with secondary hyperparathyroidism

The aim was to study the effect of calcium supplementation 477 mg twice daily on BP in patients with secondary hyperparathyroidism during an intervention study (6 weeks) and after 954 mg during a short study (3 h). The intervention study was a placebo-controlled, double-blind, cross-over, while the short study gave a placebo and calcium in random order on separate days. The participants were obtained from an epidemiological survey in Troms? 1994-1995 that included more than 27.000 subjects. The re-examination was performed in 2000/2001 at the University Hospital of North Norway, Norway. There were 18 subjects with secondary hyperparathyroidism and 28 control subjects in the intervention study while there were 14 cases and 8 control subjects in the short study. The results showed that in the subjects with secondary hyperparathyroidism after calcium supplementation in the intervention study there was an increase in serum calcium from 2.28 +/- 0.09 to 2.36 +/- 0.06 mmol/l (mean +/- SD) and a decrease in serum PTH from 8.6+/-1.6 to 6.5+/-2.4 pmol/l. However, there was no significant difference in either systolic or diastolic BP between calcium supplementation and placebo (138.3 +/- 21.0 vs 135.9 +/- 17.0 mm Hg and 80.9 +/- 11.1 vs 78.9+/-9.5 mm Hg, respectively). Similar results were seen in the control group. In the short study, serum calcium increased and serum PTH decreased after oral calcium, but the BP did not differ as compared to when placebo was given. To conclude, in the present setting we did not find any effect on BP by calcium supplementation in subjects with moderate secondary hyperparathyroidism.     

Bone disease in vitamin D-deficient patients with Crohn's disease

Vitamin D deficiency is frequently observed in patients with Crohn's disease and may be associated with an increased risk of development of metabolic bone disease. To estimate the incidence of metabolic bone disease by noninvasive methods, 31 patients (17–75 years old) with Crohn's disease and low 25-hydroxy vitamin D (25-OHD) levels in winter were investigated in the following summer by measuring the bone mineral content (BMC) of the distal radius by single photon absorptiometry and the cortical area ratio (CAR) calculated from radiographs of the right hand and by x-ray of the lumbar spine. Forty-five percent of the patients showed signs of metabolic bone disease. BMC and CAR correlated with 25-OHD serum levels (P<0.05), especially in men. Furthermore, the amount of sun exposure has an influence not only on 25-OHD serum levels both in summer and in winter (P=0.0006), but also on the BMC (P=0.07). Consequently, vitamin D deficiency is of major importance for the development of metabolic bone disease in patients with Crohn's disease. Vitamin D deficiency can be prevented by increasing sun exposure and long-term vitamin D supplementation.     

Cinacalcet and the prevention of secondary hyperparathyroidism in rats with aldosteronism

BACKGROUND: In rats receiving aldosterone/salt treatment (ALDOST), increased Ca2+ excretion leads to a fall in plasma-ionized Ca2+ and appearance of secondary hyperparathyroidism (SHPT) with parathyroid hormone (PTH)-mediated intracellular Ca2+ overloading inducing oxidative stress in diverse tissues. Parathyroidectomy prevents this scenario. Rats with ALDOST were cotreated with cinacalcet (Cina), a calcimimetic that raises the threshold of the parathyroids' Ca(2+)-sensing receptor. METHODS AND RESULTS: We monitored plasma-ionized [Ca2+]o, PTH, and total Ca2+ in heart and peripheral blood mononuclear cells (PBMC), and evidence of oxidative stress in heart, PBMC, and plasma. Cina-treated rats for 4 weeks were compared with 4 weeks of ALDOST alone and with untreated age-/gender-matched controls. In comparison to controls, ALDOST led to a fall (P < 0.05) in Ca2+ (1.16 +/- 0.01 vs 1.03 +/- 0.01 mmol/L), which was not prevented by Cina (1.01 +/- 0.03 mmol/L); a rise (P < 0.05) in plasma PTH (36 +/- 7 vs 134 +/- 19 pg/mL) that was attenuated by Cina (69 +/- 12 pg/mL); increased (P < 0.05) cardiac [Ca2+] (3.92 +/- 0.25 vs 6.78 +/- 0.35 nEq/mg FFDT) and PBMC [Ca2+]i (29.8 +/- 2.3 vs 50.2 +/- 2.3 nmol/L), each of which was prevented with Cina (3.65 +/- 0.10 nEq/mg FFDT and 32.5 +/- 6.0 nmol/L, respectively); increased cardiac MDA (0.56 +/- 0.03 vs 0.94+/-0.07 nmol/mg protein) and PBMC H2O2 production (63.5 +/- 7.5 vs 154.0 +/- 25.2 mcb) and reduced (P < 0.05) plasma alpha1-AP activity (39.8 +/- 0.6 vs 29.6 +/- 1.8 mM), each prevented by Cina (0.66 +/- 0.04 mmol/mg protein, 58.2 +/- 12.7 mcb and 37.0 +/- 1.2 mM, respectively). CONCLUSIONS: PTH-mediated intracellular Ca2+ overloading accounts for the induction of oxidative stress in diverse tissues in rats with aldosteronism and which can be prevented by Cina.     

Effects of hemodialysis on secondary hyperparathyroidism in patients with chronic renal failure

In the first few weeks after the initiation of maintenance hemodialysis in nine patients with chronic renal failure, there was a progressive rise in both total and ionized serum calcium associated with a reciprocal and significant fall in the concentration of plasma parathyroid hormone. Studies in 36 additional patients with chronic renal failure already on hemodialysis indicated that this favorable trend did not continue; a progressive rise in parathyroid hormone concentration was associated with increasing duration of hemodialysis against the calcium concentration generally used by most centers. These observations are consistent with the increase in bone disease often associated with hemodialysis. Experimental increases in dialysate calcium concentration from 2.6 to 3.5 meq/liter for a 2-mo period failed to decrease parathyroid hormone secretion or cause a significant increase in predialysis calcium concentration in 36 uremic patients. Use of high calcium dialysis earlier in the course of the disease, alternate means of parathyroid suppression, and even subtotal parathyroidectomy may be necessary for the management of hyperparathyroidism in uremic patients undergoing hemodialysis.     

Pathogenesis of secondary hyperparathyroidism and renal bone disease

Patients with chronic renal disease (CKD)almost always develop secondary hyperparathyroidism (SHPT) due to hypocalcemia, phosphate retention, and abnormalities in vitamin D (VD) metabolism. Concomitant decreases in VD receptor and calcium sensing receptor in the parathyroid glands render them more resistant to the action of VD and calcium, and accelerate parathyroid cell growth. Several types of bone diseases are known to occur in CKD patients. Excessive secretion of parathyroid hormone (PTH) due to SHPT causes high-turnover bone disease, called osteitis fibrosa. Among low-turnover bone disease (LTBD), osteomalacia which is characterized by calcification defect is often complicated with VD deficiency and/or aluminum accumulation. Recently, frequency of adynamic bone disease caused by PTH suppression, another type of LTBD, is increasing probably due to calcium salts as phosphate binder with or without VD treatment.     

Postmenopausal osteoporosis as a manifestation of renal hypercalciuria with secondary hyperparathyroidism

An apparently unique presentation of osteoporosis was encountered in eight postmenopausal women (mean age, 56.8 yr). They had renal hypercalciuria, since they had fasting hypercalciuria [0.17 +/- 0.04 (+/- SD) mg/100 ml glomerular filtrate (GF)] in the setting of normocalcemia and parathyroid stimulation (high serum immunoreactive PTH and/or urinary cAMP). Serum 1,25-dihydroxyvitamin D was not significantly different (28 +/- 7 vs. 34 +/- 2 pg/ml) from that in a nonelderly control group, but fractional intestinal calcium (Ca) absorption was significantly lower (0.382 +/- 0.123 vs. 0.49 +/- 0.06; P less than 0.025). Thus, the patients did not have compensatory intestinal hyperabsorption of Ca despite PTH excess. Treatment with hydrochlorothiazide (50 mg/day) produced a decline in fasting urinary Ca (to 0.07 +/- 0.02 mg/100 ml GF; P less than 0.01), serum PTH (from 39 +/- 19 to 21 +/- 1 microliters eq/ml; P less than 0.05), and urinary cAMP excretion (from 5.30 +/- 0.57 to 3.57 +/- 0.59 nmol/100 ml GF; P less than 0.0025). The results suggested that hyperparathyroidism was secondary. Histomorphometric analysis of bone showed reduced trabecular bone volume without mineralization defect, compatible with osteoporosis. Four of eight patients had high or high normal fractional resorption surfaces, fractional formation surfaces, and fractional osteoid volumes. That these abnormalities may reflect PTH-dependent osteoclastic resorption and bone turnover was supported by the reduction of these indices after correction of secondary hyperparathyroidism with hydrochlorothiazide therapy. The remaining four patients, however, had normal histomorphometric results. In summary, postmenopausal osteoporosis may occur sometimes with renal hypercalciuria and secondary hyperparathyroidism. The lack of compensatory intestinal hyperabsorption of Ca predisposes to negative Ca balance, and the hyperparathyroid state may be manifested by stimulated osteoclastic and osteoblastic activities.     

Parathyroid hormone-related protein and calcium regulation in vitamin D-deficient sea bream (Sparus auratus)

Gilthead sea bream (Sparus auratus L.) were fed a vitamin D-deficient diet for 22 weeks. Growth rate, whole body mineral pools and calcium balance were determined. Plasma parathyroid hormone-related protein (PTHrP) and calcitriol levels were assessed. Expression of mRNA for pthrp and pth1r was quantified in gills and hypophysis. Fish on vitamin D-deficient diet (D- fish) showed reduced growth and lower calcium turnover (calcium influx, efflux and accumulation rates decreased) and unaltered plasma calcium levels. Plasma calcitriol levels became undetectable, PTHrP levels decreased in the D- fish. In controls, a significant increase in plasma PTHrP level over time was seen, i.e. it increased with body mass. Relationships were found between plasma PTHrP and the whole body pools of calcium, phosphorus and magnesium, indicative of a role for PTHrP in bone development. Expression of pthrp and pth1r mRNA was down-regulated in the hypophysis of D-fish, whereas in gill tissue, pthrp and pth1r mRNA were up-regulated. We conclude that lower pthrp mRNA expression and plasma values in D- fish reflect lower turnover of PTHrP under conditions of hampered growth; up-regulation of pthrp mRNA in gills indicate compensatory paracrine activity of PTHrP during calcitriol deficiency to guarantee well-regulated branchial calcium uptake. This is the first report to document a relation between PTHrP and calcitriol in fish.     

On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency

The effect of prolonged (60 days) dietary phosphate restriction on divalent ion metabolism was studied in four patients with moderate renal insufficiency in an effort to delineate the mechanisms of secondary hyperparathyroidism in renal failure. The patients had low normal serum phosphorous and normal vitamin D metabolite levels but had evidence of disturbances in target organs for vitamin D, including impaired intestinal absorption of calcium, reduced calcemic response to PTH, low serum ionized calcium levels, and, consequently, elevated PTH levels. After dietary phosphate restriction, there was marked improvement or normalization of intestinal absorption of calcium, calcemic response to PTH, and ionized calcium and PTH levels. There was also a significant rise (44%) in serum 1,25-dihydroxyvitamin D levels. The data suggest that intracellular phosphorous retention, which may develop as renal insufficiency ensues, may interfere with the action and production of 1,25-dihydroxyvitamin D. This leads to defective intestinal calcium absorption and reduced calcemic responses to PTH. As a result, hypocalcemia develops, causing secondary hyperparathyroidism. Our data assign a critical role for a disturbance(s) in vitamin D metabolism in genesis of the hyperparathyroidism of renal failure.     

The calcimimetic NPS R-568 decreases plasma PTH in rats with mild and severe renal or dietary secondary hyperparathyroidism

NPS R-568 is a Ca²⁺ receptor agonist (“calcimimetic”) compound that reduces circulating parathyroid hormone (PTH) levels in rats and humans with mild secondary hyperparathyroidism (2°HPT) resulting from chronic renal insufficiency (CRI). These studies extend those observations to show that NPS R-568 is equally effective in decreasing plasma PTH and Ca²⁺ levels in rats with mild or severe 2°HPT, resulting either from CRI or from dietary calcium deficiency. Male rats were 5/6 nephrectomized and fed either normal chow or a high-phosphorus diet; other normal rats were fed a low-calcium diet. When 2°HPT had developed, NPS R-568 was administered and blood samples were collected for up to 6 h. PTH levels decreased to a minimum level within 30 min in both CRI and calcium deficiency models of 2°HPT. PTH and Ca²⁺ levels remained significantly depressed for >3 h after dosing. The percentage decrease in PTH levels was unaffected by the severity of 2°HPT or the basal plasma Ca²⁺ or phosphate levels. In rats with severe 2°HPT, the minimum plasma PTH level after NPS R-568 was greater than the basal level in mild 2°HPT. Thus, NPS R-568 is equally effective in suppressing plasma PTH and Ca²⁺ levels in rats with mild or severe renal or nutritional 2°HPT.     

终末期肾病继发性甲状旁腺功能亢进患者甲状旁腺切除术后并发症的研究进展

继发性甲状旁腺功能亢进(SHPT)是慢性肾脏病透析患者的常见并发症之一。随着透析方式及技术的提高,患者的人均寿命延长,透析期间SHPT的发病率逐渐增加。一部分难治性SHPT患者需要手术治疗。该文将主要介绍SHPT患者甲状旁腺切除术后相关并发症的研究进展。     

Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor, calcium sensing receptor, and cell cycle regulating factors

The parathyroid gland (PTG) is a unique endocrine organ in which the quiescent glandular cells begin to proliferate in response to the demand for maintaining calcium (Ca) homeostasis in the progressive course of renal failure, leading to secondary hypereparathyroidism (SHPT). SHPT is characterized with continuous over-secretion of parathyroid hormone (PTH) and high turn-over bone disease, osteitis fibrosa, and the major factors include a deficiency of active vitamin D, hypocalcemia, and phosphate retention. With long-term end-stage renal failure, SHPT becomes resistant to conventional medical treatment such as phosphate binders and active vitamin D supplementation, and the growth of the PTG accelerates with the pattern of hyperplasia changing from diffuse to nodular type. In this process, the sigmoid curve between extracellular Ca concentration (exCa) and the plasma level of PTH shifts to the upper-rightward, indicating both an absolute increase in PTH secretion and the resistance of PT cells to exCa. Many experimental and human studies have revealed down-regulation of vitamin D receptor (VDR), calcium-sensing receptor (CaSR), and retinoid X receptor (RXR) in PT cells. The sustained proliferation of PT cells after obtaining autonomicity is another characteristic feature of SHPT. In this context, it has been demonstrated that the cell cycle is markedly progressed, where the expression of cyclin-dependent kinase inhibitor (CDKI), p21 and p27, is depressed in a VDR-dependent manner. These pathological features are most evident in nodular hyperplasia, in which monoclonal proliferation is obvious, indicating the phenotypic changes have occured in PT cells. It has been observed by Fukagawa and colleagues that pharmacologically high dose of active vitamin D administered orally can cause small-size PTG hyperplasia to regress in patients with advanced SHPT. Successful renal transplantation may also restore VDR and CaSR expressions in the diffuse type, in association with increasing TUNEL-positive cells. Thus, it is important to vigorously treat SHPT when the PT cell proliferation is in the reversible stage of diffuse hyperplasia.