Effect of aluminium hydroxide on serum ionised calcium,immunoreactive parathyroid hormone,and aluminium in chronic renal failure.

According to the Bricker-Slatopolsky theory, secretion of parathyroid hormone (PTH) is switched on in chronic renal failure by hypocalcaemia due to phosphate retention. In an attempt to reverse this process 20 patients in preterminal renal failure (plasma creatinine 569 +/- 195 mumol/l) were given aluminium hydroxide, 3.8 g daily. They were studied for four weeks and all measurements were made at the start and weekly, except measurements of serum aluminium concentration, which were made at the start and at the end of the fourth week. Mean serum phosphate fell from 1.89 to 1.47 mmol/l (5.9 to 4.6 mg/100), mean serum calcium rose from 2.07 to 2.24 mmol/l (8.3 to 9.0 mg/100 ml), and serum ionised calcium rose from 1.07 to 1.20 mmol/l (4.3 to 4.8 mg/100 ml), but serum immunoreactive PTH did not fall. Thirteen patients had initial serum immunoreactive PTH concentrations at or near to normal and 11 were taking beta-blockers but even in those with neither explanation, PTH concentrations did not fall. Serum aluminium concentrations rose from 0.4 to 1.02 mumol/l (10.9 to 27.4 microgram/l). Aluminium hydroxide corrects serum phosphate, total calcium, and ionised calcium at the price of a rise in serum aluminium concentration; in this study it did not affect serum immunoreactive PTH. The Bricker-Slatopolsky theory still needs verification in studies of patients with chronic renal failure.     

Ultrasonic examination of the parathyroid glands, bone x-ray and calcium deposits of the eye in diagnosis of secondary hyperparathyroidism in light of 12 observed cases]

Twelve patients with chronic renal failure treated with repeated dialysis underwent subtotal parathyroidectomy. Histologic examination revealed hyperplasia parathyroidal adenoma in all patients. Diagnostic correlation between bone X-ray, ultrasound of parathyroid glands, calcium deposits in cornea and conjunctiva, and histological findings has been analysed. Radiological abnormalities have been noted in 8 patients (66%), parathyroid glands hyperplasia in 9 (75%), and corneal and conjunctival calcium deposits in 10 (83%) patients. These data confirm the value of techniques under study for the diagnosis of the secondary hyperparathyroidism in patients with chronic renal failure.     

Familial hypocalciuric hypercalcaemia and acute pancreatitis.

Four families with familial hypocalciuric hypercalcaemia were studied. The probands presented with abdominal pain, which in three was due to acute pancreatitis; in two the condition was life threatening. Serum concentrations of calcium, magnesium, phosphate, and immunoassayable parathyroid hormone, urinary calcium excretion, and the rate of renal tubular reabsorption of phosphate were measured; the findings were compared with results in 10 patients with primary hyperparathyroidism matched for serum calcium concentration to establish differences between the diseases. Familial hypocalciuric hypercalcaemia should be suspected in patients with hypercalcaemia in whom daily urinary calcium excretion is below 5 mmol (200 mg) provided renal insufficiency, vitamin D deficiency, and ingestion of drugs that reduce calcium excretion have been excluded. Most cases appear to run a benign course, but some may suffer considerable morbidity. Surgical treatment should be reserved for patients with severe complications, when all parathyroid tissue should be removed.     

Metabolic Bone Disease Secondary to Renal and Intestinal Disorders

Metabolic bone disease occurring in renal or intestinal disorders has been reviewed with particular reference to etiological factors.Hyperparathyroidism is seen as a recurring cycle of renal damage—hyperphosphatemia—hypocalcemia—parathyroid stimulation—mobilization of bone calcium and phosphate—renal tubular phosphate rejection. In intestinal cases, the initial stimulus is presumably hypocalcemia.Osteomalacia is seen as resulting from phosphate depletion for the following reasons:1. Experimentally, rickets results from dietary phosphate restriction in rats.2. Such rickets is not prevented by the presence of normally adequate amounts of dietary vitamin D, and may therefore be termed “resistant” in the clinical sense.3. Osteomalacia or rickets in intestinal malabsorption and renal tubular disorders is associated with hypophosphatemia due to excessive fecal or urinary loss.4. Renal tubular rickets has been healed by oral phosphate loading in some studies.5. Acidosis may induce osteomalacic changes, experimentally and clinically (for example, in uretero-sigmoidostomy). Reversal of systemic acidosis with oral bicarbonate has resulted in phosphate retention and a rising serum phosphate in one such case.6. Preliminary data from analysis of full-thickness bone biopsy in two osteomalacic patients shows a significant reduction in calcium and phosphate content.7. Despite the hyperphosphatemia of azotemic renal failure, over-all phosphate depletion may be present in this situation also due to: • Diminished dietary phosphate in low protein diets • Nausea and vomiting • Occasional diarrhea • The use of oral phosphatebinding antacids • Perpetuation of urinary phosphate losses by reduction in proportion of tubular reabsorbed phosphate (secondary hyperparathyroidism) and possibly high filtered load per nephron • Repeated losses of phosphate to bath fluid during dialysis.     

Significance of Elevated Parathyroid Hormone After Parathyroidectomy

ObjectiveTo review the prevalence of parathyroid hormone elevation after parathyroidectomy for primary hyperparathyroidism and to discuss possible mechanisms.MethodsA Medline search of the English-language literature published between 1990 and 2009 was performed using the search terms “elevated PTH after parathyroidectomy.” All of the identified articles reported either prospective or retrospective studies without control groups. Studies that included patients with secondary or tertiary hyperparathyroidism were not reviewed.ResultsWithin 1 week to 5 years after parathyroidectomy, 9% to 62% of patients with a normal serum calcium concentration are reported to have an elevated parathyroid hormone concentration. No evidence suggests that postoperative normocalcemic parathyroid hormone elevation is an indication of surgical failure and recurrent hypercalcemia. Preoperative findings in patients with postoperative parathyroid hormone elevation include lower vitamin D concentration, higher concentrations of bone turnover markers, and higher parathyroid hormone concentration. Potential mechanisms for parathyroid hormone elevation in the setting of normocalcemia include vitamin D deficiency, hungry bone syndrome, and parathyroid hormone resistance. Study findings suggest a possible benefit of postoperative calcium and vitamin D supplementation, but no randomized trials have been done.ConclusionElevation of parathyroid hormone commonly occurs after parathyroidectomy for primary hyperparathyroidism, although the underlying mechanism remains unclear. (Endocr Pract. 2010;16:112-117)     

A case of normocalcemic primary hyperparathyroidism with osteomalacia

A 59 year-old patient had lumbago and pain in hip joints, knees, and ribs of long duration. Severe hypophosphatemia and high serum ionized calcium were found in spite of normal level of total serum calcium. The serum parathyroid hormone and alkaline phosphatase levels were elevated, and diffuse demineralization of the bones and renal stones were found by x-ray examination. Parathyroid adenoma was diagnosed from the subtraction image of the 99mTc O-4 and 201Tl-Cl2 scintigrams. Osteomalacia was demonstrated by bone biopsy at the right iliac crest. A right lower parathyroid adenoma of 2.0 X 1.8 cm, weighing 4.0 g was removed. The long standing phosphate depletion and hypophosphatemia, due to hyperparathyroidism causing renal damage with nephrocalcinosis and reduced synthesis of active vitamin D, and milk tolerance due to gastroduodenostomy were probably responsible for producing the clinical picture of normocalcemic hyperparathyroidism complicated with osteomalacia.     

Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure.

OBJECTIVE--To determine whether alfacalcidol--used in management of overt renal bone disease--may safely prevent renal bone disease when used earlier in course of renal failure. DESIGN--Double blind, prospective, randomised, placebo controlled study. SETTING--17 nephrology centres from Belgium, France, the Netherlands, and the United Kingdom. SUBJECTS--176 patients aged 18-81 with mild to moderate chronic renal failure (creatinine clearance 15-50 ml/min) and with no clinical, biochemical, or radiographic evidence of bone disease. INTERVENTIONS--Alfacalcidol 0.25 micrograms (titrated according to serum calcium concentration) or placebo given for two years. MAIN OUTCOME MEASURES--Quantitative histology of bone to assess efficacy of treatment and renal function to assess safety. RESULTS--132 patients had histological evidence of bone disease at start of study. Biochemical, radiographic, and histological indices of bone metabolism were similar for the 89 patients given alfacalcidol and the 87 controls given placebo. After treatment, mean serum alkaline phosphatase activity and intact parathyroid hormone concentration had increased by 13% and 126% respectively in controls but had not changed in patients given alfacalcidol (P < 0.001). Hypercalcaemic episodes occurred in 10 patients given alfacalcidol (but responded to decreases in drug dose) and in three controls. Histological indices of bone turnover significantly improved in patients given alfacalcidol and significantly deteriorated in controls: among patients with abnormal bone histology before treatment, bone disease resolved in 23 (42%) of those given alfacalcidol compared with two (4%) of the controls (P < 0.001). There was no difference in rate of progression of renal failure between the two groups. CONCLUSION--Early administration of alfacalcidol can safely and beneficially alter the natural course of renal bone disease in patients with mild to moderate renal failure.     

2-methylene-19-nor-20(S)-1alpha-hydroxy-bishomopregnacalciferol [20(S)-2MbisP], an analog of vitamin D3 [1,25(OH)2D3], does not stimulate intestinal phosphate absorption at levels previously shown to suppress parathyroid hormone

Chronic kidney disease results in a reduction in 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) synthesis and an accumulation of phosphorus in the blood, leading to secondary hyperparathyroidism and renal osteodystrophy. Vitamin D analogs that retain the ability to suppress PTH but that are less calcemic and phosphatemic than the native hormone are preferred therapies for secondary hyperparathyroidism. However, even the most favored analog currently approved for the treatment of chronic kidney disease patients, i.e. 1,25-dihydroxy-19-nor-vitamin D2 (19-nor-D2, Zemplar), still retains some ability to stimulate intestinal absorption of calcium and phosphate. A recently described analog of vitamin D3, 2-methylene-19-nor-20(S)-1alpha-hydroxy-bishomopregnacalciferol [20(S)-2MbisP], suppresses PTH levels, but is unable to stimulate intestinal calcium absorption or bone resorption in rats. The present study shows that 20(S)-2MbisP is unable to stimulate intestinal phosphate absorption at levels known to suppress PTH secretion. Further, 19-nor-vitamin D2 under the same circumstances does stimulate phosphate absorption. Thus, 2MbisP has significant potential in the management of secondary hyperparathyroidism of renal failure.     

Parathyroid hormone in urinary stone patients

To evaluate the role of parathyroids in calculus disease, the parathyroid hormone levels were determined in 22 control subjects and 42 stone (14 with bladder stone and 28 with kidney stone) patients. Serum calcium, inorganic phosphate, alkaline phosphatase and parathyroid hormone and urinary excretion of calcium and inorganic phosphate were determined. It was found that normocalcemic and normocalciuric stone patients had slightly higher levelsss of parathyroid hormone (irrespective of the site of the stone) and the difference was not statistically significant as compared with control subjects although some of the patients with calculus disease were hyperparathyroid. Serum alkaline phosphatase was increased while there was an increase in urinary calcium excretion in kidney stone patients and oxalate in all patients as compared with control subjects. The increase in inorganic phosphate was, however, not different from the control subjects. The subclinical hyperparathyroidism and stone formation in these patients are not correlated.     

The morphology and function of rat C-cells. 4. Determination of calcium, inorganic phosphorus and total nitrogen in the femora of untreated parathyroidectomized or thyreoparathyroidectomized and hormonally substituted female rats]

Female Wistar rats of a live weight of about 160 g and fed with a standard laboratory diet, were parathyroidectomized, or thyroparathyroidectomized and treated with thyroxine, parathyroid hormone, calcitonin. thyroxine and parathyroid hormone, or thyroxine and calcitonin. On the 15th day post operationem, and after twelve days of hormone treatment, the concentrations of calcium, inorganic phosphorus and total nitrogen were determined in the femur bone. Parathyroidectomy resulted in a decrease of phosphorus concentration in bone. After thyroparathyroidectomy (Tx), the concentrations of inorganic phosporus and nitrogen diminished during some days, whereas the calcium content decreased continuously. Thyroxine application normalized the concentration of inorganic phosphorus. The osteolytic and nitrogen-anabolic effect of parathyroid hormone took place only in simultaneous treatment with thyroxine. The injection of calcitonin had a nitrogen-anabolic effect on bone; the simultaneous treatment with thyroxine induced a loss of calcium out of bone, and a deposition of calcium phosphate in renal tissue. Calcitonin did not inhibit a significant decrease of calcium concentration in the femur bone; the hypophosphatemic effect was always present. The metabolism of bone tissue, influenced by hormonal actions, probably determined the localization of the deposition of inorganic phosphorus, deserting the serum under the influence of calcitonin.     

A Magnesium Based Phosphate Binder Reduces Vascular Calcification without Affecting Bone in Chronic Renal Failure Rats

The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover.     

Normal responsiveness of serum parathyroid hormone to beta-adrenergic blockade in patients with secondary hyperparathyroidism

Infusion of calcium gluconate (15 mg Ca++/kg body weight in 4 h) to 6 patients with secondary hyperparathyroidism (due to mild renal insufficiency) decreased serum parathyroid hormone (PTH) levels to the same degree (on a percent basis) as in normal subjects. Serum PTH values at 4 h were 60 +/- 4.5 (SEM)% of baseline in the patients and 59 +/- 2.9% of baseline in the normal subjects. Infusion of propranolol (1 mg i.v. bolus followed by an infusion of 60 micrograms/min for 2 h) to 7 additional patients with secondary hyperparathyroidism also decreased serum PTH to the same degree as in normal subjects. Serum PTH values at 2 h were 68 +/- 10.4% of baseline in the patients and 68 +/- 3.3% of baseline in the normal subjects. The studies indicate normal responsiveness of serum PTH to calcium or beta-adrenergic blockade in secondary hyperparathyroidism due to mild renal insufficiency.     

Bone and the kidney: a systems biology approach to the molecular mechanisms of renal osteodystrophy

Despite its apparent static condition, the skeleton undergoes a permanent process of remodeling mediated by osteoblasts and osteoclasts. The activity of these cells is regulated by a plethora of factors, ranging from mechanical stress to the effects of hormones to the immune system. One well-studied regulatory system involves the maintenance of calcium homeostasis through a network whose main regulatory components include ionized calcium, phosphate, parathyroid hormone and active vitamin D. This system establishes the link between bone and kidney, as one of the kidney's endocrine functions is the activation of vitamin D, while electrolyte homeostasis is one of its excretory functions. Impaired renal function leads to disturbances in this regulatory system, resulting in the complex syndrome of renal osteodystrophy that affects the majority of patients with chronic renal failure. This review summarizes the current understanding of bone physiology on a molecular level, examines some of the pathological pathways related to renal disease, and concludes with an outlook on how the emerging field of systems biology may contribute to a more dynamic and quantitative understanding of the physiology and pathophysiology of renal bone disease.     

Surgical treatment of primary hyperparathyroidism in the elderly.

Twelve patients aged over 70 with primary hyperparathyroidism (persistent hypercalcaemia and raised serum parathyroid hormone concentrations) underwent parathyroidectomy, which was well tolerated by all. After operation serum calcium concentrations returned to normal and the commonest symptoms before operation (muscle weakness, malaise, and mild to severe dementia), although not related in severity to the degree of hypercalcaemia, improved. Mental function was greatly improved. The findings suggest that primary hyperparathyroidism should be sought in any elderly patient with hypercalcaemia and that more such patients with the diagnosis should be considered for parathyroidectomy irrespective of age.     

Effect of intravenous administration of cimetidine on renal excretion of calcium, phosphates, magnesium and adenosine cyclic monophosphate

An effect of cimetidine on parathyroid glands functioning in healthy subjects was evaluated. Serum calcium, phosphate, and magnesium concentrations together with renal excretion++ of these ions in healthy subjects as well as cAMP excretion++ in selected individuals were determined before and following intravenous administration of cimetidine (Altratmet Lek Ljublijana) in total dose of 500 mg (50 mg injected rapidly as a bolus following with 450 mg in an intravenous infusion during 60 minutes). No significant changes in serum calcium, phosphates, and magnesium concentrations were noted. Renal clearance of calcium and magnesium remained unchanged whereas renal phosphate excretion++ increased from 10.69 +/- 4.9 mL/min to 15.1 +/- 5.41 mL/min (p less than 0.02). Excretion++ of 3.5 cAMP increased from 2.65 +/- 2.19 nM/min to 5.16 +/- 2.0 nM/min (p less than 05). The obtained results do not exclude stimulating effect of intravenous cimetidine on parathyroid glands. Cimetidine given intravenously in the bleeding gastric or duodenal ulcers in the course of the primary hyperparathyroidism+ may decrease serum phosphate levels due to increased exretion of this ion with the urine.     

Surgically induced uremia in rats I: Effect on bone strength and metabolism

During the course of chronic renal failure (CRF) in man, renal osteodystrophy (osteitis fibrosa and/or osteomalacia) gradually develops. The present study aimed to establish a similar type of CRF leading to renal osteodystrophy in rats.During progressive CRF development over 225 days after 5/6 nephrectomy, the following serum variables were measured: creatinine, immunoreactive parathryoid hormone (iPTH), 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), a25-hydroxyvitamin D₃, (25(OH)D₃), alkaline phosphatase, albumin, phosphate, urea nitrogen, total calcium, and other blood electrolytes. Subsequent to sacrifice, mechanical properties of the rat femur, bone histomorphometry (osteoid and eroded surfaces) and bone contents of calcium, phosphate and hydroxyproline were also examined.Serum creatinine in rats with CRF gradually escalated by some 70%, while circulating 1,25(OH)₂D₃ was reduced beneath detection level. Total plasma calcium and phosphate concentrations were, however, almost unchanged indicating that PTH-induced bone remodeling due to moderate hyperparathyroidism sustained calcium homeostasis. Alkaline phosphatase levels were reduced by some 50%, which reflects chronically impeded bone formation. Bone histomorphometry assessment revealed substantial elevation of resorption with moderate accompanying fibrosis in about 70% of afflicted animals. Bone calcium, phosphate and hydroxpyroline contents remained unaltered. However, hydroxoproline/calcium ratio was marginally reduced. These results, together with altered mechanical bending stress characteristics and diminished diaphysis cross section area, confirm development of mixed bone lesions in the uremic animals.Our results are compatible with the early development of CRF in man. The established rat model is therefore useful in elucidating the precipitation and early treatment of renal osteodystrophy in humans.     

Calcium,Parathyroid Hormone,and Vitamin D in Patients with Primary Hyperparathyroidism: Normograms Developed from 10000 Cases

ObjectiveTo better define the typical and atypical biochemical profiles of patients with surgically proven primary hyperparathyroidism.MethodsIn this single-center, prospectively conducted study of consecutive patients with surgically proven primary hyperparathyroidism over a 7-year period, we analyzed serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations.ResultsA total of 10 000 patients were included, and more than 210 000 calcium, parathyroid hormone, and 25-hydroxyvitamin D values were evaluated. Both calcium and parathyroid hormone levels demonstrated a Gaussian distribution with the average calcium concentration being 10.9 ± 0.6 mg/dL and the average parathyroid hormone concentration being 105.8 ± 48 pg/mL. The average highest calcium and parathyroid hormone concentrations were 11.4 ± 0.7 mg/dL and 115.3 ± 50 pg/mL, respectively. At least 1 calcium value of 11.0 mg/dL was seen in 87% of patients, but only 21% had 1 or more calcium value above 11.5 mg/dL. Only 7% had a single serum calcium level reaching 12.0 mg/dL. Normocalcemic hyperparathyroidism was seen in just under 3% of patients who had identical findings at surgery. An average parathyroid hormone concentration less than 65 pg/mL was seen in 16%, with 10% of patients who had no high parathyroid hormone values. The average 25-hydroxyvitamin D concentration was 22.4 ± 9 ng/mL, with levels decreasing as calcium levels increased (P < .001); 36% had 25-hydroxyvitamin D levels below 20 ng/mL.ConclusionsPatients with PHPT present with a number of distinct biochemical profiles, but as a group, they present with a near-normal Gaussian distribution of both calcium and parathyroid hormone levels. Either serum calcium or parathyroid hormone remained normal in 13% of patients, yet the findings at surgery are similar to those of patients with elevated calcium or parathyroid hormone. Low 25-hydroxyvitamin D is an expected finding in patients with PHPT, decreasing as serum calcium levels increase. (Endocr Pract. 2011;17:384-394)     

Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1: comparison with sporadic parathyroid adenomas.

A prospective study on the natural course of primary hyperparathyroidism has recently been reported. Since hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is genetically distinct from most forms of sporadic hyperparathyroidism, it is important to know the natural course of hyperparathyroidism in MEN 1 for better clinical management. For this purpose, we retrospectively reviewed clinical parameters of patients with MEN 1 when they were diagnosed as having hyperparathyroidism, and compared them with those of patients with sporadic primary hyperparathyroidism. In patients with MEN 1: 1) levels of intact PTH (i-PTH) gradually increased with age, which accelerated over 40 years; 2) compared to the steep rise in i-PTH levels in aged patients, increase in serum calcium or decrease of serum inorganic phosphate concentration was relatively mild, and 3) the high concentrations of i-PTH in aged patients were not due to renal insufficiency. These features were not observed in patients with sporadic primary parathyroid adenomas. Clinical features of untreated hyperparathyroidism in MEN 1 may be significantly affected by the age of the patient. The effect, if any, of age-dependent deterioration on recurrence rate after subtotal or total parathyroidectomy requires further elucidation.     

西那卡塞治疗血液透析患者继发性甲状旁腺功能亢进症的临床研究

通过研究两个相同随机、双盲、安慰剂对照试验,本研究评估了拟钙剂盐酸西那卡塞治疗血液透析患者继发性甲状旁腺功能亢进症的临床效果。将接受血液透析及进行标准治疗仍控制不佳的继发性甲状旁腺功能亢进患者随机分配接受西那卡塞(80名患者)或安慰剂(80名患者)治疗26周。每日一次的剂量从30 mg增加到180 mg,以达到患者体内每毫升250 mg或更少的完整甲状旁腺激素水平。主要终点是进行为期14周的疗效评估阶段的患者在该范围内的值的百分比。西那卡塞组有43%的患者达到主要终点,而安慰剂组仅为5%(p<0.001)。总体而言,接受西那卡塞治疗的患者平均甲状旁腺激素水平下降43%,而安慰剂组平均甲状旁腺激素水平下降9%(p<0.001)。西那卡塞组患者体内血清钙磷乘积下降15%,安慰剂组则维持不变(p<0.001)。西那卡塞可有效降低甲状旁腺激素水平,而不依赖于疾病严重程度或维生素D甾醇剂量的变化。西那卡塞可降低接受血液透析的不受控制继发性甲状旁腺功能亢进症患者体内的甲状旁腺激素水平,提高钙磷稳态。