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.     

Intramuscular calcitriol for uraemic children with severe hyperparathyroidism and hypercalcaemia

The effect of intramuscular calcitriol was evaluated in five children (aged 1–16 years) with severe chronic renal failure and hyperparathyroidism [range of intact parathyroid hormone (PTH) 400–1,200 pg/ml]. All five children had been on oral calcitriol or 1-hydroxyvitamin D₃ treatment (5–20 ng/kg per day), but an adequate, efficacious dosage could not be achieved since any attempt of increasing the dosage resulted in severe hypercalcaemia (>2.9 mmol/l). Intramuscular calcitriol was given three times weekly for 5 months at an initial dosage of 65–70 ng/kg to all but one patient who received 100 ng/kg. In the first three patients, treatment resulted in an 86%–98% fall in serum PTH compared with baseline levels and serum calcium never exceeded 2.65 mmol/l, except for one episode of hypercalcaemia in one patient. In the last two patients, serum calcium rose above normal limits, thus calcitriol had to be discontinued several times and then restarted at a lower dosage (40 ng/kg); PTH fell by 61% and 73%, respectively, compared with basal values. All patients had very low pre-treatment levels of serum 1,25-dihydroxyvitamin D₃ (5–15 pg/ml) which were normalized (35–56 pg/ml) by the intramuscular calcitrioltreatment. Serum phosphorus and magnesium did not vary in any of the five patients. No side effects were observed at the injection site. Intramuscular calcitriol seems a useful therapeutic option for patients with severe hyperparathyroidism associated with a high serum calcium level when treated with conventional oral calcitriol.     

肾性骨病的矿物代谢与调节激素关系

本文报道肾性骨营养不良和钙、磷与调节激素变化的关系．８２例中男性４３例，女性３９例。发病年龄８～７１岁，平均４４岁。病程１～１０年，平均３．２±１．４年。骨质变化以骨质疏松３９例占多数，其次为骨软化和／或佝偻病２３例，其它有纤维囊性骨炎１０例，骨硬化１０例。其中１８例骨畸形和１５例骨折。血钙平均值低于正常（１．５４±０．４１ｍｍｏ１／Ｌ），血磷升高（１．７９±０．７６ｍｍｏ１／Ｌ），２４小时尿钙与尿磷减少。血清甲状旁腺激素（ＰＴＨ）、降钙素（ＣＴ）、骨钙素（ＢＧＰ）、酸性磷酸酶（ＡＣＰ）、抗酒石酸酸性磷酸酶（ＴｒＡＣＰ）、碱性磷酸酶（ＡＫＰ）、血清尿素氮（ＢＵＮ）与血清肌酐（Ｃｒ）均升高，且差异具有显著性（Ｐ＜０．０５～０．０１）。     

Growth hormone and renal osteodystrophy: a case report

A 14-year-old male with end-stage renal disease on hemodialysis was treated with recombinant growth hormone for growth retardation. He developed severe renal osteodystrophy, which responded only to the discontinuation of growth hormone. Received January 24, 1997; received in revised form August 19, 1997; accepted August 22, 1997     

Bone histomorphometry in children prior to commencing renal replacement therapy

Renal osteodystrophy (ROD) develops early in the course of chronic kidney disease (CKD). With improving patient survival it's importance and relevance has increased. The last published bone biopsy data in children prior to renal replacement therapy (RRT) was in 1982, which demonstrated abnormal histology in all patients with a glomerular filtration rate (GFR) <20 ml/min per 1.73 m(2). Studies investigating the relationship between bone histology and parathyroid hormone levels (PTH) and/or growth in children with CKD are few (seven). These were mostly undertaken in patients already initiated on RRT-dialysis. We investigated the presence of ROD in children at the commencement of RRT and to investigate any relationship between histology, growth and PTH levels. Following double tetracycline labelling, bone biopsies were taken from patients at the time of RRT surgery. Histological classification was based on the newly proposed turnover/mineralisation/volume (TMV) system. Eleven patients underwent bone biopsy. Patients were followed for an average of 1.1 years (0.5-1.8) prior to biopsy over an average of eight clinic visits (3-14), when routine biochemical data were collected. Time-integrated median calcium, phosphate and PTH levels were calculated. PTH levels were within the normal range in two patients with low turnover, 1.1-1.4 times the upper limit of normal (ULN) in three with mixed osteodystrophy and >2.9 times the ULN in four patients with high bone turnover. There was no relationship between bone turnover and growth. The presence of ROD was universal in these children with severe CKD. Low bone turnover was associated with normal-range mean PTH levels, and high bone turnover occurred at lower PTH levels than current guidelines would suggest.     

Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines

Childhood renal osteodystrophy (ROD) is the consequence of disturbances of the calcium-regulating hormones vitamin D and parathyroid hormone (PTH) as well as of the somatotroph hormone axis associated with local modulation of bone and growth cartilage function. The resulting growth retardation and the potentially rapid onset of ROD in children are different from ROD in adults. The biochemical changes of ROD as well as its prevention and treatment affect calcium and phosphorus homeostasis and are directly associated with the development of cardiovascular disease in pediatric renal patients. The aims of the clinical and biochemical surveillance of pediatric patients with CRF or on dialysis are prevention of hyperphosphatemia, avoidance of hypercalcemia and keeping the calcium phosphorus product below 5 mmol²/l². The PTH levels should be within the normal range in chronic renal failure (CRF) and up to 2–3 times the upper limit of normal levels in dialysed children. Prevention of ROD is expected to result in improved growth and less vascular calcification.The authors are members of the European Pediatric Dialysis Working Group (EPDWG)     

Is severe renal osteodystrophy a contraindication for recombinant human growth hormone treatment?

Recent extension of the use of recombinant growth hormone (rhGH) to non-growth hormone-deficient patients necessitates close attention to possible complications in these patients, including effects on bone. Recent studies on the use of rhGH in children with chronic renal failure (CRF) provide some early data. No significant differences in radiographic osteodystrophy scores, serum calcium, phosphorus, or parathyroid hormone (PTH) levels were found between treated and untreated groups. Alkaline phosphatase increased transiently. The effect of renal osteodystrophy on growth response has not yet been reported. Animal models demonstrate that GH stimulates chondrocyte proliferation. Experimental data further suggest that GH can weaken the epiphyseal plate. Slipped capital femoral epiphysis has been reported in GH-deficient patients, before, during, and after GH therapy. In CRF patients treated with GH, slipped capital femoral epiphysis has also been reported. As renal osteodystrophy and hypocalcemia are risk factors for this condition, the relationship to GH therapy is unclear in these patients. Avascular necrosis, known to be associated with slipped capital femoral epiphysis and CRF, has also been reported in patients receiving GH, although the relationship to the therapy is unknown. Children with CRF treated with rhGH should be serially monitored for renal osteodystrophy, slipped capital femoral epiphysis, and avascular necrosis with serial radiographs and serum calcium, phosphorus, alkaline phosphatase, and PTH levels.     

Recent advances and controversies in childhood renal osteodystrophy

Renal osteodystrophy starts very early in chronic renal failure. Although vitamin D levels are normal in patients with 70–80% function, the levels are not appropriate to the prevailing biochemical milieu. Renal osteodystrophy may contribute to renal growth failure but a correlation between the degree of renal osteodystrophy and growth failure is not observed. Catch-up growth cannot be obtained over a longer period of time with vitamin D. The main reason for osteomalacia is Al intoxication. Aluminium osteopathy is more common in pediatric renal patients than anticipated. The mechanism whereby Al produces its effect on bone is uncertain. Guidelines for the diagnosis and therapy of renal osteopathy are presented. Prophylaxis of renal osteopathy can be attempted by phosphate restriction and/or vitamin D and by avoiding Al-containing drugs. All vitamin D compounds can be used for treatment and all have their advantages and disadvantages.     

Intestinal calcium absorption,serum phosphate,and parathyroid hormone in patients with chronic renal failure and osteodystrophy before and during hemodialysis

Summary In 34 patients with chronic renal failure (CRF), fractional⁴⁷calcium absorption (Fa⁴⁷Ca) was measured by an external counting method. A significant correlation was found with impairment of renal function, as expressed by the creatinine clearance. There was also a significant correlation of Fa⁴⁷Ca with the serum phosphate (SeP) level and of immunoreactive parathyroid hormone (iPTH) with renal function. When the relationship of both SeP and Fa⁴⁷Ca with creatinine clearance was excluded, no partial correlation between SeP and Fa⁴⁷Ca appeared to exist. A significant increase of Fa⁴⁷Ca and serum Ca and a significant decrease of SeP and iPTH were found in 12 patients 2 to 15 months after they were put on intermittent hemodialysis. The possible influence of SeP on intestinal calcium absorption is discussed, and it is suggested that impairment of intestinal absorption of calcium is not a main factor in development of renal osteodystrophy.     

The novel bone alkaline phosphatase B1x isoform in children with kidney disease

The bone alkaline phosphatase (BALP) B1x isoform has previously only been identified in some adults with chronic kidney disease on dialysis and in human bone tissue. Twenty-nine patients, 3–20 years of age, with reduced renal function due to a variety of kidney diseases were examined. We measured parathyroid hormone (PTH), biointact (whole 1-84) PTH, osteoprotegerin (OPG), CrossLaps (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) type I procollagen intact amino-terminal propeptide (PINP), osteocalcin, total alkaline phosphatase (ALP), and BALP isoforms B/I, B1x, B1, and B2. Fifty percent higher levels were detected of PTH vs. biointact PTH, demonstrating non-(1-84) PTH fragments detected by the PTH assay. Increased activities were found in five, four, and three patients for total ALP, B1, and B2, respectively. Sixteen (55%) patients had increased B/I levels. B1x was identified in two (7%) patients, who had OPG levels in the higher range independently of age, glomerular filtration rate (GFR), and biointact PTH. B1x was identified prior to and after 9 days of growth hormone (GH) therapy in one patient but not after 1, 3, 6, and 12 months, however. In conclusion, our study demonstrates that the novel BALP B1x isoform is occasionally found to be present in children with kidney disease but to a lesser degree in comparison with adults with chronic kidney disease on dialysis. It is essential to perform bone histomorphometry for future investigations in order to elucidate the exact nature of circulating B1x in patients with kidney disease for accurate classification of type of renal bone disease.     

Calcitriol pulse therapy is not more effective than daily calcitriol therapy in controlling secondary hyperparathyroidism in children with chronic renal failure

Calcitriol oral pulse therapy has been suggested as the treatment of choice for secondary hyperparathyroidism, but its efficacy and safety are still under discussion. The present randomized multicenter study compares the effect of an 8-week course of daily versus intermittent (twice weekly) calcitriol therapy on parathyroid hormone (PTH) suppression in 59 children (mean age 8.4±4.7 years) with chronic renal insufficiency (mean C_cr 22.4±11.6 ml/min per 1.73 m²) and secondary hyperparathyroidism. After a 3-week washout period, the patients were randomly assigned to treatment with daily oral calcitriol (10 ng/kg per day) or intermittent oral calcitriol (35 ng/kg given twice a week). The calcitriol dose was not changed throughout the study period of 8 weeks. At start of the study, the median intact PTH (iPTH) level was 485 pg/ml (range 83–2032) in the daily group (n=29) and 315 pg/ml (range 93–1638) in the intermittent group (n=30). After 8 weeks, the respective median iPTH concentrations were 232 pg/ml (range 63–1614) and 218 pg/ml (range 2–1785) (ns). The mean iPTH decrease from baseline was 19.2±57.8% and 13.7±46.7% respectively (not significant). Calcitriol reduced the iPTH concentration in 23/29 patients in the daily group and in 21/30 in the intermittent group. One episode of hypercalcemia (>11.5 mg/dl) was observed in both groups and a single episode of hyperphosphatemia (>7.5 mg/dl) was observed in the daily group. It is concluded that oral calcitriol pulse therapy does not control secondary hyperparathyroidism more effectively than the daily administration of calcitriol in children with chronic renal failure prior to dialysis. Received: 29 September 1999 / Revised: 2 February 2000 / Accepted: 9 February 2000     

Multiple endocrine neoplasia type 1 in end-stage renal failure

A 59-year-old woman with chronic renal failure due to type 2 diabetes mellitus (DM) is presented. Her father and a brother had a history of brain tumor. Her blood urea nitrogen and serum creatinine levels were 102mg/dl and 4.5mg/dl, respectively. Her serum Ca²⁺ and Pi were within the normal range (9.4mg/dl and 5.4mg/dl, respectively). Her intact parathyroid hormone (PTH) level was 1730000pg/ml. A ^99mTc-methoxy-isobutylisonitrile scintigraphy showed high uptake in three parathyroid glands. A magnetic resonance image showed microadenoma in the pituitary gland. The serum gastrin level was high. Genetic examination revealed a mutation of the MEN1 gene (894–9 G A). From these findings, she was diagnosed with multiple endocrine neoplasia (MEN) type 1. Subsequently, a parathyroidectomy was performed successfully, a parathyroid gland was transplanted to her right forearm, and her serum Ca²⁺ level was controlled at 8.5–9.0mg/dl. It is very important to identify MEN1 if an end-stage renal disease (ESRD) patient has hyperparathyroidism with multigland involvement. Examination of the MEN1 gene may be valuable to make an accurate diagnosis and choose the appropriate therapy in some ESRD patients with hyperparathyroidism.     

Potential factors regulating serum parathyroid hormone in maintenance hemodialysis patients: 4-year retrospective study

Background. This study was carried out to evaluate potential factors affecting long-term parathyroid function in patients on maintenance hemodialysis. Methods. Biochemical parameters, including intact parathyroid hormone (i-PTH) and intact osteocalcin (i-OC) were analyzed retrospectively in 120 outpatients receiving hemodialysis, for the 4 years between 1992 and 1996. Patients were classified into the following three groups according to their serum i-PTH levels in 1996: low PTH (<100 pg/ml), normal PTH (100–450 pg/ml), and high PTH (≧450 pg/ml). Results. Among the three PTH groups, no differences were found in age, sex, duration of dialysis, and laboratory parameters, except for serum levels of alkaline phosphatase (ALP), i-PTH, and i-OC. The percentage of diabetic patients was higher in the low PTH group than in the other two PTH groups. Both serum ALP and i-PTH levels increased in the high PTH group, and serum i-PTH level decreased in the low PTH group during the 4 years. The change in serum calcium (Ca) level was negatively correlated with that in serum i-PTH level (1994–1996, r = −0.623, 1992–1996, r = −0.565; P <0.0001). A higher correlation coefficient was observed in the low PTH group than in the other PTH groups, although the difference was not significant. A weak positive correlation of the changes in serum inorganic phosphorus (IP) level (1994–1996) and i-PTH level (1994–1996) was found in the high PTH group (r = 0.379, P < 0.05). Conclusion. Serum Ca level may play a determinant role in suppressing serum i-PTH level in hemodialysis patients. Serum IP level may stimulate serum i-PTH level in patients with hyperparathyroidism, although the physiological role of serum IP is yet to be established. Received: March 23, 1999 / Accepted: September 1, 1999     

小剂量钙三醇对慢性肾衰竭继发性甲旁亢早期的疗效研究

目的:研究小剂量口服罗盖全治疗慢性肾衰竭(CRF)继发性甲旁亢(SHPT)早期患者的疗效和副作用.方法:将观察期间(3～12个月)血清全段甲状旁腺激素(iPTH)浓度动态升高且高达正常值3～5倍的180名CRF患者随机分为A、B两组,A组予罗盖全0.125 μg/d, B组予罗盖全0.25 μg/d口服,以血清 iPTH浓度降至正常值2.5倍即160 ng/L为观察终点;另将血清iPTH浓度高达正常值5倍以上的153例患者随机分为C、D两组,C组予罗盖全0.5 μg/d上午口服,D组以相同剂量于晚上10 h口服,以血清iPTH浓度降至正常值3倍即195 ng/L为观察终点.以到达终点的例数和时间为指标判断疗效,分别比较A、B两组及C、D两组疗效和高钙血症等副作用.结果:各组均取得良好疗效.B组有效率90.91%,明显高于A组的57.30%(P<0.01),B组到达终点时间(8.66±3.2)个月,明显早于A组(15.24±3.7)个月(P<0.01).C、D两组疗效相近,有效率分别为86.89%和84.29%(P>0.05),到达终点的时间分别为(9.51±3.1)个月和(9.97±2.9)个月(P>0.05).各组均无发生血清iPTH浓度过低(<130 ng/L).A、B两组极少发生高钙血症,发生率分别为1.11%和2.22%;D组高钙血症发生率为9.72%,明显低于C组的32.88%(P<0.01).各组肝肾功能稳定.结论:根据血清iPTH水平给予小剂量(0.125～0.5 μg/d)罗盖全治疗早期SHPT安全、有效而且经济,0.5 μg/d罗盖全于夜间使用可以减少高钙血症发生率.     

Calcitriol administration in end-stage renal disease: intravenous or oral?

1,25-Dihydroxyvitamin D deficiency plays an important role in the pathogenesis of secondary hyperparathyroidism, and adequate replacement of this hormone is considered essential to normalize parathyroid gland function and restore bone homeostasis in patients with advanced renal failure. Although initial uncontrolled clinical trials suggested the superiority of intravenous calcitriol treatment, more recent controlled investigations show that different routes (oral versus intravenous), frequency (daily versus intermittent), and dosing (physiological versus pharmacological) of calcitriol administration are clinically equivalent. Overall, the response to calcitriol treatment depends more on the severity of secondary hyperparathyroidism and the presence of confounding variables, such as hyperphosphatemia and acquired abnormalities of parathyroid cell function, than the method of calcitriol administration.     

Spinal cord compression in renal osteodystrophy

Summary A patient undergoing regular haemodialysis for chronic renal insufficiency developed neck pain followed by progressive spinal cord compression due to subluxation at the level C3-4. Decompression, laminectomy and osteosynthesis led to an almost complete recovery. A review of all the histological specimens suggested that hyperparathyroidism and not amyloidosis caused the vertebral destruction.     

Strontium oral load test in children with idiopathic hypercalciuria

Increased intestinal calcium absorption may play an important role in the pathogenesis of idiopathic hypercalciuria in children. Calcium absorption was assessed by an oral strontium load test in 22 prepubertal children (13 male) with idiopathic hypercalciuria, urinary calcium excretion 6.48 ± 0.60 mg/kg per day (range 4.12–13.40 mg/kg per day), and ten healthy, young, normocalciuric controls (six male). After administration of 2.65 mg/kg of strontium chloride (SrCl₂), the serum concentrations of strontium at 30 min, 60 min, 120 min, 240 min, and the fraction of the absorbed dose (FAD%) at 30 min, 60 min and 240 min, were similar in both groups. FAD% at 120 min was lower (P < 0.05) in hypercalciuric children than in controls (11.84 ± 0.96% vs 15.87 ± 1.77%). Values of the area under the curve were not different between both groups. In children with idiopathic hypercalciuria, serum basal intact parathyroid hormone (PTH) (r = −0.59, P = 0.004) and the 1,25-dihydroxyvitamin D/PTH ratio (r = 0.65; P = 0.001) were correlated with the serum concentration of strontium at 60 min. The study reported here provides, for the first time, the results of a strontium oral load test in children with idiopathic hypercalciuria. With this method no major alterations of intestinal calcium absorption were found in this disorder.