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     

Subtotal Parathyroidectomy in Renal Failure: Still Needed after All These Years

There are scant data on the frequency of parathyroidectomy (PTX) for end-stage renal disease (ESRD). Medical therapy for ESRD and secondary hyperparathyroidism has evolved to include better dialytic urea removal and the use of calcitriol. The aim of this study was to determine whether medical therapy has changed the frequency or indications for PTX in the management of renal failure. Hospital and clinic records were analyzed to gather information on all patients undergoing PTX for secondary hyperparathyroidism (2HPT) (n= 48) and tertiary hyperparathyroidism (3HPT) (n= 26) from 1986 through 1998 at our institution. Prospective computer databases were queried for information concerning both chronic dialysis and renal transplant patients at our center. The patients were divided based on date of operation before or after 1991, a divider that separated the patients into groups before or after the widespread adoption of intravenous calcitriol treatment during hemodialysis at our institution. Over the 12 year period, the proportion of our chronic dialysis patients undergoing PTX did not change significantly, ranging from 0% to 2.5% per year. Comparing all patients undergoing PTX for 2HPT during 1986–1991 versus 1992–1998, there was no significant difference in time on dialysis [7.0 ± 4.2 (n= 11) vs. 7.5 ± 4.6 (n= 36) years, mean ± SD]. The later group had higher intact parathyroid hormone (iPTH) levels [765 ± 415 (n= 6) vs. 1377 ± 636 (n= 28) pg/ml; p= 0.03], lower serum calcium [11.2 ± 1.0 (n= 12) vs. 9.9 ± 1.5 (n= 34) mg/dl; p= 0.006], and higher serum phosphate [5.7 ± 1.6 (n= 12) vs. 7.2 ± 2.3 (n= 31) mg/dl; p= 0.042]. Among the population of patients with transplants undergoing PTX for 3HPT, the average percent per year undergoing PTX ranged from 0% to 4.2% and did not change during the study period. Comparing the 1986–1991 group to the 1992–1998 group, the time from transplantation to PTX did not change during the study period (3.3 ± 2.3 vs. 2.9 ± 3.0 years; p= 0.391), and there were no significant differences between preoperative calcium levels or iPTH levels. Despite advances in dialysis technique and pharmacologic therapy, there has been no change in the proportion of dialysis patients requiring PTX for 2HPT or 3HPT. There was also no change in the time on dialysis for patients with 2HPT or the time from transplant to PTX for patients with 3HPT. Analysis of preoperative biochemical markers as evidence of disease severity suggests there was no change in indications for PTX during our study. From this information we conclude that parathyroid pathophysiology is incompletely understood and medical therapy is not optimal, resulting in a continuing need for PTX in some patients.     

Local Calcitriol Injections as a Suppressive Treatment of Secondary Hyperparathyroidism in Chronic Dialysis Patients

Aim. A prospective study was made of the effectiveness of repeatable local calcitriol injections therapy to suppress secondary hyperparathyroidism resistant to conventional therapy in chronic dialysis patients. Methods. Under ultrasonographic guidance, six injections at an interval of two days were performed in 14 chronic dialysis patients. The total amount of calcitriol to be injected each time was estimated as 100% of the calculated gland volume. Calcitriol was given in doses 1 μg of medicine per 1 cubic cm (as measured by USG) of parathyroid tissue. Parathormone concentration, total calcium, ionized calcium, phosphate, and alkaline phosphatase levels were assessed on the first and last day of the treatment period. Results. Prior to therapy, the mean gland volumes were 0.62 (0.15–3.0) ml, and they increased to 0.85 (0.2–3.9) after 14 days (NS). Seven patients were found to have decreased their PTH levels to 909 ± 387 pg/mL after 14 days of treatment when compared with the first day mean values of 1588 ± 440 pg/mL (p < 0.05). After completion of the therapy, four patients were reported to be free from any clinical symptoms of ostalgia or arthralgia. Others reported an alleviation of pain. Conclusions. Parathyroid adenoma injection is an alternative method of treatment for some patients resistant to treatment by means of vitamin D3 pulses or intravenous administration of calcitriol. The success of treatment is to a great extent determined by proper selection of patients and the taking of decisions when the period of secondary hyperparathyroidism is not very advanced.     

1.25 (OH)2 cholecalciferol pulse therapy and the effects of different dialysis membranes on serum PTH levels of haemodialysis patients

Either oral, intravenous or subcutaneous 1.25 (OH)₂ cholecalciferol is used in the therapy of hyperparathyroidism, which is a serious complication in patients on haemodialysis. We studied a total of 30 patients (10 women and 20 men) and divided them into two groups depending on the different types of dialysis membranes used. In the poly sulfone group, mean age was 43.7±0.97 years and the average dialysis period lasted 29.9±1.23 months. For the 15 cases in which we used cuprophane membrane the mean age was 40.2±1.31 years and the average dialysis period lasted 16.2±0.86 months. The calcium level of the dialysate in both groups was 1.5 mmol/l. According to the study protocol, the determined oral calcitriol dose was 0.07 mg/kg and it was administered intermittently. After one month on high dose calcitriol therapy, treatment was continued with a maintenance dose of 0.03 mg/kg for a further six months. As a phosphate binding agent, daily 3 g calcium carbonate was administered. Before starting this treatment protocol, patients went on a 1 mg/day calcitriol therapy, although the mean PTH level was 424.63 pg/ml and the mean serum alkaline phosphatase level was 290.2 U/l. During the pretreatment period, levels of PTH, alkaline phosphatase, ionized calcium, and total calcium remained significantly within normal limits as a result of the new therapy protocol applied. PTH and phosphorus clearance rates were compared in the patient groups in which different dialysis membranes had been used. PTH and phosphorus clearances were 15.2±3 ml/min and 239.1±19.2 ml/min, respectively, in the polysulfone membrane group, and 1.1±0.3 ml/min and 112.8±9.88 ml/min, respectively, in the cuprophane membrane group (p<0.05).     

Pharmacokinetics of calcitriol in continuous ambulatory and cycling peritoneal dialysis patients

Oral calcitriol is commonly used for the treatment of secondary hyperparathyroidism in patients undergoing long-term dialysis, but it has been suggested that intravenous (IV) or intraperitoneal (IP) administration enhances the therapeutic efficacy of the sterol. To examine potential mechanisms for this difference, the bioavailability of calcitriol was evaluated after single oral (PO), IV, and IP doses of 60 ng/kg in each of six adolescent patients with osteitis fibrosa undergoing continuous ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis (CCPD). Serum calcitriol levels were 3.6 +/- 4.3, 8.2 +/- 7.5, and 2.5 +/- 3.0 pg/mL, respectively, before IV, PO, and IP doses of the sterol; these values increased to similar levels at 24 hours: 55.6 +/- 14.6 pg/mL after PO, 56.4 +/- 17.6 pg/mL after IV, and 53.8 +/- 20.1 pg/mL after IP. Serum calcitriol levels were higher 1, 3, and 6 hours after IV injections than after PO or IP doses; values thereafter did not differ among groups. The bioavailability of calcitriol, determined from the 24-hour area under the curve (AUC0-24) for the increase in serum calcitriol concentration above baseline values was 50% to 60% greater after IV, 2,340 +/- 523 pg.mL-1.h-1, than after PO, 1,442 +/- 467 pg.mL-1.h-1, or IP, 1,562 +/- 477 pg.mL-1.h1, dosages, P less than 0.05. These differences were due to higher values for AUC during the first 6 hours after calcitriol administration. Although IP calcitriol did not increase sterol bioavailability, radioisotope tracer studies indicated that 35% to 40% of the hormone adheres to plastic components of the peritoneal dialysate delivery system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sevelamer controls parathyroid hormone-induced bone disease as efficiently as calcium carbonate without increasing serum calcium levels during therapy with active vitamin D sterols

Little is known about the impact of various phosphate binders on the skeletal lesions of secondary hyperparathyroidism (2 degrees HPT). The effects of calcium carbonate (CaCO3) and sevelamer were compared in pediatric peritoneal dialysis patients with bone biopsy-proven 2 degrees HPT. Twenty-nine patients were randomly assigned to CaCO3 (n = 14) or sevelamer (n = 15), concomitant with either intermittent doses of oral calcitriol or doxercalciferol for 8 mo, when bone biopsies were repeated. Serum phosphorus, calcium, parathyroid hormone (PTH), and alkaline phosphatase were measured monthly. The skeletal lesions of 2 degrees HPT improved with both binders, and bone formation rates reached the normal range in approximately 75% of the patients. Overall, serum phosphorus levels were 5.5 +/- 0.1 and 5.6 +/- 0.3 mg/dl (NS) with CaCO3 and sevelamer, respectively. Serum calcium levels and the Ca x P ion product increased with CaCO3; in contrast, values remained unchanged with sevelamer (9.6 +/- 01 versus 8.9 +/- 0.2 mg/dl; P < 0.001, respectively). Hypercalcemic episodes (>10.2 mg/dl) occurred more frequently with CaCO3 (P < 0.01). Baseline PTH levels were 980 +/- 112 and 975 +/- 174 pg/ml (NS); these values decreased to 369 +/- 92 (P < 0.01) and 562 +/- 164 pg/ml (P < 0.01) in the CaCO3 and the sevelamer groups, respectively (NS between groups). Serum alkaline phosphatase levels also diminished in both groups (P < 0.01). Thus, treatment with either CaCO3 or sevelamer resulted in equivalent control of the biochemical and skeletal lesions of 2 degrees HPT. Sevelamer, however, maintained serum calcium concentrations closer to the lower end of the normal physiologic range, thereby increasing the safety of treatment with active vitamin D sterols.     

Paricalcitol versus calcitriol treatment for hyperparathyroidism in pediatric hemodialysis patients

Secondary hyperparathyroidism (SHPT) remains a treatment dilemma in pediatric dialysis patients. Recent experience with paricalcitol (P), a vitamin D analogue, in adults with SHPT has shown equal efficacy and improved survival compared to traditional treatment with calcitriol (C). We present our experience with (C) compared to (P) treatment in our pediatric dialysis patients with SHPT. Twenty-one patients (mean age 11.5±5 years) with SHPT (intact parathyroid hormone (iPTH) averaging 1,228±496 pg/ml) were studied. Seventeen received (C) followed by (P); while an additional four were treated with either (C=1) or (P=3) alone. After 26±8 weeks, average percent (%) decrease in iPTH was similar with (C) and (P) (−60.4±34% versus −65.4±28%, respectively; p=0.6). In the (P) group, the effective dose in children was greater than in adult trials based on kilogram weight. Episodes of hypercalcemia between the treatment groups were not different. However, episodes of elevated calcium × phosphorus product (Ca×P)≥70 mg²/dl² occurred more frequently in the (C) group (odds ratio=1.5; p=0.01). Paricalcitol appears to be safe and effective in pediatric patients. Data suggest that dosing should be gauged according to degree of SHPT. This should serve as impetus for future pharmacokinetic studies in pediatric dialysis patients.     

Effect of the mode of calcitriol administration on PTH-ionized calcium relationship in uraemic patients with secondary hyperparathyroidism

To assess the effect of the different modes of calcitriol administrationon PTH-ionized calcium relationship we conducted a prospectiveclinical trial in 33 patients on chronic haemodialysis withsecondary hyperparathyroidism (four times upper normal limitintact PTH) who were randomly assigned, with stratificationto PTH levels, to receive daily oral, intermittent oral, orintermittent intravenous calcitriol at the same dose of 0.045µg/kg/weekly. PTH-iCa curves were generated by inducinghypo- or hypercalcaemia in sequential haemodialysis 1 week apart,before and after 10 weeks on treatment. All patients were dialysedagainst a dialysate calcium concentration of 2.5 mEq/l throughoutthe study period. After drop-outs, 26 patients completed the study: 11 on intravenouscalcitriol (mean basal PTH±SD: 666±280 pg/ml),eight on intermittent oral calcitriol (mean basal PTH: 831±361),and seven on daily oral calcitriol (mean basal PTH: 719±280).Serum ionized calcium and phosphorus significantly increasedin intravenous and daily oral groups after calcitriol treatment,but not in the intermittent oral group. Basal PTH did not significantlychange in the three groups after 10 weeks on treatment. MaximalPTH significantly decreased in intravenous group (1449±660versus 1122±691 pg/ml, P=0.0085) and at the limit ofstatistical significance in the intermittent oral group (1701±774versus 1445±634, P=0.12), but it did not change in thedaily oral group. Minimal PTH did not modify in the three groups.In all three groups, a shift to the right in the PTH-iCa relationshipswere observed, with significant changes in the set point ofcalcium. The slope of the post-treatment curves only becameless steep in the intermittent oral and intravenous groups. In conclusion, intermittent administration of calcitriol seemsto be more effective in reducing maximal PTH than daily oraladministration, but at the conditions under which this studywas carried out all the modes of calcitriol administration shiftedPTH-iCa relationships to the right.     

The effect of long-term intravenous calcitriol administration on parathyroid function in hemodialysis patients.

Secondary hyperparathyroidism is common in dialysis patients. Intravenous calcitriol has proven to be an effective therapy for the reduction of parathyroid hormone (PTH) levels. However, the effect of i.v. calcitriol on parathyroid function, defined as the sigmoidal PTH-calcium curve developed during hypocalcemia and hypercalcemia, has not been evaluated during the prolonged administration of i.v. calcitriol. Six hemodialysis patients with marked secondary hyperparathyroidism, PTH levels greater than 500 pg/mL (normal, 10 to 65 pg/mL), were treated for 42 wk with 2 micrograms of i.v. calcitriol after each hemodialysis. Parathyroid function was evaluated before and after 10 and 42 wk of calcitriol therapy. Between baseline and 42 wk, the basal PTH level decreased from 890 +/- 107 to 346 +/- 119 pg/mL (P less than 0.02) and the maximally stimulated PTH level decreased from 1293 +/- 188 to 600 +/- 140 pg/mL (P less than 0.01). In addition, calcitriol administration significantly decreased PTH levels throughout the hypocalcemic range of the PTH-calcium curve. Although the slope of the PTH-calcium curve (with maximal PTH as 100%) decreased between baseline and 42 wk (P less than 0.05), the set point of calcium did not change. Two patients with a decrease in both basal and maximally stimulated PTH levels after 10 wk of calcitriol, developed marked hyperphosphatemia between 10 and 42 wk; this resulted in an exacerbation of hyperparathyroidism despite continued calcitriol therapy. In conclusion, prolonged i.v. calcitriol administration is an effective treatment for secondary hyperparathyroidism in hemodialysis patients provided that reasonable control of the serum phosphate is achieved. In addition, the slope of the PTH-calcium curve may be a better indicator of parathyroid cell sensitivity than the set point of calcium.     

Beneficial role of intravenous calcitriol on bone mineral density in children with severe secondary hyperparathyroidism

Objectives: In this prospective study, the effect of calcitriol therapy on bone mineral density and osteopenia in patients with severe secondary hyperparathyroidism has been investigated. Materials and methods: The study was carried out on 24 chronic dialysis patients consisting of 13 boys and 11 girls, aged between 8–18 years. Patients were divided into 3 groups according to the severity of hyperparathyroidism and therapy regimens. Group I consisted of 5 patients with normal parathormon levels who did not receive calcitriol therapy. In group II and III, there were patients with secondary hyperparathyroidism. Group II consisted of 10 patients receiving oral calcitriol therapy. Group III consisted of 9 patients receiving intravenous (IV) calcitriol. Bone mineral density was measured by dual energy x-ray absorptiometry. Osteopenia was defined as a Z-score worse than −2. Bone mineral density was assessed as baseline and at the end of one year. Results: A significant improvement was observed in Z-score in the group III whereas the mean value of Z-score tended to be worse in group I and it was not significantly different in group II from the initial values. The better Z-score in group III was associated with more effective stabilization of alkaline phosphatase level and bone specific alkaline phosphatases (BAP) concentrations. Conclusion: Significant improvement of Z-score in group III suggested the beneficial role in IV administration of calcitriol in chronic dialysis patients. This revised version was published online in August 2006 with corrections to the Cover Date.     

Safety and efficacy of pulse and daily calcitriol in patients on CAPD: a randomized trial

Background: Calcitriol therapy is the mainstay of therapy for the treatment of secondary hyperparathyroidism. Oral administration of calcitriol is necessary in CAPD patients, but no studies have directly compared different routes of administration in this patient population. Methods: To determine if the peak serum calcitriol level (pulse therapy) is more important than the total delivered dose, we randomized CAPD patients with mild to moderate secondary hyperparathyroidism to receive either pulse (3.0 &mgr;g twice a week, n=10) or daily (0.75 &mgr;g a day, n=8) oral calcitriol in comparable weekly doses. The main comparison was the rate of decline of serum intact parathyroid hormone (PTH) levels to reach the desired end-point of 100 pg/ml. The patients were dialysed with low-calcium dialysate and received only calcium-containing phosphate binders. Results: Pharmacokinetic analysis after a single dose of 3.0 &mgr;g (pulse) vs 0.75 &mgr;g (daily) revealed 1,25(OH)2-vitamin D levels to be higher in the pulse group at 3 and 6 h, but equivalent by 12 h. The area under the curve for 1 week of daily and 1 week of pulse therapy was equal. The patients in the 2 arms had equivalent basal serum levels of PTH (pulse=562±291 vs daily=454±113 pg/ml), calcium (pulse=2.32±0.20 vs daily=2.32±0.12 mmol/l) and phosphorus (pulse=1.32±0.52 vs daily=1.35±0.26 mmol/l). The time required for the PTH to decrease to 100 pg/ml and rate of decline in PTH were similar (time: pulse=14.2±6.8 weeks, daily=12.2±7 weeks; rate: pulse=7.4±4.2 vs daily=8.4±4.2% PTH/week; P=NS). The serum calcium increased similarly in both groups. Hypercalcaemia (>2.9 mmol/l) was rare (pulse=3, daily=2 episodes). Conclusions: This study demonstrates that pulse and daily calcitriol are similarly effective and safe for the treatment of mild to moderate secondary hyperparathyroidism in CAPD patients despite higher peak levels of 1,25(OH)2-vitamin D with pulse therapy. Key words: calcitriol; calcium balance; CAPD; dialysis; hyperparathyroidism; renal osteodystrophy      

Direct injections of calcitriol into enlarged parathyroid glands in chronic dialysis patients with severe parathyroid hyperfunction

Summary: Severe secondary hyperparathyroidism in chronic dialysis patients has been recently treated by supraphysiological concentration of calcitriol achieved through pulse therapy. However, there are many patients resistant to this therapy, who usually have larger parathyroid gland(s). to overcome this resistance, calcitriol was injected directly into the enlarged glands under ultrasonographic guidance. We injected 70–90% of the calculated gland volume of calcitriol solution (1 μg/mL) into the glands of 7 patients three times per week for 2 weeks. the parathyroid hormone (PTH) levels decreased significantly after 2 weeks of direct injections of calcitriol. Following a further 4 weeks of calcitriol pulse therapy, PTH levels remained suppressed and serum alkaline phosphatase activity and the volume of parathyroid glands also decreased. During the long-term follow up, five patients remained well controlled with calcitriol pulse therapy, while two patients needed ethanol injections to control hyperparathyroidism. Although we could not completely rule out a toxic effect of the vehicle, direct injection of calcitriol into parathyroid glands may be another treatment option for chronic dialysis patients. Our data further support the important role of resistance of parathyroid cells to calcitriol in the pathogenesis of parathyroid hyper function in uraemic patients.     

Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism

To evaluate the response of circulating intact parathyroid hormone (iPTH) on myocardial hypertrophy in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT), echocardiographic and neurohormonal assessments were performed over a 15-week period in 15 HD patients with SHPT before and after calcitriol treatment and 10 HD control patients with SHPT not receiving calcitriol therapy. We prospectively studied a group of 15 patients with significantly elevated iPTH levels (iPTH >450 pg/mL) receiving calcitriol (2 microg after dialysis twice weekly). Clinical assessment, medication status, and biochemical and hematological measurements were performed once a month. Throughout the study, calcium carbonate levels were modified to maintain serum phosphate levels at less than 6 mg/dL, but body weight, antihypertensive medication, and ultrafiltration dose remained constant. In patients treated with calcitriol, an adequate reduction of iPTH levels was found (1,112 +/- 694 v 741 +/- 644 pg/mL; P < 0.05) without changes in values of serum ionized calcium (iCa++), phosphate, or hematocrit. Blood pressure (BP), cardiac output (CO), and total peripheral resistance (TPR) did not significantly change. After 15 weeks of treatment with calcitriol, M-mode echocardiograms showed pronounced reductions in interventricular wall thickness (13.9 +/- 3.6 v 12.8 +/- 3.10 mm; P = 0.01), left ventricular posterior wall thickness (12.5 +/- 2.4 v 11.3 +/- 1.8 mm; P < 0.05), and left ventricle mass index (LVMi; 178 +/- 73 v 155 +/- 61 g/m2; P < 0.01). However, in control patients, these changes were not found after the treatment period. In addition, sequential measurements of neurohormonal mediator levels in patients receiving calcitriol showed that plasma renin (18.5 +/- 12.7 v 12.3 +/- 11.0 pg/mL; P = 0.007), angiotensin II (AT II; 79.7 +/- 48.6 v 47.2 +/- 45.7 pg/mL; P = 0.001), and atrial natriuretic peptide (ANP; 16.6 +/- 9.7 v 12.2 +/- 4.4 pg/mL; P = 0.03) levels significantly decreased, whereas antidiuretic hormone (ADH), epinephrine, and norepinephrine levels did not change significantly. The percent change in LVMi associated with calcitriol therapy had a strong correlation with the percent change in iPTH (r = 0.52; P < 0.05) and AT II (r = 0.47; P < 0.05) levels. We conclude that the partial correction of SHPT with intravenous calcitriol causes a regression in myocardial hypertrophy without biochemical or hemodynamic changes, such as heart rate, BP, and TPR. The changes in plasma levels of iPTH and, secondarily, plasma levels of neurohormones (especially AT II) after calcitriol therapy may have a key role in attenuating ventricular hypertrophy in SHPT.     

A controlled trial of the early treatment of secondary hyperparathyroidism with calcitriol in hemodialysis patients

BACKGROUND: Calcitriol is widely used in conjunction with phosphorus-binders containing calcium to treat secondary hyperparathyroidism in dialysis patients. Its efficacy in patients with severe hyperparathyroidism is diminished, in part, due to glandular hyperplasia associated with decreased calcitriol and calcium receptors. SUBJECTS AND METHODS: We, therefore, developed a prospective, randomized trial comparing i.v. calcitriol plus calcium carbonate (CaCO3) compared to CaCO3 alone (control) in patients with mild to moderate hyperparathyroidism who were within the first year of initiating hemodialysis. Patients underwent calcium (Ca) suppression/stimulation testing at baseline and after six and twelve months of treatment to indirectly assess parathyroid gland hyperplasia. RESULTS: In the calcitriol group, the amino-terminal parathyroid hormone (N-PTH) decreased significantly from a baseline value of 70 +/- 12 pg/ml at month zero to 22 +/- 7 and 19 +/- 6 pg/ml at months 6 and 12, respectively (the conversion factor of amino-terminal PTH to intact PTH is 6, i.e., 10 pg/ml N-PTH equals 60 pg/ml intact PTH). In contrast, the N-PTH levels in the CaCO3 alone group did not change. The change in nadir N-PTH levels at month 12 compared to month zero decreased by 14 +/- 7% in the calcitriol group but increased by 96 +/- 59% in the control group (p < 0.05). In addition, the increment in N-PTH levels during hypocalcemic stimulation decreased by 68 +/- 6% at month 12 compared to month zero but increased by 61 +/- 42% in the control group. Although total calcium and phosphorus levels were not different between the two groups, ionized calcium values were higher in the calcitriol group. The incidence of hypercalcemia was the same in both groups and the episodes were asymptomatic. CONCLUSION: Pulse calcitriol therapy is effective in preventing progression of secondary hyperparathyroidism in hemodialysis patients with mild to moderate disease. Based on Ca suppression/stimulation tests, calcitriol was more successful in preventing gland growth than CaCO3 alone. Further studies are needed to determine if the strategy of early treatment of mild to moderate hyperparathyroidism by pulse calcitriol is safe and effective in hemodialysis in patients.     

Effect of hyperparathyroidism on response to erythropoietin in children on dialysis

The response to recombinant human erythropoietin (rHuEPO), 50 units/kg thrice weekly, was studied prospectively in 17 children and adolescents with end-stage renal disease who were either transfusion dependent or had hematocrits <25%. For convenience, rHuEPO was given intravenously to 12 hemodialysis (HD) patients and subcutaneously to 5 peritoneal dialysis (PD) patients. Blood pressure, hematocrit, iron indices, and serum potassium, calcium, phosphorus, alkaline phosphatase, urea nitrogen, and intact parathyroid hormone (PTH) were monitored serially. When serum ferritin was <100 ng/ml during therapy, 6 patients received iron supplementation. rHuEPO therapy eliminated frequent transfusions in all patients; 11 of 17 patients reached the target hematocrit of 30% – 33% by week 16 of rHuEPO, 50 units/kg thrice weekly. The 5 PD patients treated subcutaneously reached target at week 6±1; 6 HD patients treated intravenously reached target at week 11±3; 6 additional HD patients never reached target at this dose; 5 of 6 had pre-rHuEPO serum PTH levels >400 pg/ml, significantly higher than those of the other patients (P <0.005); 3 of 6 later reached a hematocrit of 30% – 33% after the rHuEPO dose was increased to 120 – 130 units/kg thrice weekly. We conclude that most pediatric dialysis patients can be treated successfully with rHuEPO, 50 units/kg thrice weekly, unless the serum PTH concentration is markedly elevated, in which case a higher dose is likely to be needed. Received May 8, 1997; received in revised form September 16, 1997; accepted September 19, 1997     

Incidence and Risk Factors of Persistent Hyperparathyroidism After Kidney Transplantation

Persistent hyperparathyroidism after kidney transplantation is related to graft function, but pre-transplantation risk factors of persistent hyperparathyroidism have not been evaluated in detail. We enrolled 86 patients who had undergone kidney transplantation between 2008 and 2014. Nine patients showed persistent hyperparathyroidism characterized by the following: 1) serum parathyroid hormone levels >65 pg/mL and serum calcium levels >10.5 mg/dL at 1 year after kidney transplantation; 2) parathyroidectomy after kidney transplantation; and 3) reintroduction of cinacalcet after kidney transplantation. Compared with other patients, these 9 patients had significantly longer duration of dialysis therapy (186 ± 74 mo vs 57 ± 78 mo) and more frequent treatment with cinacalcet during dialysis (89% vs 12%). Multivariate analysis showed that dialysis vintage, calcium phosphate products, and cinacalcet use before kidney transplantation were independent risk factors of persistent hyperparathyroidism after kidney transplantation. A receiver operating characteristic curve showed 72 months as the cutoff value of dialysis vintage and 55 as the cutoff value of calcium phosphate products. In conclusion, dialysis vintage >6 years, calcium phosphate products >55 (mg/dL)², and cinacalcet use before kidney transplantation are strong predictors of persistent hyperparathyroidism. High-risk patients should be evaluated for parathyroid enlargement, and parathyroidectomy must be considered before kidney transplantation.     

Local calcitriol injections as a suppressive treatment of secondary hyperparathyroidism in chronic dialysis patients

AIM: A prospective study was made of the effectiveness of repeatable local calcitriol injections therapy to suppress secondary hyperparathyroidism resistant to conventional therapy in chronic dialysis patients. METHODS: Under ultrasonographic guidance, six injections at an interval of two days were performed in 14 chronic dialysis patients. The total amount of calcitriol to be injected each time was estimated as 100% of the calculated gland volume. Calcitriol was given in doses 1 mug of medicine per 1 cubic cm (as measured by USG) of parathyroid tissue. Parathormone concentration, total calcium, ionized calcium, phosphate, and alkaline phosphatase levels were assessed on the first and last day of the treatment period. RESULTS: Prior to therapy, the mean gland volumes were 0.62 (0.15-3.0) ml, and they increased to 0.85 (0.2-3.9) after 14 days (NS). Seven patients were found to have decreased their PTH levels to 909 +/- 387 pg/mL after 14 days of treatment when compared with the first day mean values of 1588 +/- 440 pg/mL (p < 0.05). After completion of the therapy, four patients were reported to be free from any clinical symptoms of ostalgia or arthralgia. Others reported an alleviation of pain. CONCLUSIONS: Parathyroid adenoma injection is an alternative method of treatment for some patients resistant to treatment by means of vitamin D3 pulses or intravenous administration of calcitriol. The success of treatment is to a great extent determined by proper selection of patients and the taking of decisions when the period of secondary hyperparathyroidism is not very advanced.     

Different effects of calcitriol and parathyroidectomy on the PTH--calcium curve in dialysis patients with severe hyperparathyroidism

BACKGROUND: The PTH–calcium sigmoidal curve is shifted to the right,the slope of the curve is steeper, and the set point of calciumis increased in dialysis patients with secondary hyperparathyroidism,compared to patients with low-turnover bone disease. These findingscould be related to increased parathyroid cell mass and increasedsensitivity of parathyroid cells to serum calcium variationsin these patients. Calcitriol therapy has been documented toreduce PTH levels by shifting the curve to the left and downward.The effect of a surgical reduction of parathyroid gland masson the PTH-calcium curve has not yet been investigated. In thisstudy we compared the effects of calcitriol and subtotal parathyroidectomy(PTH) on the dynamics of PTH secretion in response to acutechanges of serum calcium in two groups of dialysis patientswith severe hyperparathyroidism. METHODS: Fourteen dialysis patients treated for 6 months with high-dosei.v. calcitriol (1–2 µg thrice weekly), and 10 dialysispatients who underwent subtotal PTx were studied. The PTH–calciumrelationship obtained by inducing hypo- and hypercalcaemia bymeans of low and high calcium dialysis was evaluated beforeand 2–6 months after treatment. RESULTS: Both calcitriol and subtotal PTx significantly decreased PTH(respectively from 797±595 to 380±244 and from1036±250 to 70±34 pg/ml), as well as maximal PTHresponse to hypocalcaemia (PTHmax), and maximal PTH suppressionduring hypercalcaemia (PTHmin). When the PTH–calcium curveswere constructed using PTHmax as 100% to factor for differencesin absolute PTH levels and to provide an assessment of individualparathyroid cell function, a shift of the sigmoidal curve tothe left and downward, and a significant decrease in the setpoint of ionized calcium (from 1.31±0.05 to 1.26±0.05and from 1.36±0.09 to 1.22±0.07 mmol/1) was documentedwith both treatments. However, the slope of the PTH–calciumcurve increased after subtotal PTx indicating that the sensitivityof the parathyroid cell to serum calcium changes increased withPTx, while on the contrary it decreased with calcitriol. CONCLUSIONS: PTH secretion decreases proportionally more with calcitriolthan with surgery for a given decrease in the functional massof parathyroid cells. The change in the PTH–ICa sigmoidalcurve induced by subtotal PTx is due to the removal of a largemass of parathyroid tissue with advanced hyperplasia.     

Prevention and treatment of renal osteodystrophy in children with chronic renal insufficiency and end-stage renal disease

Histologic features associated with secondary hyperparathyroidism remain the predominant skeletal lesion in adults and children with chronic renal failure. When instituted early, vitamin D therapy has been shown to ameliorate the development and progression of the biochemical, radiographic, and histologic evidence of secondary hyperparathyroidism in patients with chronic renal insufficiency. Aggressive parathyroid hormone suppression, however, has led to the increased prevalence of adynamic bone. Adynamic bone has been attributed partly to aggressive calcitriol therapy, administration of high amounts of exogenous calcium either as a phosphate binding agent or during dialysis therapy, presence of diabetes, older age, or previous parathyroidectomy. Several vitamin D analogues are currently being evaluated in patients with chronic renal failure to prevent complications associated with calcitriol therapy. In addition, calcium-free phosphate binding agents and the use of calcimimetic drugs may play a significant role in the effective management of secondary hyperparathyroidism in children with chronic renal failure.     

Parathyroid Subcutaneous Pre-sternal Transplantation after Parathyroidectomy for Renal Hyperparathyroidism. Long-term Graft Function

Background In the setting of total parathyroidectomy (TPT) and parathyroid transplantation (PTx) for renal hyperparathyroidism (RHP), we evaluated long-term parathyroid graft function after subcutaneous pre-sternal transplantation (SCPTx). Because parathyroid glands are surrounded by fatty tissue, we postulated that results of subcutaneous implantation of parathyroid tissue after total parathyroidectomy for renal hyperparathyroidism could be at least as successful as intramuscular grafting, but without its complications Patients and Methods The study, a prospective open efficacy study of postoperative (po) diagnostic monitoring of intact parathyroid hormone (iPTH) on a cohort of surgical patients, was conducted within a university hospital with a dialysis unit. Thirty five patients (19 women and 16 men) operated on for renal hyperparathyroidism underwent TPT and SCPTx for RHP at the Department of General Surgery and the Department of Nephrology. Donostia Hospital. San Sebastián. Gipuzkoa. Spain, from January 2002 to December 2005. Follow-up ranges from 6 months to 42 months (median: 15.4 months). The main outcome measure was evaluation of graft function by measurement of iPTH plasma level, based on serum levels of iPTH before operation and 24 h and 1, 3, 5, 15, 30, 60, 100, and 150 weeks after surgery Results Average preoperative iPTH values were 1,341.52 + 367.78 pg/ml (mean ± SD) (range: 493–2,180). After TPT and PSCTx, iPTH levels became undetectable in all patients at 24 h. A level of 50 pg/ml was established as the criterion of adequate parathyroid graft function. Values obtained at the various time intervals were as follows: 14.14 + 7.73 1 pg/ml (mean ± SD) (range: 6–36) after 1 week, 53 + 77.33 pg/ml (mean ± SD) (range: 35–74) after 5 weeks, 62.95 + 20.93 pg/ml (mean ± SD) (range: 11–89) after 15 weeks, 77.54 + 18.84 pg/ml (mean ± SD) (range: 24.6–104.2) after 30 weeks, 109.29 + 50.22 pg/ml (mean ± SD) (range: 54–327) after 60 weeks, 134.21 + 128.64 pg/ml (mean ± SD) (range: 43–712) after 100 weeks, and 122.84 + 117.54 pg/ml (mean ± SD) (range: 68–723) after 150 weeks. Prevalence of hypoparathyroidism (intact parathyroid hormone serum level < 20 pg/ml with a normal or low serum calcium concentration) was 2/35 (5.71%) by week 60 and recovered by week 100. Graft-related recurrence was 2.85% (1/35). Conclusions Subcutaneous pre-sternal transplantation (SCPTx) after TPT and PTx for secondary (RHP) is an adequate method to replace muscular forearm parathyroid transplantation and avoid its complications. Functioning results of total parathyroidectomy and presternal subcutaneous grafting compare favorably with the published data on other surgical techniques proposed for the treatment of renal hyperparathyroidism. Results of long-term follow-up exceed previously reported results.