Inhibition of parathyroid hormone: a dose equivalency study of paricalcitol and doxercalciferol

INTRODUCTION: Paricalcitol and doxercalciferol are effective in reducing parathyroid hormone PTH concentrations in patients with secondary hyperparathyroidism. The purpose of this study was to determine the relative dose of doxercalciferol (compared to paricalcitol) required to maintain equivalent PTH concentrations in dialysis patients. METHODS: Chronic hemodialysis patients treated with a stable dose of paricalcitol for at least 3 months were randomized to receive doxercalciferol at either 35, 50, or 65% of the paricalcitol dose for 6 weeks. Serum iPTH, calcium, phosphorus, and albumin were determined at baseline and monitored every 2 weeks. A linear regression analysis of percent change in iPTH values by dose group was performed to determine the conversion factor. RESULTS: 27 patients were enrolled. Initial iPTH, adjusted serum calcium, serum phosphorus, and CaxP were similar among the treatment groups. Linear regression analysis demonstrated a conversion factor of 0.57 for the dose of doxercalciferol relative to paricalcitol resulting in equivalent suppression of iPTH. Corrected serum calcium, phosphorus, CaxP product, as well as incidence of hypercalcemia, hyperphosphatemia and CaxP >50 were similar for all groups. CONCLUSION: In patients on a maintenance dose of paricalcitol, dosing doxercalciferol at 55-60% of the paricalcitol dose results in comparable inhibition of PTH.     

Efficacy and tolerability of intravenous paricalcitol in calcitriol-resistant hemodialysis patients with secondary hyperparathyroidism: 12-month prospective study

RATIONALE/OBJECTIVES: Data are limited regarding the use of paricalcitol in calcitriol-resistant patients with secondary hyperparathyroidism (SHPT). We aimed to evaluate the effects of paricalcitol in calcitriol-resistant hemodialysis patients with SHPT. METHODS: This is a 12-month, open-label, prospective study. Forty patients with calcitriol-resistant and/or calcitriol-intolerant SHPT were included. After a washout period, all patients converted to paricalcitol with a 1:3 conversion ratio. Serum calcium and phosphorus were monitored monthly, while serum intact parathyroid hormone (iPTH) once in every 3 months. Paricalcitol dose was reduced or discontinued in case of hypercalcemia and/or hyperphosphatemia. Pre- and posttreatment electrolyte and iPTH values were compared with Student's t-test and Wilcoxon signed-rank test, respectively. MAIN FINDINGS: Forty patients completed the study. Mean initiation dose of paricalcitol was 23 ± 7 μg/week. Mean serum calcium was 8.9 ± 0.8 mg/dL at baseline and 9.4 ± 0.7 mg/dL at study end (p = 0.07). Mean monthly serum phosphorus levels stayed stable. Paricalcitol was effective in reducing iPTH levels when compared with pretreatment values (747.9 ± 497.2 pg/mL, 307.3 ± 417.1 pg/mL, respectively; p < 0.001). Thirty-two patients had to discontinue intravenous (IV) paricalcitol at some time during their treatment. Main reasons for discontinuation were as follows: hyperphosphatemia (58%), hypercalcemia (25%), and iPTH < 150 pg/mL (17%). PRINCIPLE CONCLUSIONS: Paricalcitol was found to be effective in reducing iPTH levels in calcitriol-resistant patients with SHPT despite relatively frequent drug discontinuation rates.     

A long-term, multicenter study of the efficacy and safety of paricalcitol in end-stage renal disease.

BACKGROUND: Paricalcitol is a vitamin D analog approved for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure. This study was designed to evaluate the long-term efficacy and safety of paricalcitol. Additional analysis evaluated the effects of paricalcitol in hypocalcemic and hyperphosphatemic subpopulations. PATIENTS AND METHODS: One hundred sixty-four end-stage renal disease (ESRD) patiesnts on hemodialysis were treated in an open-label, multicenter study lasting up to 13 months in duration. After a baseline or washout period, an initial starting dose of 0.04-0.393 microg/kg was given 2-3 times per week. This dose was adjusted at the discretion of the investigator according to the patient's intact parathyroid hormone level (iPTH), calcium level, and calcium-phosphorus (Ca x P) product. The therapy was intended to reproduce expected clinical use of paricalcitol. Patients represented a wide cross-section of the ESRD population, and were not excluded from the study based on age or underlying disease. RESULTS: The mean paricalcitol dose level throughout the study was 0.10 microg/kg. The mean iPTH levels (baseline mean 628.3 +/- 27.65 pg/ml) decreased rapidly during the first 4 months of therapy, and reached the designated target range (100-300 pg/ml) by month 5 (mean 295.3 +/- 25.69 pg/ml). A maximum mean decrease in iPTH level of 409 +/- 35.01 pg/ml was seen at month 13. Throughout the course of the study, the mean normalized calcium level was maintained well within the normal range (9.44-9.94 mg/dl). The mean phosphorus level was maintained in an acceptable range throughout the study (5.92-6.53 mg/dl). Mean Ca x P product was maintained between 52 and 65. Mean alkaline phosphatase levels decreased significantly from baseline with a maximum mean decrease of 62 +/- 17.3 U/l observed at month 9. In 34 initially hypocalcemic patients (mean of 7.7 mg/dl) iPTH levels decreased from baseline, on average, by 443 +/- 81.86 pg/ml while mean calcium levels rose by 1.2 +/- 0.23 mg/dl to reach the normal range. In 35 initially hyperphosphatemic patients (mean of 8.0 mg/dl) iPTH levels decreased, on average, by 515 +/- 103.31 pg/ml with an associated mean decrease in phosphorus of 0.57 +/- 0.52 mg/dl. Adverse events that were considered by the investigator to have a possible. probable, or definite relationship to study drug occurred in 26% of patients. Other than expected temporary effects of hypercalcemia and hyperphosphatemia. the only possible trends for causally-related adverse events were for nausea/vomiting and metallic taste. CONCLUSIONS: This long-term study of paricalcitol demonstrates that it rapidly and effectively suppresses iPTH levels in a wide spectrum of ESRD patients and caused no unexpected adverse events.     

帕立骨化醇治疗维持性血液透析患者继发性甲状旁腺功能亢进症的前瞻性研究

目的 观察帕立骨化醇治疗维持性血液透析患者继发性甲状旁腺功能亢进症（secondary hyperparathyroidism,SHPT）的疗效及安全性.方法 选择我科血液净化中心进行维持性血液透析治疗的13例患者,血全段甲状旁腺素（intact parathyroid hormone,iPTH）≥33 pmol/L,血钙水平＜2.55 mmol/L,钙磷乘积＜65,根据iPTH水平使用帕立骨化醇1～18 μg治疗,于每次透析治疗后给药,共观察12周.分别于治疗前及治疗后第2、4、6、8、10、12周测定患者的iPTH、血钙、血磷水平.结果 13例患者的血清iPTH水平在治疗后第2、4周已开始下降,但与治疗前相比差异无统计学意义.从治疗后第6周开始,iPTH水平与治疗前相比存在统计学差异（P＜0.05）,治疗后第12周时下降至（46.68±38.06） pmol/L,与治疗前（78.30±52.13） pmol/L比较,有统计学差异（P＜0.01）.治疗后第2、4周血钙水平升高,与治疗前比较有统计学差异（P＜0.05）,其中治疗后第4周时血钙水平升高尤为显著（P＜0.01）.经调整帕立骨化醇剂量后,治疗后第6周患者的血钙水平逐渐恢复正常并保持稳定,血磷、钙磷乘积水平在治疗前、后均无明显统计学差异.治疗过程中,患者耐受性良好,无相关不良反应的发生.结论 使用帕立骨化醇治疗维持性血液透析患者SHPT是有效、安全的.     

Converting hemodialysis patients from intravenous paricalcitol to intravenous doxercalciferol - a dose equivalency and titration study

AIMS: Doxercalciferol and paricalcitol are used to treat hyperparathyroidism in chronic kidney disease. This study was conducted to define equivalent dose requirements to convert patients from intravenous paricalcitol to intravenous doxercalciferol. METHODS: Following a 4-week baseline period using a fixed dose of paricalcitol, 42 adult hemodialysis subjects were assigned to receive a fixed dose of doxercalciferol for 4 weeks using a conversion factor of either 50 or 65% of the prior paricalcitol dose. During a 12-week titration period the doxercalciferol dose was adjusted to optimize iPTH levels into the range of 150 - 300 pg/ml. Annual costs to achieve equivalent iPTH control were calculated for both vitamin D analogs. RESULTS: During the doxercalciferol fixed-dose period, the average dose of doxercalciferol was 2.1 +/- 1.3 microg and 3.1 +/- 1.8 microg in the 50 and 65% dose conversion groups, respectively. During this period mean iPTH in the 50% dose conversion group increased by 24 pg/ml (p = 0.017). During the dose titration period, doxercalciferol was increased to bring iPTH within the target range. Calcium control was maintained with both conversion factors, while slightly better phosphorus control was seen in the 65% dose conversion group. Annualized treatment cost for doxercalciferol was 28% less expensive per patient than paricalcitol. CONCLUSION: Patients can be managed safely and effectively with conversion and dose titration from paricalcitol to doxercalciferol. Both conversion strategies maintained iPTH at clinically satisfactory levels. Furthermore, doxercalciferol therapy resulted in drug acquisition cost-savings.     

帕立骨化醇治疗维持性血液透析患者继发性甲状旁腺功能亢进的疗效观察

目的观察帕立骨化醇对维持性血液透析患者继发性甲状旁腺功能亢进症的治疗效果。方法选择2018年7月至2019年7月对非选择性维生素D受体激动剂(VDRA)疗效不佳或不能耐受拟钙剂或不愿手术治疗的继发性甲状旁腺功能亢进(SHPT)的维持性血液透析患者56例,根据血液全段甲状旁腺素(iPTH)水平将所有患者分为三个组别:A组(300 pg/mL≤iPTH<600 pg/mL)、B组(600 pg/mL≤iPTH<800 pg/mL)、C组(iPTH≥800 pg/mL)。根据体重给予不同剂量的静脉帕立骨化醇注射液,分别检测患者治疗前、初始使用1个月以及达到帕立骨化醇维持剂量时,iPTH、血钙、血磷、钙磷乘积的变化情况。结果患者骨痛、瘙痒、疲乏等症状明显改善。所有患者初始治疗1个月,iPTH达标率为51.8%(29/56),达到帕立骨化醇注射液维持治疗剂量百分比为57.1%(32/56)。患者初始治疗1个月与治疗前相比,iPTH水平显著下降[(718.76±457.56)pg/mL vs.(956.68±375.61)pg/mL,P<0.001],血钙、血磷以及钙磷乘积无明显改变[(2.28±0.23)mmol/L vs.(2.23±0.27)mmol/L,(2.15±0.49)mmol/L vs.(2.29±0.48)mmol/L,(58.49±17.71)mg^2/dl2 vs.(62.90±13.93)mg^2/dl2,P>0.05]。进入维持治疗阶段的患者,维持治疗与初始治疗相比,iPTH水平仍有下降趋势,但差异无统计学意义[(424.82±221.23)pg/mL vs.(517.55±325.77)pg/mL,P>0.05],血钙、血磷以及钙磷乘积比较差异无统计学意义[(2.33±0.20)mmol/L vs.(2.31±0.24)mmol/L,(2.13±0.44)mmol/L vs.(2.00±0.42)mmol/L,(61.24±12.25)mg^2/dl2 vs.(55.76±15.66)mg^2/dl2,P>0.05]。结论帕立骨化醇对非选择性VDRA疗效不佳或不能耐受拟钙剂或不愿手术治疗的维持性血液透析患者SHPT有较好的疗效,明显缓解患者骨痛、瘙痒、疲乏等症状,显著降低iPTH水平,且不增加高钙血症的发生风险。     

Differential effects of very high doses of doxercalciferol and paricalcitol on serum phosphorus in hemodialysis patients

BACKGROUND: Treatment of secondary hyperparathyroidism (SHPT) includes use of calcitriol (1,25D(3)) to suppress parathyroid hormone (PTH), but dosing of 1,25D(3) is limited by the development of hypercalcemia and a high calcium x phosphorus (Ca x P) product due to gut absorption of calcium and phosphorus as well as enhanced bone resorption. The vitamin D analog 19-Nor-1,25(OH)2-vitamin D2 (paricalcitol) and the prohormone 1alpha-OH-vitamin D2 (doxercalciferol) have been proposed as alternatives which may cause less hypercalcemia and elevated Ca x P, while still suppressing PTH. METHODS: We performed a prospective study to assess the acute bone mobilization effects of very high doses of paricalcitol and doxercalciferol. 13 hemodialysis patients received 160 mcg of paricalcitol and 120 mcg of doxercalciferol on 2 separate occasions in a research center while on a low calcium, low phosphorus diet, and sevelamer alone as a phosphorus binder. Changes in Ca, PO4, and PTH were measured over 36 h. RESULTS: Serum phosphorus rose faster, and peaked significantly higher at 36 h following doxercalciferol (2.12 +/- 0.11 mmol/l) than paricalcitol (1.85 +/- 0.07 mmol/l; p = 0.025). Ca x P product also rose more following doxercalciferol than paricalcitol, and peaked higher at 36 h (5.02 +/- 0.26 vs. 4.54 +/- 0.21 mmol/l; p = 0.061). In contrast, suppression of PTH at 36 h was comparable (63% after paricalcitol and 65% with doxercalciferol). CONCLUSION: Consistent with animal studies, paricalcitol provides profound PTH suppression, while stimulating bone resorption and/or intestinal absorption less than doxercalciferol, resulting in less elevation of serum phosphorus and Ca x P.     

Intravenous calcitriol versus paricalcitol in haemodialysis patients with severe secondary hyperparathyroidism

Aim:   Secondary hyperparathyroidism (SHPT) is common among haemodialysis patients. Intensive treatment with calcitriol is often complicated by hypercalcaemia, hyperphosphataemia and elevated calcium phosphorus (Ca X PO₄) product. Paricalcitol is a vitamin D analogue developed to overcome some of the limitations of calcitriol therapy. The study objectives were to compare the response of intact parathyroid hormone (iPTH) and the incidence of hypercalcaemia, hyperphosphataemia and elevated Ca X PO₄ product in patients with severe SHPT treated with either i.v. calcitriol or i.v. paricalcitol.
Methods:   This was a single centre randomized open label study. Patients with serum intact iPTH of 50 pmol/L or more were randomized to receive either i.v. calcitriol (0.01 ug/kg) or i.v. paricalcitol (0.04 ug/kg) during every haemodialysis treatment. Serum iPTH, calcium, phosphorus and alkaline phosphatase were measured at the beginning of the study and every 3 weeks for 12 weeks.
Results:   Twenty-five patients were enrolled into the study – 12 were randomized into the calcitriol group and 13 into the paricalcitol group. There were no differences in the baseline study parameters between both groups. Serum iPTH levels were significantly reduced ( P  = 0.003) only in the paricalcitol group but not in the calcitriol group ( P  = 0.101). On the other hand, serum calcium levels were significantly increased only in the calcitriol group ( P  = 0.004 vs P  = 0.242). Serum phosphorus, alkaline phosphatase and Ca X PO₄ product were not different.
Conclusion:   Intravenous paricalcitol may be superior to i.v. calcitriol for the treatment of severe SHPT in our chronic haemodialysis population. A larger randomized controlled trial is indicated to confirm these initial findings.     

Long-term outcomes of cinacalcet and paricalcitol titration protocol for treatment of secondary hyperparathyroidism

Long-term outcomes of combined cinacalcet and paricalcitol therapy for secondary hyperparathyroidism (SHPT) in patients failing traditional therapies with phosphate binders and active vitamin D compound analogs are not well described. We implemented a titration protocol for cinacalcet and paricalcitol and assessed its long-term effects on bone metabolism and disease in hemodialysis (HD) patients. Thirty-five patients were started on 30 mg of cinacalcet daily. After 12 months, median cinacalcet dose was 60 mg. There was a 33% increase in number of patients receiving paricalcitol. Average corrected serum calcium (Ca) decreased from 9.5 to 8.8 mg/dl (p = 0.003, 95% CI 0.34-1.04); phosphorus (P) from 6.2 to 5.5 mg/dl (p = 0.047, 95% CI 0.01-1.34); Ca x P product from 58 to 48 (p = 0.001, 95% CI 4.2-15.7); and intact PTH (iPTH) from 426 +/- 274 to 300 +/- 228 pg/ml (p = 0.03, 95% CI 19.3-401.7). Number of patients achieving three or more K/DOQI criteria increased by 29% (p = 0.009).     

No difference between alfacalcidol and paricalcitol in the treatment of secondary hyperparathyroidism in hemodialysis patients: a randomized crossover trial

Alfacalcidol and paricalcitol are vitamin D analogs used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease, but have known dose-dependent side effects that cause hypercalcemia and hyperphosphatemia. In this investigator-initiated multicenter randomized clinical trial, we originally intended two crossover study periods with a washout interval in 86 chronic hemodialysis patients. These patients received increasing intravenous doses of either alfacalcidol or paricalcitol for 16 weeks, until parathyroid hormone was adequately suppressed or calcium or phosphate levels reached an upper threshold. Unfortunately, due to a period effect, only the initial 16-week intervention period for 80 patients was statistically analyzed. The proportion of patients achieving a 30% decrease in parathyroid hormone levels over the last four weeks of study was statistically indistinguishable between the two groups. Paricalcitol was more efficient at correcting low than high baseline parathyroid hormone levels, whereas alfacalcidol was equally effective at all levels. There were no differences in the incidence of hypercalcemia and hyperphosphatemia. Thus, alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in hemodialysis patients while calcium and phosphorus were kept in the desired range.     

Nicotinamide suppresses hyperphosphatemia in hemodialysis patients

BACKGROUND: The use of calcium- or aluminum-based phosphate binders against hyperphosphatemia is limited by the adverse effects of hypercalcemia or aluminum toxicity in long-term hemodialysis. Because nicotinamide is an inhibitor of sodium-dependent phosphate cotransport in rat renal tubule and small intestine, we examined whether nicotinamide reduces serum levels of phosphorus and intact parathyroid hormone (iPTH) in patients undergoing hemodialysis. METHODS: Sixty-five hemodialysis patients with a serum phosphorus level of more than 6.0 mg/dL after a 2-week washout of calcium carbonate were enrolled in this study. Nicotinamide was administered for 12 weeks. The starting dose was 500 mg/day, and the dose was increased by 250 mg/day every 2 weeks until serum phosphorus levels were well controlled at less than 6.0 mg/dL. A 2-week posttreatment washout period followed the cessation of nicotinamide. Blood samples were collected every week for measurement of serum calcium, phosphorus, lipids, iPTH, and blood nicotinamide adenine dinucleotide (NAD). RESULTS: The mean dose of nicotinamide was 1080 mg/day. The mean blood NAD concentration increased from 9.3 +/- 1.9 nmol/105 erythrocytes before treatment to 13.2 +/- 5.3 nmol/105 erythrocytes after treatment (P < 0.01). The serum phosphorus concentration increased from 5.4 +/- 1.5 mg/dL to 6.9 +/- 1.5 mg/dL with the pretreatment washout, then decreased to 5.4 +/- 1.3 mg/dL after the 12-week nicotinamide treatment (P < 0.0001), and rose again to 6.7 +/- 1.6 mg/dL after the posttreatment washout. Serum calcium levels decreased during the pretreatment washout from 9.1 +/- 0.8 mg/dL to 8.7 +/- 0.7 mg/dL with the cessation of calcium carbonate. No significant changes in serum calcium levels were observed during nicotinamide treatment. Median serum iPTH levels increased with pretreatment washout from 130.0 (32.8 to 394.0) pg/mL to 200.0 (92.5 to 535.0) pg/mL and then decreased from the maximum 230.0 (90.8 to 582.0) pg/mL to 150.0 (57.6 to 518.0) pg/mL after the 12-week nicotinamide treatment (P < 0.05). With nicotinamide, serum high-density lipoprotein (HDL) cholesterol concentrations increased from 47.4 +/- 14.9 mg/dL to 67.2 +/- 22.3 mg/dL (P < 0.0001) and serum low-density lipoprotein (LDL) cholesterol concentrations decreased from 78.9 +/- 18.8 mg/dL to 70.1 +/- 25.3 mg/dL (P < 0.01); serum triglyceride levels did not change significantly. CONCLUSION: Nicotinamide may provide an alternative for controlling hyperphosphatemia and hyperparathyroidism without inducing hypercalcemia in hemodialysis patients.     

Growth in children with chronic renal failure on intermittent versus daily calcitriol

Calcitriol (C) treatment strategies for secondary hyperparathyroidism remain controversial regarding efficacy and safety. In children, intermittent C administration has been suspected of impairing body growth. In a prospective, randomized multicenter study, we compared the effect of daily versus twice weekly C on plasma intact parathyroid hormone (iPTH) levels and growth in 24 prepubertal children with chronic renal insufficiency (mean creatinine clearance 20+/-9 ml/min per 1.73 m(2)). After a 3-week washout period, the patients were randomly assigned to 10 ng/kg per day or 35 ng/kg twice a week oral C. The C dose was kept constant for 2 months and could then be adapted to maintain an iPTH target range of 140-280 pg/ml. Median (range) baseline iPTH levels were 567 (114-1209) pg/ml in the daily and 332 (93-614) pg/ml in the intermittent treatment group ( P=NS). After 12 months, iPTH had decreased to 255 (85-710) and 179 (51-443) pg/ml ( P<0.01). The average weekly dose of C was 76+/-34 and 62+/-34 ng/kg ( P=NS). Five episodes of calcium phosphate product>/=70 occurred in the daily group and four in the intermittent group. The change in height standard deviation score during the study period was not affected by either treatment modality (-0.18+/-0.34 vs. -0.05+/-0.52, P=NS). Daily and intermittent C do not differentially affect growth rate and are equally effective in controlling secondary hyperparathyroidism in children with chronic renal failure.     

Oral Paricalcitol Reduces the Prevalence of Posttransplant Hyperparathyroidism: Results of an Open Label Randomized Trial

Postkidney transplant hyperparathyroidism is a significant problem. Vitamin D receptor agonists are known to suppress parathyroid hormone (PTH) secretion. We examined the effect of oral paricalcitol on posttransplant secondary hyperparathyroidism by conducting an open label randomized trial in which 100 incident kidney transplant recipients were randomized 1:1 to receive oral paricalcitol, 2 μg per day, for the first year posttransplant or no additional therapy. Serial measurements of serum PTH, calcium and bone alkaline phosphatase, 24‐h urine calcium and bone density were performed. The primary endpoint was the frequency of hyperparathyroidism 1‐year posttransplant. Eighty‐seven patients completed the trial. One‐year posttransplant, 29% of paricalcitol‐treated subjects had hyperparathyroidism compared with 63% of untreated patients (p = 0.0005). Calcium supplementation was discontinued in two control and 15 treatment patients due to mild hypercalcemia or hypercalcuria. Paricalcitol was discontinued in four patients due to hypercalcuria/hypercalcemia and in one for preference. Two subjects required decreasing the dose of paricalcitol to 1 μg daily. Hypercalcemia was asymptomatic and reversible. Incidence of acute rejection, BK nephropathy and renal function at 1 year were similar between groups. Moderate renal allograft fibrosis was reduced in treated patients. Oral paricalcitol is effective in decreasing posttransplant hyperparathyroidism and may have beneficial effects on renal allograft histology.     

Safety and efficacy of long-term treatment of secondary hyperparathyroidism by low-dose intravenous calcitriol.

To assess the safety and efficacy of low-dose intravenous (IV) calcitriol therapy for the treatment of secondary hyperparathyroidism, 21 hemodialysis patients with amino-terminal parathyroid hormone (N-PTH) levels greater than 4 times normal were treated for 12 to 24 months in a prospective trial. The initial dose was 0.50 microgram, which was titrated every 3 months thereafter, as dictated by predialysis calcium, phosphorus, and N-PTH concentration. Dialysate calcium concentration was 1.5 mmol/L. Low-dose IV calcitriol decreased the N-PTH concentration to 48 +/- 6% and 29 +/- 5% of baseline following 12 and 24 months of therapy, respectively. The maximum dose of calcitriol was 0.92 +/- 0.11 microgram (0.50 to 2.25 micrograms). After 12 months of therapy, serum calcium increased from 2.22 +/- 0.04 to 2.41 +/- 0.03 mmol/L (8.9 +/- 0.2 to 9.7 +/- 0.1 mg/dL) without change thereafter. Baseline serum phosphorus was 1.44 +/- 0.09 mmol/L (4.5 +/- 0.3 mg/dL), and was unaltered by calcitriol therapy. Control of serum phosphorus was achieved with calcium-containing phosphate binders, except in three patients who were subsequently withdrawn from the study after 12 months because of persistent hyperphosphatemia due to noncompliance. We conclude that long-term, low-dose IV calcitriol is a safe and effective therapy for most hemodialysis patients with secondary hyperparathyroidism. In contrast to conventional dosing regimens, low-dose IV therapy does not necessitate the use of aluminum-containing phosphate binders and/or a low-calcium dialysate bath.     

Treatment of secondary hyperparathyroidism in hemodialyzed patients with high-dose calcium carbonate without vitamin D3 supplements.

BACKGROUND: Vitamin D compounds are usually indicated for the treatment of secondary hyperparathyroidism in dialysis patients. The possibility to induce a reversal of hyperparathyroidism with calcium supplementation alone is controversial. The present study was conducted to assess if oral calcium carbonate may constitute a therapeutic option for the control of hyperparathyroidism in patients with high PTH concentrations at the beginning of the treatment with chronic hemodialysis. METHODS: Thirty-one patients with end-stage renal failure with an intact PTH concentration above 250 pg/ml at the beginning of chronic hemodialysis therapy were treated with high doses of calcium carbonate; no patient received either aluminium-containing binders or vitamin D compounds. To minimize hypercalcemia, a calcium dialysate concentration of 2.5 mEq/l was used in all patients. The goal of the study was to reduce the intact PTH concentration to 250 pg/ml with oral calcium carbonate supplements alone. RESULTS: Throughout the first year on hemodialysis treatment, the intact PTH concentration decreased from 538 +/- 256 to 251 +/- 218 pg/ml (p < 0.001). By the end of the study, the therapeutic objective was achieved in 22 patients (71%) ('responder' group). The remaining 9 patients were classified as the 'treatment failure' group. The basal intact PTH concentration was not different between both groups (508 +/- 235 vs. 612 +/- 303 pg/ml, respectively, p = n.s.), but 5 'treatment failure' patients admitted to take a dose of calcium carbonate lower than that prescribed. There were 40 episodes of hyperphosphatemia (11% of all measurements) in 7 of 31 patients, 5 of them belonged to the noncompliance 'treatment failure' patients. Only 15 episodes (4% of all measurements) of transient hypercalcemia (range 11.1 - 11.9 mg/dl) were detected in 8 patients. CONCLUSIONS: Secondary hyperparathyroidism in hemodialysis patients can often be reverted by oral calcium carbonate alone. But a good adherence to treatment is absolutely necessary.     

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.     

Acute effects of repetitive hemodialysis on circulating immunoreactive parathyroid hormone levels in uremic patients undergoing vitamin D (calcitriol) therapy

The acute effects on parathyroid gland activity of repetitive hemodialysis with a dialysate calcium concentration of between 3.5 and 4 mEq/l were evaluated in 21 hemodialysis patients on calcitriol therapy for 1 year or more. In this study circulating immunoreactive parathyroid hormone (iPTH) levels were measured using radioimmunoassay specific for C-terminal iPTH (C-PTH), middle molecule iPTH (MM-PTH) and intact iPTH (I-PTH), before the dialysis session at the end of the week (I), after 4 h regular hemodialysis (II) and after a further 72 h (III). C-PTH was abnormally high (202 +/- 64 pmol/l) (I) in 18 patients with no documented parathyroid hyperplasia and showed no significant difference in subsequent controls. MM-PTH was also high (379 +/- 125.5 pmol/l) (I), but decreased to 348 +/- 136.7 (II) (p less than 0.05) and returned to predialysis levels (III). I-PTH (I) was 8.2 +/- 5.3 pmol/l (normal levels in 8 patients), fell to 3.4 +/- 2.6 pmol/l (II) (p less than 0.01), and increased (p less than 0.01) with respect to the basal levels of 11.1 +/- 7.5 pmol/l (III). Three patients presented echographically documentable parathyroid hyperplasia and, despite constantly high iPTH levels, showed a similar I-PTH behavior while MM-PTH and C-PTH revealed no constant pattern. The decrease in iPTH levels was accompanied by a significant increase in total calcium and ionized calcium during the hemodialysis session. No significant changes in iCa and Ca together with I-PTH levels were found in 4 volunteers before and after the hemodialysis session with dialysate calcium 2.75 mEq/l. We conclude that I-PTH assay has been shown to capture acute changes in parathyroid gland activity in hemodialyzed patients for both low and high iPTH levels. High calcium dialysate hemodialysis inhibits acutely intradialytic PTH secretion but the effect is just temporary and the 72-hour interdialytic period, despite vitamin D therapy, stimulates parathyroid secretion significantly. Nevertheless, I-PTH fluctuations occur in some patients within the normal range, and high dialysate and calcitriol therapy seem to be capable of controlling parathyroid activity; as regards the remaining population, we suggest that a personalized therapeutic approach should be studied with a view to achieving a better control of interdialytic calcium homeostasis.     

Mineral and bone disorder in patients with chronic kidney disease: a cross - sectional single center study

Objective To investigate and analyze the mineral and bone disorder (MBD) in the patients with chronic kidney disease (CKD), reveal the change of related indexes of CKD-MBD. Methods A cross-sectional study was carried out in the First Affiliated Hospital of Harbin Medical University. From October 2011 to May 2014, 1318 inpatients and hemodialysis outpatients were enrolled. Parameters related to MBD, including serum phosphorus (P), total calcium (t - Ca), intact parathyroid hormone (iPTH) and alkaline phosphatase (AKP) were analyzed. Last, it was analyzed with multiple regression analysis to related factors of the secondary hyperparathyroidism (SHPT) in patients with CKD. Results Serum calcium, phosphorus and iPTH had no obvious abnormalities at the early stages of CKD [GFR＞60 ml•min-1•(1.73 m2）-1], and relatively stable before GFR＞30 ml•min-1•(1.73 m2)-1. After entering the CKD4 stage, serum phosphorus, iPTH increased sharply and serum calcium decreased obviously along with the decreased glomerular filtration rate (GFR). Serum P, t-Ca and iPTH levels were statistically significant in CKD 1 to 5D patients, respectively, serum P: (1.13±0.20) mmol/L, (1.14±0.22) mmol/L, (1.26±0.23) mmol/L, (1.48±0.34) mmol/L, (2.05±0.61) mmol/L and (2.08±0.58) mmol/L; serum t-Ca (mmol/L) (2.35±0.13) mmol/L, (2.35±0.12) mmol/L, (2.35±0.15) mmol/L, (2.26± 0.18) mmol/L, (2.07±0.29) mmol/L and (2.31±0.26) mmol/L; iPTH: 57.8(45.6, 91.8) ng/L, 54.1(37.8, 74.6) ng/L, 71.6(45.8, 102.2) ng/L, 131.1(81.7, 205.1) ng/L, 277.5(173.6, 395.3) ng/L and 354.9 (194.4, 720.3) ng/L; The stepwise logistic regression analysis showed: hypocalcemia (OR=3.32, P＜0.01) and decreased GFR (OR=5.28, P＜0.01) were independent risk factors of iPTH elevation at stage CKD3～5. Conclusions From the beginning of the CKD3 stage, serum t - Ca, P, iPTH level began to be relatively abnormal as renal function declined. Hyperphosphatemia, SHPT has not been improved significantly in CKD5D stage patients even with hemodialysis. The regulation of hemodialysis on serum calcium showed "overcorrecting" phenomenon.     

The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism

BACKGROUND: A need exists for a therapy that lowers parathyroid hormone (PTH) without increasing calcium x phosphorus in patients with secondary hyperparathyroidism. The calcimimetic AMG 073 increases the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium, thereby reducing PTH secretion. Consequently, AMG 073 may provide a novel therapy for secondary hyperparathyroidism. METHODS: Seventy-eight hemodialysis patients with secondary hyperparathyroidism were enrolled into this 18-week, double-blind, randomized, placebo-controlled, dose titration study. Daily oral AMG 073 doses were administered to determine the effect on PTH, serum calcium, phosphorus, and calcium x phosphorus. RESULTS: The mean baseline PTH was similar in patients administered AMG 073 or placebo (632 +/- 280.1 pg/mL vs. 637 +/- 455.9 pg/mL, respectively). PTH decreased by 26.0% in the AMG 073-treated group, compared with an increase of 22.0% in the placebo group (P < 0.001). A greater proportion in the AMG 073 group (38%) had a decrease in PTH >or=30%, compared with the placebo group (8%) (P = 0.001). Decreases in PTH were independent of baseline vitamin D usage. Patients receiving AMG 073 had an 11.9% decrease in calcium x phosphorus compared with a 10.9% increase in the placebo group (P < 0.001). Use of vitamin D sterols, as well as both calcium and noncalcium-containing phosphate binders. were similar between treatment groups. Administration of AMG 073 was safe and well tolerated in this 18-week study. CONCLUSIONS: The calcimimetic AMG 073 decreases both PTH and calcium x phosphorus levels in hemodialysis patients with secondary hyperparathyroidism.     

Plasma bone-specific alkaline phosphatase changes in hemodialysis patients treated by alfacalcidol

Vitamin D derivatives correct high bone remodeling by decreasing plasma iPTH concentration in uremic patients with secondary hyperparathyroidism. However, without bone biopsy, plasma iPTH alone might not provide sufficient information regarding vitamin D-induced bone changes. Plasma bone-specific alkaline phosphatase (bAP) seems more sensitive than iPTH in assessing the degree of bone remodeling. We prospectively studied the evolution of iPTH and bAP in 14 adult hemodialysis patients treated for 1 year by i.v. alfacalcidol pulses. The mean total alfacalcidol dose was 0.08 +/- 0.02 g/kg/week. Ten patients completed the study, 2 patients had to be parathyroidectomized before week 24 because of hypercalcemia and uncontrolled hyperphosphatemia, and 2 other patients died before week 36. Mean iPTH levels diminished from 826 +/- 300 pg/ml (range 507 - 1,500 pg/ml) at baseline to 436 +/- 371 pg/ml (range 18 - 1,095 pg/ml) after 52 weeks of treatment (48% of decrease). Only 2 patients normalized plasma iPTH levels while 8/10 normalized bAP. Five patients remained with plasma iPTH concentrations higher than 5-fold the normal value. In contrast, plasma bAP levels declined from 47.6 +/- 32.2 ng/ml (range 15.4 - 130.0 ng/ml) at baseline to 17.8 +/- 9.9 ng/ml (range 8.0 +/- 38.0 ng/ml) at week 52 (63% of decrease). Bone histomorphometry was available in 6 patients after 15.8 +/- 5.1 months of alfacalcidol treatment. None of them met the criteria of adynamic bone disease as they had increased bone resorption and marrow bone fibrosis. Bone formation rate was normal in 2 patients and unmeasurable in the other 4. Two patients showed signs of osteomalacia. In conclusion, alfacalcidol preferentially reduced bone formation rate rather than the other histological parameters of secondary hyperparathyroidism. It reduced plasma bAP more efficiently than iPTH.