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     

High-dose oral calcitriol and zero calcium peritoneal solutions in CAPD patients with refractory secondary hyperparathyroidism

Abstract. We evaluated the effect of pulse oral calcitriol (4µg three times weekly for 6 months) on parathyroid functionin nine CAPD patients with hyperparathyroidism refractory toconventional lowdose oral calcitriol. Zero calcium peritonealsolutions were used to prevent the development of hypercalcaemia.The peritoneal loss of calcium increased from 168á40to 417á48 mg/day using zero calcium solutions. Pulseoral calcitriol resulted in a significant decrease in PTH (from617á272 to 382á299 pg/ml) by the 15th day of therapy,while serum iCa did not change from baseline. During the firstmonth of therapy the mean PTH levels remained significantlyreduced compared to baseline, thereafter PTH increased in fourof nine patients. Hyperphosphataemia was not satisfactorilycontrolled in four patients, despite large amounts of bindersused; seven of nine patients developed hypercalcaemia and requiredeither the substitution of calcium acetate for calcium carbonateor reduction of calcitriol dose. Three patients showed a progressiveincrease in PTH. In conclusion our data suggest that in mostCAPD patients with severe hyperparathyroidism oral calcitriolpulse therapy is not effective in maintaining a permanent suppressionin PTH levels.     

Randomized trial comparing pulse calcitriol and alfacalcidol for the treatment of secondary hyperparathyroidism in haemodialysis patients

Aim: Calcitriol and alfacalcidol are used extensively for the treatment of secondary hyperparathyroidism. Unfortunately, there is limited published data comparing the efficacy and tolerability of both active vitamin D sterols. This study was undertaken to determine whether calcitriol provides a therapeutic advantage to alfacalcidol. Methods: This was a randomized, active controlled study. Patients with intact parathyroid hormone (iPTH) >32 pmol/L were randomized to receive orally calcitriol or alfacalcidol after each haemodialysis for up to 24 weeks. Reduction of PTH, changes of plasma albumin‐corrected calcium and phosphorus were analysed. The initial dose of alfacalcidol was twice that of calcitriol. Results: Sixteen patients were randomized into each group. At baseline, plasma albumin‐corrected calcium, phosphorus and PTH were no different between groups. At 24 weeks, PTH changes were ?50.8 ± 31.8% and ?49.4 ± 32.5% from the baseline in the calcitriol and alfacalcidol groups, respectively (P = 0.91). The patients who achieved target PTH of 16–32 pmol/L were 82% in the calcitriol and 67% in the alfacalcidol group (P = 0.44). Plasma albumin‐corrected calcium and phosphorus were not significantly different but showed trends toward gradually increasing from baseline in both groups (calcium, 6.0 ± 7.2% vs 10.9 ± 6.5% (P = 0.10); phosphorus, 13.0 ± 29.4% vs 16.7 ± 57.2% (P = 0.83) in calcitriol and alfacalcidol, respectively). The mean dose of calcitriol and alfacalcidol were 4.1 and 6.9 µg/week, respectively (P < 0.0001). Conclusion: Alfacalcidol can be used to control secondary hyperparathyroidism at doses of 1.5–2.0 times that of calcitriol. The two drugs are equally efficacious and lead to similar changes in calcium and phosphorus.     

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.     

Comparison of the efficacy of an oral calcitriol pulse or intravenous 22-oxacalcitriol therapies in chronic hemodialysis patients

Background 1,25-dihydroxy-22-ovavitamin D₃ (22-oxacalcitriol, OCT) was recently introduced commercially as an analogue of 1,25 (OH)₂ vitamin D₃, but one which has less pronounced calcemic activity. Methods To examine the efficacy and tolerability of OCT, 46 hemodialysis patients with secondary hyperparathyroidism were randomly assigned to receive either intravenous OCT or oral calcitriol pulse therapies. The patients were monitored for serum calcium, phosphate, intact parathyroid hormone (PTH), and bone alkaline phosphatase (BAP) for 24 weeks. The efficacy of intravenous OCT was also examined in 24 additional patients who were refractory to oral calcitriol pulse therapy. Results In the randomized trial, intact PTH levels were significantly suppressed within 4 weeks after the initiation of each therapy, and this effect was well maintained thereafter in both treatment groups. While intact PTH was significantly lower at 4 weeks in the calcitriol pulse group than in the OCT group (P = 0.02), no statistical differences were observed during later treatment periods. BAP was reduced equally by each treatment. At 4 weeks (P = 0.02) and thereafter (P = 0.06), serum calcium was higher among calcitriol-treated patients than among those who received OCT treatment. Eight of 24 patients who were refractory to oral calcitriol pulse therapy responded to intravenous OCT. The patients who responded tended to have lower serum intact PTH and phosphorus levels and smaller parathyroid glands at the start of OCT treatment than nonresponders. Conclusions OCT is as effective as oral calcitriol pulse therapy in suppressing intact PTH and BAP in chronic hemodialysis patients. It was confirmed that OCT exhibits less calcemic activity than calcitriol. Moreover, under certain conditions, switching to OCT may help in the treatment of hyperparathyroidism, which is refractory to conventional oral calcitriol pulse therapy.     

Cytokines and adhesion molecules in renal vasculitis and lupus nephritis

Background: Plasma levels of some pro-inflammatory cytokines and soluble adhesion molecules have been suggested to be useful parameters to assess the activity of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis and lupus nephritis. We hypothesized that the renal activity of these diseases is better reflected by the urinary excretion and fractional excretion of these molecules. Methods: Plasma levels and urinary excretion of tumour necrosis factor-&agr; (TNF-&agr;), interleukin (IL)-6, IL-8, and the soluble cell adhesion molecules sICAM-1 and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) in 15 patients with ANCA-positive renal vasculitis (eight active, ANCA-A; six in remission, ANCA-R), six patients with active lupus nephritis (LN), 15 patients with IgA nephropathy (IgAN) and nine healthy subjects. Fractional excretion of selected cytokines and adhesion molecules was also calculated. Results: Patients with ANCA-A had increased urinary excretion and fractional excretion of TNF-&agr; (9.27±3.19% vs 0.58±0.02%, P<0.01), IL-6 (120.79±65.83% vs 1.89±0.34%, P<0.01) and increased fractional excretion of IL-8 (23.34±6.38% vs 2.56±1.07%, P<0.01) and sVCAM-1 (0.81±0.33% vs 0.03±0.02%, P<0.01) compared with controls. Urinary excretion of TNF-&agr; and IL-6 and fractional excretion of TNF-&agr;, IL-6 and IL-8 were higher in ANCA-A than in ANCA-R. Patients with LN had increased plasma TNF-&agr; (20.52±2.01 pg/ml vs 12.33±0.23 pg/ml, P<0.05) and sVCAM-1 (1537.88±276.36 ng/ml vs 692.26±44.42 ng/ml, P<0.05) and increased urinary excretion of TNF-&agr; (2.81±0.51 &mgr;g/mol creat vs 0.98±0.05 &mgr;g/mol creat, P<0.01), IL-8 (35.78±14.03 &mgr;g/mol creat vs 12.46±5.19 &mgr;g/mol creat, P<0.05) and sVCAM-1 (48.98±20.20 &mgr;g/mol creat vs 2.92±1.35 &mgr;g/mol creat, P<0.01) compared with controls. Patients with IgAN had, in comparison with controls only increased plasma TNF-&agr; (18.10±0.57 pg/ml vs 12.33±0.23 pg/ml, P<0.05). Conclusions: Urinary excretion and fractional excretion, but not plasma levels of selected proinflammatory cytokines (TNF-&agr;, IL-6 and IL-8) were increased in patients with active ANCA-positive renal vasculitis, but not in ANCA positive vasculitis in remission. These parameters may be useful to monitor the activity of this disease.     

Sequential changes of biochemical bone parameters after kidney transplantation

Background. Persistant hyperparathyroidism after renal transplantation (Rtx) has been reported in several studies. However these studies evaluated biochemical bone parameters either only during a short time period (up to 6 months) or for a longer time period, but with long intervals in between. Therefore, we prospectively evaluated biochemical bone parameters of kidney transplant recipients at short intervals for 2 years after surgery. Methods. Biochemical bone parameters were prospectively investigated in 129 patients 2, 3, 5, 8, 12, 18 and 24 months after Rtx. All patients received prednisone and cyclosporin A as immunsuppressive therapy, and 75 patients was treated with calcium, phosphorus, or vitamin D preparations. Results. Serum creatinine levels decreased from 166.8±5.4 &mgr;mol/l to 140.0±4.9 two years after Rtx; (data are expressed as mean±s.e.m.). Serum phosphorus levels increased slightly from 0.9±0.022 mmol/l to 0.98±0.025 (12m), but remained within the lower normal range. We observed a rise in total and albumin adjusted calcium concentrations 3 months after Rtx. 52% of all patients had serum calcium levels above 2.62 mmol/l (upper normal limit in our laboratory) 3 months after renal transplantation with a gradual decrease thereafter. There was no correlation of calcium and PTH levels. We observed a significant rise in biochemical bone parameters from 2 to 5 months after renal transplantation (P<0.001): alkaline phosphatase (AP) increased from 164.3±9.4 to 236±12.7 U/l (normal 50-180), bone specific alkaline phosphatase (BAP) rose from 17.7±1.36 to 23.2±1.7 ng/ml (normal:4-20) and osteocalcin (OC) increased from 20.2±1.5 to 26.7±1.9 ng/ml (normal 4-12). AP and BAP levels values normalized 12 months after renal transplantation, whereas OC was still above normal throughout the study period. Patients were subdivided into two groups: those with good and those with impaired graft functions. Patients with good graft function had stable serum creatinine levels (⩽132 &mgr;mol/l or ⩽1.5 mg/dl) well below the mean serum creatinine concentration during the study period. The significant changes in AP, BAP, and OC occurred irrespective of renal function. However, patients with impaired graft function (n=65) had significantly higher PTH-levels (70 pg/ml higher) than patients with good graft function (n=64), P<0.01. PTH was positively correlated with serum creatinine (r=0.0.001). Moreover, patients with low 25(OH) vitamin D levels (n=63) had significantly higher PTH concentrations (between 40 and 80pg/ml, P<0.01) throughout the sudy period compared to patients (n=66) with a sufficient 25(OH)D supply irrespective of graft function. There was a negative correlation of 25(OH)D levels and PTH; (r=-0.49, P<).001). 1,25(OH)2D3 (evaluated in 24 patients) levels increased from 46.5±6.6 to 76.9±7.6pg/ml (normal: 35-90) at 12 months. Conclusion: Hypercalcaemia is a common phenomenon in the early period after kidney transplantation and occurs in the presence of low normal phosphorus levels. It is most probably related to improved PTH action and 1-hydroxylation of vitamin D. The rise in biochemical bone parameters between 3 and 5 months occurs irrespective of graft function and normalization is only achieved 1 year after transplantation. PTH is constantly elevated for up to 2 years after kidney transplantation and is most probably related (a)to impaired graft function and (b) to suboptimal 25 OH vitamin D supply. Keywords: hypercalcaemia; biochemical bone parameters; renal transplantatiom; secondary hyperparathyroidism; vitamin D      

Twice versus thrice weekly administration of intravenous calcitriol in dialysis patients: a randomized prospective trial. Gruppo Italiano di Studio dell'Osteodistrofia Renale

BACKGROUND: Administration of intravenous (i.v.) calcitriol three times weekly effectively controls the synthesis and secretion of PTH in most uremic patients. Administration of a single dose of 1.25(OH)2D3 reduces synthesis of PTH-mRNA for 6 days in rats. Moreover, it can lower PTH levels for up to 4 days in chronic hemodialysis patients. Therefore, a good response to the administration of i.v. calcitriol two times weekly can be expected. We studied - in a multicenter randomized study in patients with moderate to severe secondary hyperparathyroidism - the effects of the same doses of intravenous calcitriol, administered two or three times weekly. METHODS: Twenty-two hemodialysis patients were randomized into two frequencies of treatment groups: two times (G-2/w) and three times weekly (G-3/w). Both groups were treated with increasing doses of intravenous calcitriol for 3 months (first month 3 microg, second month 4 microg, third month 6 microg weekly). RESULTS: After 12 weeks of therapy with intravenous calcitriol the G-2/w group showed a significant reduction in serum PTH levels (from 821 +/- 392 to 350 +/- 246 pg/ml; mean reduction = 57.4%) comparable to the decrease observed in the G-3/w group (from 632 +/- 116 to 246 +/- 190 pg/ml; mean reduction = 61.2%). Ionized calcium (G-2/w from 1.13 +/-0.10 to 1.14 +/- 0.08 and G-3/w 1.21 +/- 0.13 to 1.26 +/- 0.18 mmol/l) and phosphate levels (G-2/w from 4.99 +/- 1.01 to 5.99 +/- 1.78 and G-3/w 5.31 +/- 0.73 to 5.81 +/- 1.18 mg/dl) did not change significantly and phosphate binders were not modified during the study. CONCLUSION: This study confirms that intravenous calcitriol is an effective therapy for moderate to severe secondary hyperparathyroidism. The administration of two doses per week of intravenous calcitriol is as efficacious as three doses per week in suppressing PTH secretion.     

Vitamin D receptor genotype influences parathyroid hormone and calcitriol levels in predialysis patients.

BACKGROUND: BsmI vitamin D receptor (VDR) gene polymorphism has been associated with the severity of hyperparathyroidism in patients on hemodialysis. The aim of this study was to analyze the influence of this polymorphism on parathyroid function and serum calcitriol levels in patients with different degrees of chronic renal failure (CRF) before dialysis. METHODS: A total of 248 CRF patients, divided into three groups according to creatinine clearance (CCr; mild CRF group> 60 to 35 to 10 to 2.5 mmol/liter and serum phosphorus levels of> 1.6 mmol/liter or who needed phosphorus binding agents were excluded. The statistical analysis was done with the general factorial analysis of variance entering first PTH and then calcitriol as the dependent variable; the genotype (BB, Bb and bb), sex and CCr group were defined as factors; and covariables included serum calcium, serum phosphorus, 1/creatinine versus time slope, PTH when calcitriol was the dependent variable, and calcitriol when PTH was the dependent variable. RESULTS: When serum PTH levels were entered as the dependent variable, serum calcium, CCr group, and the interaction of genotype with the CCr group were found to be significant factors (P = 0.025, P <0.001 and P = 0.039, respectively). When serum calcitriol levels were entered as the dependent variable, genotype, the interaction of genotype with CCr, the CCr group, and the 1/creatine versus time slope were found to be significant (P = 0.027, P = 0.028, P <0.001 and P = 0.044, respectively). The marginal means of PTH, adjusted with the general factorial analysis of variance across the three groups were: (a) mild CRF group, BB 5.3 pmol/liter (CI 0 to 13.8), Bb 5.5 pmol/liter (CI 2 to 9), bb 5.4 pmol/liter (CI 0.6 to 10.2); (b) moderate CRF group, BB 6.2 pmol/liter (CI 1.5 to 10.9), Bb 7.8 pmol/liter (CI 5.3 to 10.3), bb 7.5 pmol/liter (CI 4.8 to 10.1); (c) severe CRF group, BB 9.3 pmol/liter (CI 4.2 to 14.3), Bb 17.1 pmol/liter (CI 13.9 to 20.2), bb 21.9 pmol/liter (CI 18.7 to 25.2). The marginal means of calcitriol adjusted with the general factorial analysis of variance across the three groups were: (a) mild CRF group, BB 47 pg/ml (CI 37 to 57), Bb 40.9 pg/ml (CI 37 to 44.8), bb 32.6 pg/ml (CI 26.8 to 38. 4); (b) moderate CRF group, BB 24.1 pg/ml (CI 18.3 to 29.8), Bb 26.6 pg/ml (CI 23.5 to 29.7), bb 25.3 pg/ml (CI 22 to 28.6); (c) severe CRF group, BB 27.4 pg/ml (CI 21.3 to 33.5), Bb 19.4 pg/ml (CI 15.5 to 23.2), bb 20.4 pg/ml (CI 16.1 to 24.7). CONCLUSION: The progression of hyperparathyroidism is slower in predialysis patients with BB genotypes than in the other genotypes. Also, calcitriol levels are less reduced in the BB genotype, which may act to lessen the severity of secondary hyperparathyroidism.     

Alphacalcidol oral pulses normalize uremic hyperparathyroidism prior to dialysis

Alphacalcidol oral pulse therapy was given for secondary hyperparathyroidism to 22 children (mean age of 5.6 years) with renal insufficiency. At the beginning of the study, the glomerular filtration rate was <50% of normal, serum intact parathyroid hormone (PTH) was >100 ng/l and the serum phosphate and calcium concentrations were within the normal range. Alphacalcidol (0.5–3.0 g) was given orally thrice weekly in the evening and adjusted according to PTH, ionized calcium and phosphate concentrations. Serum PTH (mean ± SEM) decreased significantly from a pre-treatment level of 393±81 ng/l to 122±34 ng/l after 12 months, and stabilized at this level. Mean vitamin D metabolite concentrations were within the normal range. 1,25-Dihydroxyvitamin D did not increase during therapy, while PTH decreased. The estimated creatinine clearance remained almost unchanged (20±3 and 21±6 ml/min per 1.73 m²). Growth remained low normal (height standard deviation score –1.8±0.3 initially and –1.7±0.4 12 months later) and bone mineral density did not decrease. We concluded that feedback regulation of PTH with oral alphacalcidol pulse therapy is effective in the treatment of hyperparathyroidism in children with renal failure prior to dialysis.     

Pulse oral calcitriol for the treatment of hyperparathyroidism in patients on continuous ambulatory peritoneal dialysis: preliminary observations.

A direct effect of calcitriol on the regulation of the secretion of parathyroid hormone (PTH) has been shown in vitro and in vivo. In patients with renal failure on maintenance hemodialysis, it has been shown that intravenous (IV) administration of calcitriol appears to be superior to continuous oral administration. This may be due to the higher levels of calcitriol obtained in blood with consequent improved delivery of calcitriol to peripheral target tissues including the parathyroid glands. However, IV administration of calcitriol, is not practical for patients with end-stage renal disease (ESRD) who are maintained on continuous ambulatory peritoneal dialysis (CAPD). The present studies were designed to investigate whether intermittent administration of large doses of calcitriol orally ("pulse therapy") could mimic the effects of IV calcitriol in hemodialysis patients and achieve suppression of PTH secretion. Studies were performed in five patients who had been maintained on CAPD for more than 6 months. After basal determinations of calcium, phosphorus, and PTH, therapy was begun with calcitriol administered orally in a dose of 5 micrograms given twice per week. Calcium carbonate was continued as a phosphate binder. Dialysate calcium concentration was 1.75 mmol/L (3.5 mEq/L). With this therapy, PTH levels decreased rapidly, and, after 4 to 6 weeks of therapy, reached values 60% lower than pretreatment values. Mean values for serum calcium did not change significantly (2.29 +/- 0.12 mmol/L [9.6 +/- 0.5 mg/dL] before treatment compared with 2.32 +/- 0.08 mmol/L [9.7 +/- 0.25 mg/dL] after therapy). Mean serum phosphorus was also unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effects of calcitriol and maxacalcitol on secondary hyperparathyroidism in patients on chronic haemodialysis: a randomized prospective multicentre trial.

BACKGROUND: To identify differences between the effects of calcitriol and the calcitriol analogue, maxacalcitol, on parathyroid hormone (PTH) and bone metabolisms, we conducted a randomized prospective multicentre study on patients on chronic haemodialysis. METHODS: We randomly assigned 91 patients with secondary hyperparathyroidism [intact PTH (iPTH) > or =150 pg/ml] to have either calcitriol (47 patients) or maxacalcitol (44 patients) therapy, for 12 months after a 1 month control period. Serum electrolytes, bone alkaline phosphatase (bAP), iPTH, total PTH and PTH(1-84) (whole PTH) levels were measured periodically. The first end point was a serum iPTH of <150 pg/ml, the second was the iPTH levels obtained. RESULTS: Treatment was discontinued for various reasons in nine patients in each group, but no serious side effects were observed in either group. The numbers of cases reaching the first end point were not significantly different between the two groups. Serum calcium concentration was significantly higher in the maxacalcitol than the calcitriol group during early treatment, but not at the end of treatment. Throughout the treatment period there were no significant differences between the two groups in serum iPTH, inorganic phosphate, the product of the serum calcium and inorganic phosphorus concentrations, bAP, or the ratio of whole PTH to total PTH minus whole PTH. Nor were the changes in these parameters significantly different between the two groups comparing the patients with moderate to severe hyperparathyroidism (basal iPTH > or =500 pg/ml). CONCLUSION: Calcitriol and maxacalcitol are equally effective on PTH and bone metabolism.     

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.     

Advantages of adjusting the initial dose of intravenous calcitriol according to PTH levels

BACKGROUND: To assess the usefulness of starting calcitriol therapy with a dose proportional to the degree of hyperparathyroidism, 141 patients from 28 centers were treated with intravenous calcitriol for 6 months. The aim was to achieve a final PTH between 125 and 250 pg/mL. Patients with serum PTH>250 pg/mL were included in the study and divided into 4 groups according to baseline PTH levels. METHODS: The study was completed by 100 patients, a third of which were treated strictly according to the protocol, labeled "compliants"; thus, calcitriol was started according to baseline PTH levels. Two thirds of patients, labeled "noncompliants," showed one or more violation in the dosage regimen. RESULTS: After 2 months of treatment with calcitriol, 59% of the "compliants" and 35% of the "noncompliants" decreased their PTH levels>40% (P = 0.022), 70%, and 49%, respectively after 3 months of treatment. After 3 months of treatment, 67% of the "compliants" reached the target (PTH 125 to 250 pg/mL) in contrast with 23% of the "noncompliants" (P < 0.001). The number of hypercalcemic and hyperphosphatemic episodes was significantly lower in the "compliants" group (P < 0.006). CONCLUSION: These results demonstrate several advantages when calcitriol therapy is started with a dose proportional to the severity of hyperparathyroidism.     

High-normal calcium (1.35 mmol/I) dialysate in patients on CAPD: efficient and safe long-term control of plasma calcium, phosphate, and parathyroid hormone

AIM.: The aim of the present study was to examine the long-term efficacyand safety of treatment with a high-normal calcium dialysatewith a calcium concentration of 1.35 mmol/l in patients on CAPD.This dialysate calcium concentration is close to the high-normalplasma ionized calcium level aimed at in dialysis patients inorder to suppress the parathyroid hormone secretion. The end-pointsof the study were (1) plasma ionized calcium (iCa) and phosphate(P) levels, (2) plasma intact parathyroid hormone (PTH) levels,(3) doses of calcium carbonate and alfacalcidol, (4) requirementsof Al-containing phosphate binders, and (5) bone mineral density(BMD). RESULTS.: Thirty-seven non-selected patients on CAPD treatment were followedfor an average of 10 months after switching from a dialysateCa of 1.75 to 1.35 mmol/l. After 1 week, a significant decreaseof mean iCa from 1.26±0.01 to 1.23±0.01 mmol/l(P<0.05) and an increase of median PTH from 80 to 135 pg/ml(P<0.01) were seen. From the 2nd week and onwards, however,basal levels of iCa and PTH were restored and remained stable.Mean plasma iCa was kept within 1.23–1.31 mmol/l; meanplasma P below 1.65 mmol/l and median PTH within 52–135pg/ml. Episodes of hypercalcaemia were few (1.2 cases of plasmaiCa>1.45 mmol/l per 100 treatment weeks), and the need forAl-containing P binders low with only five patients requringthis treatment for isolated and four patients for repeated episodesof hyperphosphataemia or hypercalcaemia. After switching froma dialysate Ca of 1.75 to 1.35 mmol/l, the doses of calciumcarbonate and alfacalcidol could be significantly increased.Furthermore, using the dialysate Ca of 1.35 mmol/l made it possibleto induce a controlled increase of PTH levels to 80–100pg/ml by a temporarily discontinuation of alfacalcidol and/ora reduction of calcium carbonate dosage in the patients wherePTH had become suppressed to levels below the upper normal limit.The intention of the treatment was to maintain PTH levels within1.5–2.5 times the upper normal limit for non-uraemic patients.Pre-study BMD of the vertebral bodies L2–L4 and of thefemoral neck were normal and not significantly different frompost-study measurements. CONCLUSIONS.: The present study demonstrated that when using a high-normaldialysate Ca concentration of 1.35 mmol/l in non-selected patientson CAPD treatment, high-normal plasma iCa and near-normal plasmaP levels could be readily achieved with a minimal risk of incidentalhypercalcaemia despite use of calcium carbonate as the mainP binder. As a consequnce of the tight Ca and P regulation,minimal doses of alfacalcidol were required to keep PTH withinacceptable limits. We recommend this dialysate Ca concentrationas a first-choice therapy for the majority of patients startingon CAPD treatment.     

Prevalence, determinants, and clinical significance of hyperhomocyst(e)inaemia in renal-transplant recipients

Background: Previous studies have demonstrated that hyperhomocyst(e)inaemia is present in patients with impaired renal function and is correlated with cardiovascular disease. Because conflicting data are available on the prevalence, determinants, and clinical significance of hyperhomocyst(e)inaemia in renal-transplant recipients, we conducted the largest cross-sectional study on homocysteine determinants and clinical correlates in renal transplant recipients. Methods: Plasma homocyst(e)ine concentrations and factors known to influence homocysteine metabolism were analysed in 224 renal transplant recipients. Atherosclerotic complications were evaluated with respect to plasma homocysteine concentrations. Results: Mean plasma homocyst(e)ine was 21.3±9.7 &mgr;mol/l. After adjusting for age, gender, transplant duration and creatinine clearance, patients with and without cyclosporin A (CsA) had similar plasma homocyst(e)ine concentrations (16.9±5.9 &mgr;mol/l in CsA(+) patients vs 16.3±5.2 &mgr;mol/l in CsA(-) patients; P=0.3). We found a significant inverse relationship between plasma homocyst(e)ine and folate concentrations in both CsA(+) (r=-0.243; P<0.005) and CsA(-) (r=-0.396; P<0.05) patients. Patients with a past history of cardiovascular events had higher plasma homocyst(e)ine concentrations (25.2±11.7 mmol/l vs 20.5±8.8 mmol/l; P<0.005). Conclusion: Homocyst(e)inaemia is closely related to renal function and folate concentration in renal-transplant recipients. CsA does not seem to have direct effects on homocysteine metabolism. Hyperhomocyst(e)inaemia is associated with cardiovascular disease in renal-transplant recipients. Prospective placebo-controlled homocysteine-lowering therapy studies are required in this patient category.     

Modulation of endochondral bone formation: roles of growth hormone, 1,25-dihydroxyvitamin D and hyperparathyroidism

Impairment of linear growth occurs invariably in children with chronic renal failure. Recombinant human growth hormone and 1,25-dihydroxyvitamin D (calcitriol) are widely utilized to improve linear growth in children. Large doses of calcitriol, however, have been shown to suppress chondrocyte proliferation and may lead to the development of adynamic bone. Substantial reductions of growth have been shown in children with chronic renal failure treated with intermittent calcitriol therapy. These findings suggest that calcitriol can modify chondrocyte proliferation and/or differentiation in epiphyseal growth plate cartilage and may counteract the effects of growth hormone therapy in increasing linear growth in children with chronic renal failure. Parathyroid hormone related peptide (PTHrP) and its receptor (PTH/PTHrP receptor) play critical roles in regulating chondrocyte differentiation in the growth plate. The expression of PTH/PTHrP receptor mRNA is downregulated in animals with chronic renal failure and advanced secondary hyperparathyroidism; calcitriol and growth hormone therapy may modify the expression of PTH/PTHrP receptor. This article summarizes the separate and combined effects of growth hormone and calcitriol on endochondral bone formation in chronic renal failure and secondary hyperparathyroidism. Received: 10 September 1999 / Revised: 23 December 1999 / Accepted: 30 December 1999     

Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism

BACKGROUND: Management of secondary hyperparathyroidism has included the use of active vitamin D or vitamin D analogs for the suppression of parathyroid hormone (PTH) secretion. Although, these agents are effective, therapy is frequently limited by hypercalcemia, hyperphosphatemia, and/or elevations in the calcium-phosphorus (Ca x P) product. In clinical studies, paricalcitol was shown to be effective at reducing PTH concentrations without causing significant hypercalcemia or hyperphosphatemia as compared to placebo. A comparative study was undertaken in order to determine whether paricalcitol provides a therapeutic advantage to calcitriol. METHODS: A double-blind, randomized, multicenter study comparing the safety and effectiveness of intravenous paricalcitol and calcitriol in suppressing PTH concentrations in hemodialysis patients was performed. A total of 263 randomized patients were enrolled at domestic and international sites. Following the baseline period, patients with serum Ca x P < 75, and a PTH level > or =300 pg/mL were randomly assigned to receive either paricalcitol or calcitriol in a dose-escalating fashion for up to 32 weeks. Dose adjustments were based on laboratory results for PTH, calcium, and Ca x P. The primary end point was the greater than 50% reduction in baseline PTH. Secondary end points were the occurrence of hypercalcemia and elevated Ca x P product. RESULTS: Paricalcitol-treated patients achieved a > or =50% reduction from baseline PTH significantly faster than did the calcitriol-treated patients (P = 0.025) and achieved a mean reduction of PTH into a desired therapeutic range (100 to 300 pg/mL) at approximately week 18, whereas the calcitriol-treated patients, as a group, were unable to achieve this range. Moreover, paricalcitol-treated patients had significantly fewer sustained episodes of hypercalcemia and/or increased Ca x P product than calcitriol patients (P = 0.008). CONCLUSION: Paricalcitol treatment reduced PTH concentrations more rapidly with fewer sustained episodes of hypercalcemia and increased Ca x P product than calcitriol therapy.     

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.     

Effect of calcitriol replacement on serum calcitonin and parathyroid hormone levels in CAPD patients

Calcitonin-secreting cells, ‘C cells’, have specificreceptors for calcitriol, thus the calcitriol deficiency inuraemia may affect calcitonin secretion and/or production. Theaim of the present study was to evaluate in CAPD patients theeffect of calcitriol replacement (4 weeks of oral calcitriol,0.5 ng/day) on both, basal calcitonin concentration and calcitoninresponse to calcium infusion (calcium gluconate, 3 mg/kg/h). Calcitriol replacement produced a normalization of serum calcitriollevel without a significant change in serum calcium concentration.After calcitriol replacement, basal calcitonin increased from78 ± 15 to 101 ± 13pg/ml, P<0.05. The incrementin calcitonin induced by a calcium infusion was lower after(15±4pg/ml) than before (29±4pg/ml) calcitriolreplacement. In addition, calcitriol administration induceda decrease in serum PTH level. Replacement of calcitriol in CAPD patients produced an increasein serum calcitonin concentration and a decrease in the calcitoninresponse to hypercalcaemia.