NDT Advance Access originally published online on February 3, 2007
Nephrology Dialysis Transplantation 2007 22(6):1639-1644; doi:10.1093/ndt/gfl840
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Implementation of ‘K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease’ after the introduction of cinacalcet in a population of patients on chronic haemodialysis
1Nephrology Department, Hospital Perpetuo Socorro, Plaza Dr Gomez ulla, 15, 03013 Alicante and 2Hospital General, Segovia, Spain
Correspondence and offprint requests to: M. D. Arenas, Hospital Perpetuo Socorro, Plaza Dr Gómez Ulla, 15, 03013 Alicante, Spain. Email: lola{at}olemiswebs.com; arenasd{at}perpetuosocorro.nehos.com
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Abstract |
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Background. The purpose of the present study was to evaluate the impact of cinacalcet administration on the attainment of Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation (NFK-K/DOQI) targets, in a group of dialysis patients with secondary hyperparathyroidism that were not controlled with vitamin D metabolites due to inadequate elevations in serum calcium and/or phosphorus.
Methods. Twenty-eight patients undergoing haemodialysis that presented secondary hyperparathyroidism (PTH > 300 pg/ml) with difficulty to use vitamin D either because of hypercalcaemia (>10.2 mg/dl) and/or hyperphosphoraemia (>5.5 mg/dl) were included in this study. The follow-up period was 9 months before and after the introduction of cinacalcet. We started by adding 30 mg of cinacalcet orally once daily to their previous vitamin D metabolite treatment. The following variables were calculated and recorded: the mean of all measurements of serum Ca, P and parathyroid hormones (PTH), and Ca x P in each patient; calcium in dialysate (mEq/l); doses of vitamin D administered; doses of cinacalcet used, and the average prescription of calcium–based phosphate binders, sevelamer hydrochloride and aluminum binders, corresponding to two periods according to the introduction of cinacalcet. The proportions of patients with different serum Ca levels as well as serum P levels; serum PTH levels and CaxP at the beginning and at the end of the nine month period of treatment with cinacalcet were calculated.
Results. Serum PTH (826.9 ± 325 vs 248.1 ± 77.3, P < 0.001), serum calcium (9.9 ± 0.6 vs 8.6 ± 0.4, P < 0.001) and the Ca x P product (94.7 ± 7.3 vs 43.6 ± 8.5; P < 0.001) diminished significantly whereas serum phosphorus remained unchanged (4.8 ± 1.5 vs 4.3 ± 1.1; P = NS). Before cinacalcet, 23 patients had severe hyperparathiroidism (serum PTH > 500) and 15 patients hypercalcaemia (serum calcium >10.2 mg/dl). After 9 months of treatment, all 28 patients showed serum PTH < 500 pg/ml and serum calcium <10.2 mg/dl; 64.7% of the patients achieved Ca, P, Ca x P and PTH objectives simultaneously.
While the mean dose of cinacalcet increased along the 9 months of treatment (P < 0.001), there were no significant changes in vitamin D metabolites (P = 0.5), neither in the mean doses of calcium-containing agents, nor in the mean prescribed doses of sevelamer (P < 0.01), and aluminium-containing agents diminished significantly (P < 0.05).
Conclusions. In summary, the combination of cinacalcet and low doses of vitamin D improved significantly the control of PTH and Ca x P in patients with severe secondary hyperparathiroidism on chronic haemodialysis, without adverse effects and with lower doses of phosphate binders.
Keywords: bone metabolism; calcium; calcimimetics, K/DOQI targets; PTH; vitamin D
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Introduction |
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The K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Renal Disease were published in October 2003 [1], but assessment of the results obtained from the application of those guidelines is essential for evaluating their true applicability and the consequences of its application. A previous study [2], carried out before calcimimetics was available in Spain, and based on monitoring of quality indicators following the publication of the K/DOQI Guidelines, showed that in spite of the application of K/DOQI recommendations, a large proportion of our patients remained outside the proposed targets and pointed to the need for more effective therapeutic options.
Calcimimetics suppress the secretion of parathyroid hormone (PTH) by increasing the sensitivity of the calcium receptors of parathyroid cells to extracellular ionized calcium [3]. Cinacalcet HCL was recently approved by the US FDA and European Medicines Agency for treatment of secondary hyperparathyroidism of dialysis patients [4,5]. A recent study showed that cinacalcet-treated subjects were more likely to achieve the Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation (NFK-K/DOQI) recommended goals for CaxP (65%) and concurrent CaxP and PTH (41%) [6]. Post-hoc analysis of long-term data from 1184 patients has shown that cinacalcet HCl treatment might reduce the risk of parathyroidectomy compared with placebo [7].
The purpose of the present study was to evaluate the impact of cinacalcet administration on the attainment of NFK-K/DOQI targets, in a group of dialysis patients with secondary hyperparathyroidism that were not controlled with vitamin D metabolites due to inadequate elevations in serum calcium and/or phosphorus.
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Patients
The criteria for using calcimimetics in our unit are secondary hyperparathyroidism (PTH > 300 pg/ml) with difficulty to use vitamin D either because of hypercalcaemia (>10.2 mg/dl) and/or hyperphosphoraemia (>5.5 mg/dl). The exclusion criteria is a serum calcium <8.4 mg/dl. All the 28 patients undergoing haemodialysis in our unit that presented such criteria were included in this study. The follow-up period was 9 months after the introduction of cinacalcet.
All patients received regular haemodialysis sessions, lasting from 3.5 to 4 h, three times weekly, using 1.8–2.1 m2 polysulphone dialysers of varying permeability. They were all maintained in a stable haemodialysis regimen and similar schedule of dialysis in all studied periods.
Objectives, quality standards and NFK-K/DOQI recommendations
From October 2003, NFK-K/DOQI recommendations were introduced in our haemodialysis units and the objectives were to maintain PTH levels between 150 and 300 pg/ml (Guideline 1.4), serum Ca levels between 8.4 and 9.5 mg/dl (Guideline 6.2), P levels between 3.5 and 5.5 mg/dl (Guideline 3.2), and Ca x P <55 mg2/dl2 (Guideline 6.5). Guidelines 7 and 8 state that vitamin D metabolites should be reduced or discontinued if serum calcium levels are >10.2 mg/dl, phosphorus levels are >5.5 mg/dl, the Ca x P product is >55 mg2/dl2, or PTH levels are decreased <150 pg/ml (Guideline 7). Guideline 5 states that the total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1500 mg/day and that non-calcium-containing phosphate binders are preferred in dialysis patients with severe vascular and/or other soft-tissue calcifications. Guideline 9 recommends the use of dialysates with a calcium content of 2.5 mEq/l.
Treatments
In those 28 patients, we started by adding 30 mg of cinacalcet orally once daily to their previous vitamin D metabolite treatment (Alphacalcidol: Etalpha®; Leo Pharma) that was being given in intravenous pulses immediately after haemodialysis sessions. When NFK-K/DOQI recommendations were introduced, a 2.5 mEq/l dialysate calcium concentration was preferentially used; but after calcimimetric introduction the dialysate calcium content changed to 3 mEq/l in order to avoid the hypocalcaemia associated with cinacalcet administration. A combination of calcium-based phosphate-binding agents (calcium acetate), aluminium-containing phosphate-binding agents (aluminium hydroxide) and non-calcium, non-aluminium, non-magnesium-containing phosphate-binding agents (sevelamer) were used to achieve the serum P target: such schedule was initially maintained without changes when cinacalcet was introduced.
Doses were adjusted according to patient response. Criteria for vitamin D metabolites and/or cinacalcet dosage adjustment were based on the K/DOQI Guideline's recommended levels of calcium, phosphorus and/or PTH. When PTH levels were >300 pg/ml, if serum calcium was <8.4 mg/dl and there was no hyperphosphoraemia (phosphorus >5.5 mg/dl), the dose of vitamin D was increased; if serum calcium was >9.5 mg/dl or serum phosphorus >5.5 mg/dl, the dose of cinacalcet was increased. In the case of PTH < 150 pg/ml, the dose of vitamin D metabolites or cinacalcet were reduced to calcium and/or phosphorus levels as previously stated. The objective was to maintain a combination of the lowest possible doses of both drugs, in order to reach the K/DOQI recommended objectives with minimal side-effects.
Monitoring
PTH was routinely measured every 2 months, and serum Ca and P levels, every month. In patients in whom drug dosage changes were made or calcimimetics were introduced, PTH, Ca, and P were measured more frequently (PTH monthly, and calcium and phosphorus weekly or biweekly).
The following variables were calculated and recorded: the mean of all measurements of serum Ca, P and PTH, and Ca x P in each patient; calcium in dialysate (mEq/l); doses of vitamin D administered; doses of cinacalcet used, and the average prescription of calcium-based phosphate binders (expressed as milligrams of elemental calcium/day), sevelamer hydrochloride (expressed as number of sevelamer 800 mg tablets/day) and aluminum binders, corresponding to two periods according to the introduction of cinacalcet: the 9 months before (pre-cinacalcet period) and the 9 months after (post-cinacalcet period).
The proportions of patients with different serum Ca levels were calculated: <8.4 mg/dl, between 8.4 and 9.5 mg/dl, between 9.5 mg/dl and 10.2 mg/dl and >10.2 mg/dl; as well as serum P levels less than and >5.5 mg/dl; serum PTH levels <150 pg/ml, between 150 and 300 pg/ml, between 300 and 500 pg/ml and >500 pg/ml; and Ca x P less than and >55 mg2/dl2 at the beginning and at the end of the 9 month period of treatment with cinacalcet.
Laboratory tests
Calcium (by UV-Vis spectrophotometry; normal laboratory range, 8.6–10.4 mg/dl), phosphorus (by UV-Vis spectrophotometry; normal laboratory range, 2.7–4.5 mg/dl) and intact PTH (using an electro-chemoluminescence technique; normal laboratory range, 10–65 pg/ml) were measured just before the mid-week dialysis session. There were no changes in laboratory techniques and commercial kits used in both periods.
Statistical analysis
The statistical analysis was carried out with SPSS 12.1 software. A paired Student's t-test was used to compare the means of all Ca, P, Ca x P and PTH measurements in every patient in both periods. Percentages were compared using a Mc Nemar test.
The statistical significance level used was P < 0.05.
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Demographic characteristics
The mean age at the beginning of study was 53.1 ± 14.8 years, and the mean time on haemodialysis was 426.1 ± 264.9 months; 18 patients (64.2%) were male and 10 patients (35.7%) were female. No significant differences were found in mean sKTV levels and mean haemoglobin values between the pre-cinacalcet (1.46 ± 0.54 and 12.4 ± 0.5 g/dl, respectively) and the post-cinacalcet (1.47 ± 0.54 and 12.3 ± 0.4 g/dl, respectively) periods.
Comparison between the pre- and post-cinacalcet periods
Following the introduction of cinacalcet treatment, there was a significant decrease in mean serum PTH (590.4 ± 259.1 pre-cinacalcet period and 414.2 ± 198.3 post-cinacalcet period; P < 0.05); mean pre-dialysis serum calcium levels (9.8 ± 0.5 pre-cinacalcet period and 8.9 ± 0.4 post-cinacalcet period; P < 0.001); mean serum phosphorus levels (5.29 ± 0.7 pre-cinacalcet period and 4.3 ± 0.9 post-cinacalcet period; P < 0.01) and calcium x phosphorus product (47.8 ± 15.3 pre-cinacalcet period and 37. ± 10.6 post-cinacalcet period; P < 0.01)
In the post-cinacalcet period, mean dialysate calcium content increased (2.5 ± 0.0 pre-cinacalcet period and 2.8 ± 0.1 post-cinacalcet period; P < 0.001), and mean vitamin D metabolite doses decreased significantly (5.3 ± 3.5 pre-cinacalcet period and 3.45 ± 1.5 post-cinacalcet period; P < 0.05). At the same time the mean prescribed dose of sevelamer significantly decreased (12.8 ± 3.5 tablets/day pre-cinacalcet period and 8.6 ± 5.3 tablets/day post-cinacalcet period; P < 0.05) whereas the mean prescribed daily amount of elemental calcium remained unchanged (391.4 ± 401.2 pre-cinacalcet period and 320.6 ± 360.5 post-cinacalcet period; P = NS).
Achievement of NFK-K/DOQI recommended goals
Table 1 shows the changes in serum levels of PTH, calcium, phosphorus and Ca x P after the introduction of cinacalcet. As it can be seen, serum PTH, serum calcium and the Ca x P product diminished significantly whereas serum phosphorus remained unchanged. Before cinacalcet, 23 patients had severe hyperparathiroidism (serum PTH > 500) and 15 patients hypercalcaemia (serum calcium >10.2 mg/dl). After 9 months of treatment, all 28 patients showed serum PTH < 500 pg/ml and serum calcium <10.2 mg/dl.
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Table 2 shows the percentages of achievement of NFK-K/DOQI recommended goals, at the time of cinacalcet introduction (month 0) and at the end of the 9 months of cinacalcet treatment.
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Changes in the different components of bone metabolism treatment
Table 3 shows the evolution of the different components of bone metabolism treatment after the introduction of cinacalcet. While the mean dose of cinacalcet increased along the nine months of treatment, there were no significant changes in vitamin D metabolites neither in the mean doses of calcium-containing agents, nor in the mean prescribed doses of sevelamer, and aluminium-containing agents diminished significantly.
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At the end of the study, 12 patients had increased the dose of alfacalcidol by 2.0 ± 1.2 mcg/session, four patients maintained the same dose, and 12 patients diminished the dose in 2.9 ± 0.9 mcg/session.
The dose of cinacalcet at the end of the 9 months was 30 mg in 17 patients, 60 mg in eight patients, 90 mg in two patients and 120 mg in one patient. Three patients complained of gastrointestinal discomfort (nausea/vomiting and diarrhoea) that improved after nightly administration of cinacalcet. No clinical signs or symptoms of hypocalcaemia (muscle spasms, confusion or abdominal pain) were reported. Two consecutive measurements of serum Ca <8.4 mg/dl were reported in three patients and two consecutive measurements of serum Ca <7.5 mg/dl were reported in two subjects. No patient was withdrawn from the study due to hypocalcaemia.
At the beginning of cinacalcet treatment, all 28 patients were changed to a dialysate with a calcium content of 3.0 mEq/l; after 9 months, 12 patients could be changed to a dialysate with 2.5 mEq/l of calcium.
At the end of the study 85.7% of the patients were using sevelamer; 50% calcium-containing agents and 28.5% aluminium-containing agents.
After the introduction of cinacalcet the mean monthly cost per patient increased by 192 euros; at 9 months the cost could be reduced by 21.4 euros due to the reduction in sevelamer and alphacalcidol doses (Table 4).
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Discussion |
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The 2003 guidelines for the management of hyperparathyroidism in chronic kidney diseases compiled by NFK-K/DOQI were formulated on the basis of work published up until 2001, before calcimimetics was available.
Guideline 6 states that, in patients with stage 5 CKD: (i) corrected serum calcium levels should be kept within the ‘normal laboratory range’, preferably in the lower limit (between 8.4 and 9.5 mg/dl); (ii) the Ca x P product should be kept below 55 mg2/dl2; (iii) if corrected Ca levels exceed 10.2 mg/dl, oral calcium sources should be suppressed. Guidelines 7 and 8 state that vitamin D metabolites should be reduced or discontinued if serum calcium levels are >10.2 mg/dl, phosphorus levels are >5.5 mg/dl, the Ca x P product is >55 mg2/dl2 or PTH levels are decreased <150 pg/ml (Guideline 7). Guideline 5 states that the total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1500 mg/day and that non-calcium-containing phosphate binders are preferred in dialysis patients with severe vascular and/or other soft-tissue calcifications. Guideline 9 recommends the use of dialysates with a calcium content of 2.5 mEq/l [1].
Previous studies [2], carried out in our unit, showed that the application of the K/DOQI recommendations resulted in the following changes: (i) a decreased use of dialysates with a calcium content of 3.0 and 3.5 mEq/l and an increased use of concentrates with 2.5 mEq/l of calcium; (ii) a decreased prescription of calcium salts as phosphate binding agents, and an increased prescription of sevelamer (a non-calcium, non-aluminium, non-magnesium-containing phosphate binding agent) and (iii) a diminution and/or discontinuation of vitamin D in patients whose calcium levels were over the new objectives defined in K/DOQI guidelines. Positive and negative consequences after applying the DOQI guidelines were observed. As positive consequences, Ca decreased significantly, as did the percentage of patients with Ca > 10.2 mg/dl, in relation to a decrease in Ca provision in the form of calcium chelating agents and vitamin D. As negative consequences, the PTH levels, the percentage of patients with severe secondary hyperparathyroidism, and the serum P levels all increased. At that time we concluded that current therapeutic strategies based on vitamin D compounds and calcium-containing phosphate binders are difficult to implement effectively because both agents are associated with substantial, and often dose-limiting, calcaemic actions that prevent the attainment of treatment targets. In fact, the 28 patients included in the present study were those that had shown the worse results after the implementation of the K/DOQI guidelines: their mean serum PTH had increased from 325.1 ± 154.9 to 590.4 ± 259.1 (P < 0.001).
From January 2006, calcimimetics were available in our unit. Calcimimetics are novel agents that increase the sensitivity of calcium-sensing receptors in the parathyroid glands. Consequently, they allow simultaneous reduction of both PTH and extracellular calcium concentrations, thus differing from currently available vitamin D therapies [3–5]. Reduction of the calcium-phosphorus product (Ca x P) is a consistent feature of calcimimetic therapy and may facilitate the achievement of secondary hyperparathyroidism treatment targets [8].
In this study, the combined use of cinacalcet and vitamin D metabolites improved the achievement of K/DOQI objectives, and particularly the control of patients with severe hyperparathyroidism. In fact, 64.7% of the patients achieved Ca, P, Ca x P and PTH objectives simultaneously. Using traditional therapies, only a small fraction (6%) of patients can be brought within all four of the K/DOQI biochemical goals [9].
The combined use of vitamin D metabolites and cinacalcet allowed for the use of lower doses of both drugs: mean doses at 9 months were 2.9 mcgs/week for alfacalcidol and 62.3 mg/day for cinacalcet. The majority of patients reached K/DOQI objectives with 30 mg of cinacalcet; only one patient needed 120 mg/day. These relatively low doses, probably contributed to the scarce number of secondary effects due to both drugs. There was a significant reduction in the number of episodes of hypercalcaemia (the percentage of patients with Ca >10.2 mg/dl was 52.9% before cinacalcet and 0% after cinacalcet) and hyperphosphoraemia (the percentage of patients with serum phosphorus >5.5 mg/dl was 29.4% before and 11.7% after cinacalcet). Only three patients complained of gastrointestinal discomfort that improved after changing the time of administration of cinacalcet to bedtime (we do not know the reason for this effect of change in time administration). We only detected six asymptomatic hypocalcaemic episodes in five patients. No patient had to stop cinacalcet due to secondary effects. Besides, recent evidence has suggested that vitamin D can have numerous other physiological functions, including protection against certain autoimmune diseases, such as diabetes and multiple sclerosis, and inhibition of proliferation of a number of malignant cells including breast and prostate cancer cells [10], which might be another reason to justify the combined use of both drugs.
The calcimimetic cinacalcet sensitizes the parathyroid cells to the extracellular calcium signal, suppressing PTH release and synthesis and preventing parathyroid cell proliferation. This primary PTH suppression decreases the release of calcium and phosphate from bone without increasing intestinal absorption of calcium and phosphate. Therefore, cinacalcet increases the risk of hypocalcaemia. This could justify its combined use with high doses of calcium-containing oral phosphate binders and a dialysate calcium concentration of up to 3.5 mEq/l, in order to prevent hypocalcaemia. Nevertheless, the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) has recommended restriction of supplemental elemental calcium to 1.5 g/day (Guideline 5) and Guideline 9 recommends the use of dialysates with a calcium content of 2.5 mEq/l. In fact, in this study, after a few months of combined treatment, the mean dose of calcium-containing oral phosphate binders could be stablized and were well below the 1500 mg/day recommended in K/DOQI guidelines.
The recommendation of a routine dialysate calcium concentration of up to 2.5 mEq/l (Guideline 9), is controversial [11] since concentrations within this range might stimulate PTH and exacerbate radiological osteitis fibrosa cystica. In fact, various studies have shown an inverse association between PTH levels and calcium concentrations in dialysate, as well as a worsening of secondary hyperparathyroidism in dialyzed patients with low calcium content in the dialysate [12,2], probably as a consequence of the stimulating effect on PTH of negative calcium balance during the haemodialysis session. Administration of calcimimetics, which decrease serum calcium levels, permits the use of a higher dialysate calcium concentration. At the beginning of this study, we decided to increase the calcium in the dialysate from 2.5 mEq/l to 3.0 mEq/l, with the intention of avoiding the probable hypocalcaemias described with cinacalcet. We did not need to use higher calcium containing dialysates (3.5 mEq/l), and most patients were kept on 3.0 mEq/l baths, that assures a neutral or slightly positive calcium balance during dialysis; in fact, at the end of the study 42.8% of the patients were using a 2.5 mEq/l dialysate.
A collateral effect of cinacalcet treatment was a better control of phosphate levels, as it has been described by others [13,14] that allowed for a reduction in the doses of phosphate binding agents: sevelamer dose diminished from a mean of 11.4–7.2 tablets/day and aluminium-containing agents passed from 2.7 to 1.4 tablets/day.
The use of cinacalcet increased significantly the costs of treatment in these patients. Nevertheless, the achievement of objectives improved drastically at the same time, as there was a significant reduction in the frequency of undesirable effects. Further studies are needed to evaluate the impact of this treatment on morbimortality so as to be able to calculate the relationship between costs and benefits of the combined use of both vitamin D metabolites and cinacalcet vs cinacalcet alone.
In summary, the combination of cinacalcet and low doses of vitamin D significantly improved the control of PTH and CaxP in patients with severe secondary hyperparathiroidism on chronic haemodialysis, without adverse effects and with lower doses of phosphate binders.
Conflict of interest statement. None declared.
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[Abstract/Free Full Text]
Accepted in revised form: 26.12.06
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