Bixalomer in Hyperphosphatemic Patients With Chronic Kidney Disease Not on Dialysis: Phase 3 Randomized Trial

Currently, calcium‐ or metal‐containing phosphate binders are available to treat hyperphosphatemia in predialysis patients with chronic kidney disease. Bixalomer, a non‐calcium, metal‐free phosphate binder, has not been studied in these patients. We evaluated the efficacy and safety of bixalomer versus placebo for treatment of hyperphosphatemia in Japanese predialysis patients with chronic kidney disease. This multicenter, randomized, double‐blind, phase 3 trial, randomized eligible patients 1:1 to receive bixalomer or placebo for 12 weeks. Bixalomer was started at 1500 mg/day and adjusted up to 7500 mg/day depending on serum phosphorus concentrations. The primary endpoint was change in serum phosphorus concentration from baseline to end of treatment. After a 4‐week pre‐investigational period, 163 patients (bixalomer: N = 81; placebo: N = 82) were randomized. The adjusted mean change (95% confidence interval) from baseline to end of treatment in serum phosphorus was significantly greater with bixalomer (–0.78 [–0.98, –0.57] mg/dL) versus placebo (0.20 [–0.00, 0.41] mg/dL); mean difference: –0.98 (–1.27, –0.69), P < 0.001. At end of treatment, 57.5% of bixalomer‐treated patients achieved target serum phosphorus concentrations, mean serum intact parathyroid hormone and fibroblast growth factor‐23 decreased, and there were no significant changes in corrected serum calcium. The safety and tolerability of bixalomer was similar to placebo. The most common drug‐related adverse events were gastrointestinal (>24% patients per group). There was a significant increase in bicarbonate concentrations with bixalomer versus placebo (P = 0.003). Bixalomer was superior to placebo for hyperphosphatemia in Japanese predialysis patients with chronic kidney disease and may constitute a new treatment option.     

Long‐Term Safety and Efficacy of Bixalomer in Hyperphosphatemic Patients With Chronic Kidney Disease Not on Dialysis

Bixalomer, a metal‐free, nonabsorbable phosphate binder, is approved in Japan to treat hyperphosphatemia in dialysis patients. Bixalomer is effective and has a favorable safety profile in predialysis patients with hyperphosphatemia. This study examined the long‐term effectiveness and safety of bixalomer in predialysis patients with hyperphosphatemia. This was a 48‐week, multicenter, open‐label, phase 3 study in Japanese predialysis patients with hyperphosphatemia. Patients received bixalomer at an initial dose of 1500 mg/day, which was titrated to a maximum of 7500 mg/day depending on patients’ serum phosphorus responses to bixalomer. A total of 105 patients received bixalomer treatment, and 39 completed the study. The most common reason for discontinuation was initiation of dialysis. Mean serum phosphorus concentrations decreased from 5.15 mg/dL at baseline to 4.67 mg/dL at Week 12 and then fluctuated slightly around this level until it reached 4.58 mg/dL at Week 48. The proportion of total patients achieving the target serum phosphorus concentration (≥2.5 to <4.6 mg/dL) increased after treatment to a maximum of 66.2% at Week 20 and subsequently decreased to 51.3% by Week 48. Most adverse events (AEs) occurred in the first 12 weeks of treatment. The incidence of AEs did not increase with long‐term treatment. Common AEs reported included nasopharyngitis (29.5%), constipation (19%), and upper respiratory tract inflammation (12.4%). These findings suggest that long‐term treatment with bixalomer is effective, well tolerated, and has no new safety concerns. Bixalomer may be an alternative treatment option for the long‐term management of hyperphosphatemia in patients with chronic kidney diseases.     

Long‐Term Treatment of Hyperphosphatemia With Bixalomer in Japanese Hemodialysis Patients

Bixalomer is a nonabsorbable polymer that binds phosphate in the gastrointestinal tract and lowers the serum phosphate level by inhibiting phosphate absorption. The safety and efficacy of long‐term bixalomer treatment were assessed in Japanese hemodialysis patients with hyperphosphatemia. This was a multicenter open‐label study with a 48‐week treatment period. The main efficacy endpoints were the serum phosphate level and rate of achieving the target serum phosphate range (3.5–6.0 mg/dL). Bixalomer was initiated at a dose of 1.5 g/day, which was increased to a maximum of 7.5 g/day depending on the serum phosphate response. Of 248 subjects who started treatment, 179 completed the study. The mean serum phosphate level decreased over time and remained around 5.5 mg/dL from weeks 16 to 48. The target serum phosphate level was reached in >50% of subjects by week 7 and was maintained in 65.2% to 75.9% until week 48. The incidence of adverse events and adverse drug reactions was 94.4% and 29.4%, respectively. There was a potential relationship with the study drug for four serious adverse events (ischemic colitis, hemorrhagic intestinal diverticulum, esophageal ulcer, and acute cholecystitis), which occurred in one patient each. Constipation was the most common adverse drug reaction (21.0%). Most adverse events and adverse drug reactions occurred soon after starting administration, and their incidence did not increase during long‐term treatment. Bixalomer did not reduce the bicarbonate level or promote metabolic acidosis. Bixalomer is clinically useful for the long‐term treatment of hyperphosphatemia.     

Efficacy of combined sevelamer and calcium carbonate therapy for hyperphosphatemia in Japanese hemodialysis patients

In Japan, calcimimetics and other phosphate binders such as lantanum carbonate are not available for patients on long-term hemodialysis (HD), so we prospectively evaluated the clinical efficacy of the combination of sevelamer hydrochloride and calcium carbonate (CaCO3) for hyperphosphatemia. The study group comprised 65 HD patients who had been administered CaCO3 (>or=1500 mg/day) for hyperphosphatemia [>or=6.0 mg/dL (>or=1.94 mmol/L)]. At the beginning of the study the dose of CaCO3 was reduced by 1500 mg/day and the patients divided into two groups according to the dose of additional sevelamer hydrochloride: group A 2250 mg/day; group B 3000 mg/day. Oral active vitamin D therapy was unchanged. Fourteen patients (21.5%) dropped out because of adverse effects and of the 51 remaining patients 35 (53.8%) suffered from gastrointestinal problems. Serum phosphate concentration decreased significantly [from 7.5+/-0.8 mg/dL (2.42+/-0.26 mmol/L) to 6.6+/-1.3 mg/dL (2.13+/-0.42 mmol/L), P<0.01] in group B only after the 8 weeks of combination therapy. The calcium-phosphate product (CaxPi) also decreased in group B only [from 74.4+/-13.4 mg2/dL2 (5.99+/-1.07 mmol2/l2) to 63.7+/-15.8 mg2/dL2 (5.13+/-1.27 mmol2/l2), P<0.001]. The combination of sevelamer hydrochloride and CaCO3 is a suitable regimen for hyperphosphatemia treatment in HD patients because it avoids both the hypercalcemia of CaCO3 and the adverse effects of sevelamer hydrochloride when each is used as single-drug therapy. The ability of sevelamer hydrochloride to decrease the serum phosphate concentration is 2/3 (2250/1500 mg) that of CaCO3.     

Prospective randomized multicenter trial of sevelamer hydrochloride and calcium carbonate for the treatment of hyperphosphatemia in hemodialysis patients in Japan

A prospective, randomized open-label trial of sevelamer hydrochloride with or without calcium carbonate (CC) involved 86 hemodialysis patients in Japan. The dosage of CC was fixed at 3.0 g/day for the 12-week study. After the first 4 weeks all subjects were changed from CC to sevelamer 3.0 g/day for another 4 weeks, then allocated randomly to three groups for the final 4 weeks: group A, sevelamer 6.0 g/day; group B, sevelamer 3.0 g/day and CC 3.0 g/day; group C, CC 3.0 g/day. The target serum phosphorous concentration (P)=5.5 mg/dL and the corrected calcium concentration (Ca) was 9.0-10.0 mg/dL. Of the 86 patients, 62 finished the study without a change of dosage and their data were analyzed (group A, N=16; group B, N=26; group C, N=20). At week 8 compared with week 4, the concentration of P increased from 5.7+/-1.4 to 6.4+/-1.7 mg/dL in group A, and decreased significantly in groups B and C, and in group B compared with groups A and C; groups A and C had similar concentrations at week 8. The Ca concentration decreased significantly from 9.7+/-1.0 to 9.1+/-0.7 mg/dL after the change to sevelamer. At week 8 Ca was not significantly changed in group A, whereas a significant increase occurred in groups B and C. Side-effects with sevelamer administration occurred in 34 of the 86 patients and 24 dropped out of the study, with a high frequency in group A (13/29; 44.8%). In conclusion, there was an additive effect of sevelamer for the treatment of hyperphosphatemia with CC. The combination therapy was better tolerated and showed higher patient compliance than CC or sevelamer monotherapy.     

Influence of sevelamer on mineral metabolism and hyperparathyroidism in Japanese hemodialysis patients

In June 2003, sevelamer hydrochloride became widely available in Japan and was expected to control hyperphosphatemia in hemodialysis patients without inducing hypercalcemia. To evaluate the impact of sevelamer therapy on mineral metabolism, we recruited 954 hemodialysis patients from 21 renal units just before the general release of sevelamer in Japan. The serum calcium, phosphate, and parathyroid hormone levels determined on enrollment were compared with those later measured in June 2004. Sevelamer was prescribed for 169 of the 859 patients for whom data were available in 2004. The mean calcium level, phosphate level, and calcium x phosphate product were all significantly reduced during the 12-month study period, but the intact parathyroid hormone (iPTH) level did not change. As a result, the percentage of patients who achieved a calcium x phosphate product of <55 mg(2)/dL(2) was significantly increased, but there were no changes in that of patients who achieved the target ranges for phosphate (3.5-5.5 mg/dL) or iPTH (150-300 pg/mL). Among sevelamer-treated patients, iPTH significantly increased, and this change was more marked in the patients with an initial iPTH level <150 pg/mL. Sevelamer was useful for reducing the serum calcium level and calcium x phosphate product, but hyperphosphatemia and hyperparathyroidism were not improved in our study population at 12 months after the release of sevelamer. A decrease in the calcium load might result in the exacerbation of hyperparathyroidism. However, among patients with relative hypoparathyroidism, sevelamer therapy may be beneficial for the prevention of adynamic bone disease.     

Sevelamer hydrochloride improves hyperphosphatemia in hemodialysis patients with low bone turnover rate and low intact parathyroid hormone levels

Sevelamer improves hyperphosphatemia without increasing the calcium load. However, it remains unknown whether sevelamer restores bone metabolism in hemodialysis patients with low bone turnover osteodystrophy and hypoparathyroidism. We investigated the changes in serum intact parathyroid hormone (iPTH) and bone metabolic marker levels after replacing calcium carbonate with sevelamer in these patients. We also conducted stratified analysis based on patient background and multivariate analysis to determine the factors affecting these parameters. During sevelamer replacement therapy, serum calcium and phosphate concentrations, and the calcium phosphate product were measured at 0, 1, 3, and 6 months. Serum iPTH, bone alkaline phosphatase and osteocalcin concentrations were measured at 0 and 6 months. In hemodialysis patients (71 men and 46 women, 63 +/- 12 years old) serum calcium levels and the calcium phosphate product decreased significantly at 1 month. Serum iPTH, bone alkaline phosphatase and osteocalcin levels increased significantly at 6 months. Increases in serum iPTH concentrations were observed in all stratified groups. Significant increases in serum bone alkaline phosphatase and osteocalcin concentrations were found only in the relative hypoparathyroidism group (iPTH levels > or =51.5 pg/mL, the median pretreatment level). Multivariate analysis showed that the factors affecting change in serum iPTH level are baseline serum iPTH, baseline calcium level (> or =9.5 mg/dL), and dialysis duration of 10 years or longer. Sevelamer appears useful for the treatment of hyperphosphatemia in these patients. Particularly, in the relative hypoparathyroidism group, the iPTH secretory response is probably enhanced and bone turnover may have been improved as a result of reducing the calcium load.     

Comparison of sevelamer hydrochloride with colestimide, administered alone or in combination with calcium carbonate, in patients on hemodialysis

Since hyperphosphatemia in hemodialysis patients can cause secondary hyperparathyroidism and promotes vascular calcification, serum phosphate (Pi) levels must be controlled by phosphate binders. Although sevelamer and colestimide are known as similar non-calcium, non-aluminum phosphate binders in hemodialysis patients, there are no studies that compare the effects of the two agents as either a monotherapy or in combination with calcium carbonate (CaCO3). We randomly allocated 62 hemodialysis patients with hyperphosphatemia to treatment with sevelamer (3.0 g/day) and colestimide (3.0 g/day). During the study, 35 subjects dropped out, leaving 13 in the sevelamer group and 14 in the colestimide group. After a 2-week CaCO3 washout, all subjects received the monotherapy for 4 weeks and then CaCO3 (3.0 g/day) was added for another 4 weeks. Serum corrected calcium levels tended to decrease in both groups during the washout period and monotherapy, but there was no significant difference between the two groups after the addition of CaCO3. Although the calcium x phosphorus product (Ca x P) in the two groups increased during the washout period, there was no significant change or difference between the two groups during monotherapy. However, the addition of CaCO3 significantly reduced serum Pi at Week 8 compared to that at Week 0 in both groups, and significantly lowered Ca x P only in the sevelamer group, but not in the colestimide group(.) In this short-term study, sevelamer and colestimide similarly ameliorated hyperphosphatemia, but the combination of sevelamer and CaCO3 was more effective than colestimide with CaCO3 in controlling the Ca x P product, and it may improve cardiovascular mortality in hemodialysis patients.     

Combination therapy with sevelamer hydrochloride and calcium carbonate in Japanese patients with long-term hemodialysis: alternative approach for optimal mineral management

Calcium (Ca) overload by Ca-containing phosphorus (P) binder has been suggested to be implicated in the pathogenesis of soft tissue and vascular calcification, which contribute to increased morbidity and mortality of cardiovascular disease in patients undergoing dialysis. Recently, a noncalcium P binder, sevelamer hydrochloride (sevelamer), has become available in Japan. However, Japanese patients undergoing dialysis might be less tolerant of sevelamer treatment, and it is likely to cause hypocalcemia because their dietary Ca intake is less than that in European and American patients. We evaluated the effects of combination therapy with sevelamer and calcium carbonate (CC) on mineral metabolism in Japanese hemodialysis patients, as an alternative form of P management. A total of 210 hemodialysis patients were enrolled, and were given a small dose of sevelamer (0.75-1.5 g/day) on CC treatment. Sevelamer dose was gradually increased, while CC decreased during 24 weeks. Five patients discontinued sevelamer treatment because of severe constipation, anorexia, and parathyroidectomy for severe secondary hyperparathyroidism. After 24 weeks, the dose of sevelamer was significantly increased to 3.29 g/day (initial dose: 1.47 g/day), while CC was decreased by 54%. Adjusted serum Ca significantly decreased (9.63 +/- 0.57-9.45 +/- 0.67 mg/dL; P = 0.0012), although serum P increased (5.89 +/- 1.32-6.25 +/- 1.32 mg/dL; P = 0.017). Serum intact PTH (iPTH) significantly increased in patients with a low or normal iPTH level (< or =300 pg/mL), while it did not change in patients with secondary hyperparathyroidism (>300 pg/mL). The results suggest that the therapeutic regimen is more tolerant and reduces Ca load in Japanese hemodialysis patients while avoiding hypocalcemia. In addition, the mitigated Ca overload could improve PTH hyposecretion in patients with adynamic bone disease, which is associated with soft tissue calcification and higher mortality in uremia.     

Sevelamer hydrochloride prevents ectopic calcification of blood vessels

Sevelamer hydrochloride is a non-absorbed calcium- and metal-free phosphate binder that lowers the serum phosphorus levels in hemodialysis patients. Sevelamer contains multiple amines, which are partially protonated and interact with phosphate molecules through ionic and hydrogen bonding. We show the in vitro phosphate binding assay data and the efficacy of sevelamer to lower the serum phosphorus and calcium phosphorus product in several animal models. Furthermore, we indicate the vivid data that sevelamer prevented the ectopic calcification of aorta in adenine induced renal failure model, which represent severe hyperphosphatemia and the related dialysis complications.     

Sevelamer is an Effective Drug in Treating Hyperphosphatemia Due to Tumor Lysis Syndrome in Children: A Developing World Experience

We report here a study on efficacy of sevelamer hydrochloride in treating hyperphosphatemia due to tumor lysis syndrome (TLS) in a developing world setting. Twenty one children with hyperphosphatemia due to TLS were included. All received hyper-hydration, allopurinol and sevelamer. Efficacy was assessed by decrease in serum phosphate level, calcium-phosphate product and TLS score as per Cairo Bishop definition. Four children who underwent dialysis were excluded from analysis. Among the remaining 17 patients with hyperphosphatemia, laboratory TLS was recorded in 15 patients and clinical TLS in five. Sevelamer was given according to weight, most often 400 mg twice to thrice daily. Mean phosphatemia decreased from 8.3 ± 3.0 to 6.7 ± 2.1 mg/dl within 24 h of starting sevelamer (p = 0.02), 6.0 ± 2.1 mg/dl at 48 h, 4.9 ± 1.5 mg/dl at 72 h and 4.39 ± 1.7 mg/dl at 96 h. TLS was corrected in 72 h in 14 patients, 96 h in 1 and 120 h in another patient. Mean calcium-phosphate product decreased from 63.0 ± 14.0 to 49.2 ± 9.7 mg/dl (p = 0.002) at 24 h, 46.1 ± 17.0 mg/dl at 48 h and 39.7 ± 13.5 mg/dl at 72 h. There was no mortality due to hyperphosphatemia. Sevelamer is efficacious in children with malignancy-associated hyperphosphatemia in the developing world.     

Sevelamer Hydrochloride Dose‐Dependent Increase in Prevalence of Severe Acidosis in Hemodialysis Patients: Analysis of Nationwide Statistical Survey in Japan

Metabolic acidosis has a negative impact on prognosis of dialysis patients. The aim of this study was to determine the prevalence of severe metabolic acidosis in dialysis patients treated with sevelamer hydrochloride. In 2004, a nationwide survey (101 516 dialysis patients) was conducted by the Japanese Society for Dialysis Therapy. We analyzed 32 686 dialysis patients whose bicarbonate levels were measured in the survey. Sevelamer hydrochloride was prescribed to 9231 dialysis patients while 23 455 dialysis patients were not prescribed sevelamer hydrochloride. In the present study, we defined severe acidosis as bicarbonate <15.8 mmol/L. The mean serum bicarbonate level correlated significantly and negatively with the daily dose of sevelamer hydrochloride (R² = 0.806, P < 0.0001). Logistic regression analysis indicated that the percentage of patients with severe acidosis increased significantly with increased dose of sevelamer hydrochloride (R² = 0.885, P < 0.00001). The estimated doses of sevelamer hydrochloride associated with severe acidosis in 10% and 15% of patients were 3.5 g/day (95% confidence interval [95%CI], 2.8‐4.4) and 7.7 g/day (95%CI = 5.9–10.9), respectively. Severe acidosis was noted in 4.5% of patients who were not treated with sevelamer hydrochloride and in 16.1% of patients treated with sevelamer hydrochloride at ≥5.25 g/day (P < 0.0001). The results call for careful monitoring of serum bicarbonate level in hemodialysis patients treated with sevelamer hydrochloride.     

Adherence to Phosphate Binder Therapy Is the Primary Determinant of Hyperphosphatemia Incidence in Patients Receiving Peritoneal Dialysis

We investigated the major determinant of hyperphosphatemia incidence among patients receiving peritoneal dialysis. Seventy‐six patients aged 25–55 years who had received peritoneal dialysis for more than 3 months were recruited. The patients were divided into three groups according to their serum phosphorus levels (Group 1, ≥6 mg/dL; Group 2, 5.9–4.8 mg/dL; and Group 3, <4.8 mg/dL). Renal dietitians interviewed the patients to determine their phosphate intake and adherence to phosphate binder therapy. No statistical differences in demographics or phosphate intake were identified among the groups. However, adherence to phosphate binders was greater in Group 3 than in Groups 1 and 2 (96.3% vs. 21.4% and 52.4%, respectively; P < 0.001). Multivariate analysis showed that adherence to phosphate binder therapy was the only significant contributor to serum phosphorus levels (P= 0.0001). Adherence to diet was better than adherence to phosphate binder therapy among patients receiving peritoneal dialysis, and the latter determined the incidence of hyperphosphatemia.     

Severe hypophosphatemia: a rare cause of intravascular hemolysis

A 3-year-old child presented with severe hyperphosphatemia (phosphate 45 mg/dL) secondary to chronic enema use. Following aggressive correction of the hyperphosphatemia, hypophosphatemia ensued (phosphate 1.7 mg/dL). Concurrently, the patient developed severe intravascular hemolysis and RBC morphologic defects. The hemolysis and morphologic defects corrected with return to normal serum phosphate levels. Severe hypophosphatemia is a rare cause of intravascular hemolysis.     

Is 2.5 mEq/L the Optimal Calcium Concentration of Dialysate in the Use of Sevelamer Hydrochloride? A Study of the Dialysate Calcium Concentration Recommended by K/DOQI Guidelines

We tested the effect of three different dialysate calcium concentrations on calcium-phosphorus metabolism during the use of sevelamer hydrochloride. After a calcium-containing phosphate binder was switched to sevelamer, the serum calcium, phosphorus, and intact parathyroid hormone levels and the markers of bone turnover were measured in the patients whose dialysate calcium concentrations were 2.5, 2.75, and 3.0 mEq/L. As a result, in the 2.75-mEq/L group, the serum calcium concentrations decreased and the intact parathyroid hormone level increased significantly. In the 2.5-mEq/L group, transient hypocalcemia occurred and the levels of both bone-alkaline phosphatase and osteocalcin increased. In the 3.0-mEq/L group, the serum calcium concentrations did not change significantly and only bone-alkaline phosphatase increased. If a calcium-containing phosphate binder is completely switched to sevelamer, dialysis using a dialysate calcium concentration below 3.0 mEq/L may result in hypocalcemia and acceleration of bone turnover.     

Hyperphosphatemia in renal failure

The recent recognition that hyperphosphatemia is a strong predictor of survival on dialysis has rekindled interest in the regulation and control of serum phosphate. In incipient renal failure hyperphosphatemia is prevented by increased fractional renal phosphate excretion mediated via an increase in parathyroid hormone and the novel phosphaturic hormone FGF-23 (and possibly others). At a glomerular filtration rate of approximately 30 ml/min this compensatory mechanism fails and hyperphosphatemia ensues. Pre-dialytic serum phosphate concentrations of >6 mg/dl increase cardiac mortality presumably to a large extent, but not exclusively, via promoting vascular calcification. It has recently been recognized that vascular calcification is not only a passive precipitation process following transgression of the critical Ca-x-P product, but is an active process accompanied by expression of osteoblastic bone markers in the vessel wall. Because of the recent recognition of the relation between vascular calcification and serum phosphate as well as serum calcium, there is a need for novel calcium-free phosphate binders. Currently sevelamer and lanthanum carbonate have been introduced and trivalent iron preparations are under development.     

Impact of sevelamer hydrochloride and the K/DOQI guidelines

Sevelamer hydrochloride (SH) was registered as a new drug under the Japanese national health insurance scheme in 2003, and the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for the treatment of renal osteodystrophy were released the same year. At that time, treatment objectives for hemodialysis outpatients at the Kojinkai Ishimaki Clinic were settled established and the outcomes reviewed 18 months later. The relationship between the type and dosage of phosphate binder (PB), and the concentrations of adjusted calcium (Ca), phosphorus (P), intact parathyroid hormone (PTH), and bone alkaline phosphatase (BAP) was examined. Patients receiving calcitriol or maxacalcitol intravenous pulse therapy, or who had undergone simultaneous pancreas-kidney transplant, were excluded from this analysis. The PB was CaCO3 in 60% of cases, SH in 33.3%, and a combination of both in 21.9%; no PB was used in 6.7% of cases. The dosage of CaCO3 was 2.8+/-1.0 g/day, and 1alpha-hydroxy activated vitamin D3 (VD) was 0.46+/-0.24 microg/day; the respective concentrations of adjusted Ca, P, intact PTH, and BAP were 9.4+/-0.7 mg/dL, 5.6+/-1.7 mg/dL, 104+/-83.9 pg/mL, and 22.7+/-10.9 IU/L. In the SH monotherapy group, the dosage of SH was 3.9+/-0.725 g/day, and VD 0.62+/-0.21 microg/day, and the concentrations for adjusted Ca, P, intact PTH, and BAP were 9.6+/-0.4 mg/dL, 6.2+/-1.5 mg/dL, 150+/-42.9 pg/mL, and 38.5+/-14.2 IU/L, respectively. In the combined therapy group, the dosage of CaCO3 was 2.9+/-0.9 g/day, SH was 3.3+/-1.1 g/day, VD was 0.53+/-0.27 microg/day, and the respective concentrations were 9.2+/-1.0 mg/dL, 5.7+/-1.4 mg/dL, 160+/-107.8 pg/mL, and 31.3+/-42.0 IU/L. One-third of all subjects were administered SH, either as monotherapy or in combination with CaCO3, and in these patients the dosage of VD was able to increase.     

Role of sevelamer hydrochloride in the coronary artery calcification score

The coronary artery calcification score (CACS) is higher in hemodialysis (HD) patients than in non-HD patients for each age group from the fifth to the eighth decade of life. In order to clarify the relationship between the rate of change in the CACS and several factors related to calcium (Ca) and phosphate (P) metabolism in HD patients, we determined the CACS twice in 144 HD outpatients at an interval of approximately 12 months (2003 and 2004). The dosage of vitamin D formulations (alfacalcidol or maxacalcitol) was reduced or ceased if the serum Ca concentration exceeded 5.0 mEq/L, or the serum P concentration exceeded 6.0 mg/dL, and the dosage of combined sevelamer hydrochloride (SH) and calcium carbonate (CaCO3), as the phosphate binder, was adjusted to maintain the concentrations below these levels. The study parameters were: (1) the total dosage of alfacalcidol (microg), maxacalcitol (microg), SH (mg), and CaCO3 at the time of each CACS measurement; and (2) serum concentrations of Ca, P, alkaline phosphatase, high-sensitivity parathyroid hormone (HS-PTH), total protein, albumin, total cholesterol, triglycerides (TG). Regression analysis showed a significant correlation among the total SH dosage, TG, and alphaCACS. Future investigations will include the differences in alphaCACS between patients treated with SH who experience a rise in Ca and/or P and those with a decrease in Ca and/or P.     

The influence of dialysate calcium on the therapeutic effects of sevelamer hydrochloride in hemodialysis patients with secondary hyperparathyroidism under treatment of intravenous vitamin d metabolites

The management of hyperphosphatemia is essential to treat secondary hyperparathyroidism and to prevent ectopic calcification. Sevelamer hydrochloride (sevelamer), a new phosphate binder that contains neither aluminum nor calcium, which could be theoretically beneficial for the management of hyperphosphatemia in dialysis patients with secondary hyperparathyroidism who are receiving intravenous vitamin D metabolites (maxacalcitol or calcitriol). To reduce calcium loads, a dialysate calcium concentration of 2.5 mEq/L is recommended by Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines. In Japan, a dialysate calcium concentration of 3.0 mEq/L prevails. We investigated the influence of dialysate calcium on the therapeutic effect of sevelamer in 40 hemodialysis patients who are under treatment of intravenous vitamin D metabolites for secondary hyperparathyroidism (VD(+)) and compared the results with those of 41 patients who had not received vitamin D metabolites (VD(-)). Serum phosphorus and calcium-phosphorus products showed no significant change by sevelamer in either the VD(+) subgroup of patients receiving hemodialysis with dialysate calcium of 2.5 mEq/L (DCa2.5) or those receiving hemodialysis with dialysate calcium of 3.0 mEq/L (DCa3.0), while serum phosphorus and calcium-phosphorus products decreased in both the VD(-) subgroups. Serum calcium decreased in the DCa2.5 subgroup and did not change in the DCa3.0 subgroup in both the VD(+) and the VD(-) subjects. Parathyroid hormone and alkaline phosphatase increased in the DCa2.5 subgroup and did not change in the Ca 3.0 subgroup in the VD(+) subjects. Serum calcium decreased in both subgroups in the VD(-) subjects. Parathyroid hormone obtained after sevelamer administration in the VD(-) group was within the target range of the K/DOQI guidelines. In conclusion, the concomitant use of sevelamer as a phosphate binder and the dialysate of calcium concentration of 2.5 mEq/L have possibilities for worsening secondary hyperparathyroidism in patients receiving intravenous vitamin D.     

Efficacy and Tolerability of Sevelamer Carbonate in Hyperphosphatemic Patients Who Have Chronic Kidney Disease and Are Not on Dialysis

Background and objectives: Sevelamer carbonate is an improved, buffered form of sevelamer hydrochloride developed for the treatment of hyperphosphatemia in patients with chronic kidney disease. This study investigated the ability of sevelamer carbonate to control serum phosphorous in hyperphosphatemic patients who had chronic kidney disease and were not on dialysis.Design, setting, participants, & measurements: This was an open-label, dosage-titration study. Patients with serum phosphorus ≥5.5 mg/dl were enrolled (n = 46). Sevelamer carbonate was administered for 8 wk. Patients were supplemented with native vitamin D (400 IU). The primary efficacy parameter was the change from baseline in serum phosphorous. Secondary measures included the percentage of serum phosphorus responders; changes in serum lipids, calcium-phosphorus product, and bicarbonate; and safety and tolerability.Results: Sevelamer carbonate treatment resulted in a statistically significant decrease in mean serum phosphorous levels from baseline to end of treatment. A total of 75% of patients with stage 4 and 70% of patients with stage 5 chronic kidney disease achieved the target serum phosphorous at the end of treatment. There were statistically significant decreases in serum calcium-phosphorus product and total and low-density lipoprotein cholesterol at the end of treatment and a statistically significant increase in mean serum bicarbonate levels (from 16.6 to 18.2 mEq/L). Sevelamer carbonate was well tolerated.Conclusions: Sevelamer carbonate is an effective and well-tolerated therapy for the control of phosphorous levels in hyperphosphatemic patients who have chronic kidney disease and are not on dialysis.In early to moderately advanced chronic kidney disease (CKD), serum phosphorus levels are maintained at near-normal levels by compensatory enhanced phosphorus excretion (fibroblast growth factor-23, parathyroid hormone [PTH]) by the residual nephrons, resulting in preservation of net phosphorus excretion. As renal failure progresses, the GFR decreases, resulting in the loss of preservation or balance of net phosphorus excretion and the subsequent development of hyperphosphatemia. There is considerable experimental and clinical evidence indicating that hyperphosphatemia is associated with a number of deleterious consequences, such as secondary hyperparathyroidism, arterial calcification, and renal osteodystrophy (1–3). Hyperphosphatemia has also emerged as one of the more important risk factors for mortality in dialysis patients, and this association reproducibly seems to show concentration-dependent characteristics in epidemiologic studies (4).Recent studies demonstrated that incident dialysis patients already carry a significant cardiovascular disease burden and show a high prevalence of vascular calcifications (5). Moreover, patients in advanced stages of CKD have higher risk for death than of reaching the dialysis stage (6). It is unclear whether dialysis modalities in themselves change the pathophysiologic consequences of hyperphosphatemia, but it is certainly more likely that the adverse effects of hyperphosphatemia are independent of the dialysis status of a patient with CKD. The data showing the clinical consequences of hyperphosphatemia in patients who have CKD and are not on dialysis are less abundant because this population has not been closely studied, but both Kestenbaum et al. (7) and Voormolen et al. (8) found an association between serum phosphate level and mortality in patients who had CKD and were not on dialysis. This suggests that it is correct to consider that these patients are subject to the harmful effects of hyperphosphatemia similar to those seen in patients who are on dialysis.As in patients who are on dialysis, the management of hyperphosphatemia is based initially on limiting phosphate intake through appropriate dietary measures. Failure to control serum phosphorus adequately by these means should be followed by pharmacologic intervention. Phosphate binder therapy is advocated for the treatment of hyperphosphatemia in patients who have CKD and are not yet on dialysis by a number of guidelines, including the widely accepted National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) guidelines on bone and mineral metabolism (9). The currently available phosphate binders are sevelamer hydrochloride (Renagel; Genzyme Corporation, Cambridge, MA), lanthanum (Fosrenol; Shire US Inc., Wayne, PA), calcium acetate (PhosLo; Fresenius Medical Care North America, Waltham, MA), calcium carbonate, and aluminum hydroxide. There are no recently published studies of phosphate binders in patients who had CKD and were not on dialysis, and none of the phosphate binders has an indication specifically for the treatment of hyperphosphatemia in patients who have CKD and are not on dialysis.Sevelamer carbonate (Renvela; Genzyme Corporation, Cambridge, MA) has been developed as an improved, buffered form of sevelamer hydrochloride (Renagel). Sevelamer carbonate is an anion exchange resin with the same active moiety as sevelamer hydrochloride in which carbonate replaces chloride as the anion. The replacement of the chloride with carbonate provides bicarbonate ions that may be a benefit to patients who have CKD and are not receiving dialysis, who are prone to acidosis and do not receive the benefits of renal replacement therapy. Sevelamer carbonate has been found to have the same safety and efficacy profile as sevelamer hydrochloride in hemodialysis patients (10). This study was designed to investigate the effects of sevelamer carbonate on the control of serum phosphorus levels, calcium-phosphorus product, lipids, and bicarbonate in hyperphosphatemic patients who had CKD and were not on dialysis.