A randomized, double-blind, crossover design study of sevelamer hydrochloride and sevelamer carbonate in patients on hemodialysis

AIMS: Sevelamer carbonate is an anion exchange resin with the same polymeric structure as sevelamer hydrochloride in which carbonate replaces chloride as the anion. The study investigated the effects of sevelamer carbonate and sevelamer hydrochloride on serum phosphorus, lipids and bicarbonate levels in hemodialysis patients. MATERIALS AND METHODS: This was a double-blind, randomized, crossover study. 79 hemodialysis patients were randomly assigned to either sevelamer carbonate or sevelamer hydrochloride for 8 weeks followed by a crossover to the other regimen for an additional 8 weeks of treatment. RESULTS: The mean serum phosphorus was 4.6+/-0.9 and 4.7+/-0.9 mg/dl during sevelamer carbonate and sevelamer hydrochloride treatment, respectively. Sevelamer carbonate and sevelamer hydrochloride were equivalent in controlling serum phosphorus, the geometric least square mean ratio was 0.99 (90% CI, 0.95-1.03). Mean total and LDL cholesterol were 144.0+/-33.9 and 59.5+/-24.9 mg/dl, respectively, during sevelamer carbonate treatment and 139.0+/-33.6 and 56.0+/-23.3 mg/dl, respectively, during sevelamer hydrochloride treatment. Serum bicarbonate levels increased by 1.3+/-4.1 mEq/l during sevelamer carbonate treatment. There were fewer gastrointestinal adverse events with sevelamer carbonate. CONCLUSIONS: Sevelamer carbonate and sevelamer hydrochloride were equivalent in controlling serum phosphorus and serum bicarbonate levels increased with sevelamer carbonate. Lipid profiles for both were well-below the levels suggested by KDOQI. Sevelamer carbonate may have advantages over sevelamer hydrochloride in the treatment of hyperphosphatemia in hemodialysis patients.     

Effects of sevelamer hydrochloride and calcium carbonate on renal osteodystrophy in hemodialysis patients

Disturbances in mineral metabolism play a central role in the development of renal bone disease. In a 54-wk, randomized, open-label study, 119 hemodialysis patients were enrolled to compare the effects of sevelamer hydrochloride and calcium carbonate on bone. Biopsy-proven adynamic bone disease was the most frequent bone abnormality at baseline (59%). Serum phosphorus, calcium, and intact parathyroid hormone were well controlled in both groups, although calcium was consistently lower and intact parathyroid hormone higher among patients who were randomly assigned to sevelamer. Compared with baseline values, there were no changes in mineralization lag time or measures of bone turnover (e.g., activation frequency) after 1 yr in either group. Osteoid thickness significantly increased in both groups, but there was no significant difference between them. Bone formation rate per bone surface, however, significantly increased from baseline only in the sevelamer group (P = 0.019). In addition, of those with abnormal microarchitecture at baseline (i.e., trabecular separation), seven of 10 in the sevelamer group normalized after 1 yr compared with zero of three in the calcium group. In summary, sevelamer resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation increased and trabecular architecture improved with sevelamer. Further studies are required to assess whether these changes affect clinical outcomes, such as rates of fracture.     

Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients

Elevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification but it is unknown whether sevelamer affects mortality or morbidity. In a multicenter, randomized, open-label, parallel design trial we compared sevelamer and calcium-based binders on all-cause and cause-specific mortality (cardiovascular, infection, and other) in prevalent hemodialysis patients. A total of 2103 patients were initially randomized to treatment and 1068 patients completed the study. All-cause mortality rates and cause-specific mortality rates were not significantly different. There was a significant age interaction on the treatment effect. Only in patients over 65 years of age was there a significant effect of sevelamer in lowering the mortality rate. There was a suggestion that sevelamer was associated with lower overall, but not cardiovascular-linked, mortality in older patients. We suggest that further research is needed to confirm these findings.     

Chronic acid-base perturbations in hemodialysis patients treated with sevelamer hydrochloride: a two-year follow-up study

Abstract:  Sevelamer hydrochloride (HCl) contains multiple amines that may cause a significant dietary acid load. To evaluate the impact of sevelamer on arterial blood gases, we followed two groups of stable hemodialysis patients for 24 months. The Sevelamer Group ( n  = 7) did not achieve the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) goals for phosporus and Ca × P product and was switched from a calcium-based to sevelamer-based regimen. The Calcium Group ( n  = 7) achieved those goals and remained on calcium salts. Following sevelamer administration, a deterioration of chronic metabolic acidosis was revealed, which lasted throughout the study. Sevelamer therapy was associated with reduced cholesterol levels, improved serum phosphate, and Ca × P product, which facilitated the management of secondary hyperparathyroidism. No significant changes in acid–base status or other parameter tested were found in the Control Group. In conclusion, sevelamer intake caused small but persistent acid–base disturbances, which did not neutralize sevelamer's beneficial effects on mineral and lipid metabolism.     

Plasma osteoprotegerin, arterial stiffness, and mortality in normoalbuminemic Japanese hemodialysis patients

Summary  

A high circulating osteoprotegerin (OPG) level may be a risk factor for vascular calcification and mortality in hemodialysis patients. OPG and pulse wave velocity (PWV) were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients who were prospectively followed for 6 years. In long-term normoalbuminemic Japanese hemodialysis patients, OPG levels were strongly linked with both arterial stiffness and worse outcome.     

Influence of parathyroidectomy on mortality in hemodialysis patients: a prospective observational study

BACKGROUND: In hemodialysis patients, the relationships between serum PTH and phosphorus levels and mortality are debated because both high and low turnover bone diseases increase the risk of vascular calcifications. Furthermore, the prevalence of hypoparathyroidism is increasing, and there is a fear that this state is associated with an increase in bone fractures. METHODS: We performed a cross-sectional study to determine the prevalence and the causes of hypoparathyroidism (defined as basal and post-hypocalcemic-challenge serum PTH levels < 55 pg/mL) in 97 patients undergoing chronic hemodialysis treatment in our unit. We then prospectively observed patients with low PTH levels (< 55 pg/mL, n = 26) and those with hyperparathyroidism defined as a PTH levels > 200 pg/mL (n = 25) during eight years for all causes of mortality and bone fractures. Kaplan-Meyer survival curves were adjusted for age and sex. RESULTS: Hypoparathyroidism was present in 30% of our patients. The main causes of hypoparathyroidism were parathyroidectomy (77%) and aluminium and iron overload. Survival did not differ between patients with hypoparathyroidism and hyperparathyroidism and between patients with serum phosphorus < or > 2 mmol/L. Parathyroidectomy was associated with better survival (p < 0.01). Similarly, incidence of bone fractures did not differ for the two groups. CONCLUSIONS: Parathyroidectomy is the main cause of hypoparathyroidism in hemodialysis patients and is associated with a lower mortality risk. This result suggests that a more aggressive treatment of secondary hyperparathyroidism could decrease mortality in this high-risk population.     

Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients: results of a randomized clinical trial.

BACKGROUND: Elevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Sevelamer, a phosphate-binding polymer, attenuates the progression of arterial calcification; it is unknown whether this improves outcomes. PATIENTS AND INTERVENTIONS: A randomized comparison of sevelamer and calcium-based phosphate binders was performed in hemodialysis patients treated up to 45 months. The primary endpoint was mortality. Secondary endpoints included cause-specific mortality and hospitalization; 2103 patients were randomized, 2040 received treatment, and 1065 completed treatment. RESULTS: Overall mortality was not significantly reduced by sevelamer (adjusted relative risk = 0.92; 95% confidence interval, 0.78 to 1.09; log-rank P = .40). Among patients > or = 65 years of age, sevelamer reduced the risk of death (adjusted relative risk = 0.77; 95% confidence interval, 0.62 to 0.97; log-rank P = .02). Sevelamer patients had a trend toward fewer hospitalizations (P = .06) and fewer hospital days (P = .09). CONCLUSIONS: A statistically significant reduction in mortality in the overall study population was not observed. Sevelamer was associated with a survival benefit among patients > or = 65 years of age.     

Long-term effects of sevelamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients.

BACKGROUND: Short-term studies have suggested that sevelamer hydrochloride, a non-aluminium- and non-calcium-containing hydrogel, is an effective phosphate binder in haemodialysis patients, and may produce favourable changes in the lipid profile. METHODS: To determine the long-term effectiveness of sevelamer hydrochloride, we performed an open-label clinical trial in 192 adult patients with end-stage renal disease on haemodialysis. Drug-related changes in the concentrations of serum phosphorus, calcium, calcium x phosphate product, parathyroid hormone, and low- and high-density lipoprotein cholesterol concentrations were the major outcomes of interest. RESULTS: Treatment with sevelamer was associated with a mean change in serum phosphorus of -0.71+/-0.77 mmol/l, serum calcium of 0. 08+/-0.22 mmol/l, and calcium x phosphate product of -1.46+/-1.78 mmol/l (P<0.0001 for all comparisons). There were no significant overall treatment-related changes in parathyroid hormone. Serum levels of LDL cholesterol decreased by 0.81+/-0.75 mmol/l (mean -30%, P<0.0001) and HDL cholesterol increased by a mean of 0.15+/-0.29 mmol/l (mean +18%, P<0.0001). Drug-related adverse events were infrequent and most were of mild intensity. CONCLUSION: Sevelamer is a safe and effective phosphate binder that leads to significant improvements in the calcium x phosphate product and lipid profile of haemodialysis patients.     

Total arterial revascularisation: effect of avoiding cardiopulmonary bypass on in-hospital mortality and morbidity in a propensity-matched cohort.

OBJECTIVE: The combination of total arterial revascularisation and avoidance of cardiopulmonary bypass may provide additional benefits to patients receiving complete arterial grafting with cardiopulmonary bypass. We performed a propensity-matched cohort study of complete arterial off-pump and on-pump coronary surgery and examined differences in in-hospital mortality and morbidity. METHODS: Three hundred and sixty patients who underwent off-pump coronary surgery with complete arterial grafting between April 1997 and September 2002 were matched to 360 patients who received coronary surgery with cardiopulmonary bypass and complete arterial grafting. To match off-pump with unique on-pump patients, logistic regression was used to develop a propensity score for off-pump surgery. The C statistic for this model was 0.79. Off-pump patients were matched to unique on-pump patients with an identical 5-digit propensity score. If this could not be done, we then proceeded to a 4-, 3-, 2-, or 1-digit match. RESULTS: Patient characteristics were well matched. There was no difference in in-hospital mortality between the groups. Off-pump patients were less likely to develop sternal wound infections compared to the on-pump group (2.5 versus 5.8%; P=0.03), and had significantly lower blood loss (675 versus 780 ml; P<0.001), red blood cell unit transfusion (8.6 versus 38.9%; P<0.001), enzyme rises (13 versus 23 U/l; P<0.001), inotrope support (11.9 versus 28.9%; P<0.001), and ventilation times (5 versus 8 h; P<0.001). Intensive care unit and hospital stay were also significantly lower in the off-pump patients. CONCLUSIONS: Off-pump coronary surgery with complete arterial revascularisation can significantly reduce in-hospital morbidity and lengths of stay compared to conventional on-pump coronary surgery.     

盐酸司维拉姆治疗维持性血液透析患者高磷血症的短期疗效

目的 评价盐酸司维拉姆治疗终末期肾病维持性血液透析（MHD）患者高磷血症的短期疗效和安全性。 方法 来自国内5所综合性医院共138例并发高磷血症（透析前血磷＞1.78 mmol/L）的MHD患者纳入本研究。经过2周磷结合剂洗脱后,根据患者血磷水平予以相应口服剂量的盐酸司维拉姆片剂治疗,疗程为10周,随后为2周的停药观察期,总观察期为14周。给药期间每2周根据患者血清钙磷水平调整药物剂量。 结果 共有111例患者完成全部试验。经盐酸司维拉姆治疗2周后,患者血磷和血清钙磷乘积水平明显下降。10周疗程结束时,与用药前比较,患者血磷[（1.85±0.50）比（2.57±0.54） mmol/L,P < 0.01]、钙磷乘积[（4.16±1.72）比（5.79±1.50） mmol2/L2,P < 0.01]和血清低密度脂蛋白水平[（1.64±0.76）比（2.31±0.87） mmol/L,P < 0.01] 显著下降,而血浆全段甲状旁腺激素（iPTH）水平和血清校正血钙水平无显著变化。停药后2周,血磷和钙磷乘积水平高于10周治疗结束时,但仍显著低于基线水平[（2.26±0.7）比（2.57±0.54） mmol/L;（5.12±1.63）比（5.79±1.50） mmol2/L2,P < 0.01]。 纳入研究的138例患者中,106例（76.8%）发生了214件不良事件,其中89例（64.5％）的121件为不良反应。胃肠道不良事件总发生率为68.11%（94/138）,以轻至中度的便秘最为常见,经对症处理后可缓解或消失。 结论 盐酸司维拉姆可有效纠正终末期肾病MHD患者的高磷血症,并能降低血清钙磷乘积和血清低密度脂蛋白水平。用药后便秘等胃肠道症状较常见。     

Treatment of hyperphosphatemia with sevelamer hydrochloride in hemodialysis patients: a comparison with calcium acetate

BACKGROUND: Sevelamer hydrochloride is a recently approved calcium- and aluminium-free phosphate binder. A randomized study comparing sevelamer and calcium acetate was performed to assess the control of hyperphosphatemia in hemodialysis patients. METHODS: Administration of phosphate binders was discontinued during a two-week washout period. The patients were then randomized to receive sevelamer or calcium acetate. The laboratory tests were performed monthly for 34 weeks. RESULTS: There was a statistically significant decrease of serum phosphorus in both sevelamer and calcium acetate treatments. In addition, sevelamer improved the lipid profile. CONCLUSION: This study confirms that sevelamer is effective at lowering serum phosphorus in hemodialysis patients and that it has several striking properties that could be beneficial in atherosclerosis in dialysis patients.     

Efficacy and safety of sevelamer hydrochloride and calcium acetate in patients on peritoneal dialysis

Background. Inadequate phosphorus control is associated withincreased morbidity and mortality in patients with CKD stage5. Although phosphate binders are often used in patients onperitoneal dialysis (PD), no large randomized controlled studiesevaluating their use solely in this population have previouslybeen reported. Methods. In this multicentre, open-label study, adult patientson PD with serum phosphorus >5.5 mg/dl were randomized (2:1)to 12 weeks of treatment with sevelamer hydrochloride or calciumacetate. Doses were titrated to achieve serum phosphorus of3.0–5.5 mg/dl. Changes in serum phosphorus, calcium, intactparathyroid hormone (iPTH), lipids and plasma biomarkers wereassessed. Results. A total of 253 patients were screened, 143 of whomwere randomized (sevelamer hydrochloride, n = 97; calcium acetate,n = 46). Treatment groups were well balanced with regard tobaseline demographics. Serum phosphorus levels were significantlyreduced after 12 weeks with both sevelamer hydrochloride andcalcium acetate (P < 0.001). Serum PTH was also reduced inboth groups while serum calcium increased in the calcium acetategroup (P = 0.001) but not in the sevelamer hydrochloride group.Sevelamer hydrochloride was also associated with decreases intotal cholesterol, low-density lipoprotein cholesterol and uricacid and an increase in bone-specific alkaline phosphatase (allP < 0.001 versus baseline). Both treatments were well toleratedand safety profiles were consistent with previous reports inhaemodialysis patients. Hypercalcaemia was experienced by morecalcium acetate-treated patients (18 versus 2%; P = 0.001). Conclusions. In summary, sevelamer hydrochloride provides areduction in serum phosphorus compared to that obtained withcalcium-based binders in PD patients. The effects of sevelamerhydrochloride appear similar in both PD and haemodialysis populations.     

Effects of exercise training on physical impairment,arterial stiffness and health-related quality of life in patients with chronic kidney disease: a pilot study

Background  

Patients with chronic kidney disease (CKD) have impaired performance in physical tasks, lower health-related quality of life and high cardiovascular morbidity and mortality. Moderate intensity exercise has been shown to provide cardiovascular and metabolic benefits in healthy individuals and patients without CKD. Long-term exercise training is recommended as a vital component in the management of a number of chronic diseases. This randomized controlled pilot project examined the effects of exercise in predialysis CKD patients.     

Effect of gastric acid suppression with pantoprazole on the efficacy of sevelamer hydrochloride as a phosphate binder in haemodialysis patients: a pilot study

Sevelamer hydrochloride (HCL) is thought to require an appropriately acidic environment in order to bind gastrointestinal phosphate. Changes in gastric acidity with acid suppressants may therefore alter the efficacy of sevelamer HCL. Given the widespread use of acid suppression therapy in chronic kidney disease patients, there is potential for a common significant drug interaction to occur. This pilot study evaluated the in vivo effect of gastric acid suppression with pantoprazole on the efficacy of sevelamer HCL as a phosphate binder in maintenance haemodialysis patients. The study protocol was a cross-over, double-blinded, randomized, placebo-controlled trial in 10 haemodialysis patients randomly assigned to pantoprazole 40 mg daily or placebo for two consecutive 6-week periods. Serum phosphate was not significantly altered during pantoprazole compared with placebo treatment (1.61 ± 0.45 mmol/L vs 1.76 ± 0.42 mmol/L, P = 0.204). There were no differences in serum calcium, parathyroid hormone and bicarbonate. This pilot study demonstrates preliminary in vivo evidence for no effect of gastric acid suppression on the effectiveness of sevelamer HCL. Our results are limited by small sample size and therefore, larger experimental studies should be conducted. Although our study did not find a significant drug interaction, given the high prevalence of acid suppressant use in dialysis patients, physicians should be aware of the potential influence of acid suppression on the efficacy of phosphate binders and regularly assess the clinical need for acid suppression therapy.     

Potential influence of sevelamer hydrochloride on responsiveness to erythropoiesis-stimulating agents in haemodialysis patients

Aim: Vitamin D analogues, cinacalcet, and sevelamer play pivotal roles in the management of chronic kidney disease‐mineral bone disorder, and are noted to have pleiotropic effects. We examined whether these agents might be associated with the responsiveness to erythropoiesis‐stimulating agents (ESA). Methods: In this cross‐sectional study including haemodialysis patients treated with ESA, we searched for clinical parameters associated with the ESA resistance index, which was calculated as the weekly ESA dose divided by the patient's haemoglobin value. Results: Among 45 patients (male: female = 28 : 17, age 68 ± 10 years, haemodialysis duration 84 ± 60 months), vitamin D analogue, cinacalcet, and sevelamer were used in 95.6%, 26.7%, and 84.4% of the patients, respectively. Univariate analysis showed significant association of the ESA resistance index with transferrin saturation rate (TSAT), vitamin D analogue dose, and sevelamer dose. In multivariate analysis, the sevelamer dose and TSAT were found to be independent determinants of the ESA resistance index. Conclusion: Our preliminary data showed an independent association between sevelamer dose and the responsiveness to ESA in haemodialysis patients. Further studies are required to investigate the causal relationship between sevelamer and ESA responsiveness.     

盐酸司维拉姆对维持性血液透析患者心血管钙化影响的荟萃分析

目的 评价盐酸司维拉姆（sevelamer hydrochloride,盐酸聚丙烯胺,Renagel?誖）和含钙的磷结合剂对维持性血液透析（MHD）患者心血管钙化的影响。 方法 在Medline、CENTRAL和中国生物医学文献数据库中检索国内外已发表和未发表的相关文献,选择针对MHD患者、使用盐酸司维拉姆和含钙的磷结合剂两种药物进行比较的随机对照临床试验。两位评价者分别按检索策略收集资料,根据入选标准和排除标准筛选文献,对符合标准的文献进行荟萃分析。 结果 共有5篇文献（697例）符合入选标准。与使用钙磷结合剂的患者比较,使用盐酸司维拉姆的患者冠状动脉钙化积分较低,合并加权均数差（WMD）＝-66.84,95％可信区间（CI）为-126.90～-6.77;主动脉的钙化积分较低,合并WMD＝-140.26,95％CI为-224.04 ～ -56.47;住院率较低,合并相对危险度（RR）为0.75（95％CI：0.59～0.95,P=0.02）;而病死率在两组药物使用者间差异无统计学意义,合并RR为0.76（95％CI：0.37～1.57,P=0.45）。 结论 与钙磷结合剂比较,盐酸司维拉姆可以明显改善MHD患者的心血管钙化程度,进而降低患者的住院率。