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Background Phosphate binders are commonly used in the treatment of patients with hyperphosphatemia. While phosphate binders are used to lower phosphate, the effects of specific phosphate binder types on vitamin D metabolism are unknown. Methods We performed a secondary analysis of the Phosphate Normalization Trial in which patients with moderate to advanced chronic kidney disease were randomized to receive either placebo, sevelamer carbonate, lanthanum carbonate or calcium acetate for 9 months. We evaluated changes in serum concentrations of vitamin D metabolites including 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the ratio of 24,25(OH)2D3 to 25-hydroxyvitamin D [the vitamin D metabolite ratio (VMR)] and the ratio of serum 1,25(OH)2D to 25-hydroxyvitamin D. Results Compared with placebo, randomization to the calcium acetate arm was associated with a 0.6 ng/mL (95% CI 0.2, 1) and 13.5 pg/ng (95% CI 5.5, 21.5) increase in 24,25(OH)2D and VMR, respectively, and a 5.2 pg/mL (95% CI 1.1, 9.4) reduction in 1,25(OH)2D. Randomization to sevelamer carbonate was associated with a 0.5 ng/mL (95% CI −0.9, −0.1) and 11.8 pg/ng (95% CI −20, −3.5) reduction in 24,25(OH)2D3 and VMR, respectively. There was no association of the sevelamer arm with the change in 1,25(OH)2D3, and randomization to lanthanum carbonate was not associated with a change in any of the vitamin D metabolites. Conclusion Administration of different phosphate binders to patients with moderate to severe CKD results in unique changes in vitamin D metabolism.

Background and Aims Tenapanor, a first-in-class, phosphate absorption inhibitor blocks the paracellular absorption of phosphate in the GI tract by local inhibition of the sodium-hydrogen exchanger (NHE3). It therefore provides a novel, non-binder approach for managing hyperphosphatemia. Tenapanor is dosed as one small pill twice daily. In three pivotal trials, tenapanor met its primary phosphorus-lowering outcome. This report evaluates long-term safety data from the longest of these trials. Method This 52-week study consisted of a 26-week, open-label, randomized treatment period with a 12-week placebo-controlled randomized withdrawal period, followed by a 14-week open label safety extension period. Maintenance dialysis patients with serum phosphorus ≥ 6.0 mg/dL and a 1.5 mg/dL increase in serum phosphorus following phosphate binder washout were randomized 3:1 to receive tenapanor 30 mg twice daily or sevelamer carbonate, dosed per package insert. At end of the randomized treatment period all patients in the tenapanor arm were re-randomized 1:1 to either tenapanor or placebo for the randomized withdrawal period followed by tenapanor for the safety extension period. Sevelamer was used as a safety control for comparisons of serious adverse events/hospitalizations to tenapanor. Results Tenapanor was generally well tolerated, with diarrhea the only adverse event reported by >5% of patients during the randomized treatment period. Diarrhea was typically mild-to-moderate in severity, transient, and occurred more commonly during the randomized treatment period than the randomized withdrawal or safety extension periods. Rates of serious adverse events leading to hospitalization were higher in patients treated with sevelamer than tenapanor (35.8% vs 24.6%). The highest reported percentages of serious adverse events were infections and infestations (16.1% vs 9.3%) cardiac disorders (8.0% vs 5.7%), respiratory, thoracic and mediastinal disorders (8.8% vs 5.5%), and metabolism and nutritional disorders (7.3% vs 3.6%) for sevelamer and tenapanor, respectively. Adverse events leading to death were higher in patients treated with sevelamer than tenapanor (3.6% vs 2.9%). Conclusion Among maintenance dialysis patients with hyperphosphatemia, tenapanor, a novel, non-binder, phosphate absorption inhibitor that blocks paracellular absorption of phosphorus with a one tablet twice daily dose, has an acceptable safety profile, and, if approved, may offer a new approach to the treatment of hyperphosphatemia.

Background and Aims Low 25-hydroxyvitamin D (25(OH)D) level is common in patients with chronic kidney disease and hemodialysis (HD) patients . It has been associated with high bone turnover, secondary hyperparathyroidism (SHPT), and decreased bone mineral density (BMD). We aimed to investigate the efficacy of equivalent doses of pulse oral cholecalciferol (25,000 IU weekly for 12 weeks) versus single intramuscular cholecalciferol (300,000 IU) in correcting serum 25 (OH) D levels in HD patients. Method Prospective randomized open label Clinical trial. 40 prevalent HD patients with vitamin D deficiency were enrolled. Serum 25 hydroxy-vitamin D (25 (OH) D) level < 20 ng/m and Serum parathyroid hormone level ( iPTH) >100 pg/ml. Exclusion Criteria were serum calcium > 10 .5mg/dl, Calcium phosphorus product ≥ 55, tertiary hyperparathyroidism and Parathyroidectomy among others. Patients were randomized equally into two groups. 36 patients were compliant and completed the study. Group I :17 HD patients received oral cholecalciferol 25000 IU weekly of (Vidrop® 2800 IU/ml ) for 12 weeks. Group II: 19 HD patients received a single intramuscular injection (IM) of cholecalciferol 300,000 IU (Devarol® 200000 IU/ ampoule). Vitamin D supplements were stopped if serum calcium >10.5mg/dl or 25(OH) D level > 100 ng /ml (toxic level) during study. Serum calcium (albumin-adjusted), phosphorus, 25(OH) D by ELISA, Alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) were monitored at baseline, 6 and 12 weeks of intervention. Both groups were maintained on their regular medications used to control mineral bone disorder as: alfacalcidol, sevelamer or a calcium-based chelator. Results Significant increase in serum 25(OH) D level in group II patients who received single dose IM Cholecalciferol after 12 w. Means of 25 (OH)D levels basal and 12 w of study were (10.54±5.14 and 13.45 ±5.72) ng/ml respectively. There was a significant increase in the mean of serum calcium basal and at 12 w (8.19±0.69 and 8.42 ±0.54) mg/dl respectively. No significant reduction in the iPTH level or any significant change in the serum phosphorus level was noticed. compared to group I with oral vitamin D, there was an insignificant change in the mean of serum 25(OH) D basal and at 12 w were (11.91±6.13 and 9.30±5.29) ng/ml respectively, associated with insignificant increase in serum calcium and an insignificant change in either the level of phosphorus or iPTH level. Conclusion Cholecalciferol 300,000 IU IM single dose showed better response on serum 25 (OH) D and calcium levels as a treatment of hemodialysis patients with Vitamin D deficiency compared to weekly oral dose for 3 months.

Background and Aims Hyperphosphatemia in chronic kidney disease (CKD) patients is associated with adverse outcomes, including vascular calcification, increasing risks of disease progression and even death. Sevelamer carbonate have been approved in Europe for phosphate lowering treatment in pre-dialysis CKD patient, its efficacy and safety in Chinese CKD hyperphosphatemia patients are not previously reported. Method This was a phase III, multi-center, randomized, double blind, placebo-controlled, balanced (1:1, sevelamer: placebo) parallel-group study to evaluate the efficacy and safety of sevelamer carbonate versus placebo over 8 weeks’ duration in hyperphosphatemic CKD patients not on dialysis in China (Registration number NCT03001011). The primary objective of this study is to demonstrate efficacy of sevelamer carbonate tablets in the reduction of serum phosphorus in hyperphosphatemia in patients with chronic kidney disease (CKD) not on dialysis. Results In all, 202 patients were randomized (sevelamer, n=101; placebo, n=101); mean age was 50.7 years, 53.5% were male and the mean time of CKD diagnosis was 3.4 years with mean eGFR 7.5 ml/min/1.73 m2. The baseline phosphorous were 2.13±0.35 mmol/L and 2.12±0.37 mmol/L in sevelamer and placebo group, respectively. The mean serum phosphorous decreased significantly in patients treated with sevelamer carbonate (-0.22±0.47 mmol/L) compared with placebo (0.05±0.44 mmol/L) (mean difference between sevelamer carbonate and placebo was -0.26 mmol/L, P Conclusion This study demonstrated that sevelamer carbonate has produced a significant reduction of serum phosphorous, and is safe and tolerated in Chinese pre-dialysis CKD patients with hyperphosphatemia.

Nephrology, dialysis, transplantation 30(6), 1037-1046 (2015). doi:10.1093/ndt/gfv006, Published by Oxford Univ. Press, Oxford

Whether convective therapies allow better control of serum phosphate (P) is still undefined, and no data are available concerning on-line haemofiltration (HF). The objectives of the study are to evaluate the effect of convective treatments (CTs) on P levels in comparison with low-flux haemodialysis (HD) and to evaluate the correlates of serum phosphate in a post hoc analysis of a randomized clinical trial.This analysis was performed in the database of a multicentre, open label and randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: on-line pre-dilution HF (36 patients) or on-line pre-dilution haemodiafiltration (40 patients).CTs did not affect P (P = 0.526), calcium (Ca) (P = 0.849) and parathyroid hormone levels (P = 0.622). P levels were associated with the use of phosphate binders including aluminium-based phosphate binders (P0.001) and sevelamer (P0.001), pre-dialysis bicarbonate levels (P0.001) and pre-dialysis blood K levels (P0.001). On multivariate analysis (generalized linear model), serum P was again largely unassociated with CTs (P = 0.631). Notably, participating centres were by far the strongest independent correlate of serum P, explaining 45.3% of the variance of serum P over the trial and this association was confirmed at multivariate analysis. Bicarbonate (P0.001) and, to a weaker extent, serum K (P = 0.032) were independently related to serum P.In comparison with low-flux HD, CTs did not significantly affect serum P levels. Participating centres were the main source of P variability during the trial followed by treatment with phosphate binders, serum bicarbonate and, to a weak extent, serum potassium levels (ClinicalTrials.gov Identifier: NCT011583309).

BACKGROUND: This study compared the effects of short-term titrated colestilan (a novel non-absorbable, non-calcium, phosphate binder) with placebo, and evaluated the safety and efficacy of colestilan over 1 year compared with sevelamer, in patients with chronic kidney disease (CKD) 5D. METHODS: This prospective multicentre study comprised a 4-week phosphate binder washout period, a 16-week short-term, flexible-dose, treatment period (including a 4-week placebo-controlled withdrawal period) and a 40-week extension treatment phase. RESULTS: At Week 16 (the end of the 4-week placebo-controlled withdrawal period), serum phosphorus level was 0.43 mmol/L (1.32 mg/dL) lower with colestilan than placebo (P < 0.001; primary end point). Serum LDL-C level was also lower with colestilan than with placebo (P < 0.001). Both colestilan and sevelamer produced significant reductions from baseline in serum phosphorus levels (P < 0.001), maintained for 1 year, and the proportion of patients achieving target levels of ≤1.78 mmol/L (5.5 mg/dL) or ≤1.95 mmol/L (6.0 mg/dL) at study end were similar (65.3 and 73.3%, respectively, for colestilan, and 66.9 and 77.4%, respectively, for sevelamer). Serum calcium level remained stable in the colestilan group but tended to increase slightly in the sevelamer group (end-of-study increase of 0.035 mmol/L over baseline). Both binders produced similar reductions from baseline in LDL-C level (P < 0.001), and responder rates after 1 year, using a target of

End-stage renal disease impairs functional status, diminishes quality of life and shortens lifespan. Despite recent improvements in survival of affected individuals in the USA, 50% of patients will die within 3 years of initiating hemodialysis [1]. Nephrologists, dialysis clinic providers, insurers and patients are all in need of therapeutic advances that can further impact mortality in this population. In the current era of growing emphasis on healthcare quality and safety and increasing attention to patient-centered outcomes, an ideal intervention is one that would safely improve clinical outcomes and have beneficial effects on the patients' overall health and well-being. This framework has fostered renewed vigor in addressing a long-standing question about the management of hyperphosphatemia in the dialysis population: what is the ‘optimal’ serum phosphate? Large observational studies have repeatedly demonstrated a strong independent relationship between hyperphosphatemia and increased risk of mortality in patients undergoing dialysis treatment [2–4]. Experimental studies attest to the biological plausibility of these consistent epidemiologic findings. Phosphate excess has been implicated as a potent inducer of vascular calcification [5], which may contribute to increased rates of cardiovascular events and death through effects on arterial stiffness and left ventricular hypertrophy. However, randomized clinical trials evaluating the efficacy of lowering serum phosphate levels on reduction of mortality are lacking. Indeed, all phosphate binders in the USA have been approved solely on the basis of efficacy studies that demonstrated ability to reduce serum phosphate levels in hyperphosphatemic patients undergoing dialysis. In this evidence-free zone, several well-designed pharmaco-epidemiologic studies employing propensity score methods to address confounding by indication have expanded our knowledge base [6–8]. In a prospective observational cohort study of 8610 incident hemodialysis patients in the USA, initiation of treatment with phosphate binders during the first 90 days on hemodialysis was independently associated with an 18–30% lower risk of subsequent 1-year all-cause mortality compared with no early treatment [6]. The results were unchanged in an analysis that matched treated and untreated patients on their baseline serum phosphate levels and propensity score of receiving phosphate binders. A subsequent study using data from the prevalent European dialysis population followed for 3 years yielded similar findings [7]. In this prospective cohort of 6797 patients, propensity score-adjusted analyses also demonstrated a significant association between phosphate binder use and lower all-cause and cardiovascular disease mortality. Importantly, with the exception for aluminum-based binders, there were no major differences in associations with mortality by phosphate binder class, with the hazard ratios (HR) ranging from 0.28 to 0.73. In contrast, a propensity score-matched analysis conducted in another USA cohort of incident dialysis patients found no significant association between use of calcium-based phosphate binders and 1-year survival (HR 0.89; 95% confidence interval [CI], 0.72–1.10) [8]. In this issue of Nephrology, Dialysis and Transplantation, Komaba and colleagues extend the existing data by reporting the findings from 2269 prevalent dialysis patients in Japan and by focusing on lanthanum carbonate as the pharmacological exposure variable. Similar to prior studies [6–8], the authors used rigorous statistical methodologies to address confounding. Uniquely, the data set captured information immediately prior to and during market introduction of lanthanum carbonate in Japan. This allowed the authors to study incident users of lanthanum carbonate, capture covariate information immediately prior to exposure and generate a sufficient number of matched treated and untreated individuals. As expected, compared with serum phosphate levels of 4.6 to 5.3 mg dL−1, levels above 6.4 mg dL−1 were significantly associated with higher mortality during a mean follow-up time of 2.7 years. Following market introduction of lanthanum carbonate, its prescription increased gradually to 27% over 3 years. Lanthanum carbonate use was associated with ∼0.5 mg dL−1 decline in serum phosphate levels and gradual reduction in use of other phosphate binders. In propensity score-matched analyses, mortality was not significantly different in lanthanum carbonate users compared with nonusers (HR 0.71; 95% CI 0.47–1.09). However, among patients with serum phosphate levels of >6 mg dL−1, the relationship was significant and favored lanthanum carbonate users (HR 0.52; 95% CI 0.28–0.95). As the authors suggest, the expected phosphate binding afforded by lanthanum carbonate and dietary liberalization are the most likely explanation for these new findings. These inferences are in line with the findings from the Dialysis Outcomes and Practice Patterns Study, which reported an association between favorable nutritional status, phosphate binder use and improved survival in hemodialysis patients [9]. The authors also acknowledge that reduction in calcium containing phosphate binder use may have contributed to the improved survival, a finding consistent with a recent comparative effectiveness analysis of calcium acetate versus sevelamer carbonate in elderly hemodialysis patients (n = 31 776), which demonstrated an improvement in survival with sevelamer carbonate (HR 0.94; 95% CI 0.91–0.98) in propensity-matched cohorts [10]. Taken together, these pharmaco-epidemiologic studies suggest the possibility of a survival advantage associated with phosphate binder use, particularly with non-calcium containing phosphate binders. However, because propensity score matching only allows for balancing of measured covariates, unmeasured differences between users and nonusers could still account for the observed results. Thus, we are left with the conclusion that existing observational data are inadequate to guide clinical decisions and that randomized, controlled clinical trials are needed to confirm or disprove the survival benefit related to phosphate binder use. The burgeoning cost of phosphate binders (which is now estimated to be over $1.5 billion in the USA), an expanded number of ‘novel’ phosphate binders and a long absent consideration of patient-centered outcomes has re-focused awareness of the need for definitive trials in this area. Despite a lack of evidence on the efficacy of phosphate binders on hard clinical outcomes or on the clinical utility of strict phosphate control, over 80% of prevalent dialysis patients are prescribed phosphate binders [9, 11], and guideline groups recommend that the target serum phosphate should approach normal levels [12, 13]. However, achieving an unproven serum phosphate target may come at the cost of excessive pill burden [14], clinically important gastrointestinal side effects related to phosphate binder use, un-necessary restrictions on dietary and lifestyle choices, and labeling individuals who are unable to reach the desired target as noncompliant. In the USA, there is also the added financial cost related to co-payments. Finally, excessive amounts of calcium-based binders appear likely to contribute to vascular calcification, which is a risk factor for mortality [15, 16]. Given the dearth of evidence, the End Stage Renal Disease Quality Measure Development and Maintenance Mineral and Bone Disorder Clinical Technical Expert Panel convened by the Center for Medicare and Medicaid Services in 2013 recommended a randomized, controlled clinical trial to compare the effects of different serum phosphate targets on hard clinical outcomes (mortality, fractures, hospitalizations and cardiovascular events) in patients undergoing dialysis. Several other expert groups, including guideline work groups, have also endorsed this idea [17]. Recent developments in pragmatic clinical trial methodologies and funding initiatives for patient-centered outcomes research position the nephrology community and all the relevant stakeholders to step up to the plate and work together to deliver the high-level evidence that will inform clinical care decisions. Management of hyperphosphatemia in dialysis is fraught with evidence gaps. Chief among them is inattention to patient experiences with phosphate binders and dietary phosphate restriction. The next landmark study in this area must finally evaluate clinically relevant, rather than biochemical, outcomes and should address the long over-looked domain of patient-reported outcomes.

Background. Epicardial adipose tissue (EAT) has been described in the general population as an independent risk marker for incident coronary artery disease. In hemodialysis patients, it correlates with other markers of cardiovascular disease, but it is unknown if it is associated with adverse events. Methods. post hoc analysis of the Renagel in New Dialysis (RIND) patients study, a randomized trial of sevelamer versus calcium-based phosphate binders in 109 incident hemodialysis patients, followed for all-cause mortality for a median of 49.3 months. Patients underwent baseline cardiac computed tomography imaging within 120 days of dialysis initiation. Results. Baseline EAT measurements were available in 95 patients; EAT was positively correlated with age, body mass index, triglycerides, C-reactive protein, coronary artery calcium and aortic calcium, and negatively correlated with systolic and diastolic blood pressure, serum high density lipoprotein (HPL) cholesterol and serum phosphate (all P< 0.05). During followup, a total of 27 (28.4%) patients expired [mortality per 1000 patients/year: 95% confidence interval (95% CI)= 77 (64–94)]. Five-year survival rate was 44. 6% (95% CI: 21.1–65.7) and 71.2% (95% CI: 45.95–86.25) in patients with EAT above or below the median, respectively. Each 10 cc increase in EAT volume was associated with a significant 6% increase in the risk of death during follow-up [hazard ratio (HR): 1.060; 95% CI: 1.013–1.109; P-value =0.012]. Conclusions. In this subanalysis of a randomized trial, EAT was an independent predictor of mortality in incident hemodialysis patients after ∼4 years of follow-up. These hypothesisgenerating findings will need confirmatory evidence.

Background Atherosclerosis and vascular calcification (VC) progression in chronic kidney disease is favored by disturbances of mineral metabolism. We compared the effect of phosphate binder lanthanum (La) carbonate with sevelamer-HCl on atherosclerosis, VC and bone structure and function in mice with chronic renal failure (CRF). Methods Apolipoprotein E-deficient (apoE(-/-)) mice were randomized to one non-CRF and three CRF groups, fed with standard diet (one non-CRF and one CRF) or diet supplemented with either 3% lanthanum carbonate (La3%) or 3% sevelamer-HCl (Sev3%). Results Both La3% and Sev3% supplemented CRF mice displayed a decrease of serum phosphorus, calcification at both intimal and medial aortic sites and atherosclerosis. This was associated with a reduction of plaque Type I collagen expression by both binders and of positive nitrotyrosine staining in response to sevelamer-HCl only. Increased mineral apposition and bone formation rates in unsupplemented CRF mice were reduced by Sev3% but not by La3%. Conclusions The beneficial effects of La carbonate and sevelamer-HCl on the progression of VC and atherosclerosis in CRF mice could be mainly due to a decrease in phosphate retention and likewise a reduction of arterial Type I collagen expression. The effect of La carbonate differed from that of sevelamer-HCl in that it did not appear to exert its vascular effects via changes in oxidative stress or bone remodeling in the present model.

Background. Strict control of serum calcium and phosphate concentrations is paramount to prevent secondary hyperparathyroidism in haemodialysis (HD) patients. Standard intermittent low-flux HD (Lf-HD) is not sufficient to reach this goal. The aim of this study was to evaluate the effect of on-line haemodiafiltration (Ol-HDF) on serum calcium (sCa), phosphate (sPO4) and parathyroid hormone (PTHint) concentrations. Methods. Of the 220 patients screened, 65 met the inclusion criteria for the study; 30 of whom agreed to participate in the study (Study group), the others were considered as the control group (Controls). Protocol for Study the group consisted of 6 months conventional Lf-HD (Period 1) and 6 months of post-dilutional Ol-HDF (Period 2). Controls continued their usual Lf-HD and were followed for 12 months. The main variables evaluated at the start and at the end of each period were sCa, sPO4 and PTHint. Results. The switchover from Lf-HD to Ol-HDF resulted in a significant reduction of sPO4 (from 5.1 6 1.0 to 4.0 6 0.7; P < 0.0001) and PTHint concentrations (from 307 6 167 to 194 6 98; P < 0.0001), no significant changes were found in both sCa concentrations (from 9.1 6 0.7 to 8.9 6 0.6) and phosphate binder dose. Kt/Vurea increased significantly, and beta2 microglobulin concentrations decreased significantly. In the Controls, no significant variations of the same variables were observed over time, except for a significant increase in sevelamer intake. Conclusion. This study supports the idea that Ol-HDF could be better than Lf-HD in controlling mineral metabolism in HD patients.

correlates of prevalent coronary calcification. Int J Cardiol 2005; 98: 325–330 45. Shisen J, Leung DY, Juergens CP. Gender and age differences in the prevalence of coronary artery calcification in 953 Chinese subjects. Hearth Lung Circ 2005; 14: 69–73 46. London GM, Marchais SJ, Guerin AP et al. Association of bone activity, calcium load, aortic stiffness, and calcifications in ESRD. J Am Soc Nephrol 2008; 19: 1827–1835 47. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney DiseaseMineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009; 113: S1–S130 48. Stenvinkel P, Wang K, Qureshi AR et al. Low fetuin-A levels are associated with cardiovascular death: impact of variations in the gene encoding fetuin. Kidney Int 2005; 67: 2383–2392 49. Chiu YW, Teitelbaum I, Misra M et al. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J Am Soc Nephrol 2009; 4: 1089–1096 50. Giachelli CM. The emerging role of phosphate in vascular calcification. Kidney Int 2009; 75: 890–897 51. Fan S, Ross C, Mitra S et al. A randomized, crossover design study of sevelamer carbonate powder and sevelamer hydrochloride tablets in chronic kidney disease patients on haemodialysis. Nephrol Dial Transplant 2009; 24: 3794–3799 52. Fishbane S, Delmez J, Suki WN et al. A randomized, parallel, openlabel study to compare once-daily sevelamer carbonate powder dosing with thrice-daily sevelamer hydrochloride tablet dosing in CKD patients on hemodialysis. Am J Kidney Dis 2010; 55: 307–315 53. Oliveira RB, Cancela AL, Graciolli FG et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy?. Clin J Am Soc Nephrol 2010; 5: 286–291 54. Brandenburg VM, Jahnen-Dechent W, Ketteler M. Sevelamer and the bone-vascular axis in chronic kidney disease: bone turnover, inflammation, and calcification regulation. Kidney Int Suppl 2009; 114: S26–S33

Background. Lanthanum carbonate and sevelamer carbonate are non-calcium-based phosphate binders used to manage hyperphosphataemia in patients with chronic kidney disease (CKD). Patients with CKD may require intravenous or oral active vitamin D. We investigated the effects of lanthanum carbonate and sevelamer carbonate on the bioavailability of oral calcitriol. Methods. This was a three-period, crossover study in healthy volunteers. Forty-one individuals were randomized to one of six possible sequences, each consisting of three treatment periods separated by washouts. The treatments were calcitriol (1 μg at lunch), calcitriol with lanthanum carbonate (3000 mg/day) and calcitriol with sevelamer carbonate (7200 mg/day). Serum calcitriol levels were assessed at baseline and throughout the study. Results. Co-administration of lanthanum carbonate with calcitriol had no significant effect on area under the curve over 48 h (AUC0–48) for serum exogenous calcitriol [least-squares (LS) mean, calcitriol with lanthanum carbonate vs calcitriol alone: 429 pg h/mL vs 318 pg h/mL, respectively; P = 0.171]. Similarly, there was no significant effect on maximum concentration (Cmax). In contrast, co-administration with sevelamer was associated with a significant reduction in bioavailability parameters for calcitriol (calcitriol with sevelamer carbonate vs calcitriol alone, LS mean AUC0–48: 137 pg h/mL vs 318 pg h/mL, respectively; P = 0.024; LS mean Cmax: 40.1 pg/mL vs 49.7 pg/mL, respectively; P < 0.001). Conclusions. Sevelamer carbonate significantly reduces serum concentrations of exogenous calcitriol when administered concomitantly with oral calcitriol, whereas lanthanum carbonate has no significant effect. This should be considered when treating CKD patients who require phosphate binders and oral vitamin D.

Background. Abnormalitiesinmineralmetabolisminchronic kidney disease are associated with increased morbidity and mortality. The Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines were established in 2003toaddressissuesinthemanagement ofmineral andbone metabolism. The goal of this study was to compare (i) mineral metabolism control among Canadian haemodialysis (HD) patients with K/DOQI-defined targets and Dialysis Outcomes and Practice Patterns Study II (DOPPS II) data and (ii) the effect of different treatment strategies. Methods. A cross-sectional study of 2215 HD patients was conducted. Phosphorus (P), calcium (Ca), intact parathyroid hormone (iPTH) and calcium-phosphate product (CaXP) were analysed. In addition, management was compared between provinces with more or less restricted access to the phosphate binder sevelamer. Results.K/DOQItargetsfor P,Ca, iPTH and CaXPK/DOQI targets were met by 59.7%, 58.6%, 29.7% and 83.3%, respectively.Agreater proportionofpatientswerewithintarget comparedwiththoseinDOPPSII(2002–2004).Targetswere more likely to be reached by patients residing in provinces with formularies allowing less restricted access to sevelamer: P: 61.8% vs 55.7% (P = 0.01); CaXP: 85.5% vs 79.1% (P = 0.0006). As expected, patients in provinces with more restrictive formularies were more often receiving doses of elemental calcium >1.5g/day thanthosewith moreopenlistings (62.1% vs 14.0%, P < 0.0001) and were less likely to receive sevelamer (14.1% vs 42.4%, P = 0.0001). Conclusion. Mineral metabolism parameters were more frequently within the target range amongst (i) patients in the current study compared with those in the DOPPS II era and (ii) patients in provinces with less restricted access to sevelamer.

Background. Phosphate binders are required to control serum phosphorus in dialysis patients. A phosphate binder combining calcium and magnesium offers an interesting therapeutic option. Methods. This controlled randomized, investigator-masked, multicentre trial investigated the effect of calcium acetate/magnesium carbonate (CaMg) on serum phosphorus levels compared with sevelamer hydrochloride (HCl). The study aim was to show non-inferiority of CaMg in lowering serum phosphorus levels into Kidney Disease Outcome Quality Initiative (K/DOQI) target level range after 24 weeks. Three hundred and twenty-six patients from five European countries were included. After a phosphate binder washout period, 255 patients were randomized in a 1:1 fashion. Two hundred and four patients completed the study per protocol (CaMg, N = 105; dropouts N = 18; sevelamer-HCl, N = 99; dropouts N = 34). Patient baseline characteristics were similar in both groups. Results. Serum phosphorus levels had decreased significantly with both drugs at week 25, and the study hypothesis of CaMg not being inferior to sevelamer-HCl was confirmed. The area under the curve for serum phosphorus (P = 0.0042) and the number of visits above K/DOQI (≤1.78 mmol/L, P = 0.0198) and Kidney disease: Improving global outcomes (KDIGO) targets (≤1.45 mmol/L, P = 0.0067) were significantly lower with CaMg. Ionized serum calcium did not differ between groups; total serum calcium increased in the CaMg group (treatment difference 0.0477 mmol/L; P = 0.0032) but was not associated with a higher risk of hypercalcaemia. An asymptomatic increase in serum magnesium occurred in CaMg-treated patients (treatment difference 0.2597 mmol/L, P < 0.0001). There was no difference in the number of patients with adverse events. Conclusion. CaMg was non-inferior to the comparator at controlling serum phosphorus levels at Week 25. There was no change in ionized calcium; there was minimal increase in total serum calcium and a small increase in serum magnesium. It had a good tolerability profile and thus may represent an effective treatment of hyperphosphataemia.

Background. Cardiovascular morbidity and mortality are massively increased in patients with chronic kidney disease (CKD). Sevelamer hydrochloride has been shown to attenuate cardiovascular calcifications in CKD and end-stage renal disease (ESRD) patients. We assessed how sevelamer hydrochloride influences th ee volution of serum fetuin-A and other serological factors predicting cardiovascular outcome and survival in haemodialysis patients. Methods. Fifty-seven prevalent haemodialysis patients were included in a three-phase prospective interventional trial (A‐B‐A design; 8 weeks per phase). Sevelamer was only administered in the middle phase of the study. Within the other two phases, ! 90% of the patients received calcium acetate for phosphate binding. Detailed time courses of serum biochemistries were analysed in order to obtain detailed insight into the influence of sevelamer upon CKD‐ mineral and bone disorder (MBD) parameters as well as serum fetuin-A, fibroblast growth factor 23 (FGF23) and uraemic toxin levels [uric acid, indoxyl sulphate, hippuric acid, indole acetic acid, p-cresol and 3-carboxy-4-methyl5-propyl-2-furanpropionic acid (CMPF)]. Results. Forty-one patients finished the three prospective study phases (intention-to-treat analysis). After treatment with sevelamer, serum fetuin-A significantly increased (+21%), showing a delayed increase outlasting the third (non-sevelamer) study period. Total and low-density lipoprotein (LDL) cholesterol levels, as well as serum calcium, decreased significantly. The opposite occurred with albumin, C-reactive protein and intact parathyroid hormone (iPTH). FGF23, uric acid, indoxyl sulphate, hippuric acid, indole acetic acid, CMPF and serum phosphate did not change significantly during sevelamer treatment. In contrast, in parallel to sevelamer treatment, there was a significant rise in serum p-cresol. Conclusions. In haemodialysis patients, treatment with sevelamer over 8 weeks was associated with a delayed yet long-lasting increase in serum fetuin-A levels. Increasing the serum level of fetuin-A, a negative acute-phase protein and systemic calcification inhibitor, might be one of the potential anti-calcification mechanisms of sevelamer. Since we failed to detect a decrease in systemic inflammation and uraemic toxins, the exact mechanisms by which sevelamer treatment affects serum fetuin-A remain to be determined.

Background Sevelamer carbonate is an improved, buffered form of sevelamer hydrochloride developed for the treatment of hyperphosphataemia in CKD patients. Sevelamer carbonate formulated as a powder for oral suspension presents a novel, patient-friendly alternative to tablet phosphate binders. This study compared the safety and efficacy of sevelamer carbonate powder with sevelamer hydrochloride tablets in CKD patients on haemodialysis. Methods This was a multi-centre, open-label, randomized, crossover design study. Thirty-one haemodialysis patients were randomly assigned to either sevelamer carbonate powder or sevelamer hydrochloride tablets for 4 weeks followed by a crossover to the other regimen for an additional 4 weeks. Results The mean serum phosphorus was 1.6 +/- 0.5 mmol/L (5.0 +/- 1.5 mg/dL) during sevelamer carbonate powder treatment and 1.7 +/- 0.4 mmol/L (5.2 +/- 1.1 mg/dL) during sevelamer hydrochloride tablet treatment. Sevelamer carbonate powder and sevelamer hydrochloride tablets are equivalent in controlling serum phosphorus; the geometric least square mean ratio was 0.95 (90% CI 0.87-1.03). No statistically significant or clinically meaningful differences were observed in calcium x phosphorus product and lipid levels between sevelamer carbonate powder and sevelamer hydrochloride tablets. Serum bicarbonate levels increased 2.7 +/- 3.7 mmol/L (2.7 +/- 3.7 mEq/L) during sevelamer carbonate treatment. No statistically significant change in bicarbonate was observed during sevelamer hydrochloride treatment. Sevelamer carbonate powder and sevelamer hydrochloride were well tolerated during this study. Conclusions Sevelamer carbonate powder and sevelamer hydrochloride tablets are equivalent in controlling serum phosphorus and well tolerated in CKD patients on haemodialysis. Bicarbonate levels improved only during sevelamer carbonate treatment. Sevelamer carbonate powder should provide a welcomed new option for the treatment of hyperphosphataemia for CKD patients on dialysis.

Inadequate phosphorus control is associated with increased morbidity and mortality in patients with CKD stage 5. Although phosphate binders are often used in patients on peritoneal dialysis (PD), no large randomized controlled studies evaluating their use solely in this population have previously been reported.In this multicentre, open-label study, adult patients on PD with serum phosphorus5.5 mg/dl were randomized (2:1) to 12 weeks of treatment with sevelamer hydrochloride or calcium acetate. Doses were titrated to achieve serum phosphorus of 3.0-5.5 mg/dl. Changes in serum phosphorus, calcium, intact parathyroid hormone (iPTH), lipids and plasma biomarkers were assessed.A total of 253 patients were screened, 143 of whom were randomized (sevelamer hydrochloride, n = 97; calcium acetate, n = 46). Treatment groups were well balanced with regard to baseline demographics. Serum phosphorus levels were significantly reduced after 12 weeks with both sevelamer hydrochloride and calcium acetate (P0.001). Serum PTH was also reduced in both groups while serum calcium increased in the calcium acetate group (P = 0.001) but not in the sevelamer hydrochloride group. Sevelamer hydrochloride was also associated with decreases in total cholesterol, low-density lipoprotein cholesterol and uric acid and an increase in bone-specific alkaline phosphatase (all P0.001 versus baseline). Both treatments were well tolerated and safety profiles were consistent with previous reports in haemodialysis patients. Hypercalcaemia was experienced by more calcium acetate-treated patients (18 versus 2%; P = 0.001).In summary, sevelamer hydrochloride provides a reduction in serum phosphorus compared to that obtained with calcium-based binders in PD patients. The effects of sevelamer hydrochloride appear similar in both PD and haemodialysis populations.

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.Twenty-eight patients undergoing haemodialysis that presented secondary hyperparathyroidism (PTH300 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.Serum PTH (826.9 +/- 325 vs 248.1 +/- 77.3, P0.001), serum calcium (9.9 +/- 0.6 vs 8.6 +/- 0.4, P0.001) and the Ca x P product (94.7 +/- 7.3 vs 43.6 +/- 8.5; P0.001) diminished significantly whereas serum phosphorus remained unchanged (4.8 +/- 1.5 vs 4.3 +/- 1.1; P = NS). Before cinacalcet, 23 patients had severe hyperparathyroidism (serum PTH500) and 15 patients hypercalcaemia (serum calcium10.2 mg/dl). After 9 months of treatment, all 28 patients showed serum PTH500 pg/ml and serum calcium10.2 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 (P0.001), 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 (P0.01), and aluminium-containing agents diminished significantly (P0.05).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 hyperparathyroidism on chronic haemodialysis, without adverse effects and with lower doses of phosphate binders.

Background. Dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion, synthesis, and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI), independently of serum calcium and 1,25(OH) 2 D 3 levels. This study was conducted to examine whether sevelamer hydrochloride (sevelamer), a metal-free phosphate binder, could regress an advanced parathyroid gland (PTG) hyperplasia and enlargement in rats with CRI. Methods. Male Sprague-Dawley rats were fed a diet containing adenine for 6 weeks to establish CRI. Normal rats and adenine-treated rats were sacrificed to obtain the PTG (baseline group). The adenine diet was changed to a normal diet or diet containing 1 or 3% sevelamer for another 4 weeks. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of the study, the PTG was weighed and examined histologically. Results. Adenine-treated rats developed severe CRI with marked elevation of serum phosphorus and PTH. The PTG weight markedly increased with enlarged cell volume (i.e. cell hypertrophy) at baseline. Sevelamer treatment rapidly lowered serum phosphorus and PTH levels within 6 days, and after 4 weeks, reduced the PTG weight by 38% compared to adenine-treated rats at baseline. The reduction in PTG weight was due to regression of cell hypertrophy, but not to decreased cell number by apoptosis. Decreased expression of calcium receptor in the PTG at baseline was partially recovered by the sevelamer treatment. Conclusions. The sevelamer treatment can reduce the PTG weight with a reduction in serum PTH levels via regression of cell hypertrophy but not apoptosis in rats with CRI. Reduced PTG function might contribute to the regression of cell hypertrophy.

BACKGROUND Calcium-based phosphate binders may induce tissue calcification, and little is known about their effects on bone density. We compared the effects of a calcium with a non-calcium phosphate binder on both arterial calcification and bone density measured by computed tomography. METHODS Seventy-two adult haemodialysis patients were randomized to treatment with calcium carbonate (CC) or sevelamer (SEV) for 2 years. Electron beam CT scans were performed at baseline and at 6, 12 and 24 months. Serum phosphorus, calcium, calcium x phosphorus product and intact parathyroid hormone (iPTH) were measured and other routine laboratory tests were also carried out. RESULTS The average calcium x phosphorus product was similar in the two treatment groups. However, patients receiving CC had significantly lower average iPTH (P

Background. After renal transplantation, patients with insufficient graft function may require phosphate binders. It is still unknown if sevelamer, a new calcium-free phosphate binder, interferes with the uptake of immunosuppressants. We studied its effects on the pharmacokinetics of cyclosporin A (CsA) and mycophenolate mofetil. Methods. We examined 10 adults and eight children with stable renal graft function and stable CsA trough levels. A 12 h pharmacokinetic profile (10 observation points) was conducted without sevelamer, after a single dose and after 4 days of treatment with it. CsA levels were measured with both a monoclonal antibody assay (CEDIA) and a polyclonal antibody assay (FPIA), mycophenolic acid (MPA) levels by EMIT assay and CsA metabolites AM1, AM9 and AM4N by a modified HPLC method. Results. Sevelamer had no significant effect on CsA kinetics [area under the curve (AUC), peak concentration (C max ), time of C max ]. The AUC of AM1 was decreased by 30% and C max by 25% after 4 days of sevelamer intake. MPA levels were significantly reduced by a mean of 25% of the AUC (P < 0.05) and by 30% of the C max after a single dose of sevelamer. Conclusions. A single sevelamer dose reduces the C max and the AUC of MPA. Its intake for several days does not significantly influence CsA kinetics.

Vascular calcification is the most common type of extra-osseous calcification in end-stage renal disease (ESRD), manifesting as both medial and intimal calcification of large arteries. It is highly prevalent, often progressive and is associated with reduced arterial elasticity and increased mortality. Risk factors for calcification in ESRD include age, duration of dialysis, diabetes mellitus, most probably an elevated calcium-phosphorus product (Ca x P) level, the dose of calcium-containing phosphate binders and the induction of the systemic inflammatory response. Uraemic calcification was thought to be a largely physico-chemical process facilitated by elevated Ca x P (i.e. "metastatic" calcification). It is now well established, however, that vascular smooth muscle cells actively take up phosphate to form bioapatite. This process is associated with a phenotypic transformation of vascular smooth muscle cells during which they express osteoblast markers. In addition to phosphate, various other factors are likely to increase bioapatite formation, e.g. lipids and inflammatory cytokines. There have also been relatively new insights relating to the role of endogenous inhibitors of calcification [i.e. matrix Gla protein and fetuin-A (alpha(2)-Heremans-Schmid glycoprotein)], in particular the downregulation of fetuin-A in systemic inflammation. Decreased serum fetuin-A has been shown to be associated with a reduced capacity to inhibit calcium phosphate precipitation in vitro and is predictive of mortality in dialysis patients. These new insights into pathogenesis may lead to better prevention and treatment of calcification (e.g. with calcimimetics, anti-cytokines, etc.). However, the only preventive approach to have been established prospectively to date is the replacement of calcium-containing phosphate binders with sevelamer HCl, a non-calcaemic phosphate binder. Yet, it remains unclear whether sevelamer HCl reduces vascular calcification by preventing episodes of hypercalcaemia and/or by reducing low-density lipoprotein (LDL)-cholesterol levels.

Background. We determined recently that targeted treatment with calcium-based phosphate binders (calcium acetate and carbonate) led to progressive coronary artery and aortic calcification by electron beam tomography (EBT), while treatment with the non-calcium-containing phosphate binder, sevelamer, did not. Aside from the provision of calcium, we hypothesized that other factors might be related to the likelihood of progressive calcification in both or either treatment groups. Methods. We explored potential determinants of progressive vascular calcification in 150 randomized study subjects who underwent EBT at baseline and at least once during follow-up (week 26 or 52). Results. Among calcium-treated subjects, higher timeaveraged concentrations of calcium, phosphorus and the calcium-phosphorus product were associated with more pronounced increases in EBT scores; no such associations were demonstrated in sevelamer-treated subjects. The relation between parathyroid hormone (PTH) and the progression of calcification was more complex. Lower PTH was associated with more extensive calcification in calcium-treated subjects, whereas higher PTH was associated with calcification in sevelamer-treated subjects. Serum albumin was inversely correlated with progression in aortic calcification. Sevelamer was associated with favourable effects on lipids, although the link between these effects and the observed attenuation in vascular calcification remains to be elucidated. Conclusion. Calcium-based phosphate binders are associated with progressive coronary artery and aortic calcification, especially when mineral metabolism is not well controlled. Calcium may directly or indirectly (via PTH) adversely influence the balance of skeletal and extraskeletal calcification in haemodialysis patients.

Abnormalities in calcium and phosphorus metabolism are common, and metabolic bone disease develops often in patients with chronic renal failure (CRF). Effective clinical management includes measures to control phosphorus retention and prevent hyperphosphataemia, to maintain serum calcium concentrations within the normal range and to prevent excess parathyroid hormone (PTH) secretion by the judicious use of vitamin D sterols. Certain of these interventions appear to increase the risk of soft tissue and vascular calcification in patients with end-stage renal disease (ESRD), changes that may contribute to the development of cardiovascular disease. Current therapeutic approaches are thus being re-evaluated in an effort to limit these risks. Despite the importance of controlling phosphorus retention and preventing hyperphosphataemia in patients with CRF, current management strategies often are inadequate, particularly in those ingesting diets containing adequate amounts of protein. Results from clinical trials using daily haemodialysis strongly suggest that thrice-weekly haemodialysis regimens are only marginally adequate for achieving weekly phosphorus balance in many patients with ESRD. The safety of large oral doses of calcium as a phosphate-binding agent in patients with ESRD has also been questioned because excess amounts of calcium that are absorbed from the gastrointestinal tract may lead to ongoing calcium retention in those with little or no residual renal function. Arterial calcification and cardiac valve calcification are two serious complications that adversely affect cardiovascular haemodynamics. The use of large, often supraphysiological, doses of calcitriol or other vitamin D sterols to treat secondary hyperparathyroidism may aggravate hypercalcaemia and hyperphosphataemia, further increasing the risk of soft tissue and vascular calcification. Phosphate-binding agents that do not contain calcium, new vitamin D analogues and calcimimetic compounds offer new therapeutic alternatives for managing renal osteodystrophy. The integration of these novel agents into existing treatment regimens may provide safer and more effective methods for controlling secondary hyperparathyroidism and renal bone disease, while limiting the risks of soft tissue and vascular calcification in patients with CRF.

Background. Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO3 alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)3 in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO3 alone vs sevelamer in conjunction with measures to increase calcium balance. Methods. Forty-two patients were randomized: 21 continued their treatment with 4.8 guday CaCO3 and 21 were switched to sevelamer (initial dose: 2.4 guday, increased to 4.4 guday). Each month, when serumcorrected calcium decreased below 2.30 mmolul, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO4 levels. The following parameters were monitored: serum Ca, PO4, bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. Results. Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. Conclusions. Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO3. The transient decrease of serum bicarbonate after discontinuation of CaCO3 in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.

In the past nephrologists were aware that the hyperphosphataemia of advanced renal failure triggered hyperparathyroidism, but because only few patients die from skeletal problems, hyperphosphataemia was treated with benign neglect. The panorama has abruptly changed after evidence accrued suggesting that hyperphosphataemia has adverse cardiovascular consequences. In some observational studies w1x, but not consistently in all w2x, pre-dialysis serum P concentrations )6.5 mgudl were associated with a higher relative risk of cardiovascular death. Furthermore, with the availability of electronbeam-CT, a high prevalence of vascular, particularly coronary, calcification was noted in dialysed patients, which was progressive with time w3,4x. Furthermore, the group of London has shown that active wall stiffness is correlated to vascular calcification w5x. Vascular calcifications are presumably more than the result of passive precipitation of Ca and P, and under certain conditions vascular smooth muscle cells can even acquire, at least partially, an osteoblastic phenotype. Against this background, the control of serum phosphate concentration has obvious clinical importance. This issue has recently generated much interest, but problems persist both with respect to understanding the underlying pathomechanisms and translating novel insights into clinical practice. This brief editorial comment provides some background information and reflects our admittedly subjective thoughts on the principles guiding the selection of phosphate binders.

BACKGROUND: It has been demonstrated that dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI) independently of serum calcium and 1,25(OH)(2)D3 levels. This study was conducted to examine whether sevelamer hydrochloride (Renagel); hereafter referred to as sevelamer), a non-calcaemic phosphate binder could inhibit the parathyroid gland (PTG) hyperplasia in rats with progressive CRI. METHODS: Male Sprague-Dawley rats were injected twice with low doses of adriamycin (ADR). Two weeks after the last injection of ADR, rats were fed a diet containing 1 or 3% sevelamer for 84 days. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of study, serum 1,25(OH)(2)D3 levels were measured and the maximal two-dimension area of the PTG in paraffin section was calculated using an imaging analyser. RESULTS: Dietary sevelamer treatment inhibited the elevations of serum phosphorus, calciumxphosphorus product, and PTH levels that occurred as the study progressed. Sevelamer also suppressed maximal PTG area and there existed positive strong correlation between maximal PTG area and serum PTH levels at the end of the study. Serum phosphorus levels positively correlated well with serum PTH levels and maximal PTG area. In contrast, serum calcium or 1,25(OH)(2)D3 levels did not show any correlation with serum PTH levels and maximal PTG area. CONCLUSIONS: Sevelamer treatment arrested hyperphosphataemia and PTG hyperplasia accompanied by the elevation of serum PTH levels. The correlation analysis suggests that reduced serum phosphorus levels contributed to the suppression of PTG hyperplasia and resulted in the reduction of PTH levels in this animal model after the sevelamer treatment. The management of phosphorus control started from early stage of CRI could prevent PTG hyperplasia and facilitate later management of secondary hyperparathyroidism.

Calcium-based phosphate binders have traditionally been considered standard first-line treatment for control of hyperphosphataemia in chronic kidney disease (CKD). However, several cross-sectional studies have observed that prescribed calcium intake from phosphate binders is dose-dependently associated with the degree of vascular calcification in CKD patients [1,2]. Other studies have demonstrated an association between vascular calcification scores and an increased risk of cardiovascular disease [3– 5]. Although there is presently no proof that interventions that reduce the surrogate outcome of vascular calcification lead to reduced cardiovascular events in CKD patients, the K/DOQI guidelines have recommended that the ‘total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1500 mg/day (opinion), and the total intake of elemental calcium (including dietary calcium) should not exceed 2000 mg/day (opinion)’ [6]. If these guidelines are followed, there is likely to be a substantial shift in clinical practice away from the use of calciumbased phosphate binders to non-calcium-based phosphate binders, such as sevelamer, which are considerably more expensive. This raises the important question of just how good is the evidence that sevelamer therapy results in superior patient-level outcomes (i.e. ‘hard’ clinical end-points) compared with calcium-based phosphate binder therapy? To date, there has only been one randomized controlled trial (RCT) of sevelamer versus calcium-based binders, which has been adequately powered for mortality. The Dialysis Clinical Outcomes Revisited (DCOR) study involved 75 centres and 2103 haemodialysis patients randomly allocated to receive either sevelamer or a calcium-based phosphate binder for a mean follow-up period of ∼20 months [7]. Sevelamer-treated patients experienced comparable allcause mortality [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.79–1.10] and cardiovascular mortality (HR 0.93, 95% CI 0.74–1.17) to patients receiving calciumbased binders. Based on a significant interaction between the pre-specified variable of age and treatment effect (P = 0.02), a subsequent age-stratified analysis demonstrated that sevelamer was associated with a reduction in mortality in patients aged 65 years or older (HR 0.77, 0.61– 0.96). However, these results were limited by the fact that the authors did not correct their interaction assessments for multiple comparisons, which would have yielded a nonsignificant result. A subsequent intention-to-treat analysis of the DCOR study using pre-planned secondary analyses and Centers for Medicare & Medicaid Services data demonstrated no significant differences in overall or cardiovascular mortality and no significant interaction between age and treatment effect [8]. A meta-analysis of RCTs, including the DCOR study, observed that sevelamer treatment was associated with similar all-cause mortality (risk difference −2%, 95% CI −6%– 2%; 5 RCTs and 2429 participants) and cardiovascular mortality (risk difference −1%, 95% CI −4%–2%; 3 RCTs and 2102 participants) compared with calcium-based phosphate binder therapy [9]. The authors concluded that there was ‘no convincing evidence that sevelamer improves clinically relevant outcomes in ESRD patients’ and that ‘recommendations for the routine use of sevelamer in dialysis patients are not supported by current data.’ In this issue of Nephrology Dialysis and Transplantation, Jamal et al. report the results of an updated systematic review of the effects of calcium-based versus non-calciumbased phosphate binders on mortality in CKD patients [10]. Eight RCTs of sevelamer versus calcium-based binders were selected. The study was sponsored by Genzyme (manufacturers of sevelamer) and one of the authors declared a potential conflict of interest with Genzyme. Similar to the findings of the previous meta-analysis, Jamal et al. reported no significant differences between patients treated with sevelamer or calcium-based phosphate binders with respect to coronary artery calcification (WMD −76.35, 95% CI −158.25–5.55; 5 RCTs and 469 participants), cardiovascular events [relative risk (RR) 0.85, 95% CI 0.35– 2.03; two RCTs and 153 participants] or all-cause mortality (RR 0.68, 95% CI 0.41–1.11; eight RCTs and 2873 participants). In spite of the non-significant differences between the groups, the authors concluded that there were ‘trends’ towards decreased all-cause mortality, cardiovascular mortality and coronary artery calcification associated with noncalcium-based phosphate binders and that future studies are needed to conduct ‘research on the mechanism by which non-calcium-based phosphate binders reduce mortality or

Background Available phosphate binders contain aluminium or calcium which can be associated with undesirable effects. RenaGel, cross-linked poly (allylamine hydrochloride), is a non-absorbed phosphate-binding polymer, free of calcium and aluminium. We conducted this study to examine the safety and phosphate binding efficacy of RenaGel in volunteers. Methods During 18 days (days 0-17) at the clinical study unit, 24 subjects consumed a phosphate-controlled diet designed to provide 37.5 mmol (1200 mg) elemental phosphorus per day. From the morning of day 5 to the morning of day 9, urine and faeces were collected. Average baseline urine and faecal phosphorus contents were determined. On days 9-16, the subjects received either RenaGel 1 g, 2.5 g, or 5 g or placebo three times per day immediately prior to the meals. From the morning of day 13 to the morning of day 17, urine and faeces were again collected and phosphorus contents on treatment were determined. Results RenaGel inhibited dietary phosphate absorption as measured by a decline in average daily urinary phosphorus excretion and an increase in average daily fecal phosphorus excretion. Average urine phosphorus contents on treatment were 27.2 mmol (870 mg) per day in the placebo group vs 23.8 mmol (762 mg), 19.5 mmol (625 mg), and 16.6 mmol (530 mg) per day in the RenaGel 1-g, 2.5-g, and 5-g groups. Average daily faecal phosphorus content on treatment was markedly higher in the RenaGel 5-g group, 19.1 mmol (611 mg) per day vs 10.7 mmol (342 mg) per day for the placebo group. RenaGel also decreased total serum cholesterol by 0.71 mmol/L (27.5 mg/dl), 0.55 mmol/l (21.3 mg/dl), and 1.08 mmol/l (41.8 mg/dl) for the RenaGel 1-g, 2.5-g, and 5-g groups. RenaGel was well tolerated with adverse events similar to placebo. Conclusions RenaGel is a safe, effective, and well tolerated phosphate binder in normal volunteers. The degree of phosphate binding consistent with its potential use as a phosphate binder in renal failure patients.

Background It remains unclear which phosphate binders should be preferred for hyperphosphatemia management in chronic kidney disease (CKD). Methods We performed a systematic review and meta-analysis of randomized trials comparing sevelamer or lanthanum with other phosphate binders in CKD. Results Fifty-one trials (8829 patients) were reviewed. Compared with calcium-based binders, all-cause mortality was nonsignificantly lower with sevelamer {risk ratio [RR] 0.62 [95% confidence interval (CI) 0.35-1.08]} and lanthanum [RR 0.73 (95% CI 0.18-3.00)], but risk of bias was concerning. Compared with calcium-based binders, sevelamer reduced the risk of hypercalcemia [RR 0.27 (95% CI 0.17-0.42)], as did lanthanum [RR 0.12 (95% CI 0.05-0.32)]. Sevelamer reduced hospitalizations [RR 0.50 (95% CI 0.31-0.81)], but not lanthanum [RR 0.80 (95% CI 0.34-1.93)]. The presence/absence of other clinically relevant outcomes was infrequently reported. Compared with calcium-based binders, sevelamer reduced serum calcium, low-density lipoprotein and coronary artery calcification, but increased intact parathyroid hormone. The clinical relevance of these changes is unknown since corresponding clinical outcomes were not reported. Lanthanum had less favorable impact on biochemical parameters. Sevelamer hydrochloride and sevelamer carbonate were similar in three studies. Sevelamer was similar to lanthanum (three studies) and iron-based binders (three studies). Conclusion Sevelamer was associated with a nonsignificant reduction in mortality and significantly lower hospitalization rates and hypercalcemia compared with calcium-based binders. However, differences in important outcomes, such as cardiac events, fractures, calciphylaxis, hyperchloremic acidosis and health-related quality of life remain understudied. Lanthanum and iron-based binders did not show superiority for any clinically relevant outcomes. Future studies that fail to measure clinically important outcomes (the reason why phosphate binders are prescribed in the first place) will be wasteful.

More than 60% of patients on chronic haemodialysis (HD) have a serum phosphate level above 5.5 mg/dl (1.75 mmol/l), which recently has been recommended as an appropriate target in patients with end-stage renal disease (ESRD). Preventing hyperphosphataemia and elevated Ca x P product not only ameliorates the progression of secondary hyperparathyroidism and bone disease, but also appears to reduce cardio-vascular morbidity and mortality from vascular calcifications. Dietary phosphate restriction and the administration of aluminium and calcium salts have been the principal means of phosphate control over the last decade. Unfortunately, the protean disturbances of toxic aluminium accumulation in the body virtually eliminated aluminium from clinical practice. Calcium-based therapy, although well tolerated, results in frequent hypercalcaemia when administered concurrently with vitamin D analogues, despite a decrease in the concentration of dialysate calcium. Sevelamer (Renagel((R))) has been a novel, non-absorbable calcium- and aluminium-free synthetic polymer. In initial studies, sevelamer reduced serum phosphate, Ca x P product and parathyroid hormone (PTH) in a manner comparable with calcium acetate therapy. However, the effect on PTH levels may prove to be inconsistent. It seems somewhat less effective in binding phosphate than aluminium, although no direct comparisons have been made. In a recent study, it attenuated the progression of vascular calcification in HD patients. It also binds bile acids, resulting in substantially lower low-density lipo-protein cholesterol levels. The major obstacle to its current use is a substantial increase in the cost associated with sevelamer therapy.

Particularly because the risk of harm cannot be safely excluded, the use of phosphate binders in chronic kidney disease (CKD) patients demands caution. Yet, the clinical inertia concerning phosphate burden is unjustified. Inorganic, phosphate esters added to preserve food represent an important component of dietary phosphate load. These compounds are easily absorbable and have a measurable effect on serum phosphate, and therefore their use should be avoided in CKD patients. The ongoing CKD Optimal management with Binders and NicotinamidE (COMBINE) study, applying chelation by phosphate binders and intestinal Na-P channel blockade by nicotinamide, will establish whether this combination may effectively reduce serum phosphate and fibroblast growth factor 23 in pre-dialysis CKD patients and produce improvements in surrogate measures of cardiovascular and renal damages. On the other hand, the ANSWER study will ascertain whether phosphate reduction by sevelamer carbonate may have an antiproteinuric effect in CKD patients with residual proteinuria despite effective blockade of the renin-angiotensin system. At this stage of knowledge, the use of phosphate binders in pre-dialysis CKD patients cannot be recommended. Ongoing studies will tell us whether the application of these drugs may have beneficial health effects in CKD patients at the pre-dialysis stage.