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Background Hyperphosphataemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate, have been shown to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K binding by PBs may offset the beneficial effects of phosphate reduction in reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC. Methods We performed 3/4 nephrectomy in rats, after which warfarin was given for 3 weeks to induce vitamin K deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for 8 weeks. The primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-computed tomography (µCT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analysed in vasculature using uncarboxylated matrix Gla protein (ucMGP) specific antibodies. Results The combination of a high vitamin K2 diet and PB treatment significantly reduced VC as measured by µCT for both the thoracic (P = 0.026) and abdominal aorta (P = 0.023), compared with MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2–treated groups in both the thoracic (P < 0.01) and abdominal aorta (P < 0.01) as compared with high vitamin K2–treated groups. Moreover, a high vitamin K diet and PBs led to reduced vascular oxidative stress. Conclusion In an animal model of kidney failure with vitamin K deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC.

Background Hyperphosphataemia is a common complication of chronic kidney disease (CKD). PT20 (ferric iron oxide adipate) is an investigational molecule engineered to offer enhanced phosphate-binding properties relative to other phosphate binders. Methods In this double-blind, parallel-group, placebo-controlled, dose-ranging study (ClinicalTrials.gov identifier NCT02151643), the efficacy and safety of 28 days of oral PT20 treatment were evaluated in patients with dialysis-dependent CKD. Participants were randomly assigned in an 8:8:8:13:13 ratio to receive PT20 (400, 800, 1600 or 3200 mg) or placebo three times daily. Results Among 153 participants, 129 completed treatment [7 discontinued because of adverse events (AEs), 2 because of hyperphosphataemia and 15 for other reasons]. PT20 treatment for 28 days resulted in a statistically significant and dose-dependent reduction in serum phosphate concentration. There were no statistically significant effects of PT20 treatment on changes in haemoglobin or ferritin concentrations or transferrin saturation between Days 1 and 29. The incidence of treatment-emergent AEs was broadly similar across the PT20 and placebo groups (42–59% versus 44%). The most common PT20 treatment-related AEs were gastrointestinal, primarily diarrhoea (13–18%) and discoloured faeces (3–23%). No serious AEs were considered to be related to study treatment. There were no clinically significant changes in laboratory results reflecting acid/base status or increases in ferritin that could indicate the absorption of components of PT20. Conclusions In this first study investigating the efficacy and safety of PT20 in patients with hyperphosphataemia and dialysis-dependent CKD, PT20 significantly lowered serum phosphate concentrations and was generally well tolerated., Graphical Abstract

Background The iron-based phosphate binders, sucroferric oxyhydroxide (SFOH) and ferric citrate (FC), effectively lower serum phosphorus in clinical studies, but gastrointestinal iron absorption from these agents appears to differ. We compared iron uptake and tissue accumulation during treatment with SFOH or FC using experimental rat models. Methods Iron uptake was evaluated during an 8-h period following oral administration of SFOH, FC, ferrous sulphate (oral iron supplement) or control (methylcellulose vehicle) in rat models of anaemia, iron overload and inflammation. A 13-week study evaluated the effects of SFOH and FC on iron accumulation in different organs. Results In the pharmacokinetic experiments, there was a minimal increase in serum iron with SFOH versus control during the 8-h post-treatment period in the iron overload and inflammation rat models, whereas a moderate increase was observed in the anaemia model. Significantly greater increases (P Conclusions Iron uptake was higher from FC versus SFOH following a single dose in anaemia, iron overload and inflammation rat models and 13 weeks of treatment in normal rats. These observations likely relate to different physicochemical properties of SFOH and FC and suggest distinct mechanisms of iron absorption from these two phosphate binders.

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. Optimal phosphate control is an unmet need in chronic kidney disease (CKD). High serum phosphate increases calcification burden and is associated with mortality and cardiovascular disease in CKD. Nicotinamide (NA) alone or in combination with calcium-free phosphate binders might be a strategy to reduce phosphate levels and calcification and thus impact cardiovascular disease in CKD.Methods. We studied the effect of NA alone and in combination with magnesium carbonate (MgCO3) as a potential novel treatment strategy. CKD was induced in dilute brown non-agouti/2 mice by subtotal nephrectomy followed by a high-phosphate diet (HP) and 7 weeks of treatment with NA, MgCO3 or their combination. Control mice underwent subtotal nephrectomy and received an HP or underwent sham surgery and received standard chow plus NA.Results. CKD mice showed increased serum fibroblast growth factor 23 and calcium-phosphate product that was normalized by all treatment regimes. NA alone increased soft tissue and vascular calcification, whereas any treatment with MgCO3 significantly reduced calcification severity in CKD. While MgCO3 supplementation alone resulted in decreased calcification severity, it resulted in increased intestinal expression of the phosphate transporters type II sodium-dependent phosphate transporter 1 (Pit-1). Combined therapy of MgCO3 and NA reduced tissue calcification and normalized expression levels of intestinal phosphate transporter proteins.Conclusions. In conclusion, the data indicate that NA increases while MgCO3 reduces ectopic calcification severity. Augmented expression of intestinal phosphate transporters by MgCO3 treatment was abolished by the addition of NA. However, the clinical relevance of the latter remains to be explored. Importantly, the data suggest no benefit of NA regarding treatment of calcification in addition to MgCO3.

Background and Aims Hyperphosphatemia is common in end-stage renal disease (ESRD) because of impaired renal phosphate excretion and is treated by dietary measures, dialysis techniques and the use of phosphate binder medication. It is one of the most important cardiovascular risk factors for dialysis patients. Our goal was to involve dialysis patients in the achievement of phosphate targets by self-adjusting the dose of Phosphate Binders (PB) on a meal-to-meal basis, according to the individual dietary P intake Method We conducted an interventional prospective single-arm study with a pre-post design. The inclusion criteria were patients with ESRD who had been receiving dialysis for more than three months, with dialysis schedule for four hours per session, three times per week, and who were older than 18 years of age. The primary endpoints of the study were the number of patients who reached the goal of serum phosphate before and after the training program and the weekly mean serum phosphate levels evaluated after the intervention period and compare them with the pre-intervention baseline levels. The secondary end-point was the burden of PB daily. All patients were trained in a self-administer PB program. A self-adjusted PB dose card was developed based on the phosphate food content list published by the National Technical University of Athens. The aim was to allow patients to immediately calculate the iP content of any food they consume easily. Phosphate Equivalent (PEQ) was defined as the weight of phosphorus having the same phosphate impact as a given weight of food. One PEQ corresponded in 100 mg of inorganic phosphorous and to one tablet of PB (one tablet of 800 mg of sevelamer). After 4 weeks (weeks 1-4) of washout from previous phosphate binders, eligible patients with serum phosphorus concentrations ≥ 6 mg/dl were included in the study. All patients received standard dietary phosphate counseling and a fixed dosing regimen of sevelamer PB was prescribed according to KDIGO and dialysis unit protocols for eight weeks (weeks 5-12 – pre-intervention period) In the 13th week, patients were asked to practice the self-administer PB program for eight more weeks. Results A total of 97 patients were screened for the study. 21 patients were excluded. 74 patients completed the study. The percentage of patients with uncontrolled phosphate levels reduced from 56.76% (42 out of 74) to 36.48 % (27 out of 74) in the post-intervention period. Of 9 patients who initially had a serum phosphorus level ≥9 mg/dl, 8 were reverted to phosphorus levels < 6 mg/dl at the end of the PEQ intervention period. There was a significant reduction of phosphate levels (prePEQ 7.42 ± 1.43 mg/dl vs. postPEQ 5.59 ± 1.82 mg/dL, p=0.036) and Ca × P levels (prePEQ: 67.1 ± 11.5 mg2/dL2; postPEQ: 51.9 ± 13.4 mg2/dL2, p=0.021) after patient education. There was a non-significant increase on serum calcium (pre PEQ: 8.13 ± 1.18 mg/dL; post PEQ: 8.56 ± 0.83mg/dL, p=0.515) and iPTH (prePEQ: 411 ± 376 pg/mL; postPEQ: 381 ± 321 pg/mL,p=0.13) Conclusion Our work shows that providing the patients with a relatively simple tool about the use of phosphate binders as PEQ is, we had a positive effect on the dialysis patients’ knowledge about the use of PB, phosphate content of their meals, and increase their sense of the necessity of the treatment and it was proved more effective than the standard fixed dose method. Using the PEQ education system was rewarding in an additional 20% of the patients with previous uncontrolled hyperphosphatemia. The PEQ education system is an efficient self-adjustment phosphate binder dosage tool in dialysis patients in reducing the serum phosphate level in our hemodialysis patients.

Background and Aims Iron-based phosphate binder (IPB) is a noncalcium phosphate binder that demonstrated sustained serum phosphorus control, good tolerability and lower pill burden compared with sevelamer carbonate in a Phase 3 study conducted in dialysis patients. These efficacy of IPB has been demonstrated for hemodialysis (HD) patients, but few studies have focused on patients undergoing peritoneal dialysis (PD). We evaluated efficacy of IPB and focused on effects for anemia and iron metabolism in patients on PD. Method This study was a cross-sectional, longitudinal multicenter study conducted by PD OASIS, organized committee in Kanagawa Japan. We analyzed the effects of IPB during a 6 months observation period in chronic kidney disease patients on PD who had administrated IPB, Ferric citrate hydrate and Sucroferric oxyhydroxide, between 2017 and 2019. The primary endpoint was the changes of phosphate, and several secondary endpoints were assessed: calcium, intact PTH, RBC, hemoglobin, MCH, RDW-VC, Fe, TSAT, Ferritin, albumin, CRP, monthly dosage of Erythropoietin stimulating agents (ESA) and ESA resistance index (ERI). In addition, we assessed the association between these markers and iron metabolism utilizing multivariate logistic regression analysis. Results A total of 102 patients were registered in the study who had received IPB. The initial doses of Ferric citrate hydrate and Sucroferric oxyhydroxide were 1010.9 ±400.9 mg and 941.7 ±502.9 mg daily, finally increased to 1213.6 ±559.9 mg and 1310.0 ±521.8 mg respectively at the end of the observation. We observed a significant reduction of serum phosphate to 5.27 ± 0.98 mg/dL from 6.56 ± 1.52 mg/dL with follow-up of six months (p < 0.01). At the end of the study, 76.4% of participants had achieved the target of less than 6 mg/dL. The hemoglobin, TSAT and Ferritin increased significantly from 10.47 ±1.26 g/dl, 27.95 ±11.05 % and 139.0 ±147.6 ng/mL to 11.17 ±1.16 g/dl, 40.46 ±15.00 % and 305.9 ±232.0 ng/mL respectively in six months (p < 0.01). No significant changes of serum calcium, intact parathyroid hormone (PTH) and CRP occurred over the study period. The monthly dosage of ESA was significantly decreased after administration with IPB and ERI significantly improved to 0.11±0.12 (μg/month/kg/g Hb) from 0.21±0.16 (μg/month/kg/g Hb) (p Additionally, we assessed the factors of ferritin increase because it was remarkable in follow-up six months compared to HD patients. In multivariate analysis, phosphate (Odds ratio 5.85, 95%CI 1.18-91.77, p=0.027), intact PTH (0.99, 0.97-1.15, p=0.015), hemoglobin (Odds ratio 0.10, 95%CI 0.05-0.59, p=0.025), RBC (Odds ratio 1.16, 95%CI 1.04-1.41, p=0.003), and RDW-CV (Odds ratio 0.44, 95%CI 0.10-0.99, p=0.046) were significantly associated with ferritin increase more than 300 ng/ml ,after adjusted. Conclusion This study confirmed the efficacy of Iron-based phosphate binder, Ferric citrate hydrate and Sucroferric oxyhydroxide, in the treatment of hyperphosphatemia in PD patients. In addition, IBP caused secondary effects of anemia improvement and ESA dosage reduction resulting in ERI improvement. However, in this study, the increase in ferritin levels was remarkable. It may be because PD does not lose iron by treatment compared to HD. Therefore, we should check iron metabolism more frequently for PD patients taking IPB than HD patients. It is necessary to further investigate the effects of IPB on anemia and iron metabolism in PD patients.

Background Elevated serum fibroblast growth factor 23 (FGF23) is strongly associated with cardiovascular risk and mortality. Tenapanor, an inhibitor of gastrointestinal sodium/hydrogen exchanger isoform 3, decreased serum phosphate in a randomized, double-blind, placebo-controlled Phase 2 trial (ClinicalTrials.gov identifier NCT02081534) of patients receiving hemodialysis with hyperphosphatemia. Here, we report a secondary analysis of effects on serum FGF23 during that study. Methods After 1–3 weeks of washout of phosphate binders, 162 patients were randomized to receive 4 weeks of treatment with placebo or one of six tenapanor regimens (3 or 30 mg once daily, or 1, 3, 10 or 30 mg twice daily). Intact FGF23 concentrations were determined from serum samples collected at screening, post-washout and end of treatment, assayed in duplicate in a single batch at the end of the study. Results After phosphate-binder washout, serum FGF23 concentrations increased in all groups [range of geometric means: 1430–2605 pg/mL before, to 2601–6294 pg/mL after washout (P

Recent reports have shown that novel phosphate binders containing iron are not only efficacious for the treatment of hyperphosphatemia but also may reduce the need for erythropoiesis-stimulating agents and intravenous (IV) iron for anemia management in patients on maintenance hemodialysis (MHD). Possible healthcare cost savings, which have not been demonstrated in a long-term study, may be an additional advantage of using such multi-pronged treatment strategies for the control of both hyperphosphatemia and iron needs. It is currently assumed that oral iron supplementation is less efficient than the IV route in patients with chronic kidney disease (CKD). The unexpected efficacy of novel iron-containing phosphate binders, such as ferric citrate, in repleting insufficient iron stores and improving the anemia of CKD could change this view. Previous assumptions of self-controlled iron uptake by 'mucosal block' or hepcidin, or else by impaired intestinal iron absorption due to CKD-associated inflammation cannot be reconciled with recent observations of the effects of ferric citrate administration. Citrate in the intestinal lumen may partly contribute to the acceleration of iron absorption. Animal experiments and clinical studies have also shown that oral iron overload can cause excessive iron accumulation despite high hepcidin levels, which are not able to block iron absorption completely. However, like with IV iron agents, no long-term safety data exist with respect to the effects of iron-containing phosphate binders on 'hard' patient outcomes. Future randomized prospective studies in patients with CKD are necessary to establish the safety of oral iron-containing phosphate binders for the control of both hyperphosphatemia and renal anemia.

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

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

Background. Establishing an optimal dialysate calcium (DCa) concentration in haemodialysis patients is crucial. DCa individualization has been advocated but most dialysis centres use a fixed DCa, preferably 1.25 mmol/L in the USA and 1.5 mmol/L in European countries. The aim of the study was to assess the short-term biological impact of individual DCa prescription aiming at maintaining normal serum calcium and serum parathyroid hormone (PTH) between 150 and 300 pg/mL. Methods. Between January 2008 and December 2010, all prevalent patients were checked for the need for DCa change according to our usual strategy. Baseline (T0) and after 3 months (T3), values were compared for serum calcium, phosphate, total alkaline phosphatases (t-ALP) and PTH. Results. Seventy-eight patients were followed up for analysis with only one DCa change. Vitamin D derivatives, oral calcium and cinacalcet doses remained stable. Increasing DCa from 1.25 to 1.5 mmol/L and from 1.5 to 1.75 mmol/L led to a significant increase of calcaemia (+2.2 and +1.7%) and a decrease of phosphataemia (−7 and −9%), t-ALP (−10 and −12%) and PTH (−50 and −62%). Decreasing DCa from 1.75 to 1.5 mmol/L and from 1.5 to 1.25 mmol/L led to a decrease of calcaemia (−2.5 and −1.7%) and an increase of phosphataemia (+11 and +12%), t-ALP (+12 and +10%) and PTH (+138 and +175%). Conclusions. DCa individualization has a significant impact on mineral metabolism parameters, especially on serum PTH levels, and could be considered as an additional therapy in a more global strategy together with phosphate binder, vitamin D and calcimimetics prescription.

Background. Increased blood levels of fibroblast growth factor-23 (FGF-23) are associated with increased mortality. We evaluated the effect of combined therapy with lanthanum carbonate (LaC), a new phosphate binder and calcium carbonate (CaC) on serum levels of phosphate and FGF-23. Methods. This was a single-arm, open-label, multicenter study. Hemodialysis patients with a serum phosphate level >6.0 mg/dL despite CaC therapy were also given LaC for 16 weeks at a dose up to 2250 mg/day. CaC was given at a fixed dose throughout the 16-week period. Results. Of 42 patients enrolled, 36 completed the 16-week study. The serum phosphate level showed a significant decrease from 6.9 6 1.4 mg/dL at week 0 to 5.5 1 1.2 mg/dL at week 16 (� 20.0%, P < 0.05). The median FGF-23 level showed a significant decrease from 8250 ng/ L at week 0 to 5000 ng/L at week 16 (� 39.2%, P < 0.05). In contrast, corrected serum calcium and the serum parathyroid hormone level showed no significant changes. A significant positive correlation (r 5 0.442, P 5 0.007) was demonstrated between the percent reduction of serum FGF23 and that of serum phosphate. Conclusion. Both serum phosphate and FGF-23 levels were significantly decreased by treatment with LaC plus CaC.

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.

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. Lanthanum carbonate (FOSRENOL®, Shire Pharmaceuticals) is an effective non-calcium, non-resin phosphate binder for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). In this study, we used a rat model of chronic renal failure (CRF) to examine the long-term effects of controlling serum phosphorus with lanthanum carbonate treatment on the biochemical and bone abnormalities associated with CKD–mineral and bone disorder (CKD–MBD). Methods. Rats were fed a normal diet (normal renal function, NRF), or a diet containing 0.75% adenine for 3 weeks to induce CRF. NRF rats continued to receive normal diet plus vehicle or normal diet supplemented with 2% (w/w) lanthanum carbonate for 22 weeks. CRF rats received a diet containing 0.1% adenine, with or without 2% (w/w) lanthanum carbonate. Blood and urine biochemistry were assessed, and bone histomorphometry was performed at study completion. Results. Treatment with 0.75% adenine induced severe CRF, as demonstrated by elevated serum creatinine. Hyperphosphataemia, hypocalcaemia, elevated calcium × phosphorus product and secondary hyperparathyroidism were evident in CRF + vehicle animals. Treatment with lanthanum carbonate reduced hyperphosphataemia and secondary hyperparathyroidism in CRF animals (P

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. Hyperphosphataemia in patients with chronic kidney disease (CKD) is associated with mineral and bone disorder and increased cardiovascular mortality. Despite phosphate binders (PB), nutrition counselling and dialysis therapy, the prevalence of hyperphosphataemia remains unacceptably high. It was hypothesized that an inadequate relation of PB dose to meal inorganic phosphorus (iP) content may be an important factor for failure of phosphate management. Methods. The innovative ‘Phosphate Education Program’ (PEP) bases on patient empowerment to eye-estimate meal iP content by newly defined ‘Phosphate Units’ (PU; 1 PU per 100 mg phosphorus) and self-adjust PB dosage to dietary iP intake by an individually prescribed PB/PU ratio (PB pills per PU). In a prospective study, 16 children (aged 4–17 years) with CKD and their parents were trained with the PEP concept and followed up for 24 weeks for changes in serum electrolyte levels, dietary behaviour and PB dose. Results. Within 6 weeks after PEP training, the percentage of children with serum phosphate (PO) >1.78 mmol/ l dropped from 63% (10/16) to 31% (5/16). Mean serum PO level decreased from 1.94 ± 0.23 at baseline to 1.68 ± 0.30 (SD)mmol/l in Week 7–12 (P = 0.02) and to 1.78 ± 0.36 (SD)mmol/l in Week 19–24 (P = 0.2), whereas serum calcium [2.66 ± 0.3 vs 2.60 ± 0.23 (SD)mmol/l in Weeks 7–12 (P = 0.45) and 2.66 ± 0.23 (SD)mmol/l in Week 19– 24 (P = 0.21)] and serum potassium [4.69 ± 0.48 vs 4.58 ± 0.68 (SD)mmol/l in Week 7–12 (P = 0.40) and 4.65 ± 0.49 (SD) mmol/l in Week 19–24 (P = 0.73)] remained unchanged. The mean daily PB dose rose from 6.3 ± 2.9 to 8.2 ± 5.4 (SD) pills during observation period with an increased meal-to-meal variability (P = 0.04). Dietary iP intake was not affected by PEP concept. Conclusion. The empowerment of children with CKD and their parents to self-adjust PB dose to eye-estimated meal iP content significantly improved management of hyperphosphataemia without reducing dietary iP intake.

Background. Hyperphosphataemia in patients on haemodialysis (HD) can lead to, or worsen, secondary hyperparathyroidism (with associated bone disease) and extra-skeletal calcifications associated with increased cardiovascular morbidity and mortality. MCI-196 is a new, non-absorbed, non-calcium-based phosphate binder. The aim of this study was to determine the effect of three fixed doses of MCI-196, on serum phosphorus level and other parameters relevant to HD patients. Methods. A total of 120 chronic kidney disease (CKD) stage 5 patients on HD and with the serum phosphorus level >2.1 mmol/l were randomized to receive double-blind treatment with either 3, 6 and 9 g/day MCI-196 or placebo for 3 weeks. Results. Serum phosphorous decreased in all three treatment groups (−0.038, −0.268 and −0.257 mmol/l in the 3, 6 and 9 g/day groups, respectively). The difference between treatment and placebo groups was significant for the 6 and 9 g/day groups (P < 0.05 in both cases). Changes in the mean serum calcium were minimal and without relevant differences between groups. However, calcium– phosphorus product (Ca × P) was significantly reduced in the 6 and 9 g/day groups P < 0.05). MCI-196 at all doses decreased serum intact PTH between baseline and endpoint, and differences between treatment groups and placebo were statistically significant for the 3 and 9 g/day groups (P < 0.02 in both cases). Both serum total and LDL cholesterol decreased significantly in all treatment groups compared to placebo (by 0.71–1.05 mmol/l, for total cholesterol and 0.68–0.94 mmol/l for LDL cholesterol P < 0.001 in all cases). There was minimal change in serum HDL cholesterol. MCI-196 at all doses decreased significantly serum uric acid between baseline and endpoint compared to placebo (P < 0.005 in all cases). The drug was well tolerated. Conclusion. MCI-196 significantly reduced serum phosphorus, Ca × P and PTH, without effecting serum calcium levels. The additional reduction in total cholesterol and LDL cholesterol indicates a possible dual mechanism of action of MCI-196 that has the potential to reduce cardiovascular morbidity in CKD stage 5 patients.

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.