scholarly journals Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality

2021 ◽  
pp. 1-10
Author(s):  
Peter A. McCullough
Keyword(s):  
Calcium Acetate ◽  
Paracellular Pathway ◽  
Ferric Citrate ◽  
Morbidity And Mortality ◽  
Phosphate Binders ◽  
Phosphate Absorption ◽  
Phosphate Retention ◽  
Sevelamer Carbonate ◽  
Prescribing Information ◽  
Phosphate Control

<b><i>Background:</i></b> Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality. <b><i>Summary:</i></b> Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to &#x3c;5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels &#x3c;5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. <b><i>Key Messages:</i></b> Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.

scholarly journals Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats

2020 ◽  
Author(s):  
Andrew J. King ◽  
Jill Kohler ◽  
Cyra Fung ◽  
Zhengfeng Jiang ◽  
Allison Quach ◽  
...  
Keyword(s):  
Male Rats ◽  
Phosphate Binders ◽  
Phosphate Absorption ◽  
Phosphorus Excretion ◽  
Sevelamer Carbonate ◽  
Sodium Hydrogen Exchanger ◽  
Intestinal Phosphate Absorption ◽  
Urinary Phosphorus Excretion ◽  
Dose Levels ◽  
Nhe3 Inhibitor

The majority of patients with chronic kidney disease (CKD) receiving dialysis do not reach target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a non-binder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This pre-clinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-hour urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer (0-3% w/w). We also evaluated the effect of the addition of tenapanor or vehicle on 24-hour urinary phosphorus excretion to rats on a stable dose of sevelamer (1.5% w/w). When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose (1.5% w/w) reduced mean (±standard error of the mean) urinary phosphorus excretion by 42±3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37±6% (P < 0.05). While both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.

scholarly journals Differential effects of phosphate binders on vitamin D metabolism in chronic kidney disease

2020 ◽  
Vol 35 (4) ◽  
pp. 616-623 ◽  
Author(s):  
Charles Ginsberg ◽  
Leila R Zelnick ◽  
Geoffrey A Block ◽  
Glenn M Chertow ◽  
Michel Chonchol ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Calcium Acetate ◽  
Phosphate Binders ◽  
Vitamin D Metabolites ◽  
Vitamin D Metabolism ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Sevelamer Carbonate ◽  
25 Hydroxyvitamin D

Abstract 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.

scholarly journals Effects of Sevelamer Carbonate versus Calcium Acetate on Vascular Calcification, Inflammation, and Endothelial Dysfunction in Chronic Kidney Disease

2021 ◽  
Author(s):  
Darius Mason ◽  
Kavitha Godugu ◽  
Daryl Nnani ◽  
Shaker A. Mousa
Keyword(s):  
Chronic Kidney Disease ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Hdl Cholesterol ◽  
Calcium Acetate ◽  
Phosphate Binders ◽  
Sevelamer Carbonate ◽  
Stage Renal Disease ◽  
End Stage

Rationale & Objective: Hyperphosphatemia is present in most patients with end-stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium-based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. Study Design: We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with Chronic Kidney Disease (CKD) treated with sevelamer carbonate versus calcium acetate. Setting & Participants: We enrolled 50 CKD patients (stages 3 and 4) and treated them with sevelamer carbonate and calcium acetate for 12 weeks. Outcomes: At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. Results: A significant increase in HDL-cholesterol was observed with sevelamer carbonate but not with calcium acetate. Treatment with sevelamer carbonate reduced serum phosphate, calcium phosphate, and FGF-23 levels and there was no change with calcium acetate treatment. The inflammatory markers IL-8, IFN-γ, and TNFα decreased with response to both treatments. The levels of IL-6 significantly increased with calcium acetate treatment and no change was observed in the sevelamer carbonate treatment group. Conclusion: Sevelamer carbonate showed favorable effects on anti-inflammatory and vascular calcification biomarkers compared to calcium acetate treatment. Funding: Funding was received from Sanofi/Genzyme. Trial Registration: Registered at trial.com, registration number NCT01277497.

scholarly journals Small Intestinal Phosphate Absorption: Novel Therapeutic Implications

2021 ◽  
pp. 1-9
Author(s):  
Jerry Yee ◽  
David Rosenbaum ◽  
Jeffrey W. Jacobs ◽  
Stuart M. Sprague
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Paracellular Pathway ◽  
Phosphate Binders ◽  
Phosphate Absorption ◽  
Therapeutic Implications ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Dietary Phosphate ◽  
Intestinal Phosphate Absorption

<b><i>Background:</i></b> Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention and, eventually, hyperphosphatemia. As hyperphosphatemia is associated with numerous adverse outcomes, including increased cardiovascular mortality, reduction in phosphorus concentrations is a guideline-recommended, established clinical practice. Dietary phosphate restriction, dialysis, and phosphate binders are currently the only options for phosphate management. However, many patients with hyperphosphatemia have phosphorus concentrations &#x3e;5.5 mg/dL, despite treatment. <b><i>Summary:</i></b> This review pre­sents recent advances in the understanding of intestinal phosphate absorption and therapeutic implications. Dietary phosphate is absorbed in the intestine through two distinct pathways, paracellular absorption and transcellular transport. Recent evidence indicates that the paracellular route accounts for 65–80% of total phosphate absorbed. Thus, the paracellular pathway is the dominant mechanism of phosphate absorption. Tenapanor is a first-in-class, non-phosphate binder that inhibits the sodium-hydrogen exchanger 3 or solute carrier family 9 member 3 (SLC9A3) encoded by the SLC9A3 gene, and blocks paracellular phosphate absorption. <b><i>Key Messages:</i></b> Targeted inhibition of sodium-hydrogen exchanger 3 effectively reduces paracellular permeability of phosphate. Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease.

Phosphate binders in patients with chronic kidney disease: Between the new and the old.

2019 ◽  
pp. 2-3
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Estimated Glomerular Filtration Rate ◽  
Chronic Kidney Disease Stage ◽  
Disease Stage ◽  
Phosphate Binders ◽  
Advanced Chronic Kidney Disease ◽  
Phosphate Retention ◽  
Stage 4 ◽  
Dietary Phosphate

Impaired phosphate excretion by the kidney leads to Hyperphosphatemia. It is an independent predictor of cardiovascular disease and mortality in patients with advanced chronic kidney disease (stage 4 and 5) particularly in case of dialysis. Phosphate retention develops early in chronic kidney disease (CKD) due to the reduction in the filtered phosphate load. Overt hyperphosphatemia develops when the estimated glomerular filtration rate (eGFR) falls below 25 to 40 mL/min/1.73 m2. Hyperphosphatemia is typically managed with oral phosphate binders in conjunction with dietary phosphate restriction. These drugs aim to decrease serum phosphate by binding ingested phosphorus in the gastrointestinal tract and its transformation to non-absorbable complexes [1].

scholarly journals Implementation and effectiveness of an intensive education program on phosphate control among hemodialysis patients: a non-randomized, single-arm, single-center trial

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jinmei Yin ◽  
Jun Yin ◽  
Rongli Lian ◽  
Peiqiu Li ◽  
Jing Zheng
Keyword(s):  
Education Program ◽  
Hemodialysis Patients ◽  
Serum Phosphorus ◽  
Phosphate Binders ◽  
Maintenance Hemodialysis ◽  
Single Center ◽  
Clinical Trial Registry ◽  
Before And After ◽  
Intensive Education ◽  
Phosphate Control

Abstract Background Hyperphosphatemia is a common complication in patients on maintenance hemodialysis. Patients’ adherence to phosphorus control can be improved by consistent education. However, few studies have focused on the model construction and effects of health education on phosphate control for hemodialysis patients. Objective To develop an intensive education program focusing on phosphate control among hemodialysis patients and to analyze the effectiveness of this program. Design A non-randomized, single-arm, single-center trial lasting for 6 months. Setting This program was conducted in a hemodialysis center in a teaching hospital in Zhuhai, China. Participants Patients on maintenance hemodialysis with hyperphosphatemia. Methods An intensive hyperphosphatemia control education program lasting for 6 months was conducted among 366 hemodialysis patients applying the First Principles of Instruction model, which focused on mastering four stages: (a) activation of prior experience, (b) demonstration of skills, (c) application of skills and (d) integration of these skills into real-world activities. The controlled percentage of serum phosphorus, knowledge of hyperphosphatemia, and adherence to phosphate binders before and after the education program were assessed. Results The proportion of controlled serum phosphorus was significantly increased from 43.5 to 54.9% (P<0.001). The scores on the knowledge of phosphate control were improved significantly from 59.0 ± 18.9 to 80.6 ± 12.4 (P < 0.001). The proportion of high adherence to phosphate binders was increased dramatically from 21.9 to 44.5% (P < 0.001). Conclusion The intensive education program can effectively improve serum phosphorus, knowledge of hyperphosphatemia, and adherence to phosphate binders among hemodialysis patients. Trial registration Chinese Clinical Trial Registry, ChiCTR2100042017. Retrospectively registered January 12th, 2021.

scholarly journals P1404A PHASE 2 OPEN-LABEL, SINGLE-ARM, FIRST JAPANESE STUDY OF TENAPANOR, A NOVEL PHOSPHATE ABSORPTION INHIBITOR, FOCUSING ON PILL BURDEN DECREASE IN PATIENTS WITH HYPERPHOSPHATEMIA UNDERGOING HEMODIALYSIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Tadao Akizawa ◽  
Hironori Kanda ◽  
Masayuki Takanuma ◽  
Jun Kinoshita ◽  
Masafumi Fukagawa
Keyword(s):  
Primary Endpoint ◽  
Serum Phosphorus ◽  
Phosphate Binders ◽  
Pill Burden ◽  
Phosphorus Level ◽  
Serum Phosphorus Level ◽  
Open Label ◽  
Serious Adverse Events ◽  
Phosphate Absorption ◽  
Phosphorus Control

Abstract Background and Aims Phosphate binders (PB) are usually prescribed to dialysis patients with hyperphosphatemia. Several studies have reported that higher PB pill burden may reduce adherence and lead to insufficient phosphorus control. Tenapanor is an investigational, minimally absorbed, orally administered, non-binder, small-molecule that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in development for the control of serum phosphorus. A previous Ph3 study sponsored by Ardelyx, Inc. (NCT02675998) showed a significant phosphorus decrease compared to the placebo in patients with hyperphosphatemia undergoing hemodialysis (HD) in the US. Tenapanor was expected to reduce PB pill burden since it is administered as one small pill, taken twice a day. This was the first study in Japanese HD patients, which aimed to confirm whether tenapanor reduces the pill burden of PB. Method This was a multicenter, open-label, single-arm Ph2 study. The study consists of a screening period, a 3-week observation period, and a 26-week treatment period. Patients whose serum phosphorus level was ≥ 3.5 and ≤ 7.0 mg/dL, taking at least two PB pills three times a day were enrolled. The patients started to receive 30 mg of tenapanor twice daily. The tenapanor dose could be reduced in a step-wise manner (60, 40, 20 and 10 mg/day) at the investigator’s discretion, based on GI tolerability. PB treatment was continued according to individual regimens, however, the dose could be adjusted appropriately to maintain serum phosphorus level within ±0.5 mg/dL from the baseline. The primary endpoint was an achievement of at least a 30% decrease in the mean of the total number of PB and tenapanor pills compared to the number of PB pills at baseline. The proportion of patients who achieved at least a 30 % decrease were tested using binomial test with a threshold level of 20% and a one-sided significance level of 0.025. The analysis was conducted using the data as of Dec25, 2019. Results The primary endpoint was met. Of 67 enrolled patients at the timing of analysis, 48 patients (71.6%, [95% CI: 59.3% - 82.0%], p&lt;0.001) achieved a 30% decrease in the total number of PB and tenapanor pills, and of those, 35 patients (52.2%, [95% CI: 39.7% - 64.6%]) achieved a 50% decrease and 18 patients (26.9%) no longer required the use of any PB at week 26. Mean phosphorus levels were maintained during the study from 5.2 mg/dL at the baseline to 4.7 mg/dL at week 26. The most frequent adverse event was diarrhea (76.1%), which was mostly mild to moderate. Only four patients discontinued the study due to diarrhea. Serious adverse events were reported in five patients, only two of which were related to tenapanor (diarrhea and acute myocardial infarction). Conclusion Tenapanor was able to provide phosphorus control with significantly fewer pills compared to PB. AE profile was similar to previous US studies. This result suggests that tenapanor, a non-binder, phosphate absorption inhibitor that provides a novel approach to the management of hyperphosphatemia, could potentially improve drug adherence by reducing PB pill burden while maintaining effective phosphorus control.

scholarly journals Effects of the Use of Non-Calcium Phosphate Binders in the Control and Outcome of Vascular Calcifications: A Review of Clinical Trials on CKD Patients

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Piergiorgio Bolasco
Keyword(s):  
Calcium Phosphate ◽  
Mortality Rates ◽  
Morbidity And Mortality ◽  
Phosphate Binders ◽  
Vascular Calcifications ◽  
Mineral Bone Disorder ◽  
Bone Disorder ◽  
Advanced Stages ◽  
The Impact ◽  
Specific Contribution

Vascular calcifications produce a high impact on morbidity and mortality rates in patients affected by chronic kidney disease and mineral bone disorder (CKD-MBD). Effects are manifested from the more advanced stages of CKD (stages 3-4), particularly in patients undergoing dialysis (CKD5D). In recent years, a large number of therapeutic options have been successfully used in the treatment of secondary hyperparathyroidism (SHPT), despite eliciting less marked effects on nonbone calcifications associated with CKD-MBD. In addition to the use of Vitamin D and analogues, more recently treatment with calcimimetic drugs has also been undertaken. The present paper aims to analyze comparative and efficacy studies undertaken to assess particularly the impact on morbidity and mortality rates of non-calcium phosphate binders. Moreover, the mechanism of action underlying the depositing of calcium and phosphate along blood vessel walls, irrespective of the specific contribution provided in reducing the typical phosphate levels observed in CKD largely at more advanced stages of the disease, will be investigated. The aim of this paper therefore is to evaluate which phosphate binders are characterised by the above action and the mechanisms through which these are manifested.

scholarly journals A comparison between the combined effect of calcium carbonate with sucroferric oxyhydroxide and other phosphate binders: an in vitro and in vivo experimental study

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Atsushi Yaguchi ◽  
Kenji Akahane ◽  
Kumi Tsuchioka ◽  
Saori Yonekubo ◽  
Shota Yamamoto ◽  
...  
Keyword(s):  
Calcium Carbonate ◽  
Lanthanum Carbonate ◽  
Combined Effect ◽  
Ferric Citrate ◽  
Phosphate Binders ◽  
Phosphate Solution ◽  
Phosphate Binding ◽  
Sevelamer Hydrochloride

Abstract Background Approximately 30% of patients on dialysis received combination therapy for their phosphate binder prescription; however, few studies for combined effects of phosphate binders are reported. For the purpose of evaluating the efficacy of combination therapy, we compared the efficacy of sucroferric oxyhydroxide (PA21) combined with calcium carbonate with that of lanthanum carbonate hydrate, sevelamer hydrochloride, and ferric citrate hydrate combined with calcium carbonate. Methods For in vitro studies, calcium carbonate and the other phosphate binders alone or in combination were stirred in phosphate solution at pH 2–8 for 2 h. After centrifuging the suspension, the phosphorus level in the supernatant was determined. For in vivo studies, rats were orally administered calcium carbonate and the other phosphate binders (except for sevelamer hydrochloride) alone or in combination, followed by oral administration of phosphate solution adjusted to pH 2 or 7. Serum samples were collected from the rats at predetermined timepoints and the serum phosphorus levels were determined and analyzed using a two-way analysis of variance. Results In the in vitro study, the measured phosphate-binding capacity of combining sevelamer hydrochloride, PA21, and lanthanum carbonate hydrate with calcium carbonate was approximately equal to or greater than the theoretical values under most conditions. Furthermore, these combined effects were insensitive to pH in that order. The measured phosphate-binding capacity of ferric citrate hydrate combined with calcium carbonate was smaller than the theoretical values, and the combination did not exhibit efficacy under any of the tested conditions. In the in vivo study, the combined effect of PA21 and calcium carbonate at both pH values and that of lanthanum carbonate hydrate and calcium carbonate at pH 2 were additive. In contrast, the combined effect of lanthanum carbonate hydrate and calcium carbonate at pH 7 and that of ferric citrate hydrate and calcium carbonate at pH 2 were antagonistic. Conclusions These results suggest that coadministration of PA21 and calcium carbonate showed good and relatively stable efficacy throughout the range of the gastrointestinal pH and that combining lanthanum carbonate hydrate and ferric citrate hydrate with calcium carbonate may not produce the expected efficacy under certain conditions.

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