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New Directions in Phosphorus Management in Dialysis

  • Jamie P. Dwyer
    Correspondence
    Address correspondence to Jamie P. Dwyer, MD, Professor of Medicine, Utah DCC and CRSO, Clinical and Translational Research Institute, Division of Nephrology & Hypertension, University of Utah Health, Salt Lake City, UT.
    Affiliations
    Professor of Medicine, Division of Nephrology & Hypertension, University of Utah, Salt Lake City, Utah
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  • Ellie Kelepouris
    Affiliations
    Professor of Clinical Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania
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Open AccessPublished:May 18, 2022DOI:https://doi.org/10.1053/j.jrn.2022.04.006
      Current phosphate management strategies in end-stage renal disease (dietary phosphate restriction, dialysis, and phosphate binders) are inadequate to maintain target phosphate levels in most patients. Dietary phosphate restriction is challenging due to “hidden phosphates” in processed foods, and dialysis and phosphate binders are insufficient to match average dietary phosphate intake. As phosphate binders must be taken with each meal, patients need to ingest many, large pills several times a day, negatively impacting quality of life. Recent advances in our understanding of phosphate absorption pathways have led to the development of new nonbinder therapies that block phosphate absorption. This review describes the limitations of current phosphate management strategies and discusses new therapies in development that inhibit phosphate absorption pathways. These new therapies present an opportunity to rethink phosphate management, potentially by prescribing phosphate absorption inhibitors as a primary therapy and adding phosphate binders if needed.

      Introduction

      The management of hyperphosphatemia in end-stage renal disease (ESRD) has centered around the dietary restriction of phosphorus, removal of phosphorus using dialysis, and binding phosphorus to prevent absorption by the gastrointestinal tract using phosphorus binders.
      K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.
      However, these approaches are all limited. First, we live in an era where our diet contains high amounts of “hidden phosphates” from food additives, making dietary restriction of phosphorus in the traditional sense difficult and unreliable. Based on data from nutritional databases, average phosphate intake in the modern Western diet is ∼1,400 mg/day,
      • McClure S.T.
      • Chang A.R.
      • Selvin E.
      • Rebholz C.M.
      • Appel L.J.
      Dietary Sources of phosphorus among adults in the United States: results from NHANES 2001-2014.
      but these databases have been shown to underestimate actual phosphate quantities.
      • Sullivan C.M.
      • Leon J.B.
      • Sehgal A.R.
      Phosphorus-containing food additives and the accuracy of nutrient databases: implications for renal patients.
      Moreover, phosphate additives can contribute an additional ∼1,000 mg/day.
      • Bell R.R.
      • Draper H.H.
      • Tzeng D.Y.
      • Shin H.K.
      • Schmidt G.R.
      Physiological responses of human adults to foods containing phosphate additives.
      Thus, daily phosphate intake in a typical Western diet may approach ∼2,400 mg/day, more than 300% of the recommended daily allowance of 700 mg.
      Phosphorus
      In. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride.
      Of course, the maximum amount of phosphate that can be removed by dialysis or bound by binders is limited.
      • Hou S.H.
      • Zhao J.
      • Ellman C.F.
      • et al.
      Calcium and phosphorus fluxes during hemodialysis with low calcium dialysate.
      • Daugirdas J.T.
      • Finn W.F.
      • Emmett M.
      • Chertow G.M.
      The phosphate binder equivalent dose.
      • Martin P.
      • Wang P.
      • Robinson A.
      • et al.
      Comparison of dietary phosphate absorption after single doses of lanthanum carbonate and sevelamer carbonate in healthy volunteers: a balance study.
      Our current inability to consistently achieve recommended target phosphorus levels in the majority of patients on dialysis argues for the need for innovations in phosphate management.
      Serum phosphorus (3 month average), categories. DOPPS Practice Monitor.
      The recent development of novel compounds to block phosphorus absorption affords us the chance to rethink our approach to the management of hyperphosphatemia, given the mechanistic understanding of phosphate absorption. Therapies with mechanisms that directly target the absorption of phosphorus rather than chemically binding it are being developed. This approach is notably different than that of currently available phosphate binders. One class of such therapies is inhibitors of sodium-dependent phosphate cotransporter type 2b (NaPi2b, also called SLC34A2) (e.g., ASP3325).
      • Taniguchi K.
      • Terai K.
      • Terada Y.
      Novel NaPi-IIb inhibitor ASP3325 inhibits phosphate absorption in intestine and reduces plasma phosphorus level in rats with renal failure.
      ,
      • Eto N.
      • Miyata Y.
      • Ohno H.
      • Yamashita T.
      Nicotinamide prevents the development of hyperphosphataemia by suppressing intestinal sodium-dependent phosphate transporter in rats with adenine-induced renal failure.
      Another that was more recently developed is the sodium-hydrogen exchanger 3 (NHE3) inhibitor tenapanor.
      • King A.J.
      • Siegel M.
      • He Y.
      • et al.
      Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability.
      Inhibition of NHE3 may prove to be a useful therapeutic strategy for phosphate control, given the evidence that the NHE-mediated paracellular phosphate absorption pathway is the dominant site of intestinal phosphate absorption in humans.
      • Larsson T.E.
      • Kameoka C.
      • Nakajo I.
      • et al.
      NPT-IIb inhibition does not improve hyperphosphatemia in CKD.
      ,
      • Davis G.R.
      • Zerwekh J.E.
      • Parker T.F.
      • Krejs G.J.
      • Pak C.Y.
      • Fordtran J.S.
      Absorption of phosphate in the jejunum of patients with chronic renal failure before and after correction of vitamin D deficiency.
      In this review, we discuss the limitations of current phosphate management approaches and describe new, targeted, nonbinder therapies that have been developed.

      Mechanisms of Phosphate Absorption and the Role of the Paracellular Pathway

      Dietary phosphate absorption occurs in the gastrointestinal tract via 2 distinct mechanisms, namely the transcellular and paracellular pathways. Active transcellular phosphate transport occurs primarily through the NaPi2b.
      • Sabbagh Y.
      • O'Brien S.P.
      • Song W.
      • et al.
      Intestinal npt2b plays a major role in phosphate absorption and homeostasis.
      Davis et al.
      • Davis G.R.
      • Zerwekh J.E.
      • Parker T.F.
      • Krejs G.J.
      • Pak C.Y.
      • Fordtran J.S.
      Absorption of phosphate in the jejunum of patients with chronic renal failure before and after correction of vitamin D deficiency.
      demonstrated that active transport saturates at a luminal phosphate concentration of ∼6 mg/dL (∼2 mmol/L) and that this pathway mediates phosphate absorption when phosphate concentrations are low. Passive paracellular diffusion occurs along concentration gradients through tight junction complexes between cell membranes.
      • Knöpfel T.
      • Himmerkus N.
      • Günzel D.
      • Bleich M.
      • Hernando N.
      • Wagner C.A.
      Paracellular transport of phosphate along the intestine.
      This pathway does not saturate and is responsible for the majority of intestinal phosphate absorption when luminal phosphate concentrations are high.
      • Davis G.R.
      • Zerwekh J.E.
      • Parker T.F.
      • Krejs G.J.
      • Pak C.Y.
      • Fordtran J.S.
      Absorption of phosphate in the jejunum of patients with chronic renal failure before and after correction of vitamin D deficiency.
      ,
      • Knöpfel T.
      • Himmerkus N.
      • Günzel D.
      • Bleich M.
      • Hernando N.
      • Wagner C.A.
      Paracellular transport of phosphate along the intestine.
      It is estimated that transcellular transport accounts for 20-35% of total intestinal phosphate absorption, and paracellular diffusion constitutes 65-80%.
      The bulk of evidence suggests that the primary mechanism of phosphate absorption in the gastrointestinal tract for individuals with Western diets is the paracellular pathway, not the transcellular pathway. Although the NaPi2b inhibitor ASP3325 effectively reduced phosphate concentrations in rats with renal failure,
      • Taniguchi K.
      • Terai K.
      • Terada Y.
      Novel NaPi-IIb inhibitor ASP3325 inhibits phosphate absorption in intestine and reduces plasma phosphorus level in rats with renal failure.
      no changes in serum, urinary, or fecal phosphate were observed in human trials of healthy volunteers or hyperphosphatemic ESRD patients, irrespective of dose.
      • Larsson T.E.
      • Kameoka C.
      • Nakajo I.
      • et al.
      NPT-IIb inhibition does not improve hyperphosphatemia in CKD.
      EOS789, a pan-inhibitor of NaPi2b, pituitary-specific positive transcription factor 1, and pituitary-specific positive transcription factor 2, reduced fractional phosphate absorption compared to placebo in a phase 1 study, but the efficacy of this molecule has not been evaluated in phase 2 and 3 studies.
      • Hill Gallant K.M.
      • Stremke E.R.
      • Trevino L.L.
      • et al.
      EOS789, a broad-spectrum inhibitor of phosphate transport, is safe with an indication of efficacy in a phase 1b randomized crossover trial in hemodialysis patients.
      A targeted NHE3 inhibitor effectively reduced paracellular phosphate absorption and decreased urinary phosphate excretion in an animal model and lowered phosphate concentrations in human trials.
      • King A.J.
      • Siegel M.
      • He Y.
      • et al.
      Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability.
      ,
      • Block G.A.
      • Rosenbaum D.P.
      • Yan A.
      • Chertow G.M.
      Efficacy and safety of tenapanor in patients with hyperphosphatemia receiving Maintenance hemodialysis: a randomized phase 3 trial.

      Novel Molecules in Development Target Paracellular Uptake of Phosphate in the Gastrointestinal Tract

      Tenapanor, an investigational first-in-class NHE3 inhibitor, produces modest intracellular proton retention which is proposed to induce conformational change(s) in claudin proteins present in tight junctions, thereby reducing paracellular phosphate absorption
      • King A.J.
      • Siegel M.
      • He Y.
      • et al.
      Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability.
      (Fig. 1). By reducing paracellular phosphate absorption, tenapanor directly and efficiently reduces serum phosphorus concentrations.
      • King A.J.
      • Siegel M.
      • He Y.
      • et al.
      Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability.
      The long-term efficacy and safety of tenapanor as monotherapy was studied in a 1-year trial of patients with ESRD on dialysis.
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      Subjects who experienced an increase in serum phosphorus of at least 1.5 mg/dL after the washout period of up to 4 weeks and who had a post binder washout baseline phosphorus concentration between 6 and 10 mg/dL were randomized to receive tenapanor (30 mg twice daily) or sevelamer (per label) as an active safety control.
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      After a 26-week treatment period, subjects randomized to tenapanor entered a 12-week withdrawal period in which they were randomized to continue treatment with tenapanor or switch to placebo.
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      The primary outcome of this study was the difference in change in phosphate concentrations between the pooled tenapanor-treated patients and the placebo-treated patients in the efficacy analysis set (defined as patients with at least a 1.2 mg/dL decrease in serum phosphorus concentration over the randomized treatment period) from the beginning to the end of the withdrawal period.
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      The trial met its primary outcome, with the least-squares mean difference in phosphorus concentration change between tenapanor and placebo of −1.4 mg/dL (P < .0001) in the efficacy analysis set.
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      Figure thumbnail gr1
      Figure 1Illustration of phosphate absorption pathways. NaPi2b, sodium-dependent phosphate cotransporter type 2b.
      • McCullough P.A.
      Phosphate control: the Next Frontier in dialysis cardiovascular mortality.
      Mean serum phosphorus concentrations decreased from 7.7 mg/dL at baseline to 5.1 mg/dL at the end of the 26-week randomized treatment period in the efficacy analysis set, a mean decrease of 2.6 mg/dL.
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      In the tenapanor intent-to-treat analysis, 77% of subjects demonstrated a clinical response (defined as a decrease in serum phosphorus of ≥0.1 mg/dL) with a mean decrease of 2.0 mg/dL.
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      The only adverse event reported by more than 5% of patients on tenapanor was diarrhea (53% of patients during the randomized treatment period).
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      However, diarrhea was typically transient and mild-to-moderate in severity.
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      The majority of patients who experienced diarrhea continued treatment (68.9%).
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      Rates of serious adverse events were higher in patients treated with sevelamer carbonate (16.4-23.4%) compared to tenapanor (11.2-17.4%) across all study periods.
      • Chertow G.M.
      • Yang Y.
      • Rosenbaum D.P.
      Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
      Three phase 3 studies have been completed thus far. The sponsor of tenapanor (Ardelyx, Inc, Fremont, CA) has received a complete response letter from the Food and Drug Administration regarding the New Drug Application for tenapanor and is pursuing options for obtaining approval.

      Previous Clinical Trials for Other Phosphate-Lowering Therapies

      Other trials to test efficacy of phosphate binders have used similar study design. The second phase 3 trial of ferric citrate in ESRD employed a similar study design in which the primary outcome compared the effect of ferric citrate to placebo.
      • Lewis J.B.
      • Sika M.
      • Koury M.J.
      • et al.
      Ferric citrate controls phosphorus and delivers iron in patients on dialysis.
      After a binder washout period, subjects on dialysis were randomized to receive ferric citrate or active control (sevelamer and/or calcium acetate) during the 52-week safety assessment period, followed by a 4-week placebo-controlled efficacy assessment period.
      • Lewis J.B.
      • Sika M.
      • Koury M.J.
      • et al.
      Ferric citrate controls phosphorus and delivers iron in patients on dialysis.
      The primary endpoint was the difference in serum phosphorus concentrations in ferric citrate versus placebo during the efficacy assessment period.
      • Lewis J.B.
      • Sika M.
      • Koury M.J.
      • et al.
      Ferric citrate controls phosphorus and delivers iron in patients on dialysis.
      Mean baseline phosphorus was similar in the 2 arms at the beginning of the efficacy assessment period (ferric citrate: 5.1 mg/dL; placebo: 5.4 mg/dL) and lower in the ferric citrate group by the end (ferric citrate: 4.9 mg/dL; placebo: 7.2 mg/dL), with an adjusted mean difference of 2.2 mg/dL (P < .001).
      • Lewis J.B.
      • Sika M.
      • Koury M.J.
      • et al.
      Ferric citrate controls phosphorus and delivers iron in patients on dialysis.
      In contrast, other recent phosphate binder trials have been designed to demonstrate noninferiority to active control. Floege et al. evaluated sucroferric oxyhydroxide versus sevelamer carbonate over 24 weeks in subjects on dialysis with hyperphosphatemia.
      • Lewis J.B.
      • Sika M.
      • Koury M.J.
      • et al.
      Ferric citrate controls phosphorus and delivers iron in patients on dialysis.
      Serum phosphorus concentrations decreased from 7.7 mg/dL at baseline to 5.3 mg/dL in the sucroferric oxyhydroxide and 7.4 mg/dL to 5.0 mg/dL in the sevelamer carbonate at week 24.
      • Floege J.
      • Covic A.C.
      • Ketteler M.
      • et al.
      A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients.
      Another phase 3 trial compared the same therapies for phosphate management in patients with chronic kidney disease on dialysis over a 12-week treatment period.
      Noninferiority of sucroferric oxyhydroxide to sevelamer carbonate was demonstrated in both trials.
      • Floege J.
      • Covic A.C.
      • Ketteler M.
      • et al.
      A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients.
      ,
      Figure 2 summarizes the primary outcomes of the approved phosphate binders in the United States.
      Figure thumbnail gr2
      Figure 2Efficacy of phosphate binders in their phase 3 trials.
      • Floege J.
      • Covic A.C.
      • Ketteler M.
      • et al.
      A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients.
      ,
      • Emmett M.
      • Sirmon M.D.
      • Kirkpatrick W.G.
      • Nolan C.R.
      • Schmitt G.W.
      • Cleveland M.B.
      Calcium acetate control of serum phosphorus in hemodialysis patients.
      • Bleyer A.J.
      • Burke S.K.
      • Dillon M.
      • et al.
      A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients.
      • Mehrotra R.
      • Martin K.J.
      • Fishbane S.
      • Sprague S.M.
      • Zeig S.
      • Anger M.
      Higher strength lanthanum carbonate provides serum phosphorus control with a low tablet burden and is preferred by patients and physicians: a multicenter study.

      Dietary Phosphorus Content Overwhelms Typical Options for Phosphorus Control

      Dietary phosphate restriction is complicated by the high amounts of “hidden” phosphate additives in the modern diet, which contribute significantly to the overall phosphate burden.
      • Benini O.
      • D'Alessandro C.
      • Gianfaldoni D.
      • Cupisti A.
      Extra-phosphate load from food additives in commonly eaten foods: a real and insidious danger for renal patients.
      Given that a modern diet is high in processed foods containing large amounts of phosphate additives, the normal daily phosphate intake is estimated to exceed 2,500 mg/day.
      • Haugen M.
      • Frøyland L.
      • Henjum S.
      • et al.
      Assessment of dietary intake of Manganese in Relation to Tolerable Upper intake level.
      ,
      • Hutchison A.J.
      • Smith C.P.
      • Brenchley P.E.
      Pharmacology, efficacy and safety of oral phosphate binders.
      Some patients on dialysis may have no choice but to consume processed foods. An estimated 17% of the US population, or approximately 54 million people, live in low-income and low-access areas far from supermarkets,
      so they likely need to rely on highly processed foods due to the lack of readily available healthy, fresh groceries. Current phosphate intake is more than 300% of the recommended dietary allowance.
      Phosphorus
      In. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride.
      ,
      • Moshfegh A.J.
      • Kovalchik A.F.
      • Clemens J.C.
      Phosphorus Intake of American, What We Eat in America, NHANES 2011-2012.
      Dialysis is said to remove <20% of the phosphorus consumed, so binders were developed to make up for this difference.
      • Hou S.H.
      • Zhao J.
      • Ellman C.F.
      • et al.
      Calcium and phosphorus fluxes during hemodialysis with low calcium dialysate.
      It should be noted that thrice-weekly in-center nocturnal hemodialysis was shown to result in a statistically significant decline in phosphorus levels from 5.7 to 5.0 mg/dL (P < .001).
      • Lacson Jr., E.
      • Xu J.
      • Suri R.S.
      • et al.
      Survival with three-times weekly in-center nocturnal versus conventional hemodialysis.
      However, the time commitment per session (mean of 7.9 hours)
      • Lacson Jr., E.
      • Xu J.
      • Suri R.S.
      • et al.
      Survival with three-times weekly in-center nocturnal versus conventional hemodialysis.
      and the requirement to stay in a dialysis center overnight may make this option impractical and unpleasant for many patients.

      Limitations to the Current Approach to Phosphorus Control in End-Stage Renal Disease

      Phosphate binders, as a class, generally cannot achieve and maintain guideline recommended phosphorus concentrations <5.5 mg/dL
      • Lewis J.B.
      • Sika M.
      • Koury M.J.
      • et al.
      Ferric citrate controls phosphorus and delivers iron in patients on dialysis.
      ,
      • Emmett M.
      • Sirmon M.D.
      • Kirkpatrick W.G.
      • Nolan C.R.
      • Schmitt G.W.
      • Cleveland M.B.
      Calcium acetate control of serum phosphorus in hemodialysis patients.
      • Bleyer A.J.
      • Burke S.K.
      • Dillon M.
      • et al.
      A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients.
      ,
      • Lacson Jr., E.
      • Xu J.
      • Suri R.S.
      • et al.
      Survival with three-times weekly in-center nocturnal versus conventional hemodialysis.
      (Fig. 2). Phosphate binders work by binding phosphate in the gastrointestinal tract to create nonabsorbable compounds that are then excreted.
      • Emmett M.
      • Sirmon M.D.
      • Kirkpatrick W.G.
      • Nolan C.R.
      • Schmitt G.W.
      • Cleveland M.B.
      Calcium acetate control of serum phosphorus in hemodialysis patients.
      • Bleyer A.J.
      • Burke S.K.
      • Dillon M.
      • et al.
      A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients.
      • Mehrotra R.
      • Martin K.J.
      • Fishbane S.
      • Sprague S.M.
      • Zeig S.
      • Anger M.
      Higher strength lanthanum carbonate provides serum phosphorus control with a low tablet burden and is preferred by patients and physicians: a multicenter study.
      This mechanism of action is inefficient because binders do not target either of the phosphate absorption pathways
      and, importantly, do not target/directly act on the paracellular pathway, which is the primary site of phosphate absorption.
      • Davis G.R.
      • Zerwekh J.E.
      • Parker T.F.
      • Krejs G.J.
      • Pak C.Y.
      • Fordtran J.S.
      Absorption of phosphate in the jejunum of patients with chronic renal failure before and after correction of vitamin D deficiency.
      In vivo binding capacities for binders have been found to range from 21 to 135 mg phosphate per capsule/tablet. Limited binding capacity per pill leads to the requirement for large and/or many pills (and pill burden increases as intake increases).
      The intrinsic mechanism of action implies a short duration of action that leads to the requirement that binders need to be taken every time the patient eats (e.g., with each meal/snack) to bind the phosphorus in that individual meal.
      Off-target binding, while hypothesized to be beneficial (e.g., sevelamer can lower low-density lipoprotein cholesterol but without impact on cardiovascular outcomes),
      • Wilkes B.M.
      • Reiner D.
      • Kern M.
      • Burke S.
      Simultaneous lowering of serum phosphate and LDL-cholesterol by sevelamer hydrochloride (RenaGel) in dialysis patients.
      can be detrimental and result in suboptimal efficacy of other drugs and drug-drug interactions.
      • Bover Sanjuán J.
      • Navarro-González J.F.
      • Arenas M.D.
      • et al.
      Pharmacological interactions of phosphate binders.
      Despite best efforts and currently available approaches (dietary phosphate restriction, dialysis, and phosphate binders), most patients are unable to consistently achieve target serum phosphorus concentrations
      Serum phosphorus (3 month average), categories. DOPPS Practice Monitor.
      ,
      • Lopes M.B.
      • Karaboyas A.
      • Bieber B.
      • et al.
      Impact of longer term phosphorus control on cardiovascular mortality in hemodialysis patients using an area under the curve approach: results from the DOPPS.
      (Fig. 3).
      Figure thumbnail gr3
      Figure 3Percent of dialysis patients who achieved target phosphate from 2011 to 2021.
      Serum phosphorus (most recent), categories. DOPPS Practice Monitor.

      Conclusions and Future of Phosphorus Control in End-Stage Renal Disease

      Given the mechanistic understanding of phosphate absorption, new targeted therapeutic innovations, high dietary phosphorus content, and the limitations of the current treatment approach, it is time to consider novel phosphorus management strategies. In the future, one can consider an approach that starts with blocking the paracellular pathway of phosphate absorption. In that case, phosphorus binders become potentially adjunctive, if necessary, in cases of difficult-to-control phosphorus. Phosphate absorption inhibitors are targeted: rather than binding to individual phosphate ions or “soaking up” dietary phosphate, phosphate absorption inhibitors directly block phosphate absorption, reducing phosphate absorption through this targeted mechanism. Paracellular phosphate absorption inhibitors like tenapanor may improve our ability to achieve sustained phosphate control. Tenapanor also likely offers a lower pill burden than phosphate binders and presents an opportunity to target phosphorus control for the study of harder outcomes, particularly bone health. Regulatory changes, such as mandatory labeling of phosphate content (in milligram and percent of daily value) on packaged foods, drugs, and dietary supplements, should also be implemented to help patients curtail dietary phosphorus intake.
      • Calvo M.S.
      • Sherman R.A.
      • Uribarri J.
      Dietary phosphate and the forgotten kidney patient: a critical need for FDA regulatory action.
      Identifying kidney-friendly foods using an easily recognized symbol would also be an effective strategy to help reduce phosphorus intake, particularly for patients with poor health or English literacy.
      • Calvo M.S.
      • Sherman R.A.
      • Uribarri J.
      Dietary phosphate and the forgotten kidney patient: a critical need for FDA regulatory action.

      Practical Application

      Novel therapies that target gastrointestinal phosphate absorption pathways present an opportunity to rethink hyperphosphatemia management. Clinicians may consider using phosphate absorption inhibitors as a first-line treatment, with adjunctive phosphate binders, if necessary, in hyperphosphatemia.

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