Phosphate Absorption and Hyperphosphatemia Management in Kidney Disease: A Physiology-Based Review
2021; Elsevier BV; Volume: 3; Issue: 6 Linguagem: Inglês
10.1016/j.xkme.2021.07.003
ISSN2590-0595
AutoresSteven Fishbane, Sagar U. Nigwekar,
Tópico(s)Genetic and Kidney Cyst Diseases
ResumoPhosphate absorption occurs in the gastrointestinal tract through paracellular absorption and transcellular transport. The paracellular pathway does not saturate and has a significantly higher absorption capacity than does the transcellular pathway. Evidence indicates that this pathway is the primary mechanism of intestinal phosphate absorption, particularly with Western diets containing high amounts of phosphorus. Elevated serum phosphorus concentrations are associated with cardiovascular morbidity and mortality but serum phosphorus concentrations > 5.5 mg/dL are highly prevalent despite best efforts with dietary phosphate restriction, dialysis, and the use of phosphate binders. The efficacy of phosphate binders may be inherently limited because the mechanism of action does not target any phosphate absorption pathway. Thus, therapeutic innovations are needed to address the limitations of phosphate binders. Novel therapies leveraging new mechanistic understandings of phosphate absorption and the primacy of the paracellular pathway may improve phosphate control. Phosphate absorption inhibitors that target the pathway are a novel therapeutic class. Tenapanor is an investigational first-in-class nonbinder phosphate absorption inhibitor that inhibits the sodium-hydrogen exchanger isoform 3 to reduce paracellular permeability specific to phosphate. Phosphate absorption inhibitors may represent a new mechanistic approach to phosphate management with the potential to improve clinical outcomes. Phosphate absorption occurs in the gastrointestinal tract through paracellular absorption and transcellular transport. The paracellular pathway does not saturate and has a significantly higher absorption capacity than does the transcellular pathway. Evidence indicates that this pathway is the primary mechanism of intestinal phosphate absorption, particularly with Western diets containing high amounts of phosphorus. Elevated serum phosphorus concentrations are associated with cardiovascular morbidity and mortality but serum phosphorus concentrations > 5.5 mg/dL are highly prevalent despite best efforts with dietary phosphate restriction, dialysis, and the use of phosphate binders. The efficacy of phosphate binders may be inherently limited because the mechanism of action does not target any phosphate absorption pathway. Thus, therapeutic innovations are needed to address the limitations of phosphate binders. Novel therapies leveraging new mechanistic understandings of phosphate absorption and the primacy of the paracellular pathway may improve phosphate control. Phosphate absorption inhibitors that target the pathway are a novel therapeutic class. Tenapanor is an investigational first-in-class nonbinder phosphate absorption inhibitor that inhibits the sodium-hydrogen exchanger isoform 3 to reduce paracellular permeability specific to phosphate. Phosphate absorption inhibitors may represent a new mechanistic approach to phosphate management with the potential to improve clinical outcomes. Systemic phosphate homeostasis is maintained primarily through urinary excretion.1Turner NN, Lameire N, Goldsmith DJ, Winearls CG, Himmelfarb J, Remuzzi G. Oxford Textbook of Clinical Nephrology. Oxford University Press; 2015.Google Scholar As chronic kidney disease (CKD) progresses, kidney function declines, leading to phosphate retention.2Shaman A.M. Kowalski S.R. Hyperphosphatemia management in patients with chronic kidney disease.Saudi Pharm J. 2016; 24: 494-505Crossref PubMed Scopus (57) Google Scholar Elevated serum phosphorus concentrations, or hyperphosphatemia, are seen in most patients with advanced CKD and those receiving dialysis.3Block G.A. Hulbert-Shearon T.E. Levin N.W. Port F.K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2092) Google Scholar Diet is the primary source of phosphate intake and absorption of dietary phosphate occurs in the gastrointestinal (GI) tract through 2 distinct pathways: paracellular absorption and transcellular transport (Fig 14Davis G.R. Zerwekh J.E. Parker T.F. Krejs G.J. Pak C.Y. Fordtran J.S. 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Absorption of phosphate in the jejunum of patients with chronic renal failure before and after correction of vitamin D deficiency.Gastroenterology. 1983; 85: 908-916Abstract Full Text PDF PubMed Scopus (61) Google Scholar Paracellular absorption occurs passively along concentration gradients through the tight junction complexes (eg, claudins and occludins) between cell membranes.5Knöpfel T. Himmerkus N. Günzel D. Bleich M. Hernando N. Wagner C.A. Paracellular transport of phosphate along the intestine.Am J Physiol Gastrointest Liver Physiol. 2019; 317: G233-G241Crossref PubMed Scopus (36) Google Scholar The paracellular pathway is not limited by a saturation point and has been shown to be responsible for most intestinal phosphate absorption, particularly when luminal phosphate concentrations are high.4Davis 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.Gastroenterology. 1983; 85: 908-916Abstract Full Text PDF PubMed Scopus (61) Google Scholar The transcellular sodium-dependent pathway takes in phosphate primarily through the action of the sodium-dependent phosphate cotransporter 2b (NaPi2b).6Sabbagh Y. O'Brien S.P. Song W. et al.Intestinal npt2b plays a major role in phosphate absorption and homeostasis.J Am Soc Nephrol. 2009; 20: 2348-2358Crossref PubMed Scopus (244) Google Scholar Evidence suggests that NaPi2b is responsible for phosphate absorption in the presence of low amounts of dietary phosphate4Davis 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.Gastroenterology. 1983; 85: 908-916Abstract Full Text PDF PubMed Scopus (61) Google Scholar,6Sabbagh Y. O'Brien S.P. Song W. et al.Intestinal npt2b plays a major role in phosphate absorption and homeostasis.J Am Soc Nephrol. 2009; 20: 2348-2358Crossref PubMed Scopus (244) Google Scholar but because this pathway saturates,4Davis 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.Gastroenterology. 1983; 85: 908-916Abstract Full Text PDF PubMed Scopus (61) Google Scholar it is less relevant for people who consume Western diets, which typically have high amounts of phosphorus.7McClure 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.Nutrients. 2017; 9: 95Crossref Scopus (44) Google Scholar New studies have found that the paracellular pathway is the primary mechanism of phosphate absorption under typical conditions of phosphate availability in individuals consuming standard Western diets, not the transcellular pathway as previously believed. Although transcellular phosphate transport by NaPi2b plays a significant role in rodents,8Marks J. Lee G.J. Nadaraja S.P. Debnam E.S. Unwin R.J. Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon.Physiol Rep. 2015; 3: e12281Crossref PubMed Scopus (47) Google Scholar,15Taniguchi 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.J Am Soc Nephrol. 2015; 26 (FR-PO936): 582AGoogle Scholar recent clinical evidence shows this pathway to be less physiologically relevant in humans.16Larsson T.E. Kameoka C. Nakajo I. et al.NPT-IIb inhibition does not improve hyperphosphatemia in CKD.Kidney Int Rep. 2018; 3: 73-80Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Furthermore, maximum absorption through the transcellular pathway is reached at a very low luminal concentration of ∼2 mmol/L.4Davis 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.Gastroenterology. 1983; 85: 908-916Abstract Full Text PDF PubMed Scopus (61) Google Scholar Based on reported gastric volumes of 750 to 1,500 mL,17Fordtran J.S. Locklear T.W. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating.Am J Dig Dis. 1966; 11: 503-521Crossref PubMed Scopus (283) Google Scholar a typical Western diet of ∼2,500 mg of phosphate per day7McClure 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.Nutrients. 2017; 9: 95Crossref Scopus (44) Google Scholar,18Bell R.R. Draper H.H. Tzeng D.Y. Shin H.K. Schmidt G.R. Physiological responses of human adults to foods containing phosphate additives.J Nutr. 1977; 107: 42-50Crossref PubMed Scopus (138) Google Scholar translates to luminal concentrations of 18 to 36 mmol/L,4Davis 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.Gastroenterology. 1983; 85: 908-916Abstract Full Text PDF PubMed Scopus (61) Google Scholar far exceeding the maximum concentration that the transcellular pathway can accommodate. Paracellular absorption is biologically favored by the intestinal electrochemical gradient and has much higher capacity for absorption than the transcellular transport system.5Knöpfel T. Himmerkus N. Günzel D. Bleich M. Hernando N. Wagner C.A. Paracellular transport of phosphate along the intestine.Am J Physiol Gastrointest Liver Physiol. 2019; 317: G233-G241Crossref PubMed Scopus (36) Google Scholar Phosphate is one of the most abundant minerals in the body, and serum phosphorus concentration must be maintained within the normal range (2.5-4.5 mg/dL) for optimal functioning of many biological processes.19Bansal V.K. Chapter 198. Serum inorganic phosphorus.in: Walker H.K. Hall W.D. Hurst J.W. Clinical Methods: The History, Physical, and Laboratory Examinations. 3 ed. Butterworths, 1990: 895-899Google Scholar Elevated serum phosphorus concentrations are associated with significant negative clinical outcomes, and management of phosphate is a guideline-recommended established clinical practice.9National Kidney FoundationK/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201PubMed Google Scholar,20Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar National Kidney Foundation-Kidney Disease Outcomes Quality Initiative/ (NKF-KDOQI) 2003 guidelines recommend targeting phosphorus concentrations of 2.7 to 4.6 mg/dL in patients with stages 3 and 4 CKD and 3.5 to 5.5 mg/dL in patients with stage 5 CKD and those receiving dialysis.9National Kidney FoundationK/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201PubMed Google Scholar These recommendations are based on the association between elevated serum phosphorus concentrations and adverse clinical outcomes, as well as the expert opinion of the KDOQI working group.9National Kidney FoundationK/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201PubMed Google Scholar The KDIGO (Kidney Disease: Improving Global Outcomes) 2017 guideline recommends that patients with CKD stages 3A-5D lower elevated phosphate levels toward the normal range.20Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work GroupKDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar Phosphate binders, which reduce the quantity of absorbable phosphate by binding to dietary phosphate to create insoluble compounds, are currently the only US Food and Drug Administration–approved treatment for hyperphosphatemia21Sawin D.A. Ma L. Stennett A. et al.Phosphates in medications: impact on dialysis patients.Clin Nephrol. 2020; 93: 163-171Crossref PubMed Scopus (2) Google Scholar and are prescribed to ∼80% of US patients receiving dialysis (Table 18Marks J. Lee G.J. Nadaraja S.P. Debnam E.S. Unwin R.J. Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon.Physiol Rep. 2015; 3: e12281Crossref PubMed Scopus (47) Google Scholar,15Taniguchi 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.J Am Soc Nephrol. 2015; 26 (FR-PO936): 582AGoogle Scholar, 16Larsson T.E. Kameoka C. Nakajo I. et al.NPT-IIb inhibition does not improve hyperphosphatemia in CKD.Kidney Int Rep. 2018; 3: 73-80Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 17Fordtran J.S. Locklear T.W. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating.Am J Dig Dis. 1966; 11: 503-521Crossref PubMed Scopus (283) Google Scholar, 18Bell R.R. Draper H.H. Tzeng D.Y. Shin H.K. Schmidt G.R. Physiological responses of human adults to foods containing phosphate additives.J Nutr. 1977; 107: 42-50Crossref PubMed Scopus (138) Google Scholar).22Phosphate binder use, last 3 months. DOPPS Practice Monitor. Accessed December 3, 2020. https://www.dopps.org/DPM-HD/Files/maxPBINDER_use_c_overallTAB.htmGoogle Scholar Although phosphate binders are widely used, a disturbingly large proportion of patients are unable to consistently achieve and maintain phosphate levels ≤ 5.5 mg/dL.23RealWorld Dynamix: Dialysis US. Spherix Global Insights.https://www.spherixglobalinsights.com/reports/nephrology-reports/dialysis-us/Date accessed: December 3, 2020Google Scholar A total of 77% of dialysis patients receiving binders are unable to maintain levels ≤ 5.5 mg/dL over a 6-month period.23RealWorld Dynamix: Dialysis US. Spherix Global Insights.https://www.spherixglobalinsights.com/reports/nephrology-reports/dialysis-us/Date accessed: December 3, 2020Google Scholar An even greater proportion of patients receiving dialysis are unable to achieve more normal phosphate levels.24Serum phosphorus (3 month average), categories. DOPPS Practice Monitor. Accessed December 3, 2020. https://www.dopps.org/DPM-HD/Files/meanphosphmgdl_c_overallTAB.htmGoogle Scholar 25Lopes 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.Nephrol Dial Transplant. 2020; 35: 1794-1801Crossref PubMed Scopus (10) Google Scholar Modern diets are high in phosphate, primarily from phosphate additives,26Ritz E. Hahn K. Ketteler M. Kuhlmann M.K. Mann J. Phosphate additives in food--a health risk.Dtsch Arztebl Int. 2012; 109: 49-55PubMed Google Scholar which makes it challenging for patients to take sufficient binders to consistently maintain target phosphate levels.27Daugirdas J.T. Finn W.F. Emmett M. Chertow G.M. The phosphate binder equivalent dose.Semin Dial. 2011; 24: 41-49Crossref PubMed Scopus (109) Google Scholar,28Martin 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.Am J Kidney Dis. 2011; 57: 700-706Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarTable 1Overview of Available Phosphate BindersDrugInitial US ApprovalMechanismCalcium acetate (PHOSLO15Taniguchi 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.J Am Soc Nephrol. 2015; 26 (FR-PO936): 582AGoogle Scholar)1990Combines with dietary phosphate to form an insoluble calcium phosphate complex, which is excreted in feces, resulting in decreased serum phosphate concentrationSevelamer carbonate (RENVELA8Marks J. Lee G.J. Nadaraja S.P. Debnam E.S. Unwin R.J. Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon.Physiol Rep. 2015; 3: e12281Crossref PubMed Scopus (47) Google Scholar,19Bansal V.K. Chapter 198. Serum inorganic phosphorus.in: Walker H.K. Hall W.D. Hurst J.W. Clinical Methods: The History, Physical, and Laboratory Examinations. 3 ed. Butterworths, 1990: 895-899Google Scholar)2000By binding phosphate in the GI tract and decreasing absorption, sevelamer carbonate lowers the phosphate concentration in serum (serum phosphate)Lanthanum carbonate (FOSRENOL16Larsson T.E. Kameoka C. Nakajo I. et al.NPT-IIb inhibition does not improve hyperphosphatemia in CKD.Kidney Int Rep. 2018; 3: 73-80Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar)2004Reduces absorption of phosphate by forming insoluble lanthanum phosphate complexes that pass through the GI tract unabsorbedReduces both serum phosphate and calcium phosphate product by reducing dietary phosphate absorptionSucroferric oxyhydroxide (VELPHORO17Fordtran J.S. Locklear T.W. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating.Am J Dig Dis. 1966; 11: 503-521Crossref PubMed Scopus (283) Google Scholar)2013In the GI tract, phosphate binding takes place by ligand exchange between hydroxyl groups and/or water in sucroferric oxyhydroxide and phosphate in the diet. The bound phosphate is eliminated with feces.Reduces both serum phosphate and calcium phosphate product by reducing dietary phosphate absorptionFerric citrate (AURYXIA18Bell R.R. Draper H.H. Tzeng D.Y. Shin H.K. Schmidt G.R. Physiological responses of human adults to foods containing phosphate additives.J Nutr. 1977; 107: 42-50Crossref PubMed Scopus (138) Google Scholar)2014Ferric iron binds dietary phosphate in the GI tract and precipitates as ferric phosphate. This compound is insoluble and is excreted in the stoolBy binding phosphate in the GI tract and decreasing absorption, ferric citrate lowers the phosphate concentration in the serumAbbreviation: GI, gastrointestinal. Open table in a new tab Abbreviation: GI, gastrointestinal. As evidenced by these data, current phosphorus management strategies that include phosphate binders, reduction in phosphorus dietary intake, and dialysis are insufficient to achieve and maintain phosphate levels ≤ 5.5 mg/dL (or more normal levels) for most patients. Phosphate binders have a fundamentally inefficient mechanism of action that potentially explains the continuing clinical challenge of consistently achieving and maintaining target serum phosphorus concentrations. Instead of directly acting on phosphate absorption pathways,29PhosLo gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America; 2011.Google Scholar, 30VELPHORO (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America; 2013.Google Scholar, 31FOSRENAL (lanthanum carbonate) [prescribing information]. Shire US Inc; 2016.Google Scholar, 32AURYXIA (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc; 2017.Google Scholar, 33RENVELA (sevelamer carbonate) [prescribing information]. Genzyme Corp; 2020.Google Scholar either the secondary transcellular pathway or the primary paracellular pathway, phosphate binders "scavenge" particles of dietary phosphate in the GI tract. To scavenge and bind the phosphorus before it is absorbed, the binders must be in the gut at the same time as the dietary phosphorus. Thus, most patients are instructed to take phosphate binders with every meal and snack,29PhosLo gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America; 2011.Google Scholar, 30VELPHORO (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America; 2013.Google Scholar, 31FOSRENAL (lanthanum carbonate) [prescribing information]. Shire US Inc; 2016.Google Scholar, 32AURYXIA (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc; 2017.Google Scholar, 33RENVELA (sevelamer carbonate) [prescribing information]. Genzyme Corp; 2020.Google Scholar resulting in a high dosing frequency. Moreover, in vivo, each pill can only bind a discrete amount of phosphorus.27Daugirdas J.T. Finn W.F. Emmett M. Chertow G.M. The phosphate binder equivalent dose.Semin Dial. 2011; 24: 41-49Crossref PubMed Scopus (109) Google Scholar,23RealWorld Dynamix: Dialysis US. Spherix Global Insights.https://www.spherixglobalinsights.com/reports/nephrology-reports/dialysis-us/Date accessed: December 3, 2020Google Scholar Thus, patients typically require many large pills every time they eat (Fig 27McClure 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.Nutrients. 2017; 9: 95Crossref Scopus (44) Google Scholar,8Marks J. Lee G.J. Nadaraja S.P. Debnam E.S. Unwin R.J. Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon.Physiol Rep. 2015; 3: e12281Crossref PubMed Scopus (47) Google Scholar,15Taniguchi 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.J Am Soc Nephrol. 2015; 26 (FR-PO936): 582AGoogle Scholar, 16Larsson T.E. Kameoka C. Nakajo I. et al.NPT-IIb inhibition does not improve hyperphosphatemia in CKD.Kidney Int Rep. 2018; 3: 73-80Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 17Fordtran J.S. Locklear T.W. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating.Am J Dig Dis. 1966; 11: 503-521Crossref PubMed Scopus (283) Google Scholar, 18Bell R.R. Draper H.H. Tzeng D.Y. Shin H.K. Schmidt G.R. Physiological responses of human adults to foods containing phosphate additives.J Nutr. 1977; 107: 42-50Crossref PubMed Scopus (138) Google Scholar,27Daugirdas J.T. Finn W.F. Emmett M. Chertow G.M. The phosphate binder equivalent dose.Semin Dial. 2011; 24: 41-49Crossref PubMed Scopus (109) Google Scholar, 28Martin 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.Am J Kidney Dis. 2011; 57: 700-706Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 29PhosLo gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America; 2011.Google Scholar, 30VELPHORO (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America; 2013.Google Scholar, 31FOSRENAL (lanthanum carbonate) [prescribing information]. Shire US Inc; 2016.Google Scholar, 32AURYXIA (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc; 2017.Google Scholar, 33RENVELA (sevelamer carbonate) [prescribing information]. Genzyme Corp; 2020.Google Scholar, 34Cupisti A. Kalantar-Zadeh K. Management of natural and added dietary phosphorus burden in kidney disease.Semin Nephrol. 2013; 33: 180-190Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar) in an effort to bind a meaningful amount of dietary phosphate. Studies have shown that on average, patients receiving dialysis are prescribed 10.8 phosphate-binder pills per day, accounting for ∼50% of their total daily pill burden (Fig 327Daugirdas J.T. Finn W.F. Emmett M. Chertow G.M. The phosphate binder equivalent dose.Semin Dial. 2011; 24: 41-49Crossref PubMed Scopus (109) Google Scholar, 28Martin 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.Am J Kidney Dis. 2011; 57: 700-706Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 29PhosLo gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America; 2011.Google Scholar, 30VELPHORO (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America; 2013.Google Scholar, 31FOSRENAL (lanthanum carbonate) [prescribing information]. Shire US Inc; 2016.Google Scholar, 32AURYXIA (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc; 2017.Google Scholar, 33RENVELA (sevelamer carbonate) [prescribing information]. Genzyme Corp; 2020.Google Scholar,35Chiu Y.-W. Teitelbaum I. Misra M. de Leon E.M. Adzize T. Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (349) Google Scholar).36Chiu Y.W. Teitelbaum I. Misra M. de Leon E.M. Adzize T. Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (379) Google ScholarFigure 3Percent of dialysis patients pill burden per day by medications.29PhosLo gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America; 2011.Google Scholar, 30VELPHORO (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America; 2013.Google Scholar, 31FOSRENAL (lanthanum carbonate) [prescribing information]. Shire US Inc; 2016.Google Scholar, 32AURYXIA (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc; 2017.Google Scholar, 33RENVELA (sevelamer carbonate) [prescribing information]. Genzyme Corp; 2020.Google Scholar,35Chiu Y.-W. Teitelbaum I. Misra M. de Leon E.M. Adzize T. Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (349) Google Scholar Labeled dosing instructions require patients to take 1 to 4 binders with each meal or snack (∼3 to 5 times per day).29PhosLo gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America; 2011.Google Scholar, 30VELPHORO (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America; 2013.Google Scholar, 31FOSRENAL (lanthanum carbonate) [prescribing information]. Shire US Inc; 2016.Google Scholar, 32AURYXIA (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc; 2017.Google Scholar, 33RENVELA (sevelamer carbonate) [prescribing information]. Genzyme Corp; 2020.Google Scholar On average, phosphate binders account for almost half the daily pill burden for patients receiving dialysis.35Chiu Y.-W. Teitelbaum I. Misra M. de Leon E.M. Adzize T. Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (349) Google Schola
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