Phosphate binders, as a class, generally cannot achieve and maintain guideline recommended phosphorus concentrations 21Lewis J.B. Sika M. Koury M.J. et al.Ferric citrate controls phosphorus and delivers iron in patients on dialysis.

J Am Soc Nephrol. 2015; 26: 493-503

,24Emmett 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.

Am J Kidney Dis. 1991; 17: 544-550

, 25Bleyer 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.

Am J Kidney Dis. 1999; 33: 694-701

, 26

Data on file. Akebia Therapeutics, Inc, Washington, DC2008

,33Lacson Jr., E. Xu J. Suri R.S. et al.Survival with three-times weekly in-center nocturnal versus conventional hemodialysis.

J Am Soc Nephrol. 2012; 23: 687-695

(Fig. 2). Phosphate binders work by binding phosphate in the gastrointestinal tract to create nonabsorbable compounds that are then excreted.24Emmett 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.

Am J Kidney Dis. 1991; 17: 544-550

, 25Bleyer 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.

Am J Kidney Dis. 1999; 33: 694-701

, 26

Data on file. Akebia Therapeutics, Inc, Washington, DC2008

, 27Mehrotra 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.

Clin J Am Soc Nephrol. 2008; 3: 1437-1445

This mechanism of action is inefficient because binders do not target either of the phosphate absorption pathways34

RENVELA ® (sevelamer carbonate) [prescribing information]. Genzyme Corp., Cambridge, MA2000

, 35

FOSRENOL® (lanthanum carbonate) [prescribing information]. Shire US Inc., Lexington, MA2004

, 36

PhosLo ® gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America, Waltham, MA2011

, 37

VELPHORO® (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America, Waltham, MA2013

, 38

AURYXIA® (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc., Cambridge, MA2017

and, importantly, do not target/directly act on the paracellular pathway, which is the primary site of phosphate absorption.14Davis 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: 908-916

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).34

RENVELA ® (sevelamer carbonate) [prescribing information]. Genzyme Corp., Cambridge, MA2000

, 35

FOSRENOL® (lanthanum carbonate) [prescribing information]. Shire US Inc., Lexington, MA2004

, 36

PhosLo ® gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America, Waltham, MA2011

, 37

VELPHORO® (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America, Waltham, MA2013

, 38

AURYXIA® (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc., Cambridge, MA2017

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.34

RENVELA ® (sevelamer carbonate) [prescribing information]. Genzyme Corp., Cambridge, MA2000

, 35

FOSRENOL® (lanthanum carbonate) [prescribing information]. Shire US Inc., Lexington, MA2004

, 36

PhosLo ® gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America, Waltham, MA2011

, 37

VELPHORO® (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America, Waltham, MA2013

, 38

AURYXIA® (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc., Cambridge, MA2017

Off-target binding, while hypothesized to be beneficial (e.g., sevelamer can lower low-density lipoprotein cholesterol but without impact on cardiovascular outcomes),39Wilkes B.M. Reiner D. Kern M. Burke S. Simultaneous lowering of serum phosphate and LDL-cholesterol by sevelamer hydrochloride (RenaGel) in dialysis patients.

Clin Nephrol. 1998; 50: 381-386

can be detrimental and result in suboptimal efficacy of other drugs and drug-drug interactions.40Bover Sanjuán J. Navarro-González J.F. Arenas M.D. et al.Pharmacological interactions of phosphate binders.

Nefrologia. 2018; 38: 573-578

Despite best efforts and currently available approaches (dietary phosphate restriction, dialysis, and phosphate binders), most patients are unable to consistently achieve target serum phosphorus concentrations9Serum phosphorus (3 month average), categories. DOPPS Practice Monitor.,41Lopes 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 Transpl. 2020; 35: 1794-1801

(Fig. 3).Figure 3Percent of dialysis patients who achieved target phosphate from 2011 to 2021.42Serum phosphorus (most recent), categories. DOPPS Practice Monitor.