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State-of-the-Art Management of Hyperphosphatemia in Patients With CKD: An NKF-KDOQI Controversies Perspective

Published:August 06, 2020DOI:https://doi.org/10.1053/j.ajkd.2020.05.025
      Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney disease (CKD). In patients with CKD glomerular filtration rate category 3a (G3a) or worse, including those with kidney failure who are receiving dialysis, clinical practice guidelines suggest “lowering elevated phosphate levels towards the normal range” with possible strategies including dietary phosphate restriction or use of binders. Additionally, guidelines suggest restricting the use of oral elemental calcium often contained in phosphate binders. Nutrition guidelines in CKD suggest <800-1,000 mg of calcium daily, whereas CKD bone and mineral disorder guidelines do not provide clear targets, but <1,500 mg in maintenance dialysis patients has been previously recommended. Many different classes of phosphate binders are now available and clinical trials have not definitively demonstrated the superiority of any class of phosphate binders over another with regard to clinical outcomes. Use of phosphate binders contributes substantially to patients’ pill burden and out-of-pocket costs, and many have side effects. This has led to uncertainty regarding the use and best choice of phosphate binders for patients with CKD or kidney failure. In this controversies perspective, we discuss the evidence base around binder use in CKD and kidney failure with a focus on comparisons of available binders.

      Index Words

      Introduction

      Gastrointestinal phosphate binders are one of the most widely prescribed medications for patients with kidney failure treated by dialysis and are also commonly used in chronic kidney disease (CKD) glomerular filtration rate categories 3-5 (G3-G5).
      • St Peter W.L.
      • Wazny L.D.
      • Weinhandl E.D.
      Phosphate-binder use in US dialysis patients: prevalence, costs, evidence, and policies.
      Although recognizing low-level evidence, clinical practice guidelines suggest “lowering elevated phosphate towards normal” in CKD G3a-G5D (in which 5D signifies kidney failure treated by dialysis) with potential strategies including reducing dietary phosphate intake and use of binders.
      Kidney Disease: Improving Global Outcomes (KDIGO) Chronic Kidney Disease Mineral and Bone Disorder Working Group
      KDIGO clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD).
      Practitioners also reveal substantial uncertainty in best practices for binder choice. For instance, a 2017 online poll performed by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) asked the question “Should patients with CKD stage 3-5 (non-dialysis) and hyperphosphatemia receive non-calcium containing binders only?” Among 979 respondents, only 46% said “Yes,” indicating substantial uncertainty within the clinical community on whether non–calcium-based phosphate binders should be preferred in patients with CKD. US practice pattern data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) confirms heavy use of phosphate binders in CKD G5D and relative parity across major classes, with ~40% using calcium-based binders alone, ~30% using sevelamer-based products alone, ~15% using a combination of these, and the rest using other phosphate-binding agents, including lanthanum carbonate and the relatively new iron-based binding agents.
      DOPPS Practice Monitor
      Mineral and bone disorder data.
      This perspective discusses the current state of knowledge and evidence gaps for use of phosphate binders with an emphasis on the choice of phosphate-binding agents in CKD and kidney failure.

      Overall Evidence for Phosphate-Binding Therapy

       CKD G3-G5

      The risks and benefits of phosphate-lowering therapy in patients with CKD who are not treated by dialysis are largely unknown. Serum phosphate concentrations typically remain normal until late in CKD, with clinically important rates of hyperphosphatemia not evident until CKD G4.
      • Isakova T.
      • Wahl P.
      • Vargas G.S.
      • et al.
      Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.
      Normal serum phosphate levels are maintained by activation of the regulatory hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23). Both PTH and FGF-23 increase the fractional excretion of phosphate in urine to promote excretion as glomerular filtration rate decreases. FGF-23 also limits gastrointestinal phosphate absorption by reducing 1,25-dihydroxyvitamin D levels. In addition to known effects on bone, changes in many of these biochemical parameters are associated with risks for cardiovascular disease and death. Multiple recent reviews and commentaries have provided detail on this abnormal physiology.
      • Lunyera J.
      • Scialla J.J.
      Update on chronic kidney disease mineral and bone disorder in cardiovascular disease.
      • Felsenfeld A.J.
      • Levine B.S.
      • Rodriguez M.
      Pathophysiology of calcium, phosphorus, and magnesium dysregulation in chronic kidney disease.
      • Naveh-Many T.
      • Silver J.
      The pas de trois of vitamin D, FGF23, and PTH.
      • Blau J.E.
      • Collins M.T.
      The PTH-vitamin D-FGF23 axis.
      Few long-term trials of phosphate binders in CKD G3-G5 (excluding 5D) have been conducted. Table 1 lists the randomized clinical trials that have compared different phosphate binders for patients with CKD who are not receiving dialysis over periods of at least 3 months. In a single-center trial of approximately 150 patients with CKD, random assignment to 1 of 3 phosphate binders (lanthanum carbonate, sevelamer carbonate, or calcium acetate) versus placebo resulted in modestly lower serum phosphate levels and lower urinary phosphate excretion compared with placebo. FGF-23 level was not lowered overall, but was lowered by sevelamer carbonate in secondary stratified analyses.
      • Block G.A.
      • Wheeler D.C.
      • Persky M.S.
      • et al.
      Effects of phosphate binders in moderate CKD.
      In the recently published COMBINE study of 205 patients, use of lanthanum carbonate at 1 g 3 times daily for 12 months did not lower serum phosphate levels but modestly lowered urinary phosphate excretion and FGF-23 levels in secondary analyses.
      • Ix J.H.
      • Isakova T.
      • Larive B.
      • et al.
      Effects of nicotinamide and lanthanum carbonate on serum phosphate and fibroblast growth factor-23 in CKD: the COMBINE Trial.
      Other trials have found similar results, with phosphate binders largely affecting urine phosphate excretion, but not serum levels of phosphate or its regulatory hormones.
      • Ruggiero B.
      • Trillini M.
      • Tartaglione L.
      • et al.
      Effects of sevelamer carbonate in patients with CKD and proteinuria: the ANSWER randomized trial.
      • Urena-Torres P.
      • Prie D.
      • Keddad K.
      • et al.
      Changes in fibroblast growth factor 23 levels in normophosphatemic patients with chronic kidney disease stage 3 treated with lanthanum carbonate: results of the PREFECT study, a phase 2a, double blind, randomized, placebo-controlled trial.
      • Liabeuf S.
      • Ryckelynck J.P.
      • El Esper N.
      • et al.
      Randomized clinical trial of sevelamer carbonate on serum klotho and fibroblast growth factor 23 in CKD.
      In a small single-center study of ferric citrate in CKD G4-G5, random assignment to ferric citrate resulted in stabilization of FGF-23 levels.
      • Block G.A.
      • Block M.S.
      • Smits G.
      • et al.
      A pilot randomized trial of ferric citrate coordination complex for the treatment of advanced CKD.
      Table 1Clinical Trials That Have Compared Phosphate Binders for at Least 3 Months in Adults With CKD G1-G5 (Not G5D)
      TrialNMean eGFR, mL/min/1.73 m2Intervention ArmsDuration, moEnd PointResultsComment
      Russo et al
      • Russo D.
      • Miranda I.
      • Ruocco C.
      • et al.
      The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer.
      9033 vs 26 vs 26Diet, diet + CaCO3, diet + sevelamer24 ± 4.21. CAC score

      2. Biochemical changes
      1. CAC progression w/ diet + CaCO3; stable w/ sevelamer

      2. Urine P decreased in binder groups

      3. ALP decreased in diet and diet + sevelamer group
      Excluded those w/ diabetes; excluded previous coronary procedures; CONSORT criteria not described in publication
      Block et al
      • Block G.A.
      • Wheeler D.C.
      • Persky M.S.
      • et al.
      Effects of phosphate binders in moderate CKD.
      14832Calcium acetate, lanthanum, sevelamer, placebo91. Biochemical changes

      2. VC
      1. Binders lowered serum P, urine P; PTH stable w/ binders and increased w/ placebo

      2. Calcification increased w/ binders
      Did not exclude previous coronary procedures; all patients received fixed dose vitamin D; high dropout rate (28%); only 96 patients had calcification data
      Seifert et al
      • Seifert M.E.
      • de las Fuentes L.
      • Rothstein M.
      • et al.
      Effects of phosphate binder therapy on vascular stiffness in early-stage chronic kidney disease.
      38CKD G3Lanthanum, placebo121. Biochemical changes

      2. PWV, cIMT, and VC
      None of the studied parameters were different between lanthanum and placeboPilot study; matching performed between the 2 groups
      Ureña-Torres et al
      • Urena-Torres P.
      • Prie D.
      • Keddad K.
      • et al.
      Changes in fibroblast growth factor 23 levels in normophosphatemic patients with chronic kidney disease stage 3 treated with lanthanum carbonate: results of the PREFECT study, a phase 2a, double blind, randomized, placebo-controlled trial.
      3542 vs 48Lanthanum, placebo31. Biochemical changes1. No sustained reduction in FGF-23

      2. Decrease in urine P
      GFR was measured; imbalance in characteristics between the 2 groups
      Kovesdy et al
      • Kovesdy C.P.
      • Lu J.L.
      • Wall B.M.
      • et al.
      Changes with lanthanum carbonate, calcium acetate, and phosphorus restriction in CKD: a randomized controlled trial.
      12032Diet, lanthanum, calcium acetate121. CAC, PWV, FMD

      2. Biochemical changes
      1. bALP lower after 1 y

      2. No other changes compared to baseline

      3. Calcium acetate suppressed PTH
      Randomized, open-label, 2-center trial; predominantly men; powered to detect changes in bone-mineral parameters
      Di Iorio et al
      • Di Iorio B.
      • Bellasi A.
      • Russo D.
      INDEPENDENT Study Investigators
      Mortality in kidney disease patients treated with phosphate binders: a randomized study.
      21232.7Sevelamer, CaCO3361. Predialysis mortality

      2. Dialysis start
      1. Biochemical results more favorable w/sevelamer

      2. Mortality lower w/sevelamer

      3. Dialysis start less frequent w/sevelamer
      Randomized nonblinded study; RCT was not registered; benefits implausibly large
      Ix et al
      • Ix J.H.
      • Isakova T.
      • Larive B.
      • et al.
      Effects of nicotinamide and lanthanum carbonate on serum phosphate and fibroblast growth factor-23 in CKD: the COMBINE Trial.
      20532NAM + lanthanum, NAM + placebo, lanthanum + placebo, double placebo121. Biochemical changesNo significant change in serum P or FGF-23 concentrations between the 4 armsRandomized, blinded, placebo-controlled trial; suboptimal adherence due to GI side effects
      Ruggiero et al
      • Ruggiero B.
      • Trillini M.
      • Tartaglione L.
      • et al.
      Effects of sevelamer carbonate in patients with CKD and proteinuria: the ANSWER randomized trial.
      5349Sevelamer, no sevelamer31. Proteinuria

      2. Biochemical changes
      1. No change in proteinuria

      2. Sevelamer reduced urine P; no change in serum P, FGF-23, klotho, PTH, vitamin D
      Randomized, open label, 2-center, crossover trial; GFR was measured
      Block et al
      • Block G.A.
      • Block M.S.
      • Smits G.
      • et al.
      A pilot randomized trial of ferric citrate coordination complex for the treatment of advanced CKD.
      199CKD G4-G5Ferric citrate, usual care91. Biochemical changes

      2. Hospital-ization

      3. Kidney failure, death
      1. Iron parameters and Hb increased on ferric citrate

      2. FGF-23 stabilized on ferric citrate compared to increasing on usual care

      3. Event rates lower on ferric citrate
      Randomized population imbalanced; high drop-out rate for biochemical end points due to dialysis transition; reported event end points were exploratory (not registered)
      Abbreviations: ALP, alkaline phosphatase; bALP, bone-specific alkaline phosphatase; CAC, coronary artery calcification;: CaCO3, calcium carbonate; cIMT, carotid intimal medial thickness; CKD, chronic kidney disease; CONSORT, Consolidated Standards of Reporting Trials; eGFR, estimated glomerular filtration rate; FGF-23, fibroblast growth factor 23; FMD, flow-mediated dilation; GI, gastrointestinal; Hb, hemoglobin; NAM, nicotinamide; P, phosphate; PTH, parathyroid hormone; PWV, pulse wave velocity; RCT, randomized controlled trial; VC, vascular calcification.
      The major challenge in phosphate-binder trials in CKD G3-G5 is that all were designed for surrogate outcomes and not patient-centered or clinical outcomes. Surrogate outcomes such as biochemical variables are attractive because they can be easily measured and quickly modified and are often less complex than the true patient-centered or clinical outcome that we hope to affect. In this way, surrogates can provide initial proof-of-concept evidence for a therapy as it progresses through clinical development. However, exclusive reliance on surrogate outcomes to guide patient care is ill advised. Historical examples abound of promising therapies with favorable effects on surrogates that did not translate to health benefits or even resulted in clinical harm.
      • Svensson S.
      • Menkes D.B.
      • Lexchin J.
      Surrogate outcomes in clinical trials: a cautionary tale.
      For the surrogate outcome to fully capture the effect of the treatment on the more important clinical outcome, the surrogate must both lie in the causal pathway and constitute the only pathway causally linking a treatment to an outcome.
      • DeMets D.L.
      • Psaty B.M.
      • Fleming T.R.
      When can intermediate outcomes be used as surrogate outcomes?.
      If surrogates are not causally related to the outcome or there are other favorable or unfavorable pathways between the treatment and the outcome, reliance on a surrogate will fail (Fig 1). Practically, trial data are needed to confirm that effects on surrogate outcomes translate directly to effects on patient-centered or clinical outcomes before they should be widely used to guide care.
      • Inker L.A.
      • Heerspink H.L.
      Evaluation of surrogate end points for progression to ESKD: necessary and challenging.
      These features have not been validated for surrogates used in phosphate-binder trials in CKD G3-G5, such as biochemical markers or vascular calcification. In our view, patient-centered and clinical outcome studies are needed before use of phosphate binders of any type can be recommended in patients with CKD G3-G5 except to control symptomatic or severe hyperphosphatemia.
      Figure thumbnail gr1
      Figure 1Schematic model demonstrates potentially violated assumptions of current surrogate outcomes in trials of phosphate binders. (A) The idealized surrogate outcome in which the intervention influences the patient-centered or clinical outcome exclusively through the surrogates. In this scenario, the intervention is correlated with the outcome but is also a cause of the patient-centered or clinical outcome. The intervention does not affect the outcome through any other pathways. (B) Several more likely scenarios in the conceptualization of phosphate binder trials. First, multiple confounding pathways (red arrows) likely exist between surrogate outcomes and patient-centered or clinical outcomes that may induce correlation without causation (ie, the green arrow may not exist). Additionally, alternative pathways between the intervention and patient-centered clinical outcome, both favorable (blue arrows) and unfavorable (purple arrows), may also exist such that the surrogate outcome cannot capture the full effect of the intervention on the patient-centered or clinical outcome. Other violations not depicted here are also possible, including a variety of pathways between the surrogate outcomes and patient-centered or clinical outcomes that could be a mix of favorable and unfavorable effects.

       CKD G5D

      Phosphate binding has favorable effects on many surrogate biochemical outcomes in CKD G5D. In recent trials of iron-based phosphate binders, binders decreased serum phosphate levels by 0.7 to 2.2 mg/dL compared with wash-out periods in which prior binder use was removed.
      • 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.
      ,
      • Lewis J.B.
      • Sika M.
      • Koury M.J.
      • et al.
      Ferric citrate controls phosphorus and delivers iron in patients on dialysis.
      These effect sizes are generally consistent with the overall serum phosphate–lowering effects observed for pooled binders in meta-analyses.
      • Ruospo M.
      • Palmer S.C.
      • Natale P.
      • et al.
      Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).
      In TARGET, serum phosphate levels were 1.2 mg/dL lower among participants treated more versus less intensively with binders, confirming that more aggressive use of binders can help control serum phosphate levels.
      • Wald R.
      • Rabbat C.G.
      • Girard L.
      • et al.
      Two phosphAte taRGets in End-stage renal disease Trial (TARGET): a randomized controlled trial.
      Along with effects on serum phosphate levels, binders may help normalize the phosphate-regulatory hormones PTH and FGF-23.
      • Lin H.H.
      • Liou H.H.
      • Wu M.S.
      • Lin C.Y.
      • Huang C.C.
      Long-term sevelamer treatment lowers serum fibroblast growth factor 23 accompanied with increasing serum Klotho levels in chronic haemodialysis patients.
      ,
      • Ketteler M.
      • Sprague S.M.
      • Covic A.C.
      • et al.
      Effects of sucroferric oxyhydroxide and sevelamer carbonate on chronic kidney disease–mineral bone disorder parameters in dialysis patients.
      In CKD G5D, no trials have been powered to evaluate effects on important patient-centered or clinical outcomes compared with placebo.
      • Lin H.H.
      • Liou H.H.
      • Wu M.S.
      • Lin C.Y.
      • Huang C.C.
      Long-term sevelamer treatment lowers serum fibroblast growth factor 23 accompanied with increasing serum Klotho levels in chronic haemodialysis patients.
      ,
      • Ketteler M.
      • Sprague S.M.
      • Covic A.C.
      • et al.
      Effects of sucroferric oxyhydroxide and sevelamer carbonate on chronic kidney disease–mineral bone disorder parameters in dialysis patients.
      Hyperphosphatemia may become severe in CKD G5D, resulting in symptoms and well-described clinical complications such as bone disease, calciphylaxis, and itching. For this reason, use of binders to prevent clinically important hyperphosphatemia is justified.
      In our view, intensive use of phosphate binders to specific targets aiming to prevent potential cardiovascular consequences requires evaluation in trials. Ongoing trials such as the Hi-Lo and PHOSPHATE Trials (ClinicalTrials.gov identifiers NCT03573089 and NCT04095039) will help fill this gap by evaluating more- and less-intensive phosphate targets on hard outcomes in prevalent dialysis patients. The Hi-Lo trial will compare phosphate targets of <5.5 to >6.5 mg/dL on a composite of mortality and all-cause hospitalization in prevalent hemodialysis patients. The PHOSPHATE Trial will compare targets of ≤4.65 mg/dL (≤1.5 mmol/L) versus 6.20 to 7.75 mg/dL (2.0-2.5 mmol/L) on a composite of cardiovascular events in prevalent patients with CKD G5D treated with hemodialysis or peritoneal dialysis.

      Classes of Phosphate-Binding Therapy

       Overview

      During the last 2 decades, expansion of new classes of phosphate binders and phosphate-lowering therapy has changed the landscape sufficiently that the calcium content of the binder may no longer be relevant as the defining feature (Table 2). Calcium-based binders in common use include calcium carbonate and calcium acetate. Non–calcium-based binders include sevelamer-based binders, lanthanum carbonate, sucroferric oxyhydroxide, and ferric citrate. Sevelamer-based binders are the original non–calcium-based phosphate binders with the longest experience and most clinical data in head-to-head trials.
      • Ruospo M.
      • Palmer S.C.
      • Natale P.
      • et al.
      Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).
      Sevelamer is a nonabsorbable polymer complexed with either hydrochloride (approved as Renagel [GelTex Pharmaceuticals] in 1998) or with carbonate (approved as Renvela [Genzyme Corporation] in 2007).
      Table 2Comparison of Clinical Features of Currently Available Phosphate Binders for Long-term Use in the United States
      BinderMechanism of ActionPotential AdvantagesPotential DisadvantagesFormsDose Considerations~P Binder Equivalence
      Reference is 1.0 for binding with 1g of calcium carbonate. Based on calculations by Daugirdas et al64 and updates reported in Gutekunst.69
      ,
      • Daugirdas J.T.
      • Finn W.F.
      • Emmett M.
      • Chertow G.M.
      Frequent Hemodialysis Network Trial Group. The phosphate binder equivalent dose.
      ,
      • Gutekunst L.
      An update on phosphate binders: a dietitian’s perspective.
      Calcium carbonateForms insoluble Ca and P complexesInexpensive; available over the counter; long-term experienceHypercalcemia; risk for VC; GI side effects; low-turnover bone diseaseChewable tablet; capsule; liquid; gum40% elemental Ca (200 mg/500-mg total dose)
      Total dose of elemental calcium from all sources not recommended to exceed ~2,000mg/d, with<1,500mg from oral phosphate binders in some guidelines.54
      0.75 for 750-mg tablet
      Calcium acetateForms insoluble Ca and P complexesInexpensive; readily available; long-term experience; less calcium absorption than calcium carbonateHypercalcemia; risk for VC; GI side effects; low-turnover bone diseaseTablet; capsule; liquid25% elemental Ca (~170 mg/667-mg capsule)
      Total dose of elemental calcium from all sources not recommended to exceed ~2,000mg/d, with<1,500mg from oral phosphate binders in some guidelines.54
      0.67 for 667-mg tablet
      Lanthanum carbonateForms insoluble metal and P complexesCalcium freeExpensive; unclear risk for metal accumulation; GI side effects; no long-term dataChewable tablet; powder500-1,000 mg 3×/d1.0 for 500-mg tablet
      Sevelamer hydrochlorideExchanges chloride for PCalcium free; pleiotropic effects; may reduce VCExpensive; GI side effects; metabolic acidosis; limit fat soluble vitamin absorptionTablet800-1,600 mg 3×/d (maximum dose: 13 g/d)0.6 for 800-mg tablet
      Sevelamer carbonateExchanges carbonate for PCalcium free; pleiotropic effects; no metabolic acidosis; may reduce VCExpensive; GI side effects; limit fat-soluble vitamin absorptionTablet; powder800-1,600 mg 3×/d (maximum dose: 14 g/d)0.6 for 800-mg tablet
      Sucroferric oxyhydroxideExchanges hydroxyl for PCalcium free; lower pill burdenExpensive; GI side effects; interferes with oral levothyroxine; long-term side effects unknown; unclear risk for iron accumulationChewable tablet2.5 g 3×/d (500 mg iron/2.5-g tablet; maximum dose: 6 tablets/d)1.6 for 2.5-g tablet
      Ferric citrateForms insoluble Fe3+ and P complexesCalcium free; raises iron stores and Hb; decreases iron and ESA useExpensive; GI side effects; long-term side effects unknown; unclear risk for iron accumulationTablet2 g 3×/d (210 mg ferric iron/1-g tablet; maximum dose: 12 tablets/d)0.64 for 1-g tablet
      Abbreviations: Ca, calcium; ESA, erythropoiesis-stimulation agent; Fe3+, ferric iron; GI, gastrointestinal; Hb, hemoglobin; P, phosphate; VC, vascular calcification.
      Adapted from Kendrick and Chonchol
      • Kendrick J.
      • Chonchol M.
      Novel therapeutic options for the treatment of mineral metabolism abnormalities in end stage renal disease.
      with the permission of the copyright holder, John Wiley and Sons.
      a Reference is 1.0 for binding with 1 g of calcium carbonate. Based on calculations by Daugirdas et al
      • Daugirdas J.T.
      • Finn W.F.
      • Emmett M.
      • Chertow G.M.
      Frequent Hemodialysis Network Trial Group. The phosphate binder equivalent dose.
      and updates reported in Gutekunst.
      • Gutekunst L.
      An update on phosphate binders: a dietitian’s perspective.
      b Total dose of elemental calcium from all sources not recommended to exceed ~2,000 mg/d, with <1,500 mg from oral phosphate binders in some guidelines.
      National Kidney Foundation
      K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.
      In addition to lowering serum phosphate levels, sevelamer-based binders also lower serum cholesterol levels and reduce levels of inflammatory markers.
      • Ruggiero B.
      • Trillini M.
      • Tartaglione L.
      • et al.
      Effects of sevelamer carbonate in patients with CKD and proteinuria: the ANSWER randomized trial.
      ,
      • Chue C.
      • Townend J.
      • Moody W.
      • et al.
      Cardiovascular effects of sevelamer in stage 3 CKD.
      Lanthanum carbonate is a minimally absorbed metal cation binder approved under the trade name Fosrenol (Shire Pharmaceuticals) in 2004. Efficacy for lanthanum carbonate appears similar to other binders.
      • Block G.A.
      • Wheeler D.C.
      • Persky M.S.
      • et al.
      Effects of phosphate binders in moderate CKD.
      Long-term outcome data support safety, without the nervous system or bone side effects previously observed with aluminum-based binders.
      • Hutchison A.
      • Whelton A.
      • Thadhani R.
      • et al.
      Long-term mortality and bone safety in patients with end-stage renal disease receiving lanthanum carbonate.
      Like other phosphate binders, the benefits of sevelamer-based or lanthanum carbonate versus placebo on clinical outcomes have never been tested in trials.
      Newer iron-based phosphate binders included ferric citrate coordination complex (ferric citrate), approved as Auryxia (Keryx Biopharmaceuticals) in 2014, and sucroferric oxyhydroxide, approved as Velphoro (Fresenius Medical Care) in 2013.
      • Ganz T.
      • Bino A.
      • Salusky I.B.
      Mechanism of action and clinical attributes of Auryxia® (ferric citrate).
      Ferric citrate has the potential advantage of also improving iron homeostasis in CKD,
      • Lewis J.B.
      • Sika M.
      • Koury M.J.
      • et al.
      Ferric citrate controls phosphorus and delivers iron in patients on dialysis.
      ,
      • Floege J.
      • Covic A.C.
      • Ketteler M.
      • et al.
      Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients.
      reducing use of intravenous iron and erythropoiesis-stimulating agents and thereby resulting in net cost savings.
      • Brunelli S.M.
      • Sibbel S.P.
      • Van Wyck D.
      • Sharma A.
      • Hsieh A.
      • Chertow G.M.
      Net budgetary impact of ferric citrate as a first-line phosphate binder for the treatment of hyperphosphatemia: a Markov microsimulation model.
      ,
      • Rodby R.A.
      • Umanath K.
      • Niecestro R.
      • et al.
      Ferric citrate, an iron-based phosphate binder, reduces health care costs in patients on dialysis based on randomized clinical trial data.
      In addition to its effects on serum phosphate levels, ferric citrate may lower FGF-23 levels by correction of iron deficiency, which is an additional stimulus for transcription of the gene encoding FGF-23.
      • Van Buren P.N.
      • Lewis J.B.
      • Dwyer J.P.
      • et al.
      The phosphate binder ferric citrate and mineral metabolism and inflammatory markers in maintenance dialysis patients: results from prespecified analyses of a randomized clinical trial.
      ,
      • Block G.A.
      • Pergola P.E.
      • Fishbane S.
      • et al.
      Effect of ferric citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis-dependent chronic kidney disease: path analyses.

       Rationale for Class Selection

      The accumulation of calcium in patients with CKD and kidney failure has limited enthusiasm for high doses of calcium-based phosphate binders. These concerns arise justifiably from observed vascular calcification present even in young otherwise healthy patients with advanced CKD,
      • Goodman W.G.
      • Goldin J.
      • Kuizon B.D.
      • et al.
      Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.
      and findings from small short-term balance studies in patients with CKD G3-G5 suggesting net positive balance with calcium supplementation.
      • Hill K.M.
      • Martin B.R.
      • Wastney M.E.
      • et al.
      Oral calcium carbonate affects calcium but not phosphorus balance in stage 3-4 chronic kidney disease.
      ,
      • Spiegel D.M.
      • Brady K.
      Calcium balance in normal individuals and in patients with chronic kidney disease on low- and high-calcium diets.
      However, studies of binders more generally, including multiple classes of calcium- and non–calcium-based binders in patients with CKD G3-G5, have also raised concern about promoting vascular calcification.
      • Block G.A.
      • Wheeler D.C.
      • Persky M.S.
      • et al.
      Effects of phosphate binders in moderate CKD.
      Further, mechanisms other than calcium balance are likely to contribute to these effects.
      • Jono S.
      • Shioi A.
      • Ikari Y.
      • Nishizawa Y.
      Vascular calcification in chronic kidney disease.
      Hypercalcemia is common in patients receiving dialysis and is associated with increased risk for nonfatal cardiovascular events and mortality.
      • Floege J.
      • Kim J.
      • Ireland E.
      • et al.
      Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population.
      • Fukagawa M.
      • Kido R.
      • Komaba H.
      • et al.
      Abnormal mineral metabolism and mortality in hemodialysis patients with secondary hyperparathyroidism: evidence from marginal structural models used to adjust for time-dependent confounding.
      • Coen G.
      • Pierantozzi A.
      • Spizzichino D.
      • et al.
      Risk factors of one year increment of coronary calcifications and survival in hemodialysis patients.
      • Gallieni M.
      • Caputo F.
      • Filippini A.
      • et al.
      Prevalence and progression of cardiovascular calcifications in peritoneal dialysis patients: a prospective study.
      Although it is likely that use of non–calcium-based binders yields lower serum calcium levels and less hypercalcemia than calcium-based agents,
      • Van Buren P.N.
      • Lewis J.B.
      • Dwyer J.P.
      • et al.
      The phosphate binder ferric citrate and mineral metabolism and inflammatory markers in maintenance dialysis patients: results from prespecified analyses of a randomized clinical trial.
      other interventions in CKD G5D, such as changes in dialysate calcium concentration, use of calcimimetics, and other co-interventions, may also affect calcium balance and levels. Low dialysate calcium concentrations have recently been associated with increased risk for arrhythmia and sudden cardiac death; thus, the optimal balance of exogenous calcium in binders and reduction due to calcium baths or calcimimetics is unknown.
      • Pun P.H.
      • Horton J.R.
      • Middleton J.P.
      Dialysate calcium concentration and the risk of sudden cardiac arrest in hemodialysis patients.
      ,
      • Brunelli S.M.
      • Sibbel S.
      • Do T.P.
      • Cooper K.
      • Bradbury B.D.
      Facility dialysate calcium practices and clinical outcomes among patients receiving hemodialysis: a retrospective observational study.
      Current guidelines do not expressly address considerations about the use of calcium-based binders when combined with these other aspects of CKD mineral and bone disorder (CKD-MBD) care in CKD G5D because limited data are available and balance in CKD G5D has not been rigorously evaluated.
      In addition to the desire to restrict calcium, different classes of non–calcium-based binders may have other effects that could be beneficial and provide a specific rationale for their use. Low-density lipoprotein cholesterol–lowering and anti-inflammatory effects are well demonstrated for sevelamer-based products.
      • Ruggiero B.
      • Trillini M.
      • Tartaglione L.
      • et al.
      Effects of sevelamer carbonate in patients with CKD and proteinuria: the ANSWER randomized trial.
      ,
      • Van Buren P.N.
      • Lewis J.B.
      • Dwyer J.P.
      • et al.
      The phosphate binder ferric citrate and mineral metabolism and inflammatory markers in maintenance dialysis patients: results from prespecified analyses of a randomized clinical trial.
      Ferric citrate may also treat anemia.
      • Block G.A.
      • Block M.S.
      • Smits G.
      • et al.
      A pilot randomized trial of ferric citrate coordination complex for the treatment of advanced CKD.
      Sucroferric oxyhydroxide may provide a lower pill burden.
      • 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.
      Table 2 compares major clinical features of the different phosphate-binding drugs that are available.
      Other important factors in phosphate-binder selection are the cost of the medication and associated side effects. Without clear advantages in clinical outcomes, the higher costs of non–calcium-based binders may not be outweighed by reduced health care costs.
      • St Peter W.L.
      • Fan Q.
      • Weinhandl E.
      • Liu J.
      Economic evaluation of sevelamer versus calcium-based phosphate binders in hemodialysis patients: a secondary analysis using Centers for Medicare & Medicaid Services data.
      • Dasgupta I.
      • Shroff R.
      • Bennett-Jones D.
      • McVeigh G.
      NICE Hyperphosphataemia Guideline Development Group
      Management of hyperphosphataemia in chronic kidney disease: summary of National Institute for Health and Clinical Excellence (NICE) guideline.
      • Dasgupta I.
      • Shroff R.
      Phosphate binders and mortality: there is a need for more evidence.
      Additionally, a recent Cochrane review noted, with varying levels of certainty, that sevelamer, lanthanum, and iron-based binders may cause gastrointestinal side effects, including constipation, vomiting, and diarrhea.
      • Ruospo M.
      • Palmer S.C.
      • Natale P.
      • et al.
      Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).
      Finally, providers sometimes combine different phosphate binders to use lower doses that limit side effects while maximizing phosphate binding. It should be noted that there is little research available about combination use and most trials have primarily examined the use of 1 phosphate binder at a time.

       Evidence for Class Selection

      In CKD G3-G5, some trials have exclusively used non–calcium-based binders, whereas others have included calcium- and non–calcium-based classes.
      • Block G.A.
      • Wheeler D.C.
      • Persky M.S.
      • et al.
      Effects of phosphate binders in moderate CKD.
      ,
      • Ix J.H.
      • Isakova T.
      • Larive B.
      • et al.
      Effects of nicotinamide and lanthanum carbonate on serum phosphate and fibroblast growth factor-23 in CKD: the COMBINE Trial.
      No studies have been powered for clinical outcomes versus placebo or for the comparative effectiveness of different classes on clinical outcomes. Theoretically, non–calcium-based binders may more effectively control the increasing FGF-23 levels in CKD G3-G5D because of the effects of exogenous calcium itself in stimulating FGF-23.
      • Scialla J.J.
      Evidence basis for integrated management of mineral metabolism in patients with end-stage renal disease.
      The clinical benefits of FGF-23 control in CKD G3-G5D have not been clearly demonstrated at this time.
      In CKD G5D, studies of calcium- versus non–calcium-based binders were relatively frequent, particularly when sevelamer was undergoing initial marketing. Multiple systematic reviews and meta-analyses of these trials have been reported. In each review, risk of bias was moderate to high. Reasons for potential bias include many open-label studies, selective outcome reporting, incomplete outcome data, high rates of attrition, frequent sponsorship by industry, and very small study size, which itself can induce bias.
      • Ruospo M.
      • Palmer S.C.
      • Natale P.
      • et al.
      Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).
      ,
      • Habbous S.
      • Przech S.
      • Acedillo R.
      • Sarma S.
      • Garg A.X.
      • Martin J.
      The efficacy and safety of sevelamer and lanthanum versus calcium-containing and iron-based binders in treating hyperphosphatemia in patients with chronic kidney disease: a systematic review and meta-analysis.
      • Patel L.
      • Bernard L.M.
      • Elder G.J.
      Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: a meta-analysis of randomized controlled trials.
      • Palmer S.C.
      • Gardner S.
      • Tonelli M.
      • et al.
      Phosphate-binding agents in adults with CKD: a network meta-analysis of randomized trials.
      Most of the included studies were not designed for clinical events as a primary outcome. One large study, the DCOR Trial, was powered for mortality but had severely limited retention during follow-up.
      • Suki W.N.
      • Zabaneh R.
      • Cangiano J.L.
      • et al.
      Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.
      Based on these limitations, reviews have reached different conclusions about the current evidence, including support,
      • Patel L.
      • Bernard L.M.
      • Elder G.J.
      Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: a meta-analysis of randomized controlled trials.
      ,
      • Jamal S.A.
      • Vandermeer B.
      • Raggi P.
      • et al.
      Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis.
      lack of support,
      • Habbous S.
      • Przech S.
      • Acedillo R.
      • Sarma S.
      • Garg A.X.
      • Martin J.
      The efficacy and safety of sevelamer and lanthanum versus calcium-containing and iron-based binders in treating hyperphosphatemia in patients with chronic kidney disease: a systematic review and meta-analysis.
      and uncertainty for the superiority of sevelamer over calcium-based binders.
      • Ruospo M.
      • Palmer S.C.
      • Natale P.
      • et al.
      Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).
      ,
      • Palmer S.C.
      • Gardner S.
      • Tonelli M.
      • et al.
      Phosphate-binding agents in adults with CKD: a network meta-analysis of randomized trials.
      The largest and most comprehensive Cochrane review reported a point estimate consistent with superiority of sevelamer versus calcium-based binders on mortality, but grade this finding as “low certainty” due to methodologic limitations and heterogeneity.
      • Ruospo M.
      • Palmer S.C.
      • Natale P.
      • et al.
      Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).
      Sensitivity analyses focusing on high-quality studies provided stronger evidence, but were limited to only 6 studies.
      • Ruospo M.
      • Palmer S.C.
      • Natale P.
      • et al.
      Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).
      Other binder classes could not be compared with calcium-based binders due to few studies. The LANDMARK Study comparing lanthanum carbonate to calcium carbonate on risk for cardiovascular events among 2,309 enrolled hemodialysis participants may shed light on this controversy (ClinicalTrials.gov identifier NCT01578200).
      • Ogata H.
      • Fukagawa M.
      • Hirakata H.
      • et al.
      Design and baseline characteristics of the LANDMARK study.
      High degrees of heterogeneity in the mortality effects of calcium- versus non–calcium-based binders has been noted in all systematic reviews of the topic.
      • Patel L.
      • Bernard L.M.
      • Elder G.J.
      Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: a meta-analysis of randomized controlled trials.
      For instance, although some studies such as the DCOR Study estimated a hazard ratio (HR) of 0.93 (95% confidence interval [CI], 0.79-1.10),
      • Suki W.N.
      • Zabaneh R.
      • Cangiano J.L.
      • et al.
      Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.
      other studies, such as the INDEPENDENT-HD trial, estimate an HR of 0.23 (95% CI, 0.15-0.35).
      • Di Iorio B.
      • Molony D.
      • Bell C.
      • et al.
      Sevelamer versus calcium carbonate in incident hemodialysis patients: results of an open-label 24-month randomized clinical trial.
      These vastly different effects suggest potential differences in study conduct or meaningfully different populations or could indicate publication bias, which was difficult to ascertain in many reviews due to the low number of studies.
      • Ruospo M.
      • Palmer S.C.
      • Natale P.
      • et al.
      Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).
      In this vacuum of randomized data, observational comparative effectiveness studies can be useful. A recent study by Spoendlin et al
      • Spoendlin J.
      • Paik J.M.
      • Tsacogianis T.
      • Kim S.C.
      • Schneeweiss S.
      • Desai R.J.
      Cardiovascular outcomes of calcium-free vs calcium-based phosphate binders in patients 65 years or older with end-stage renal disease requiring hemodialysis.
      evaluated the comparative effectiveness of sevelamer versus calcium acetate among adults 65 years and older initiating in-center hemodialysis in the United States. Patients within 180 days of their initial dialysis date who were new users of sevelamer or calcium acetate were analyzed using propensity scoring to balance clinical differences across the groups. In this balanced population, the HR for both cardiovascular events and all-cause mortality was 0.96 and was not significant. However, the population in this study was small and the confidence limits include up to 20% difference in risk between groups, an estimate consistent with prior meta-analyses. Summarizing these considerations, the evidence base is currently not strong enough to favor one class of binders over another for all patients with kidney failure.

      Guideline Recommendations Related to Calcium Intake From Phosphate Binders

      Clinical practice guidelines in CKD have historically recommended restriction of calcium from phosphate binders. The first clinical practice guideline for the evaluation and management of bone and mineral disease in CKD, from what was then called K/DOQI, recommended in 2003 that elemental calcium from phosphate binders not exceed 1,500 mg/d (approximately 8-9 tablets daily).
      National Kidney Foundation
      K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.
      The next guideline, published by KDIGO (Kidney Disease: Improving Global Outcomes) in 2009, recommended limits to elemental calcium exposure in the setting of hypercalcemia, arterial calcification, adynamic bone disease, or suppressed PTH without exact dose limits.
      Kidney Disease: Improving Global Outcomes (KDIGO) Chronic Kidney Disease Mineral and Bone Disorder Working Group
      KDIGO clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD).
      KDIGO guideline recommendations for CKD-MBD were updated in 2017 to incorporate new data.
      Kidney Disease: Improving Global Outcomes (KDIGO) Chronic Kidney Disease Mineral and Bone Disorder Working Group
      KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD).
      The updated guidance states that “restricting the dose of calcium-based phosphate binders” in patients with CKD G3a-5D is suggested. The KDOQI commentaries on both these KDIGO guidelines considered this recommendation “discretionary” in the US environment, highlighting substantial evidence gaps underlying the recommendations.
      • Uhlig K.
      • Berns J.S.
      • Kestenbaum B.
      • et al.
      KDOQI US commentary on the 2009 KDIGO clinical practice guideline for the diagnosis, evaluation, and treatment of CKD-mineral and bone disorder (CKD-MBD).
      ,
      • Isakova T.
      • Nickolas T.L.
      • Denburg M.
      • et al.
      KDOQI US Commentary on the 2017 KDIGO clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).
      The newly published KDOQI guideline on nutrition in CKD suggests that total elemental calcium intake, including dietary calcium, calcium supplementation, and calcium-based phosphate binders, be kept in the range of 800 to 1,000 mg/d for patients with CKD G3-G4 to maintain a neutral calcium balance. They also suggest adjustment of calcium intake to avoid hypercalcemia in CKD G5D. The evidence for these suggestions is rated 2B (CKD G3-G4) and OPINION (CKD 5GD).
      • Ikizler T.A.
      • Burrowes J.D.
      • Byham-Gray L.D.
      • et al.
      KDOQI Nutrition in CKD Guideline Work Group
      KDOQI clinical practice guideline for nutrition in CKD: 2020 update.

      Beyond Binders in Phosphate Management

      In addition to classic phosphate binders, other CKD-MBD therapies affect phosphate management. Medical nutrition therapy, which provides phosphate-focused education and counseling to patients with CKD G5D, may also improve serum phosphate levels, although the effects may be modest and the evidence is short term.
      • Ikizler T.A.
      • Burrowes J.D.
      • Byham-Gray L.D.
      • et al.
      KDOQI Nutrition in CKD Guideline Work Group
      KDOQI clinical practice guideline for nutrition in CKD: 2020 update.
      For patients with CKD G3-G5, medical nutrition therapy can improve adherence to dietary restrictions, including phosphate.
      • Ikizler T.A.
      • Burrowes J.D.
      • Byham-Gray L.D.
      • et al.
      KDOQI Nutrition in CKD Guideline Work Group
      KDOQI clinical practice guideline for nutrition in CKD: 2020 update.
      ,
      • de Waal D.
      • Heaslip E.
      • Callas P.
      Medical nutrition therapy for chronic kidney disease improves biomarkers and slows time to dialysis.
      Pharmacologically, selection of calcimimetics over active vitamin D for the treatment and control of secondary hyperparathyroidism affects phosphate control, with active vitamin D exacerbating and calcimimetics mitigating hyperphosphatemia.
      • Scialla J.J.
      Evidence basis for integrated management of mineral metabolism in patients with end-stage renal disease.
      Adjustment of dialysis duration and frequency can also be alternative methods to control phosphate levels in CKD G5D.
      • Copland M.
      • Komenda P.
      • Weinhandl E.D.
      • McCullough P.A.
      • Morfin J.A.
      Intensive hemodialysis, mineral and bone disorder, and phosphate binder use.
      Tenapanor, an experimental luminal blocker of sodium hydrogen exchange, was recently found to lower paracellular phosphate transport in the gut as an indirect effect. In short-term studies sponsored by the manufacturer, tenapanor shows reduction in serum phosphate levels over 8 weeks in patients receiving hemodialysis of ~1 mg/dL
      • Block G.A.
      • Rosenbaum D.P.
      • Leonsson-Zachrisson M.
      • et al.
      Effect of tenapanor on serum phosphate in patients receiving hemodialysis.
      ,
      • 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.
      and modest reductions in FGF-23 levels (by 10%-30%).
      • Block G.A.
      • Rosenbaum D.P.
      • Leonsson-Zachrisson M.
      • et al.
      Effect of tenapanor on serum phosphate in patients receiving hemodialysis.
      • 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.
      • Block G.A.
      • Rosenbaum D.P.
      • Yan A.
      • Greasley P.J.
      • Chertow G.M.
      • Wolf M.
      The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia.
      At the time of writing, only short-term studies are available and tenapanor remains experimental and in phase 3 studies. With the limited binding efficacy of many phosphate binders, particularly if taken incorrectly,
      • Daugirdas J.T.
      • Finn W.F.
      • Emmett M.
      • Chertow G.M.
      Frequent Hemodialysis Network Trial Group. The phosphate binder equivalent dose.
      these treatments may be important adjuvants for phosphate control in the future.

      Conclusions and Need for Further Evidence

      Calcium- versus non–calcium-based binders is now an old yet unsettled question in nephrology. With the ubiquity of phosphate-binding classes and agents, pooling binders according to calcium status may no longer be appropriate, and prior head-to-head studies of sevelamer versus calcium acetate, for instance, may not suffice in modern practice. In addition, the quality of data available to determine this question is poor, characterized by numerous biases highlighted throughout this perspective (Table 3). In our view, data are currently inadequate to justify regular use of phosphate binders in patients with CKD G3-G5, intensive use of binders to specific phosphate targets in CKD G5D, or preference for one class of binders over another. With the evolving landscape of CKD-MBD drugs, including new phosphate binders, increased use of calcimimetics, decreased use of vitamin D, and changes in dialysate composition, prior studies may not adequately inform the treatment of patients with kidney disease in the modern practice environment. New trials designed to test intensive versus less-intensive phosphate targets and compare binder classes in the current treatment environment should provide better answers to guide our field and provide more definitive recommendations in kidney failure.
      Table 3Major Biases in Existing Clinical Studies of Phosphate Binders and Proposed Remedy
      Proposed BiasDescriptionProposed Remedy
      Small sample sizeIn addition to inadequate power, small randomized samples are more likely to have poor balance by randomization leading to bias; meta-analysis does not improve this bias
      • Multicenter study networks for important clinical questions
      • Adequate power in individual studies
      Selective outcome reportingNot all trials clearly prespecified outcomes or used standard core outcomes that are easily compared across studies
      • Trial registration
      • Use of standard core outcomes
      Use of unvalidated surrogate outcomesCalcium balance, vascular calcification, and biochemical markers of mineral metabolism are not validated surrogates for cardiovascular disease
      • Use of patient-centered clinical outcomes
      • Establishment of validated surrogates for cardiovascular disease in CKD
      • Acceptance of unvalidated surrogates as hypothesis-generating and not actionable by nephrology community
      Lack of placebo controlComparative effectiveness studies outpace efficacy studies in the field
      • Embrace of equipoise and need for clinical studies when indicated
      Publication biasSmall studies with significant results are published whereas those with no effects may be hard to publish
      • Trial registration with mandated outcome reporting

      Article Information

      Authors’ Full Names and Academic Degrees

      Julia J. Scialla, MD, MHS, Jessica Kendrick, MD, MPH, Jaime Uribarri, MD, Csaba P. Kovesdy, MD, Orlando M. Gutiérrez, MD, MMSc, Elizabeth Yakes Jimenez, PhD, RDN, LD, and Holly J. Kramer, MD, MPH.

      Support

      This perspective was produced without any direct financial support. Individual authors were supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases ( R01DK111952 to Dr Scialla) and the National Heart, Lung, and Blood Institute ( R01HL132868 to Dr Kendrick).

      Financial Disclosure

      Dr Scialla has received consulting fees from Tricida and modest research support for clinical event activities related to trials sponsored by Eli Lilly & Co, Sanofi, and GlaxoSmithKline. Dr Kramer is Vice Chair for KDOQI Commentaries and President of the National Kidney Foundation. Dr Kovesdy received consulting fees from Amgen, Astra Zeneca, Bayer, Cara Therapeutics, Reata, Takeda, and Tricida. Dr Kendrick has received consulting fees and research support from Fresenius Renal Therapies. Dr Gutiérrez has received consulting fees and grant funding from Amgen and Akebia Biopharmaceuticals; grant funding from GlaxoSmithKline; and consulting fees from QED Therapeutics. Dr Jimenez is on the Scientific Advisory Board for the National Kidney Foundation and has a contract with the Academy of Nutrition and Dietetics that involves overseeing a study funded by the Renal Dietitians Dietetic Practice Group and Relypsa via the Academy of Nutrition and Dietetics Foundation. The remaining authors declare that they have no relevant financial interests.

      Peer Review

      Received November 22, 2019, in response to an invitation from the journal. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor, who served as Acting Editor-in-Chief. Accepted in revised form May 16, 2020. The involvement of an Acting Editor-in-Chief was to comply with AJKD’s procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.

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