Original Investigation

Phosphate Binder Use and Mortality Among HemodialysisPatients in the Dialysis Outcomes and Practice PatternsStudy (DOPPS): Evaluation of Possible Confounding by

Nutritional StatusAntonio Alberto Lopes, MD, MPH, PhD,1 Lin Tong, MS,2 Jyothi Thumma, MS,2

Yun Li, PhD,3 Douglas S. Fuller, MS,2 Hal Morgenstern, PhD,4,5 Jürgen Bommer, MD,6

Peter G. Kerr, PhD, MB,7 Francesca Tentori, MD,2 Takashi Akiba, MD,8

Brenda W. Gillespie, PhD,3 Bruce M. Robinson, MD, MS,2 Friedrich K. Port, MD, MS,2

and Ronald L. Pisoni, PhD, MS2

Background: Poor nutritional status and both hyper- and hypophosphatemia are associated with increasedmortality in maintenance hemodialysis (HD) patients. We assessed associations of phosphate binder prescrip-tion with survival and indicators of nutritional status in maintenance HD patients.

Study Design: Prospective cohort study (DOPPS [Dialysis Outcomes and Practice Patterns Study]),1996-2008.

Setting & Participants: 23,898 maintenance HD patients at 923 facilities in 12 countries.Predictors: Patient-level phosphate binder prescription and case-mix–adjusted facility percentage of

phosphate binder prescription using an instrumental-variable analysis.Outcome: All-cause mortality.Results: Overall, 88% of patients were prescribed phosphate binders. Distributions of age, comorbid

conditions, and other characteristics showed small differences between facilities with higher and lowerpercentages of phosphate binder prescription. Patient-level phosphate binder prescription was associatedstrongly at baseline with indicators of better nutrition, ie, higher values for serum creatinine, albumin,normalized protein catabolic rate, and body mass index and absence of cachectic appearance. Overall,patients prescribed phosphate binders had 25% lower mortality (HR, 0.75; 95% CI, 0.68-0.83) when adjustedfor serum phosphorus level and other covariates; further adjustment for nutritional indicators attenuated thisassociation (HR, 0.88; 95% CI, 0.80-0.97). However, this inverse association was observed for only patientswith serum phosphorus levels �3.5 mg/dL. In the instrumental-variable analysis, case-mix–adjusted facilitypercentage of phosphate binder prescription (range, 23%-100%) was associated positively with betternutritional status and inversely with mortality (HR for 10% more phosphate binders, 0.93; 95% CI, 0.89-0.96).Further adjustment for nutritional indicators reduced this association to an HR of 0.95 (95% CI, 0.92-0.99).

Limitations: Results were based on phosphate binder prescription; phosphate binder and nutritional data werecross-sectional; dietary restriction was not assessed; observational design limits causal inference due to possible residualconfounding.

Conclusions: Longer survival and better nutritional status were observed for maintenance HD patients prescribedphosphate binders and in facilities with a greater percentage of phosphate binder prescription. Understanding themechanisms for explaining this effect and ruling out possible residual confounding require additional research.Am J Kidney Dis. 60(1):90-101. © 2012 by the National Kidney Foundation, Inc.

INDEX WORDS: DOPPS; hemodialysis; instrumental variable; mortality; nutrition; phosphate binder; serumphosphorus; survival.

Editorial, p. 3

Poor nutritional status and both hyper- and hy-pophosphatemia have been associated with in-

creased mortality in maintenance hemodialysis (HD)

From the 1Faculdade de Medicina da Bahia, UniversidadeFederal da Bahia, Salvador, BA, Brazil; 2Arbor Research Collab-orative for Health; 3Department of Biostatistics, University ofMichigan; Departments of 4Epidemiology and 5EnvironmentalHealth Sciences, University of Michigan School of Public Health,Ann Arbor, MI; 6University of Heidelberg, Heidelberg, Germany;7Monash Medical Centre and Monash University, Victoria, Austra-

lia; and 8Tokyo Women’s Medical University, Tokyo, Japan.

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patients.1-5 To control hyperphosphatemia in thesepatients, both a low-phosphorus diet and phosphatebinders are used.6 The survival benefit of dietaryrestriction of phosphorus intake compared with phos-phate binders to control hyperphosphatemia in main-tenance HD patients is uncertain. One potential limita-

Received June 10, 2011. Accepted in revised form December 19,2011. Originally published online March 5, 2012.

Address correspondence to Ronald L. Pisoni, PhD, MS, 340 EHuron St, Ste 300, Ann Arbor, MI 48104. E-mail: ronald.pisoni@arborresearch.org

© 2012 by the National Kidney Foundation, Inc.0272-6386/$36.00

doi:10.1053/j.ajkd.2011.12.025

Am J Kidney Dis. 2012;60(1):90-101

Phosphate Binder Use and Mortality in the DOPPS

tion of dietary phosphorus restriction is that it can beassociated with reduced protein intake, which maycontribute to poor nutrition and increased mortalityrisk.7,8 Controlling serum phosphorus levels with phos-phate binders for dialysis patients has the potentialadvantage of permitting a diet with less protein restric-tion, which may contribute to improved nutritionalstatus and survival.

An observational study by Isakova et al9 foundlonger survival for HD patients prescribed versus notprescribed phosphate binders, even in subgroups withphosphorus concentrations within the range recom-mended by both the European Best Practice Guide-lines10 and KDOQI (Kidney Disease Outcomes Qual-ity Initiative).6 Results of the Isakova et al studysuggest that phosphate binders are associated withimproved survival of maintenance HD patients inde-pendent of their effects on serum phosphorus concen-tration. One plausible explanation between associa-tions of phosphate binder use and survival is thatpatients who eat more are more likely to maintainbetter nutritional status and more likely to be pre-scribed a phosphate binder because of a higher ten-dency toward hyperphosphatemia.

Using a representative sample of HD patients from12 countries enrolled in the Dialysis Outcomes andPractice Patterns Study (DOPPS), the present studywas developed to extend prior work on the associationbetween phosphate binders and survival in HD pa-tients.9,11 Our study assessed the association of phos-phate binder prescription with mortality and indica-tors of nutritional status in maintenance HD patientsfrom the perspectives of patient-level phosphate binderprescription and facility-level percentage of phos-phate binder prescription. This latter facility practice–based perspective was examined using an instrumental-variable methodology intended to reduce effects ofunmeasured patient-level confounders. We also ex-plored whether indicators of nutritional status couldexplain the inverse association between phosphatebinder prescription and mortality in maintenance HDpatients.

METHODS

Data Source

Data were from phases I-III of the DOPPS, an internationalprospective cohort study in 12 countries.12,13 The DOPPS is basedon nationally representative samples of randomly selected dialysisfacilities and patients. Within each participating facility, 20-40patients were randomly selected, depending on facility size. Insti-tutional review boards in each country approved the study, andinformed patient consent was obtained in accordance with localrequirements.

The main analyses were based on 23,898 adult patients withend-stage renal disease on HD therapy for at least 90 days atDOPPS entry: DOPPS I (1996-2001; n � 7,292 patients in 303

facilities from France, Germany, Italy, Japan, Spain, the United

Am J Kidney Dis. 2012;60(1):90-101

Kingdom, and the United States), DOPPS II (2002-2004; n �8,512 patients in 320 facilities from the countries in DOPPS I plusAustralia, Belgium, Canada, New Zealand, and Sweden), andDOPPS III (2005-2008; n � 8,094 patients in 300 facilities fromthe 12 countries in DOPPS II). In addition, a sensitivity mortalityanalysis was performed that included incident patients (n � 6,181)who initiated maintenance HD therapy within 30 days of studyentry.

Outcomes andPredictors

All-cause mortality was the primary outcome. Time at risk wasanalyzed from study entry until the earliest of end-of-study follow-up, kidney transplant, or 7 days after the transfer to another dialysismodality or transfer to another dialysis facility. For the analysis ofpatient-level phosphate binder prescription, the primary predictorvariable was phosphate binder prescription status (yes or no) at thestart of follow-up. For analysis by facility phosphate binder pre-scription, the primary predictor variable was the case-mix–adjusted percentage of maintenance HD patients prescribed phos-phate binders at the start of follow-up in a prevalent cross-sectionof patients in each facility. Indicators of nutritional status (serumcreatinine, serum albumin, normalized protein catabolic rate[nPCR], body mass index [BMI], and cachectic [ie, undernour-ished or malnourished] appearance) and other covariates were themost recent data reported for the patient on or before the patient’sdate of study entry.

Statistical Analysis

Baseline patient characteristics (eg, mean, median, or percent-age) were calculated by patient-level phosphate binder prescrip-tion. Logistic regression was used to calculate the odds of phos-phate binder prescription by patient characteristic with eitherminimal or extensive adjustments and applied generalized estimat-ing equations to account for clustering at the facility level, assum-ing a compound symmetry covariance structure.14 Logistic modelsfor the minimally adjusted odds ratios (ORs) included geographicregion, study phase, and age and accounted for facility clusteringeffects. Logistic models for the extensively adjusted ORs includedgeographic region, study phase, age, race, male, residual kidneyfunction (yes/no), years with end-stage renal disease, and 13summary comorbid conditions (coronary heart disease, cancer,other cardiovascular disease, cerebrovascular disease, congestiveheart disease, diabetes mellitus, gastrointestinal bleeding, hyperten-sion, lung disease, neurological disorders, psychological disorders,peripheral vascular disease, and recurrent cellulitis/gangrene), andaccounted for facility clustering effects. The relationship of patient-level phosphate binder prescription with mortality was analyzedusing Cox proportional hazards regression. To possibly reduce theimpact of unmeasured patient-level confounders in mortality anal-yses, an instrumental-variable approach was applied using thedialysis facility as the instrument. Two different instrumental-variable methods, without and with adjustments for nutritionalindicators, were used, and results were compared for consistency.The first method was based on a generalization of the linear 2-stageinstrumental-variable model to accommodate a nonlinear second-stage model. In the first stage, linear regression was used withphosphate binder prescription (yes/no) as the outcome, as a linearapproximation to logistic regression, and with predictors includingDOPPS facility indicator in addition to the following covariates:age, sex, black race, years on dialysis therapy, coronary arterydisease, congestive heart failure, hypertension, diabetes, peripheralartery disease, recurrent cellulitis/gangrene, neurologic disease,lung disease, gastrointestinal bleeding in the prior 12 months,cancer, catheter use for vascular access, and baseline serum phos-

phorus level. This first-stage linear regression yields the case-mix–

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Lopes et al

adjusted facility percentage of phosphate binder prescription as afixed effect for each dialysis unit included in the analysis. In thisfirst-stage model using facilities as the instruments, a partial Fstatistic of 4.21 was observed, suggesting a weak instrument.However, even when instruments are weak, the potential bias forthe treatment-effect estimate from a 2-stage least squares methodusually is smaller than that obtained using conventional patient-level regression methods.15 In the second stage, Cox regressionwithout and with adjustments for nutritional indicators was used toestimate the hazard ratio (HR) of patient-level mortality associatedwith the predicted case-mix–adjusted facility percentage of phos-phate binder prescription obtained from the first stage. All Coxmodels were stratified by region and study phase and used thesandwich estimator to account for facility clustering effects.16

The second instrumental-variable method was based on limitedinformation maximum likelihood (LIML) regression. LIML isconsidered more robust than the 2-stage least squares instrumental-variable method when instruments are weak17; in other words,when the first-stage partial F statistic for the instrument(s) is lessthan 10.18 LIML uses linear models for both the first and secondstage. We used 1-year mortality as the second-stage outcome,modeled as a dichotomous variable using linear regression as anapproximation to logistic regression. This analysis assumes thatvital status is known for all patients at the end of the 1-yearfollow-up period. Facilities that dropped out of the study within thefirst 6 months were excluded, but patients who dropped out withinthe first year (�10%) were assumed to be survivors. This conven-tion may lead to underestimation of death probabilities; the alterna-tive of deleting these patients would lead to overestimation ofdeath probabilities. Covariates from the first instrumental-variablemethod described were included.

The proportional hazards assumption in Cox regression wasconfirmed graphically and by testing an interaction term betweeneach covariate and log-transformed follow-up time. Missing datawere imputed using IVEware (www.isr.umich.edu/src/smp/ive),based on the sequential regression imputation method.19 Descrip-tive tables were based on a single imputation, whereas analyticalresults were based on combining results from 5 imputed data setsusing Rubin’s formula.19 Analyses were performed using SASsoftware, version 9.2 (SAS Institute, www.sas.com). STROBE(Strengthening the Reporting of Observational Studies in Epidemi-ology) guidelines were followed for reporting observational stud-ies for a cohort study.20

RESULTS

Patient Characteristics byPhosphateBinder Prescription

Patient characteristics by phosphate binder prescrip-tion and ORs for phosphate binder prescription bypatient characteristic are listed in Table 1 for the23,898 maintenance HD patients receiving HD for atleast 90 days at study entry. Patients prescribed phos-phate binders represented 88.1% of the sample. Pa-tients prescribed a phosphate binder had a lowerprevalence of several comorbid conditions and a pro-file consistent with better nutritional status for each ofthe 5 nutritional measures: lower frequency of ca-chexia and higher mean serum albumin, serum creati-nine, BMI, and nPCR values. These patterns wereobserved within each of the 3 study regions of NorthAmerica, Japan, and Europe/Australia/New Zealand

(Table S1, available as online supplementary mate-

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rial). After extensive adjustments, some comorbidconditions (eg, diabetes, cardiovascular disease, de-mentia, and ascites) were associated only weakly ornot significantly with phosphate binder prescriptionstatus. However, even after extensive adjustments forpatient characteristics, phosphate binder prescriptionremained strongly and significantly (ie, P � 0.05)associated with each indicator of better nutritionalstatus (ie, lower likelihood of cachexia and greaterodds of higher serum albumin, serum creatinine, BMI,and nPCR values). Furthermore, patients prescribed aphosphate binder had a lower adjusted odds of beingbothered by lack of appetite (14% lower for thoseprescribed a calcium-based phosphate binder alone[OR, 0.86; 95% confidence interval (CI), 0.78-0.95],12% for sevelamer alone [OR, 0.88; 95% CI, 0.76-1.02], and 20% for sevelamer plus a calcium-basedphosphate binder [OR, 0.80; 95% CI, 0.69-0.92]).(Data on lack of appetite are not shown.)

Variability in PhosphateBinder Prescription

Figure 1 shows the distribution of facility percent-ages of patients with phosphate binder prescription byDOPPS country and study phase. Median values forphosphate binder prescription varied modestly bycountry, showing a general trend toward slightlygreater phosphate binder prescription over time insome countries. The distribution of prescription wasskewed toward facilities prescribing phosphate bind-ers for most of their patients, with �90% of patientsreceiving phosphate binder prescription in approxi-mately half the facilities. The percentage of patientsprescribed phosphate binders varied across the 923dialysis facilities, ranging from 31%-82% in the low-est quartile and 96%-100% in the highest quartile.

Figure 2 shows the frequency of patients withphosphate binder prescription by serum phosphoruslevel. Phosphate binder prescription was lower forpatients with lower serum phosphorus levels. Forpatients with serum phosphorus levels �5.5 mg/dL, aphosphate binder was prescribed for �89%. How-ever, substantial phosphate binder prescription wasobserved even for patients with low serum phospho-rus levels (79% phosphate binder prescription forpatients with serum phosphorus �2.5 mg/dL). Forpatients prescribed phosphate binders in DOPPS III(2005-2008), types of phosphate binders prescribedincluded calcium-containing phosphate binder only(46%), sevelamer only (16%), calcium-containingphosphate binder and sevelamer (21%), aluminum-containing phosphate binder only (6%), lanthanum-containing phosphate binder only (3%), and otherphosphate binders or other combinations of phosphatebinders (8%). (Data by type of phosphate binder are

not shown.)

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Phosphate Binder Use and Mortality in the DOPPS

Table 1. Patient Characteristics by Phosphate Binder Prescription

Characteristic

Phosphate Binder Odds Ratio (95% CI)a

Yes (21,061; 88.1%) No (2,837; 11.9%)MinimallyAdjusted

ExtensivelyAdjusted

Age (y) 61.4 � 14.6 65.6 � 14.1 0.76 (0.71-0.82)b 0.78 (0.73-0.84)b

Black 12.3 11.6 0.78 (0.64-0.96) 0.76 (0.62-0.93)

Black, analysis restricted to US 37.7 37.3 0.88 (0.71-1.09) 0.86 (0.70-1.06)

Hispanic, analysis restricted to US 9.7 9.6 0.78 (0.51-1.19) 0.77 (0.50-1.17)

Male 57.3 56.5 1.01 (0.93-1.10) 1.02 (0.93-1.11)

Presence of residual kidney function 26.2 29.4 0.83 (0.75-0.93) 0.86 (0.77-0.96)

Median duration of ESRD (y) 3.4 2.6 1.02 (1.01-1.03) 1.02 (1.01-1.03)

Comorbid conditionsCoronary artery disease 45.7 47.7 0.94 (0.85-1.04) 0.96 (0.87-1.06)Cancer 10.8 12.2 0.99 (0.87-1.14) 1.00 (0.87-1.14)Other cardiovascular disease 36.1 39.4 0.93 (0.85-1.03) 0.93 (0.84-1.03)Cerebrovascular disease 16.7 20.5 0.84 (0.76-0.94) 0.93 (0.82-1.04)Congestive heart failure 32.9 33.3 0.96 (0.85-1.07) 1.02 (0.90-1.15)Diabetes 34.9 37.7 0.86 (0.78-0.95) 0.91 (0.82-1.01)Gastrointestinal bleed 5.8 7.4 0.80 (0.67-0.94) 0.84 (0.71-0.99)Hypertension 78.3 73.1 1.22 (1.09-1.36) 1.31 (1.17-1.47)Lung disease 10.9 11.4 0.95 (0.83-1.10) 0.98 (0.85-1.12)Neurologic disorder 10.2 14.7 0.64 (0.56-0.73) 0.67 (0.58-0.78)Psychological disorder 16.4 17.7 0.79 (0.69-0.89) 0.84 (0.74-0.96)Peripheral vascular disease 25.6 27.3 0.91 (0.83-1.01) 0.96 (0.85-1.09)Cellulitis, skin infection, or gangrene 8.2 8.4 0.87 (0.75-1.01) 0.96 (0.81-1.14)Alcohol abuse 2.9 3.9 0.60 (0.45-0.81) 0.72 (0.52-1.01)Dementia 3.2 6.3 0.58 (0.47-0.71) 0.82 (0.64-1.05)Ascites within the past 12 mo 1.3 1.9 0.67 (0.46-0.97) 0.75 (0.51-1.09)Hepatitis B or C 12 12 0.98 (0.86-1.13) 0.92 (0.80-1.06)

Vascular access by catheter 13.7 15 0.83 (0.72-0.96) 0.89 (0.77-1.03)

Hospitalization in the last 3 mo 19 26.8 0.69 (0.62-0.78) 0.74 (0.66-0.84)

Prescription of vitamin D and analogues 49.3 39.7 1.45 (1.29-1.64) 1.44 (1.27-1.62)

Hemoglobin (g/dL) 11.2 � 1.6 10.9 � 1.7 1.07 (1.04-1.12) 1.06 (1.03-1.10)

Hemoglobin �9 g/dL 8.1 12.8 0.73 (0.63-0.86) 0.75 (0.64-0.88)

spKt/V 1.44 � 0.29 1.41 � 0.33 1.02 (0.99-1.04)c 1.01 (0.98-1.03)c

Serum phosphorus (mg/dL) 5.6 � 1.8 5.2 � 1.8 1.17 (1.12-1.21) 1.16 (1.11-1.21)

Serum phosphorus �3.0 mg/dL 4 7.2 0.59 (0.49-0.71) 0.60 (0.49-0.72)

Serum phosphorus �7.0 mg/dL 18.1 13.5 1.39 (1.20-1.60) 1.37 (1.19-1.58)

Serum calcium, albumin corrected (mg/dL) 9.5 � 0.89 9.4 � 0.97 1.12 (1.05-1.19) 1.10 (1.03-1.16)

PTH (pg/mL) 165 157.5 0.99 (0.98-1.01)d 0.99 (0.98-1.01)d

Cachectic appearance 8 13.7 0.54 (0.47-0.63) 0.57 (0.50-0.66)

Body mass index (kg/m2) 24.4 � 5.6 23.41 � 5.1 1.04 (1.02-1.05) 1.04 (1.03-1.06)

Body mass index �18.5 kg/m2 10 15.2 0.65 (0.56-0.74) 0.63 (0.55-0.73)

Serum albumin (g/dL) 3.8 � 0.5 3.7 � 0.5 1.59 (1.41-1.80) 1.52 (1.35-1.72)

Serum albumin �3 g/dL 3.9 7.7 0.49 (0.41-0.59) 0.53 (0.44-0.63)

Serum creatinine (mg/dL) 9.6 � 3.0 8.2 � 3.0 1.25 (1.21-1.30) 1.27 (1.23-1.32)

Serum creatinine �8 mg/dL 30.5 51.9 0.38 (0.34-0.43) 0.38 (0.34-0.42)

nPCR (g/kg/d) 1.04 � 0.2 0.96 � 0.3 1.14 (1.12-1.17)e 1.13 (1.11-1.16)e

nPCR �1 g/kg/d 46.1 59.9 0.60 (0.54-0.66) 0.62 (0.56-0.69)

Note: n � 23,898. Continuous variables given as mean unless otherwise indicated; categorical variables given as percentage. Conversion factors forunits: serum albumin and hemoglobin in g/dL to g/L, �10; serum calcium in mg/dL to mmol/L, �0.2495; serum creatinine in mg/dL to �mol/L, �88.4; serumphosphorus in mg/dL to mmol/L, �0.3229. No conversion needed for PTH in pg/mL and ng/L.

Abbreviations: CI, confidence interval; ESRD, end-stage renal disease; nPCR, normalized protein catabolic rate; PTH, parathyroid hormone; spKt/V,single-pool Kt/V; US, United States.

aUnless otherwise indicated, odds ratios indicate likelihood of phosphate binder prescription per 1-unit increase (continuous variables) or compared withthe referent group (dichotomous variables).

bPer 10 years older.cPer 0.1 higher.d

Per 100 pg/mL higher.ePer 0.1 g/kg/day higher.

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Lopes et al

Nutritional Indicators byPatient-Level PhosphateBinder Prescription

As shown in Fig 3A-E, patients prescribed a phos-phate binder had a lower prevalence of cachexia andhigher mean values for BMI, serum creatinine, nPCR,and serum albumin across a wide range of serumphosphorus levels. Table 2 lists distributions of serumphosphorus levels and indicators of nutritional statusby type of phosphate binder or combination of phos-phate binders prescribed across all 3 DOPPS phases.Compared with patients not prescribed phosphatebinders, those prescribed any type or combination ofphosphate binders had a significantly lower preva-

Figure 1. Distribution of facility percentage of patients with phPractice Patterns Study) country and study phase (N � 23,898 pAustralia and New Zealand; BE, Belgium; CA, Canada; FR, Fraprescription; SP, Spain; SW, Sweden; UK, United Kingdom; US,

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lence of cachectic appearance and higher mean valuesfor serum phosphorus, serum albumin, serum creati-nine, BMI, and nPCR; each P � 0.001.

Facility-Level PhosphateBinder PrescriptionCase-mix–adjusted facility percentage of phos-

phate binder prescription was calculated for eachstudy site (minimum, 23%; median, 86%; 25th-75thpercentile, 77%-91%). Across categories of the case-mix–adjusted percentage of facility patients pre-scribed phosphate binders (Table 3), only small differ-ences were observed in patient and in selected facilitycharacteristics (facility median treatment time, facil-

Figure 2. Percentage of patients withphosphate binder (PB) prescription (Rx) bybaseline serum phosphorus level. Conver-sion factor for serum phosphorus in mg/dL to

ate binder (PB) prescription by DOPPS (Dialysis Outcomes andts, DOPPS I-III [1996-2008], 923 facilities). Abbreviations: ANZ,GE, Germany; IT, Italy; JPN, Japan; PB, phosphate binder; Rx,d States.

osphatiennce;

mmol/L, �0.3229.

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Phosphate Binder Use and Mortality in the DOPPS

ity percentage of patients with single-pool Kt/V �1.2,serum hemoglobin �10 g/dL, or using an arterio-venous fistula).

Case-mix–adjusted facility percentage of phos-phate binder prescription also was examined for oddsof a patient having each nutritional indicator at or lessthan the 25th percentile of the indicator’s distribution(Fig 4). For serum creatinine level, BMI, and nPCR,the odds of poorer nutritional status were higher infacilities with a lower case-mix–adjusted percentageof phosphate binder prescription.

HazardofDeathbyPrescriptionof PhosphateBinder

In 23,894 prevalent patients, 6,283 deaths wereobserved (median time at risk, 1.92 years). Phosphatebinder prescription was associated with a 25% lowerdeath rate (adjusted HR [aHR], 0.75; 95% CI, 0.68-0.83) in Cox models adjusted for numerous covari-ates, including achieved serum phosphorus level, butnot for nutritional factors. A similar association wasobserved in a model excluding patients with dementiaor cancer or who had been hospitalized in the previous

Figure 3. Nutritional indicator levels byphosphate binder (PB) prescription and se-rum phosphorus category. (A-E) Based onseparate mixed linear regression models es-timating the mean level of the indicated nutri-tional indicator within each serum phospho-rus concentration depending on whetherpatients were prescribed a phosphate binder.The associations accounted for facility clus-tering effects and were adjusted for age,male sex, race, 13 summary comorbid condi-tions, region, and study phase. Abbrevia-tions: BMI, body mass index; No PB, phos-phate binder was not prescribed; nPCR,normalized protein catabolic rate. Conver-sion factors for units: serum albumin in g/dLto g/L, �10; serum creatinine in mg/dL to�mol/L, �88.4; serum phosphorus in mg/dLto mmol/L, �0.3229.

3 months (aHR, 0.76; 95% CI, 0.67-0.86; P � 0.002).

Am J Kidney Dis. 2012;60(1):90-101

However, the strength of the association betweenphosphate binder prescription and mortality risk wasreduced after adjusting for nutritional factors (aHR,0.88; 95% CI, 0.80-0.97). Similar associations be-tween phosphate binder prescription and lower mortal-ity risk were observed in analyses comparing calcium-based phosphate binder with no phosphate binderprescription and comparing sevelamer with no phos-phate binder prescription. Also, in a Cox model ad-justed for all covariates except nutritional indicators,similar results were observed in a sensitivity analysisrestricted to 6,181 incident patients who had initiatedmaintenance HD therapy within 30 days of study. Forthese incident patients, an 18.7% lower hazard ofdeath was observed during the first year on mainte-nance HD therapy for patients prescribed a phosphatebinder at the time of study entry (aHR, 0.81; 95% CI,0.71-0.93; P � 0.002).

Figure 5A and B shows the aHR of death for jointcategories of phosphate binder prescription status andserum phosphorus concentration without and withadjustment for nutritional indicators; the reference

category is composed of patients with serum phospho-

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rus levels of 3.5-5.5 mg/dL who were prescribedphosphate binders. Without adjusting for nutritionalindicators, the mortality rate was consistently higherfor patients not prescribed a phosphate binder (com-pared with patients prescribed any phosphate binder)at all serum phosphorus concentrations �3.5 mg/dL(Fig 5A). The lowest mortality rate was observed forpatients prescribed a phosphate binder and having aserum phosphorus level of 3.5-5.5 mg/dL. Differencesin aHRs of patients not prescribed and those pre-scribed a phosphate binder with serum phosphoruslevels �3.5 mg/dL (Fig 5A) were reduced after adjust-ments for nutritional indicators (Fig 5B). Figure S1illustrates the effect of phosphate binders on mortalityacross categories of nutritional indicators.

An instrumental-variable analysis was applied toexamine the relationship of mortality with phosphatebinder prescription as a facility practice, representedas case-mix–adjusted facility percentage of phosphatebinder prescription. Results indicate a 7% lower haz-ard of death for every 10-percentage-point greatercase-mix–adjusted facility phosphate binder prescrip-tion when adjusted for numerous covariates, but notfor nutritional indicators (aHR, 0.93; 95% CI, 0.89-0.96; P � 0.001). The strength of the association wasreduced after adjusting for nutritional indicators (aHR,0.95; 95% CI, 0.92-0.99; P � 0.01).

As a sensitivity analysis, LIML regression modelswere used to assess the association between case-mix–adjusted phosphate binder prescription and 1-yearsurvival (yes/no) and provided results consistent withthose from the Cox regression models. In the LIMLregression, the 1-year survival probability was signifi-cantly (P � 0.001) higher in facilities with a higherpercentage of patients prescribed phosphate binders(difference per 10% greater case-mix–adjusted facil-ity phosphate binder prescription, 1.1%; 95% CI,0.5%-1.8%). The difference was reduced from 1.1%to 0.9% (difference, 0.9%; 95% CI, 0.3%-1.6%; P �0.007) after adjusting for nutritional indicators. The

Table 2. Serum Phosphorus and Indicators of Nutritional S

Type/Combination ofPhosphate Binder

PrescribedNo. of

Patients

SerumPhosphorus

(mg/dL)

SeruAlbum

(g/d

None 2,304 5.15 � 1.83 3.69 �

Ca-based alone 13,892 5.48 � 1.73 3.77 �

Sevelamer alone 1,861 5.72 � 1.68 3.81 �

Sevelamer plus Ca-based 2,547 5.81 � 1.70 3.80 �

Note: Unless otherwise indicated, values shown are mean �Outcomes and Practice Patterns Study) phases I-III (1998-2008none, P � 0.001. Conversion factors for units: serum albumin inphosphorus in mg/dL to mmol/L, �0.3229.

Abbreviations: BMI, body mass index; Ca, calcium; nPCR, nor

Cox regression model without adjustment for nutri-

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tional indicators showed estimated 1-year mortality of18% for those not prescribed phosphate binders and1-year mortality of 16.6% for those prescribed phos-phate binders (HR, 0.92; 95% CI, 0.87-0.96; P �0.001). The estimated unadjusted decrease in mortal-ity risk was 1.4% per each 10-percentage-point greatercase-mix–adjusted facility phosphate binder prescrip-tion. This unadjusted decrease in mortality risk associ-ated with phosphate binder prescription estimated inthe Cox regression model is comparable to the 1.1%decrease in mortality risk estimated in the LIMLmodel. After adjusting for nutritional indicators in theCox regression model, the strength of the associationsbetween phosphate binder prescription and 1-yearmortality also was reduced (aHR, 0.94; 95% CI,0.90-0.99; P � 0.02). The estimated decrease inmortality risk after adjustment for nutritional indica-tors in the Cox regression model was 1.1% per each10-percentage-point greater case-mix–adjusted facil-ity phosphate binder prescription.

DISCUSSION

Results of this large international prospective co-hort study indicate greater survival for maintenanceHD patients prescribed a phosphate binder and infacilities with a higher percentage of patients with aphosphate binder prescription. Sensitivity analysessuggest a similar survival benefit in prevalent andincident maintenance HD patients. The longer first-year survival associated with phosphate binder pre-scription in incident maintenance HD patients is con-sistent with results from a prospective cohort study byIsakova et al9 in both their unmatched analysis (usingdata from 8,610 patients) and propensity score–matching analysis (using data from 6,372 patients).Kovesdy et al21 recently reported a survival benefitwith phosphate binder prescription in non–dialysis-dependent male patients with chronic kidney disease.Winkelmayer et al11 observed lower mortality ratesduring the first year of dialysis therapy in a 1996-1997

by Type or Combination of Phosphate Binder Prescription

SerumCreatinine

(mg/dL) BMI (kg/m2) nPCR

CachecticAppearance

(%)

8.09 � 2.97 23.16 � 5.02 0.96 � 0.27 14.0

9.61 � 3.12 24.00 � 5.48 1.04 � 0.27 8.3

9.20 � 2.94 25.66 � 5.87 1.03 � 0.27 7.9

9.88 � 2.96 25.56 � 6.00 1.08 � 0.26 6.8

dard deviation. Values represent data from the DOPPS (Dialysishin each column, comparisons of each prescription type versusto g/L, �10; serum creatinine in mg/dL to �mol/L, �88.4; serum

ed protein catabolic rate.

tatus

min

L)

0.51

0.44

0.46

0.43

stan). Witg/dL

cohort of incident US dialysis patients prescribed

Am J Kidney Dis. 2012;60(1):90-101

Phosphate Binder Use and Mortality in the DOPPS

versus not prescribed phosphate binders. However,this association was no longer statistically significantwhen analyzed by a propensity score methodologyused to diminish differences in patient case-mix be-tween study groups (aHR, 0.89; 95% CI, 0.72-1.10).The lack of statistical significance observed in thepropensity-matched analysis in the study by Winkel-mayer et al11 could reflect the smaller sample size of1,600 participants in that study compared with the 5-to 15-fold larger sample in the Isakova et al9 study andour present study, respectively.

Patients prescribed a phosphate binder had highermean serum phosphorus concentrations. This also has

Table 3. Patient Characteristics by Quartile of Case-Mix–

<78%

No. of patients 6,353

Patient characteristicsAge (y) 61.6Men 57.1Black 11.2Duration of ESRD (y) 5.5Coronary artery disease 39.6Congestive heart failure 26.1Cerebrovascular disease 15.8Other cardiovascular disease 32.7Hypertension 70.3Diabetes 30.7Peripheral arterial disease 21.8Lung disease 8.4Gastrointestinal bleed in prior 12 mo 4.8Neurologic disease 9.6Psychological disorder 14.1Cancer 10.1Recurrent cellulitis/gangrene 6.4Catheter as vascular access 11.0Serum calcium, albumin-corrected (mg/dL) 9.45Serum phosphorus (mg/dL) 5.70

Facility characteristicsTreatment time (min)b 232.9Patients with spKt/V �1.2 (%) 73.2Patients with Hb �10 g/dL (%) 70.8Patients with AVF (%) 68.3

Note: n � 23,898. Continuous variables given as mean unValues represent data from DOPPS (Dialysis Outcomes and Prfacility percentage of phosphate binder prescription was estimatfor age, sex, race, years on dialysis therapy, coronary artery diseadisease, recurrent cellulitis/gangrene, neurologic disease, lung duse for vascular access, and baseline serum phosphorus leve�0.2495; Hb in g/dL to g/L, �10; serum phosphorus in mg/dL to

Abbreviations: AVF, arteriovenous fistula; Hb, hemoglobin; ESaTrend analysis was based on a linear regression model

case-mix–adjusted facility percentage of phosphate binder presregions and study phase. Similar results for trend analyses weremodeled as an ordinal variable.

bMedian.

been reported in previous studies9,11 and likely is due

Am J Kidney Dis. 2012;60(1):90-101

to the preferential prescription of phosphate binders topatients with a serum phosphorus concentration higherthan the recommended target; in other words, dosingby indication. In contrast, facility-based analyses of-ten are more independent of treatment-by-indicationbias, and in the present study, facilities prescribingphosphate binders for a larger fraction of patientsshowed slightly lower mean serum phosphorus concen-trations. This latter observation is consistent with theknown action of phosphate binders in reducing serumphosphorus levels in randomized clinical trials.

The simple nutritional indicators used in ourstudy (serum albumin, serum creatinine, BMI,

ted Facility Percentage of Phosphate Binder Prescription

Prescription of Phosphate Binder

P forTrenda79%-<86% 86%-<91% >91%

6,145 5,787 5,613

61.4 61.6 63.0 0.956.8 58.7 56.2 0.0812.4 9.3 16.0 0.25.3 5.4 4.6 0.3

46.4 46.2 52.5 0.132.2 33.1 41.1 0.00315.8 17.3 19.7 0.136.3 37.6 39.6 0.00377.8 81.4 82.4 0.00134.4 36.1 40.1 0.124.7 26.7 30.7 0.0210.2 10.7 14.8 0.016.8 5.3 7.3 0.03

10.5 10.5 12.7 0.817.3 16.0 19.2 0.510.7 11.1 12.5 0.78.0 8.3 10.7 0.001

13.0 12.3 19.5 0.89.49 9.51 9.50 �0.0015.62 5.50 5.40 �0.001

230.2 235.3 231.6 0.278.1 78.6 81.2 0.00274.3 81.0 85.6 �0.00163.3 67.3 59.4 0.4

otherwise indicated; categorical variables given as percentage.e Patterns Study) phases I-III (1998-2008). Case-mix–adjusteda linear regression model with fixed effects for facility, adjustedongestive heart failure, hypertension, diabetes, peripheral arterye, gastrointestinal bleeding in prior 12 months, cancer, catheternversion factors for units: serum calcium in mg/dL to mmol/L,/L, �0.3229.nd-stage renal disease; spKt/V, single-pool Kt/V.icting levels of each patient characteristic in relationship toion modeled as a continuous variable adjusting for geographicned when case-mix–adjusted phosphate binder prescription was

Adjus

lessacticed byse, ciseasl. CommolRD, epredcript

obtai

nPCR, and cachectic appearance) have been found

97

Lopes et al

to be associated with mortality risk, mediators ofdisease process (such as inflammation and intakes ofprotein and calories), and change in body compositionin patients on maintenance HD or peritoneal dialysistherapy.2,22-24 The association between phosphate

Figure 4. Odds ratios of the associations of quintile of case-mix–adjusted facility percentage of patients who received aprescription of phosphate binders with the odds of nutritionalmeasures below the 25th percentile (n � 23,952). Results arebased on data for 23,898 prevalent hemodialysis patients withend-stage renal disease (ESRD) duration at least 90 days from923 facilities in the DOPPS (Dialysis Outcomes and PracticePatterns Study) I-III (1996-2008). Case-mix–adjusted facility per-centage of phosphate binder prescription was calculated frommixed linear regression adjusted for age, male sex, ESRD dura-tion, 10 comorbid conditions, serum phosphorus level, catheteruse, and serum calcium level (albumin adjusted). Second-stagelogistic regression models used the same adjustments as in thefirst stage, phase, and region and accounted for facility cluster-ing. Abbreviations: nPCR, normalized protein catabolic rate; Ref,reference group. Conversion factors for units: serum albumin ing/dL to g/L, �10; serum creatinine in mg/dL to �mol/L, �88.4.

binder prescription and better nutritional status as

98

assessed by these 5 indicators was seen consistentlywithin each of the 3 study regions (ie, North America,Japan, and Europe/Australia/New Zealand) and across5 categories of serum phosphorus level (Fig 3). Fur-thermore, our results indicate that patients in facilitieswith high phosphate binder prescription show bettercontrol of hyperphosphatemia, better nutritional sta-tus, and a lower mortality rate, even after adjusting fordifferences in achieved serum phosphorus levels andnumerous patient characteristics. Higher mean valuesfor serum creatinine, BMI, and nPCR were seen infacilities prescribing phosphate binders for nearly allpatients compared with facilities prescribing phos-phate binders for a lower fraction of patients (eg, for�82% of facility patients). Previously, we showedthat lack of appetite was associated with poor nutri-tional status as assessed by serum albumin level,nPCR, serum creatinine level, BMI, and cachecticappearance.1 The present study suggests that the oddsof lack of appetite are lower in patients prescribedphosphate binders. These findings support the possibil-ity that the better nutritional status and improvedsurvival observed in patients prescribed phosphatebinders may be due in part to their lower odds of lackof appetite.

It should be noted that prescription of phosphatebinders was associated with improved survival evenfor patients with serum phosphorus levels within therecommended range (ie, 3.5-5.5 mg/dL). The differ-ence was reduced after adjustment for nutritionalindicators, supporting the hypothesis that the associa-tion between phosphate binder prescription and lowermortality risk is explained in part by better nutritionalstatus in those prescribed phosphate binders. Thefacility-level analysis suggests that nearly 30% of thereduced hazard of all-cause death associated with agreater percentage of patients prescribed phosphatebinders at the facility may be explained by betternutritional status of patients in facilities prescribingphosphate binders for a larger fraction of patients. Theobservation of improved nutritional status of mainte-nance HD patients with greater facility percentage ofphosphate binder prescription perhaps could be ex-plained by a more liberal diet that may require fre-quent use of phosphate binders to control hyperphos-phatemia. This possibility also is consistent with apost hoc analysis of the HEMO (Hemodialysis) Studyshowing that an increased level of dietary phosphorusrestriction was associated with poorer nutritional sta-tus and higher mortality risk.8

Although approximately half the dialysis units inthis study prescribed phosphate binders for at least90% of their HD patients, the lowest quartile pre-scribed phosphate binders for a substantially smaller

fraction of patients, ranging from 23%-78%. This

Am J Kidney Dis. 2012;60(1):90-101

mas

Phosphate Binder Use and Mortality in the DOPPS

difference in facility phosphate binder prescriptionlikely in part reflects differences in provider prefer-ences for phosphate binder prescription. Some facili-ties prescribe phosphate binders based on a differentserum phosphorus target than others.

Because of its randomized sampling design, theDOPPS findings may be viewed as generalizableto the broad maintenance HD population in eachparticipating country.12,13 However, methodologicallimitations cannot be ignored. Because the study isobservational, it does not allow conclusions aboutcause-effect association between phosphate bindersand mortality risk. It is possible that the better sur-vival in patients with a phosphate binder prescriptionis due in part to unmeasured confounders. However,the facility-level phosphate binder prescription analy-sis based on instrumental-variable methods used inthe present study should have reduced the influence ofunmeasured patient-level confounders. This instrumen-tal-variable approach relates outcomes to a facilitypractice of phosphate binder prescription rather thanactual treatment received. It is worth noting that theinstrumental-variable model showed a fairly balanceddistribution of patient characteristics among facilitieswith higher and lower phosphate binder prescription.The association of greater facility percentage of phos-

Figure 5. Adjusted hazard ratios (aHRs) and 95% confidencphosphate binder prescription by serum phosphorus levels (A) wbased on data for 23,898 prevalent hemodialysis patients withfacilities in the DOPPS (Dialysis Outcomes and Practice Patternswith serum phosphorus levels of 3.5-5.5 mg/dL and with phosphESRD duration, residual kidney function, 13 comorbid conditionsadjusted); stratified by phase and region; and accounted for facrate, cachexia, serum albumin level, creatinine level, and bodymmol/L, �0.3229.

phate binder prescription and lower mean serum phos-

Am J Kidney Dis. 2012;60(1):90-101

phorus levels observed in the instrumental-variablemodel is a finding consistent with the pharmacologiceffect of phosphate binders. The consistency of resultsobserved in the patient-based analysis and the 2 instru-mental-variable methods should be viewed as addi-tional evidence that phosphate binder use is associ-ated with a lower mortality risk in maintenance HDpatients.25,26

Another methodological limitation is that the assess-ment of phosphate binder effect and predictor covari-ates was based on baseline data, whereas adherence tomedication use and phosphate binder prescriptionduring follow-up were not assessed. There are data toindicate that a considerable proportion of mainte-nance HD patients do not adhere to phosphate binderprescription.27,28 Nonadherence to phosphate binderprescription and phosphate binder prescription forpatients who did not have a prescription at baselineare likely to bias the association of phosphate binderswith survival toward the null hypothesis. This sug-gests that the independent associations between phos-phate binder prescription and improved survival ob-served in the present study could be even stronger ifall patients prescribed phosphate binders had closelyadhered to taking the phosphate binders as prescribed.The study could not assess whether the higher mortal-

ervals of the association of all-cause mortality with patient-levelut and (B) with adjustment for nutritional indicators. Results aretage renal disease (ESRD) duration at least 90 days from 923y) I-III (1996-2008). Reference group was composed of patientsinder prescription. All models were adjusted for age, male sex,m phosphorus level, catheter use, serum calcium level (albuminlustering. �Nutritional factors were normalized protein catabolics index. Conversion factor for serum phosphorus in mg/dL to

e intitho

end-sStudate b

, seruility c

ity rate in patients not prescribed phosphate binders

99

Lopes et al

was due to lower dietary protein intake in an attemptto control hyperphosphatemia by dietary restriction ofphosphorus. This possibility should be viewed as animportant question for future research. Studies arestill needed to assess whether the positive relationshipof phosphate binder prescription with maintenanceHD patient survival also may be due to direct effectsof phosphate binders on mediators of mineral metabo-lism, for example, fetuin A and fibroblast growthfactor 23,29,30 although this is less likely becausephosphate binders are designed not to be absorbed andas such, should have minimal systemic effects.

In conclusion, results of the present study providenew perspectives of the relationship between facility-level phosphate binder prescription and maintenanceHD patient outcomes. Patients in facilities with higherphosphate binder prescription show better control ofhyperphosphatemia, better nutritional status, and lon-ger survival. The association of case-mix–adjustedfacility phosphate binder prescription with greatersurvival was seen even after controlling for differ-ences in achieved serum phosphorus levels and numer-ous patient characteristics. The results suggest that theimproved patient survival in facilities with a higherpercentage of patients prescribed a phosphate bindermay be explained in part by the better nutritionalstatus of their patients. The results also are consistentwith the possibility that greater prescription of phos-phate binders may be due to more liberal dietaryintake, which potentially may contribute to improvedsurvival in maintenance HD patients.

ACKNOWLEDGEMENTSInitial research was presented as an abstract entitled “Phosphate

binder use and mortality among hemodialysis (HD) patients in theDOPPS: influence of nutritional adjustment” at Renal Week 2009,October 27-November 1, San Diego, CA.

Support: The DOPPS is administered by Arbor Research Collab-orative for Health and is supported by scientific research grantsfrom Amgen (since 1996), Kyowa Hakko Kirin (since 1999, inJapan), Sanofi/Genzyme (since 2009), Abbott (since 2009), Baxter(since 2011), and Vifor Fresenius Renal Pharma (since 2011)without restrictions on publications.

Financial Disclosure: The authors declare that they have noother relevant financial interests.

SUPPLEMENTARY MATERIALTable S1: Patient characteristics by phosphate binder prescrip-

tion and geographic region.Figure S1: Association of phosphate binder use and mortality

within subgroups of nutritional status.Note: The supplementary material accompanying this article

(doi:10.1053/j.ajkd.2011.12.025) is available at www.ajkd.org.

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