The Association Between Intradialytic Symptom Clusters and Recovery Time in Patients Undergoing Maintenance Hemodialysis: An Exploratory Analysis.

Background: Individuals receiving hemodialysis often experience concurrent symptoms during treatment and frequently report feeling unwell after dialysis. The degree to which intradialytic symptoms are related, and which specific symptoms may impair health-related quality of life (HRQoL) is uncertain. Objectives: To explore intradialytic symptoms clusters, and the relationship between intradialytic symptom clusters with dialysis treatment recovery time and HRQoL. Design/setting: We conducted a post hoc analysis of a prospective cohort study of 118 prevalent patients receiving hemodialysis in two centers in Calgary, Alberta and Hamilton, Ontario, Canada. Participants: Adults receiving hemodialysis treatment for at least 3 months, not scheduled for a modality change within 6 weeks of study commencement, who could provide informed consent and were able to complete English questionnaires independently or with assistance. Methods: Participants self-reported the presence (1 = none to 5 = very much) of 10 symptoms during each dialysis treatment, the time it took to recover from each treatment, and weekly Kidney Disease Quality of Life 36-Item-Short Form (KDQoL-36) assessments. Principal component analysis identified clusters of intradialytic symptoms. Mixed-effects, ordinal and linear regression examined the association between symptom clusters and recovery time (categorized as 0, >0 to 2, >2 to 6, or >6 hours), and the physical component and mental component scores (PCS and MCS) of the KDQoL-36. Results: One hundred sixteen participants completed 901 intradialytic symptom questionnaires. The most common symptom was lack of energy (56% of treatments). Two intradialytic symptom clusters explained 39% of the total variance of available symptom data. The first cluster included bone or joint pain, muscle cramps, muscle soreness, feeling nervous, and lack of energy. The second cluster included nausea/vomiting, diarrhea and chest pain, and headache. The first cluster (median score: -0.56, 25th to 75th percentile: -1.18 to 0.55) was independently associated with longer recovery time (odds ratio [OR] 1.62 per unit difference in score, 95% confidence interval [CI]: 1.23-2.12) and decreased PCS (-0.72 per unit difference in score, 95% CI: -1.29 to -0.15) and MCS scores (-0.82 per unit difference in score, 95% CI: -1.48 to -0.16), whereas the second cluster was not (OR 1.24, 95% CI: 0.97-1.58; PCS 0.19, 95% CI -0.46 to 0.83; MCS -0.72, 95% CI: -1.50 to 0.06). Limitations: This was an exploratory analysis of a small data set from 2 centers. Further work is needed to externally validate these findings to confirm intradialytic symptom clusters and the generalizability of our findings. Conclusions: Intradialytic symptoms are correlated. The presence of select intradialytic symptoms may prolong the time it takes for a patient to recover from a dialysis treatment and impair HRQoL.

Contexte: Il arrive fréquemment que les personnes qui reçoivent des traitements d'hémodialyse éprouvent des symptômes concomitants pendant la dialyze et signalent un malaise après le traitement. On en sait toutefois peu sur le degré de corrélation de ce malaise avec les symptômes intradialytiques et sur les symptômes précis qui peuvent altérer la qualité de vie liée à la santé (QVLS). Objectifs: Explorer différents groupes de symptômes intradialytiques et la relation de ceux-ci avec le temps de récupération post-dialyze et la QVLS. Cadre et conception de l'étude: Nous avons procédé à une analyze post-hoc d'une étude de cohorte prospective portant sur 118 patients prévalents recevant une hémodialyse dans deux centers, soit à Calgary (Alberta) et à Hamilton (Ontario) au Canada. Sujets: Des adultes qui recevaient des traitements d'hémodialyse depuis au moins trois mois ­ sans changement de modalité prévu dans les six semaines suivant le début de l'étude ­ qui pouvaient donner leur consentement éclairé et qui étaient en mesure de remplir des questionnaires en anglais de façon autonome ou avec de l'aide. Méthodologie: Pour chaque traitement de dialyze, les participants devaient autoévaluer le degré de présence (de 1 [non présent] à 5 [très présent]) de dix symptômes et le temps nécessaire pour récupérer de chaque traitement, puis remplir des évaluations hebdomadaires à l'aide du questionnaire KDQoL-36. Une analyze des composantes principales a permis de définir des groupes de symptômes intradialytiques. Une régression à effets mixtes, ordinale et linéaire, a servi à examiner l'association entre les groupes de symptômes et le temps de récupération (0 heure; de 0 à 2 heures; de 2 à 6 hures; plus de 6 heures), et les scores des composantes physiques et psychologiques du KDQoL-36. Résultats: Cent seize patients ont rempli un total de 901 questionnaires sur les symptômes intradialytiques. Le symptôme le plus fréquemment déclaré était le manque d'énergie (56 % des traitements). Deux groupes de symptômes intradialytiques ont expliqué 39 % de la variance totale des données disponibles sur les symptômes. Le premier groupe comprenait des douleurs osseuses ou articulaires, des crampes musculaires, des douleurs musculaires, une sensation de nervosité et un manque d'énergie. Le deuxième groupe comprenait des nausées/vomissements, de la diarrhée, des douleurs thoraciques et des maux de tête. Le premier groupe (score médian : ­0,56; du 25e au 75e percentile : ­1, 18 à 0,55) a été indépendamment associé à un temps de récupération plus long (rapport de cotes : 1,62 par unité de différence de score; IC 95 % : 1,23 à 2,12) et à une diminution des scores des composantes physiques (RC : ­0,72; IC 95 % : ­1, 29 à ­0,15) et des scores des composantes psychologiques (RC : ­0,82; IC 95 % : ­1, 48 à ­0,16). Le deuxième groupe n'a pas été associé avec le temps de récupération (RC : 1,24; IC 95 % : 0,97 à 1,58) ni avec le score des composantes physiques (RC : 0,19; IC 95 % : ­0,46 à 0,83) et les scores des composantes psychologiques (RC : ­0,72; IC 95 % : ­1, 50 à 0,06). Limites: Il s'agissait d'une analyze exploratoire d'un petit ensemble de données provenant de deux centers. D'autres études externes sont nécessaires pour valider ces résultats et, ainsi, confirmer nos groupes de symptômes intradialytiques et la généralisabilité de nos résultats. Conclusion: Les symptômes intradialytiques sont corrélés. La présence de certains symptômes intradialytiques peut prolonger le temps de récupération post-dialyze et altérer la qualité de vie des patients.

Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT.

BACKGROUND: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. OBJECTIVES: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. DESIGN: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. SETTING: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. PARTICIPANTS: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. INTERVENTIONS: Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. PRIMARY OUTCOME: The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. RESULTS: The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). CONCLUSIONS: Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. FUTURE WORK: A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. LIMITATIONS: This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. TRIAL REGISTRATION: This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Anti-neutrophil cytoplasm antibody vasculitis is a rare and severe disease in which the patient makes antibodies that damage their blood vessels. It can cause lung damage, kidney failure and early death. Treatment aims to suppress the harmful effects of the antibodies and associated inflammation. In particular: Plasma exchange aims to remove the antibodies from the bloodstream.Steroids aim to reduce the harmful activity of the antibodies. Unfortunately, plasma exchange is expensive and time-consuming, and we do not know if it really works long term to reduce kidney damage or the risk of death. We know steroids work, but they have many severe side effects that are related to higher doses. Again, we do not know if lower doses are equally effective. We conducted a randomised trial, PEXIVAS (Plasma Exchange In VASculitis), to measure the clinical effectiveness of plasma exchange and of reduced steroid doses. Anti-neutrophil cytoplasm antibody vasculitis patients with severe kidney or lung disease were allocated randomly to either plasma exchange or no plasma exchange. The same patients were then randomly allocated to a 'reduced' or 'standard' steroid dose. All patients received an immunosuppressive drug: cyclophosphamide or rituximab. The primary end point for both trials was the occurrence of either kidney failure or death. A total of 704 patients were recruited between 2010 and 2016, and they were followed up until the end of the trial in July 2017. Ninety-nine patients died and 138 developed kidney failure. Plasma exchange did not reduce the chances of death or kidney failure. There was also no difference between the two steroid dose groups in the number of deaths or patients developing kidney failure. However, there were fewer serious infections in the reduced steroid dose group. These results do not support the routine use of plasma exchange for all patients with severe vasculitis. They do show that the reduced-dose steroid regimen is just as effective as, and safer than, a 'standard'-dose steroid regimen. These results have the potential to save money and make the treatment of vasculitis patients safer in the future.

Variability in Cardiac Biomarkers during Hemodialysis: A Prospective Cohort Study.

BACKGROUND: The effect of hemodialysis on cardiac biomarkers is unclear. We sought to evaluate the degree and causes of intradialytic variability of high sensitivity troponin I (hs-TnI), galectin-3 (gal-3), and heart-type fatty acid binding protein (hFABP). METHODS: hs-TnI, gal-3, and hFABP were prospectively measured pre-dialysis and post-dialysis for 1 week every month for 6 months in 178 prevalent adult hemodialysis patients at a single center in Hamilton, Canada. The degree of change from pre-dialysis to post-dialysis for each cardiac biomarker was estimated with multilevel linear regression models. RESULTS: The median change in the concentration of hs-TnI during hemodialysis was -1 ng/L (interquartile range [IQR] -1 to 2 ng/L) while gal-3 and hFABP changed by -36.3 ng/mL (IQR -27.7 to -46.8 ng/mL) and -19.41 ng/mL (IQR -13.61 to -26.87 ng/mL), respectively. The median (IQR) percentage intradialytic changes for hs-TnI, gal-3, and hFABP were 2.6% (-4.4% to 12.5%), -59.8% (-54.7% to -64.8%) and -35.3% (-28.4% to -42.1%), respectively. Ultrafiltration was associated with an increase in concentration of hs-TnI, gal-3, and hFABP (mean 0.99 ng/L, 1.05 ng/mL, and 1.9 ng/mL per L ultrafiltration, respectively, P < 0.001). Both gal-3 and hFABP concentrations decreased in association with the volume of blood processed (P < 0.001) and with hemodialysis treatment time (P = 0.02 and P = 0.04) while hs-TnI concentration decreased only in association with hemodialysis treatment time (P < 0.001). CONCLUSIONS: Ultrafiltration volume and hemodialysis treatment time influenced hs-TnI, gal-3, and hFABP concentrations during hemodialysis and should be considered when interpreting their measurement.

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

Screening questions for the diagnosis of restless legs syndrome in hemodialysis.

BACKGROUND: Restless legs syndrome (RLS) is common in end-stage renal disease and is associated with reduced health-related quality of life. Simple and accurate screening instruments are needed since RLS is underdiagnosed and treatable. We examined the operating characteristics of screening questions and a disease-specific measurement tool for the diagnosis of RLS in hemodialysis. METHODS: We conducted a cohort study of prevalent adult hemodialysis patients in Hamilton, Canada. The diagnosis of RLS was made using the 2012 Revised International Restless Legs Syndrome Study Group (IRLSSG) criteria. All participants received three screening instruments: (i) a single screening question for RLS derived from a nondialysis population; (ii) a single question from the Edmonton Symptom Assessment System (ESAS); and (iii) the IRLSSG Rating Scale (IRLS). All instruments were compared with the reference standard using logistic regression from which receiver operating characteristics curves were generated. Cutoffs associated with maximum performance were identified. RESULTS: We recruited 50 participants with a mean (SD) age of 64 (12.4) years, of whom 52% were male and 92% were on three times weekly hemodialysis. Using the reference standard, 14 (28%) had a diagnosis of RLS. The single screening question for RLS had an area under the receiver operating curve (AUROC) of 0.72 with a sensitivity of 85.7% and specificity of 58.3%. An ESAS cutoff of ≥1 had the highest AUROC at 0.65 with a sensitivity of 79% and specificity of 56%. An IRLS cutoff of ≥20 had the highest AUROC at 0.75 with a sensitivity of 71% and specificity of 81%. CONCLUSION: IRLS had better specificity than the single question or ESAS for the diagnosis of RLS.

Single Questions for the Screening of Anxiety and Depression in Hemodialysis.

BACKGROUND: Depression and anxiety are common and underrecognized in end-stage renal disease (ESRD), are associated with poor outcomes and reduced health-related quality of life, and are potentially treatable. Simple, accurate screening tools are needed. OBJECTIVE: We examined the operating characteristics of single questions for anxiety and depression from the Edmonton Symptom Assessment System (ESAS) in hemodialysis. DESIGN: Cross-sectional study. SETTING: Two outpatient hemodialysis units (1 tertiary, 1 community) in Hamilton, Canada. PATIENTS: Adult prevalent hemodialysis patients. MEASUREMENTS: ESAS and Hospital Anxiety and Depression Scale (HADS). METHODS: Participants were asked the degree to which they experienced anxiety and depression using the ESAS. ESAS single questions for anxiety and depression were compared with the reference standard of the HADS using dialysis population specific cutoffs (HADS anxiety subscale ≥6 and HADS depression subscale ≥7). Logistic regression was used to create receiver operating characteristics (ROC) curves. RESULTS: We recruited 50 participants with a mean age of 64 (SD = 12.4) years, of whom 52% were male and 96% were on ≥3× weekly hemodialysis. Using the reference standards, 28 (56%) had a diagnosis of anxiety and 27 (54%) had a diagnosis of depression. Areas under the ROC curves were 0.83 for anxiety and 0.81 for depression using ESAS scores of ≥2. LIMITATIONS: Sample size and the lack of a reference gold standard. CONCLUSIONS: The ESAS single questions for anxiety and depression have reasonable discrimination in a hemodialysis population. The use of more complex and time-consuming screening instruments could be reduced by adopting the ESAS questions for anxiety and depression in hemodialysis.

CONTEXTE: La dépression et l'anxiété sont fréquentes quoique peu reconnues chez les patients souffrant d'insuffisance rénale terminale (IRT). Ces troubles sont associés à une évolution défavorable de la maladie et à une diminution de la qualité de vie liée à l'état de santé. Cependant, ils sont potentiellement traitables. Des outils de détection simples et précis sont requis. OBJECTIF: Nous avons évalué la fonction d'efficacité de questions uniques sur l'anxiété et la dépression provenant du Système d'évaluation des symptômes d'Edmonton (ESAS) en contexte d'hémodialyse. TYPE D'ÉTUDE: Étude transversale. CADRE: Deux unités d'hémodialyse ambulatoire (une en soins tertiaires, une en milieu communautaire) à Hamilton, au Canada. SUJETS: Des patients adultes hémodialysés. MESURES: L'ESAS et l'Échelle d'anxiété et de dépression en milieu hospitalier (HADS). MÉTHODOLOGIE: Nous avons demandé aux participants, par l'entremise de l'ESAS, dans quelle mesure ils éprouvaient de l'anxiété et de la dépression. Les questions uniques de l'ESAS sur l'anxiété et la dépression ont été comparées à l'étalon de référence de la HADS en utilisant les seuils spécifiques à une population dialysée (sous-échelle de la HADS pour l'anxiété ≥ 6 et sous-échelle de la HADS pour la dépression ≥ 7). Une régression logistique a été utilisée pour établir les courbes de fonction d'efficacité de l'observateur (courbes ROC). RÉSULTATS: Nous avons recruté 50 patients (52 % d'hommes) âgés de 64 ans en moyenne (écart-type : 12,4 ans). La plupart des sujets (96 %) étaient dialysés au moins trois fois par semaine. Selon l'étalon de référence, 28 patients (56 %) vivaient de l'anxiété et 27 (54 %) souffraient de dépression. La surface sous la courbe ROC était de 0,83 pour l'anxiété et de 0,81 pour la dépression selon les scores ESAS ≥ 2. LIMITES: Le faible échantillon de sujets et le fait que l'étude ne comportait pas d'étalon-or. CONCLUSION: Les questions uniques de l'ESAS sur l'anxiété et la dépression ont discriminé adéquatement dans une population de patients hémodialysés. L'adoption du questionnaire ESAS sur l'anxiété et la dépression avec les patients hémodialysés pourrait limiter le recours à des outils de détection chronophages et complexes.

Two phosphAte taRGets in End-stage renal disease Trial (TARGET): A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Hyperphosphatemia is common among recipients of maintenance dialysis and is associated with a higher risk of mortality and cardiovascular events. A large randomized trial is needed to determine whether lowering phosphate concentrations with binders improves patient-important outcomes. To inform such an effort we conducted a pilot randomized controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a randomized controlled trial of prevalent hemodialysis recipients already receiving calcium carbonate as a phosphate binder at five Canadian centers between March 31, 2014 and October 2, 2014. Participants were randomly allocated to 26 weeks of an intensive phosphate goal of 2.33-4.66 mg/dl (0.75-1.50 mmol/L) or a liberalized target of 6.20-7.75 mg/dl (2.00-2.50 mmol/L) by titrating calcium carbonate using a dosing nomogram. The primary outcome was the difference in the change in serum phosphate from randomization to 26 weeks. RESULTS: Fifty-three participants were randomized to the intensive group and 51 to the liberalized group. The median (interquartile range) daily dose of elemental calcium at 26 weeks was 1800 (1275-3000) mg in the intensive group, and 0 (0-500) mg in the liberalized group. The mean (SD) serum phosphate at 26 weeks was 4.53 (1.12) mg/dl (1.46 [0.36] mmol/L) in the intensive group and 6.05 (1.40) mg/dl (1.95 [0.45] mmol/L) in the liberalized group. Phosphate concentration in the intensive group declined by 1.24 (95% confidence interval, 0.75 to 1.74) mg/dl (0.40 [95% confidence interval, 0.24 to 0.56] mmol/L) compared with the liberalized group. There were no statistically significant differences between the two groups in the risk of hypercalcemia, hypocalcemia, parathyroidectomy, or major vascular events. CONCLUSIONS: It is feasible to achieve and maintain a difference in serum phosphate concentrations in hemodialysis recipients by titrating calcium carbonate. A large trial is needed to determine if targeting a lower serum phosphate concentration improves patient-important outcomes.