Diuretic prescriptions in the first year of haemodialysis: international practice patterns and associations with outcomes.

Background: The use of diuretics in patients on haemodialysis (HD) is thought to maintain diuresis. However, this assumption and the optimal dose are based on little scientific evidence, and associations with clinical outcomes are unclear. Methods: We reported international variations in diuretic use and loop diuretic dose across 27 759 HD patients with dialysis vintage <1 year in the Dialysis Outcomes and Practice Patterns Study phases 2-5 (2002-2015), a prospective cohort study. Doses of torsemide (4:1) and bumetanide (80:1) were converted to oral furosemide-equivalent doses. Adjusted Cox, logistic and linear regressions were used to investigate the association of diuretic use and dose with outcomes. Results: Diuretic utilization varied widely by country at vintage <3 months, ranging from >80% in Germany and Sweden to <35% in the USA, at a median dose ranging from 400-500 mg/day in Germany and Sweden to <100 mg/day in Japan and the USA. Neither diuretic use nor higher doses were associated with a lower risk of all-cause mortality, a higher risk of hospitalization for fracture or elevated parathyroid hormone levels, but the prescription of higher doses (>200 mg/day) was associated with a higher risk of all-cause hospitalization. Conclusions: Substantial international differences exist in diuretic prescriptions, with use and doses much higher in some European countries than the USA. The prescription and higher doses of loop diuretics was not associated with improved outcomes.

Associations of vitamin D receptor activators and calcimimetics with falls and effect modifications by physical activity: A prospective cohort study on the Japan Dialysis Outcomes and Practice Patterns Study.

INTRODUCTION: This study aimed to examine the associations of vitamin D receptor activators (VDRA) and calcimimetics use with falls. METHODS: This is a prospective cohort study on hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. We excluded those who were unable to walk. The associations of VDRA or calcimimetics use with falls and effect modifications by physical activity were analyzed using marginal structural models. RESULTS: In total, 1875 patients were included. VDRA and calcimimetics use was not associated with falls (risk ratio [95% CI]: 1.13 [0.84-1.51] and 1.02 [0.72-1.44]). The risk ratio for falls associated with VDRA use was lower among those with poor physical activity (p for interaction <0.1). CONCLUSIONS: Although vitamin D receptor activators and calcimimetics use was not associated with falls, the lower risk ratio for falls with vitamin D receptor activators use among those with poor physical activity suggests that vitamin D receptor activators use might be beneficial among these patients.

Clinical Outcomes in Patients on Hemodialysis with Congestive Heart Failure.

Introduction: Congestive heart failure (CHF) is one of the common complications in patients with end-stage kidney disease. In the general population, CHF increases the risk of the death. However, there is no well-designed relevant study in the Chinese hemodialysis (HD) population addressing the risks associated with CHF. The aim of this study was to explore the impact of CHF on clinical outcomes in HD patients. Methods: Data from a prospective cohort study, the China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5 (2012-2015), were analyzed. Demographic data, comorbidities, lab data, and death records were extracted. CHF was defined by the diagnosis records upon study inclusion. Our primary outcome was all-cause and cardiovascular (CV) mortality; secondary outcomes were all-cause and cause-specific hospitalization risk. Associations between CHF and outcomes were evaluated using Cox regression models. Stepwise multivariate logistic regression was used to identify the related risk factors, and subgroup analyses were carried out. Results: Of 1,411 patients without missing CHF history information, 24.1% (340) had CHF diagnosis at enrollment. The overall mortality rates were 21.8% versus 12.0% (p < 0.001) in patients with and without CHF during follow-up, respectively. CHF was associated with higher all-cause mortality (adjusted HR: 1.72, 95% confidence interval [CI]: 1.17-2.53, p = 0.006), and the association with CV death was of similar magnitude (HR: 1.60, 95% CI: 0.91-2.81, p = 0.105). CHF patients had more episodes of hospitalization due to heart failure (HR: 2.93, 95% CI: 1.49-5.76, p < 0.01). However, compared with patients without CHF, the all-cause hospitalization risk was not much higher in CHF patients (HR: 1.09, 95% CI: 0.90-1.33, p = 0.39). Subgroup analysis found that the effect of CHF on all-cause mortality was stronger for male patients, patients with residual renal function, the elderly (≥60 years of age), patients with arteriovenous fistulae vascular accesses, nondiabetic patients, low-flux dialyzer users, and inadequately dialyzed patients (standardized Kt/V <2). Conclusion: In HD patients, CHF was found to be associated with a higher risk of all-cause mortality and cause-specific hospitalization risk. Further research is needed to identify opportunities to improve care for HD patients combined with CHF.

Development and Validation of a Predictive Risk Algorithm for Bleeding in Individuals on Long-term Hemodialysis: An International Prospective Cohort Study (BLEED-HD).

Background: Individuals with kidney disease are at a high risk of bleeding and as such tools that identify those at highest risk may aid mitigation strategies. Objective: We set out to develop and validate a prediction equation (BLEED-HD) to identify patients on maintenance hemodialysis at high risk of bleeding. Design: International prospective cohort study (development); retrospective cohort study (validation). Settings: Development: 15 countries (Dialysis Outcomes and Practice Patterns Study [DOPPS] phase 2-6 from 2002 to 2018); Validation: Ontario, Canada. Patients: Development: 53 147 patients; Validation: 19 318 patients. Measurements: Hospitalization for a bleeding event. Methods: Cox proportional hazards models. Results: Among the DOPPS cohort (mean age, 63.7 years; female, 39.7%), a bleeding event occurred in 2773 patients (5.2%, event rate 32 per 1000 person-years), with a median follow-up of 1.6 (interquartile range [IQR], 0.9-2.1) years. BLEED-HD included 6 variables: age, sex, country, previous gastrointestinal bleeding, prosthetic heart valve, and vitamin K antagonist use. The observed 3-year probability of bleeding by deciles of risk ranged from 2.2% to 10.8%. Model discrimination was low to moderate (c-statistic = 0.65) with excellent calibration (Brier score range = 0.036-0.095). Discrimination and calibration of BLEED-HD were similar in an external validation of 19 318 patients from Ontario, Canada. Compared to existing bleeding scores, BLEED-HD demonstrated better discrimination and calibration (c-statistic: HEMORRHAGE = 0.59, HAS-BLED = 0.59, and ATRIA = 0.57, c-stat difference, net reclassification index [NRI], and integrated discrimination index [IDI] all P value <.0001). Limitations: Dialysis procedure anticoagulation was not available; validation cohort was considerably older than the development cohort. Conclusion: In patients on maintenance hemodialysis, BLEED-HD is a simple risk equation that may be more applicable than existing risk tools in predicting the risk of bleeding in this high-risk population.

Contexte: Les personnes atteintes d'insuffisance rénale présentent un risque élevé d'hémorragie. Des outils permettant de déceler les personnes les plus exposées au risque pourrait aider à mettre en œuvre des stratégies d'atténuation. Objectifs: Nous avons mis au point et validé une équation prédictive (BLEED-HD) afin d'identifier les patients sous hémodialyse d'entretien qui présentent un risque élevé d'hémorragie. Type d'étude: Étude de cohorte prospective internationale (développement); étude de cohorte rétrospective (validation). Cadre: Développement: dans 15 pays (étude DOPPS phases 2 à 6 entre 2002 et 2018); validation: en Ontario (Canada). Sujets: Développement: 53 147 patients; validation: 19 318 patients. Mesures: Hospitalisation pour un événement hémorragique. Méthodologie: Modèles à risques proportionnels de Cox. Résultats: Dans la cohorte DOPPS (âge moyen: 63,7 ans; 39,7 % de femmes), 2 773 patients avaient subi un événement hémorragique (5,2 %; taux d'événements: 32 pour 1 000 années-personnes) avec un suivi médian de 1,6 an (ÉIQ: 0,9 à 2,1). BLEED-HD prend six variables en compte: âge, sexe, pays d'origine, saignement gastro-intestinal antérieur, présence d'une valve cardiaque prothétique et utilisation d'un antagoniste de la vitamine K. La probabilité observée de saignements dans les 3 ans par déciles de risque allait de 2,2 à 10,8 %. La discrimination du modèle variait de faible à modérée (statistique c: 0,65) avec un excellent étalonnage (plage de score de Brier: 0,036-0,095). La discrimination et l'étalonnage de se sont avérés semblables lors de la validation externe auprès de 19 318 patients de l'Ontario (Canada). Par rapport aux scores d'hémorragie existants, l'équation BLEED-HD a démontré une meilleure discrimination et un meilleur étalonnage (statistique c: HEMORRHAGE 0,59; HAS-BLED 0,59 et ATRIA 0,57; différence dans les c-stat, indices NRI et IDI toutes valeurs de p < 0,0001). Limites: L'information sur l'anticoagulant utilisé dans la procédure de dialyse n'était pas disponible; la cohorte de validation était beaucoup plus âgée que la cohorte de développement. Conclusion: Pour les patients sous hémodialyse d'entretien, BLEED-HD est une équation simple de calcul du risque qui peut être plus facilement applicable que les outils existants pour prédire le risque d'hémorragie dans cette population à haut risque.

Adverse Gastrointestinal Events With Sodium Polystyrene Sulfonate Use in Patients on Maintenance Hemodialysis: An International Cohort Study.

Background: There are concerns regarding the gastrointestinal (GI) safety of sodium polystyrene sulfonate (SPS), a medication commonly used in the management of hyperkalemia. Objective: To compare the risk of GI adverse events among users versus non-users of SPS in patients on maintenance hemodialysis. Design: International prospective cohort study. Setting: Seventeen countries (Dialysis Outcomes and Practice Patterns Study [DOPPS] phase 2-6 from 2002 to 2018). Patients: 50 147 adults on maintenance hemodialysis. Measurements: An adverse GI event defined by a GI hospitalization or GI fatality with SPS prescription compared with no SPS prescription. Methods: Overlap propensity score-weighted Cox models. Results: Sodium polystyrene sulfonate prescription was present in 13.4% of patients and ranged from 0.42% (Turkey) to 20.6% (Sweden) with 12.5% use in Canada. A total of 935 (1.9%) adverse GI events (140 [2.1%] with SPS, 795 [1.9%] with no SPS; absolute risk difference 0.2%) occurred. The weighted hazard ratio (HR) of a GI event was not elevated with SPS use compared with non-use (HR = 0.93, 95% confidence interval = 0.83-1.6). The results were consistent when examining fatal GI events and/or GI hospitalization separately. Limitations: Sodium polystyrene sulfonate dose and duration were unknown. Conclusions: Sodium polystyrene sulfonate use in patients on hemodialysis was not associated with a higher risk of an adverse GI event. Our findings suggest that SPS use is safe in an international cohort of maintenance hemodialysis patients.

Contexte: Des préoccupations sont soulevées quant à l'innocuité gastro-intestinale (GI) du sulfonate de polystyrène sodique (SPS), un médicament couramment utilisé dans la gestion de l'hyperkaliémie. Objectif: Comparer dans une population de patients sous hémodialyse d'entretien le risque d'effets indésirables gastro-intestinaux chez les utilisateurs du SPS par rapport aux patients non-utilisateurs. Conception: Étude de cohorte prospective internationale. Cadre: 17 pays (phases 2 à 6 de l'essai DOPPS [de 2002 à 2018]). Sujets: 50 147 adultes sous hémodialyse d'entretien. Mesures: La comparaison entre les événements gastro-intestinaux indésirables, définis par une hospitalisation ou un décès en lien avec un problème gastro-intestinal, selon que les patients avaient ou non une prescription de SPS. Méthodologie: Modèles de Cox pondérés par le score de propension au chevauchement. Résultats: Dans l'ensemble de la cohorte, 13,4 % des patients avaient une prescription de SPS; l'usage de SPS variait selon les pays entre 0,42 % (Turquie) et 20,6 % (Suède) avec 12,5 % au Canada. En tout, 935 (1,9 %) événements GI indésirables sont survenus dans l'ensemble de la cohorte, soit 140 (2,1 %) chez les patients avec prescription de SPS et 795 (1,9 %) chez les patients sans prescription de SPS (différence de risque absolue: 0,2 %). Le rapport de risque (RR) pondéré d'un événement GI n'était pas plus élevé avec l'utilisation de SPS (RR = 0,93; IC 95 %: 0,83-1,6). Les résultats étaient cohérents lorsque l'on a examiné séparément les événements gastro-intestinaux (hospitalisation et/ou décès). Limites: La dose et la durée du traitement par SPS étaient inconnues. Conclusion: L'utilisation de SPS chez les patients sous hémodialyse n'a pas été associée à un risque plus élevé d'événements indésirables d'origine gastro-intestinale. Nos résultats suggèrent que l'utilisation du SPS est sans danger dans la cohorte internationale de patients sous hémodialyse d'entretien étudiée.

Thrombocytopenia predicts mortality in Chinese hemodialysis patients- an analysis of the China DOPPS.

BACKGROUND: Hemodialysis (HD) patients have a higher mortality rate compared with general population. Our previous study revealed that platelet counts might be a potential risk factor. The role of platelets in HD patients has rarely been studied. The aim of this study is to examine if there is an association of thrombocytopenia (TP) with elevated risk of all-cause mortality and cardiovascular (CV) death in Chinese HD patients. METHODS: Data from a prospective cohort study, China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5, were analyzed. Demographic data, comorbidities, platelet counts and other lab data, and death records which extracted from the medical record were analyzed. TP was defined as the platelet count below the lower normal limit (< 100*109/L). Associations between platelet counts and all-cause and CV mortality were evaluated using Cox regression models. Stepwise multivariate logistic regression was used to identify the independent associated factors, and subgroup analyses were also carried out. RESULTS: Of 1369 patients, 11.2% (154) had TP at enrollment. The all-cause mortality rates were 26.0% vs. 13.3% (p < 0.001) in patients with and without TP. TP was associated with higher all-cause mortality after adjusted for covariates (HR:1.73,95%CI:1.11,2.71), but was not associated with CV death after fully adjusted (HR:1.71,95%CI:0.88,3.33). Multivariate logistic regression showed that urine output < 200 ml/day, cerebrovascular disease, hepatitis (B or C), and white blood cells were independent impact factors (P < 0.05). Subgroup analysis found that the effect of TP on all-cause mortality was more prominent in patients with diabetes or hypertension, who on dialysis thrice a week, with lower ALB (< 4 g/dl) or higher hemoglobin, and patients without congestive heart failure, cerebrovascular disease, or hepatitis (P < 0.05). CONCLUSION: In Chinese HD patients, TP is associated with higher risk of all-cause mortality, but not cardiovascular mortality. Platelet counts may be a useful prognostic marker for clinical outcomes among HD patients, though additional study is needed.

Worldwide Early Impact of COVID-19 on Dialysis Patients and Staff and Lessons Learned: A DOPPS Roundtable Discussion.

As the worst global pandemic of the past century, coronavirus disease 2019 (COVID-19) has had a disproportionate effect on maintenance dialysis patients and their health care providers. At a virtual roundtable on June 12, 2020, Dialysis Outcomes and Practice Patterns Study (DOPPS) investigators from 15 countries in Asia, Europe, and the Americas described and compared the effects of COVID-19 on dialysis care, with recent updates added. Most striking is the huge difference in risk to dialysis patients and staff across the world. Per-population cases and deaths among dialysis patients vary more than 100-fold across participating countries, mirroring burden in the general population. International data indicate that the case-fatality ratio remains at 10% to 30% among dialysis patients, confirming the gravity of infection, and that cases are much more common among in-center than home dialysis patients. This latter finding merits urgent study because in-center patients often have greater community exposure, and in-center transmission may be uncommon under optimal protocols. Greater telemedicine use is a welcome change here to stay, and our community needs to improve emergency planning and protect dialysis staff from the next pandemic. Finally, the pandemic's challenges have prompted widespread partnering and innovation in kidney care and research that must be sustained after this global health crisis.

Serum total indoxyl sulfate and clinical outcomes in hemodialysis patients: results from the Japan Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Uremic toxins are associated with various chronic kidney disease-related comorbidities. Indoxyl sulfate (IS), a protein-bound uremic toxin, reacts with vasculature, accelerating atherosclerosis and/or vascular calcification in animal models. Few studies have examined the relationship of IS with clinical outcomes in a large cohort of hemodialysis (HD) patients. METHODS: We included 1170 HD patients from the Japan Dialysis Outcomes and Practice Patterns Study Phase 5 (2012-15). We evaluated the associations of serum total IS (tIS) levels with all-cause mortality and clinical outcomes including cardiovascular (CV)-, infectious- and malignancy-caused events using Cox regressions. RESULTS: The median (interquartile range) serum tIS level at baseline was 31.6 µg/mL (22.6-42.0). Serum tIS level was positively associated with dialysis vintage. Median follow-up was 2.8 years (range: 0.01-2.9). We observed 174 deaths (14.9%; crude rate, 0.06/year). Serum tIS level was positively associated with all-cause mortality [adjusted hazard ratio per 10 µg/mL higher, 1.16; 95% confidence interval (CI) 1.04-1.28]. Association with cause-specific death or hospitalization events, per 10 µg/mL higher serum tIS level, was 1.18 (95% CI 1.04-1.34) for infectious events, 1.08 (95% CI 0.97-1.20) for CV events and 1.02 (95% CI 0.87-1.21) for malignancy events after adjusting for covariates including several nutritional markers. CONCLUSIONS: In a large cohort study of HD patients, serum tIS level was positively associated with all-cause mortality and infectious events.

The effect of transportation modality to dialysis facilities on health-related quality of life among hemodialysis patients: results from the Japanese Dialysis Outcomes and Practice Pattern Study.

BACKGROUND: For hemodialysis (HD) patients, travel to the dialysis facility is an issue that can affect their quality of life (QOL), both physically and mentally. However, evidence on this association of transportation modality with health-related QOL (HRQOL) is scarce. METHODS: We conducted a cohort study among maintenance HD patients participating in the Japanese Dialysis Outcomes and Practice Pattern Study Phase 5. The study included patients who were functionally independent and able to walk. The primary exposure was the means of transportation to the dialysis facility, categorized into three groups, namely transportation by other drivers (Group 1), transportation via self-driving (Group 2) and transportation by bicycle or walking with or without public transportation (Group 3). The primary outcomes were physical and mental health composite scores (PCS and MCS) in the 12-item Short Form at 1 year after study initiation. RESULTS: Among 1225 eligible patients (Group 1, 34.4%; Group 2, 45.0%; Group 3, 20.7%), 835 were analyzed for the primary outcomes. Linear regression analyses revealed that patients in Groups 2 and 3 had significantly higher PCS and MCS at 1 year than those in Group 1 {adjusted mean differences of PCS 1.42 [95% confidence interval (CI) 0.17-2.68] and 1.94 [95% CI 0.65-3.23], respectively, and adjusted mean differences of MCS 2.53 [95% CI 0.92-4.14] and 2.20 [95% CI 0.45-3.95], respectively}. CONCLUSIONS: Transportation modality was a significant prognostic factor for both PCS and MCS after 1 year in maintenance HD patients.

Inflammation and Erythropoiesis-Stimulating Agent Response in Hemodialysis Patients: A Self-matched Longitudinal Study of Anemia Management in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

RATIONALE & OBJECTIVE: Previous studies of inflammation and anemia management in hemodialysis (HD) patients may be biased due to patient differences. We used a self-matched longitudinal design to test whether new inflammation, defined as an acute increase in C-reactive protein (CRP) level, reduces hemoglobin response to erythropoiesis-stimulating agent (ESA) treatment. STUDY DESIGN: Self-matched longitudinal design. SETTING & PARTICIPANTS: 3,568 new inflammation events, defined as CRP level > 10 mg/L following a 3-month period with CRP level ≤ 5 mg/L, were identified from 12,389 HD patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 6 (2009-2018) in 10 countries in which CRP is routinely measured. PREDICTOR: "After" (vs "before") observing a high CRP level. OUTCOMES: Within-patient changes in hemoglobin level, ESA dose, and ESA hyporesponsiveness (hemoglobin < 10 g/dL and ESA dose > 6,000 [Japan] or >8,000 [Europe] U/wk). ANALYTICAL APPROACH: Linear mixed models and modified Poisson regression. RESULTS: Comparing before with after periods, mean hemoglobin level decreased from 11.2 to 10.9 g/dL (adjusted mean change, -0.26 g/dL), while mean ESA dose increased from 6,320 to 6,960 U/wk (adjusted relative change, 8.4%). The prevalence of ESA hyporesponsiveness increased from 7.6% to 12.3%. Both the unadjusted and adjusted prevalence ratios of ESA hyporesponsiveness were 1.68 (95% CI, 1.48-1.91). These associations were consistent in sensitivity analyses varying CRP thresholds and were stronger when the CRP level increase was sustained over the 3-month after period. LIMITATIONS: Residual confounding by unmeasured time-varying risk factors for ESA hyporesponsiveness. CONCLUSIONS: In the 3 months after HD patients experienced an increase in CRP levels, hemoglobin levels declined quickly, ESA doses increased, and the prevalence of ESA hyporesponsiveness increased appreciably. Routine CRP measurement could identify inflammation as a cause of worsened anemia. In turn, these findings speak to a potentially important role for anemia therapies that are less susceptible to the effects of inflammation.

Parathyroid Hormone Serum Levels and Mortality among Hemodialysis Patients in the Gulf Cooperation Council Countries: Results from the DOPPS (2012-2018).

Background: The prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) has collected data since 2012 in all six Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and United Arab Emirates). We report the relationship of PTH with mortality in this largest GCC cohort of patients on hemodialysis studied to date. Methods: Data were from randomly selected national samples of hemodialysis facilities in GCC-DOPPS phases 5 and 6 (2012-2018). PTH descriptive findings and case mix-adjusted PTH/mortality Cox regression analyses were based on 1825 and 1422 randomly selected patients on hemodialysis, respectively. Results: Mean patient age was 55 years (median dialysis vintage, 2.1 years). Median PTH ranged from 259 pg/ml (UAE) to 437 pg/ml (Kuwait), with 22% having PTH <150 pg/ml, 24% with PTH of 150-300 pg/ml, 34% with PTH 301-700 pg/ml, and 20% with PTH >700 pg/ml. Patients with PTH >700 pg/ml were younger; on dialysis longer; less likely to be diabetic; have urine >200 ml/d; be prescribed 3.5 mEq/L dialysate calcium; had higher mean serum creatinine and phosphate levels; lower white blood cell counts; and more likely to be prescribed cinacalcet, phosphate binders, or IV vitamin D. A U-shaped PTH/mortality relationship was observed with more than two- and 1.5-fold higher adjusted HR of death at PTH >700 pg/ml and <300 pg/ml, respectively, compared with PTH of 301-450 pg/ml. Conclusions: Secondary hyperparathyroidism is highly prevalent among GCC patients on hemodialysis, with a strong U-shaped PTH/mortality relationship seen at PTH <300 and >450 pg/ml. Future studies are encouraged for further understanding this PTH/mortality pattern in relationship to unique aspects of the GCC hemodialysis population.

Combinations of mineral and bone disorder markers and risk of death and hospitalizations in the international Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Prior studies have developed a chronic kidney disease-mineral and bone disorder (CKD-MBD) composite score based on combinations of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) that have been shown to be associated with an increased risk of clinical outcomes in the USA. We examined this association in a contemporary, international cohort of hemodialysis patients. METHODS: We studied 19 313 patients surviving ≥12 months in the Dialysis Outcomes and Practice Patterns Study Phases 3-5 (2005-15) from Europe, Canada and the USA. The CKD-MBD composite score was defined as the number of markers above target levels (P, 3.5-5.5 mg/dL; Ca, 8.4-10.2 mg/dL; PTH, 150-600 pg/mL). Using Cox models, we estimated hazard ratios (HRs) for death and a composite event (death or hospitalization), contrasting MBD 2/3 (2-3 parameters above target) with MBD 0 (all in target), adjusted for a disease risk score (DRS). RESULTS: MBD 2/3 above target was observed in 10-14% of patients across regions and was associated with greater DRS-adjusted mortality {HR 1.41 [95% confidence interval (CI) 1.10-1.82]} and composite events [HR 1.23 (95% CI 1.10-1.38)] in the USA compared with MBD 0; the mortality association was stronger for patients ≥ 65 years of age [HR 1.82 (95% CI 1.28-2.58)] compared with patients <65 years of age [HR 1.11 (95% CI 0.80-1.55)]. HRs observed in Canada and Europe were generally consistent but weaker. Estimates for MBD 2/3 outside target (above or below) were slightly lower in all regions. CONCLUSIONS: Simultaneous consideration of Ca, P and PTH may help in identifying patients on dialysis with a higher risk of major clinical outcomes related to CKD-MBD.

Facility Variation and Predictors of Do Not Resuscitate Orders of Hemodialysis Patients in Canada: DOPPS.

BACKGROUND: Life expectancy in patients with end-stage kidney disease treated with hemodialysis (HD) is limited, and as such, the presence of an advanced care directive (ACD) may improve the quality of death as experienced for patients and families. Strategies to discuss and implement ACDs are limited with little being known about the status of Do Not Resuscitate (DNR) orders in the Canadian HD population. OBJECTIVES: Using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), we set out to (1) examine the variability in DNR orders across Canada and its largest province, Ontario and (2) identify clinical and functional status measures associated with a DNR order. DESIGN: We conducted a retrospective cohort study using data from the DOPPS Canada Phase 4 to 6 from 2009 to 2017. SETTING: DOPPS facilities in Canada. PATIENTS: All adults (>18 years) who initiated chronic HD with a documented ACD were included. MEASUREMENTS: ACD and DNR orders. METHODS: Descriptive statistics were compared for baseline characteristics (demographics, comorbidities, medications, facility characteristics, and patient functional status) and DNR status. The crude proportion of patients per facility with a DNR order was calculated across Canada and Ontario. Functional status was determined by activities of daily living and components of the Kidney Disease Quality of Life (KDQOL)-validated questionnaire. We used generalized estimating equations (GEEs) to create sequential multivariable models (demographics, comorbidities, and functional status) of variables associated with DNR status. RESULTS: A total of 1556 (96% of total) patients treated with HD had a documented ACD and were included. A total of 10% of patients had a DNR order. The crude variation of DNR status differed considerably across facilities within Canada, between Ontario and non-Ontario, and within Ontario (interprovince variation = 6.3%-17.1%, Ontario vs non-Ontario = 8.2% vs 11.7%, intraprovincial variation [Ontario] = 1%-26%). Patients with a DNR order were more commonly older, white, with cardiac comorbidities, with less or shorter predialysis care compared with those without a DNR order. Patients with a DNR order reported lower energy, more difficulty with transfers, meal preparation, household tasks, and financial management. In a multivariate model, age, cardiac disease, stroke, dialysis duration, and intradialytic weight gain were associated with DNR status. LIMITATIONS: Relatively small number of events or measures in certain categories. CONCLUSIONS: A large inter- and intraprovincial (Ontario) variation was observed regarding DNR orders across Canada highlighting areas for potential quality improvement. While functional status did not appear to have a bearing on the presence of a DNR order, the presence of various comorbidities was associated with the presence of a DNR order.

CONTEXTE: L'espérance de vie des patients atteints d'insuffisance rénale terminale (IRT) traités par hémodialyse (HD) est limitée et, de ce fait, la présence de directives médicales anticipées (DMA) peut améliorer la qualité du décès tel qu'il sera vécu par les patients et leurs proches. Les stratégies de discussion et de mise en œuvre de DMA sont limitées et on en sait peu sur le statut des ordonnances de non-réanimation (statut des ONR) dans la population des patients canadiens hémodialysés. OBJECTIFS: À partir des données de l'étude DOPPS (Dialysis Outcomes and Practice Patterns Study), nous avons analysé la variabilité du statut des ONR à travers le Canada et au sein de sa plus grande province, l'Ontario, puis nous avons défini des mesures des états cliniques et fonctionnels associés à une ONR. TYPE D'ÉTUDE: Étude de cohorte rétrospective. SOURCE: Les données canadiennes des phases 4 à 6 de l'étude DOPPS. PARTICIPANTS: Ont été inclus tous les adultes ayant amorcé un traitement d'HD chronique entre 2009 et 2017 et qui avaient rédigé des DMA. MESURES: La non-réanimation (statut de l'ONR) et le statut fonctionnel selon les activités de la vie quotidienne et les composantes du questionnaire validé KDQOL (Kidney Disease Quality of Life) sur la qualité de vie des personnes dialysées. MÉTHODOLOGIE: Les statistiques descriptives ont été comparées sur la base des caractéristiques à l'inclusion (données démographiques, comorbidités, médicaments, caractéristiques de l'établissement de santé et statut fonctionnel du patient) et du statut de l'ONR. La proportion brute de patients par établissement avec une ONR a été calculée pour l'ensemble du Canada et pour l'Ontario seulement. Nous avons utilisé des équations d'estimation généralisées (EEG) pour créer des modèles multivariés séquentiels (données démographiques, comorbidités et statut fonctionnel) des variables associées au statut de l'ONR. RÉSULTATS: Au total, nous avons inclus 1 556 patients hémodialysés (96 % des patients répertoriés) qui avaient des DMA documentées, et 10 % d'entre elles contenaient une ONR. La variation brute du statut de l'ONR différait considérablement d'un établissement à l'autre au Canada, entre l'Ontario et les autres provinces et entre les établissements ontariens (variation entre provinces: 6,3 à 17,1 %; Ontario par rapport aux autres provinces: 8,2 contre 11,7 %; variation intraprovinciale [Ontario]: 1 à 26 %). Les patients avec une ONR étaient généralement de race blanche et plus âgés, présentaient des comorbidités cardiaques et avaient reçu moins de soins de prédialyse et sur une plus courte durée comparativement aux patients sans ONR. Les patients ayant une ONR ont signalé des pertes d'énergie et une plus grande difficulté avec les transferts, la préparation des repas, les tâches ménagères et la gestion financière. Dans un modèle multivarié, l'âge, la maladie cardiaque, les accidents vasculaires cérébraux, la durée de la dialyse et une perte de poids intradialyse ont été associés à l'existence d'une ONR. LIMITES: Un nombre limité d'événements dans certaines catégories; les mesures de l'état fonctionnel étaient transversales. CONCLUSIONS: Une importante variation inter et intraprovinciale (Ontario) a été observée quant au statut des ONR à travers le Canada, ce qui met en évidence les domaines d'amélioration potentielle de la qualité. Bien que l'état fonctionnel du patient n'ait pas semblé avoir d'incidence sur l'existence ou non d'une ONR, on a noté une association entre la présence de comorbidités et l'existence d'une ONR.

Cardiovascular Event Rates Among Hemodialysis Patients Across Geographical Regions-A Snapshot From The Dialysis Outcomes and Practice Patterns Study (DOPPS).

INTRODUCTION: Cardiovascular (CV) morbidity and mortality are excessively high among hemodialysis (HD) patients. Anemia is a common complication of chronic kidney disease (CKD) and a known risk factor for CV events. To understand the impact of the recent regulatory and guideline changes in anemia management, we examined regional CV event rates in high-risk and erythropoiesis-stimulating agent (ESA)-hyporesponsive HD patients. METHODS: A prospective cohort study including 16,560 HD patients, 8660 CV high-risk, and 884 hyporesponsive to ESAs, from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 4 (2009-2011) and phase 5 (2012-2015) was conducted to quantify all-cause mortality, major adverse cardiovascular events (MACE), and MACE plus heart failure and thromboembolic events (MACE+). RESULTS: The MACE+ rates (per 100 patient-years) were highest in North America (NA) (19.4; 95% CI = 18.2-20.7), followed by Europe (EU) (17.4; 95% CI = 16.6-18.1) and lowest in Japan (7.5; 95% CI = 6.9-8.1). When restricted to the high CV risk population, rates increased by 36% in NA, 45% in EU, and 72% in Japan. Mortality accounted for >74% of MACE+ events. MACE+ rates in ESA-hyporesponsive patients and high CV risk patients were similar in NA and EU cohorts. There were minimal differences in outcomes between the DOPPS phases 4 and 5. CONCLUSION: Cardiovascular event rates are high in the HD population, vary by geographic region, and are substantially higher in high CV risk patients and ESA-hyporesponsive patients; however, the rates appear not to be affected by anemia guideline changes. The findings from this study will be essential to contextualize the design of future CV anemia-related outcome studies and clinical trials.

Variability in Cinacalcet Prescription across US Hemodialysis Facilities.

BACKGROUND AND OBJECTIVES: Calcimimetic drugs used to treat secondary hyperparathyroidism are being considered for inclusion in the Medicare ESRD Prospective Payment System bundle after an evaluation period. Understanding of utilization patterns of calcimimetics across dialysis facilities may help align financial incentives with clinical objectives. Our study's purpose was to describe the distribution of cinacalcet prescription across United States hemodialysis facilities and to explore factors that may influence cinacalcet utilization. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used monthly cross-sectional data from the Dialysis Outcomes and Practice Patterns Study in 2014 to characterize the distribution of cinacalcet prescription across 203 United States hemodialysis facilities (10,521 patients). On the basis of associations with parathyroid hormone levels from patient-level analyses, we used linear mixed-effects regressions to estimate the associations between three facility-level exposures (black race, <65 years old, and having ≥3 years on dialysis [vintage]) and the prevalence of cinacalcet prescription, adjusting for facility- and patient-level potential confounders. RESULTS: The mean percentage of patients in each facility with cinacalcet prescription was 23% in June 2014 (median, 22%; interquartile range, 13%-30%). Adjusted for facility-level and nonexposure patient-level variables, the difference in prevalence of cinacalcet prescription between facilities with the highest and lowest quartiles of percentage of black patients was 7.8% (95% confidence interval [95% CI], 0.8% to 14.8%; P for trend =0.03). The adjusted prevalence difference was 7.3% for the percentage of patients aged <65 years (95% CI, -0.1% to 14.7%; P for trend =0.06) and 11.9% for the percentage of patients with ≥3 years of dialysis (95% CI, 2.4% to 21.4%; P for trend =0.02). These associations changed appreciably, becoming much weaker or even reversing, after further adjusting for the patient-level exposure variables. CONCLUSIONS: Facilities treating more patients who are black, under age 65 years, and having dialysis vintage ≥3 years have higher average levels of cinacalcet prescription. However, these differences were strongly attenuated after accounting for the unbalanced distributions of these patient case-mix variables.

International and Racial Differences in Mineral and Bone Disorder Markers and Treatments Over the First 5 Years of Hemodialysis in the Dialysis Outcomes and Practice Patterns Study.

RATIONALE & OBJECTIVE: Normalization of parathyroid hormone (PTH), serum calcium, and phosphorus levels may prevent coronary and bone disease in hemodialysis (HD) patients. We describe the trajectory of these mineral bone disorder parameters and treatments during the first 5 years of HD by international region and race. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 33,517 US black/African American, US non-black/African American, European, and Japanese HD patients from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 5 (2009-2015). PREDICTOR: Time since HD initiation. OUTCOMES: Monthly cross-sections of mineral bone disorder parameters (PTH, serum calcium, and phosphorus) and medications (cinacalcet, active vitamin D, and phosphate binders). RESULTS: Mean PTH levels declined precipitously during the first 4 months of HD in all 4 groups, then steadily increased during the next 4.5 years in the United States/Europe but not in Japan. 3 years after HD initiation (month 36), mean PTH level was highest in US black/African Americans (496 pg/mL), despite greater prescription of cinacalcet (23%) and active vitamin D (85%), and lowest in Japan (151 pg/mL). Mean serum calcium and phosphorus levels increased during the first 4 months of HD. By month 36, the mean calcium level was lower in Japan (8.8 mg/dL) than United States/Europe (9.0-9.1 mg/dL), while the mean phosphorus level was lower in Europe (4.8 mg/dL) than United States/Japan (5.1-5.3 mg/dL). LIMITATIONS: Lack of data for medication dosages; most patients were not followed from HD onset. CONCLUSIONS: Large differences exist in the levels, trajectories, and therapies for PTH, calcium, and phosphorus by country and race in the first 5 years of HD. Higher PTH levels were observed in the United States, especially among black/African American patients, despite greater use of cinacalcet and active vitamin D than in Japan or Europe. Potential contributors to differences in PTH levels should be explored to study their impact on PTH management strategies and consequent bone and cardiovascular complications.

DOPPS data suggest a possible survival benefit of renin angiotensin-aldosterone system inhibitors and other antihypertensive medications for hemodialysis patients.

The benefits of renin angiotensin-aldosterone system inhibitors (RAASi) are well-established in the general population, particularly among those with diabetes, congestive heart failure (CHF), or coronary artery disease (CAD). However, conflicting evidence from trials and concerns about hyperkalemia limit RAASi use in hemodialysis patients, relative to other antihypertensive agents, including beta blockers and calcium channel blockers. Therefore, we investigated prescription patterns and associations with mortality for RAASi and other antihypertensive agents using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS). Cox regression was used to estimate the effect of the prescription of RAASi and other antihypertensive agents at study entry on mortality in 11,421 incident (120 days or less) hemodialysis and 37,124 prevalent (over 120 days) hemodialysis patients from DOPPS phases 2-5 (2002-2015). Over 95% of RAASi were angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. RAASi prevalence was 39% and varied minimally by CHF and CAD. The adjusted hazard ratio for RAASi (vs. no RAASi) was 0.89 (95% confidence interval 0.80-0.99) among incident and 0.94 (0.90-0.99) among prevalent hemodialysis patients, with no convincing evidence of interaction with diabetes, CAD or CHF. Inverse associations with mortality were also observed for beta blockers and calcium channel blockers, and were stronger for angiotensin receptor blockers than angiotensin-converting enzyme inhibitors, but this latter finding requires further study. Thus, our observations suggest a relatively small survival benefit of RAASi and other antihypertensive agents in hemodialysis patients, though randomized prospective studies are needed to potentially change prescribing criteria.

International Differences in the Location and Use of Arteriovenous Accesses Created for Hemodialysis: Results From the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Vascular access practice is strongly associated with clinical outcomes. There is substantial international variation in the use of arteriovenous fistulas (AVFs) and grafts (AVGs), as well as AVF maturation time and location. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Hemodialysis patients participating in the prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) from the United States, Japan, and Europe/ANZ (Belgium, France, Germany, Italy, Spain, Sweden, United Kingdom, Australia, and New Zealand), including 3,850 patients receiving 4,247 new AVFs and 842 patients receiving 1,129 new AVGs in 2009 to 2015. AVF location trends were based on 38,868 AVFs recorded in DOPPS 1 to 5 cross-sections (1996-2015). PREDICTORS: Demographics, comorbid conditions, dialysis vintage, body mass index, facility percentage AVF use, median blood flow rate, and AVF location. OUTCOMES: AVF location; successful AVF/AVG use (≥30 days of continuous use); time-to-first successful AVF/AVG use (maturation). RESULTS: During DOPPS 1 to 5, the percentage of AVFs created in the lower arm was consistently ≥93% in Japan and 65% to 77% in Europe/ANZ, but in the United States, this value declined from 70% (DOPPS 1) to 32% (DOPPS 5). Patient characteristics associated with AVF location differed by region. Successful AVF use was 87% in Japan, 67% in Europe/ANZ, and 64% in the United States, whereas successful AVG use was 86%, 75%, and 78%, respectively. Successful AVF use was greater for upper- versus lower-arm AVFs in the United States, with little difference in Europe/ANZ and the opposite pattern in Japan. Median time until first successful AVF use was 10 days in Japan, 46 days in Europe/ANZ, and 82 days in United States; until first successful AVG use: 6, 24, and 29 days, respectively. LIMITATIONS: Potential measurement error related to chart data abstraction in multiple hemodialysis facilities. CONCLUSIONS: Large international differences exist in AVF location, predictors of AVF location, successful use of AVFs, and time to first AVF/AVG use, challenging what constitutes best practice. The large US shift from lower- to upper-arm AVFs raises serious concerns about long-term health implications for some patients and how policies and practices aimed at increasing AVF use have affected AVF placement location.

Initiation of Sevelamer and Mortality among Hemodialysis Patients Treated with Calcium-Based Phosphate Binders.

BACKGROUND AND OBJECTIVES: Prior studies have shown that sevelamer attenuates progression of arterial calcification and may reduce the risk of death compared with calcium-based phosphate binders. In clinical practice, however, sevelamer is used not only as an alternative but also as an add-on therapy in patients already being treated with calcium-based phosphate binders. We analyzed the Dialysis Outcomes and Practice Patterns Study (DOPPS) data to test the hypothesis that the initiation of sevelamer is associated with improved survival in patients on hemodialysis treated with calcium-based phosphate binders. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We included 12,564 patients from DOPPS phase 3 and phase 4 (2005-2011) who were prescribed calcium-based phosphate binders at baseline or before sevelamer treatment. Mortality risk was assessed using a sequential stratification method to identify as-yet-untreated patients who were appropriately matched to the newly treated patients on the basis of their risk of death. RESULTS: Of 12,564 patients, 2606 were subsequently treated with sevelamer hydrochloride or sevelamer carbonate. After beginning sevelamer therapy, mean serum phosphorus levels decreased by 0.3 mg/dl in the first 4 months and gradually decreased thereafter. We matched 2501 treated patients with at least one as-yet-untreated patient. Patients treated with sevelamer had a 14% lower risk for mortality compared with as-yet-untreated patients (hazard ratio, 0.86; 95% confidence interval, 0.76 to 0.97). Similar results were observed in the sensitivity analyses when changing the matching calipers or the treated and as-yet-untreated ratios, and by using propensity score matching. CONCLUSIONS: The use of sevelamer as an add-on or alternative therapy to calcium-based phosphate binders is associated with improved survival in patients on maintenance hemodialysis.

Unique hemoglobin A1c level distribution and its relationship with mortality in diabetic hemodialysis patients.

Diabetic hemodialysis patients with hemoglobin A1c (HbA1c) levels below 6.5% and over 8.0% face a higher mortality risk. To determine the optimal glycemic control in Japanese patients, we examined the association between HbA1c and mortality in 2,300 Japanese diabetic patients on maintenance hemodialysis with HbA1c levels determined at enrollment in the Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS) phases 2-5, using Cox regression analysis with adjustment for baseline age, sex, dialysis vintage, 12 general comorbidities, hemoglobin, albumin and creatinine levels, and insulin use; stratification by JDOPPS phase; and facility clustering taken into account. Overall, 54% of patients had HbA1c levels under 6.0, including 14% with HbA1c levels under 5.0. Insulin or oral diabetes medications were used less frequently in patients with higher HbA1c levels. The dependence of mortality on HbA1c level was U shaped. When the group with the lowest mortality (HbA1c 6.0-7.0) was used as a reference, the hazard ratios for HbA1c categories under 5.0, 5.0-6.0, 7.0 to under 8.0, and 8.0 and greater were, respectively, 1.56 (95% confidence interval, 1.05-2.33), 1.26 (0.92-1.71), 1.23 (0.79-1.89), and 2.10 (1.32-3.33) in the adjusted model. The HbA1c level was not associated with self-reported hypoglycemic episodes in JDOPPS phase 5. The HbA1c levels in diabetic hemodialysis patients differ considerably between Japan and those reported from Western countries. Thus, our findings highlight the importance of domestic guidelines for glycemic control by race and country.