Serum Phosphorus Level Rises in US Hemodialysis Patients Over the Past Decade: A DOPPS Special Report.

Mineral bone disorder (MBD) is a frequent consequence of chronic kidney disease, more so in patients with kidney failure treated by kidney replacement therapy. Despite the wide availability of interventions to control serum phosphate and parathyroid hormone levels, unmet gaps remain on optimal targets and best practices, leading to international practice pattern variations over time. In this Special Report, we describe international trends from the Dialysis Outcomes and Practice Patterns Study (DOPPS) for MBD biomarkers and treatments from 2002-2021, including data from a group of 7 European countries (Belgium, France, Germany, Italy, Spain, Sweden, United Kingdom), Japan, and the United States. From 2002-2012, mean phosphate levels declined in Japan (5.6 to 5.2 mg/dL), Europe (5.5 to 4.9 mg/dL), and the United States (5.7 to 5.0 mg/dL). Since then, levels rose in the United States (to mean 5.6 mg/dL, 2021), were stable in Japan (5.3 mg/dL), and declined in Europe (4.8 mg/dL). In 2021, 52% (United States), 27% (Europe), and 39% (Japan) had phosphate >5.5 mg/dL. In the United States, overall phosphate binder use was stable (80%-84% over 2015-2021), and parathyroid hormone levels rose only modestly. Although these results potentially stem from pervasive knowledge gaps in clinical practice, the noteworthy steady increase in serum phosphate in the United States over the past decades may be consequential to patient outcomes, an uncertainty that hopefully will soon be addressed by ongoing clinical trials. The DOPPS will continue to monitor international trends as new interventions and strategies ensue for MBD management in chronic kidney disease.

Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia.

BACKGROUND: Approximately 30%-45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks. METHODS: The study included 5145 patients from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study, with first available transferrin saturation (TSAT) and ferritin levels as exposure variables. We used Cox models to estimate hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACE), with progressive adjustment for potentially confounding variables. We also used linear spline models to further evaluate functional forms of the exposure-outcome associations. RESULTS: Compared with patients with a TSAT of 26%-35%, those with a TSAT ≤15% had the highest adjusted risks for all-cause mortality and MACE. Spline analysis found the lowest risk at TSAT 40% for all-cause mortality and MACE. Risk of all-cause mortality, but not MACE, was also elevated at TSAT ≥46%. Effect estimates were similar after adjustment for hemoglobin. For ferritin, no directional associations were apparent, except for elevated all-cause mortality at ferritin ≥300 ng/ml. CONCLUSIONS: Iron deficiency, as captured by TSAT, is associated with higher risk of all-cause mortality and MACE in patients with nondialysis CKD, with or without anemia. Interventional studies evaluating the effect on clinical outcomes of iron supplementation and therapies for alternative targets are needed to better inform strategies for administering exogenous iron.

A real-world longitudinal study of anemia management in non-dialysis-dependent chronic kidney disease patients: a multinational analysis of CKDopps.

Previously lacking in the literature, we describe longitudinal patterns of anemia prescriptions for non-dialysis-dependent chronic kidney disease (NDD-CKD) patients under nephrologist care. We analyzed data from 2818 Stage 3-5 NDD-CKD patients from Brazil, Germany, and the US, naïve to anemia medications (oral iron, intravenous [IV] iron, or erythropoiesis stimulating agent [ESA]) at enrollment in the CKDopps. We report the cumulative incidence function (CIF) of medication initiation stratified by baseline characteristics. Even in patients with hemoglobin (Hb) < 10 g/dL, the CIF at 12 months for any anemia medication was 40%, and 28% for ESAs. Patients with TSAT < 20% had a CIF of 26% and 6% for oral and IV iron, respectively. Heart failure was associated with earlier initiation of anemia medications. IV iron was prescribed to < 10% of patients with iron deficiency. Only 40% of patients with Hb < 10 g/dL received any anemia medication within a year. Discontinuation of anemia treatment was very common. Anemia treatment is initiated in a limited number of NDD-CKD patients, even in those with guideline-based indications to treat. Hemoglobin trajectory and a history of heart failure appear to guide treatment start. These results support the concept that anemia is sub-optimally managed among NDD-CKD patients in the real-world setting.

Physical health-related quality of life at higher achieved hemoglobin levels among chronic kidney disease patients: a systematic review and meta-analysis.

BACKGROUND: The impact of anemia treatment with erythropoietin stimulating agents (ESA) on health-related quality of life (HRQOL) in chronic kidney disease (CKD) patients is controversial, particularly regarding optimal hemoglobin (Hb) target ranges. METHODS: We conducted a systematic review and meta-analysis of observational studies and randomized controlled trials (RCT) with ESA to estimate the effect of different achieved Hb values on physical HRQOL and functionality. We searched PubMed, EMBASE, CENTRAL, PEDro, PsycINFO and Web of Science databases, until May 2020. Two authors independently extracted data from studies. We included observational and RCTs that enrolled CKD patients undergoing anemia treatment with ESA with different achieved Hb levels among groups. We excluded studies with achieved Hb < 9 g/dL. For the meta-analysis, we included RCTs with control groups achieving Hb 10-11.5 g/dL and active groups with Hb > 11.5 g/dL. We analyzed the standardized mean difference (SMD) between groups for physical HRQOL. RESULTS: Among 8496 studies, fifteen RCTs and five observational studies were included for the systematic review. We performed the meta-analysis in a subset of eleven eligible RCTs. For physical role and physical function, SMDs were 0.0875 [95% CI: - 0.0025 - 0.178] and 0.08 [95% CI: - 0.03 - 0.19], respectively. For fatigue, SMD was 0.16 [95% CI: 0.09-0.24]. Subgroup analysis showed that trials with greater achieved Hb had greater pooled effects sizes - 0.21 [95% CI: 0.07-0.36] for Hb > 13 g/dL vs. 0.09 [95% CI: 0.02-0.16] for Hb 11.5-13 g/dL. Proportion of older and long-term diabetic patients across studies were associated with lower effect sizes. CONCLUSION: Achieved hemoglobin higher than currently recommended targets may be associated with small but potentially clinically significant improvement in fatigue, but not in physical role or physical function. Younger and non-diabetic patients may experience more pronounced benefits of higher Hb levels after treatment with ESAs.

Associations of Hemoglobin Levels With Health-Related Quality of Life, Physical Activity, and Clinical Outcomes in Persons With Stage 3-5 Nondialysis CKD.

OBJECTIVE: Conflicting findings and knowledge gaps exist regarding links between anemia, physical activity, health-related quality of life (HRQOL), chronic kidney disease (CKD) progression, and mortality in moderate-to-advanced CKD. Using the CKD Outcomes and Practice Patterns Study, we report associations of hemoglobin (Hgb) with HRQOL and physical activity, and associations of Hgb and physical activity with CKD progression and mortality in stage 3-5 nondialysis (ND)-CKD patients. DESIGN AND METHODS: Prospectively collected data were analyzed from 2,121 ND-CKD stage 3-5 patients, aged ≥18 years, at 43 nephrologist-run US and Brazil CKD Outcomes and Practice Patterns Study-participating clinics. Cross-sectional associations were assessed of Hgb levels with HRQOL and physical activity levels (from validated Kidney Disease Quality of Life Instrument and Rapid Assessment of Physical Activity surveys). CKD progression (first of ≥40% estimated glomerular filtration rate [eGFR] decline, eGFR<10 mL/min/1.73 m2, or end-stage kidney disease) and all-cause mortality with Hgb and physical activity levels were also evaluated. Linear, logistic, and Cox regression analyses were adjusted for country, demographics, smoking, eGFR, serum albumin, very high proteinuria, and 13 comorbidities. RESULTS: HRQOL was worse, with severe anemia (Hgb<10 g/dL), but also evident for mild/moderate anemia (Hgb 10-12 g/dL), relative to Hgb>12 g/dL. Odds of being highly physically active were substantially greater at Hgb>10.5 g/dL. Lower Hgb was strongly associated with greater CKD progression and mortality, even after extensive adjustment. Physical inactivity was strongly associated with greater mortality and weakly associated with CKD progression. Possible residual confounding is a limitation. CONCLUSION: This multicenter international study provides real-world observational evidence for greater HRQOL, physical activity, lower CKD progression, and greater survival in ND-CKD patients with Hgb levels >12 g/dL, exceeding current treatment guideline recommendations. These findings help inform future studies aimed at understanding the impact of new anemia therapies and physical activity regimens on improving particular dimensions of ND-CKD patient well-being and clinical outcomes.

Prescription of renin-angiotensin-aldosterone system inhibitors (RAASi) and its determinants in patients with advanced CKD under nephrologist care.

Renin-angiotensin-aldosterone system inhibitors (RAASi) are recommended for chronic kidney disease (CKD) patients. In this study, we describe RAASi prescription patterns in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, Germany, France, and the United States (US). 5870 patients (mean age 66-72 years; congestive heart failure [CHF] in 11%-19%; diabetes in 43%-54%; serum potassium ≥5 in 20%-35%) were included. RAASi prescription was more common in Germany (80%) and France (77%) than Brazil (66%) and the United States (52%), where the prevalence of prescription decreases particularly in patients with CKD stage 5. In the multivariable regression model, RAASi prescription was least common in the United States and more common in patients who were younger, had diabetes, hypertension, or less advanced CKD. In conclusion, RAASi prescription patterns vary by country, and by demographic and clinical characteristics. RAASi appear to be underused, even among patients with strong class-specific recommendations. Although the reasons for this variation could not be fully identified in this cross-sectional observation, our data indicate that the risk of hyperkalemia may contribute to the underuse of this class of agents in moderate to advanced CKD.

Additional Contribution of the Malnutrition-Inflammation Score to Predict Mortality and Patient-Reported Outcomes as Compared With Its Components in a Cohort of African Descent Hemodialysis Patients.

OBJECTIVE: The malnutrition-inflammation score (MIS) combines ten components to assess nutritional status. Higher MIS has been associated with higher mortality and poorer health-related quality of life (HRQOL) in maintenance hemodialysis (MHD) patients. It is interesting to investigate associations of each component with mortality and patient-reported outcomes (PROs), that is, HRQOL and depression symptoms, and if MIS associations are generalizable for diverse populations. This study assessed associations of MIS and its components with mortality and PROs in an African descent MHD population. DESIGN: Prospective cohort for mortality and cross-sectional design for PROs using data of the Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO). SUBJECTS: A total of 632 MHD patients (92% black or mixed race) treated in Salvador, Brazil. PREDICTORS: MIS (range: 0-30, higher worse) and each of its ten components (range: 0-4, higher worse). MAIN OUTCOME MEASURES: Mortality, HRQOL using the KDQOL-SF, and depression symptoms using the 20-item Center for Epidemiological Studies Depression Scale. STATISTICAL ANALYSIS: Linear regression for comparing scores and Cox regression for mortality. RESULTS: After extensive adjustments, MIS ≥6 was associated with 52% higher mortality (hazard ratio = 1.52; 95% confidence interval = 1.13-2.05), higher depression symptoms, and poorer HRQOL, including physical, mental, and kidney disease-targeted HRQOL measures. Weight change, comorbidity, muscle wasting, and albumin were the MIS components indicating associations between poor nutrition and higher mortality. By contrast, gastrointestinal symptoms and functional capacity were the MIS components denoting detrimental associations of poorer nutritional status with PROs. LIMITATION: Causal conclusions are not possible. CONCLUSIONS: The PROHEMO results indicate that MIS components associated with mortality are not the same associated with PROs. However, the MIS showed consistent associations with mortality and PROs. These results in a population that were not the target of previous investigations, add support for using tools combining nutritional components, such as MIS, to predict outcomes in MHD populations.

The chronic kidney disease outcomes and practice patterns study Brazil (CKDopps-Brazil): design, data and methodology.

INTRODUCTION: The chronic kidney disease outcomes and practice patterns study (CKDopps) is an international observational, prospective, cohort study involving patients with chronic kidney disease (CKD) stages 3-5 [estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, with a major focus upon care during the advanced CKD period (eGFR < 30 ml/min/1.73 m2)]. During a 1-year enrollment period, each one of the 22 selected clinics will enroll up to 60 advanced CKD patients (eGFR < 30 ml/min/1.73 m2 and not dialysis-dependent) and 20 earlier stage CKD patients (eGFR between 30-59 ml/min/1.73 m2). EXCLUSION CRITERIA: age < 18 years old, patients on chronic dialysis or prior kidney transplant. The study timeline include up to one year for enrollment of patients at each clinic starting in the end of 2013, followed by up to 2-3 years of patient follow-up with collection of detailed longitudinal patient-level data, annual clinic practice-level surveys, and patient surveys. Analyses will apply regression models to evaluate the contribution of patient-level and clinic practice-level factors to study outcomes, and utilize instrumental variable-type techniques when appropriate. CONCLUSION: Launching in 2013, CKDopps Brazil will study advanced CKD care in a random selection of nephrology clinics across Brazil to gain understanding of variation in care across the country, and as part of a multinational study to identify optimal treatment practices to slow kidney disease progression and improve outcomes during the transition period to end-stage kidney disease.

The chronic kidney disease outcomes and practice patterns study Brazil (CKDopps-Brazil): Design, data and methodology / Estudo dos desfechos de doenca renal cronica e padroes da pratica atual - Brasil (CKDopps-Brazil): Desenho, dados e metodologia

Introduction: The chronic kidney disease outcomes and practice patterns study (CKDopps) is an international observational, prospective, cohort study involving patients with chronic kidney disease (CKD) stages 3-5 [estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, with a major focus upon care during the advanced CKD period (eGFR < 30 ml/min/1.73 m2)]. During a 1-year enrollment period, each one of the 22 selected clinics will enroll up to 60 advanced CKD patients (eGFR < 30 ml/min/1.73 m2 and not dialysis-dependent) and 20 earlier stage CKD patients (eGFR between 30-59 ml/min/1.73 m2). Exclusion criteria: age < 18 years old, patients on chronic dialysis or prior kidney transplant. The study timeline include up to one year for enrollment of patients at each clinic starting in the end of 2013, followed by up to 2-3 years of patient follow-up with collection of detailed longitudinal patient-level data, annual clinic practice-level surveys, and patient surveys. Analyses will apply regression models to evaluate the contribution of patient-level and clinic practice-level factors to study outcomes, and utilize instrumental variable-type techniques when appropriate. Conclusion: Launching in 2013, CKDopps Brazil will study advanced CKD care in a random selection of nephrology clinics across Brazil to gain understanding of variation in care across the country, and as part of a multinational study to identify optimal treatment practices to slow kidney disease progression and improve outcomes during the transition period to end-stage kidney disease. .

Introdução: O Estudo de padrões da prática e desfechos das doenças renais crônicas (CKDopps) é um estudo internacional observacional, prospectivo, com uma coorte composta de pacientes com doenças renais crônicas (DRC) nos estágios 3-5 [taxa de filtração glomerular estimada (eGFR) < 60 ml/min/1,73 m2, com um grande foco sobre o tratamento durante o período de doença renal crônica avançada (eGFR < 30 ml/min/1,73 m2)]. Durante o período de recrutamento de participantes, de 1 ano, cada uma das 22 clínicas selecionadas inscreverá até 60 pacientes com DRC avançada (eGFR < 30 ml/min/1,73 m2 e não dependente de diálise) e 20 pacientes com DRC em estágios anteriores (eGFR entre 30-59 ml/min/1,73 m2). Os critérios de exclusão são: idade < 18 anos; pacientes em diálise crônica ou transplante de rim prévio. O cronograma de estudo inclui até um ano para a inscrição dos pacientes em cada clínica a partir do final de 2013, sendo então acompanhados por 2-3 anos, com coleta de dados longitudinais detalhados dos pacientes, pesquisas anuais dos níveis da prática na clínica e levantamentos de informação dos pacientes. As análises aplicarão modelos de regressão para avaliar a contribuição de fatores relacionados à clínica e aos próprios pacientes para estudar os desfechos, e utilizar técnicas do tipo: variável instrumental, quando apropriado. Conclusão: Lançado em 2013, o CKDopps-Brasil, avaliará o tratamento de DRC avançada em uma seleção aleatória de clínicas de nefrologia em todo o Brasil para entender como o tratamento varia em nosso país, e como parte de um estudo multinacional para identificar as práticas de tratamento ideal para retardar ...

Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): evaluation of possible confounding by nutritional status.

BACKGROUND: Poor nutritional status and both hyper- and hypophosphatemia are associated with increased mortality in maintenance hemodialysis (HD) patients. We assessed associations of phosphate binder prescription 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 lower percentages of phosphate binder prescription. Patient-level phosphate binder prescription was associated strongly 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 adjusted for serum phosphorus level and other covariates; further adjustment for nutritional indicators attenuated this association (HR, 0.88; 95% CI, 0.80-0.97). However, this inverse association was observed for only patients with serum phosphorus levels ≥3.5 mg/dL. In the instrumental-variable analysis, case-mix-adjusted facility percentage of phosphate binder prescription (range, 23%-100%) was associated positively with better nutritional 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 were cross-sectional; dietary restriction was not assessed; observational design limits causal inference due to possible residual confounding. CONCLUSIONS: Longer survival and better nutritional status were observed for maintenance HD patients prescribed phosphate binders and in facilities with a greater percentage of phosphate binder prescription. Understanding the mechanisms for explaining this effect and ruling out possible residual confounding require additional research.

Assessment of the psychological burden associated with pruritus in hemodialysis patients using the kidney disease quality of life short form.

PURPOSE: To assess whether depression symptoms, poor sleep and dry skin bother explain association between pruritus and the burden of kidney disease in maintenance hemodialysis (MHD) patients. METHODS: Cross-sectional study of 980 patients from a prospective study in dialysis units of Salvador, Brazil (PROHEMO). The Kidney Disease Quality of Life Short Form was used to determine scores of kidney disease burden (KDB) and sleep with higher scores indicating lower perceived burden and better sleep quality, respectively. The Center for Epidemiological Studies Depression Scale was used for depression symptoms. RESULTS: Prevalence of severe pruritus (very much or extreme) was 19.4%. Significantly (P < 0.001) lower mean KDB score by 11.44 points was observed for patients with severe pruritus (34.18 ± 27.51) than for those with no pruritus (45.62 ± 30.73). Severe pruritus was associated with poorer sleep quality, higher odds of dry skin bother and higher depression symptoms score. Association of pruritus with KDB score was virtually eliminated after adjustment for sleep, dry skin bother and depression symptoms. CONCLUSIONS: This study shows strong associations of severe pruritus with higher depression symptoms, poorer sleep and dry skin bother among MHD patients. The results support special attention to MHD patients with pruritus who often face high psychological burden.

Depression as a potential explanation for gender differences in health-related quality of life among patients on maintenance hemodialysis.

BACKGROUND/AIMS: The reasons for lower health-related quality of life (HRQOL) scores in women compared to men on maintenance hemodialysis (MHD) are unknown. We investigated whether depression accounts for gender differences in HRQOL. METHODS: Cross-sectional study of 868 (40.9% women) Brazilian MHD patients (PROHEMO Study). We used the Kidney Disease Quality of Life Short Form to assess HRQOL and the Center for Epidemiological Studies Depression (CES-D) scale (scores from 0-60) to assess depression with scores >or=18 indicating high depression probability. RESULTS: Higher depression scores were associated with lower HRQOL in both sexes. Women had higher depression scores; 51.8% of women versus 38.2% of men (p < 0.001) had CES-D scores >or=18. Women scored lower on all 9 assessed HRQOL scales. The female-to-male differences in HRQOL were slightly reduced with inclusion of Kt/V and comorbidities in regression models. Substantial additional reductions in female-to-male differences in all HRQOL scales were observed after including depression scores in the models, by 50.9% for symptoms/problems related to renal failure, by 71.6% for mental health and by 87.1% for energy/vitality. CONCLUSIONS: Lower HRQOL among women was largely explained by depression symptoms. Results support greater emphasis on treating depression to improve HRQOL in MHD patients, particularly women.

Prescription of antihypertensive agents to haemodialysis patients: time trends and associations with patient characteristics, country and survival in the DOPPS.

BACKGROUND: Haemodialysis patients were studied in 12 countries to identify practice patterns of prescription of antihypertensive agents (AHA) associated with survival. METHODS: The sample included 28 513 patients enrolled in DOPPS I and II. The classes of AHA studied were beta blocker (BB), angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), peripheral blocker, central antagonist, vasodilator, long-acting dihydropyridine calcium channel blocker (CCB), short-acting dihydropyridine CCB and non-dihydropyridine CCB. To reduce bias due to unmeasured confounders, the associations with mortality were assessed by separate Cox models based on patient-level prescription and facility prescription practice. RESULTS: An increase in prescription of ARBs (9.5%) and BBs (9.1%) was observed from DOPPS I to II. Prescription of AHA classes varied significantly by country, ranging for BBs from 9.7% in Japan to 52.7% in Sweden and for ARBs from 5.5% in Italy to 21.3% in Japan in DOPPS II. Facilities that treated 10% more patients with ARBs had, on average, 7% lower all-cause mortality, independent of patient characteristics and the prescription patterns of other antihypertensive medications (P = 0.05). Significant and independent associations with reduction in cardiovascular mortality were observed for ARBs (RR = 0.79; P = 0.005) and BBs (RR = 0.87, P = 0.004) in analyses of patient-level prescriptions. These associations in the facility-level model followed the same direction. CONCLUSIONS: DOPPS data show large variations across countries in AHA prescription for haemodialysis patients. The data suggest an association between ARB use and reduction in all-cause mortality, as well as with the use of BBs and reduction in cardiovascular mortality among haemodialysis patients.