Etelcalcetide Utilization, Dosing Titration, and Chronic Kidney Disease-Mineral and Bone Disease (CKD-MBD) Marker Responses in US Hemodialysis Patients.

RATIONALE & OBJECTIVE: Clinical trial data have demonstrated the efficacy of etelcalcetide for reducing parathyroid hormone (PTH) levels in hemodialysis (HD) patients. We provide a real-world summary of etelcalcetide utilization, dosing, effectiveness, and discontinuation since its US introduction in April 2017. STUDY DESIGN: New-user design within prospective cohort. SETTING & PARTICIPANTS: 2,596 new users of etelcalcetide from April 2017 through August 2019 in a national sample of adult maintenance HD patients in the US Dialysis Outcomes and Practice Patterns Study (DOPPS). PREDICTORS: Baseline PTH, prior cinacalcet use, initial etelcalcetide dose. OUTCOME: Trajectories of etelcalcetide dose, chronic kidney disease-mineral and bone disease (CKD-MBD) medications, and levels of PTH, serum calcium, and phosphorus in the 12 months after etelcalcetide initiation. ANALYTICAL APPROACH: Cumulative incidence methods for etelcalcetide discontinuation and linear generalized estimating equations for trajectory analyses. RESULTS: By August 2019, etelcalcetide prescriptions increased to 6% of HD patients from their first use in April 2017. Starting etelcalcetide dose was 15 mg/wk in 70% of patients and 7.5 mg/wk in 27% of patients; 49% of new users were prescribed cinacalcet in the prior 3 months. Etelcalcetide discontinuation was 9%, 17%, and 27% by 3, 6, and 12 months after initiation. One year after etelcalcetide initiation, mean PTH levels declined by 40%, from 948 to 566 pg/mL, and the proportion of patients with PTH within target (150-599 pg/mL) increased from 33% to 64% overall, from 0 to 60% among patients with baseline PTH ≥ 600 pg/mL, and from 30% to 63% among patients with prior cinacalcet use. The proportion of patients with serum phosphorus > 5.5 mg/dL decreased from 55% to 45%, while the prevalence of albumin-corrected serum calcium < 7.5 mg/dL remained at 1%-2%. There were increases in use of active vitamin D (from 77% to 87%) and calcium-based phosphate binders (from 41% to 50%) in the 12 months after etelcalcetide initiation. LIMITATIONS: Data are unavailable for provider dosing protocols, dose holds, or reasons for discontinuation. CONCLUSIONS: In the 12 months after etelcalcetide initiation, patients had large and sustained reductions in PTH levels. These results support the utility of etelcalcetide as an effective therapy to achieve the KDIGO-recommended guidelines for CKD-MBD markers in HD patients.

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.

Secondary hyperparathyroidism, weight loss, and longer term mortality in haemodialysis patients: results from the DOPPS.

BACKGROUND: Wasting is a common complication of kidney failure that leads to weight loss and poor outcomes. Recent experimental data identified parathyroid hormone (PTH) as a driver of adipose tissue browning and wasting, but little is known about the relations among secondary hyperparathyroidism, weight loss, and risk of mortality in dialysis patients. METHODS: We included 42,319 chronic in-centre haemodialysis patients from the Dialysis Outcomes and Practice Patterns Study phases 2-6 (2002-2018). Linear mixed models were used to estimate the association between baseline PTH and percent weight change over 12 months, adjusting for country, demographics, comorbidities, and labs. Accelerated failure time models were used to assess 12 month weight loss as a mediator between baseline high PTH and mortality after 12 months. RESULTS: Baseline PTH was inversely associated with 12 month weight change: 12 month weight loss >5% was observed in 21%, 18%, 18%, 17%, 15%, and 14% of patients for PTH ≥600 pg/mL, 450-600, 300-450, 150-300, 50-150, and <50 pg/mL, respectively. In adjusted analyses, 12 month weight change compared with PTH 150-299 pg/mL was -0.60%, -0.12%, -0.10%, +0.15%, and +0.35% for PTH ≥600, 450-600, 300-450, 50-150, and <50 pg/mL, respectively. This relationship was robust regardless of recent hospitalization and was more pronounced in persons with preserved appetite. During follow-up after the 12 month weight measure [median, 1.0 (interquartile range, 0.6-1.7) years; 6125 deaths], patients with baseline PTH ≥600 pg/mL had 11% [95% confidence interval (CI), 9-13%] shorter lifespan, and 18% (95% CI, 14-23%) of this effect was mediated through weight loss ≥2.5%. CONCLUSIONS: Secondary hyperparathyroidism may be a novel mechanism of wasting, corroborating experimental data, and, among chronic dialysis patients, this pathway may be a mediator between elevated PTH levels and mortality. Future research should determine whether PTH-lowering therapy can limit weight loss and improve longer term dialysis outcomes.

Beta-2 microglobulin and all-cause mortality in the era of high-flux hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Beta-2 microglobulin (ß2M) accumulates in hemodialysis (HD) patients, but its consequences are controversial, particularly in the current era of high-flux dialyzers. High-flux HD treatment improves ß2M removal, yet ß2M and other middle molecules may still contribute to adverse events. We investigated patient factors associated with serum ß2M, evaluated trends in ß2M levels and in hospitalizations due to dialysis-related amyloidosis (DRA), and estimated the effect of ß2M on mortality. METHODS: We studied European and Japanese participants in the Dialysis Outcomes and Practice Patterns Study. Analysis of DRA-related hospitalizations spanned 1998-2018 (n = 23 976), and analysis of ß2M and mortality in centers routinely measuring ß2M spanned 2011-18 (n = 5332). We evaluated time trends with linear and Poisson regression and mortality with Cox regression. RESULTS: Median ß2M changed nonsignificantly from 2.71 to 2.65 mg/dL during 2011-18 (P = 0.87). Highest ß2M tertile patients (>2.9 mg/dL) had longer dialysis vintage, higher C-reactive protein and lower urine volume than lowest tertile patients (≤2.3 mg/dL). DRA-related hospitalization rates [95% confidence interval (CI)] decreased from 1998 to 2018 from 3.10 (2.55-3.76) to 0.23 (0.13-0.42) per 100 patient-years. Compared with the lowest ß2M tertile, adjusted mortality hazard ratios (95% CI) were 1.16 (0.94-1.43) and 1.38 (1.13-1.69) for the middle and highest tertiles. Mortality risk increased monotonically with ß2M modeled continuously, with no indication of a threshold. CONCLUSIONS: DRA-related hospitalizations decreased over 10-fold from 1998 to 2018. Serum ß2M remains positively associated with mortality, even in the current high-flux HD era.

Association between Dipeptidyl Peptidase-4 Inhibitor Prescription and Erythropoiesis-Stimulating Agent Hyporesponsiveness in Hemodialysis Patients with Diabetes Mellitus.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) has been hypothesized to improve responsiveness to erythropoiesis-stimulating agent (ESA). We aimed to describe the trend in DPP-4 inhibitor prescription patterns and assess the association between DPP-4 inhibitor prescription and ESA hyporesponsiveness (eHypo) in Japanese hemodialysis (HD) patients with diabetes mellitus (DM). METHODS: We analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study phase 4-6 (2009-2017) on patients with DM who underwent HD thrice per week for at least 4 months. The primary exposure of interest was having a DPP-4 inhibitor prescription. The primary analysis outcomes were a binary indicator of eHypo (mean hemoglobin <10 and mean ESA dose >6,000 units/week over 4 months) and the natural log-transformed ESA resistance index (ERI). We used conditional logistic regression to compare within-patient changes in eHypo before and after initial DPP-4 inhibitor prescription. We used linear generalized estimating equation models to compare continuous ERI outcomes while accounting for within-patient repeated measurements with an exchangeable correlation structure. RESULTS: There was a monotonic increase in DPP-4 inhibitor prescription according to study year up to 20% in 2017. Moreover, 12.8% of patients with a DPP-4 inhibitor prescription were ESA hyporesponsive before the initial DPP-4 inhibitor prescription. After DPP-4 inhibitor prescription, the odds of eHypo and mean log-ERI remained unchanged in the whole cohort of our study. The interaction analysis of DPP-4 inhibitor and sideropenia showed that DPP-4 inhibitors attenuated eHypo in the patients without iron deficiency. CONCLUSION: Our findings indicate a recent increase in DPP-4 inhibitor prescription among Japanese HD patients with DM. DPP-4 inhibitors could improve ERI in patients undergoing HD without iron deficiency.

Serum biomarkers of iron stores are associated with worse physical health-related quality of life in nondialysis-dependent chronic kidney disease patients with or without anemia.

BACKGROUND: Iron deficiency (ID) is a common condition in nondialysis-dependent chronic kidney disease (NDD-CKD) patients that is associated with poorer clinical outcomes. However, the effect of ID on health-related quality of life (HRQoL) in this population is unknown. We analyzed data from a multinational cohort of NDD-CKD Stages 3-5 patients to test the association between transferrin saturation (TSAT) index and ferritin with HRQoL. METHODS: Patients from Brazil (n = 205), France (n = 2015) and the USA (n = 293) in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps, 2013-2019) were included. We evaluated the association of TSAT and ferritin (and functional and absolute ID, defined as TSAT ≤20% and ferritin ≥300 or <50 ng/mL) on pre-specified HRQoL measures, including the 36-item Kidney Disease Quality of Life physical component summary (PCS) and mental component summary (MCS) as the primary outcomes. Models were adjusted for confounders including hemoglobin (Hb). RESULTS: TSAT ≤15% and ferritin <50 ng/mL and ≥300 ng/mL were associated with worse PCS scores, but not with MCS. Patients with composite TSAT ≤20% and ferritin <50 or ≥300 ng/mL had lower functional status and worse PCS scores than those with a TSAT of 20-30% and ferritin 50-299 ng/mL. Patients with a lower TSAT were less likely to perform intense physical activity. Adjustment for Hb only slightly attenuated the observed effects. CONCLUSIONS: Low TSAT levels, as well as both low TSAT with low ferritin and low TSAT with high ferritin, are associated with worse physical HRQoL in NDD-CKD patients, even after accounting for Hb level. Interventional studies of iron therapy on HRQoL among NDD-CKD individuals are needed to confirm these findings.

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.

International Comparisons of Native Arteriovenous Fistula Patency and Time to Becoming Catheter-Free: Findings From the Dialysis Outcomes and Practice Patterns Study (DOPPS).

RATIONALE & OBJECTIVE: Optimizing vascular access use is crucial for long-term hemodialysis patient care. Because vascular access use varies internationally, we examined international differences in arteriovenous fistula (AVF) patency and time to becoming catheter-free for patients receiving a new AVF. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,191 AVFs newly created in 2,040 hemodialysis patients in 2009 to 2015 at 466 randomly selected facilities in the Dialysis Outcomes and Practice Patterns Study (DOPPS) from the United States, Japan, and EUR/ANZ (Belgium, France, Germany, Italy, Spain, Sweden, United Kingdom, Australia, and New Zealand). PREDICTORS: Demographics, comorbid conditions, dialysis vintage, body mass index, AVF location, and country/region. OUTCOMES: Primary/cumulative AVF patency (from creation), primary/cumulative functional patency (from first use), catheter dependence duration, and mortality. ANALYTICAL APPROACH: Outcomes estimated using Cox regression. RESULTS: Across regions, mean patient age ranged from 61 to 66 years, with male preponderance ranging from 55% to 66%, median dialysis vintage of 0.3 to 3.2 years, with 84%, 54%, and 32% of AVFs created in the forearm in Japan, EUR/ANZ, and United States, respectively. Japan displayed superior primary and cumulative patencies due to higher successful AVF use, whereas cumulative functional patency was similar across regions. AVF patency associations with age and other patient characteristics were weak or varied considerably between regions. Catheter-dependence following AVF creation was much longer in EUR/ANZ and US patients, with nearly 70% remaining catheter dependent 8 months after AVF creation when AVFs were not successfully used. Not using an arteriovenous access within 6 months of AVF creation was related to 53% higher mortality in the subsequent 6 months. LIMITATIONS: Residual confounding. CONCLUSIONS: Our findings highlight the need to reevaluate practices for optimizing long-term access planning and achievable AVF outcomes, especially AVF maturation. New AVFs that are not successfully used are associated with long-term catheter exposure and elevated mortality risk. These findings highlight the importance of selecting the best access type for each patient and developing effective clinical pathways for when AVFs fail to mature successfully.

Association of erythropoietin resistance and fibroblast growth factor 23 in dialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Fibroblast growth factor 23 (FGF23) plays an important role in chronic kidney disease (CKD)-related mineral and bone disorders. High FGF23 levels are associated with increased risk of anaemia in non-haemodialysis CKD patients. FGF23 also negatively regulates erythropoiesis in mice. We hypothesized that higher FGF23 levels are associated with increased erythropoietin hyporesponsiveness among haemodialysis patients. METHODS: The study included 1044 patients from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS) phase 5 (2012-2015). The outcome was erythropoiesis-stimulating agent hyporesponsiveness (ESA-hypo), defined as mean Hgb <10 g/dL and standardized mean ESA dose >6000 u/week over 4 months following FGF23 measurement. The association between ESA-hypo and FGF23 was estimated using multivariable-adjusted logistic generalized estimating equation regression models. RESULTS: Patients with higher levels of FGF23 were younger and had higher levels of serum albumin, creatinine, albumin-corrected calcium, phosphorus, PTH, 25(OH)-vitamin D, and had higher percentages of intravenous (IV) iron, IV vitamin D and cinacalcet use. ESA-hypo was present in 144 patients (13.8%). Compared with the third quintile of FGF23 levels, the odds ratio (95% CI) of ESA-hypo was 2.14 (0.99, 4.62) and 1.74 (0.74, 4.11) for the first and fifth quintiles, respectively. CONCLUSION: The lowest and highest levels of FGF23 were associated with higher odds of ESA-hypo in patients on maintenance haemodialysis, although the associations were not statistically significant. The relationship between FGF23 and anaemia, and particularly the increased risks of ESA-hypo at low FGF23 levels which might be the result of energy saving, must be confirmed in larger clinical studies.

Replicating Randomized Trial Results with Observational Data Using the Parametric g-Formula: An Application to Intravenous Iron Treatment in Hemodialysis Patients.

BACKGROUND: Reproducibility of clinical and epidemiologic research is important to generalize findings and has increasingly been scrutinized. A recently published randomized trial, PIVOTAL, evaluated high vs low intravenous iron dosing strategies to manage anemia in hemodialysis patients in the UK. Our objective was to assess the reproducibility of the PIVOTAL trial findings using data from a well-established cohort study, the Dialysis Outcomes and Practice Patterns Study (DOPPS). METHODS: To overcome the absence of randomization in the DOPPS, we applied the parametric g-formula, an extension of standardization to longitudinal data. We estimated the effect of a proactive high-dose vs reactive low-dose iron supplementation strategy on all-cause mortality (primary outcome), hemoglobin, two measures of iron concentration (ferritin and TSAT), and erythropoiesis-stimulating agent dose over 12 months of follow-up in 6325 DOPPS patients. RESULTS: Comparing high- vs low-iron dose strategies, the 1-year mortality risk difference was 0.020 (95% CI: 0.008, 0.031) and risk ratio was 1.20 (95% CI: 1.07, 1.33), compared with null 1-year findings in the PIVOTAL trial. Differences in secondary outcomes were directionally consistent but of lesser magnitude than in the PIVOTAL trial. CONCLUSION: Our findings are somewhat consistent with the recent PIVOTAL trial, with discrepancies potentially attributable to model misspecification and differences between the two study populations. In addition to the importance of our results to nephrologists and hence hemodialysis patients, our analysis illustrates the utility of the parametric g-formula for generalizing results and comparing complex and dynamic treatment strategies using observational data.

Anemia and iron deficiency among chronic kidney disease Stages 3-5ND patients in the Chronic Kidney Disease Outcomes and Practice Patterns Study: often unmeasured, variably treated.

BACKGROUND: International variation in anemia assessment and management practices in chronic kidney disease (CKD) is poorly understood. METHODS: We performed a cross-sectional analysis of anemia laboratory monitoring, prevalence and management in the prospective Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps). A total of 6766 participants with CKD Stages 3a-5ND from nephrology clinics in Brazil, France, Germany and the USA were included. RESULTS: Among patients with anemia (hemoglobin <12 g/dL), 36-58% in Brazil, the USA and Germany had repeat hemoglobin measured and 40-61% had iron indices measured within 3 months of the index hemoglobin measurement. Anemia was more common in the USA and Brazil than in France and Germany across CKD stages. Higher ferritin and lower iron saturation (TSAT) levels were observed with lower hemoglobin levels, and higher ferritin with more advanced CKD. The proportion of anemic patients with ferritin <100 ng/mL or TSAT <20% ranged from 42% in Brazil to 53% in France and Germany, and of these patients, over 40% in Brazil, Germany and the USA, compared with 27% in France, were treated with oral or intravenous iron within 3 months after hemoglobin measurement. The proportion of patients with hemoglobin <10 g/dL treated with erythropoiesis-stimulating agents ranged from 28% in the USA to 57% in Germany. CONCLUSIONS: Hemoglobin and iron stores are measured less frequently than per guidelines. Among all regions, there was a substantial proportion of anemic patients with iron deficiency who were not treated with iron, highlighting an area for practice improvement in CKD care.

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.

Adverse Drug Reactions in Patients with CKD.

BACKGROUND AND OBJECTIVES: Little is known about the burden of adverse drug reactions in CKD. We estimated the incidence of overall and serious adverse drug reactions and assessed the probability of causation, preventability, and factors associated with adverse drug reactions in patients seen by nephrologists. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Chronic Kidney Disease-Renal Epidemiology and Information Network cohort included 3033 outpatients (65% men) with CKD and eGFR<60 ml/min per 1.73 m2, with follow-up for 2 years. Adverse drug reactions were identified from hospitalization reports, medical records, and participant interviews and finally assessed for causality, preventability, and immediate therapeutic management by experts in pharmacology. RESULTS: Median (interquartile range) age was 69 (60-76) years old; 55% had eGFR≥30 ml/min per 1.73 m2, and 45% had eGFR<30 ml/min per 1.73 m2. Participants were prescribed a median (range) of eight (five to ten) drugs. Over 2 years, 536 patients had 751 adverse drug reactions, 150 (in 125 participants) classified as serious, for rates of 14.4 (95% confidence interval, 12.6 to 16.5) and 2.7 (95% confidence interval, 1.7 to 4.3) per 100 person-years, respectively. Among the serious adverse drug reactions, 32% were considered preventable or potentially preventable; 16 caused death, directly or indirectly. Renin-angiotensin system inhibitors (15%), antithrombotic agents (14%), and diuretics (10%) were the drugs to which the most adverse drug reactions were imputed, but antithrombotic agents caused 34% of serious adverse drug reactions. The drug was discontinued in 71% of cases, at least temporarily. Adjusted hazard ratios for serious adverse drug reaction were significantly higher in patients with eGFR<30 versus ≥30 ml/min per 1.73 m2 (1.8; 95% confidence interval, 1.3 to 2.6), in those prescribed more than ten versus less than five medications (2.4; 95% confidence interval, 1.1 to 5.2), or in those with poor versus good adherence (1.6; 95% confidence interval, 1.4 to 2.4). CONCLUSIONS: Adverse drug reactions are common and sometimes serious in patients with CKD. Many serious adverse drug reactions may be preventable. Some specific pharmacologic classes, particularly antithrombotic agents, are at risk of serious adverse drug reactions. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN), NCT03381950.

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.

International Anemia Prevalence and Management in Peritoneal Dialysis Patients.

Background:The optimal treatment for managing anemia in peritoneal dialysis (PD) patients and best clinical practices are not completely understood. We sought to characterize international variations in anemia measures and management among PD patients.Methods:The Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) enrolled adult PD patients from 6 countries from 2014 to 2017. Hemoglobin (Hb), ferritin levels, and transferrin saturation (TSAT), as well as erythropoiesis stimulating agents (ESAs) and iron use were compared cross-sectionally at study enrollment in Australia and New Zealand (A/NZ), Canada, Japan, the United Kingdom (UK), and the United States (US).Results:Among 3,603 PD patients from 193 facilities, mean Hb ranged from 11.0 - 11.3 g/dL across countries. The majority of patients (range 53% - 59%) had Hb 10 - 11.9 g/dL, with 4% - 12% patients ≥ 13 g/dL and 16% - 23% < 10 g/dL. Use of ESAs was higher in Japan (94% of patients) than elsewhere (66% - 79% of patients). In the US, 63% of patients had a ferritin level > 500 ng/mL, compared with 5% - 38% in other countries. In the US and Japan, 87% - 89% of PD patients had TSAT ≥ 20%, compared with 73% - 76% in other countries. Intravenous (IV) iron use within 4 months of enrollment was higher in the US (55% of patients) than elsewhere (6% - 17% patients).Conclusions:In this largest international observational study of anemia and anemia management in patients receiving PD, comparable Hb levels across countries were observed but with notable differences in ESA and iron use. Peritoneal dialysis patients in the US have higher ferritin levels and higher IV iron use than other countries.

Risk profile, quality of life and care of patients with moderate and advanced CKD: The French CKD-REIN Cohort Study.

Background: The French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study was designed to investigate the determinants of prognosis and care of patients referred to nephrologists with moderate and advanced chronic kidney disease (CKD). We examined their baseline risk profile and experience. Methods: We collected bioclinical and patient-reported information from 3033 outpatients with CKD and estimated glomerular filtration rates (eGFRs) of 15-60 mL/min/1.73 m2 treated at 40 nationally representative public and private facilities. Results: The patients' median age was 69 (60-76) years, 65% were men, their mean eGFR was 33 mL/min/1.73 m2, 43% had diabetes, 24% had a history of acute kidney injury (AKI) and 57% had uncontrolled blood pressure (BP; >140/90 mmHg). Men had worse risk profiles than women and were more likely to be past or current smokers (73% versus 34%) and have cardiovascular disease (59% versus 42%), albuminuria >30 mg/mmol (or proteinuria > 50) (40% versus 30%) (all P < 0.001) and a higher median risk of end-stage renal disease within 5 years, predicted by the kidney failure risk equation {12% [interquartile range (IQR) 3-37%] versus 9% [3-31%], P = 0.008}. During the previous year, 60% of patients reported one-to-two nephrologist visits and four or more general practitioner visits; only 25% saw a dietician and 75% were prescribed five or more medications daily. Physical and mental quality of life (QoL) were poor, with scores <50/100. Conclusions: The CKD-REIN study highlights high-risk profiles of cohort members and identifies several priorities, including improving BP control and dietary counselling and increasing doctors' awareness of AKI, polypharmacy and QoL. Trial registration: ClinicalTrials.gov identifier: NCT03381950.

Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study.

INTRODUCTION: The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients. METHODS: Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment. RESULTS: A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001). CONCLUSION: This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.

Patterns of Erythropoiesis-Stimulating Agent Use in European Hemodialysis Patients: The Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Clinicians providing dialysis care have numerous erythropoiesis-stimulating agents (ESAs) available for treating anemia. We sought to provide a contemporary description of ESA types used in hemodialysis (HD) settings in nine European countries. METHODS: Our study uses Dialysis Outcomes and Practice Patterns Study phase 5 (2012-2015) data from nine European countries (Belgium, France, -Germany, Italy, Russia, Spain, Sweden, Turkey, and the United Kingdom). A total of 164 facilities and 3,281 patients contributed cross-sectional data. ESA types captured included short-acting epoetins (e.g., epoetin alfa, beta, etc., including biosimilars), darbepoetin alfa, and continuous erythropoietin receptor agonist (CERA; methoxy polyethylene glycol-epoetin beta). RESULTS: We observed broad variability across countries in prescription of ESA types: prescription of epoetin alfa or epoetin beta ranged from 22% (France) to 78% (Russia), darbepoetin alfa prescription ranged from 13% (Russia) to 53% (UK), and CERA prescription ranged from <3% (Sweden) to 26% (France). Prescription of different ESA types varied substantially within some European countries from 2012-2015 but not across all countries in aggregate. Number of ESA types prescribed by a facility varied from 1, 2, 3, or 4 different ESA types in 32, 40, 21, and 8% of facilities, respectively. No differences were seen in the unadjusted distributions of achieved hemoglobin values by ESA type. CONCLUSION: A variety of short- and long-acting ESAs are commonly used in European HD facilities to maintain hemoglobin at remarkably similar levels with each ESA type. The availability of numerous ESA options for managing anemia has allowed European providers to optimize anemia management according to the particular circumstances of each patient.

A nationwide prospective cohort study of patients with advanced chronic kidney disease in Japan: The Reach-J CKD cohort study.

BACKGROUND: Epidemiology and outcomes of Japanese patients with advanced chronic kidney disease (CKD)-an estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2-has remained largely unexamined. METHODS: We conducted a nationwide survey to determine the distribution of Japanese CKD patients, and are conducting a cohort study of these patients. A questionnaire eliciting details about facilities and their CKD practices was sent to all clinics/hospitals with nephrologists. Based on the survey results, we recruited 2400 advanced CKD patients receiving nephrologist care from at least 30 representative facilities throughout Japan, selected randomly with stratification by region and facility size. Through patient questionnaires and nephrologist-practice surveys aligned with the international CKD Outcomes and Practice Patterns Study (CKDopps), we shall annually or semi-annually collect patient, physician and clinic data prospectively, detailing CKD practices for 5 years, with a primary outcome of death or renal replacement therapy initiation, and secondary outcomes being decline of eGFR by 30% or 50%, CKD progression to CKD G5, or a cardiovascular event. RESULTS: Of 790 eligible, responding facilities, 330 (41.8%) treat ≥80 advanced CKD patients in the average 3-month period. Regional distribution of these facilities is similar to that of persons in the general population. Hence, the 30 facilities selected for data collection appear to be geographically representative in Japan. CONCLUSIONS: Our study will enhance understanding of various CKD practices and biological data associated with CKD progression, and allow international comparisons using the CKDopps platform. This will provide evidences to improve the health and quality of life for patients with advanced CKD.