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Every hemodialysis session starts with the question of how much fluid should be removed, which can currently not be answered precisely. Herein, we first revisit the "probing-dry-weight" concept, using the historical example of Tassin/France (practicing also "long, slow dialysis"): Mortality outcomes were, in the 1980s, better than registry data, but are nowadays similar to European average. In view of the negative primary end point in a recent trial on dry weight assessment, based on lung ultrasound-guided evaluation of fluid excess in the lungs, and a meta-analysis of prospective studies failing to show that bioimpedance-based interventions for correction of volume overload had a direct effect on all-cause mortality, we ask how to ever move forward. Clinical reasoning demands that as much information as possible should be gathered on the fluid status of patients undergoing dialysis. Besides body weight and blood pressure, measurements of bioimpedance and dialysate bolus-derived absolute blood volume can in principle be automatized, whereas lung ultrasound can be obtained routinely. In the era of machine learning, fluid management could consist of flexible target weight prescriptions, adjusted on a daily basis and accounting even for fluctuations in fluid-free body mass. In view of all the negative prospective results surrounding fluid management in hemodialysis, we propose this as a "never-give-up" approach.

Background Post-transplantation diabetes mellitus (PTDM) might be preventable. Methods This open-label, multicenter randomized trial compared 133 kidney transplant recipients given intermediate-acting insulin isophane for postoperative afternoon glucose ≥140 mg/dl with 130 patients given short-acting insulin for fasting glucose ≥200 mg/dl (control). The primary end point was PTDM (antidiabetic treatment or oral glucose tolerance test-derived 2 hour glucose ≥200 mg/dl) at month 12 post-transplant. Results In the intention-to-treat population, PTDM rates at 12 months were 12.2% and 14.7% in treatment versus control groups, respectively (odds ratio [OR], 0.82; 95% confidence interval [95% CI], 0.39 to 1.76) and 13.4% versus 17.4%, respectively, at 24 months (OR, 0.71; 95% CI, 0.34 to 1.49). In the per-protocol population, treatment resulted in reduced odds for PTDM at 12 months (OR, 0.40; 95% CI, 0.16 to 1.01) and 24 months (OR, 0.54; 95% CI, 0.24 to 1.20). After adjustment for polycystic kidney disease, per-protocol ORs for PTDM (treatment versus controls) were 0.21 (95% CI, 0.07 to 0.62) at 12 months and 0.35 (95% CI, 0.14 to 0.87) at 24 months. Significantly more hypoglycemic events (mostly asymptomatic or mildly symptomatic) occurred in the treatment group versus the control group. Within the treatment group, nonadherence to the insulin initiation protocol was associated with significantly higher odds for PTDM at months 12 and 24. Conclusions At low overt PTDM incidence, the primary end point in the intention-to-treat population did not differ significantly between treatment and control groups. In the per-protocol analysis, early basal insulin therapy resulted in significantly higher hypoglycemia rates but reduced odds for overt PTDM-a significant reduction after adjustment for baseline differences-suggesting the intervention merits further study.Clinical Trial registration number: NCT03507829.

Low sodium dialysate was commonly used in the early year of hemodialysis to enhance diffusive sodium removal beyond its convective removal by ultrafiltration. However, disequilibrium syndrome was common, particularly when dialysis sessions were reduced to 4 h. The recent trend of lowering the DNa from the most common level of 140 mEq/L has been associated with intradialytic hypotension and increased risk of hospitalization and mortality. Higher DNa also has disadvantages, such as higher blood pressure and greater interdialytic weight gain, likely due to increased thirst. My assessment of the evidence leads me to choose DNa at the 140 level for most patients and to avoid DNa below 138. Patients with intradialytic symptoms may benefit from DNa 142 mEq/L, if they can avoid excessive fluid weight gains.

International audience; No abstract available

Background Beta-2 microglobulin (β2M) accumulates in hemodialysis (HD) patients, but its consequences are controversial, particularly in the current era of high-flux dialyzers. High-flux HD treatment improves β2M removal, yet β2M and other middle molecules may still contribute to adverse events. We investigated patient factors associated with serum β2M, evaluated trends in β2M levels and in hospitalizations due to dialysis-related amyloidosis (DRA), and estimated the effect of β2M 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 β2M and mortality in centers routinely measuring β2M spanned 2011–18 (n = 5332). We evaluated time trends with linear and Poisson regression and mortality with Cox regression. Results Median β2M changed nonsignificantly from 2.71 to 2.65 mg/dL during 2011–18 (P = 0.87). Highest β2M 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 β2M 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 β2M modeled continuously, with no indication of a threshold. Conclusions DRA-related hospitalizations decreased over 10-fold from 1998 to 2018. Serum β2M remains positively associated with mortality, even in the current high-flux HD era.

Purpose: Mortality among first-year hemodialysis (HD) patients remains unacceptably high. To address this problem, we estimate the proportions of early HD deaths that are potentially preventable by modifying known risk factors. Methods: We included 15,891 HD patients (within 60 days of starting HD) from 21 countries in the Dialysis Outcomes and Practice Patterns Study (1996-2015), a prospective cohort study. Using Cox regression adjusted for potential confounders, we estimated the fraction of first-year deaths attributable to one or more of twelve modifiable risk factors (the population attributable fraction, AF) identified from the published literature by comparing predicted survival based on risk factors observed vs counterfactually set to reference levels. Results: The highest AFs were for catheter use (22%), albumin = 160 mm Hg, phosphorus = 5.5 mg/dL, hemoglobin = 12 g/dL, and white blood cell count >10,000/mu L. AFs for ferritin, calcium, and PTH were 10 mg/L was 21% in facilities where it was routinely measured. Conclusion: A substantial proportion of first-year HD deaths could be prevented by successfully modifying a few risk factors. Highest priorities should be decreasing catheter use and limiting malnutrition/inflammation whenever possible.

More men than women start kidney replacement therapy (KRT) although the prevalence of chronic kidney disease (CKD) is higher in women than men. We therefore aimed at analyzing sex-specific differences in clinical outcomes among 8237 individuals with CKD in stages 3 to 5 from Brazil, France, Germany, and the United States participating in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps).Fine and Gray models, evaluating the effect of sex on time to events, were adjusted for age, Black race (model A); plus diabetes, cardiovascular disease, albuminuria (model B); plus estimated glomerular filtration rate (eGFR) slope during the first 12 months after enrollment and first eGFR after enrollment (model C).There were more men than women at baseline (58% vs. 42%), men were younger than women, and men had higher eGFR (28.9 ± 11.5 vs. 27.0 ± 10.8 ml/min per 1.73 mMen had a higher probability of commencing dialysis before death, unexplained by CKD progression alone. Although the causal mechanisms are uncertain, this finding helps interpret the preponderance of men in the dialysis population.

Unmeasured confounding almost always exists in observational studies and can bias estimates of exposure effects. Instrumental variable methods are popular choices in combating unmeasured confounding to obtain less biased effect estimates. However, we demonstrate that alternative methods may give less biased estimates depending on the nature of unmeasured confounding. Treatment preferences of clusters (e.g. physician practices) are the most frequently used instruments in instrumental variable analyses. These preference-based instrumental variable analyses are usually conducted on data clustered by region, hospital/facility, or physician, where unmeasured confounding often occurs within or between clusters. We aim to quantify the impact of unmeasured confounding on the bias of effect estimators in instrumental variable analysis, as well as several common alternative methods including ordinary least squares regression, linear mixed models, and fixed-effect models to study the effect of a continuous exposure (e.g. treatment dose) on a continuous outcome. We derive closed-form expressions of asymptotic bias of estimators from these four methods in the presence of unmeasured within- and/or between-cluster confounders. Simulations demonstrate that the asymptotic bias formulae well approximate bias in finite samples for all methods. The bias formulae show that instrumental variable analyses can provide consistent estimates when unmeasured within-cluster confounding exists, but not when between-cluster confounding exists. On the other hand, fixed-effect models and linear mixed models can provide consistent estimates when unmeasured between-cluster confounding exits, but not for within-cluster confounding. Whether instrumental variable analyses are advantageous in reducing bias over fixed-effect models and linear mixed models depends on the extent of unmeasured within-cluster confounding relative to between-cluster confounding. Furthermore, the impact of unmeasured between-cluster confounding on instrumental variable analysis estimates is larger than the impact of unmeasured within-cluster confounding on fixed-effect model and linear mixed model estimates. We illustrate the use of these methods in estimating the effect of erythropoiesis stimulating agents on hemoglobin levels. Our findings provide guidance for choosing appropriate methods to combat the dominant types of unmeasured confounders and help interpret statistical results in the context of unmeasured confounding.

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.

Background and objectives Fluid overload and intradialytic hypotension are associated with cardiovascular events and mortality in patients on hemodialysis. We investigated associations between hemodialysis facility practices related to fluid volume and intradialytic hypotension and patient outcomes. Design, setting, participants, & measurements Data were analyzed from 10,250 patients in 273 facilities across 12 countries, from phase 4 of the Dialysis Outcomes and Practice Patterns Study (DOPPS; 2009–2012). Cox regression models (shared frailty) were used to estimate associations between facility practices reported by medical directors in response to the DOPPS Medical Directors Survey and all-cause and cardiovascular mortality and hospitalization, and cardiovascular events, adjusting for country, age, sex, dialysis vintage, predialysis systolic BP, cardiovascular comorbidities, diabetes, body mass index, smoking, residual kidney function, dialysis adequacy, and vascular access type. Results Of ten facility practices tested (chosen a priori ), having a protocol that specifies how often to assess dry weight in most patients was associated with lower all-cause (hazard ratio [HR], 0.78; 99% confidence interval [99% CI], 0.64 to 0.94) and cardiovascular mortality (HR, 0.72; 99% CI, 0.55 to 0.95). Routine orthostatic BP measurement to assess dry weight was associated with lower all-cause hospitalization (HR, 0.86; 99% CI, 0.77 to 0.97) and cardiovascular events (HR, 0.85; 99% CI, 0.73 to 0.98). Routine use of lower dialysate temperature to limit or prevent intradialytic hypotension was associated with lower cardiovascular mortality (HR, 0.76; 99% CI, 0.58 to 0.98). Routine use of an online volume indicator to assess dry weight was associated with higher all-cause hospitalization (HR, 1.19; 99% CI, 1.02 to 1.38). Routine use of sodium modeling/profiling to limit or prevent intradialytic hypotension was associated with higher all-cause mortality (HR, 1.36; 99% CI, 1.14 to 1.63), cardiovascular mortality (HR, 1.34; 99% CI, 1.04 to 1.73), and cardiovascular events (HR, 1.21; 99% CI, 1.03 to 1.43). Conclusions Hemodialysis facility practices relating to the management of fluid volume and intradialytic hypotension are associated with patient outcomes.

Background Hemodialysis (HD) patients are commonly prescribed phosphate binders (PBs) to manage serum phosphorus levels, as hyperphosphatemia is strongly associated with poorer survival. Nonadherence with the PB prescription is associated with elevated serum phosphorus levels. We studied associations between patient satisfaction with their PB and serum phosphorus levels and mortality rates. Methods Adult HD patients in Germany, Italy, Spain and the UK in the Dialysis Outcomes and Practice Patterns Study were administered a survey instrument in late 2017. Patients were asked about their satisfaction with their PBs, as measured through three questions (difficulty, inconvenience and dissatisfaction) on a 5-point Likert scale, with each dichotomized into average worst versus good responses. These were used as predictors in linear regression models of continuous serum phosphorus levels and in Cox proportional hazards models of mortality, with adjustments for demographics, comorbidities and laboratory values. Results Patients having greater difficulty, inconvenience and dissatisfaction with their PB had higher serum phosphorus levels in adjusted models {+0.21 mg/dL [95% confidence interval (CI) ±0.23], +0.30 (±0.21) and 0.36 (±0.22), respectively}, and higher odds of having serum phosphorus levels ≥6.0 mg/dL. Measures of dissatisfaction were also associated with an elevated risk of mortality, with adjusted hazard ratios of 2.2 (95% CI 1.3–3.6), 1.6 (1.0–2.6) and 1.7 (1.1–2.7), respectively; this association was not strongly affected by adjustment for baseline serum phosphorous level. Conclusions Self-reported difficulty, inconvenience and dissatisfaction in taking one’s prescribed PBs were associated with elevated serum phosphorus levels and serum phosphorus levels above clinically meaningful thresholds. While the mechanism for the association with mortality is unclear, patient-reported satisfaction should be considered when attempting to manage patient serum phosphorus levels., Graphical Abstract

BACKGROUND: Metabolic acidosis is a common threat for patients on hemodialysis, managed by alkaline dialysate. The main base is bicarbonate, to which small amounts of acetic, citric, or hydrochloric acid are added. The first two are metabolized to bicarbonate, mostly by the liver. Citric acid–containing dialysate might improve dialysis efficiency, anticoagulation, calcification propensity score, and intradialytic hemodynamic stability. However, a recent report from the French dialysis registry suggested this dialysate increases mortality risk. This prompted us to assess whether citric acid–containing bicarbonate-based dialysate was associated with mortality in the international Dialysis Outcomes and Practice Patterns Study (DOPPS). METHODS: Detailed patient-based information on dialysate composition was collected in DOPPS phases 5 and 6 (2012–2017). Cox regression was used to model the association between baseline bicarbonate dialysate containing citric acid versus not containing citric acid and mortality among DOPPS countries and phases where citric acid–containing dialysate was used. RESULTS: Citric acid-containing dialysate was most commonly used in Japan, Italy, and Belgium (25%, 25%, 21% and of patients who were DOPPS phase 6, respectively) and used in

BACKGROUND: Decisions about dialysis for advanced kidney disease are often strongly shaped by sociocultural and system-level factors rather than the priorities and values of individual patients. We examined international variation in the uptake of conservative approaches to the care of patients with advanced kidney disease, in particular discontinuation of dialysis. METHODS: We employed an observational cohort study design using data collected from patients maintained on long-term hemodialysis between 1996 and 2015 in facilities across 12 developed countries participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS). The main outcome was discontinuation of dialysis therapy. We analyzed the association between several patient characteristics and time to dialysis discontinuation by country and phase of study entry. RESULTS: A total of 259 343 DOPPS patients contributed data to the study, of whom 48 519 (18.7%) died during the study period. Of the decedents, 5808 (12.0%) discontinued dialysis before death. Rates of discontinuation were higher within the first few months after initiation of dialysis, among older adults, among those with a greater number of comorbidities and among those living in an institution. After adjustment for age, sex, dialysis duration, diabetes and dialysis era, rates of discontinuation were highest in Canada, the United States and Australia/New Zealand (33.8, 31.4 and 21.5 per 1000/yr, respectively) and lowest in Japan and Italy (< 0.1 per 1000/yr). Crude discontinuation rates were highest in dialysis facilities that were more likely to offer comprehensive conservative renal care to older adults. INTERPRETATION: We found persistent international variation in average rates of dialysis discontinuation not explained by differences in patient case-mix. These differences may reflect physician-, facility- and society-level differences in clinical practice. There may be opportunities for international cross-collaboration to improve support for patients with end-stage renal disease who prefer a more conservative approach.

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., Graphical abstract

In rural regions with limited resources, the provision of clean water remains challenging. The resulting high incidence of diarrhea can lead to acute kidney injury and death, particularly in the young and the old. Membrane filtration using recycled hemodialyzers allows water purification. This study quantifies the public health effects. Between 02/2018 and 12/2018, 4 villages in rural Ghana were provided with a high-volume membrane filtration device (NuFiltration). Household surveys were collected monthly with approval from Ghana Health Services. Incidence rates of diarrhea for 5-month periods before and after implementation of the device were collected and compared to corresponding rates in 4 neighboring villages not yet equipped. Data of 1,130 villagers over 10 months from the studied communities were studied. Incidence rates showed a decline following the implementation of the device from 0.18 to 0.05 cases per person-month (ppm) compared to the control villages (0.11 to 0.08 ppm). The rate ratio of 0.27 for the study villages is revised to 0.38 when considering the non-significant rate reduction in the control villages. Provision of a repurposed hemodialyzer membrane filtration device markedly improves health outcomes as measured by diarrhea incidence within rural communities.

Background and objectives Chronic kidney disease (CKD) is commonly associated with mineral and bone metabolism disorders, but these are less frequently studied in non-dialysis CKD patients than in dialysis patients. We examined and described international variation in mineral and bone disease (MBD) markers and their treatment and target levels in Stage 3–5 CKD patients. Design, setting, participants, and measurements Prospective cohort study of 7658 adult patients with eGFR Results Over two-thirds of the patients had MBD markers measured at time intervals in line with practice guidelines. P and iPTH increased and Ca decreased gradually from eGFR 60–20 mL/min/1.73m2 and more sharply for eGFR 5.5 mg/dL, phosphate binder use was 14% to 43% across the four countries. Among patients with PTH >300 pg/mL, use of active (calcitriol and related analogs) vitamin D was 12%–51%, and use of any (active or nutritional) vitamin D was 60%–87%. Conclusions Although monitoring of CKD-MBD laboratory markers by nephrologists in CKDopps countries is consistent with guidelines, target levels vary notably and prescription of medications to treat abnormalities in these laboratory markers is generally low in these cross-sectional analyses. While there are opportunities to increase treatment of hyperphosphatemia, hyperparathyroidism, and vitamin D deficiency in advanced CKD, the effect on longer-term complications of these conditions requires study.

Introduction: In China, a quarter of patients are undergoing 2-times weekly hemodialysis. Using data from the China Dialysis Outcomes and Practice Patterns Study (DOPPS), we tested the hypothesis that whereas survival and hospitalizations would be similar in the presence of residual kidney function (RKF), patients without RKF would fare worse on 2-times weekly hemodialysis. Methods: In our cohort derived from 15 units randomly selected from each of 3 major cities (total N = 45), we generated a propensity score for the probability of dialysis frequency assignment, estimated a survival function by propensity score quintiles, and averaged stratum-specific survival functions to generate mean survival time. We used the proportional rates model to assess hospitalizations. We stratified all analyses by RKF, as reported by patients (urine output

Background Fluid overload and interdialytic weight gain (IDWG) are discrete components of the dynamic fluid balance in haemodialysis patients. We aimed to disentangle their relationship, and the prognostic importance of two clinically distinct, bioimpedance spectroscopy (BIS)-derived measures, pre-dialysis and post-dialysis fluid overload (FOpre and FOpost) versus IDWG. Methods We conducted a retrospective cohort study on 38 614 incident patients with one or more BIS measurement within 90 days of haemodialysis initiation (1 October 2010 through 28 February 2015). We used fractional polynomial regression to determine the association pattern between FOpre, FOpost and IDWG, and multivariate adjusted Cox models with FO and/or IDWG as longitudinal and time-varying predictors to determine all-cause mortality risk. Results In analyses using 1-month averages, patients in quartiles 3 and 4 (Q3 and Q4) of FO had an incrementally higher adjusted mortality risk compared with reference Q2, and patients in Q1 of IDWG had higher adjusted mortality compared with Q2. The highest adjusted mortality risk was observed for patients in Q4 of FOpre combined with Q1 of IDWG [hazard ratio (HR) = 2.66 (95% confidence interval 2.21–3.20), compared with FOpre-Q2/IDWG-Q2 (reference)]. Using longitudinal means of FO and IDWG only slightly altered all HRs. IDWG associated positively with FOpre, but negatively with FOpost, suggesting a link with post-dialysis extracellular volume depletion. Conclusions FOpre and FOpost were consistently positive risk factors for mortality. Low IDWG was associated with short-term mortality, suggesting perhaps an effect of protein-energy wasting. FOpost reflected the volume status without IDWG, which implies that this fluid marker is clinically most intuitive and may be best suited to guide volume management in haemodialysis patients.

Background: Abnormal chronic kidney disease-mineral and bone disorder (CKD-MBD) markers have been associated with adverse outcomes in hemodialysis (HD) patients. Dialysate calcium concentration (D-Ca) likely influences serum calcium and phosphorus levels. Optimal D-Ca level remains unclear. We hypothesized that higher D-Ca is associated with cardiovascular events and mortality among Japanese HD patients. Methods: Enrollment data of chronic HD patients in the prospective observational study JDOPPS, phases 1–5 (1999–2015), provided exposures and covariates. All-cause mortality, non-arrhythmic cardiovascular events (NonAR-CVE), or their composites were analyzed by D-Ca, and divided into 2.5, 2.75, and 3.0 mEq/L. To minimize confounding by indication, analyses were restricted to facilities in which at least 90% of patients received the same D-Ca prescription. Association of D-Ca level with outcomes was evaluated in Cox models stratified by phase and accounting for facility clustering. Covariates describing patient demographics, comorbidities, laboratory values, CKD-MBD therapy, and facility attributes provided adjustment. Results: Of 9,201 patients included, 25.0% had D-Ca of 2.5 mEq/L; 6.8% D-Ca 2.75; and 68.2% D-Ca 3.0. Median follow-up time was 2.03 years. D-Ca was not associated with all-cause mortality, with hazards ratios for 2.5 vs. 3.0 mEq/L of 0.90 and 95% CI (0.73–1.11), nor with other outcomes. One effect modification occurred, protective for lower D-Ca on NonAR-CVE in the absence of cardiovascular comorbidities (p = 0.032), although corresponding D-Ca effects were not significant after multiple comparisons adjustment (p = 0.261 [D-Ca 2.5] and 0.125 [D-Ca 2.75]). Conclusion: Lowering D-Ca level below 3.0 mEq/L seems not to have a meaningful effect on patient outcomes.

Background Anemia management protocols in hemodialysis (HD) units differ conspicuously regarding optimal intravenous (IV) iron dosing; consequently, patients receive markedly different cumulative exposures to IV iron and erythropoiesis-stimulating agents (ESAs). Complementary to IV iron safety studies, our goal was to gain insight into optimal IV iron dosing by estimating the effects of IV iron doses on Hgb, TSAT, ferritin, and ESA dose in common clinical practice. Methods 9,471 HD patients (11 countries, 2009-2011) in the DOPPS, a prospective cohort study, were analyzed. Associations of IV iron dose (3-month average, categorized as 0

Introduction: In rural communities in regions with limited resources the provision of clean water remains challenging. Fecal contamination of water is very common and results in a high incidence of diarrhea, subsequent acute kidney injury and mortality particularly in the very young and old. Membrane filtration is a practical solution to this problem and recent innovation allows membrane filtration using recycled hemodialyzers. We, Easy Water for Everyone, have quantified the systematic effect on health outcomes. Material and Methods: Between 02/2018 and 12/2018, 4 communities in rural Ghana (in the Greater-Accra region) were each provided with a high-volume membrane filtration devices (NUF 500; NuFiltration using recycled hemodialyzers). Health data from montly household surveys and chart review in local healthcare facilities were collected with approval from Ghana Health Services. Specifically, data was collected on gastrointestinal disease, acute kidney injury and therapeutic interventions. Incidence rates for a five-months period before and after implementation of the device were calculated and compared to rates during the same months from 4 neighboring communities that were not yet provided with the device. Results: Acceptance of the devices and the purified water in the studied villages was good and self-reported data of 1130 villagers over 10 months from 9 studied communities in rural Ghana (11% younger than 5 years and 14 % older than 65 years) were included in this analysis. The overall monthly incidence rate of diarrhea showed a decline following the implementation of the device in the 4 study villages from a mean of 0.18 to 0.05 cases per person-month for a reduction in rates by 72% (rate ratio = 0.27). By contrast, the control group of 4 villages in the same region showed no decline in mean rates during the same months as the study period with mean rates changing not significantly from 0.11 to 0.08 cases per person-month. Discussion: Provision of a hemodialyzer membrane filtration device markedly improves health outcomes as measured by diarrhea incidence within rural communities. While our data awaits confirmation in a larger population and further statistical analyses accounting for village characteristics, seasonality and subject demographics, the obvious decline in incidence rates supports widespread use of hemodialyzer membrane filtration devices, particularly in rural regions. Rollout of the device in further sites will likely increase our understanding in terms of risk and other preventive factors modifying the incidence of diarrhea and subsequent acute kidney injury.

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 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.

Background The putative benefits of cinacalcet therapy for management of secondary hyperparathyroidism (SHPT) are thought to be most manifested when patients are taking it consistently and as prescribed. Real-world descriptions of cinacalcet prescription discontinuation and reinitiation in European hemodialysis patients are lacking. To address this knowledge gap, we used Dialysis Outcomes and Practice Patterns Study (DOPPS) data, based on dialysis facility medical records, from seven European countries to estimate rates and predictors of cinacalcet prescription discontinuation and reinitiation in hemodialysis patients and to describe the trajectories of CKD-MBD laboratory values after discontinuation. Methods Cox regression analyses were used to predict (1) cinacalcet discontinuation among 613 patients with ≥3 consecutive months without cinacalcet prescription immediately prior to a new cinacalcet prescription and (2) cinacalcet reinitiation among 415 patients with a newly discontinued cinacalcet prescription immediately after ≥3 consecutive months of prescribed use. Results Cinacalcet was discontinued in 21 and 35% of new users after 6 and 12 months, respectively. Cinacalcet was reinitiated in 38 and 49% of newly-discontinued users after 6 and 12 months, respectively. Predictors of discontinuation included lower parathyroid hormone (PTH) in the previous month (

BACKGROUND: Despite a higher prevalence of chronic kidney disease among women, more men than women start renal replacement therapy (RRT). We hypothesized that gender differences in health care access exist and therefore aimed at determining whether characteristics and outcomes of haemodialysis patients over time differ by sex. METHODS: We studied all 28 323 adults who began haemodialysis during 1965-2014 in the Austrian Dialysis Registry, analysing trends in patient characteristics by sex and decade with mortality (via Cox regression), which was compared with the mortality of the Austrian general population. RESULTS: More men than women started haemodialysis (60.1% men versus 39.9% women overall), with minor differences among decades and age groups. The male:female mortality rate ratio in the general population ranged from 1.2 to 2.4 for age groups >18 years and in haemodialysis patients ranged from 0.80 to 1.3 (closer to 1 than in the general population, but consistently >1 in Decades 3-5). In recent decades, diabetes and hypertension replaced glomerulonephritis as the primary cause of end-stage renal disease in both men and women. Interaction analyses showed the mortality risk associated with haemodialysis access (only recorded in Decade 5) was significantly lower for men than for women. CONCLUSIONS: The male:female mortality rate ratio and the proportion of women starting haemodialysis were remarkably stable, which does not support the hypothesis of gender differences in health care/haemodialysis access or could imply that such differences might have persisted over decades. Future research should expand to other countries and other forms of RRT.

To the Editor: The prognostic importance of residual kidney function (RKF) for maintenance hemodialysis (HD) patients has previously been recognized.1, 2, 3, 4, 5, 6 In previous studies, monitoring of RKF typically required urine collection preceding the HD session and a predialysis blood sample from the end of collection to compute the renal clearance of urea/creatinine (ie, urinary urea/creatinine divided by serum concentration2, 4, 5) and more specifically, renal Kt/Vurea.3 Urine volume, the prerequisite for RKF, can also be estimated by patient self-report.7 In the present analysis of the DOPPS, we evaluated predictors and outcomes of self-reported urine volume; specifically, whether a positive response to the question: “Did the patient have urine output > 200 mL/d or 1 cup/day at the time of enrollment?” was associated with mortality during follow-up periods of 2 to 3 years.

BackgroundChronic kidney disease (CKD) is less prevalent among men than women, but more men than women initiate kidney replacement therapy. Differences in CKD awareness may contribute to this gender gap, which may further vary by race/ethnicity. We aimed to investigate trends in CKD awareness and the association between individual characteristics and CKD awareness among US men versus women.Methods and findingsWe conducted a serial, cross-sectional analysis of 10 cycles (1999–2018) from the National Health and Nutrition Examination Survey (NHANES). Adult participants with CKD stages G3-G5 (estimated glomerular filtration rate [eGFR] 2) were included, unless they were on dialysis or medical information was missing. Serum creatinine was measured during NHANES medical exams. CKD stage was classified by eGFR, based on the CKD-EPI formula. CKD awareness was assessed with the question: “Have you ever been told by a health care professional you had weak or failing kidneys”, asked in standardized NHANES questionnaires on each survey. Using logistic regression models, we evaluated the association between sex and CKD awareness, adjusting for potential confounders including age, race/ethnicity and comorbidities. We stratified CKD awareness by 5 pre-defined calendar-year periods and conducted all analyses for the complete study population as well as the Caucasian and African American subpopulations. We found that among 101871 US persons participating in NHANES, 4411 (2232 women) had CKD in stages G3-G5. These participants were, on average, 73±10 years old, 25.3% reported diabetes, 78.0% reported hypertension or had elevated blood pressure during medical examinations and 39.8% were obese (percentages were survey-weighted). CKD awareness was more prevalent among those with higher CKD stage, younger age, diabetes, hypertension and higher body mass index. CKD awareness was generally low (ConclusionsCKD awareness is lower among US women than men. The narrowing gap between the sexes in more recent years and the results on CKD awareness by serum creatinine indicate that health care professionals have previously been relying on serum creatinine to inform patients about their condition, but in more recent years have been using eGFR, which accounts for women’s lower serum creatinine levels due to their lower muscle mass. Additional efforts should be made to increase CKD awareness among both sexes.

Introduction There is little comparable information about hemodialysis (HD) practices in low- and middle income countries, including Russia. Evaluation of HD in Russia and its international comparisons could highlight factors providing opportunities for improvement. Methods We examined treatment patterns for 481 prevalent HD patients in 20 Russian facilities, and compared them to contemporary data for 8512 patients from 311 facilities in seven European countries, Japan, and North America. Data were collected according to the uniform methodology of the Dialysis Outcomes and Practice Patterns Study, phase 5. Findings Compared to other regions, Russian patients were younger (mean age 53.4 years), had a lower percent of males (52.5%), higher arteriovenous fistula use (89.7%), and longer treatment time (mean: 252 minutes, SD: 37 minutes). Mean single pool Kt/V was 1.49 (SD 0.58). Prescription of dialysate calcium 3.5 mEq/L and aluminum-based phosphate binders were high (15.2% and 17.6% of patients, respectively), while intravenous vitamin D and cinacalcet were low (3.3% and 2.2%, respectively). The percents with parathyroid hormone >600 pg/mL (30.9%) and serum phosphate >1.78 mmol/L (37.7%) were high. Use of erythropoetin stimulating agents (78%) was lower, but hemoglobin, ferritin, and transferrin saturation were generally comparable to North America and Europe. Discussion These detailed data for hemodialysis in Russia demonstrate that many practice patterns contrasted sharply to those in Europe, Japan, and North America, while other features were similar. Our analysis revealed several positive and some less favorable treatment patterns in Russia that represent opportunities for improving patient care and outcomes.

Sex and gender differences are of fundamental importance in most diseases, including chronic kidney disease (CKD). Men and women with CKD differ with regard to the underlying pathophysiology of the disease and its complications, present different symptoms and signs, respond differently to therapy and tolerate/cope with the disease differently. Yet an approach using gender in the prevention and treatment of CKD, implementation of clinical practice guidelines and in research has been largely neglected. The present review highlights some sex- and gender-specific evidence in the field of CKD, starting with a critical appraisal of the lack of inclusion of women in randomized clinical trials in nephrology, and thereafter revisits sex/gender differences in kidney pathophysiology, kidney disease progression, outcomes and management of haemodialysis care. In each case we critically consider whether apparent discrepancies are likely to be explained by biological or psycho-socioeconomic factors. In some cases (a few), these findings have resulted in the discovery of disease pathways and/or therapeutic opportunities for improvement. In most cases, they have been reported as merely anecdotal findings. The aim of the present review is to expose some of the stimulating hypotheses arising from these observations as a preamble for stricter approaches using gender for the prevention and treatment of CKD and its complications.

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.

Background With its convective component, hemodiafiltration (HDF) provides better middle molecule clearance compared with hemodialysis (HD) and is postulated to improve survival. A previous analysis of Dialysis Outcomes and Practice Patterns Study (DOPPS) data in 1998-2001 found lower mortality rates for high replacement fluid volume HDF versus HD. Randomized controlled trials have not shown uniform survival advantage for HDF; in secondary (non-randomized) analyses, better outcomes were observed in patients receiving the highest convection volumes. Methods In a 'real-world' setting, we analyzed patients on dialysis >90 days from seven European countries in DOPPS Phases 4 and 5 (2009-15). Adjusted Cox regression was used to study HDF (versus HD) and mortality, overall and by replacement fluid volume. Results Among 8567 eligible patients, 2012 (23%) were on HDF, ranging from 42% in Sweden to 12% in Germany. Median follow-up was 1.5 years during which 1988 patients died. The adjusted mortality hazard ratio (95% confidence interval) was 1.14 (1.00-1.29) for any HDF versus HD and 1.08 (0.92-1.28) for HDF >20 L replacement fluid volume versus HD. Similar results were found for cardiovascular and infection-related mortality. In an additional analysis aiming to avoid treatment-by-indication bias, we did not observe lower mortality rates in facilities using more HDF (versus HD). Conclusions Our results do not support the notion that HDF provides superior patient survival. Further trials designed to test the effect of high-volume HDF (versus lower volume HDF versus HD) on clinical outcomes are needed to adequately inform clinical practices.

Background The Kidney Disease: Improving Global Outcomes guidelines have cautioned against administering intravenous (IV) iron to hemodialysis patients with high serum ferritin levels due to safety concerns, but prior research has shown that the association between high ferritin and mortality could be attributed to confounding by malnutrition and inflammation. Our goal was to better understand the ferritin–mortality association and relative influence of IV iron and inflammation in the USA, where ferritin levels have recently increased dramatically, and in Europe and Japan, where ferritin levels are lower and anemia management practices differ. Methods Data from 18 261 patients in Phases 4 and 5 (2009–15) of the international Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, were analyzed. Using Cox regression, we modeled the association between baseline ferritin and 1-year mortality with restricted cubic splines and assessed the impact of potential confounders. Results Median ferritin levels were 718 ng/mL in the USA, 405 in Europe and 83 in Japan. High ferritin levels were associated with elevated mortality (relative to region-specific medians) in all three regions. The strength of this association was attenuated more by adjustment for malnutrition and inflammation than by IV iron and erythropoiesis-stimulating agent dose in each region. Conclusion The utility of high ferritin as a biomarker for clinical risk due to excess iron stores may be limited, although caution regarding IV iron dosing to higher upper ferritin targets remains warranted. Research to resolve biomarker criteria for iron dosing, and whether optimal anemia management strategies differ internationally, is still needed.

For years, erythropoiesis-stimulating agent (ESA) use among patients on dialysis was much higher in the United States than in Europe or Japan. Sweeping changes to dialysis reimbursement and regulatory policies for ESA in the United States in 2011 were expected to reduce ESA use and hemoglobin levels. We used the Dialysis Outcomes and Practice Patterns Study (DOPPS) data from 7129 patients in 223 in–center hemodialysis facilities (average per month) to estimate and compare time trends in ESA dose and hemoglobin levels among patients on hemodialysis in the United States, Germany, Italy, Spain, the United Kingdom, and Japan. From 2010 to 2013, substantial declines in ESA use and hemoglobin levels occurred in the United States but not in other DOPPS countries. Between August of 2010 and April of 2013, mean weekly ESA dose in the United States decreased 40.4% for black patients and 38.0% for nonblack patients; mean hemoglobin decreased from 11.5 g/dl in black patients and 11.4 g/dl in nonblack patients to 10.6 g/dl in both groups. In 2010 and 2013, adjusted weekly ESA doses per kilogram were 41% and 11% lower, respectively, in patients in Europe and 60% and 18% lower, respectively, in patients in Japan than in nonblack patients in the United States. Adjusted hemoglobin levels in 2010 and 2013 were 0.07 g/dl lower and 0.56 g/dl higher, respectively, in patients in Europe and 0.93 and 0.01 g/dl lower, respectively, in patients in Japan than in nonblack patients in the United States. In conclusion, ESA dosing reductions in the United States likely reflect efforts in response to changes in reimbursement policy and regulatory guidance.

Background and objectives Anemia management changed substantially among dialysis patients in the United States around the time of implementation of the new Centers for Medicare & Medicaid Services bundled payment system and erythropoiesis-stimulating agent (ESA) label change in 2011. Among these, average ferritin levels increased dramatically and have remained high since; this study sought to gain understanding of this sustained rise in ferritin levels. Design, setting, participants, & measurements Trends in mean ferritin, hemoglobin, IV iron dose, and ESA dose from 2009 to 2013 were examined in 9735 patients from 91 United States Dialysis Outcomes and Practice Patterns Study facilities. Linear mixed models were used to assess the extent to which intravenous (IV) iron and ESA dose accounted for patients’ changes in ferritin over time. Results Mean ESA dose and hemoglobin levels declined throughout the study. Mean IV iron dose increased from 210 mg/mo in 2009–2010 to a peak of 280 mg/mo in 2011, then declined back to 200 mg/mo and remained stable from 2012 to 2013. Mean ferritin increased from 601 ng/ml in the third quarter of 2009 to 887 ng/ml in the first quarter of 2012; models suggest that higher IV iron dosing was a primary determinant during 2011, but lower ESA doses contributed to the sustained high ferritin levels thereafter. In a subset of 17 facilities that decreased IV iron dose in 2011, mean ferritin rose by 120 ng/ml to 764 ng/ml, which appeared to be primarily due to ESA reduction. Together, changes in IV iron and ESA doses accounted for 46% of the increase in ferritin over the study period. Conclusions In contrast to expectations, the rise in average IV iron dose did not persist beyond 2011. The sustained rise in ferritin levels in United States dialysis patients after policy changes in 2011, to average levels well in excess of 800 ng/ml, appeared to be partly due to reductions in ESA dosing and not solely IV iron dosing practices. The effect of these changes in ferritin on health outcomes requires further investigation.

Background Since the bundled end-stage renal disease prospective payment system began in 2011 in the United States, some hemodialysis practices have changed substantially, raising the question of whether vascular access practice also has changed. We describe monthly US vascular access use from August 2010 to August 2013 with international comparisons, and other aspects of US vascular access practice. Study Design Prospective observational cohort study of vascular access. Setting & Participants Maintenance hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor (DPM) in the United States (N=3,442; US patients) and 19 other nations (N=8,478). Predictors Country, patient demographics, time period. Outcomes Vascular access use, pre–end-stage renal disease access timing of first nephrologist care and arteriovenous access placement, patient self-reported vascular access preferences (United States only), treatment practices as stated by medical directors. Results In the United States from August 2010 to August 2013, arteriovenous fistula (AVF) use increased from 63% to 68%, while catheter use declined from 19% to 15%. Although AVF use did not differ greatly across age groups, arteriovenous graft use was 2-fold higher among black (26%) versus nonblack US patients (13%) in 2013. Across 20 countries in 2013, AVF use ranged from 49% to 92%, whereas catheter use ranged from 1% to 45%. Patient-reported vascular access preferences differed by sex and race, with 16% to 20% of patients feeling uninformed regarding benefits/risks of different vascular access types. Among new (incident) US hemodialysis patients, AVF use remains low, with ∼70% initiating hemodialysis therapy with a catheter (60% starting with catheter when having ≥4 months of predialysis nephrology care). In the United States, longer typical times to first AVF cannulation were reported. Limitations Noncompletion of surveys may affect the generalizability of findings to the wider hemodialysis population. Conclusions AVF use has increased, with catheter use decreasing among prevalent US hemodialysis patients since the introduction of the prospective payment system. However, AVF use at dialysis therapy initiation remains low, suggesting that reforms affecting predialysis care may be necessary to incentivize improvements in fistula rates at dialysis therapy initiation as achieved for prevalent hemodialysis patients.

Background and objectives Elevated parathyroid hormone levels may be associated with adverse clinical outcomes in patients on dialysis. After the introduction of practice guidelines suggesting higher parathyroid hormone targets than those previously recommended, changes in parathyroid hormone levels and treatment regimens over time have not been well documented. Design, setting, participants, & measurements Using data from the international Dialysis Outcomes and Practice Patterns Study, trends in parathyroid hormone levels and secondary hyperparathyroidism therapies over the past 15 years and the associations between parathyroid hormone and clinical outcomes are reported; 35,655 participants from the Dialysis Outcomes and Practice Patterns Study phases 1–4 (1996–2011) were included. Results Median parathyroid hormone increased from phase 1 to phase 4 in all regions except for Japan, where it remained stable. Prescriptions of intravenous vitamin D analogs and cinacalcet increased and parathyroidectomy rates decreased in all regions over time. Compared with 150–300 pg/ml, in adjusted models, all-cause mortality risk was higher for parathyroid hormone=301–450 (hazard ratio, 1.09; 95% confidence interval, 1.01 to 1.18) and >600 pg/ml (hazard ratio, 1.23; 95% confidence interval, 1.12 to 1.34). Parathyroid hormone >600 pg/ml was also associated with higher risk of cardiovascular mortality as well as all-cause and cardiovascular hospitalizations. In a subgroup analysis of 5387 patients not receiving vitamin D analogs or cinacalcet and with no prior parathyroidectomy, very low parathyroid hormone ( Conclusions In a large international sample of patients on hemodialysis, parathyroid hormone levels increased in most countries, and secondary hyperparathyroidism treatments changed over time. Very low and very high parathyroid hormone levels were associated with adverse outcomes. In the absence of definitive evidence in support of a specific parathyroid hormone target, there is an urgent need for additional research to inform clinical practice.

When randomized controlled trials are unavailable, clinicians have to rely on observational studies. However, analyses using observational data to evaluate specific treatments and their associations with outcomes often are biased through confounding by clinical indication for the treatment of interest. Given the rich observational data and limited clinical trial data available in the dialysis population, successfully accounting for this bias can lead to substantial knowledge generation. In recent decades, much has been learned about statistical methods for observational data, including the fact that even extensive adjustments may not always overcome this bias, particularly when unmeasured confounders exist. In this article, examples based on the international DOPPS (Dialysis Outcomes and Practice Patterns Study) are used to demonstrate the value of practice-based instrumental variable analyses. This methodology leverages the marked differences in practice patterns among dialysis facilities and uses the reasonable assumption that patients are assigned to a dialysis facility without consideration of its specific treatment pattern in order to minimize bias in analyses relying on observational data. Examples using the dialysis facility as an instrument that are reviewed in depth in this article include studies of dialysate sodium concentration, systolic blood pressure targets, and treatment time, demonstrate the value of this methodology to produce advanced knowledge. However, practice-based analyses have potential limitations. Specifically, observation of sufficiently large differences in practice patterns is required and these analyses should consider that the treatment of interest may be associated with other facility treatment practices. These examples from the DOPPS hopefully will stimulate advances in methodologies and critical clinical work toward improving patient care by identifying beneficial treatment practices applicable to dialysis, chronic kidney disease, and beyond.