Estimating the Fraction of First-Year Hemodialysis Deaths Attributable to Potentially Modifiable Risk Factors: Results from the DOPPS.

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 <3.5 g/dL (19%), and creatinine <6 mg/dL (12%). AFs were 5%-9% for no pre-HD nephrology care, no residual urine volume, systolic blood pressure <130 or ≥160 mm Hg, phosphorus <3.5 or ≥5.5 mg/dL, hemoglobin <10 or ≥12 g/dL, and white blood cell count >10,000/µL. AFs for ferritin, calcium, and PTH were <3%. Overall, 65% (95% CI: 59%-71%) of deaths were attributable to these 12 risk factors. Additionally, the AF for C-reactive protein >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.

Missed Hemodialysis Treatments: International Variation, Predictors, and Outcomes in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

RATIONALE & OBJECTIVE: Missed hemodialysis (HD) treatments not due to hospitalization have been associated with poor clinical outcomes and related in part to treatment nonadherence. Using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 5 (2012-2015), we report findings from an international investigation of missed treatments among patients prescribed thrice-weekly HD. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 8,501 patients participating in DOPPS, on HD therapy for more than 120 days, from 20 countries. Longitudinal and cross-sectional analyses were performed based on the 4,493 patients from countries in which 4-month missed treatment risk was > 5%. PREDICTORS: The main predictor of patient outcomes was 1 or more missed treatments in the 4 months before DOPPS phase 5 enrollment; predictors of missed treatments included country, patient characteristics, and clinical factors. OUTCOMES: Mortality, hospitalization, laboratory measures, patient-reported outcomes, and 4-month missed treatment risk. ANALYTICAL APPROACH: Outcomes were assessed using Cox proportional hazards, logistic, and linear regression, adjusting for case-mix and country. RESULTS: The 4-month missed treatment risk varied more than 50-fold across all 20 DOPPS countries, ranging from < 1% in Italy and Japan to 24% in the United States. Missed treatments were more likely with younger age, less time on dialysis therapy, shorter HD treatment time, lower Kt/V, longer travel time to HD centers, and more symptoms of depression. Missed treatments were positively associated with all-cause mortality (HR, 1.68; 95% CI, 1.37-2.05), cardiovascular mortality, sudden death/cardiac arrest, hospitalization, serum phosphorus level > 5.5mg/dL, parathyroid hormone level > 300pg/mL, hemoglobin level < 10g/dL, higher kidney disease burden, and worse general and mental health. LIMITATIONS: Possible residual confounding; temporal ambiguity in the cross-sectional analyses. CONCLUSIONS: In the countries with a 4-month missed treatment risk > 5%, HD patients were more likely to die, be hospitalized, and have poorer patient-reported outcomes and laboratory measures when 1 or more missed treatments occurred in a 4-month period. The large variation in missed treatments across 20 nations suggests that their occurrence is potentially modifiable, especially in the United States and other countries in which missed treatment risk is high.

Understanding the Recent Increase in Ferritin Levels in United States Dialysis Patients: Potential Impact of Changes in Intravenous Iron and Erythropoiesis-Stimulating Agent Dosing.

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.

Patient selection and training for home hemodialysis.

Patient selection and training is arguably the most important step toward building a successful home hemodialysis (HD) program. We present a step-by-step account of home HD training to guide providers who are developing home HD programs. Although home HD training is an important step in allowing patients to undergo dialysis in the home, there is a surprising lack of systematic research in this field. Innovations and research in this area will be pivotal in further promoting a higher acceptance rate of home HD as the renal replacement therapy of choice.

Dialysate and serum potassium in hemodialysis.

Most patients with end-stage renal disease depend on intermittent hemodialysis to maintain levels of serum potassium and other electrolytes within a normal range. However, one of the challenges has been the safety of using a low-potassium dialysate to achieve that goal, given the concern about the effects that rapid and/or large changes in serum potassium concentrations may have on cardiac electrophysiology and arrhythmia. Additionally, in this patient population, there is a high prevalence of structural cardiac changes and ischemic heart disease, making them even more susceptible to acute arrhythmogenic triggers. This concern is highlighted by the knowledge that about two-thirds of all cardiac deaths in dialysis are due to sudden cardiac death and that sudden cardiac death accounts for 25% of the overall death for end-stage renal disease. Developing new approaches and practice standards for potassium removal during dialysis, as well as understanding other modifiable triggers of sudden cardiac death, such as other electrolyte components of the dialysate (magnesium and calcium), rapid ultrafiltration rates, and safety of a number of medications (ie, drugs that prolong the QT interval or use of digoxin), are critical in order to decrease the unacceptably high cardiac mortality experienced by hemodialysis-dependent patients.

First-year outcomes of incident peritoneal dialysis patients in the United States.

BACKGROUND: Patterns of early outcomes in peritoneal dialysis (PD) are not well studied and dialysis providers need to establish a baseline of key outcomes for continuous quality improvement initiatives. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Incident PD patients from Fresenius Medical Care, North America from January 1 through December 31, 2009. FACTORS: Case-mix, comorbid illness, and baseline laboratory values. OUTCOMES: Death, hospitalization, peritonitis, and switch to hemodialysis (HD) within the first year on PD therapy. MEASUREMENTS: Event rates and outcome predictors. RESULTS: Of 1,677 incident PD patients, 1,313 started on PD therapy and 367 switched from HD therapy within the first 90 days. Normalized first-year event rates for mortality, switch to HD therapy, peritonitis, and hospitalization were 10, 27, 42, and 128 per 100 patient-years, respectively. 336 of 463 (72.6%) first peritonitis episodes and 637 of 939 (67.8%) first hospitalizations occurred within the first 6 months of PD treatment. Black race, higher body mass index, non-Hispanic ethnicity, peripheral vascular disease, and low weekly Kt/V associated with peritonitis risk. Dialysis vintage, female sex, diabetes, congestive heart failure, peripheral vascular disease, and history of limb amputation along with lower laboratory values for albumin, hemoglobin, and phosphorus and weekly Kt/V associated with hospitalization. Switchers to HD therapy (n=350) used central venous catheters 81.4% of the time as initial access (still 78.3% at 90 days later) because of lack of permanent access. LIMITATIONS: Residual confounding from unmeasured variables and exclusion of patients with a training day but who never started home PD therapy. CONCLUSIONS: Despite low first-year mortality, incident PD patients had high morbidity, particularly within the first 3-6 months. Increased focus to identify patients at greatest risk for peritonitis and hospitalization, as well as evaluation of care processes and implementation of preventive strategies, is required. Access planning for transition to HD therapy needs more attention, even during the first PD year.

Sickle trait in African-American hemodialysis patients and higher erythropoiesis-stimulating agent dose.

African Americans require higher doses of erythropoiesis-stimulating agents (ESAs) during dialysis to manage anemia, but the influence of sickle cell trait and other hemoglobinopathy traits on anemia in dialysis patients has not been adequately evaluated. We performed a cross-sectional study of a large cohort of adult African-American hemodialysis patients in the United States to determine the prevalence of hemoglobinopathy traits and quantify their influence on ESA dosing. Laboratory and clinical data were obtained over 6 months in 2011. Among 5319 African-American patients, 542 (10.2%) patients had sickle cell trait, and 129 (2.4%) patients had hemoglobin C trait; no other hemoglobinopathy traits were present. Sickle cell trait was more common in this cohort than the general African-American population (10.2% versus 6.5%-8.7%, respectively, P<0.05). Among 5002 patients (10.3% sickle cell trait and 2.4% hemoglobin C trait) receiving ESAs, demographic and clinical variables were similar across groups, with achieved hemoglobin levels being nearly identical. Patients with hemoglobinopathy traits received higher median doses of ESA than patients with normal hemoglobin (4737.4 versus 4364.1 units/treatment, respectively, P=0.02). In multivariable analyses, hemoglobinopathy traits associated with 13.2% more ESA per treatment (P=0.001). Within subgroups, sickle cell trait patients received 13.2% (P=0.003) higher dose and hemoglobin C trait patients exhibited a similar difference (12.9%, P=0.12). Sensitivity analyses using weight-based dosing definitions and separate logistic regression models showed comparable associations. Our findings suggest that the presence of sickle cell trait and hemoglobin C trait may explain, at least in part, prior observations of greater ESA doses administered to African-American dialysis patients relative to Caucasian patients.

Dialysis frequency versus dialysis time, that is the question.

We reviewed a number of prospective randomized and multiple retrospective cohort studies of different dialysis prescriptions: longer dialysis time, at a frequency of at least three times a week, or a frequency of daily hemodialysis with a shorter dialysis time. Interestingly, the retrospective analyses have generally found significant survival benefits in the intensive dialysis groups, whereas more modest effects were observed in the prospective randomized controlled trials. The reason for this discrepancy may be related to the retrospective nature of the studies and possible selection bias; for example, the patients who were prescribed more frequent dialysis may have had more difficulties with volume control or high blood pressure. In contrast, the randomized controlled trials of increased dialysis frequency, which have shown indirect and modest benefits in complex coprimary end points, have small sample sizes and are plagued with difficulties in recruitment and compliance with the randomly allocated more frequent dialysis. This review, which attempts to balance the potential benefits of more frequent dialysis with the burden on the patient's lifestyle, an increased risk of access malfunction, as well as societal costs of such intensive dialysis prescriptions, concludes in favor of the conventional three times per week dialysis (at a minimum) but at longer dialysis times than is currently prescribed based on the Kt/Vurea metric alone.

Worldwide, mortality risk is high soon after initiation of hemodialysis.

Mortality rates for maintenance hemodialysis patients are much higher than the general population and are even greater soon after starting dialysis. Here we analyzed mortality patterns in 86,886 patients in 11 countries focusing on the early dialysis period using data from the Dialysis Outcomes and Practice Patterns Study, a prospective cohort study of in-center hemodialysis. The primary outcome was all-cause mortality, using time-dependent Cox regression, stratified by study phase adjusted for age, sex, race, and diabetes. The main predictor was time since dialysis start as divided into early (up to 120 days), intermediate (121-365 days), and late (over 365 days) periods. Mortality rates (deaths/100 patient-years) were 26.7 (95% confidence intervals 25.6-27.9), 16.9 (16.2-17.6), and 13.7 (13.5-14.0) in the early, intermediate, and late periods, respectively. In each country, mortality was higher in the early compared to the intermediate period, with a range of adjusted mortality ratios from 3.10 (2.22-4.32) in Japan to 1.15 (0.87-1.53) in the United Kingdom. Adjusted mortality rates were similar for intermediate and late periods. The ratio of elevated mortality rates in the early to the intermediate period increased with age. Within each period, mortality was higher in the United States than in most other countries. Thus, internationally, the early hemodialysis period is a high-risk time for all countries studied, with substantial differences in mortality between countries. Efforts to improve outcomes should focus on the transition period and the first few months of dialysis.

Provision of antioxidant therapy in hemodialysis (PATH): a randomized clinical trial.

Increased markers of oxidative stress and acute-phase inflammation are prevalent in patients undergoing maintenance hemodialysis therapy (MHD), and are associated with increased mortality and hospitalization rates and decreased erythropoietin responsiveness. No adequately powered studies have examined the efficacy of antioxidant therapies on markers of inflammation and oxidative stress. We tested the hypothesis that oral antioxidant therapy over 6 months would decrease selected biomarkers of acute-phase inflammation and oxidative stress and improve erythropoietic response in prevalent MHD patients. In total, 353 patients were enrolled in a prospective, placebo-controlled, double-blind clinical trial and randomly assigned to receive a combination of mixed tocopherols (666 IU/d) plus α-lipoic acid (ALA; 600 mg/d) or matching placebos for 6 months (NCT00237718); 238 patients completed the study. High-sensitivity C-reactive protein (hsCRP) and IL-6 concentration were measured as biomarkers of systemic inflammation, and F2 isoprostanes and isofurans were measured as biomarkers of oxidative stress. The groups did not significantly differ at baseline. At 3 and 6 months, the treatment had no significant effect on plasma hsCRP, IL-6, F2 isoprostane, or isofuran concentrations and did not improve the erythropoietic response. No major adverse events were related to the study drug, and both groups had similar mortality and hospitalization rates during the study. In conclusion, the administration of mixed tocopherols and ALA was generally safe and well tolerated, but did not influence biomarkers of inflammation and oxidative stress or the erythropoietic response.

Improving outcomes by changing hemodialysis practice patterns.

PURPOSE OF REVIEW: This review examines recent advances in understanding of how clinical outcomes for hemodialysis patients may be improved by achieving longer or more frequent treatment times, lower ultrafiltration rates (UFRs), improving nutritional status, and individualizing dialysate composition. This review also discusses the controversy related to timing of dialysis initiation. RECENT FINDINGS: Many observational studies and several randomized controlled trials indicate longer dialysis treatment times, particularly nocturnal dialysis, and/or more frequent dialysis improve morbidity and mortality. Recent evidence also suggests that lower UFR and more consistent achievement of 'dry weight' may help minimize the damage from myocardial stunning and chronic volume overload that occurs in the majority of patients who receive conventional hemodialysis during the day with a standard schedule of 3-5 h, 3 times a week. Other aspects of the dialysis procedure such as appropriate estimated glomerular filtration rate for dialysis initiation and individualizing dialysate composition may also minimize cardiovascular risk. Finally, several studies have highlighted the benefits of oral nutritional supplementation (ONS) during dialysis. SUMMARY: Greater treatment times per week with slower UFR, consistent attainment of 'dry weight', individualized dialysate prescriptions, and administration of ONS to malnourished patients are likely to reduce hospitalizations and improve survival in this high-risk population of end-stage renal disease patients.

A quality initiative. Reducing rates of hospitalizations by objectively monitoring volume removal.

Morbidity, hospitalizations, and costs for the treatment of individuals with end-stage renal disease are simply not improving at a rate that is acceptable to many physicians and dialysis providers in the United States. Various conferences and papers have suggested what processes need to become part of the dialysis prescription to accelerate change. Controlling cardiovascular disease is a part of that change, and controlling extra-cellular volume (ECV) is necessary to accomplish this. Three dialysis providers joined in a quality initiative to objectively assess the ultrafiltration process and measure "normalized" ECV, with the outcome objective to decrease ECV-related hospitalizations. The results show a decrease in ECV-related hospitalizations by 50%. The model of dialysis prescription needs to now change to Kt/V + objective ECV control.

Hemodialysis access usage patterns in the incident dialysis year and associated catheter-related complications.

BACKGROUND: Hemodialysis (HD) access is considered a critical and actionable determinant of morbidity, with a growing literature suggesting that initial HD access type is an important marker of long-term outcomes. Accordingly, we examined HD access during the incident dialysis period, focusing on infection risk and successful fistula creation during the first dialysis year. STUDY DESIGN: Longitudinal cohort. SETTING & PARTICIPANTS: All US adults admitted to Fresenius Medical Care North America facilities within 15 days of first maintenance dialysis session between January 1 and December 31, 2007. PREDICTOR: Vascular access type at HD therapy initiation. OUTCOMES: Vascular access type at 90 days and at the end of the first year on HD therapy, bloodstream infection within the first year by access type, and catheter complication rate. RESULTS: Of 25,003 incident dialysis patients studied, 19,622 (78.5%) initiated dialysis with a catheter; 4,151 (16.6%), with a fistula; and 1,230 (4.9%), with a graft. At 90 days, 14,105 (69.7%) had a catheter, 4,432 (21.9%) had a fistula, and 1,705 (8.4%) had a graft. Functioning fistulas and grafts at dialysis therapy initiation had first-year failure rates of 10% and 15%, respectively. Grafts were seldom replaced by fistulas (3%), whereas 7,064 (47.6%) of all patients who initiated with a catheter alone still had only a catheter at 1 year. Overall, 3,327 (13.3%) patients had at least one positive blood culture during follow-up, with the risk being similar between the fistula and graft groups, but approximately 3-fold higher in patients with a catheter (P<0.001 for either comparison). Nearly 1 in 3 catheters (32.5%) will require tissue plasminogen activator use by a median of 41 days, with 59% requiring more than one tissue plasminogen activator administration. LIMITATIONS: Potential underestimation of bacteremia because follow-up blood culture results did not include samples sent to local laboratories. CONCLUSIONS: In a large and representative population of incident US dialysis patients, catheter use remains very high during the first year of HD care and is associated with high mechanical complication and bloodstream infection rates.

Prevalence and outcomes of antimicrobial treatment for Staphylococcus aureus bacteremia in outpatients with ESRD.

Staphylococcus bacteremia is a common and life-threatening medical emergency, but it is treatable with appropriate antibiotic therapy. To identify opportunities that may reduce morbidity and mortality associated with S. aureus, we analyzed data from 293,094 chronic hemodialysis outpatients to characterize practices of antibiotic selection. In the study population, the overall rate of bacteremia was 15.4 per 100 outpatient-years; the incidence rate for methicillin-sensitive (MSSA) was 2.1 per 100 outpatient-years, and the incidence rate for methicillin-resistant (MRSA) S. aureus was 1.9 per 100 outpatient-years. One week after the collection of the index blood culture, 56.1% of outpatients with MSSA bacteremia were receiving vancomycin, and 16.7% of outpatients with MSSA were receiving cefazolin. Among MSSA-bacteremic patients who did not die or get hospitalized 1 week after blood culture collection, use of cefazolin was associated with a 38% lower risk for hospitalization or death compared with vancomycin (adjusted HR=0.62, 95% CI=0.46-0.84). In conclusion, vancomycin is commonly used to treat MSSA bacteremia in outpatients receiving chronic dialysis, but there may be more risk of treatment failure than observed among those individuals who receive a ß-lactam antibiotic such as cefazolin.

Outcomes associated with intradialytic oral nutritional supplements in patients undergoing maintenance hemodialysis: a quality improvement report.

BACKGROUND: Insufficient clinical data exist to determine whether provision of oral nutritional supplements during dialysis can improve survival in hypoalbuminemic maintenance hemodialysis patients. STUDY DESIGN: Retrospective matched-cohort study. SETTING & PARTICIPANTS: All oral nutritional supplement program-eligible in-center maintenance hemodialysis patients with albumin level ≤3.5 g/dL in quarter 4 of 2009 without oral nutritional supplements in the prior 90 days at Fresenius Medical Care, North America facilities. QUALITY IMPROVEMENT PLAN: Monitored intradialytic oral nutritional supplements were provided to eligible maintenance hemodialysis patients upon physician order, to continue for a year or until serum albumin level was ≥4.0 g/dL. OUTCOME: Mortality (including deaths and withdrawals), followed up until December 31, 2010. MEASUREMENTS: Both an intention-to-treat (ITT) and an as-treated analysis was performed using a 1:1 geographic region and propensity score-matched study population (using case-mix, laboratory test, access type, 30-day prior hospitalization, and incident patient status) comparing patients treated with intradialytic oral nutritional supplements with usual-care patients. Cox models were constructed, unadjusted and adjusted for facility standardized mortality ratio and case-mix and laboratory variables. RESULTS: The ITT and as-treated analyses both showed lower mortality in the oral nutritional supplement group. The conservative ITT models with 5,227 matched pairs had 40% of controls subsequently receiving oral nutritional supplements after January 1, 2010 (because many physicians delayed participation), with comparative death rates of 30.1% versus 30.4%. The corresponding as-treated (excluding crossovers) death rates for 4,289 matched pairs were 30.9% versus 37.3%. The unadjusted ITT mortality HR for oral nutritional supplement use was 0.95 (95% CI, 0.88-1.01), and the adjusted HR was 0.91 (95% CI, 0.85-0.98); the corresponding as-treated HRs were 0.71 (95% CI, 0.66-0.76) and 0.66 (95% CI, 0.61-0.71) before and after adjustment, respectively. LIMITATIONS: Limited capture of oral nutritional supplement intake outside the facility and potential residual confounding from unmeasured variables, such as dietary intake. CONCLUSIONS: Maintenance hemodialysis patients with albumin levels ≤3.5 g/dL who received monitored intradialytic oral nutritional supplements showed survival significantly better than similar matched patient controls, with the as-treated analysis highlighting the potentially large effect of this strategy in clinical practice.