Original Article
Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis
N Engl J Med 2011; 365:1099-1107September 22, 2011
- Abstract
Background
Patients with end-stage renal disease requiring dialysis have limited tolerance of metabolic and volume-related deviations from normal ranges; in addition, the prevalence of cardiovascular disease is high among such patients. Given these problems, we hypothesized that a long interdialytic interval is associated with adverse events in patients receiving hemodialysis.
Methods
We studied 32,065 participants in the End-Stage Renal Disease Clinical Performance Measures Project, a nationally representative sample of U.S. patients receiving hemodialysis three times weekly, at the end of calendar years 2004 through 2007. We compared rates of death and cardiovascular-related hospital admissions on the day after the long (2-day) interdialytic interval with rates on other days.
Results
The mean age of the cohort was 62.2 years; 24.2% of the patients had been receiving dialysis treatment for 1 year or less. Over a mean follow-up interval of 2.2 years, the following event rates were higher on the day after the long interval than on other days: all-cause mortality (22.1 vs. 18.0 deaths per 100 person-years, P<0.001), mortality from cardiac causes (10.2 vs. 7.5, P<0.001), infection-related mortality (2.5 vs. 2.1, P=0.007), mortality from cardiac arrest (1.3 vs. 1.0, P=0.004), mortality from myocardial infarction (6.3 vs. 4.4, P<0.001), and admissions for myocardial infarction (6.3 vs. 3.9, P<0.001), congestive heart failure (29.9 vs. 16.9, P<0.001), stroke (4.7 vs. 3.1, P<0.001), dysrhythmia (20.9 vs. 11.0, P<0.001), and any cardiovascular event (44.2 vs. 19.7, P<0.001).
Conclusions
The long (2-day) interdialytic interval is a time of heightened risk among patients receiving hemodialysis. (Funded by the National Institutes of Health.)
Media in This Article
Figure 1
Annualized Mortality and Cardiovascular-Admission Rates on Different Days of the Dialysis Week.Figure 2
Annualized Mortality and Cardiovascular-Admission Rates on the Day after the Long Interdialytic Interval and on Other Days, According to Subgroup.Article Activity
- Article
Although some progress has been made in the past two decades, survival rates among patients receiving hemodialysis in the United States remain among the lowest in the world.1 As in most countries, maintenance hemodialysis in the United States is typically performed three times per week, with two 1-day intervals and one 2-day interval between dialysis sessions. Depending on scheduling, the vast majority of patients do not receive dialysis between Friday and Monday or between Saturday and Tuesday. Patients with end-stage renal disease have a limited capacity to maintain homeostasis in the presence of metabolic and volume-related deviations from normal ranges, and most patients begin maintenance dialysis with overt cardiovascular disease. Thus, there has long been concern that the 2-day interdialytic interval may unnecessarily increase the risk of death.2-4
Daily hemodialysis treatment, which has the potential to allay these concerns, has been the focus of considerable interest in the past several years, and two well-designed clinical trials from Canada and the United States showed improvements in surrogate outcomes, such as left-ventricular mass and quality of life, with this approach.5,6 These studies suggest a possible need to reexamine the issue of the timing and frequency of hemodialysis sessions. Hence, in this national study, we addressed the hypothesis that the long interdialytic interval is associated with excess mortality among U.S. patients receiving hemodialysis.
Methods
Objectives
We reviewed records of patients receiving maintenance hemodialysis three times per week in the United States in the period from 2005 through 2008 and considered events on the day of the hemodialysis session after the long (2-day) interdialytic interval as compared with those on other days of the week. Our objectives were to determine if there were differences in overall mortality; cause-specific mortality, with causes grouped as cardiac, vascular, infectious, and other; cause-specific mortality for the five most commonly cited individual causes of death (cardiac arrest, withdrawal of treatment or uremia, myocardial infarction, septicemia, and stroke); cardiovascular-admission rates, a composite of first hospitalization for myocardial infarction, congestive heart failure, stroke, or dysrhythmia; and the individual components of the composite cardiovascular outcome.
Study Patients and Measurements
Participants in the End-Stage Renal Disease Clinical Performance Measures (CPM) Project were enrolled in this study. No new data were collected, and the data-abstraction forms were authorized through the National Institutes of Health clinical exemption process. The CPM Project is a series of annual cross-sectional samples examining selected components of dialysis care, including vascular access, clearance of urea during dialysis, anemia management, and serum albumin levels. All Medicare-eligible adults (≥18 years of age) receiving hemodialysis in a hemodialysis clinic on the last day of December of each study year were eligible for inclusion in the sample; a random sample of these patients was selected, with stratification according to all 18 regional end-stage renal disease networks in the United States. The sample size for each annual national survey was such that 95% confidence intervals for the prevalence of selected clinical performance measures were within 10 percentage points for each end-stage renal disease network, and a 30% oversampling strategy was used to compensate for survey nonresponse.7-9
In each annual survey, information about the patients' demographic and clinical characteristics and about clinical variables related to the delivery of hemodialysis was collected for the last 3 months of the preceding calendar year. Race (categories included American Indian or Alaska Native, Asian or Pacific Islander, black, white, and other or unknown) and ethnic group (Hispanic or non-Hispanic) were determined by dialysis staff members. Because of the small numbers of patients in some categories of race or ethnic group, only white and black race were considered for subgroup analysis in this study. Treatment-related variables are for December of the preceding year.
Beginning in 2005, the CPM Project recorded the number of dialysis sessions that each patient received per week. Patients receiving dialysis three times per week were selected for this study, provided the last dialysis-related blood urea levels were measured on any day other than Sunday. In our study population, the date of the predialysis urea level was used to determine whether dialysis sessions were on Monday, Wednesday, and Friday or on Tuesday, Thursday, and Saturday. Of 33,927 patients screened, 1862 (5.5%) were excluded — 921 were not on a thrice-weekly hemodialysis schedule, 703 had blood urea measured on a Sunday, and 238 had both reasons for exclusion.
Publicly available United States Renal Data System (USRDS) Standard Analytical Files (SAF) were used (CPM_HD05, CPM_HD06, CPM_HD07, CPM_HD08, DEATH, HOSP1, HOSP2, PATIENTS, MEDEVID95, MEDEVID05, WAITSEQ_KI, WAITSEQ_KP), linked by the USRDS identification number (USRDS_ID). The Patients file (PATIENTS) was used to determine the date that dialysis treatment began and the original kidney disease; the Waitlist Sequence files (WAITSEQ_KI and WAITSEQ_KP) were used to determine whether patients were listed for kidney transplantation at baseline; and the Hospitalization files (HOSP1 and HOSP2) were used to determine the first hospitalization for myocardial infarction (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 410), congestive heart failure (ICD-9-CM code 428), stroke (ICD-9-CM codes 430 through 434), and dysrhythmia (ICD-9-CM codes 426 and 427) during the follow-up period. For patients who died, the date and cause of death were determined from the Death file (DEATH) (containing data elements from Centers for Medicare and Medicaid Services [CMS] form 2746).
Statistical Analysis
The hemodialysis week was defined as follows: hemodialysis session 1 (HD1) as Monday for participants on a Monday, Wednesday, and Friday schedule and as Tuesday for participants on a Tuesday, Thursday, and Saturday schedule; HD1+1 as Tuesday or Wednesday, respectively; HD2 as Wednesday or Thursday; HD2+1 as Thursday or Friday; HD3 as Friday or Saturday; HD3+1 as Saturday or Sunday; and HD3+2 as Sunday or Monday. Thus, HD1 represented the hemodialysis session after the 2-day interval between sessions. Follow-up for outcome analyses began on January 1 of the survey year for the years 2005 through 2008 and ended at the earliest occurrence of the index event or on June 30, 2009, whichever came first.
Poisson regression was used to quantify event rates and associated confidence intervals in the study population and in subgroups defined by the interval since dialysis initiation, age, sex, race or ethnic group, primary cause of end-stage renal disease, type of vascular access, and status with respect to weight gain between dialysis sessions, wait-listing for a kidney transplant, diabetes, and recent cardiovascular admission. Event rates were annualized; event-rate computation accounted for the fact that only one seventh of the follow-up interval could include events on HD1 and six sevenths of the interval (representing the other days of the week) included the other events.
For cause-specific mortality, the groupings listed on the 2004 Death Notification form (CMS-2746) were used, except that liver disease, gastrointestinal disease, and metabolic and endocrine causes were subsumed under “other” because of low event numbers; hence, the major cause-of-death categories studied were cardiac, vascular, infectious, and other.10 In addition, we examined death rates for the five most frequently reported individual causes of death: cardiac arrest, withdrawal of dialysis or uremia, myocardial infarction, septicemia, and stroke. Data were analyzed with the use of SAS software, version 9.1 (SAS Institute).
Results
Characteristics of the Study Participants
Baseline characteristics of the study population are shown in Table 1Table 1
Baseline Characteristics of the Study Population.. The mean age was 62.2 years; 24.2% of the patients had been receiving dialysis treatment for 1 year or less, 45.1% were women, 36.3% were black, and 13.9% were Hispanic. Diabetes mellitus was the cause of end-stage renal disease in 43.7% of the patients, and for 27.7%, a catheter was used for vascular access for hemodialysis.Over a mean follow-up period of 2.2 years, 41.1% of the study population died, 17.4% from cardiac causes, 2.7% from vascular causes, and 4.8% from infectious causes; 9.0% of the patients were admitted to the hospital with myocardial infarction, 33.1% with congestive heart failure, 7.1% with stroke, 25.9% with dysrhythmia, and 45.8% with any of these cardiovascular events (Table 2Table 2
Annualized Mortality and Cardiovascular-Hospitalization Rates.). The following event rates were higher on the day after the long interdialytic interval than on other days: all-cause mortality (22.1 deaths vs. 18.0 per 100 person-years), mortality from cardiac causes (10.2 vs. 7.5), infection-related mortality (2.5 vs. 2.1), mortality from cardiac arrest (1.3 vs. 1.0), mortality from myocardial infarction (6.3 vs. 4.4), and admissions for myocardial infarction (6.3 vs. 3.9), congestive heart failure (29.9 vs. 16.9), stroke (4.7 vs. 3.1), dysrhythmia (20.9 vs. 11.0), and any cardiovascular event (44.2 vs. 19.7). Although most event rates were highest on the day after the long interdialytic interval, a sawtooth pattern was apparent for all-cause mortality, mortality from cardiac causes, and cardiovascular admissions, with event rates lower on the day before and the day after a dialysis session (Figure 1Figure 1Annualized Mortality and Cardiovascular-Admission Rates on Different Days of the Dialysis Week.).Figure 2Figure 2
Annualized Mortality and Cardiovascular-Admission Rates on the Day after the Long Interdialytic Interval and on Other Days, According to Subgroup. summarizes mortality and cardiovascular-admission rates for all patients and for 25 subgroups defined by the prior duration of dialysis therapy, age, sex, race or ethnic group, cause of end-stage renal disease, type of vascular access, and status with respect to weight gain between dialysis sessions, wait-listing for a kidney transplant, diabetes, and recent cardiovascular admission. Nonoverlapping 95% confidence intervals were observed throughout, except for death rates in the following subgroups: Hispanic ethnic group, end-stage renal disease from glomerulonephritis, use of a catheter for dialysis access for at least 90 days, and wait-listed for a transplant.Discussion
In this study of a relatively contemporary, representative population of U.S. adults receiving hemodialysis, we found that most events studied occurred more frequently on the day after the long interdialytic interval than on other days, including all-cause mortality, mortality from cardiac causes, infection-related mortality, mortality from cardiac arrest, and mortality from myocardial infarction. Similar patterns were observed for hospital admissions with myocardial infarction, congestive heart failure, stroke, dysrhythmia, and any of these cardiovascular events. Subgroup analyses suggested that this excess of adverse events on the day after the long interdialytic interval was close to being a generalized phenomenon.
Despite the widespread clinical impression that the end of the long interdialytic interval is a time of heightened risk, comparatively few studies have examined associations between outcomes and hemodialysis schedules. The results of these studies, which have examined sudden death and cardiac arrest, have been similar to those reported here for death from cardiac arrest.4,11-13 For example, Bleyer et al.4 reported 7-day patterns of sudden death and death from cardiac causes in U.S. patients receiving hemodialysis between 1977 and 1997. Although proportions of deaths from noncardiac causes were homogeneous, Mondays and Tuesdays were overrepresented for sudden death and death from cardiac causes.4 Another study showed substantial escalations in the risk of sudden death during the 12-hour period starting with the dialysis procedure and during the 12-hour period at the end of the weekend interval.14 Karnik et al.11 examined 400 cardiac arrests that occurred on dialysis units between October 1998 and June 1999, among 77,000 patients receiving hemodialysis at units affiliated with Fresenius Medical Care North America. The rate of cardiac arrest was 7 per 100,000 hemodialysis sessions, equivalent to 1.1 per 100 person-years with a typical thrice-weekly hemodialysis schedule; cardiac arrest occurred more frequently on Mondays, and the associated mortality was 60% during the first 48 hours after the arrest.
For deaths that occurred on days when dialysis was scheduled, our study did not allow us to determine whether death occurred before, during, or after the time of the scheduled dialysis session; similarly, studying the effect of missed dialysis sessions on outcomes was not possible, and whether patients were assigned to morning or evening shifts was unknown. Missed or shortened dialysis treatments are known to be much more frequent in the United States than elsewhere, an occurrence that is associated with higher mortality.15,16 Regarding the timing of dialysis shifts, one study examined outcomes for 6939 patients in the United States who began treatment with hemodialysis between 1990 and 1993. Shift-associated mortality differences were present, but only in patients 60 years of age or older, with the lowest mortality during the morning shift, intermediate mortality during the afternoon shift, and the highest mortality during the evening shift.17 Morning-shift patients also had lower mortality in the study by Bliwise et al.18
Because the same population was considered when comparing outcome rates on different days, it seems unlikely that unmeasured coexisting conditions could account for the findings. As with all nonexperimental designs, causes and effects cannot be identified with certainty, and interpretations should be made with caution. For example, one could argue that because mortality and cardiovascular-admission rates are highest on the hemodialysis day after the long interdialytic interval, hemodialysis itself is responsible, and adverse outcomes could be avoided by not providing dialysis at all. This somewhat counterintuitive hypothesis is not supported by the observation that on weekends adverse-event rates were lowest on the first day after a dialysis session, intermediate on the next day, and highest on the day of the next dialysis session. To date, randomized, controlled trials have failed to conclusively identify interventions that reduce rates of cardiovascular events and death among patients receiving hemodialysis.
Apart from its nonexperimental design, the study has other limitations, including the use of retrospective data and dependence on administrative codes to identify cardiovascular events. In addition, attribution of cause-specific death is likely to be of limited accuracy in the population studied. Accurate estimates of residual renal function were not available. That being said, it was interesting that the subgroup of patients with less than 1 year of prior dialysis treatment, unlike the overall study population, did not have higher-than-expected mortality after the long interdialytic interval. Finally, cost information was not collected; given that hospitalization is very costly in the dialysis population, it might be relevant to compare the upstream costs of an extra dialysis session every 2 weeks with the downstream costs associated with the use of other health care resources.
Despite its limitations, this study has some attractive features. By design, it was broadly representative of the overall U.S. dialysis population. Regarding the long interdialytic interval, findings were similar within subgroups and across outcomes, with higher mortality, especially for deaths from cardiac causes, and higher rates of hospital admission for cardiovascular events. Unexplained disparities in event rates appeared to be clinically meaningful in several instances. Hence, this study provides clinical equipoise for a controlled trial of how dialysis services are provided.
Supported by a contract (HHSN267200715002C) from the National Institute of Diabetes and Digestive and Kidney Diseases.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank United States Renal Data System colleagues Beth Forrest for regulatory assistance and Shane Nygaard for assistance with manuscript preparation, and Nan Booth, M.S.W., M.P.H., for editorial assistance with an earlier version of the manuscript.
Source Information
From the United States Renal Data System (R.N.F., D.T.G., T.M., A.J.C.) and the University of Minnesota (R.N.F., T.M., A.J.C.) — both in Minneapolis.
Address reprint requests to Dr. Foley at the United States Renal Data System, 914 S. 8th St., Suite S-406, Minneapolis, MN 55404, or at rfoley@usrds.org.
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- Citing Articles (13)
Citing Articles
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Jiannong Liu, Robert N Foley. (2012) Alternate-day dialysis may be needed for hemodialysis patients. Kidney International 81:11, 1055-1057
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Kalaivani Mahadevan, Paul Kalra. (2012) CARDIORENAL MEDICINE IN THE CHANGING HEALTH SYSTEM. Journal of Renal Care 38:2, 65-68
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William G. Herrington, David A. Lewis. (2012) Stroke Risk in Maintenance Hemodialysis. American Journal of Kidney Diseases 59:6, 891
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Albert Power, Neill Duncan. (2012) In Reply to ‘Stroke Risk in Maintenance Hemodialysis’. American Journal of Kidney Diseases 59:6, 891-892
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Keith M. Swetz, Björg Thorsteindottir, Molly A. Feely, Kayhan Parsi. (2012) Balancing Evidence-Based Medicine, Justice in Health Care, and the Technological Imperative: A Unique Role for the Palliative Medicine Clinician. Journal of Palliative Medicine 15:4, 390-391
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M. A. C. Onuigbo. (2012) Long inter-dialytic interval and mortality among patients receiving maintenance haemodialysis for end-stage renal disease - a call for more studies on the right amount or frequency of maintenance haemodialysis for end-stage renal disease. International Journal of Clinical Practice 66:3, 327-327
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Michelle M. O’Shaughnessy, David W. Lappin, Donal N. Reddan. (2012) Sudden Cardiac Death in Dialysis: Do Current Guidelines for Implantable Cardioverter Defibrillator Therapy Apply to Patients with End-stage Kidney Disease?. Seminars in Dialysisno-no
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Monte Malach, William J. Baumol. (2012) Opportunities for Cost Reduction of Medical Care: Part 3. Journal of Community Health
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Jennie Lin, Jeffrey S. Berns. (2012) Is Hemodialysis Bad for the Heart? : IS HEMODIALYSIS BAD FOR THE HEART?. Seminars in Dialysis 25:1, 86
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Jennifer E. Flythe, Eduardo Lacson. (2012) Outcomes after the Long Interdialytic Break: Implications for the Dialytic Prescription : THE LONG INTERDIALYTIC (WEEKEND) BREAK. Seminars in Dialysis 25:1, 1
CrossRef11
(2011) Long Interdialytic Interval and Mortality. New England Journal of Medicine 365:25, 2436-2438
Full Text12
(2011) Journal Club. Kidney International 80:11, 1113-1114
CrossRef13
Raymond Vanholder, Nic Veys, Wim Van Biesen. (2011) Hemodialysis: Long weekend hemodialysis intervals—killing fields?. Nature Reviews Nephrology 8:1, 5-6
CrossRef
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