Survival by Time of Day of Hemodialysis in an Elderly Cohort FREE

Every year in the United States, more than 300 000 patients receive treatment for end-stage renal disease (ESRD) and incur an annual mortality rate of approximately 20%.¹ Most patients receive in-center hemodialysis (HD) throughout the course of their illness, customarily in the morning or afternoon. Few data suggest that the time of day when HD is performed has any functional consequence for patients undergoing the procedure. In this study, we present data from a well-characterized cohort of elderly HD patients for whom differential survival was associated with HD temporal variation and was independent of obvious medical or demographic factors that might otherwise have explained this relationship.

This study comprised 242 HD patients who were members of a previously described cohort of 349 elderly ESRD patients receiving chronic dialysis at a baseline interview in 1988.^{2 - 6} Complete derivation details about the parent cohort were reported earlier.⁶ Patients were randomly derived from a stratified sample of all Georgia patients who were aged 60 years or older and were registered in the ESRD Network as of November 1987.⁵ The ESRD Network is an administrative unit of the Health Care Financing Administration, now the Centers for Medicare and Medicaid Services, which manages ESRD Medicare in specified geographical areas. Stratification was based on race (white or black), sex, and residence (urban or rural). Selected patients' demographics (age, race, sex, or primary ESRD diagnosis) did not differ from those of the total population of dialysis patients aged 60 years or older in the Georgia ESRD Network. Patients were affiliated with 58 dialysis treatment facilities across the state. All patients gave informed consent before entering the study, which the Emory University Medical School Institutional Review Board approved.

Patients who were interviewed in 1988 and still lived in Georgia were contacted for follow-up interviews in 1991. The response rate was 95%. For inclusion in this analysis, patients had to be treated by in-center HD at baseline and at the 3-year follow-up if they survived to that date, with the exception of 2 patients who were receiving in-center HD at baseline and received successful transplants. Of the original cohort, 3 patients who underwent home HD, 42 who underwent peritoneal dialysis, and 1 who recovered renal function were ineligible for this analysis. Thus, we did not use an intent-to-treat analysis. Of the remaining 303 patients treated by in-center HD, 24 could not be included in this analysis because their dialysis shift changed after the study began, 4 could not be included because insufficient information was available about their dialysis shift times at baseline or follow-up, and 33 could not be included because of missing data on other variables included in the multivariable analyses. Thus, 242 patients were available for inclusion in this analysis. Two of these patients (morning shift) experienced failed transplants and did not receive dialysis for only a few days.

Time of day for HD was recorded at baseline (1988) and follow-up (1991) patient interviews.² Patients whose in-center HD was initiated between 6:00 and 11:00 AM were considered to have undergone morning dialysis (n = 167). Patients whose in-center dialysis was initiated between 11:30 AM and 4:00 PM were considered to have undergone afternoon dialysis (n = 75). The HD patients included and excluded in the shift analyses reported here did not have different demographic or health-status characteristics, except that included patients were more likely to be male. Between included and excluded patients, there was no significant difference in poststudy survival or months of dialysis before study entry.

A comprehensive interview and a review of medical records were conducted for all patients at the beginning of the study and for patients participating in the 3-year follow-up.² Characteristics of HD (months of dialysis before study entry and number of hours of dialysis per week) were confirmed by the dialysis facility, as was history of diabetes mellitus as a primary cause of ESRD. Cardiovascular disease was defined as a history of myocardial infarct, stroke, and treated or untreated hypertension. Body mass index (BMI; computed as weight in kilograms divided by height in meters squared) and serum albumin levels were also recorded. For further analyses, BMI was dichotomized at more than 23 kg/m² vs less than 23 kg/m², according to the median of the study population. Months of dialysis before study entry and hours of dialysis per week were dichotomized at the median of the distribution for each (36 months and 10.5 hours, respectively). Functional status was assessed on the basis of interview questions determining to what extent patients were capable of simple activities (eg, climbing stairs or walking around the block) and sedentary during the daytime. Functional impairment was classified according to Guttman scaling as most severe, moderately severe, least severe, or none.⁷ Patients' vital status was monitored from the baseline interview in 1988 (beginning of the study) to July 7, 1999. Death certificates were obtained to determine causes of death.

The primary analysis used in this study was the Cox proportional hazards model, in which continued survival in days after the beginning of the study was modeled by using a variety of demographic and health predictors. Two patients who received successful transplants were censored at the date of transplant, and the only patient who survived was censored as of the study's ending date, July 7, 1999. Binary variables were coded 1 for age at least 70 years, male sex, black race, BMI more than 23 kg/m², HD for at least 36 months, HD at least 10.5 hours weekly, higher functional status (ie, least severe or no functional impairment), diabetes as the primary cause of ESRD, and the presence of cardiovascular comorbidity. Referent categories were coded 0 for younger age, female sex, white race, lower BMI, fewer months of HD, fewer hours of HD each week, lower functional status, absence of diabetes as the cause of ESRD, and absence of cardiovascular comorbidity. Because our previous work indicated that race, sex, and BMI had a significant interaction effect on survival (ie, higher BMI was protective in black men and women and in white men),⁸ 2- and 3-way interaction terms for these variables were included in the model. The effect of dialysis shift was examined by using afternoon shift as the referent category. Examination of proportionality assumptions in the Cox model indicated no significant time × risk factor interactions for any variable in the model. Data were analyzed by using SAS Version 8 (SAS Institute, Cary, NC).

Demographic and medical characteristics of the 242 patients as a function of shift are shown in Table 1. On average, HD patients who underwent morning dialysis survived more than a year longer than patients who underwent afternoon dialysis (Figure 1). Patients who were dialyzed in the morning were more likely to be black and have higher BMI, but there were no other statistically significant differences between the 2 groups.

According to the Cox regression model, univariate tests of association with patients' continued survival in days after the beginning of the study are summarized in Table 2. Black race, higher BMI, absence of cardiovascular comorbidity, higher functional status, and morning dialysis shift were significantly associated with HD patients' continued survival (all P<.05).

Table 2 presents the results of the multivariable Cox model predicting survival as related to demographic and health variables, as well as time of day of dialysis. As we have reported elsewhere,⁸ the interaction of race, sex, and BMI affects survival in this population. Higher functional status also predicted patients' continued survival. Additionally, consistent with the data shown in Table 1 and Table 2, the protective effect for patients' survival of the morning shift was sustained in this multivariable model. Analysis of death certificates indicated no differences between morning- and afternoon-shift patients for any cause of death including cardiovascular (eg, cardiac arrest or cerebrovascular accident; 55% vs 47%), infectious (eg, septicemia or pneumonia; 13% vs 17%), or other causes (eg, malignancy, hyperkalemia, or elective withdrawal from dialysis; 32% vs 36%; P = .47). Review of death certificates indicated that only 3 patients voluntarily withdrew from HD treatment; all 3 were treated on a morning shift.

Usual weight gain between dialysis treatments was examined as an indicator of compliance with dialysis regimen.^{9 - 11} Between morning- and afternoon-shift patients, there was no significant difference in interdialytic weight gain (mean [SD] gain, 2.06 [1.06] kg vs 1.97 [1.02] kg, respectively; P = .81).

Analysis of changing comorbidities for individuals surviving to the 3-year follow-up and reinterviewed indicated that, although patients at follow-up had lower functional status, lower BMI, and greater cardiovascular comorbidity, these patterns occurred equally for morning- and afternoon-shift patients. There was also no significant difference in hours of weekly dialysis throughout the 3 years for individuals dialyzed in the morning vs the afternoon.

Both morning- and afternoon-shift patients showed a trend for decreased albumin levels throughout the 3 years preceding follow-up (0.11 g/dL vs 0.70 g/dL, respectively), but the extent of this decrease did not significantly differentiate patients in the 2 shifts (P = .19).

The risk factors we examined did not account for the higher survival rate of elderly ESRD patients undergoing HD who were dialyzed during the morning. There may be other selection factors that lead ESRD patients to be assigned to or to select morning shift, but they remain unidentified.

If the time of day of dialysis significantly affects survival, some speculation regarding putative mechanisms that underlie the effect may not be premature. For example, biochemical clearance may be optimized during morning-shift HD. In a group of 124 patients representing 4 shifts, Mattana et al¹² reported that HD patients who were dialyzed late in the day had relatively higher levels of potassium and phosphorus than those undergoing HD earlier in the day, implying less effective dialysis, perhaps owing to interaction with the evening meal. Although we did not have our population's laboratory data on hyperkalemia or hyperphosphatemia and therefore were unable to test this hypothesis, the possibility exists that some impairment of biochemical clearance might have hastened mortality in patients being dialyzed in the afternoon shift.

Optimization of medical interventions by introduction of treatments at specific times of day is not without precedent. For example, nocturnal administration of calcitriol reduced dialysis patients' risk of hypercalcemia.¹³ Perhaps the most dramatic examples of temporal optimization of treatment are from chemotherapy.^{14 - 15} In metastatic colorectal carcinoma, for example, antitumor activity was maximized and adverse effects minimized by the administration of 5-fluorouracil and leucovorin during the early morning.¹⁶ Similar time-of-day susceptibility to best chemotherapeutic response has been noted for renal cell carcinoma.¹⁷ Although the mechanisms underlying these chemotherapeutic observations are undoubtedly different from those observed in our study, these results suggest that simple manipulations of when treatments are instituted profoundly affect health, which assumes increasing importance as more frequent and longer dialysis treatment is more widely implemented.¹⁸

Sleep during HD, which is common, may also contribute to the continued survival of patients treated in the morning. Individuals undergoing HD in the morning are sleepier than those being dialyzed at other times of day,¹⁹ and the notion that sleep is vital for health and that loss of sleep hastens morbidity and mortality has been borne out amply by numerous epidemiologic human studies and experimental animal studies. For example, studies from well-defined populations suggest that chronic short sleep may be a harbinger for all causes of mortality.^{20 - 21} In experimentally sleep-deprived animals, sleep loss has been associated with compromised thermoregulatory, immunologic, and, perhaps most relevant for the current discussion, protein metabolic functions.^{22 - 23} Data such as these imply that sleep during morning dialysis may represent a beneficial compensatory response to sleep loss imposed by early waking times. This explanation assumes differences in the quantity or quality of intradialytic sleep as a function of the time of day. This hypothesis remains to be verified polysomnographically.

As a final caveat, our data indicating apparently protective effects of morning dialysis were seen in an elderly cohort. Whether younger patients undergoing HD would derive similar benefit remains unclear. For example, age-dependent sleep pattern changes that occur in elderly individuals might predispose them to the early-morning arising required for morning dialysis, and their increased tendency to nap might also enhance the likelihood of their sleeping during the procedure.^{24 - 25} To test this hypothesis, studies examining the differential effect of HD shift in younger populations would be required, and polysomnographic studies¹⁸ documenting the amount and quality of sleep occurring on various shifts would also be necessary. Randomized clinical trials may be required to determine definitively whether morning shift is protective for any age group. In the interim, further observational studies using larger databases such as the United States Renal Data System should investigate whether dialysis shift, independent of cumulative hours of weekly dialysis or duration of dialysis treatment,²⁶ significantly affects dialysis outcomes, including patients' survival.