Abstract
Background:
The population of elderly end-stage renal disease patients initiating dialysis is rapidly growing. Although longer treatment is supposed to benefit for hemodialysis patients such as through more solute clearance and slower fluid removal, it is not yet clear how treatment session length affects mortality risk in octogenarians and nonagenarians.
Methods:
In a cohort of 112,026 incident hemodialysis patients between 2007 and 2011, we examined the association of treatment session length with all-cause mortality, adjusting for demographics and comorbid conditions. We also used restricted spline functions for age to evaluate continuous changes in the association of short (<210 minutes) and extended (≥240 minutes) hemodialysis treatment (vs. 210 to <240 minutes) with all-cause mortality over age.
Results:
During the first 91 days of dialysis, patients aged ≥80 years tended to have the lowest treatment session length (median [interquartile range] 211 [193, 230] minutes), and these lengths showed fair correlations in the following periods (r>0.5). Longer treatment was associated with better survival in patients <65 and 65 to <80 years, but not in octogenarians/nonagenarians. The association of extended treatment (≥240 minutes) with better survival was attenuated across age and not significant among patients aged ≥80 years with a hazard ratio of 1.10 (95% CI, 0.99, 1.20). Shorter treatment sessions (<210 minutes) was associated with higher mortality across all age groups.
Conclusion:
Extended hemodialysis was not associated with lower mortality among octogenarians and nonagenarians while it was associated with better survival among younger patients. Further studies are needed to determine the optimal treatment session length in elderly incident hemodialysis patients.
Keywords: Extended treatment session length, elderly, mortality, hemodialysis
Introduction
Despite medical advances and improvements in patient care, the mortality of end-stage renal disease (ESRD) patients on dialysis treatment remains unacceptably high [1]. Although, there have been many studies for optimizing treatment session length in hemodialysis patients as an effort to improve survival by delivering the ideal dose of dialysis and reducing complications [2–7], it has not been clear yet which treatment session length is necessary for achieving better clinical outcomes.
Elderly patients are the fastest growing dialysis population according to the United States Renal Data System (USRDS) [1,8]. There are several factors that may warrant the need to modify the risk-benefit balance of extended dialysis particularly in this population [9–11]: 1) smaller increases in uremic burden or volumes due to lower dietary intake, compared with those in younger patients; 2) higher risk of hemodialysis-related complications; and 3) compromised quality of life by longer dialysis sessions.
Therefore, we examined whether there is a differential association between hemodialysis treatment session length and all-cause mortality risk across age groups in a contemporary cohort of incident hemodialysis patients.
Materials and Methods
The study was approved by the Institutional Review Boards of the Los Angeles Biomedical Research Institute at Harbor-UCLA and the University of California Irvine Medical Center.
Study Population
We conducted a historical cohort study of incident hemodialysis patients receiving dialysis care from a large dialysis organization (LDO) in the United States, with comprehensive longitudinal data on patients’ socio-demographics, comorbidities, laboratory tests, dialysis treatment characteristics, clinical events, and vital status. The original source population was a cohort of 208,820 incident dialysis patients receiving care in one of the LDO outpatient facilities over a 5-year period (January 2007 to December 2011). Among 133,162 incident ESRD patients who received dialysis treatment for at least 60 days and were treated only by in-center thrice-weekly hemodialysis during the follow-up, we excluded 21,036 patients if they were ≤18 years and >100 years old or had missing baseline hemodialysis treatment session length data. The follow-up time was divided into patient-quarters (i.e., 91-day periods from the date of first dialysis), where baseline was considered as the first 91-day period.
Exposure Ascertainment
Quarterly averaged values of hemodialysis treatment session length during the first quarter of dialysis treatment were grouped into the following categories: <180 minutes, 180 to <210 minutes, 210 to <240 minutes, and ≥240 minutes. Patients were also categorized according to their age at study entry: <65 years, 65 to <80 years, and ≥80 years.
Outcome Assessment
The primary outcome of interest was all-cause mortality. Patients were censored for death, kidney transplantation, transfer to a non-LDO dialysis unit, recovery of renal function or dialysis discontinuation, or at the end of the study (December 31, 2011). In the primary analyses, we sought to compare the association of treatment session length with all-cause mortality risk across age groups.
Sociodemographic, Dialysis Treatment, and Laboratory Characteristics
Information regarding socio-demographics (including self-reported race/ethnicity and primary insurance type) as well as comorbid conditions (e.g., diabetes mellitus, hypertension, atherosclerotic heart disease, congestive heart failure, other cardiac diseases, cerebrovascular disease, chronic obstructive pulmonary disease, and history of cancer or liver disease) defined by the International Classification of Diseases-9 codes was also obtained from the LDO database. The modified Deyo-Charlson comorbidity index (CCI), where we excluded the presence or absence of kidney disease, was also obtained from the LDO database [12,13].
Blood samples for laboratory tests were collected before dialysis, except for post-dialysis serum urea nitrogen, using standardized techniques in all dialysis clinics. These samples were transported to a central laboratory in Deland, Florida, normally within 24 hours, where they were measured using automated and standardized methods. Most laboratory tests were performed monthly, including serum creatinine, albumin, peripheral white blood cell count, total iron binding capacity (TIBC), calcium, phosphorus, and bicarbonate. Serum intact parathyroid hormone (PTH) was usually measured at least once per quarter. Hemoglobin was measured weekly to biweekly in most patients. The delivered dialysis dose was calculated by single-pool Kt/V using urea kinetic modeling. The normalized protein catabolic rate (nPCR) was calculated. To minimize measurement variability, all repeated measures for each 91-day interval were averaged, and the quarterly mean values were used in analyses.
Statistical Analysis
Baseline characteristics across age groups and treatment time groups are summarized as proportions, mean±SD, or medians (interquartile ranges) depending on the data type. We used logistic regression to estimate the association between various clinical characteristics and the likelihood of extended treatment session length (treatment session length ≥240 vs 180 to <240 minutes) within age groups. We stratified each age group according to treatment session length and using Cox proportional hazard models, we compared the association of treatment session length with all-cause mortality risk across age groups using three hierarchical levels of adjustment:
-
(1)
Unadjusted model: Included the main predictor, treatment session length
-
(2)
Case-mix adjusted model: Included the unadjusted model covariates as well as age, sex, race/ethnicity, primary insurance type, ten comorbid conditions (diabetes mellitus, hypertension, atherosclerotic heart disease, congestive heart failure, other cardiovascular disease, cerebrovascular disease, dyslipidemia, chronic obstructive pulmonary disease, liver disease, and history of malignancy), dialysis dose as measured by single-pool Kt/V, body mass index (BMI), and ultrafiltration rate (mL/hr/kg body weight (BW))
-
(3)
Case-mix+malnutrition-inflammation-cachexia syndrome (MICS) model: Included the case-mix adjusted model covariates as well as ten clinically relevant laboratory variables (white blood cell count, hemoglobin, serum albumin, creatinine, bicarbonate, uncorrected calcium, phosphorus, intact parathyroid hormone (iPTH), TIBC, and nPCR)
We defined the case-mix model as our preferred model, which included core sociodemographic measures and other confounders of the association between treatment session length and outcomes. The MICS model was designated an exploratory model, which included confounders as well as potential intermediates on the causal pathway of treatment session length and mortality association. We also conducted subgroup analyses in which we compared the association of short (<210 minutes) or extended treatment (≥240 minutes) vs. conventional treatment (210 to <240 minutes) with mortality across age groups.
Effect modifications of the association between treatment session length (short: <210 minutes or extended treatment: ≥240 minutes vs. the standard treatment (210-240 minutes) and all-cause death by age were examined with restricted cubic spline functions for age in the case-mix adjusted model. The frequency of missing data was low (1%) for most laboratory tests, except for nPCR (4%) and creatinine (4%), and the multiple imputation method with five datasets was used in all regression analyses. All analyses and figures were generated with STATA MP, version 13.1 (StataCorp, College Station, TX, USA) and SigmaPlot version 12.5 (Systat Software, TX, USA).
Results
Study Population Description
The study population included 112,026 incident HD patients (Supplemental Figure 1). The mean±SD age of the overall cohort was 63±15 years, and the median treatment session length [interquartile range (IQR)] was 211 [193, 230] minutes. The crude all-cause mortality rate of the overall cohort was 135 death events per 1,000 patient-years of follow-up (95% CI: 133, 136). Across all age groups, the baseline treatment session length distribution showed three distinct curves peaking at approximately 180, 210, and 240 minutes. Patients aged ≥80 years tended to have the lowest baseline treatment session length (median [IQR]: 204 [184, 217] minutes), with the highest peak at approximately 180 minutes, whereas patients aged <65 years had the greatest treatment session length (median [IQR]: 214 [199, 234] minutes), with the highest peak at approximately 240 minutes (Figure 1). Baseline characteristics of the cohort stratified by age and baseline treatment session length are presented in Table 1. Across all age groups, patients with the highest treatment session length tended to be male; were more likely to be African American and less likely to be Hispanic or Asian; were more likely to use a central venous catheter as their primary vascular access; were more likely to have diabetes, atherosclerotic heart disease, and other cardiovascular diseases; and had higher BMI and ultrafiltration values compared to those in the lowest treatment session length category.
Figure 1.
Distribution of baseline hemodialysis treatment session length across age groups with age <65, 65 to <80, and ≤80 years in 112,026 incident hemodialysis patients.
Table 1.
Baseline characteristics stratified by age and treatment session length in 112,026 incident hemodialysis patients
| characteristics | Age <65 years | Age 65 to <80 years | Age ≥80 years | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment time (minutes) | Treatment time (minutes) | Treatment time (minutes) | ||||||||||
| <180 | ≥180 to <210 | ≥210 to <240 | ≥240 | <180 | ≥180 to <210 | ≥210 to <240 | ≥240 | <180 | ≥180 to <210 | ≥210 to <240 | ≥240 | |
| Patient number | 3,962 | 19,588 | 25,688 | 8,816 | 3,306 | 14,988 | 15,830 | 4,458 | 1,921 | 7,079 | 5,273 | 1,117 |
| Age (yrs) | 50±11 | 51±11 | 51±10 | 51±10 | 72±4 | 72±4 | 72±4 | 71±4 | 84±4 | 84±4 | 84±3 | 83±3 |
| Female (%) | 57 | 48 | 38 | 28 | 60 | 52 | 41 | 32 | 59 | 51 | 39 | 27 |
| Race/Ethnicity (%) | ||||||||||||
| White | 44 | 37 | 35 | 36 | 58 | 53 | 54 | 57 | 68 | 67 | 68 | 70 |
| African American | 29 | 34 | 41 | 45 | 19 | 24 | 29 | 30 | 12 | 17 | 20 | 20 |
| Hispanic | 17 | 21 | 18 | 13 | 13 | 15 | 12 | 8 | 10 | 10 | 7 | 6 |
| Asian | 6 | 4 | 2 | 2 | 7 | 5 | 2 | 1 | 7 | 4 | 2 | 1 |
| Others | 4 | 4 | 4 | 4 | 3 | 3 | 3 | 4 | 3 | 2 | 3 | 3 |
| Primary insurance (%) | ||||||||||||
| Medicare | 36 | 38 | 40 | 43 | 65 | 66 | 67 | 68 | 70 | 73 | 74 | 73 |
| Medicaid | 14 | 13 | 10 | 8 | 4 | 3 | 2 | 1 | 2 | 2 | 1 | 1 |
| Others | 50 | 48 | 49 | 49 | 32 | 31 | 31 | 31 | 28 | 26 | 25 | 26 |
| Access type (%) | ||||||||||||
| Central venous catheter | 67 | 74 | 77 | 79 | 64 | 71 | 73 | 77 | 67 | 75 | 75 | 78 |
| Arterio-venous fistula | 20 | 15 | 13 | 11 | 22 | 17 | 16 | 12 | 20 | 15 | 14 | 11 |
| Arterio-venous graft | 5 | 4 | 3 | 2 | 6 | 5 | 5 | 3 | 7 | 5 | 4 | 3 |
| Others | 8 | 7 | 7 | 8 | 8 | 7 | 7 | 8 | 6 | 5 | 7 | 8 |
| Comorbidities (%) | ||||||||||||
| Diabetes | 52 | 57 | 60 | 63 | 52 | 60 | 63 | 66 | 41 | 45 | 50 | 54 |
| Hypertension | 45 | 47 | 51 | 54 | 51 | 49 | 50 | 52 | 59 | 58 | 59 | 61 |
| Congestive heart failure | 37 | 37 | 39 | 42 | 34 | 34 | 35 | 36 | 34 | 32 | 34 | 36 |
| Atherosclerotic heart disease | 13 | 12 | 12 | 14 | 15 | 15 | 17 | 18 | 15 | 16 | 17 | 19 |
| Other cardiac disease | 13 | 12 | 13 | 15 | 15 | 16 | 18 | 21 | 16 | 17 | 19 | 24 |
| Cerebrovascular disease | 1 | 1 | 2 | 2 | 2 | 2 | 2 | 3 | 2 | 2 | 2 | 2 |
| COPD | 4 | 4 | 4 | 5 | 6 | 6 | 7 | 8 | 6 | 5 | 6 | 7 |
| Liver disease | 2 | 2 | 2 | 2 | 1 | 1 | 1 | 2 | 1 | 1 | 1 | 2 |
| History of cancer | 1 | 1 | 1 | 2 | 4 | 3 | 3 | 4 | 3 | 3 | 4 | 6 |
| Dyslipidemia | 22 | 23 | 25 | 26 | 24 | 26 | 26 | 29 | 22 | 24 | 26 | 30 |
| BMI, kg/m2 | 25.3 [21.7,30.4] | 26.4 [22.7,31.5] | 28.2 [24.0,33.9] | 30.1 [25.5,37.2] | 24.6 [21.4,28.8] | 25.9 [22.5,30.1] | 27.1 [23.5,31.9] | 28.5 [24.6,33.7] | 23.2 [20.6,26.4] | 23.8 [21.2,27.1] | 24.7 [22.1,28.2] | 25.7 [23.1,29.1] |
| Ultrafiltration rate, ml/hr/kg BW | 7.8 [5.8, 10.8] | 7.8 [5.6, 10.3] | 7.1 [5.3, 9.3] | 6.5 [4.8, 8.4] | 7.7 [5.4, 10.3] | 7.4 [5.4, 9.6] | 6.7 [5.0, 8.7] | 6.1 [5.0, 7.9] | 8.0 [5.7, 10.5] | 7.5 [5.6 ,9.8] | 6.8 [5.1, 8.7] | 6.2 [4.6, 7.9] |
| Intradialytic hypotension (<90mmHg/session), % | 3 | 2 | 2 | 2 | 4 | 4 | 4 | 5 | 5 | 6 | 6 | 9 |
| Hgb, g/dl | 10.9±1.3 | 11.0±1.2 | 11.1±1.2 | 11.2±1.2 | 11.0±1.1 | ll.1±1.1 | 11.2±1.1 | 11.2±1.2 | 11.1±1.1 | 11.2±1.1 | 11.2±1.1 | 11.3±1.1 |
| WBC, 103μl/ml | 8.0±2.7 | 7.8±2.6 | 7.8±2.5 | 7.8±2.6 | 8.0±3.0 | 7.9±2.8 | 7.7±2.5 | 7.8±2.8 | 7.5±2.8 | 7.4±2.6 | 7.4±2.7 | 7.4±2.6 |
| Albumin, g/dl | 3.5±0.6 | 3.5±0.5 | 3.5±0.5 | 3.5±0.5 | 3.5±0.5 | 3.5±0.5 | 3.5±0.4 | 3.5±0.4 | 3.5±0.5 | 3.5±0.4 | 3.5±0.4 | 3.4±0.4 |
| Creatinine, mg/dl | 6.1±2.5 | 6.5±2.6 | 6.7±2.6 | 6.9±2.7 | 4.9±1.7 | 5.2±1.8 | 5.3±1.8 | 5.4±1.9 | 4.5±1.5 | 4.7±1.5 | 4.8±1.6 | 4.8±1.5 |
| Bicarbonate, mEq/l | 22.3±2.9 | 22.9±2.7 | 23.3±2.6 | 23.7±2.6 | 23.3±2.8 | 23.7±2.6 | 24.1±2.6 | 24.3±2.6 | 23.9±2.7 | 24.3±2.6 | 24.5±2.6 | 24.8±2.5 |
| Calcium, mg/dl | 8.6±0.7 | 8.6±0.7 | 8.7±0.6 | 8.7±0.6 | 8.7±0.6 | 8.7±0.6 | 8.7±0.6 | 8.7±0.6 | 8.7±0.6 | 8.7±0.6 | 8.7±0.6 | 8.7±0.6 |
| Phosphorus, mg/dl | 5.3±1.3 | 5.2±1.2 | 5.2±1.2 | 5.2±1.2 | 4.7±1.0 | 4.7±1.0 | 4.7±1.0 | 4.6±1.0 | 4.5±1.0 | 4.5±1.0 | 4.4±1.0 | 4.3±1.0 |
| iPTH, pg/ml | 327 [196,521] | 343 [243,531] | 357 [228,549] | 369 [234,564] | 276 [169,428] | 286 [180,436] | 290 [186,441] | 292 [189,441] | 267 [166,387] | 254 [164,380] | 259 [167,391] | 261 [169,378] |
| TIBC, mg/ml | 229±53 | 228±50 | 229±48 | 231±47 | 224±50 | 222±50 | 222±49 | 222±49 | 218±49 | 214±47 | 215±46 | 214±46 |
| nPCR, g/kg/day | 0.8±0.3 | 0.8±0.2 | 0.8±0.2 | 0.8±0.2 | 0.8±0.2 | 0.8±0.2 | 0.8±0.2 | 0.8±0.2 | 0.8±0.2 | 0.8±0.2 | 0.8±0.2 | 0.8±0.2 |
| spKt/V | 1.4±0.4 | 1.4±0.3 | 1.4±0.3 | 1.4±0.3 | 1.5±0.4 | 1.5±0.3 | 1.5±0.3 | 1.5±0.3 | 1.5±0.4 | 1.5±0.3 | 1.6±0.3 | 1.6±0.3 |
Values for categorical variables are given as number (percentage); values for continuous variables, mean± standard deviation or median [interquartile ranges] Abbreviation; yrs, years ; COPD, chronic obstructive pulmonary disease; BMI, body mass index; BW body weight; Hgb, hemoglobin; iPTH, intact parathyroid hormone; TIBC, total iron binding capacity; nPCR, normalized protein catabolic rate; spKt/V, single pool Kt/V
Clinical Characteristics Associated with Extended Treatment Time Across Age Groups
Table 2 shows the association between clinical characteristics and the likelihood of extended treatment time (treatment session length ≥240 minutes) across age groups in the case-mix adjusted logistic regression models (reference: treatment session length ≥180 to <240 minutes). Across all age groups, being female, Hispanic, or Asian; using Medicaid insurance; and having an AVF/AVG access type were associated with a lower likelihood of extended treatment time. Being African American; having a diagnosis of diabetes or other cardiac disease; and having higher baseline BMI and creatinine values were associated with a higher likelihood of extended treatment time. Ultrafiltration rate was tended to be lower in extended treatment time group in all age group. However, intradialytic hypotension was more frequent in extended treatment time group only in patients aged ≥80 years.
Table 2.
Association of clinical characteristics with extended hemodialysis treatment time (treatment session length ≥240 vs. ≥180 to <240 minutes) among the three age groups (<65, 65 to <80, and ≥80 years) in case-mix adjusted logistic regression models.
| Factor | Age (years) | ||
|---|---|---|---|
| <65 | 65 to <80 | ≥80 | |
| OR (95% CI) | OR (95% CI) | OR (95% CI) | |
| Socio-demographic factors | |||
| Age, per 5 years | 1.00 (1.00-1.00) | 0.99 (0.98-1.00) | 0.94 (0.93-0.97) |
| Female (vs. male) | 0.48 (0.45-0.51) | 0.43 (0.40-0.47) | 0.33 (0.28-0.39) |
| Race: African American (vs. White) | 1.17 (1.11-1.25) | 1.20 (1.10-1.30) | 1.26 (1.05-1.51) |
| Race: Asian (vs. White) | 0.76 (0.70-0.82) | 0.62 (0.54-0.70) | 0.67 (0.51-0.89) |
| Race: Hispanic (vs. White) | 0.64 (0.52-0.80) | 0.33 (0.24-0.46) | 0.32 (0.17-0.62) |
| Insurance: Medicaid (vs. Medicare) | 0.69 (0.63-0.75) | 0.64 (0.48-0.85) | 0.61 (0.30-1.22) |
| Insurance: Other insurance (vs. Medicare) | 0.91 (0.86-0.96) | 0.94 (0.87-1.01) | 1.09 (0.93-1.26) |
| Comorbidity factors | |||
| Diabetes | 1.18 (1.11-1.25) | 1.12 (1.04-1.21) | 1.21 (1.05-1.39) |
| Hypertension | 1.13 (1.07-1.19) | 1.06 (0.98-1.14) | 1.05 (0.91-1.21) |
| Congestive heart failure | 0.93 (0.88-0.98) | 0.91 (0.84-0.98) | 1.00 (0.87-1.16) |
| Atherosclerotic heart disease | 1.02 (0.94-1.10) | 0.98 (0.88-1.08) | 0.96 (0.80-1.15) |
| Other cardiac diseases | 1.10 (1.01-1.20) | 1.21 (1.09-1.34) | 1.30 (1.09-1.56) |
| Dialysis related factors | |||
| Access type: AVF (vs. CVC) | 0.64 (0.59-0.69) | 0.65 (0.58-0.72) | 0.62 (0.50-0.77) |
| Access type: AVG (vs. CVC) | 0.55 (0.47-0.65) | 0.51 (0.42-0.62) | 0.59 (0.41-0.85) |
| BMI, per 1kg/m2 | 1.06 (1.05-1.06) | 1.06 (1.05-1.07) | 1.06 (1.05-1.07) |
| Ultrafiltration, per 1kg | 1.49 (1.45-1.54) | 1.50 (1.44-1.57) | 1.45 (1.31-1.59) |
| Pre-HD SBP, per 10mmHg | 1.00 (0.99-1.00) | 1.00 (0.99-1.00) | 1.00 (0.99-1.00) |
| Laboratory variables | |||
| Hgb, per 1 g/dL | 1.13 (1.11-1.16) | 1.14 (1.10-1.17) | 1.17 (1.10-1.24) |
| WBC, per 103/μL | 0.98 (0.97-0.99) | 0.99 (0.98-1.01) | 0.99 (0.96-1.01) |
| Albumin, per 1g/dL | 1.00 (0.95-1.06) | 0.92 (0.84-0.99) | 0.84 (0.72-0.99) |
| Creatinine, per 1mg/dL | 1.06 (1.05-1.07) | 1.09 (1.07-1.12) | 1.09 (1.05-1.14) |
Abbreviation; OR, odd ratio; CI, confidence interval; AVF, arteriovenous fistula; AVG, arteriovenous graft; CVC, central venous catheter; BMI, body mass index; HD, hemodialysis; SBP, systolic blood pressure;
Treatment Session Length and All-Cause Mortality Across Age Groups
In the case-mix adjusted Cox regression analysis, there was a linear inverse association in mortality risk with greater treatment session length in patients aged <65 years, and extended treatment time (≥240 minutes) was associated with a lower mortality risk in the <65 years age group (HR [95% CI], 0.91 [0.86, 0.97] for age <65 years ,). Patients aged 65 to <80 years and ≥80 years also had a linear inverse association mortality risk as the treatment session length increased until <240 minutes (reference: 210->240 minutes). However, unlike patients aged <65, the treatment session length ≥240 minutes was not associated with a lower risk of mortality among patients aged 65 to <80 years and ≥80 years (HRs [95% CI], 0.95 [0.90, 1.01] and 1.10 [0.99, 1.20] respectively; Figure 2, Supplement Figure 2).
Figure 2.
The hazard ratios for all-cause mortality associated with hemodialysis treatment time across the age groups; (A) <65 years, (B) 65 to <80 years, (C) ≥80 years with hierarchical adjustments (see the Methods for detail), and (D) the combination of their case-mix adjustment
Treatment Session Length and Mortality Across Subgroups
Figure 3A and 3B shows the case-mix adjusted associations between short (<210 minutes) and extended (≥240 minutes) treatment session lengths and all-cause mortality (reference: ≥210 to ≥240 minutes) across a priori selected subgroups and stratified by age. Compared to the association of mortality with short treatment session length that did not show much difference between age groups (Figure 3A), there was an incremental change in the association of extended treatment session length with mortality between age groups (Figure 3B). Extended treatment (≥240 minutes) compared to standard treatment (≥210 to <240 minutes) tended to be associated with a lower risk of mortality in those aged <65 years especially in male, African American, non-diabetes, without congestive heart failure, low BMI (≥25), high IDWG (>3%), high spKt/V(>1.5) and low albumin (≤3.5mg/dL). It was not associated with a lower risk of mortality in any subgroups of patients aged 65 to <80 years and ≥80 years. In the subgroup of white patients aged ≥80 years, extended treatment (≥240 minutes) was associated with a higher risk of mortality.
Figure 3.
Subgroup analysis for the association of short treatment time (<210 minutes, A) and extended hemodialysis treatment time (≥240 minutes, B) with all-cause mortality across age groups. Treatment session length 210 to <240 minutes in each age group was used as a reference group.
Effect Modification by Age on the Association of Treatment Session Length with All-Cause Mortality
We then examined the effect modification by age on the association of treatment session length with all-cause mortality in a continuous pattern using a restricted cubic spline function in the case-mix adjusted model. Using patients with standard treatment (≥210 to <240 minutes) as reference, treatment session length <210 minutes was associated with a higher risk of mortality across all ages (Figure 4A). Conversely, the HR of all-cause mortality in association with extended treatment session length (≥240 minutes) was modified by age; lower risk of mortality with extended treatment session length in younger patients was incrementally attenuated across age (Figure 4B). In a sensitivity analysis using different cutoff values, age also did not modify the association of shorter treatment session length (<195 minutes) with all-cause mortality. However, the association of longer treatment time (≥225 minutes) with all-cause mortality was modified by age in a similar linear pattern, where it was associated with a higher risk of mortality in those aged 80 years, though it did not reach statistical significance (Supplemental Figure 3).
Figure 4.
Change in the association of short hemodialysis (treatment session length <210 minutes, A) and extend hemodialysis treatment (≥240 minutes, B) with all-cause mortality over age with restricted cubic spline functions in the case-mix adjusted model.
Discussion
In a nationally representative cohort of incident US hemodialysis patients, we observed an association of longer treatment session length with a lower risk of all-cause mortality in patients aged <65 years, even beyond the usual treatment session length of ≥240 minutes per session. However, better survival of patients with extended treatment session lengths ≥240 minutes was not observed among patients aged 65 to <80 years and ≥80 years. Risk for all-cause mortality in patients with an extended treatment session length (≥240 minutes) was modified by age, whereby a lower risk of mortality was attenuated incrementally across age and tended to be associated with a higher risk of mortality in patients aged ≥80 years, although this did not reach statistical significance.
Despite clinical practice guidelines and quality improvement programs to achieve optimal delivery of dialysis dose, treatment session lengths have traditionally been shorter in the United States compared with other international counterparts [14]. Although there was a lack of strong evidence based on randomized clinical trials [15,16] and earlier studies failed to show an association between session length and mortality[17,18], longer hemodialysis treatment sessions have demonstrated benefits in the care [2–4]. Recent publications reported that compared to conventional hemodialysis (210-240 minutes), an extended treatment session of more than 4 hours was associated with better survival [6,7,19,20]. But, there have been variable results regarding the association of extended dialysis treatment with mortality [6,15,16,21].
In the present study, increased treatment session length showed a linear association with improved survival in patients aged <65 years and 65 to <80 years, and extended treatment session length (≥240 minutes) was significantly associated with better survival in patients aged <65 years. However, longer treatment sessions (≥240 minutes) were not associated with better survival in patients aged 65 and older and showed a higher risk of mortality in the subgroup of white patients aged ≥80 years. Different associations of extended treatment session length ≥240 minutes with all-cause mortality between patients <80 years and ≥80 years were shown uniformly in the subgroup analysis. The association of better survival resulting from extended treatment session lengths ≥240 minutes was attenuated with increased age. The significance of the association was lost and extended treatment session length was not associated with better survival in patients aged ≥80 years. Longer hemodialysis treatment sessions are considered beneficial because they enable the delivery of larger doses of dialysis, which enhances solute clearance, such as phosphorus and unknown potential mediators that cause complications in ESRD [22,23]. These longer sessions also confer better tolerance in the management of interdialytic weight gain with preferable ultrafiltration rates, which has been known to reduce left ventricular hypertrophy and interdialytic hypotension [20,24,25]. However, our findings suggest that the association of longer hemodialysis treatment with better survival should be applied carefully, as longer treatments are not advisable for all hemodialysis patients. The benefits of extending dialysis treatment time in younger patients for the purpose of reducing the uremic burden and interdialytic weight gain may be diminished in patients aged ≥80 years. Moreover, elderly patients were likely more vulnerable to the higher risk of intradialytic hypotension probably due to higher comorbidities and advanced vascular stiffness when treatment sessions are extended (Table 1). The impact of the exacerbated loss of nutrients, hypercatabolism in extended treatment sessions may also be more significant and lead to exceed the advantage of slower and increasing dose of dialysis in older patients [26].
However, shorter treatment sessions (<210 minutes) were associated with worse survival regardless of age. Worse survival was shown to be associated with shorter treatment (<210 minutes) in all subgroups, although some of the results were not significant. The adjusted HR ratio analysis also showed worse survival in all age groups. A minimum treatment session length should be recommended to ensure the delivery of a proper dose of dialysis. Such a recommendation would also be helpful to avoid the possibility of an increased ultrafiltration rate due to a shortened dialysis time [27,28].
The strengths of our study include its examination of a large, nationally representative cohort of dialysis patients, including more than 15,000 patients aged ≥80 years; examination of incident hemodialysis patients whose characteristics are not confounded by survivor bias; and comprehensive availability of detailed, longitudinal patient-level comorbidity, laboratory, and dialysis treatment data. However, several limitations should be mentioned. First, treatment session length data in the first 91 days were used for the analysis to examine the long-term effect of hemodialysis treatment time on survival. Because it was the observational study, it could not control the treatment session length uniformly during the entire period. Though the correlations of treatment session length at baseline with the overall study period were good (r>0.5), baseline value may not reflect all the changes and effects of treatment session length on mortality. The overall distribution of treatment session length was not much changed across follow-up period in the previous study [29]. There was a good separation of treatment session length over time between groups divided by baseline treatment time, although the difference in treatment time became smaller, especially during the first 6 months (Supplement Figure 4).
Second, cause-specific mortality, which may be helpful to better elucidate the underlying mechanisms of the treatment session length-mortality association, was not examined in this study.
Third, there must be some residual and unmeasured confounders considering the limitation of observational study. Especially, a greater mortality risk associated with shorter treatment time is at least partly explained by indication bias, because dying patients are likely to have unstable hemodynamics and low dietary intake and, hence, are likely to be prescribe shorter treatment time in clinical practice. Finally, as with all observational studies, our study did not confirm a causal association between patterns of treatment session length and mortality.
In conclusion, extended treatment session length was not associated with better survival among octogenarians and nonagenarians compared with that among younger patients. However, a shorter treatment session (< 210 minutes) was associated with higher mortality risk regardless of age. Future studies are needed to determine the underlying mechanisms and to further define the optimal, individualized treatment session length management strategies for specific patient populations.
Supplementary Material
Acknowledgement
We thank DaVita Clinical Research® for providing the clinical data for this study.
Funding Source:
This work is supported the NIH/NIDDK grant K24-DK091419 (KKZ) and philanthropic grants from Mr. Harold Simmons, Mr. Louis Chang, and Dr. Joseph Lee. CPK and KKZ are supported by the NIH/NIDDK grants R01-DK096920 and U01-DK102163. CMR is supported by the NIH/NIDDK grants K23-DK102903 and R03-DK114642. ES is supported by a career development award from the Office of Research and Development of the Department of Veterans Affairs (IK2-CX001266-01). YO is supported by the Uehara Memorial Foundation Research Fellowship.
Footnotes
Statement of Ethics
The study was approved by the Institutional Review Boards of the Los Angeles Biomedical Research Institute at Harbor-UCLA and the University of California Irvine Medical Center.
Disclosure of Financial Interests: KKZ has received honoraria from Genzyme/Sanofi and Shire and was the medical director of DaVita Harbor-UCLA/MFI in Long Beach, CA during 2007-2012. Other authors have not declared any conflict of interest.
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