Patients receiving frequent hemodialysis have better health-related quality of life compared to patients receiving conventional hemodialysis
Authors: Amit X. Garg, Rita S. Suri, Paul Eggers, Fredric O. Finkelstein, Tom Greene, Paul L. Kimmel, Alan S. Kliger, Brett Larive, Robert M. Lindsay, Andreas Pierratos, Mark Unruh, Glenn M. Chertow
Journal: Kidney International (2017)

Most patients with end-stage kidney disease value their health-related quality of life (HRQoL) and want to know how it will be affected by their dialysis modality. We extended the findings of two prior clinical trial reports to estimate the effects of frequent compared to conventional hemodialysis on additional measures of HRQoL. The Daily Trial randomly assigned 245 patients to receive frequent (six times per week) or conventional (three times per week) in-center hemodialysis. The Nocturnal Trial randomly assigned 87 patients to receive frequent nocturnal (six times per week) or conventional (three times per week) home hemodialysis. All patients were on conventional hemodialysis prior to randomization, with an average feeling thermometer score of 70 to 75 (a visual analog scale from 0 to 100 where 100 is perfect health), an average general health scale score of 40 to 47 (a score from 0 to 100 where 100 is perfect health), and an average dialysis session recovery time of 2 to 3 hours. Outcomes are reported as the between-treatment group differences in one-year change in HRQoL measures and analyzed using linear mixed effects models. After one year in the Daily Trial, patients assigned to frequent in-center hemodialysis reported a higher feeling thermometer score, better general health, and a shorter recovery time after a dialysis session compared to standard thrice-weekly dialysis. After one year in the Nocturnal Trial, patients assigned to frequent home hemodialysis also reported a shorter recovery time after a dialysis session, but no statistical difference in their feeling thermometer or general health scores compared to standard home dialysis schedules. Thus, patients receiving day or nocturnal hemodialysis on average recovered approximately one hour earlier from a frequent compared to conventional hemodialysis session. Patients treated in an in-center dialysis facility reported better HRQoL with frequent compared to conventional hemodialysis. Most patients with end-stage kidney disease value their health-related quality of life (HRQoL) and want to know how it will be affected by their dialysis modality. We extended the findings of two prior clinical trial reports to estimate the effects of frequent compared to conventional hemodialysis on additional measures of HRQoL. The Daily Trial randomly assigned 245 patients to receive frequent (six times per week) or conventional (three times per week) in-center hemodialysis. The Nocturnal Trial randomly assigned 87 patients to receive frequent nocturnal (six times per week) or conventional (three times per week) home hemodialysis. All patients were on conventional hemodialysis prior to randomization, with an average feeling thermometer score of 70 to 75 (a visual analog scale from 0 to 100 where 100 is perfect health), an average general health scale score of 40 to 47 (a score from 0 to 100 where 100 is perfect health), and an average dialysis session recovery time of 2 to 3 hours. Outcomes are reported as the between-treatment group differences in one-year change in HRQoL measures and analyzed using linear mixed effects models. After one year in the Daily Trial, patients assigned to frequent in-center hemodialysis reported a higher feeling thermometer score, better general health, and a shorter recovery time after a dialysis session compared to standard thrice-weekly dialysis. After one year in the Nocturnal Trial, patients assigned to frequent home hemodialysis also reported a shorter recovery time after a dialysis session, but no statistical difference in their feeling thermometer or general health scores compared to standard home dialysis schedules. Thus, patients receiving day or nocturnal hemodialysis on average recovered approximately one hour earlier from a frequent compared to conventional hemodialysis session. Patients treated in an in-center dialysis facility reported better HRQoL with frequent compared to conventional hemodialysis. There is a growing effort to make health care and health policies more patient-centered. This requires greater knowledge of how a treatment affects patient-reported outcomes, where information comes directly from a patient without interpretation of their treatment response by a clinician.1Anker S.D. Agewall S. Borggrefe M. et al.The importance of patient-reported outcomes: a call for their comprehensive integration in cardiovascular clinical trials.Eur Heart J. 2014; 35: 2001-2009Crossref PubMed Scopus (219) Google Scholar Most patients with end-stage kidney disease place enormous value on their health-related quality of life (HRQoL), even over survival, and want to know how their HRQoL will be affected by their choice of dialysis modality.2Ramkumar N. Beddhu S. Eggers P. et al.Patient preferences for in-center intense hemodialysis.Hemodial Int. 2005; 9: 281-295Crossref PubMed Scopus (64) Google Scholar More than 2 million people worldwide receive conventional hemodialysis 3 sessions per week to sustain life.3Jain A.K. Blake P. Cordy P. Garg A.X. Global trends in rates of peritoneal dialysis.J Am Soc Nephrol. 2012; 23: 533-544Crossref PubMed Scopus (377) Google Scholar More frequent hemodialysis (5 or 6 sessions per week) results in greater weekly solute and fluid removal, and may be associated with better HRQoL (as observed in small studies4Walsh M. Culleton B. Tonelli M. Manns B. A systematic review of the effect of nocturnal hemodialysis on blood pressure, left ventricular hypertrophy, anemia, mineral metabolism, and health-related quality of life.Kidney Int. 2005; 67: 1500-1508Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 5Suri R.S. Nesrallah G.E. Mainra R. et al.Daily hemodialysis: a systematic review.Clin J Am Soc Nephrol. 2006; 1: 33-42Crossref PubMed Scopus (169) Google Scholar). We previously reported the primary results of 2 parallel 12-month follow-up randomized controlled trials of frequent hemodialysis (Frequent Hemodialysis Network [FHN] Daily and Nocturnal Trials).6Chertow G.M. Levin N.W. Beck G.J. et al.In-center hemodialysis six times per week versus three times per week.N Engl J Med. 2010; 363: 2287-2300Crossref PubMed Scopus (823) Google Scholar, 7Rocco M.V. Lockridge Jr., R.S. Beck G.J. et al.The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial.Kidney Int. 2011; 80: 1080-1091Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar One of 2 coprimary outcomes reported in the primary results of these trials was the baseline to 12-month change in a commonly used patient-reported physical health survey score (the Physical Health Composite from the RAND Short-Form 36-item survey8Suri R.S. Garg A.X. Chertow G.M. et al.Frequent Hemodialysis Network (FHN) randomized trials: study design.Kidney Int. 2007; 71: 349-359Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). After 1 year in the Daily Trial, patients assigned to frequent versus conventional in-center hemodialysis reported a better score.6Chertow G.M. Levin N.W. Beck G.J. et al.In-center hemodialysis six times per week versus three times per week.N Engl J Med. 2010; 363: 2287-2300Crossref PubMed Scopus (823) Google Scholar After 1 year in the Nocturnal Trial, we could not reliably determine whether patients assigned to frequent nocturnal versus conventional hemodialysis truly differed in this score, as the trial did not meet its recruitment target, resulting in estimates with wide confidence intervals.7Rocco M.V. Lockridge Jr., R.S. Beck G.J. et al.The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial.Kidney Int. 2011; 80: 1080-1091Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar Several additional patient-reported measures of general well-being were collected in the FHN trials to better assess the multidimensional concept of HRQoL. These measures have not been reported elsewhere. In this article, we investigated whether frequent hemodialysis compared with conventional hemodialysis affects 4 measures of HRQoL collected in the 2 FHN trials. Patient selection from both trials is presented in Figure 1a and 1b . Baseline characteristics of patients in each trial are summarized in Tables 1 and 2. As confirmed in previous reports, the baseline characteristics of patients assigned to frequent versus conventional hemodialysis were similar in each trial.Figure 1Flow diagram for Daily Trial and Nocturnal Trial. (a) Flow diagram for Daily Trial showing the number of patients enrolled and assigned to each study arm (intervention/control), and number of patients who completed the baseline and 12-month HRQoL measures, including reasons for dropout. (b) Flow diagram for Nocturnal Trial showing the number of patients enrolled and assigned to each study arm (intervention/control), and number of patients who completed the baseline and 12-month HRQoL measures, including reasons for dropout.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Baseline characteristics of the Daily TrialCharacteristicsn (%)Mean ± SDMedian [25th, 75th percentiles]All patients (N = 245)3 times/wk (n = 120)6 times/wk (n = 125)Age (yr)50.4 ± 13.950 [42, 59]52.0 ± 14.152 [43, 60]48.9 ± 13.647 [41, 58]Male151 (61.6)73 (60.8)78 (62.4)Black race102 (41.6)53 (44.2)49 (39.2)Education (completed high school or less)109 (45.1)53 (44.5)56 (45.5)Primary language English196 (80.0)101 (84.2)95 (76.0)Duration of end-stage renal disease (yr) <272 (29.4)35 (29.2)37 (29.6) 2–576 (31.0)42 (35.0)34 (27.2) > 597 (39.6)43 (35.8)54 (43.2)Diabetes100 (40.8)50 (41.7)50 (40.0)Charlson Comorbidity Index1.82 ± 1.952 [0, 3]1.88 ± 2.032 [0, 3]1.76 ± 1.892 [0, 3]Predialysis serum albumin (g/dl)3.94 ± 0.423.94 ± 0.463.94 ± 0.37Predialysis hemoglobin (mg/dl)11.9 ± 1.2612.0 ± 1.2411.9 ± 1.28Dialysis Std Kt/Vurea2.52 ± 0.352.53 ± 0.392.50 ± 0.31Antidepressant35 (14.3)15 (12.5)20 (16.0)Opioid42 (17.1)19 (15.8)23 (18.4)Physical Health Composite (RAND short form-36)38.1 ± 10.538.0 ± 9.738.1 ± 11.2Mental Health Composite (RAND short form-36)45.1 ± 11.846.0 ± 10.344.3 ± 13.0Beck Depression Inventory score12.5 ± 9.012.4 ± 9.512.6 ± 8.6Std, standard. Open table in a new tab Table 2Baseline characteristics in the Nocturnal TrialCharacteristicsn (%)Mean ± SDMedian [25th, 75th percentiles]All patients (N = 87)3 times/wk (n = 42)6 times/wk (n = 45)Age (yr)52.8 ± 13.654 [43, 69]54.0 ± 12.954 [45, 62]51.7 ± 14.453 [42, 64]Male57 (65.5)28 (66.7)29 (64.4)Black race23 (26.4)11 (26.2)12 (26.7)Education (completed high school or less)34 (39.5)14 (33.3)20 (45.5)Primary language English77 (88.5)36 (85.7)41 (91.1)End-stage renal disease vintage (yr) < 258 (66.7)30 (71.4)28 (62.2) 2–513 (14.9)5 (11.9)8 (17.8) > 516 (18.4)7 (16.7)9 (20.0)Diabetes37 (42.5)18 (42.9)19 (42.2)Charlson Comorbidity Index1.72 ± 1.752 [0, 3]1.88 ± 1.932 [0, 3]1.58 ± 1.572 [0, 2]Predialysis serum albumin (g/dl)3.91 ± 0.493.92 ± 0.513.90 ± 0.48Predialysis hemoglobin (mg/dl)11.8 ± 1.1111.9 ± 1.0911.6 ± 1.12Dialysis Std Kt/Vurea2.34 ± 0.312.34 ± 0.342.35 ± 0.28Antidepressant22 (25.3)10 (23.8)12 (26.7)Opioid18 (20.7)7 (16.7)11 (24.4)Physical Health Composite (RAND SF36)37.8 ± 8.9738.2 ± 8.337.5 ± 9.6Mental Health Composite (RAND SF36)45.8 ± 11.545.9 ± 12.645.6 ± 10.5Beck Depression Inventory score11.7 ± 8.6012.2 ± 9.211.2 ± 8.1Std, standard. Open table in a new tab Std, standard. Std, standard. The baseline and follow-up HRQoL measures for patients assigned to frequent versus conventional hemodialysis in each trial are presented in Table 3. The values of the baseline HRQoL measures were similar in patients assigned to frequent compared with conventional hemodialysis in both trials, with the exception of slight differences in the health utilities index and general health scale scores in the Nocturnal Trial.Table 3Four general measures of health-related quality of life in the Daily and Nocturnal TrialsVariableNsTrialTrtObserved dataaThe observed baseline data reflects all records for randomized patients. The observed month 4 and 12 data represent patients with data at both baseline and month 4 and at both baseline and month 12, respectively.[10th, 50th, and 90th percentiles]Mean ± SDAdjusted means and treatment effectsbMean changes and treatment effects were adjusted for the baseline value of each variable. In addition, the Daily Trial analyses adjusted for clinical center. For recovery time from dialysis, adjusted mean changes and treatment effects derived from back-transforming percent difference of geometric mean changes based on log-transformed analysis.(± SE or with 95% confidence intervals)Month 4Month 12BaselineMonth 4Month 12Change from baselineTreatment comparison (6x vs. 3x)Change from baselineTreatment comparison (6x vs. 3x)Feeling thermometerDaily3x70.5 ± 17.171.9 ± 19.171.3 ± 20.8−0.5 ± 1.7+6.1(1.9 to 10.4)P = 0.0051−0.6 ± 1.9+6.4(1.8 to 11.1)P = 0.00716x73.8 ± 18.879.3 ± 15.279.0 ± 14.1+5.6 ± 1.6+5.8 ± 1.7Noct.3x75.3 ± 13.374.3 ± 18.470.6 ± 20.2−0.4 ± 2.9+4.2(−3.0 to 11.3)P = 0.25−4.1 ± 3.3+8.0(−0.5 to 16.6)P = 0.0666x74.5 ± 16.577.5 ± 16.178.1 ± 17.9+3.7 ± 2.8+4.0 ± 3.3HUI3 scoreDaily3x0.53 ± 0.380.60 ± 0.350.63 ± 0.36+0.07 ± 0.03−0.01(−0.09 to 0.06)P = 0.75+0.09 ± 0.03−0.06(−0.14 to 0.02)P = 0.176x0.57 ± 0.390.62 ± 0.360.60 ± 0.37+0.06 ± 0.03+0.04 ± 0.03Noct.3x0.64 ± 0.340.70 ± 0.320.61 ± 0.35+0.09 ± 0.05−0.08(−0.22 to 0.05)P = 0.23−0.01 ± 0.05−0.07(−0.21 to 0.08)P = 0.366x0.53 ± 0.320.59 ± 0.330.48 ± 0.38+0.01 ± 0.05−0.08 ± 0.05General health scaleDaily3x43.7 ± 21.542.5 ± 20.641.3 ± 21.5−1.61 ± 1.66+8.12(3.84 to 12.40)P = 0.0002−3.35 ± 1.95+9.69(4.68 to 14.70)P = 0.00026x46.8 ± 21.952.6 ± 21.252.4 ± 22.76.51 ± 1.58+6.34 ± 1.83Noct.3x45.0 ± 20.447.8 ± 21.146.5 ± 18.52.45 ± 2.99−1.06(−9.07 to 6.94)P = 0.79+1.51 ± 3.04+6.56(−1.54 to 14.66)P = 0.116x40.3 ± 18.445.0 ± 23.751.8 ± 24.51.38 ± 2.95+8.07 ± 3.00Time to recovery (min)Daily3x[0, 120, 480]—[15, 180, 1440]——+46(−69 to 161)−84(−89 to −80)P<0.00016x[5, 150, 1440]—[0, 60, 180]—−79(−83 to −74)Noct.3x[0, 180, 780]—[0, 120, 1440]——+33(−109 to 176)−63(−71 to −54)P = 0.00046x[0, 180, 1440]—[0, 30, 180]—−60(−68 to −53)HUI, Health Utilities Index; Noct, nocturnal; Trt, treatment; x, times.a The observed baseline data reflects all records for randomized patients. The observed month 4 and 12 data represent patients with data at both baseline and month 4 and at both baseline and month 12, respectively.b Mean changes and treatment effects were adjusted for the baseline value of each variable. In addition, the Daily Trial analyses adjusted for clinical center. For recovery time from dialysis, adjusted mean changes and treatment effects derived from back-transforming percent difference of geometric mean changes based on log-transformed analysis. Open table in a new tab HUI, Health Utilities Index; Noct, nocturnal; Trt, treatment; x, times. The completeness of each HRQoL measure in follow-up is also presented in Table 3. Each measure was completed by more than 80% of eligible patients, after patients who died or received a kidney transplant in follow-up were excluded from consideration (14 patients in the Daily Trial and 3 patients in the Nocturnal Trial, and 24 patients in the Daily Trial and 5 patients in the Nocturnal Trial, respectively). The baseline mean (SD) score was 74 (19) in patients assigned to frequent hemodialysis and 71 (17) in patients assigned to conventional hemodialysis. Patients assigned to frequent hemodialysis demonstrated a significant improvement in their feeling thermometer score over the first 4 months of follow-up, whereas the score remained similar in patients assigned to conventional hemodialysis (change of 5.6 vs. −0.5 from baseline). These trends persisted to 12 months after randomization (5.8 vs. −0.6 from baseline). There was a significant 6.4-point between-treatment group difference in the change in score over 1 year (95% confidence interval [CI] 1.8–11.1). The baseline mean (SD) score was 47 (22) in patients assigned to frequent hemodialysis and 44 (22) in patients assigned to conventional hemodialysis. Patients assigned to frequent hemodialysis demonstrated a significant improvement in their general health scale score over the first 4 months of follow-up, whereas the score remained similar in patients assigned to conventional hemodialysis (change of 6.5 vs. −1.6 from baseline). These trends persisted to 12 months after randomization (6.3 vs. −3.4 from baseline). There was a significant 9.7-point between-treatment group difference in the change in score over 1 year (95% CI 4.7–14.7). Between baseline and 12 months of follow-up, in patients assigned to frequent hemodialysis the median recovery time (10th, 90th percentile) decreased from 150 minutes (5, 1440) to 60 minutes (0, 180), whereas in patients assigned to conventional hemodialysis the median recovery time remained similar from 120 minutes (0, 480) to 180 minutes (15, 1440) (Figure 2). The mean between-treatment group difference in the change in recovery time over 1 year was −84 minutes (95% CI −89 to −80; P < 0.0001). A recovery time of 60 minutes or more at baseline was observed in 80% of patients assigned to frequent hemodialysis and 79% assigned to conventional hemodialysis. Corresponding numbers 1 year after randomization were 43% and 63%, respectively. There was no consistent statistical difference between frequent and conventional hemodialysis in the change in the health utilities index over 4 and 12 months of follow-up, or its 8 attributes (Appendix S1). The baseline mean (SD) score was 74 (16) in patients assigned to frequent hemodialysis and 75 (13) in patients assigned to conventional hemodialysis. Patients assigned to frequent hemodialysis demonstrated an improvement in their feeling thermometer score over the first 4 months of follow-up while the score remained similar in patients assigned to conventional hemodialysis (change of 3.7 vs. −0.4 from baseline). This change persisted to 12 months after randomization (4.0 vs. −4.1 from baseline). However, the between-treatment group difference in the change in score by 1 year was not statistically significant (8.0, 95% CI −0.5 to 16.1). The baseline mean (SD) score was 40 (18) in patients assigned to frequent hemodialysis and 45 (20) in patients assigned to conventional hemodialysis. Patients assigned to frequent hemodialysis demonstrated a greater improvement in their general health scale by 12 months than patients assigned to conventional hemodialysis (change of 8.0 vs. 1.5 from baseline). However, the between-treatment group difference in the change in score by 1 year was not statistically significant (6.6, 95% CI −1.5 to 16.1). Between baseline and 12 months of follow-up, in patients assigned to frequent hemodialysis, the median recovery time (10th, 90th percentile) decreased from 180 minutes (0, 1440) to 30 minutes (0,180), whereas in patients assigned to conventional hemodialysis, the median recovery time changed from 180 minutes (0, 780) to 120 minutes (0, 1440). The between-treatment group difference in the change in score by 1 year was –60 minutes (95% CI −68 to −53). A recovery time of 60 minutes or more at baseline was observed in 58% of patients assigned to frequent hemodialysis and 63% assigned to conventional hemodialysis. Corresponding numbers 1 year after randomization were 24% and 59%, respectively. There was no consistent statistical difference between frequent and conventional hemodialysis in the change in the health utilities index over 4 and 12 months of follow-up, or its 8 attributes (Appendix S1). We performed a post hoc subgroup analysis of the Daily Trial and confirmed the observed 12-month effects of frequent hemodialysis on our HRQoL measures did not significantly differ in patients who had a daily urine volume less than or greater than 100 ml at the time of randomization (Appendix S2). We performed a post hoc subgroup analysis of the Daily Trial and found the observed benefit of frequent hemodialysis on our measures of HRQoL did not significantly differ in patients who reported a shorter or longer recovery time after a dialysis session at the time of randomization (Appendix S3). The smaller number of patients in the Nocturnal Trial precluded meaningful subgroup analyses. We performed a post hoc analysis comparing the 2 groups on the total weekly dialysis time and postdialysis session recovery time 12 months after randomization (Appendix S4). As expected, the total weekly time of dialysis treatments was higher with frequent compared with conventional dialysis (Daily Trial median [25th, 75th percentile] 12.2 [10.8, 14.4] versus 10.3 [9.1, 11.4] hours; corresponding numbers for the Nocturnal Trial were 33.1 [20.0, 40.1] versus 12.0 [11.7, 13.5] hours). However, the total weekly recovery time after dialysis sessions was lower with frequent dialysis compared with conventional dialysis (Daily Trial median [25th, 75th percentile] values 5 [0.4, 11] versus 8 [3 to 18] hours; corresponding numbers for the Nocturnal Trial were 2 [0, 5] versus 6 [2, 22] hours [Appendix S4]). Many studies in hemodialysis focus on the interests of researchers, and do not adequately study what a patient would prefer or value most. Most patients with end-stage kidney disease place a high value on their HRQoL, and want to know if it will be affected by their choice of dialysis modality. After a conventional hemodialysis session, many patients feel fatigued and not themselves for the next 2 to 3 hours (and sometimes longer). In this analysis of 2 randomized controlled trials, we found patients recovered on average approximately 1 hour earlier from frequent compared with conventional hemodialysis. This was true whether the dialysis was received in a center (in the case of the Daily Trial) or at home (in the case of the Nocturnal Trial). These results extend the findings of a smaller observational study that described marked and persistent reductions in recovery time after patients on conventional hemodialysis initiated frequent hemodialysis.9Lindsay R.M. Heidenheim P.A. Nesrallah G. et al.Minutes to recovery after a hemodialysis session: a simple health-related quality of life question that is reliable, valid, and sensitive to change.Clin J Am Soc Nephrol. 2006; 1: 952-959Crossref PubMed Scopus (160) Google Scholar Less fluid is removed during a frequent hemodialysis session, and the session time is often shortest with in-center daily hemodialysis. Although there was more time spent on dialysis with frequent compared with conventional hemodialysis each week (in the Daily and Nocturnal Trials 2 hours and 21 more hours, respectively), patients reported a sizeable reduction in the total weekly time to recover after their dialysis sessions (Appendix S4). In other words, while a patient receives more hours of hemodialysis, he or she actually experiences more hours during which he or she feels more normal, and less "washed out." These data can be used to inform patients about a potential benefit of frequent hemodialysis, particularly if they have important responsibilities soon after their hemodialysis session, such as childcare or work. Patients treated in a dialysis facility reported better HRQoL with frequent shorter hours daily hemodialysis compared with conventional hemodialysis. The feeling thermometer is a single simple measure that embodies both functional and satisfaction-based aspects of HRQoL. Patients allocated to receive shorter hours daily hemodialysis reported a 6.4-point improvement in their feeling thermometer score, which meets the accepted minimal important difference of 5 to 8 points.10Schunemann H.J. Griffith L. Jaeschke R. et al.Evaluation of the minimal important difference for the feeling thermometer and the St. George's Respiratory Questionnaire in patients with chronic airflow obstruction.J Clin Epidemiol. 2003; 56: 1170-1176Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar They also reported a 9.7-point improvement in their general health scale score, which exceeds the accepted minimal important difference of 3 to 5 points.11Hays R.D. Morales L.S. The RAND-36 measure of health-related quality of life.Ann Med. 2001; 33: 350-357Crossref PubMed Scopus (867) Google Scholar For reference, 107 patients with stage 3 and 4 chronic kidney disease randomly assigned 24 exercise sessions over 12 weeks (versus no exercise), demonstrated a between-group 6.1-point improvement in their general health scale score.12Rossi A.P. Burris D.D. Lucas F.L. et al.Effects of a renal rehabilitation exercise program in patients with CKD: a randomized, controlled trial.Clin J Am Soc Nephrol. 2014; 9: 2052-2058Crossref PubMed Scopus (68) Google Scholar From our clinical experiences, we suspect improvements in HRQoL observed with frequent dialysis in the Daily Trial also extend to nocturnal hemodialysis. Numerically, many of the effect estimates in the Daily and Nocturnal Trials were similar, but Nocturnal Trial estimates were less precise owing to a much smaller sample with inadequate statistical power to detect clinically important effects. This may be why many between-treatment group comparisons in the Nocturnal Trial were not statistically significant, although it is also possible there is simply no effect. Patients in the Nocturnal Trial had more residual renal function than patients in the Daily Trial. In both trials, there was no apparent effect of frequent hemodialysis on the health utilities index. It is plausible that this index is not responsive to change with frequent hemodialysis, even in the presence of other HRQoL and general health benefits. The FHN trials had inadequate statistical power to reliably detect modest differences in mortality or major health events; an adequately powered trial would require at least 1200 to 1800 or more patients depending on whether mortality or a composite endpoint of mortality and major cardiovascular events was considered. Knowledge of an intervention's effects on HRQoL remains important in determining whether the treatment should be adopted, and if so, whether the treatment is of sufficient value. Although the provision of frequent in-center hemodialysis is costly, expanding the capacity of home-based frequent hemodialysis programs might allow some patients to enjoy its benefits at a reasonable cost.13Lee C.P. Zenios S.A. Chertow G.M. Cost-effectiveness of frequent in-center hemodialysis.J Am Soc Nephrol. 2008; 19: 1792-1797Crossref PubMed Scopus (44) Google Scholar Randomized trials provide some of the best estimates of treatment effects. However, our analyses do have some limitations that merit consideration. The questionnaires were completed by patients who were aware of the type of hemodialysis they received, and enthusiasm for a novel therapy like frequent hemodialysis could influence responses on HRQoL measures. To improve the rigor of our measurements, 3 of our 4 HRQoL surveys were administered by personnel unaware of the dialysis regimen to which a patient was assigned. We also looked for consistency of effects at 12 months, beyond 4 months when any initial enthusiasm for frequent hemodialysis may wane. However, the best methods to assess the complex domain of patient-centric HRQoL remains controversial, and some may disagree with the feasible HRQoL measures used in the FHN trials. Furthermore, only a fraction of patients receiving conventional hemodialysis agreed to be randomized into the FHN trials. Patients who agreed to be randomized into each trial had a higher baseline HRQoL than patients who provided consent but were not randomized, and it remains possible that the effects observed in these 2 trials will not generalize well to the entire hemodialysis population.14Rocco M.V. Larive B. Eggers P.W. et al.Baseline characteristics of participants in the Frequent Hemodialysis Network (FHN) daily and nocturnal trials.Am J Kidney Dis. 2011; 57: 90-100Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Finally, these HRQoL measures were completed at a time most convenient to each patient and not at a fixed time after a hemodialysis session; it remains possible this influenced the accuracy of the measures. In conclusion, as compared with conventional thrice-weekly hemodialysis, frequent in-center hemodialysis and frequent home-based nocturnal hemodialysis both reduce the time it takes to recover from a hemodialysis session. Frequent in-center hemodialysis also yielded statistically significant and clinically important changes in general measures of HRQoL. The FHN Daily (ClinicalTrials.gov NCT00264758) and Nocturnal (ClinicalTrials.gov NCT00271999) trials are 2 multicenter, randomized, prospective trials of frequent in-center daily hemodialysis and home nocturnal hemodialysis, respectively, sponsored by the US National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) and the Centers for Medicare and Medicaid Services. The designs and inclusion and exclusion criteria of both the trials are fully described elsewhere, as are the methods of randomization, data collection procedures, and baseline clinical characteristics.8Suri R.S. Garg A.X. Chertow G.M. et al.Frequent Hemodialysis Network (FHN) randomized trials: study design.Kidney Int. 2007; 71: 349-359Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Briefly, patients receiving maintenance hemodialysis with the ability to communicate in English or Spanish were enrolled into the 2 trials across centers in the United States and Canada between 2006 and 2009 (Daily Trial 19 centers, Nocturnal Trial 8 centers). In the Daily Trial, we randomly assigned 245 patients to receive frequent (6 times per week) or conventional (3 times per week) in-center hemodialysis. In the Nocturnal Trial, we randomly assigned 87 patients to receive frequent nocturnal (6 times per week) or conventional (3 times per week) hemodialysis at home. As described elsewhere, the Daily Trial screened 6276 hemodialysis patients on 3 times weekly hemodialysis in 65 hemodialysis clinics, 3481 (55%) were considered eligible for enrollment, and 3124 (90%) were approached for consent; 378 (12%) provided consent and 245 were randomized (65% of those who provided consent); prospective patients chose not to participate primarily because of the anticipated time required for 3 extra treatments per week and the difficulties in following the trial protocol.15Sergeyeva O. Gorodetskaya I. Ramos R. et al.Challenges to enrollment and randomization of the Frequent Hemodialysis Network (FHN) Daily Trial.J Nephrol. 2012; 25: 302-309Crossref PubMed Scopus (20) Google Scholar Although not reported in detail, a similar pattern of screening and randomization occurred in the Nocturnal Trial. As previously reported, patients randomly assigned into the Daily Trial, compared with patients who provided consent but were not randomly assigned, had higher baseline measures of HRQoL.14Rocco M.V. Larive B. Eggers P.W. et al.Baseline characteristics of participants in the Frequent Hemodialysis Network (FHN) daily and nocturnal trials.Am J Kidney Dis. 2011; 57: 90-100Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar The same was also true in the Nocturnal Trial.14Rocco M.V. Larive B. Eggers P.W. et al.Baseline characteristics of participants in the Frequent Hemodialysis Network (FHN) daily and nocturnal trials.Am J Kidney Dis. 2011; 57: 90-100Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar As previously described, frequent hemodialysis resulted in more solute and fluid removal per week, with less fluid removal for each hemodialysis session.6Chertow G.M. Levin N.W. Beck G.J. et al.In-center hemodialysis six times per week versus three times per week.N Engl J Med. 2010; 363: 2287-2300Crossref PubMed Scopus (823) Google Scholar, 7Rocco M.V. Lockridge Jr., R.S. Beck G.J. et al.The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial.Kidney Int. 2011; 80: 1080-1091Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar As previously reported, a coprimary prespecified HRQoL measure in each of the FHN trials was the physical health composite score from the RAND 36-item health survey.8Suri R.S. Garg A.X. Chertow G.M. et al.Frequent Hemodialysis Network (FHN) randomized trials: study design.Kidney Int. 2007; 71: 349-359Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar This informed the target number of 250 patients who were to be randomized into each of the trials (as described elsewhere for adequate statistical power to detect a 4.6 to 5.0 between-group difference in the RAND 36).6Chertow G.M. Levin N.W. Beck G.J. et al.In-center hemodialysis six times per week versus three times per week.N Engl J Med. 2010; 363: 2287-2300Crossref PubMed Scopus (823) Google Scholar, 8Suri R.S. Garg A.X. Chertow G.M. et al.Frequent Hemodialysis Network (FHN) randomized trials: study design.Kidney Int. 2007; 71: 349-359Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Four other patient-reported measures (questionnaires) of general health were collected during the FHN trials, and we analyzed these measures for this report. Patients and providers were aware of the frequency of hemodialysis prescribed and delivered. As described elsewhere, HRQoL questionnaires were administered by telephone in English or Spanish through a centralized call center by personnel unaware of group assignment (at baseline, month 4, and month 12).16Jhamb M. Tamura M.K. Gassman J. et al.Design and rationale of health-related quality of life and patient-reported outcomes assessment in the Frequent Hemodialysis Network trials.Blood Purif. 2011; 31: 151-158Crossref PubMed Scopus (25) Google Scholar The only exception was the feeling thermometer (described in the next paragraph), which was completed with the assistance of a local research coordinator. Both trials were approved by the local institutional review board at each participating site. The feeling thermometer is a single question that asks patients to rate their own health on a visual analog scale from 0 to 100, where 0 is dead and 100 is perfect health.10Schunemann H.J. Griffith L. Jaeschke R. et al.Evaluation of the minimal important difference for the feeling thermometer and the St. George's Respiratory Questionnaire in patients with chronic airflow obstruction.J Clin Epidemiol. 2003; 56: 1170-1176Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar This commonly used scale has been responsive to various therapies in multiple different conditions.17Baldassarre F.G. Arthur H.M. Dicenso A. Guyatt G. Effect of coronary artery bypass graft surgery on older women's health-related quality of life.Heart Lung. 2001; 31: 421-431Abstract Full Text Full Text PDF Scopus (11) Google Scholar A change in the score of 5 to 8 points is considered clinically important.10Schunemann H.J. Griffith L. Jaeschke R. et al.Evaluation of the minimal important difference for the feeling thermometer and the St. George's Respiratory Questionnaire in patients with chronic airflow obstruction.J Clin Epidemiol. 2003; 56: 1170-1176Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar A general health scale can be derived from 5 items in the RAND-36 questionnaire. It is scored from 0 to 100, in which a low score is poor health likely to get worse, and a high score is excellent health.18Ware Jr., J.E. Sherbourne C.D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.Med Care. 1992; 30: 473-483Crossref PubMed Scopus (28034) Google Scholar A change in the score of 3 to 5 points or more is considered clinically important.11Hays R.D. Morales L.S. The RAND-36 measure of health-related quality of life.Ann Med. 2001; 33: 350-357Crossref PubMed Scopus (867) Google Scholar The time to recover from a dialysis session is understood by asking a patient, "How long does it take you to recover from a dialysis session and resume your normal, usual activities?" In a previous nonrandomized comparison of frequent versus conventional hemodialysis, this question was reliable, valid, and responsive to change.9Lindsay R.M. Heidenheim P.A. Nesrallah G. et al.Minutes to recovery after a hemodialysis session: a simple health-related quality of life question that is reliable, valid, and sensitive to change.Clin J Am Soc Nephrol. 2006; 1: 952-959Crossref PubMed Scopus (160) Google Scholar Since then, the question has been further validated in larger studies against concurrent symptoms and clinically meaningful outcomes.19Rayner H.C. Zepel L. Fuller D.S. et al.Recovery time, quality of life, and mortality in hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2014; 64: 86-94Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar In addition to examining the question as a continuous measure, we also considered the threshold of requiring 60 minutes or more to recover from a dialysis session. The health utilities index (The Health Utilities Index Mark 3) is a commonly used validated survey where participants rate their health on the following 8 attributes: vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain. It is scored to a final result from 0 to 1, with a function derived from community preferences for various health attributes. A final result of 0 represents death and 1 perfect health. A change in the score of 0.03 or more is considered clinically important.20Horsman J. Furlong W. Feeny D. Torrance G. The Health Utilities Index (HUI): concepts, measurement properties and applications.Health Qual Life Outcomes. 2003; 1: 54Crossref PubMed Scopus (997) Google Scholar We adhered to the intention-to-treat principle for all analyses and did not adjust for multiple comparisons. We performed parallel analyses stratified by trial. Baseline characteristics of the 2 trials were stratified by intervention status (frequent vs. conventional hemodialysis). We used linear mixed effects models incorporating baseline, month 4, and month 12 scores to assess the between-treatment group differences in the 1-year change in the HRQoL measures, with the exception of dialysis recovery time which was recorded at only baseline and month 12. The PROC MIXED procedure was chosen for its flexibility, allowing us to incorporate all available data without restriction on whether it was available or missing at baseline, month 4, or month 12. We applied an unstructured covariance matrix to obviate assumptions of data structure. In accordance with the prespecified analytic plan, we adjusted for baseline score and, in the case of the Daily Trial, we also adjusted for clinical center. We performed the analyses for dialysis recovery time after log-transforming the values, with the reported results subsequently back-transformed using the delta method. We used SAS software, version 9.2 (SAS Institute, Inc, Cary, NC) for the analysis. AG was a co-investigator on investigator-initiated research project sponsored by Fresenius, and is supported by the Dr. Adam Linton Chair in Kidney Health Analytics. His work was conducted in the Lilibeth Caberto London Kidney Clinical Research Unit. RS received an investigator-initiated research grant from the Baxter Inc Extramural Grant Program, and is supported by a research scholarship from le Fonds de recherché du Québec–Santé. MU has received research support from Baxter, Satellite Healthcare, and DCI Inc. GC served on the Board of Directors for Satellite Healthcare. All other authors declared no competing interests. Clinical trial ID numbers: NCT00264758 and NCT00271999. Download .docx (.02 MB) Help with docx files Appendix S1Short Daily and Nocturnal FHN Trials. Mean changes in attributes of the health utilities index for frequent (6 times per week) versus conventional (3 times per week) hemodialysis in each of the trials. Download .docx (.01 MB) Help with docx files Appendix S2An assessment of the effects of daily hemodialysis on 4 general measures of HRQoL in patients with a daily urine volume less than or greater than 100 ml at the time of randomization. Download .docx (.01 MB) Help with docx files Appendix S3An assessment of the effects of daily hemodialysis on 4 general measures of HRQoL in patients who reported taking less than or greater than 120 minutes to recover from a hemodialysis session. Download .docx (.02 MB) Help with docx files Appendix S4Total time to recover per week after hemodialysis sessions that week.