Evidence Table. Study Type: Randomized controlled trial. Study Aim: To compare frequent nocturnal hemodialysis and conventional in-center dialysis.

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1 Evidence Table Clinical Area: Reference: Frequent home dialysis Culleton BF, Walsh M, Klarenbach SW et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life. JAMA 2007; 298: Study Type: Randomized controlled trial. Study Aim: To compare frequent nocturnal hemodialysis and conventional in-center dialysis. Outcomes Primary: Change in left ventricular mass over 6 months. Secondary: Blood pressure, anemia, mineral metabolism, quality of life. Design Number of subjects: N=52 (n=27 nocturnal hemodialysis; n=25 conventional hemodialysis) Description of study population: Nocturnal hemodialysis: mean age=55 years; 69% male; 88% white; mean time receiving dialysis=5.5 years: Conventional hemodialysis: mean age=53 years; 56% male; 84% white; mean time receiving dialysis=4.8 years. Inclusion criteria: At least 18 years old; receiving in-center, self-care or home hemodialysis 3 times a week; willing to train for and use nocturnal hemodialysis. Exclusion criteria: Lack physical or mental capacity for home nocturnal dialysis. Intervention: Patients were randomized to receive 1) standard hemodialysis: continued pre-randomization treatment 3 times a week: 2) nocturnal dialysis: incenter training 4-5 times a week for 2-6 weeks with direct nursing supervision and monitoring of biochemical parameters. After the training period, nocturnal hemodialysis was done at home without supervision, 5-6 nights a week for a minimum of 6 hours per night. Bellco Formula machines (Ontario, Canada) were used. Source of outcome data: Laboratory and imaging data (cardiovascular magnetic resonance for left ventricular mass); self-report data for quality of life. Length of follow-up: 6 months. Validity Blinding? Assessment of primary outcome was blinded. Appropriate randomization procedures? Yes. Appropriate comparison intervention? Yes. Treatment/control groups comparable at baseline? Yes. Other than intervention, was care/follow-up similar in each group? Yes. Adequate compliance with intervention? Yes. Sufficient statistical power? Yes, 95% power to detect a 10g difference in change in LV mass, 2-tailed alpha=0.05.

2 Intention to treat analysis? Modified. ITT approach for all patients with at least 1 baseline measurement (1 patient excluded). Completeness of follow-up: Primary endpoint assessed in 44 patients. Industry funding? None reported. Conclusions regarding validity of methods: Valid methods. Results Nocturnal Conventional Difference (n=26) (n=25) (95% CI), p-value Primary outcome LV mass, mean (SD), g Baseline (51.1) (92.3) Follow-up (45.2) (84.2) Change (23.0) 1.5 (24.0) (-29.6 to -1.0), <0.05 Selected secondary outcomes Blood pressure, mean (SD), mm Hg Systolic Baseline 129 (23) 135 (19) Follow-up 122 (23) 139 (20) Change -7 (29) 4 (17) -11 (-24 to 2), NS Diastolic Baseline 75 (14) 77 (16) Follow-up 68 (16) 75 (12) Change -7 (16) -2 (12) -5 (-13 to 2), NS Anemia Hemoglobin, mean (SD), g/dl Baseline 11.9 (1.2) 11.7 (1.3) Follow-up 11.6 (1.2) 11.8 (1.1) Change -0.3 (1.3) 0.1 (1.4) -0.4 (-1.2 to 0.3), NS Mineral metabolism Calcium, mean (SD) mg/dl Baseline 9.5 (0.6) 9.1 (1.2) Follow-up 9.4 (0.7) 8.9 (0.8) Change -0.1 (0.8) -0.2 (0.5) 0.1 (-0.3 to 0.4), NS Phosphate, mean (SD), mg/dl 1 Baseline 5.5 (1.5) 4.9 (1.3) Follow-up 4.4 (1.7) 5.3 (1.9) Change -1.1 (1.8) 0.4 (1.8) -1.5 (-2.5 to -0.5), <0.01 Quality of Life (mean EuroQol-5D index) 1 Normal range is mg/dl

3 Change (-0.07 to 0.17), NS Pre-selected dimensions, Kidney Disease QOL measure (0-100) NOTE: Baseline scores, change at follow-up Symptoms/problems (-3.8 to 11.2), NS Effects of kidney disease (2.0 to 15.2), 0.01 Burden of kidney disease (1.3 to 17.5), 0.02 Sleep (-10.2 to 5.0), NS

4 Adverse events, No. patients experiencing 1 event Nocturnal (n=26) Conventional (n=25) Bacteremia 4 4 Insertion or replacement of tunneled dialysis catheter 7 5 Vascular access angiogram 8 5 Vascular access surgical intervention 3 5 Authors Conclusions This preliminary study revealed that, compared with conventional hemodialysis (3 times weekly), frequent nocturnal dialysis improved left ventricular mass, reduced the need for blood pressure medications, improved some measures of mineral metabolism and improved selected measures of quality of life. Reviewer s Conclusions In this well-conducted RCT, the primary outcome, LV mass, significantly improved (was lower) in the group assigned to nocturnal home hemodialysis compared to conventional hemodialysis 3 times a week. There was also improvement in some secondary outcomes (phosphate level) but not others (anemia, calcium level). There was no between-group difference in overall quality of life. Two of four pre-selected kidney-related QOL dimensions signficantly improved in the nocturnal hemodialysis group, the other two did not differ signficantly between groups. The study may not have had sufficient power to detect differences in secondary outcomes and was not powered to detect a difference in mortality.

5 Evidence Table Clinical Area: Reference: Frequent home dialysis Bergman A, Fenton SSA, Richardson RMA, Chan CT. Reduction in cardiovascular related hospitalization with nocturnal home hemodialysis. Clin Nephrol 2008; 69: Study Type: Cohort (Prospective) Study Aim: To compare cardiovascular hospitalizations with conventional versus nocturnal home dialysis. Outcomes Primary: Composite: Dialysis-related or cardiovascular-related admissions Secondary: Change in hospitalizations, all cause; visits to emergency, biochemical parameters. Design Number of subjects: N=32 nocturnal hemodialysis, N=42 conventional hemodialysis. Description of study population: Nocturnal hemodialysis: mean age=43 years; 60% male; mean time on dialysis=9 years: Conventional hemodialysis: mean age=44 years; 64% male; mean time on dialysis=8 years. Eligibility criteria: Consecutive patients converted to nocturnal hemodialysis. Patients in the comparison intervention were matched to intervention patients by age (±5 years), gender, length of time on dialysis (± 2 years), diabetes status and comorbidities (modified Charlson Index) Exposure/Intervention: Conventional hemodialysis was given for 4 hours, 3 times a week. Nocturnal hemodialysis was given at home for 8-10 hours, 6 nights per week. Source of outcome data: Medical records, laboratory tests. Length of follow-up: 3 years (1 year before and 2 years after conversion to nocturnal hemodialysis). Validity Is the study type appropriate for the question(s) being asked? Randomization would be preferred. Population-based sample? No. Potential selection biases: None identified. Sufficient statistical power? Not discussed. Did an objective observer assess outcomes? Not discussed. Completeness of follow-up: 100%. Results adjusted for confounding factors? No, but there was matching based on comorbidity. Conclusions regarding validity of methods: Did not adjust for confounding factors in analysis.

6 Results Primary outcome: Dialysis-related or cardiovascular-related admissions (per patient year) Nocturnal Conventional Between-group p-value Hemodialysis Hemodialysis (n=32) (n=42) Baseline 0.50 ± ± 0.14 Follow-up* 0.17 ± ± 0.12 <0.05 * 2 years post-conversion to nocturnal hemodialysis for experimental group. Selected secondary outcomes, per patient year Nocturnal Hemodialysis (n=32) Conventional Hemodialysis (n=42) All-cause hospitalization Baseline 0.53 ± ± 0.17 Follow-up 0.21 ± ± 0.12 ER visits Baseline 1.03 ± ± 0.15 Follow-up 0.93 ± ± 0.15 Note: No statistically significant between group differences were reported. Authors Conclusions Conversion to NHD (nocturnal hemodialysis) is associated with a decrease in dialysis and cardiovascular-related hospital admission. The clinical and mechanistic relevance in uremic patients of improved phosphate and anemia management requires further evaluation. Reviewer s Conclusions In this prospective cohort study, there was a significantly greater reduction in dialysisrelated and/or cardiovascular-related hospital admissions in a group converted to nocturnal hemodialysis 6 times a week versus a group that remained on conventional dialysis 3 days a week. The study was not randomized so there may have been some differences between groups that affected outcomes.

7 Evidence Table Clinical Area: Reference: Frequent home dialysis Schwartz DI, Pierratos A, Richardson RMA et al. Impact of nocturnal home hemodialysis on anemia management in patients with end-stage renal disease. Clin Nephrol 2005; 63: Study Type: Cohort (Retrospective) Study Aim: To investigate whether nocturnal hemodialysis (NHD) would improve hemoglobin (Hb) concentrations and decrease requirements for erythropoietin (EPO) compared to conventional hemodialysis (CHD) in patients in patients with end-stage renal disease (ESRD). Outcomes Primary: Change in Hb and EPO dose, baseline and 6 and 12 months. Design Number of subjects: N=63 patients receiving nocturnal home dialysis; n=32 patients on conventional hemodialysis. Description of study population: Home dialysis group: Mean age=46 ± 2 years 67% male; CHD group: Mean age=57 ± 3 years 72% male. Eligibility criteria: Enrolled in the hospitals dialysis program for at least 6 months; all participants (including the comparison group) had to be eligible for the nocturnal dialysis program and stable in their anemia management. Control patients were matched to NHD patients by sex, baseline iron repletion status, EPO dose and midweek Hb concentrations. Exposure/Intervention: Nocturnal home dialysis: Hemodialysis at home for 6-8 hours, 5-6 nights a week. CHD: Hemodialysis 4 hours, 3 times a week. Source of outcome data: Retrospective chart review. Length of follow-up: Had to be followed for at least 6 months. Validity Is the study type appropriate for the question(s) being asked? Yes, a randomized trial is ideal. Population-based sample? Clinic based. Potential selection biases: All patients were eligible for NHD, but it is possible that those selected to actually receive it were sicker, or healthier than those who continued to receive conventional dialysis. Sufficient statistical power? Not discussed. Did an objective observer assess outcomes? Yes. Completeness of follow-up: NA, only included cases for which data were available. Results adjusted for confounding factors? Used matching. Conclusions regarding validity of methods: Limitations of the study design include the possibility of residual confounding and incomplete or inaccurate reporting in medical records.

8 Results Change in hemoglobin concentration and EPO dose Baseline 6 months 12 months NHD Hb (g/l) 115 ± ± ± 2.3* EPO dose (U/week) ± ± ± 1100** EPO-free (%) * CHD Hb (g/l) 110 ± ± ± 2.2 EPO dose (U/week) 8300 ± ± ± 1000 EPO-free (%) NHD=nocturnal hemodialysis; CHD=conventional hemodialysis *p-value <0.05 between CHD and NHD groups at 12 months ** p-value<0.05 within group, repeated measures Authors Conclusions Enhancing uremic clearance by NHD resulted in a rise in Hb and a fall in EPO requirement. Reviewer s Conclusions There was a statistically significantly greater increase in Hg and percentage of patients EPO-free at 12 months in the group receiving nocturnal home hemodialysis compared to conventional hemodialysis.

9 Evidence Table Clinical Area: Reference: Frequent home dialysis Blagg CR, Kjellstrand CM, Ting GO, Young BA. Comparison of survival between short-daily hemodialysis and conventional hemodialysis using the standardized mortality ratio. Hemodialysis International 2006; 10: Study Type: Case Series (statistical analysis) Study Aim: To compare survival in patients treated with short daily dialysis (at home or in-center) with national statistics on survival on conventional dialysis. Outcomes Primary: Survival. Design Number of subjects: N=117. Description of study population: 71 males/ 46 females; mean age=55.5 years (range=19 to 89 years); men time being treated for end-stage rnal diasese=5 years.. Eligibility criteria: Patients in the U.S. with end-stage renal disease who were treated with short-daily dialysis in Consecutive patients? Not discussed. Intervention: Short daily hemodialysis was defined as hemodialysis 5 or more times a week, for 2 to 3.5 hours per session. 19 (16%) were treated in-center using standard equipment, and 98 (94%) were treated at home using the PHD System (Aksys Ltd, USA). The study was a statistical analysis of mortality data using established techniques for calculating standardized mortality rates. Source of outcome data: Medical records. Length of follow-up: Up to 2 years. Validity Was population homogenous? Reasonably. Potential selection biases: Patients who volunteered for, or were selected for home daily dialysis may have been healthier than patients receiving in-center dialysis. Did an objective observer assess outcomes? NA, used medical records and objective outcome. Outcomes were compared to national mortality rats, as reproted in the United States Renal Data Systems (USRDS). Appropriate analysis: Appeared to be, cited references for their statistical methods. Industry funding? Yes, funding by Aksys, and first author is consultant to Aksys. Conclusions regarding validity of methods: This was a statistical analysis of data from patient medical records and the USRDS. Involvement from the manufacturer of the home dialysis device may have introduced bias.

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11 Results Number of expected deaths over 2 years (statistical analysis) 25.7 (95% CI= ) Adjusted for age, sex, race and diagnosis Actual number of deaths=10 Standard mortality ratio=0.39 (95% CI= ), p<0.005 (Comparison with national mortality rates, patients receiving conventional dialysis). Authors Conclusions daily hemodialysis patients had a 61% better survival. Patients treated by short-daily hemodialysis have a better survival rate than comparable populations treated by conventional hemodialysis). Reviewer s Conclusions The analysis found a statistically significantly better survival in patients who received short daily dialysis, mainly at home, than patients receiving conventional dialysis. Industry funding may have led to bias, and there may be limits to the statistical technique of calculating standardized mortality ratios (SMR).

12 Evidence Table Clinical Area: Reference: Frequent home dialysis Mahadevan K, Pellicano R, Reid A et al. Comparison of biochemical, hematological and volume parameters in two treatment schedules of nocturnal home hemodialysis. Nephrology 2006; 11: Study Type: Cohort (Retrospective) Study Aim: To compare two schedules of nocturnal home dialysis. Outcomes Primary: Biochemical parameters 3-6 months after starting nocturnal dialysis. Design Number of subjects: N=13 six nights/week, N=21 alternate nights Description of study population: Six nights a week: mean age=52 years; 13 males/ 0 females; mean time on dialysis=29 months: every other night: mean age=45 years; 18 males/ 3 females; mean time on dialysis=33 months. Eligibility criteria: Patients stable on home dialysis for three months or longer; patients of dialysis programs at one of two hospitals in Australia. Exposure/Intervention: Nocturnal dialysis 8 hours per night in the supine posture. Patients in the program at Geelong Hospital had dialysis 6 nights a week, and patients at Monash Medical Center had dialysis every other night. Source of outcome data: Serum samples. Length of follow-up: 3-6 months. Validity Is the study type appropriate for the question(s) being asked? An RCT or prospective cohort study would be preferable. Population-based sample? No. Potential selection biases: Patients on nocturnal dialysis 6 nights a week were slightly older; otherwise groups were similar. No obvious selection biases. Sufficient statistical power? Not reported. Did an objective observer assess outcomes? Objective tests. Completeness of follow-up: Retrospective, so included patients with data. Results adjusted for confounding factors? No. Conclusions regarding validity of methods: Limitations include not adjusting for pre-intervention values in the analysis and multiple outcomes without adjustment of the significance level. A limitation of the study design is that, without randomization, there may be baseline differences between groups that affect outcomes.

13 Results Parameters 6 nights/week Every other night p-value (n=13) (n=21) Urea (mmol/l) Pre ± ± 7.06 <0.001 Post 2.32 ± ± Creatinine (umol/l) Pre 437 ± ± 204 <0.001 Post 140 ± ± 84 <0.001 Phosphate (mmol/l) Pre 1.64 ± ± Post 0.86 ± ± Calcium (mmol/l) Pre 2.57 ± ± 0.19 <0.002 Post 2.60 ± ± PTH (pmol/l) (median) Pre NS Post (3 months) Hemoglobin (g/l) 123 ± ± 16 NS Albumin (g/l) 38.3 ± ± 4.5 NS Homocysteine (mmol/l) 12.4 ± ± 3.2 NS UFR (ml/min) 249 ± ± 168 <0.002 Weight gain (kg) 2.0 ± ± PTH=parathyroid hormone; UFR=ultrafiltration rate Medication use, n (%) 6 nights/week Every other night p-value (n=13) (n=21) Phosphate binders 0 8 (38) NS Calcitrol 11 (85) 11 (52) NS BP medications 6 (46) 4 (19) NS Erythropoietin 10 (77) 18 (86) NS Authors Conclusions (nocturnal dialysis 6 nights a week) offers the optimum biochemical, volume and clinical outcome, but (nocturnal dialysis every other night) has additional appeal to providers seeking home-based cost advantages and consumable expenditure control.

14 Reviewer s Conclusions After 3-6 months on nocturnal dialysis, there were significant differences between groups in certain parameters (urea, creatinine and PTH) but not others (phosphate, calcium, albumin, homocystine). Urea, creatinine and PTH levels were all significantly lower in the group treated 6 nights/week. There were no significant differences at follow-up in the proportion of patients taking phosphate blinders, calcitrol, blood pressure medications or erythropoietin. The study was likely underpowered to detect differences in medication use, and some of the post-treatment differences in biological parameters may have been due to differences in pre-treatment values..