Table 3.

Studies evaluating interventions for PDF or TIRD

Reference	Study Design	N	Intervention	Control	Total Duration	Fatigue Results
High dialysate sodium
Sadowski, et al. 199336	Multiple crossover trial	16	3 sodium modeling protocols to decrease dialysate sodium from 148 to 138 mEq/L	Constant dialysate sodium 138 mEq/L	8 weeks	Higher odds of fatigue improvement with sodium modeling (combined data from 3 sodium modeling programs), OR 3.6 (95% CI 2.0, 6.4)
Levin, et al. 199637	Crossover RCT	16	Ramped hypertonic sodium dialysis	Standard dialysis	6 weeks	56% in the intervention group reported improved energy for recreational activities
Sang, et al. 199735	Crossover RCT	23	2 protocols (stepwise and linear) for dialysate sodium ramping from 155 to 140 mEq/L	Constant dialysate sodium 140 mEq/L	6 weeks	No difference in fatigue presence in the 12 hours after HD. Fatigue the day after dialysis was lower in the control group than the stepwise protocol (P=0.003) but not different than the linear protocol (P=0.08).
Basile, et al. 200159	Non-randomized prospective interventional study	19	Real time sodium modeling and ultrafiltration control via biofeedback mechanism	Constant dialysate conductivity	Variable, 14-30 months	Higher PDF in the sodium modeling group (6.2±0.2 vs. 4.3±0.1, P<0.0001).
Glucose-enriched dialysate
Leski, et al. 197961	Randomized multiple crossover	10	Dialysate with 400 mg/dL glucose	Glucose-free dialysate	4 weeks	PDF decreased from 0.75±0.77 at baseline to 0.50±0.72 after glucose-enriched dialysate, P<0.01.
Raju, et al. 198260	Crossover, unclear if randomized	17	Dialysate with 200 mg/dL glucose	Glucose-free dialysate	Unclear	Decrease in PDF frequency in glucose-enriched dialysate group
Raimann, et al. 201062	Crossover RCT	30	Dialysate with 200 mg/dL glucose	Dialysate with 100 mg/dL glucose	6 weeks	More severe fatigue in the 200 mg/dL group among those with DM (5.0±1.0 vs. 4.2±1.1, P<0.05) but no difference in those without DM (3.5±1.9 vs. 3.0±1.6, P=0.23)
Cool dialysate
Ayoub, et al. 200466	Non-randomized crossover trial (cool dialysate followed by standard)	10	35.0°C dialysate	36.5°C dialysate	2 weeks	8 (80%) felt more energetic with cooler dialysate
Azar, et al. 200963	Non-randomized crossover trial (standard dialysate followed by cool)	50	35.0°C dialysate	37.0°C dialysate	2 weeks	76% reported feeling more energetic with cool dialysate. TIRD 1.4±0.9 hours in 35°C group vs. 9.9±6.3 in 37°C group, P<0.001.
Teruel, et al. 200664	Non-randomized crossover trial (standard dialysate followed by cool)	31	35.5°C dialysate	37.0°C dialysate	2 weeks	PDF was lower in the cool dialysate group than the standard dialysate group, mean (SD) 1.3 (1.0) in the standard group vs. 1.0 (0.9) in the cool group, P<0.05.
Sajadi, et al. 201665	Crossover RCT	46	35.5°C dialysate	37.0°C dialysate	2 weeks	Fatigue score decreased 31.3% from baseline with cool dialysate. Behavioral, emotional, cognitive, and sensory fatigue domains improved from baseline in cool dialysate group.
Garg, et al. 202267	Pragmatic cluster RCT	15,413	Personalized cooler dialysate temperature	36.5°C dialysate	4 years	Fatigue (timing relative to HD not specified) assessed among 445 participants. No difference between groups, OR 0.81 (95% CI 0.56, 1.18).
HD frequency or duration
Maduell, et al. 200369	Single arm trial	8	Transition from on-line HDF 3 times per week to short daily online HDF	None	6 months	From baseline to 4 weeks PDF scores decreased for intensity (1.88±1.2 vs. 0.38±0.7, P<0.01) and duration (1.75±1.4 vs. 0.25±0.5, P<0.01).
Jaber, et al. 201068	Prospective cohort	239	Transition to at-home HD 6 days per week	None	12 months	TIRD decreased from baseline (473 minutes [IQR 385, 561]) to month 4 (240 minutes [IQR 172, 308], P<0.001) and month 12 (237 minutes [IQR 168, 306], P<0.001)
Garg, et al. 201770	Parallel arm RCT	245	6 days per week HD	3 days per week HD	12 months	Greater improvement in TIRD from baseline to 12 months in the frequent HD arm, between-groups difference −84 minutes (95% CI −89, −80, P<0.0001).
Davenport, et al. 201971	Retrospective cohort	709	Incremental HD*	Standard HD	12 months	Higher odds of TIRD <1 hour (OR 1.49 [95% CI 1.01, 2.18]) and <4 hours (OR 1.58 [95% CI 1.14, 2.19]) in the incremental HD group. No difference in TIRD < 8 hours or <12 hours.
Clearance of middle molecules
Karkar, et al. 201573	Parallel arm RCT	72	High efficiency post-dilution on-line HDF	High-flux HD	24 months	Improved PDF in on-line HDF arm, 61±18 vs. 10±9, P<0.0001.
Smith, et al. 201772	Crossover RCT	100	Postdilution HDF	HD	16 weeks	No difference in TIRD, median 47.5 minutes (IQR 0, 240) for HDF vs. 30 minutes (0, 210) for HD, P=0.9.
Bolton, et al. 202174	Retrospective cohort	58	Implementation of expanded dialysis**	None	12 months	Shorter median (IQR) TIRD from baseline (210 minutes [7.5, 600]) to 6 months (60 minutes [0, 210], P=0.002) and 12 months (105 [0, 180], P=0.001]).
CBT
Mehrotra, et al. 201975	Parallel arm RCT	120	CBT	Sertraline	12 weeks	Fatigue improved from baseline to week 12 in both groups and was more favorable at week 12 in the sertraline group than the CBT group (between-groups effect estimate of 10.2 points [95% CI 1.3, 19.0], P=0.02].
Picariello, et al. 202176	Parallel arm feasibility RCT	24	Tailored CBT self-management intervention aimed at fatigue	Wait list	3 months	Standardized mean difference in fatigue severity was 0.81 (95% CI −0.67, 2.29), favoring the intervention group.
Exercise and physical activity
Malagoni, et al. 200880	Non-randomized trial	31	Walking sessions on non-dialysis days	Control with no intervention	6 months	From baseline to 6 months the exercise group had improvement in PDF score (2.8±1.4 vs. 2.3±1.6, P<0.05) and TIRD (3.4±2.8 hours vs. 2.6±3.1 hours, P<0.05), but there was no significant difference between groups at 6 months.
Devagourou, et al. 202179	Non-randomized trial	64	Low intensity intra-dialytic exercises	Usual care	6 weeks	At 6 weeks fatigue was lower in the exercise group than the control group (13.1±4.9 vs. 19.2±5.0, P=0.001.
Grigoriou, et al. 202178	Single arm trial	20	Supervised intra-dialytic combined aerobic and resistance exercise	None	9 months	From baseline to 9 months there was a decrease in PDF severity (1.7±0.6 vs. 1.3±0.6, P<0.05) and duration (1.8±0.7 vs. 1.1±0.8, P<0.05), but there was no change in PDF frequency.

^*Incremental dialysis refers to individualizing HD prescription by decreasing dialysis time based on the patient’s residual kidney function. Standard dialysis refers to dialysis prescriptions that did not account for residual kidney function.

^**Expanded dialysis refers to the use of medium cut-off membranes designed to increase the clearance of large middle molecules.

Abbreviations: CBT, cognitive behavioral therapy; CI, confidence interval; ESA, erythropoietin stimulating agent; HDF, hemodiafiltration; IQR, interquartile range; OR, odds ratio; PDF, post-dialysis fatigue; RCT, randomized controlled trial; TIRD, time to recovery from hemodialysis