Self-Reported Poor Quality of Sleep in Solid Organ Transplant: A Systematic Review

Abstract

Background:

High quality sleep of sufficient duration is vital to overall health and wellbeing. Self-reported poor quality of sleep, sleep reported as irregular in timing, marked by frequent awakenings, or shortened in duration, is common across the solid-organ transplant trajectory.

Aim:

This Systematic Review aimed to summarize available literature on rates of self-reported poor quality of sleep among solid organ transplant candidates and recipients.

Methods:

A systematic search of published literature was conducted in PubMed/MEDLINE, Embase, Web of Science, CINHAL, and PsychInfo databases with no date restrictions. Original articles in the English language describing self-reported quality of sleep using standardized questionnaires in adults either waitlisted for, or who received a solid organ transplant (heart, lung, kidney, liver, pancreas, or multi-solid organ) were included.

Results:

Of a potential 2,054 articles identified, 44 were included (63.6% renal transplant, 20.5% liver transplant, 11.4% lung transplant, and 4.5% included multiple organ transplant populations), with the majority (68.2%) focusing only on post-transplant populations. No included articles focused solely on heart or pancreas transplant populations. On average, the transplant population with the greatest improvement in quality of sleep (reported as poor sleep quality, insomnia, sleep disturbance, or sleep dissatisfaction) from transplant candidacy to post-transplantation were renal transplant (from 53.5% pre, to 38.9% post) followed by liver transplant patients (from 52.8% pre, to 46.3% post), while lung transplant patients remained similar pre- to post-transplantation (55.6% pre, to 52% post). Poor quality of sleep was frequently associated with anxiety and depression, poorer quality of life, restless legs syndrome, and higher comorbidity.

Conclusions:

Reports of poor quality of sleep are highly prevalent across all solid-organ transplant populations, both pre- and post-transplantation. Future studies should assess quality of sleep longitudinally throughout all phases of the transplantation trajectory, with more research focusing on how to optimize sleep in solid organ transplant populations.

INTRODUCTION

High quality sleep of sufficient duration is of paramount importance for overall health and wellbeing [1]. Sleep aids in the regulation of immune and endocrine function [2, 3], clears metabolic wastes [4, 5], and supports memory consolidation and maintenance of cognition and vigilance [6–8]. In contrast, poor and disrupted sleep is associated with numerous negative health effects [9], including cardiovascular disease [10–12], diabetes [13, 14], neurologic disease including dementia [15, 16], psychological conditions such as anxiety and depression [17, 18], and increased all-cause mortality risk [19, 20]. Poor quality of sleep, sleep that is reported as irregular in timing, marked by frequent awakenings, or shortened in duration, can therefore contribute to worse health outcomes and poorer global wellbeing [17, 21].

Solid-organ transplant populations are at high risk for poor quality of sleep resulting from chronic illness due to their underlying disease associated with the need for transplant. Regardless of the organ transplanted, patients awaiting transplant and transplant recipients frequently have numerous comorbid conditions (such as obesity or psychological disorders) and experience symptoms (such as dyspnea, itching, pain, and nocturia) that are known to impair quality of sleep [22–26]. These patients are also frequently prescribed medications such as corticosteroids, diuretics, and immunosuppressants, which are known to negatively affect quantity and quality of sleep [27, 28]. Finally, these patients often have underlying sleep disorders, such as sleep apnea or restless legs syndrome, which further impairs quality sleep [29, 30].

Despite a growing body of literature on quality of sleep in solid organ transplant populations, the overarching rate of poor quality of sleep across transplanted groups remains unclear. Given the broad mechanisms used to evaluate sleep, and the variability in the comprehensiveness of quality of sleep measures, the severity and factors associated with poor quality of sleep have not been well characterized. The aim of this Systematic Review was to summarize available literature on the rates of poor quality of sleep among solid organ transplant candidates and recipients.

METHODS

This Systematic Review was performed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Checklist available in supplementary materials, Supp. Table 1) [31]. Specifically, our Population, Intervention, Control, Outcome question was framed as: “What is the available literature on rates of self-perception of poor quality of sleep (O) in patients waitlisted for or who were recipients of (P) a solid organ (heart, lung, kidney, liver, pancreas, or multi-solid organ) transplant (I)?” Given the desired outcome of the review, no control group (C) was required. The rate of poor quality of sleep was defined as the proportion of subjects from each article who were identified as having poor quality of sleep (e.g. poor sleep quality, symptoms of insomnia, sleep disturbance, etc.). Additional information related to this Systematic Review can be found at International Prospective Register of Systematic Reviews registration: CRD42020156678.

Search Strategy

In consultation with a medical librarian, the following literature and abstract databases were searched: PubMed/MEDLINE, Embase, Web of Science, CINHAL, and PsychInfo. Final search was performed on March 31, 2021. We included original articles reporting quality of sleep for at least one time point that included an assessment of (1) sleep timing, quality, quantity, or efficiency (2) subjectively using a standardized sleep-focused questionnaire with a reported cut-off score to indicate poor quality of sleep (or reported rate of poor quality of sleep from a sleep questionnaire) in (3) patients either waitlisted for, or who had previously received a solid organ transplant (heart, lung, kidney, liver, pancreas, or multi-solid organ). We excluded studies focused primarily on sleep disorders, quality of life, and symptom frequency/burden, studies using only qualitative methods to assess sleep, studies using a single-item to assess quality of sleep, studies reporting only objective sleep measures, pediatric studies, non-human studies, non-English publications, review articles, editorials, abstracts, case reports, and case series with ≤10 subjects. Of note, we chose to exclude studies of quality of life and symptom frequency/burden, as although they often include some element of quality of sleep within the chosen questionnaire, the questionnaires generally do not assess multiple dimensions of sleep (e.g. they only include a single sleep item), and do not have standardized cut-off scores to indicate poor quality of sleep. There were no date restrictions placed on the search.

Search Terms

The following medical subject headings and key words were used to perform the search in [title/abstract] for sleep quality (“sleep,” “circadian rhythm,” “chronobiology disorders,” “sleep wake disorders,” “sleep initiation and maintenance disorders,” “insomnia”), solid organ transplant (“organ transplantation,” “lung transplantation,” “lung transplant,” “heart transplantation,” “heart transplant,” “cardiac transplantation,” “cardiac transplant,” “kidney transplantation,” “kidney transplant,” “renal transplantation,” “renal transplant,” “liver transplantation,” “liver transplant,” “hepatic transplantation,” “hepatic transplant,” “pancreas transplantation,” “pancreas transplant”), and adults (“adult”). Full search terms and search structure for each database can be found in supplementary materials (Supp. Table 2). Results from each database were imported into a citation manager (EndNote X8), and all results were then combined and duplicates removed. The final list of articles was imported into Rayyan for review [32].

Study Selection

Two reviewers (M.C. and B.K.) independently screened all titles and abstracts for the following: 1) additional citation duplicates, 2) original articles reporting primary data that were not case reports or case series, 3) human studies in the English language, 4) studies including an adult solid organ transplant population (candidates and/or recipients), and 5) inclusion of an assessment of self-reported quality of sleep. The full text of all potentially relevant citations were reviewed by the two primary reviewers for final inclusion. Disagreements regarding article inclusion/exclusion were resolved by discussion and consensus with a third party (B.R.). Reference lists of included studies were reviewed to identify other potentially eligible articles.

Data Abstraction and Assessment of Bias

Data were extracted from each included article by two reviewers (M.C. and B.K.), and discordant entries were resolved by the third reviewer (B.R.). Relevant data collected included study design, patient population, patient characteristics, sample size, quality of sleep assessment tool, reported cut-off for determining poor quality of sleep, sleep findings, other measures of sleep if available, and factors associated with poor quality of sleep if reported. The same two primary reviewers also assessed the quality of each study using the Lewis, Olds, Williams (LOW) critical appraisal tool [33]. The LOW was chosen over other quality assessment tools since it allows for studies with different methodologies to be evaluated using the same tool. Discrepancies in scoring were discussed among all three reviewers to reach consensus. A meta-analysis was not performed due to the significant methodologic heterogeneity among studies.

RESULTS

Our search strategy identified 2,054 articles, with 1,758 unique citations (Figure). Screening of these citations resulted in 42 articles that met criteria for inclusion in the review. An additional 2 articles were identified through review of the reference lists of included articles. Of the 44 included studies, 29 were cross-sectional [34–62], 3 were observational [63–65], 5 were longitudinal [66–70], 4 were randomized trials [71–74], 1 was a pre-post design [75], 1 was a single-group experimental study [76], and 1 was a secondary analysis (original report of sleep outcomes) [77]. Eleven studies were conducted in the United States [34, 41, 54, 56, 63, 64, 67, 72, 74, 76, 77], 6 each in Turkey [35, 46, 47, 50–52] and China [45, 49, 60–62, 73], 4 each in Iran [38, 39, 69, 71] and Brazil [58, 59, 66, 75], 2 each in Switzerland [40, 44] and Japan [55, 57], and 1 each in Canada [65], Australia [53], Serbia [43], Greece [48], Italy [36], Norway [68], the United Kingdom, Hungary [37], and the Netherlands [70]. Given the high proportion of descriptive study designs, and the wide range of methodologic detail included, the quality of studies included in this systematic review are of low to moderate quality (Supp. Table 3).

Figure.

PRISMA 2020 flow diagram for study selection

From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71

The majority of studies (n=32, 72.7%) assessed subjective quality of sleep using the Pittsburg Sleep Quality Index (PSQI) [34–36, 38–41, 44, 45, 47, 49–51, 54–59, 61, 62, 66, 68–78] (Table 1). Seven studies assessed insomnia symptoms using either the Athens Insomnia Scale [37, 42, 48, 60, 79, 80] ([AIS] n=4), or the Insomnia Severity Index [43, 53, 64, 81] ([ISI], n=3), and 2 studies used both the PSQI and the ISI [46, 52]. Other subjective quality of sleep questionnaires included detailed sleep diaries [67] (n=1), the Basic Nordic Sleep Questionnaire [65, 82] (n=1), and an investigator-developed questionnaires [63] (n=1). All articles that included rates of poor quality of sleep (e.g. poor sleep quality, insomnia, sleep disturbance, etc.) reported it as the proportion of participants who’s total score exceeded a pre-specified cutoff score for their respective questionnaire.

Table 1.

Subjective Quality of Sleep Questionnaires

Assessment Tool	Number of sleep items	Scale	Domains	Higher Score is
Pittsburgh Sleep Quality Index (PSQI) [85]	19	Nine 4-point (0–3) scales, and free responses for sleep parameters, for a total “global” score ranging from 0–21.	Sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, sleep medication use, and daytime dysfunction	Worse
Athens Insomnia Scale (AIS) [86, 87]	8	Items range from 0–3, for a total score ranging from 0–24.	Sleep induction, awakenings during sleep, timing of sleep awakening, sleep duration, sleep quality, well-being, functioning capacity, daytime sleepiness	Worse
Insomnia Severity Index (ISI) [88]	7	Items range from 0–4, for a total score ranging from 0–28.	Sleep induction, maintaining sleep, timing of sleep awakening, sleep satisfactions, noticeability of sleep problems to others, sleep problem distress, sleep problem interference with daytime function	Worse
Basic Nordic Sleep Questionnaire [90]	27	Fourteen 4-point (1–5) scales, and free response for sleep parameters.	Apnea, sleep duration, sleep medication use, daytime sleepiness/napping, snoring	Worse
Sleep diary [73]	Unknown	Diaries completed each morning for 14 days. Investigator-developed diary.	Sleep onset latency, wake time after sleep onset, total sleep time, total wake time, daytime napping	NA
Original questionnaire [67]	55	Not specified	Total sleeping time, sleep latency, nighttime awakenings, daytime functioning, excessive sleepiness, naps, sleep disorders	Unk

Quality of Sleep by Transplant Organ Type

The majority of articles focused on renal transplant populations (n=28, 63.6%), followed by liver (n=9, 20.5%), lung (n=5, 11.4%), and 2 (4.5%) included multiple types of organ transplant (renal, renal/pancreas, pancreas, lung, liver, and heart) patients (Table 2). Most (n=30, 68.2%) articles included only post-transplanted populations, while 6 (13.6%) focused only on waitlisted patients, and 8 (18.2%) included both waitlisted and transplanted populations either as separate cohorts or longitudinally followed pre- to post-transplantation.

Table 2.

Number of articles included by organ transplant type

Population	Total identified	Pre-transplant only	Post-transplant only	Pre- and post-transplant	Pre-to-post-transplantation
Renal	28	3	19	4	2
Lung	5	1	4	0	0
Liver	9	2	5	2*	1*
Multiple organ types included	2	0	2	0	0

^*One study included both pre- and post-, and pre-to-post transplant patients

Kidney

Of the 28 articles that included renal transplant populations, 19 (67.9%) included post-renal transplant patients, 3 (10.7%) included pre-transplant patients, and 6 (20.0%) included patients both pre- and post-transplant (4 as separate populations, and 2 followed patients pre-to-post transplant) (Table 3).

Table 3.

Studies including renal transplant populations.

Study (First Author, year)	Country	Design	Subjects	Mean/Median Time in years from transplantation if applicable	Subjective quality of sleep measure and cut-off to indicate poor quality sleep	Frequency of sleep assessment	Reported sleep constructs	Global/Overall score on chosen quality of sleep scale	Proportion of subjects with reported poor quality of sleep
Pre-transplant only
Córdoba et al., 1998 [63]	USA	Observational	n = 44	NA	Original questionnaire Not specified	Once	Sleep satisfaction	Only reported number of subjects by sleep satisfactory Satisfactory sleep = 61.4% of subjects Unsatisfactory sleep = 38.6% of subjects	38.6%
Gross et al., 2017 [72]	USA	Randomized controlled Trial	n = 55	NA	PSQI >5	3 times	Sleep quality	MBSRa: baseline = 7.4, 8 weeks post-intervention = 7.3, 6 months post-intervention = 8.5. Control: baseline = 6.3, 8 weeks post-intervention = 6.1, 6 months post-intervention = 7.1.	55% at baseline
Gencdal et al., 2019 [50]	Turkey	Cross-sectional	n = 137	NA	PSQI >5	Once	Sleep quality	7.13	63.5%
Post-transplant only
Carpenter et al., 1998 [[34]]	USA	Cross-sectional	n = 56	5.55	PSQI >5	Once	Sleep Quality	Only reported by sex Female = 7.9 Male = 7.3	Not reported
Eryilmaz et al., 2005 [35]	Turkey	Cross-sectional	n = 100	4.2	PSQI >5	Once	Sleep Quality	4.64	30%
Kachuee et al., 2007 [38]	Iran	Cross-sectional	n = 125	Not specified	PSQI >5	Once	Sleep quality	6.45	62%
Pourfarziani et al., 2010 [39]	Iran	Cross-sectional	n = 39	Not specified	PSQI ≥5	Once	Sleep quality	6.5	67%
Burkhalter et al., 2011 [40]	Switzerland	Cross-sectional	n = 135	2	PSQI >5	Once	Sleep quality	Not reported	47.4%
Fornadi et al., 2012 [42]	Hungary	Cross-sectional	n = 100	5.5	AIS ≥10	Once	Insomnia	Not reported	16%
Knezevic et al., 2012 [43]	Serbia	Cross-sectional	n = 30	2.6	ISI Not specified	Once	Insomnia	6.17	46.7%
Silva et al., 2012 [66]	Brazil	Longitudinal	n = 60	0.3	PSQI >5	Twice	Sleep quality	3 months post: 5.4 12 months post: 5.8	3 months post: 36.7% 12 months post: 38.3%
Burkhalter et al., 2013 [44]	Switzerland	Cross-sectional	n = 926	9.42	PSQI >5	Once	Sleep quality	6	49.5%
Pooranfar et al., 2014 [71]	Iran	Randomized controlled trial	n = 44	2–3 years prior	PSQI >5	Twice (baseline and after 10 weeks)	Sleep quality	Only reported by exercise and control groups. Exercise: baseline= 7.21, 10-weeks post exercise = 5.26. Control: baseline = 9.12, 10-week later = 9.89	Not specified
Liu et al., 2015 [45]	China	Cross-sectional	n = 204	3.2	PSQI >7	Once	Sleep quality	5.81	24.5%
Yazla et al., 2015 [46]	Turkey	Cross-sectional	n = 22	Not specified	PSQI ≥5; ISI ≥10	Once	Sleep Quality Insomnia	PSQI = 4.9 ISI = 3.45	Not reported
Kahvecioglu et al., 2016 [47]	Turkey	Cross-sectional	n = 45	>6 months post-transplant	PSQI Not specified	Once	Sleep quality	4	45.5% reported insomnia using PSQI
Liaveri et al., 2017 [48]	Greece	Cross-sectional	n = 67	7.3	AIS ≥6	Once	Insomnia	4.6	28.9%
Xie et al., 2018 [49]	China	Cross-sectional	n = 438	<6 months = 100, 6–12 months = 62, 1–5 years = 144, >5 years = 132	PSQI >5	Once	Sleep quality	5.86	29.2%
Barroso et al., 2019 [75]	Brazil	Quasi-experimental	n = 20	5.8	PSQI >5	Once	Sleep quality	Only reported by exercise group. Exercise = 4.14 Sedentary = 6.6	Not specified
Han et al., 2020 [73]	China	Randomized controlled trial	n = 62	0 (in hospital post-transplant)	PSQI >7	Once	Sleep quality	Only reported by attribution training group. Attribution training = 5.00 Control = 9.65	Not specified
Küçük et al., 2020 [51]	Turkey	Cross-sectional	n = 30	5	PSQI ≥5	Once	Sleep quality	3.86	33.3%
Atas et al., 2021 [52]	Turkey	Cross-sectional	n = 106	7.7	PSQI >5 ISI ≥8	Once	Sleep quality, insomnia	PSQI = 6 ISI = 6.6	PSQI = 48.1% ISI = 37.7%
Pre- and post-transplant included
Sabbatini et al., 2005 [36]	Italy	Cross-sectional	Pre & post n = 301 post n = 90 pre	5.4	PSQI >5	Once	Sleep quality	Pre = 7.93 Post = 6.46	post = 52.5% pre = not reported
Novak et al., 2006 [37]	Hungary	Cross-sectional	Pre & post n = 884 post, n = 183 pre	5.1	AIS ≥10	Once	Insomnia	Pre = 4 Post = 3	Pre = 15% Post = 8%
Rodrigue et al., 2011 [41]	USA	Cross-sectional	Pre & post n = 100 pre n = 100 post	50% within last 2 years	PSQI >5	Once	Sleep quality	Pre = 9.55 Post = 6.84	Pre = 78% Post = 52%
Williams et al., 2016 [67]	USA	Prospective observational	Pre & post n = 25 pre n = 30 post	6.2	Sleep diary SOL or WASO >30 min, a frequency ≥6 times over two weeks, and report significant distress and daytime impairments related to their sleep problem.	Once (one 2-week assessment)	Insomnia	Pre: SOLb = 33.1 min, WASOc = 20.9 min, TSTd = 469.65 min. Post: SOL = 28.5 min, WASO = 20.1 min, TST = 444.91 min.	Insomnia: Pre = 68% Post = 48.3%
Brekke et al., 2017 [68]	Norway	Longitudinal	Pre-to- post n = 110	3.5	PSQI >5	Twice	Sleep quality	Pre = 8.8 Post = 6.6	Pre = 72% Post = 51%
Hasanzamani et al., 2020 [69]	Iran	Longitudinal	Pre-to- post n = 40	within 6 months post-transplant	PSQI >5	3 times	Sleep quality	Pre = 5.2 3 months post = 5.2 6 months post =3.3	Pre = 37.5% 3 months post = 37.5% 6 months post = 20.0%

^aMSBR = mindfulness-based stress reduction

^bSOL = sleep onset latency

^cWASO = wake after sleep onset

^dTST = total sleep time.

Transplant Candidates

Using a cutoff of >5 on the PSQI to indicate poor sleep quality, 5 articles [36, 41, 50, 69, 72] found the rate of poor sleep quality ranged from 37.5% to 78%. Using the cutoff of ≥10 to identify symptoms of insomnia using the AIS, Novak et al [37] found 15% of waitlisted patients had insomnia. Using an investigator-developed questionnaire, Cordoba et al [63] found 38.6% of waitlisted patients to have poor sleep satisfaction. Williams et al [67] used 2-week sleep diaries to identify 68% of waitlisted patients with symptoms of insomnia. Overall, the rate of poor quality of sleep using each article’s cutoff score in waitlisted renal transplant patients was approximately 53.5%.

Transplant Recipients

A total of 11 articles used a PSQI score >5 to determine poor sleep quality, and found the rate of poor sleep quality ranged from 20% to 62% (from a mean of 6 months to 9.42 years post-transplantation) [34–36, 38, 40, 41, 44, 49, 66, 71, 75]. Of articles using a PSQI cutoff of ≥5 to indicate poor sleep quality, rate of poor sleep quality ranged from 33.3% to 67% [39, 51]. Liu et al [45] used a PSQI cutoff score of >7, and found poor sleep quality in 24.5% of patients an average of 3.2 years post-transplantation. Using the cutoff of ≥10 to identify symptoms of insomnia with the AIS, Novak el al [37] and Fornandi et al [42] found 8% and 16% patients an average of 5.3 years post-transplantation to have insomnia, respectively. Liaveri et al [48] used a cutoff score of ≥6 on the AIS, and found 28.9% of patients an average of 7.3 years post-transplantation to have symptoms of insomnia. Only 1 study [43] used the ISI, and found 46.7% of patients to have symptoms of insomnia, however a cut-off score was not specified. Using sleep diaries, Williams et al [67] identify 48.3% of patients an average of 6.2 years post-transplantation to have symptoms of insomnia. Among renal transplant recipients, the overall rate of poor quality of sleep using each article’s cutoff score was approximately 38.9%.

Lung

Of the 5 total articles that included lung transplant populations, 1 (20%) included pre-lung transplant patients, and 4 (80%) included post-transplant patients (Table 4).

Table 4.

Studies including lung transplant populations.

Study (First Author, year)	Country	Design	Transplant Subjects	Mean/Median Time in years from transplantation if applicable	Subjective quality of sleep measure and cut-off to indicate poor quality sleep	Frequency of sleep assessment	Reported sleep constructs	Global/Overall score on chosen quality of sleep scale	Proportion of subjects with reported poor quality of sleep
Pre-transplant only
Tokuno et al., 2020 [55]	Japan	Cross-sectional	n = 193	NA	PSQI >5	Once	Sleep quality	6.8	52.8%
Post-transplant only
Fatigati et al., 2016 [77]	USA	Secondary analysis	n = 75	Within lst year	PSQI >8	4 times	Sleep quality	Baseline = 7.68 2 months post-transplant = 7.00 6 months post-transplant = 7.44 12 months post-transplant = 6.96	Baseline = 40.9% 2 months post-transplant = 32.1% 6 months post-transplant = 37.5% 12 months post-transplant = 32.0%
Menninga et al., 2016 [64]	USA	Observational	n = 81	7.4	ISI >10	Once	Insomnia	Only reported by RLSa groups. No RLS = 6.8 RLS = 12.5	No RLS = 27% RLS = 67%
Yo et al., 2019 [53]	Australia	Cross-sectional	n = 81	0.96	ISI ≥15	Once	Insomnia	9	32%
Sawhney et al., 2020 [54]	USA	Cross-sectional	n = 54	2.95	PSQI >5	Once	Sleep quality	Not reported	74%

^aRLS = restless legs syndrome.

Transplant Candidates

One study [55] used a PSQI score >5 to indicate poor sleep quality, and found 52.8% of waitlisted patients to have poor sleep quality.

Transplant Recipients

Using a cutoff on the PSQI of >5, Sawhney et al [54] found 74% of patients an average of 2.95 years post-transplantation to have poor sleep quality. Fatigati et al [77] followed patients for 1 year post-transplantation, and found the rate of poor sleep quality (using a PSQI cutoff of >8) to be 40.9% immediately post-transplantation, 32.1% at 2 months, 37.5% at 6 months, and 32% at 12-months post-transplantation. Using the ISI, Menninga et al [64] and Yo et al [53] used the cutoffs of >10 and ≥15 to determine the rate of insomnia of approximately 47% (27% and 67% of patients without and with restless legs syndrome respectively) and 32% respectively. Overall, the rate of poor quality of sleep, either reported as poor sleep quality or insomnia, among lung transplant recipients was approximately 46.3%.

Liver

There were 9 articles that included liver transplant populations, 2 (22.2%) included pre-liver transplant patients, 5 (55.6%) included post-transplant patients, and 2 (22.2%) included patients both pre- and post-transplant (1 as separate populations, and 1 followed patients pre-to-post transplant) (Table 5).

Table 5.

Studies including liver transplant populations.

Study (First Author, year)	Country	Design	Transplant Subjects	Mean/Median Time in years from transplantation if applicable	Subjective quality of sleep measure and cut-off to indicate poor quality sleep	Frequency of sleep assessment	Reported sleep constructs	Global/Overall score on chosen quality of sleep scale	Proportion of subjects with reported poor quality of sleep
Pre-transplant only
Marques et al., 2016 [59]	Brazil	Cross-sectional	n = 45	NA	PSQI >5	Once	Sleep quality	6.64	60%
Ni et al., 2020 [62]	China	Cross-sectional	n = 53	NA	PSQI >5	Once	Sleep quality	9.5	59.5%
Post-transplant only
van Ginneken et al., 2010 [70]	Netherlands	Longitudinal	n = 70	6.7	PSQI >5	Once	Sleep quality	6.6	51%
Akahoshi et al., 2014 [57]	Japan	Cross-sectional	n = 59	3.6	PSQI ≥7, and/or ESS ≥10	Once	Sleep Quality	Only reported by good or poor sleeper Good sleeper = 3.7 Poor sleeper = 8.9	64.4%
Mendes et al., 2014 [58]	Brazil	Cross-sectional	n = 45	3.9	PSQI >5	Once	Sleep quality	Only reported for poor sleepers: 7.11	71.1%
Lin et al., 2017 [60]	China	Cross-sectional	n = 285	5	AIS ≥6	Once	Insomnia	5.75	48.4%
Zhu et al., 2020 [61]	China	Cross-sectional	n = 124	<6 months = 32, 6–12 months = 25, 12–36 months = 38, >36 months = 29	PSQI >7	Once	Sleep quality	6.57	40.3%
Pre- and post-transplant included
Rodrigue et al., 2010 [56]	USA	Cross-sectional	Pre & post n = 110 pre n = 95 post	Not specified	PSQI >5	Once	Sleep quality	Pre = 8.94 Post = 9.68	Pre = 73% Post = 77%
Bhat et al., 2015 [65]	Canada	Observational	Pre & post, and pre-to-post n = 83 pre n = 273 post	3.5	Basic Nordic Sleep Questionnaire Not specified	Once or twice (for pre-to-post)	Sleep complaints	Not reported	Unsatisfactory sleep in pre-to-post group: Pre = 39% Post = 35% Sleep disturbances: ETOHa group: pre = 66.7%, post:20.7%; HCVb group: pre = 40%, post = 38.4%; Other group: pre = 33.1%, post = 27.2%

^aETOH = alcoholic

^b= hepatitis C.

Transplant Candidates

There were 3 studies [56, 59, 62] that used a cutoff of >5 on the PSQI to indicate poor sleep quality, and found the rate of poor sleep quality ranged from 59.5% to 73%. Using the Basic Nordic Sleep Questionnaire, Bhat et al [65] reported a rate of sleep disturbance of approximately 46.6%. Overall, the rate of poor quality of sleep, either reported as poor sleep quality or sleep disturbance, was approximately 55.6% among liver transplant candidates.

Transplant Recipients

Three studies [56, 58, 70] used the cutoff for a PSQI score >5 to indicate poor sleep quality, and found that the rate ranged from 51% to 77% (from a mean of 3.9 to 9.42 years post-transplantation). Akahoshi et al [57], and Zhu et al [61] used a PSQI cut-off of ≥7 and >7, and found the rate of poor sleep quality in 64.4%, and 40.3% of post transplanted patients respectively. Lin et al [60] found 48.4% of patients experienced insomnia (AIS ≥6). Using the Basic Nordic Sleep Questionnaire, Bhat et al [65] reported a rate of sleep disturbance of approximately 28.8%. Among liver transplant recipients, the overall rate of poor quality of sleep reported as poor sleep quality, insomnia, or sleep disturbance was approximately 52%.

Studies Including Multiple Solid Organ Transplant Patients

No studies that met inclusion criteria evaluated heart transplant or pancreas transplant patients specifically. There was 1 study [74] that included post-heart transplant patients, and 2 [74, 76] that included post-pancreas transplant patients; however specific rates of poor quality of sleep in those populations were not reported.

A total of 2 articles included more than one solid-organ population [74, 76] (Table 6). Gross et al [76] included post-transplanted renal, renal/pancreas, pancreas, and lung patients, and using the PSQI cutoff of >5, found 80% of patients overall to have poor sleep quality. Another study by Gross et al [74] included post-transplanted renal, renal/pancreas, pancreas, lung, liver, and heart patients, and using the PSQI cutoff of >8, found 42% of patients to have poor sleep quality.

Table 6.

Studies including multiple transplant populations.

Study (First Author, year)	Country	Design	Transplant Subjects	Mean/Median Time in years from transplantation if applicable	Subjective quality of sleep measure and cut-off to indicate poor quality sleep	Frequency of sleep assessment	Reported sleep constructs	Global/Overall score on chosen quality of sleep scale	Proportion of subjects with reported poor quality of sleep
Post-transplant only
Gross et al., 2004 [76]	USA	Experimental longitudinal single-group	n = 20 n = 12 kidney, n = 5 kidney/pancreas, n = 1 pancreas, n = 2 lung	50% within 3 years from transplantation	PSQI >5	Three	Sleep Quality	Baseline = 8.53, Post 8-week mindfulness intervention = 6.89 3 months post-intervention = 6.37	Baseline = 80% Post 8-week mindfulness intervention = 53% 3 months post-intervention = 47%
Gross et al., 2010 [74]	USA	Randomized-controlled trial	n = 137 n = 93 kidney and/or pancreas, n = 23 liver, n = 11 heart, n = 10 lung	6.5	PSQI >8	4 times	Sleep quality	Only reported by randomized condition. Mindfulness intervention group: Baseline = 8.3, post 8-week intervention = 6.0, 6 months post-intervention = 6.7, 1 year post intervention = 6.4 Control group: Baseline = 7.2, post 8-weeks = 6.9, at 6 months = 6.9, at 1 year = 7.8	42% at baseline

Interventions and Associated Factors

Few articles (n=6) evaluated the effect of an intervention on quality of sleep. In 2 studies (N=157 total) evaluating the effect of a Mindfulness-Based Stress Reduction (MBSR) intervention on solid organ transplant recipients (renal, renal/pancreas, pancreas, liver, and lung), overall PSQI scores were significantly reduced (average decrease of 1.97 points) following an 8-week MBSR training program compared to a control group (average decrease of 0.3 points) which was maintained after 12 months (PSQI score: intervention group 6.4; control group 7.8) [74, 76]. However, in a RCT of waitlisted renal transplant patients (n=55), [72] a telephone-adapted 8-week MBSR program did not significantly improve sleep quality (using the PSQI) compared to a telephone support group (Baseline: MBSR 7.4, Control 6.3; at 8-weeks: MBSR 7.3, Control 6.1).

Two studies evaluated the effects of exercise training on sleep quality using the PSQI. A RCT of renal transplant recipients (n=44) [71] evaluated the effect of an exercise training program (three 60–90-minute sessions per week for 10 weeks) on sleep quality compared to a control group. The exercise intervention significantly decreased PSQI scores from 7.21 to 5.26 (27% improvement) and increased self-reported sleep duration (30-minute increase) compared to the control group with no significant changes in sleep quality. Barroso [75] conducted a quasi-experimental study of renal transplant recipients (n=20) comparing sleep quality in those participating in an exercise program to a sedentary group. Patients in the exercise group had lower PSQI scores compared to the sedentary group (4.14 vs 6.6; no baseline measurement). Given the heterogeneity in study methods and sleep quality reporting, synthesizing the overall effect of an exercise training program was not possible. However, participants partaking in either exercise program had overall better reported sleep quality compared to non-exercise groups (overall mean PSQI score: 4.7 in exercise vs 8.25 in sedentary groups).

One study evaluated the effect of [73] attribution training (a cognitive therapy method performed by a trained investigator twice weekly for 4 weeks) in the early postoperative period (first 28 days) on sleep quality in kidney transplant recipients. Post-attribution training improved sleep quality (PSQI= 5) compared to the control group (PSQI= 9.65); however there were no baseline sleep quality measurements.

Several articles investigated risk factors or symptoms associated with poor quality of sleep (Table 7). The most common significantly associated factors with either poor sleep quality or insomnia were anxiety and depression [35–38, 41, 47–49, 53, 55, 58, 61, 63, 68], decreased mental and physical health and quality of life [35, 38, 45, 55, 57, 60, 66, 77], higher body mass index [41, 61, 66], female sex [37, 49, 50, 53, 77], restless legs syndrome [37, 47, 48, 64], and greater comorbidity [37–39, 41, 42, 57]. Some studies found older age to be associated with worse quality of sleep [36, 42, 47, 49], while others found younger age was associated with worse quality of sleep [35, 54]. Two of the 3 studies that investigated factors associated with poor quality of sleep in pre- vs post-transplant populations found that higher quality of sleep (e.g., improved sleep quality, less insomnia symptoms) post-transplantation was associated with concomitant improvements in depression, quality of life, fatigue, and frequency of comorbid conditions [37, 41]. The third study found that poor sleep quality was significantly associated with depressive symptoms; however depressive symptoms were not significantly improved post-transplantation [68].

Table 7.

Risk factors and associated symptoms with poor quality of sleep if reported

Study (First Author, year)	Significantly Associated Risk Factors and Symptoms of Poor Quality of Sleep
Córdoba et al., 1998 [63]	Anxiety Depression
Eryilmaz et al., 2005 [35]	Younger age Less education Depression Decreased quality of life
Sabbatini et al., 2005 [36]	Older age Psychological problems/anxiety
Novak et al., 2006 [37]	Female Depression Lower estimated glomerular filtration rate, serum albumin, hemoglobin Restless leg syndrome Risk for obstructive sleep apnea Higher number of comorbid conditions
Kachuee et al., 2007 [38]	Higher comorbidity Anxiety Worse sexual relationships Pain Lower general mental health Lower physical function
Rodrigue et al., 2010 [56]	Fatigue Hemodialysis Higher body mass index Mood disturbance Decreased quality of life
van Ginneken et al., 2010 [70]	Fatigue
Pourfarziani et al., 2010 [39]	Higher phosphate Longer end-stage renal disease duration Higher comorbidity
Rodrigue et al., 2011 [41]	Pain Unemployment History of alcohol dependency Higher body mass index Higher comorbidity Depression Anxiety Mood disturbance Fatigue
Fornadi et al., 2012 [42]	Higher IL-6 Older age Higher comorbidity
Silva et al., 2012 [66]	Higher body mass index (BMI) Decreased quality of life Higher functional impairment Benzodiazepine/anti-anxiety medication use
Akahoshi et al., 2014 [57]	Lower albumin Higher comorbidity Decreased quality of life
Mendes et al., 2014 [58]	Anxiety
Bhat et al., 2015 [65]	Liver disease from alcohol use (pre-transplant only)
Liu et al., 2015 [45]	Decreased quality of life
Fatigati et al., 2016 [77]	Female Lower mental health
Menninga et al., 2016 [64]	Restless leg syndrome
Kahvecioglu et al., 2016 [47]	Restless leg syndrome Depression Older age
Lin et al., 2017 [60]	Decreased quality of life
Brekke et al., 2017 [68]	Depression
Liaveri et al., 2017 [48]	Poorer emotional well-being Higher frequency of post-traumatic symptoms Depression Restless legs syndrome Pain Higher systolic blood pressure
Xie et al., 2018 [49]	Unemployment Living in the city Female Older age Hypertension Abnormal renal function Depression Longer time since transplantation
Yo et al., 2019 [53]	Female Depression Anxiety
Gencdal et al., 2019 [50]	Female
Zhu et al., 2020 [61]	Shorter duration since transplant Living with others Anxiety Depression Higher BMI
Sawhney et al., 2020 [54]	Younger age
Tokuno et al., 2020 [55]	Anxiety Depression Slower 6-min walking test and distance Higher dyspnea Decreased quality of life
Hasanzamani et al., 2020 [69]	Male

Changes in rates of poor quality of sleep over time and pre- to post-transplantation

Eight studies included both waitlisted and transplanted populations. Of those, 3 longitudinally followed and reported changes in quality of sleep before and after transplantation. In a follow-up study of renal transplant patients formally on dialysis, Brekke et al [68] found the proportion of poor sleep quality using the PSQI (cut-off >5) to be lower approximately 3.5 years post-transplantation (from 72% to 51%). Using the PSQI (cut-off >5), Hasanzamani et al [69] followed renal transplant patients and found the proportion of patients with poor sleep quality decreased from pre-transplant (37.5%) to 6-months post-transplantation (20%). The proportion of patients with poor sleep quality at 3-months post-transplantation was the same pre-transplant. In an observational study of liver transplant patients, Bhat et al [65] found unsatisfactory sleep (using the Basic Nordic Sleep Questionnaire) decreased after transplant (from 39% to 35%).

Only 2 studies longitudinally followed post-transplant patients over time without evaluating a specific intervention. Silva et al [66] found the rate of poor sleep quality (PSQI >5) to be similar at 3 and 12 months post-kidney transplantation (36.7% and 38.3% respectively). Fatigati et al [77] also found a similar rate of poor sleep quality (PSQI >8) at 2 and 12 months post-lung transplantation (32.1% and 32% respectively). Although the cut-off for determining poor sleep quality was higher compared to Silva, Fatigati found that the overall rate of poor sleep quality did decrease in the first 12 months following transplantation (40.9% immediately post-transplantation to 32% at 12 months).

Overall, considering all assessment tools and reported cut-off values, the rate of poor quality of sleep (reported as poor sleep quality, insomnia, sleep disturbance, or sleep dissatisfaction) improved from approximately 54% for pre-transplant waitlisted patients to 43.1% post-transplantation. Mean rate by type of questionnaire used is reported in Table 8. On average, the transplant population with the greatest improvement in quality of sleep from pre- to post-transplantation were renal transplant (from 53.5% pre, to 38.9% post) followed by lung transplant patients (from 52.8% pre, to 46.3% post), while liver transplant patients remained similar pre- to post-transplantation (from 55.6% pre, to 52% post).

Table 8.

Average rate of poor quality of sleep by questionnaire type

	PSQI >5 (n=26) or ≥5 (n=2)	PSQI ≥7 (n=1), >7 (n=2), or >8 (n=2)	AIS ≥6 (n=2) or ≥10 (n=2)	ISI ≥8 (n=1), >10 (n=1), ≥15 (n=1)
Pre-transplant	61.3% (n=9)	None	15% (n=1)	None
Post-transplant	51.3% (n=19)	42.4% (n=5)	31.4% (n=3)	38.9% (n=3)

DISCUSSION

This Systematic Review identified 44 articles assessing self-reported quality of sleep in patients waitlisted for, or who received, a solid organ transplant. These studies varied widely in sample size, quality, methodologic detail included, and type of study design. Included studies demonstrated that the rate of poor quality of sleep ranged from 15% to 78% for waitlisted patients, and 8% to 80% for post-transplanted patients. The wide range of results is likely due to the heterogeneity of populations included, and in particular the variability of questionnaires and cut-off scores used to indicate poor quality of sleep, and variability of timing of assessments either before or following transplantation; all of which limits comparisons across studies. Nonetheless, it was evident that a significant proportion of patients, regardless of transplant timing or organ type, experienced poor quality of sleep in the form of poor sleep quality, insomnia, sleep disturbance, or sleep dissatisfaction.

Normal sleep biology and circadian rhythms are often disrupted by disease pathology (e.g. obesity, diabetes, cardiopulmonary disease, sleep apnea), medications (e.g. corticosteroids, immunosuppressants), and disease-related symptoms (dyspnea, polynocturia, pain, fatigue, restless legs syndrome, etc.) common to transplant populations [22–30, 83]. Patients awaiting solid organ transplant are often worsening in their condition over time with increasing symptom frequency and severity, and are often prescribed multiple medications to manage their condition. They may also experience fear or anxiety related to their condition or unknown transplant time frame, long waitlist durations, feelings of hopelessness, and family or financial hardships, among others [84, 85]. Post-transplantation, patients may experience ongoing debilitation, family or financial hardships, and must take life-long medications to prevent organ rejection [86, 87]. Regardless of timing in the transplant trajectory, any one of these physical and/or psychological stressors can disrupt quality sleep by prolonging sleep onset latency (time it takes to fall asleep), causing awakenings during sleep (e.g. from worry, dyspnea, nocturia, etc.), or by causing early morning terminal awakenings, all of which can shorten overall sleep duration and impair sleep quality [23, 27, 28]. Importantly though, sleep and components of poor health and/or symptoms often have a bi-directional relationship where each can exacerbate, or even contribute, to the other. Meaning that worsening physical and/or psychological health can contribute to worsening quality of sleep, and the worsening quality of sleep may subsequently worsen health and wellbeing.

When globally evaluating rates of poor quality of sleep defined by each article, we found approximately 54% of pre-transplant and 43.1% of post-transplanted patients experienced poor quality of sleep. Although rates of poor quality of sleep were generally lower post-transplantation compared to pre-transplant, the majority of included studies still reported that >40% of patients met criteria for poor quality of sleep per standard cutoffs used by each measurement tool. This trend is consistent with other studies comparing pre- to post-transplant populations whereby symptoms related to their underlying disease (e.g. shortness of breath, fatigue) and overall quality of life generally improve post-transplantation, but are not resolved, and may even persist years after transplantation [37, 88, 89]. This is further supported by 2 studies included in this review that found quality sleep, in addition to depression, quality of life, and fatigue, significantly improved post-transplantation compared to pre-transplant, but were still prevalent overall [37, 90]. However, one study did not find significant improvements in in depressive symptoms even though sleep quality significantly improved post-transplantation [68].

We were unable to comprehensively compare pre- and post-transplant findings by organ type given the large variability in number and quality of studies included for each transplant phase (pre vs post) of each solid organ type. Of note, no included studies focused on just heart or pancreas transplant patients, thus they are underrepresented in this review. On the other hand, renal transplant patients were over-represented (included in 63.6% of articles), as were post-transplanted populations (included in 68.2% of articles). Our findings highlight the need for more systematic and longitudinal evaluations of quality of sleep that include heart and pancreas transplant populations, and include waitlisted patients. Importantly though, given the progressively worsening health status of waitlisted patients, and worse functional status of some transplant groups, such as heart and lung transplant patients, it is necessary to consider appropriate timing and intrusiveness of research methodologies to minimize subject burden.

Among included studies, poor quality of sleep was frequently associated with anxiety and depression, poorer quality of life, restless legs syndrome, and higher comorbidity. Unsurprisingly, concomitant sleep disorders (e.g. restless legs syndrome) and patients in poorer health also experienced worse quality of sleep. Patterns of reported factors associated with poor quality of sleep did not differ in pre- vs post-transplant populations. This is likely, in part, because few studies evaluated factors in pre-transplant populations (n=10), and because of the large heterogeneity in potential factors analyzed. Disruptions in quality of sleep that reduce sleep quality and/or sleep duration have been associated with depressed mood and impaired emotion regulation, which may contribute to anxiety and depressive symptoms [91–93]. Studies that included an assessment of anxiety and depression, quality of life or mood in pre- and/or post-transplant populations found significant associations with the worsening of these factors and worse quality of sleep. This finding is consistent with a wide body of literature examining sleep and psychologic health in patients with chronic disease [17, 18]. For example, symptoms of anxiety and depression have been shown to strongly affect sleep quality among patients with heart failure [94, 95]. Of note, many tools used to assess quality of life, anxiety, and depression concomitantly include items related to sleep, thus correlates with quality of sleep measures are unsurprising in this context. Regardless, given the high rate of poor quality of sleep in combination with frequent physical and psychologic symptoms, regular screenings for quality of sleep are warranted across all phases of transplant.

Few studies included in this review investigated interventions aimed at improving quality of sleep and sleep quality in solid-organ transplant patients. Across 2 studies evaluating MBSR which included multiple types of solid organ transplant populations, Gross et al [74, 76] found sleep quality improved after 8 weeks of MBSR training compared to a control group. A recent meta-analysis found that MBSR training was associated with a significant improvement in sleep quality and mental health [96]. Other recent meta-analysis point to MBSR training as beneficial in the reduction of insomnia symptoms [97, 98]. However, in a third study by Gross et al [72], a RCT of waitlisted renal transplant patients using a telephone-adapted MBSR training program did not result in a significant improvement in sleep quality. It may be that waitlisted patients are continuing to clinically deteriorate prior to transplant, thus are not able to gain the benefit of a MBSR program, whereas post-transplanted patients are often in a recovery and maintenance phase of disease and may benefit most from MBSR training. Overall, MBSR is a promising intervention to improve quality of sleep in solid-organ transplanted patients, though the efficacy across organ types and phase of transplantation deserves further investigation.

Two studies evaluated the effect of an exercise training program on sleep quality [71, 75]. Although they report a significant improvement in sleep quality following exercise training, neither study reported rates of poor sleep quality, and one study [75] did not include pre-intervention sleep measurements. Regardless, their findings are consistent with numerous other studies showing the benefit of exercise on improving quality of sleep and reducing insomnia symptoms [99–101]. One additional RCT of renal transplant recipients investigated attribution training to improve sleep quality. Although attribution training was found to significantly improve sleep quality, interpretation of results is limited as no pre-intervention baseline scores were reported [73]. Overall, few interventions have been investigated to improve sleep quality across the solid organ transplant trajectory. Almost all have only, or largely only, included renal transplant recipients. Given the significant rate of poor quality of sleep in the form of poor sleep quality and insomnia, there is a need for additional rigorous investigation of interventions to improve quality of sleep across all transplanted organ types, and for both waitlisted and transplant recipients.

Limitations

Sleep encompasses an expansive field and may be assessed across a multitude of domains, and in multiple ways. We only included studies using self-reported measures of poor quality of sleep, and excluded studies assessing sleep using quality of life or symptom frequency. As there was great heterogeneity in the reporting of sleep using these tools, and most only include a single-item sleep question, we chose instead to focus on studies that employed an assessment of quality of sleep using a tool that evaluated sleep from multiple dimensions to determine poor quality of reported sleep. We also excluded studies using solely objective measures of sleep such as actigraphy or polysomnography. For this review, we focused on patient’s perception of their sleep. However, objectively measured sleep may provide additional insight into poor quality of sleep that was not captured in this review. Importantly, included studies may not represent the true rate of poor quality of sleep for solid organ transplant patients given the potential bias towards inclusion of subjects who were healthy enough to participate in research. Finally, the variety of instruments and varying quality of studies did not allow for a meta-analysis which may have provided further understanding into the rate of poor quality of sleep across solid-organ transplant populations.

CONCLUSIONS

Although self-report of quality of sleep appears to improve from pre- to post-transplantation, poor quality of sleep in the form of insomnia, sleep disturbance, poor sleep quality, or sleep dissatisfaction remains highly prevalent across all solid-organ transplant populations, both pre- and post-transplant. Given the significant implications of poor quality of sleep on health outcomes, future studies should include a comprehensive measurement tool that captures sleep disrupting indices (such as difficulty falling asleep, or frequent nocturnal awakenings) with more research focusing on how to optimize sleep in solid organ transplant populations throughout all phases of the transplant trajectory.

Highlights.

• Rates of poor quality of sleep remain high among solid organ transplant patients, with more than one third of candidates and recipients reporting poor quality of sleep overall.

• Quality of sleep improved from pre- to post-transplantation, with kidney transplant recipients seeing the greatest improvement, and lung transplant recipients having the least.

• Heart and pancreas transplant patients are underrepresented among included studies investigating rates of quality of sleep, and thus should be a target population in the future.

• Although it is clear poor quality of sleep is a significant problem, and is associated with poor quality of life, psychologic distress, and higher comorbidities; few interventions to improve quality of sleep have been investigated. More evidence regarding interventions to improve quality of sleep among solid organ transplant patients are needed.