Clinical outcomes of exercise in people with pre-dialysis stages of chronic kidney disease: A systematic review with meta-analyses.

doi:10.21203/rs.3.rs-1440606/v1

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Clinical outcomes of exercise in people with pre-dialysis stages of chronic kidney disease: A systematic review with meta-analyses.

https://doi.org/10.21203/rs.3.rs-1440606/v1

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Background Chronic kidney disease (CKD) is a leading cause of death and premature morbidity. Exercise may potentially delay or prevent disease progression. We conducted a systematic review and meta-analysis of the effect of exercise in people with pre-dialysis CKD on functional ability, quality of life, renal parameters, cardiovascular risk factors and inflammatory markers.

Methods We searched 7 major databases from January 2000 to November 2021, using key terms related to pre-dialysis CKD and exercise. Trials comparing the effects of exercise with a control group were pooled. Meta-analyses used a random effects inverse variance model.

Results Twenty-six trials (860 participants) met the inclusion criteria. Significant improvements were identified in peak VO₂ (2.85mL/kg/min, 95%CI:1.31,4.40; p=0.0003); the 6 Minute Walk (54.25m, 95%CI:29.65,78.85; p<0.0001), Timed Up and Go (-0.34, 95%CI:-0.57,-0.12; p=0.003), 2 Minute Step (57.48 steps, 95%CI:27.80,87.16; p=0.0001), and Sit To Stand tests (6.45 repetitions, 95%CI:1.18,11.72; p=0.02)]; Short Form [SF]-36 General Health (5.27, 95%CI:0.25,10.28; p=0.04); SF-36 Physical Component Summary (1.91, 95%CI:0.25,3.57; p=0.02); SF-36 Mental Component Summary (2.40, 95%CI:0.37,4.42; p=0.02)]; and waist circumference (-3.17, 95%CI:-4.44,-1.89; p<0.00001).

Conclusions Exercise improved aerobic capacity, functional ability and quality of life in people with early CKD. Additional evidence is needed to determine if progression towards dialysis can be delayed.

chronic kidney disease

CKD

pre-dialysis

exercise

aerobic capacity

functional ability

quality of life

Chronic kidney disease (CKD), a largely preventable disease, is a significant global health care problem associated with high mortality and morbidity and multiple comorbidities including cardiovascular disease, diabetes and hypertension [1]. CKD poses an economic burden, with costs increasing with disease severity [2], and is predicted to be globally the 5th leading cause of death by 2040 [3].

CKD is defined by a reduction in glomerular filtration rate (eGFR) < 90 mL/min/1.73m² persistent over 3 months; or by chronic signs of kidney damage [4]. There are 5 grades of CKD, with an eGFR < 15 mL/min/1.73m² classified stage 5 or kidney failure. In the early stages of CKD (stages 1–2) symptoms are generally absent, as slightly damaged kidneys generally continue to function well. Over time, people with pre-dialysis CKD progress to stages 3 and 4, with those reaching stage 5 requiring dialysis or kidney transplant to survive [5].

CKD treatment initially aims to modify risk factors, manage comorbidity and delay progression [6, 7]. A recent health economic analysis stated progression from CKD stages 1–2 to stage 3 and then to stages 4–5, was associated with a 1.1-1.7-fold and 1.3-4.2-fold cost increase respectively, with estimated kidney failure treatment costs of GBP20K to > GBP73K per patient [2]. Interventions targeting modifiable risk factors in the pre-dialysis stages of CKD can potentially delay or prevent disease progression and provide considerable economic benefit [6].

Exercise such as aerobic training, strength training, mind-body activities (e.g. Tai Chi), or a combination of modalities, are effective in treating CKD [8], and the inclusion of exercise as a primary prevention measure for pre-dialysis CKD has the capacity to significantly change the disease course [6]. Minimal systematic reviews and meta-analyses [9–12] have been conducted regarding the benefits of exercise on various outcomes in pre-dialysis CKD. With differing study inclusion criteria, analytical methodologies and outcomes assessed, comparison between reviews is limited. Furthermore, several recent relevant publications offer potentially new insight for pooled analyses. The aim of this systematic review and meta-analysis was to provide a comprehensive analysis of randomised controlled trials (RCTs) to determine if exercise in people with pre-dialysis CKD, improved functional ability, quality of life, renal parameters, cardiovascular risk factors and inflammatory markers.

Search strategy

We conducted systematic searches of MEDLINE, PubMed, EMBASE, the Cochrane Library of Controlled Trials, CINAHL, EBSCOhost Health and SPORTDiscus up to 25th August 2021. Search criteria included both MeSH and free text terms related to exercise, physical therapy, CKD, and renal disease. Relevant systematic reviews, meta-analyses and reference lists were reviewed to identify additional studies. One reviewer (AT) conducted the search and full article eligibility was assessed by two reviewers (AT and GD/MP). In the event of disagreement, a third reviewer (NAS) was consulted. The search strategy is detailed in the supplementary information (Supplemental Table S1).

Study selection

The following criteria were applied for study identification and selection (1) randomized, controlled or prospective clinical trials in pre-dialysis CKD; (2) human studies; (3) studies must have included a non-exercise or usual care control group; (4) the exercise intervention period was ≥ 2weeks. Studies of dialysis patients or those including participants with no diagnosis of CKD or < 18 years of age were excluded. The protocol for this analysis was registered with PROSPERO (CRD42017059750).

Intervention

Exercise was defined as any method or combination of methods of structured physical activity such as aerobic exercise, resistance, combined training, and mind-body disciplines such as Tai Chi.

Outcomes

Studies were eligible to be included in the review if they reported on one or more of the following outcome categories: (1) Functional ability assessed by peak VO₂, the six-minute walk test (6MWT), the two-minute step test (2MST), the sit to stand test (STS) (number of repetitions in 30 seconds), the timed up and go test (TUG), and handgrip strength; (2) Quality of life assessed using the short form 36 (SF-36) health related quality of life (HRQOL) questionnaire and variations (e.g., RAND 36-Item SF Health Survey, Kidney Disease Quality of Life SF-36, Health Related Quality of Life SF-36, and the Medical Outcomes Study SF-36 Health Survey); (3) Renal parameters: glomerular filtration rate (eGFR), serum creatinine, serum albumin, urine albumin-to-creatinine ratio (UACR), urine protein-to-creatinine ratio (UPCR), 24-hour urine protein, and blood urea nitrogen (BUN); (4) Cardiovascular risk factors: resting systolic blood pressure (SBP) and diastolic blood pressure (DBP), resting heart rate (RHR), pulse wave velocity (PWV), augmentation index (AIx), lipid studies, blood glucose studies, body composition parameters, and energy intake; (5) Inflammatory markers: interleukin 6 (IL-6) and C-reactive protein (CRP) levels. For meta-analysis, outcomes were only pooled when 2 or more studies provided appropriate data [13].

Data extraction

One reviewer (AT) extracted the data, which was confirmed by a second reviewer (GD/MP). The following details were extracted for each study: author; year of publication; study characteristics (country, study design, sample size); participant characteristics (age, sex, CKD stage); intervention characteristics (modality and delivery, intensity, duration, frequency); and outcomes and outcome assessment methods. Data was extracted using a standardised data extraction form. Study authors were contacted to provide further data or clarification of data when required.

Data synthesis

Statistical analyses were performed using RevMan V5.4 [14]. Meta-analyses were completed for continuous data by using the mean baseline follow-up change and standard deviation (SD). Where the mean change was not reported, this was calculated by subtracting the baseline mean from the final mean at the end of the intervention. When the change SDs were not reported, but exact p values or 95% confidence interval (CI) were provided for within group changes, RevMan enabled calculations of change SDs. Where exact p values or 95% CIs were not provided, SDs were imputed using the Cochrane formula for standard deviation [15] with a correlation coefficient of 0.5, which is considered a conservative value. Where the standard error of the mean (SEM) was given instead of the SD, this value was converted to SD [16]. Data from studies that reported median and interquartile range (IQR 1st and 3rd quarter) was converted to mean and SD using the method described in Wan et al. [17]. We used a random effects inverse variance model with the effect measure of mean difference (MD). Where outcomes were measured using differing protocols, a standard mean difference (SMD) was used. Where data for the same outcomes were reported using different units across studies, all data was converted to the same units prior to data pooling using appropriate conversion factors. Further sensitivity analysis via leave-one out was performed to determine if any studies had a larger impact on results than others. Sub-analyses of exercise modality, intervention duration, intervention frequency, and the level of supervision were performed where appropriate. Exercise modalities analysed included aerobic training; resistance training; combined training of aerobic and resistance; and mind-body exercise training, for example, Tai Chi. Intervention durations analysed include less than or equal to 12 weeks; between 12 weeks and six months; and greater than six months. Levels of supervision are classified as either supervised, meaning each session was supervised through the whole trial; unsupervised, no supervision of sessions throughout the trial; initially supervised for a set number of sessions, and then unsupervised for the remainder of the trial; or a combination of supervised and unsupervised sessions each week throughout the trial.

We judged statistical significance based on a 5% level of significance and reported pooled mean results with 95% CIs. Where a study included multiple intervention groups and a control group, each intervention group was considered separately, and the sample size of the control group was divided by the number of intervention groups to eliminate overinflation of the sample size. If data were reported for multiple time points during the intervention, only relevant data comparing baseline and the end of the intervention were extracted. Where two publications referred to the same study population, and the same outcomes were indicated, only the publication with the highest number of participants was used for that outcome.

Heterogeneity and publication bias

Heterogeneity between included studies was calculated using RevMan V5.4; the I² test was utilized for consistency appraisal between studies. Values < 25% show low risk of heterogeneity, whereas > 75% shows high risk of heterogeneity. Values that fall between 25 and 75% show moderate risk of heterogeneity [16]. These values together with assessment of Egger funnel plots were used to evaluate overall heterogeneity and assess risk of publication bias [18].

Study Quality

Study quality was assessed using the TESTEX; the ‘Tool for the assEssment of Study qualiTy and reporting in EXercise’, designed specifically for use in exercise training studies [19]. This is a 15-point scale that assesses study quality (maximum 5 points) and reporting (maximum 10 points). Two reviewers (AT and GD) independently conducted the quality assessment. A study quality score < 10 was considered low quality. Sub-analyses were conducted by removing low-quality studies from pooled analyses.

We retrieved 2,648 published articles using the defined search criteria and nominated databases. One additional study was identified from reference lists. After removal of duplicates, eligibility screening excluded articles based on title and/or abstract. The remaining 397 articles were reviewed based on eligibility criteria of which 26 were included for analysis. The Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) flow diagram (Fig. 1) details the selection process. Details of excluded studies are supplied in the supplementary information (Supplemental Table S2).

Characteristics

Detailed characteristics of the 17 included RCTs (26 published articles), with a total of 860 participants (443 in exercise groups and 417 in control groups), are provided in Table 1. The mean age of the participants was 59.75yrs (range 44.5–69), with 69.83% male. Ten studies originated from the United States of America, five from Brazil, four from Australia, three from the Republic of China, and one each from, Belgium, Canada, Japan, and the United Kingdom. Most studies included a single exercise intervention group and a control group; with two [20, 21] including a home and centre-based exercise group in addition to the control group, creating a total of 28 intervention groups.

The main causes of CKD reported were hypertensive neuropathy, diabetic nephropathy, polycystic kidney disease and glomerulonephritis [20, 22–25]. Fourteen studies included participants with stages 3–4 CKD, five studies with stages 2–4, three with stage 3 only, two studies each with stages 3–5 (pre-dialysis), one with stages 1–3, and one study did not report stage of CKD (authors confirmed only participants with pre-dialysis CKD were included).

Type of intervention

Detailed intervention characteristics can be found in Supplemental Table S3. Aerobic training was utilised in 13 studies, combined training in 11, resistance in one and mind-body exercise in one. The duration of interventions ranged from three to 18 months. Exercise session frequency ranged from twice to ten times weekly, with the majority (16 studies) being three; and session durations ranging from 10 to 90 minutes. The exercise intervention was supervised in 11 intervention groups, initially supervised then unsupervised in nine, unsupervised in four, and four studies employed a combination of both. Exercise intensity differed between studies, ranging from 50–80% peak VO₂ in aerobic and up to 80% of 1 repetition maximum for resistance training. Eleven studies indicated progressive exercise programming, while six indicated that the exercise intervention was individualised.

Table 1

Characteristics of included studies
Author, date, country, trial	Date of trial	Study Population	Number analysed Exercise/ Control	% Male	Mean Age (years)	Training modality, Frequency, Duration, Intensity	Data Collection (weeks)	Drop Out Ex / C	Data Extracted
Aoike, 2015 ^*1 [36] Brazil	NS	CDK 3–4	29/14	65	55.1	AT, 3/week, 12 weeks, mild to moderate intensity	0, 12	0 0	ALB, BF, RHR
Aoike, 2018 [20] Centre based Brazil	NS	CDK 3–4	13/8	67.5	55.8	AT, 3/week, 24 weeks, moderate intensity	0, 12, 24	3/0	BMI, DBP, eGFR, HbA1c, peak VO₂, SBP, STST, TUG, 2MST, 6MWT, 24HrUP
Aoike, 2018 [20] Home based Brazil	NS	CDK 3–4	12/7	67.5	55.8	AT, 3/week, 24 weeks, moderate intensity	0, 12, 24	2/0	BMI, DBP, eGFR, HbA1c, SBP, peak VO₂, STST, TUG, 2MST, 6MWT, 24HrUP
Barcellos, 2018 [35] Brazil	NS	CDK 2–4	58/51	33	65	CT, 3/week, 16 weeks, moderate intensity	0, 8, 16	24/23	BS, BW, CRP, DBP, eGFR, HDL-C, LDL-C, SBP, STST, TC, TUG, 2MST
Baria, 2014 ^*1 [21] Centre based Brazil	NS	CDK 3–4	10/5	100	52.1	AT, 3/week, 12 weeks, moderate intensity	0, 12	0/0	Hb, LBM, WC
Baria, 2014 ^*1 [21] Home based Brazil	NS	CDK 3–4	8/4	100	52.1	AT, 3/week, 12 weeks, moderate intensity	0, 12	1/1	Hb, LBM, WC,
Beetham, 2018 [31] Australia Landmark Trial 111	2008–2011	CDK 3–4	74/68	42.5	62	CT, 2–3/week, 52 weeks, moderate intensity	0, 26, 52	8/13	BMI, BW, HF, peak VO₂, sCr, TUG, UACR, UPCR, 6MWT,
Castaneda, 2004 [43] USA	NS	CDK 3–4	14/12	65.4	65	RT, 3/week, 12 weeks, moderate intensity	0, 12	0/0	ALB, BMI, BW
Chen, 2010 [47] ROC	NS	CDK 3–4	45/49	78.7	73.2	AT, 3–5/week, 12 weeks, moderate intensity	0, 12	5/1	Hb, TC
Gomes, 2017 ^*1 [37] Brazil	NS	CDK 3–4	24/15	68.75	55.5	AT, 3/week, 24 weeks, moderate intensity	0, 24	6/0	BW, CRP, HF, IL-6, sCr
Greenwood, 2015 [23] UK	NS	CKD 3–4	8/10	83.3	53.5	CT, 3/week, 52 weeks, moderate intensity	0, 26, 52	2/0	BMI, BW, CRP, DBP, eGFR, HDL-C, LDL-C, peak VO₂, PWV, RHR, SBP, sCr, TC, WC
Gregory, 2011 *² [41] USA	NS	CKD 2–4	10/11	NS	55	CT, 3/week, 48 weeks, moderate intensity	0, 24, 48	0/0	HbA1c, sCr
Headley, 2012 [24] USA	NS	CKD 2–4	10/11	NS	55	CT, 3/week, 48 weeks, moderate intensity	0, 24, 48	4/0	BMI, BW, CRP, DBP, eGFR, HDL-C, IL-6, LDL-C, peak VO₂, SBP, TC, TG, WC, 24HrUP
Headley, 2014 [26] USA	NS	CKD 3	25/21	65.2	57.6	AT, 3/week, 16 weeks, moderate intensity	0, 16	3/2	BF, BMI, CRP, DBP, EI, peak VO₂, PWV, SBP, WC
Headley, 2017 *³ [46] USA	NS	CKD 3	25/21	65.2	57.6	AT, 3/week, 16 weeks, moderate intensity	0, 16	3/2	RHR
Hiraki, 2017 [25] Japan	2011–2014	CKD 3–4	14/14	100	68.7	CT, 7/week, 52 weeks, moderate intensity	0, 52	4/4	eGFR, HF, UPCR
Howden, 2013 *⁴ [38] Australia Landmark Trial 111	2008–2011	CKD 3–4	36/36	62.5	61.1	CT, 2–3/week, 52 weeks, moderate intensity	0, 52	5/6	AIx, ALB, eGFR, HbA1c, HDL-C, LDL-C, PWV, TC, TG
Howden, 2015 *⁴ [49] Australia Landmark Trial 111	2008–2011	CKD 3–4	32/35	62.5	61.1	CT, 2–3/week, 52 weeks, moderate intensity	0, 26, 52	9/7	CRP, Hb
Huppertz, 2020 *⁴ [45] Australia Landmark Trial 111	2008 - 2011	CKD 3–4	56/57	48	60.4	CT, 2–3/week, 52 weeks, moderate intensity	0, 52	25/23	DBP, RHR, SBP
Kirkman, 2019 [44] USA	2013–2018	CKD 3–5	15/16	71	58	AT, 3/week, 12 weeks, moderate intensity	0, 12	4/1	AIx, DBP, eGFR, peak VO₂, PWV, RHR, SBP
Leehey, 2009 [32] USA	NS	CKD 2–4	7/4	100	66	AT, 3/week, 24 weeks, moderate intensity	0, 6, 24	0/2	BUN, BW, CRP, DBP, eGFR, EI, Hb, HbA1c, HDL-C, LDL-C, peak VO₂, RHR, SBP, sCr, TC, TG, UACR, UPCR, 24HrUP
Leehey, 2016 [27] USA	NS	CKD 2–4	14/18	100	66	CT, 3/week, 52 weeks, moderate intensity	0, 12, 52	4/0	BF, BMI, CRP, eGFR, HbA1c, HDL-C, LBM, LDL-C, peak VO₂, SBP, SF-36, TC, TG, TUG, UACR, UPCR, 6MWT
Miele, 2017 *³ [39] USA	NS	CKD 3	25/21	65.2	57.6	AT, 3/week, 16 weeks, moderate intensity	0, 16	3/2	eGFR, HDL-C, LDL-C, TC, TG
Mustata, 2011 [28] Canada	NS	CKD 3–5	10/10	65	68.3	AT, 2–5/week, 52 weeks, moderate intensity	0, 52	2/0	AIx, peak VO₂, SF-36
Rossi, 2014 [33] USA	NS	CKD 3–4	48/46	52.3	68.4	CT, 2/week, 12 weeks, moderate intensity	0, 12	11/2	SF-36, 6MWT
Shi, 2014 [40] ROC	NS	CKD	11/10	71.4	69	Tai Chi, 3–5/week, 12 weeks, moderate intensity	0, 12	0/0	BUN, DBP, eGFR, HDL-C, LDL-C, RHR, SBP, sCr, TC, TG
Tang, 2017 [34] ROC	2015–2016	CKD 1–3	42/42	60.7	45.1	AT, ≥ 3/week, 12 weeks, moderate intensity	0, 12	3/3	SF-36, 6MWT
Van Craenenbroeck, 2015 [29] Belgium	2012–2014	CKD 3–4	19/21	55	53.2	AT, 4/day, 12 weeks, moderate to high intensity	0, 12	6/2	AIx, BMI, BW, CRP, eGFR, HDL-C, LDL-C, peak VO₂, PWV, RHR, SF-36, TC, WC

*¹ – same study as Aoike 2018

*² – same study as Headley 2012

*³ – same study as Headley 2014

*⁴ – same study as Beetham 2018

Landmark 111 Trial - Longitudinal Assessment of Numerous Discrete Modifications of Atherosclerotic Risk in Kidney Disease

ALB = Albumin; AIx = Augmentation Index %; AT = Aerobic Training; BF = Body Fat %; BMI = Body Mass Index; BS = Blood Sugar; BUN = Blood Urea Nitrogen; BW = Body Weight; C = Control group; CKD = Chronic Kidney Disease; CRP = C-Reactive Protein; CT = Combined Training; DBP = Diastolic Blood Pressure; eGFR = Estimated Glomerular Filtration Rate; EI = Energy Intake, Ex = Exercise group; Hb = Haemoglobin, HbA1c = Haemoglobin A1; HDL-C = High Density Lipoprotein Cholesterol; HF = Handgrip Force, IL-6 = Interleukin-6, LBM = Lean Body Mass; LDL-C = Low Density Lipoprotein Cholesterol; NS = not stated; peak VO₂ = Oxygen uptake during peak exercise; PWV = Aortic Pulse Wave Velocity; RHR = Resting Heart Rate; ROC = Republic of China; sCr = Serum Creatinine; SBP = Systolic Blood Pressure; SF-36 = Short Form 36 health questionnaire; STST = Sit To Stand Test; TC = Total Cholesterol; TG = Triglyceride; TUG = Timed Up and Go Test; UACR = Urine Albumin to Creatinine Ratio; UPCR = Urine Protein to Creatinine Ratio; UK = United Kingdom; USA = United States of America; WC = Waist circumference; 2MST = Two-Minute Step Test; 6MWT = Six-Minute Walk Test; 24HrUP = 24 Hour Urine Protein

Outcomes

A summary of all meta-analyses is provided in Table 2. Further results, including sub analyses, are available in the supplementary information (Supplemental Table S4).

Table 2

Summary of meta-analyses: Functional Ability, Quality of Life, Renal Parameters, Cardiovascular Risk Factors, and Inflammatory Markers.
Outcome	Number of Studies (intervention groups)	Participants Exercise/Control	Result: MD/SMD (95%CI), p, I²
Functional Ability
Peak VO₂ [ml/kg/min]
	10 (11)	207/194	MD 2.85 (1.31, 4.40), p = 0.0003, I² = 68%
Six-Minute Walk Test (6MWT) [metres]
	5 (6)	203/189	MD 54.25 (29.65, 78.85), p < 0.0001, I² = 58%
Timed Up and Go Test (TUG) [minutes]
	4 (5)	168/144	SMD − 0.34 (-0.57, -0.12), p = 0.003, I² = 0%
Two-Minute Step Test (2MST) [steps]
	2 (3)	80/59	MD 57.48 (27.80, 87.16), p = 0.0001, I² = 76%
Sit To Stand Test (STS) [repetitions]
	2 (3)	80/59	MD 6.45 (1.18, 11.72), p = 0.02, I² = 87%
Handgrip Strength [kg]
	3	112/97	MD 0.03 (-2.03, 2.10), p = 0.98, I² = 0%
Quality of Life (QoL) Short Form 36
General Health (GH)
	4	99/94	MD 5.27 (0.25, 10.28), p = 0.04, I² = 19%
	4	99/94	SMD 0.38 (0.09, 0.67), p = 0.009, I² = 0%
Physical Component Summary (PCS)
	3	66/70	MD 1.91 (0.25, 3.57), p = 0.02, I² = 0%
	3	66/70	SMD 0.38 (0.04, 0.72), p = 0.03, I² = 0%
Mental Component Summary (MCS)
	3	66/70	MD 2.40 (0.37, 4.42), p = 0.02, I² = 0%
	3	66/70	SMD 0.32 (-0.06, 0.71), p = 0.1, I² = 15%
Renal Parameters
Glomerular Filtration Rate (eGFR) [ml/min/1.73m²]
	12 (13)	242/225	MD 0.47 (-1.18, 2.11), p = 0.58, I² = 0%
Serum Creatinine (sCr) [mg/dL]
	10	213/195	MD -0.73 (-2.35, 0.90), p = 0.38, I² = 0%
Serum Albumin (ALB) [g/dL]
	3	64/63	MD 0.01 (-0.29, 0.31), p = 0.95, I² = 89%
Urine Albumin-to-Creatinine Ratio (UACR) [mg/g]
	3	95/90	MD -0.00 (-6.51, 6.51), p = 1.0, I² = 0%
Urine Protein-to-Creatinine Ratio (UPCR) [mg/g]
	4	109/104	MD -0.44 (-9.81, 8.93), p = 0.93, I² = 0%
24-hour Urine Protein [g/24hr]
	3 (4)	42/30	MD 0.09 (-0.55, 0.73), p = 0.79, I² = 0%
Blood Urea Nitrogen (BUN) [mg/dL]
	2	18/14	MD -4.67 (-11.61, 2.27), p = 0.19, I² = 0%
Cardiovascular Risk Factors
Blood Pressure
Systolic Blood Pressure (SBP) [mmHg]
	10 (11)	229/211	MD -3.37 (-7.68, 0.95), p = 0.13, I² = 33%
Diastolic Blood Pressure (DBP) [mmHg]
	9 (10)	215/193	MD -2.22 (-5.47, 1.03), p = 0.18, I² = 44%
Resting Heat Rate (RHR) [beats/min]
	8	155/154	MD -0.51 (-3.34, 2.32), p = 0.72, I² = 0%
Endothelial Function
Pulse Wave Velocity (PWV) aortic [m/s]
	5	103/104	MD 0.05 (-0.77, 0.87), p = 0.90, I² = 57%
Augmentation Index (AIx) central arterial [%]
	4	80/83	MD 2.01 (-1.32, 5.34), p = 0.24, I² = 6%
Lipids and blood parameters
Total Cholesterol (TC) [mg/dL]
	10	233/229	MD 6.19 (-5.35, 17.73), p = 0.29, I² = 65%
Low Density Lipoprotein (LDL-C) [mg/dL]
	9	186/178	MD 9.79 (0.90, 18.68), p = 0.03, I² = 47%
High Density Lipoprotein (HDL-C) [mg/dL]
	9	187/181	MD 0.77 (-1.09, 2.63), p = 0.42, I² = 0%
Triglyceride (TG) [mg/dL]
	6	103/100	MD -3.31 (-19.07, 12.44), p = 0.68, I² = 0%
Glycosylated Haemoglobin (HbA1c) [%]
	5 (6)	87/76	MD -0.41 (-0.88, 0.06), p = 0.09, I² = 16%
Blood Glucose (BG) [mg/dL]
	2	103/98	MD -3.26 (-16.23, 9.72), p = 0.62, I² = 51%
Haemoglobin (Hb) [g/dL]
	4 (5)	106/98	MD 0.24 (-0.03, 0.51), p = 0.09, I² = 0%
Body composition parameters
Body Weight [kg]
	7	195/170	MD -0.46 (-4.12, 3.19), p = 0.80, I² = 83%
Body Mass Index (BMI) [kg/m²]
	8 (9)	189/176	MD -0.55 (-1.67, 0.57), p = 0.34, I² = 76%
Body Fat [%]
	3	53/54	MD -0.80 (-3.95, 2.35), p = 0.62, I² = 0%
Lean Body Mass (LBM) [kg]
	2 (3)	32/27	MD 0.48 (-0.59, 1.55), p = 0.38, I² = 69%
Waist Circumference [cm]
	4 (5)	72/66	MD -3.17 (-4.44, -1.89), p < 0.00001, I² = 0%
Energy Intake [kcal/day]
	2	31/25	MD 46.54 (-292.12, 385.19), p = 0.79, I² = 1%
Inflammatory markers
Interleukin-6 (IL-6) [pg/mL]
	2	34/26	MD -0.96 (-2.16, 0.23), p = 0.11, I² = 0%
C-Reactive Protein (CRP) [mg/L]
	9	199/183	MD -0.13 (-0.96, 0.70), p = 0.75, I² = 17%
I² =percentage of variation across studies due to heterogeneity; MD = mean difference; SMD = standard mean difference

Functional ability

A range of outcomes were used to assess functional ability with all except one showing significance in favour of exercise.

Aerobic capacity

Peak VO ₂ was reported in 10 studies (11 intervention groups, 401 participants)[20, 23, 24, 26–32]. Pooled analysis showed a significant improvement in the intervention (exercise) compared to the control groups (MD 2.85mL/kg/min, 95% CI 1.31 to 4.40; p = 0.0003) (Fig. 2A). Sub-analyses removing low-quality studies from pooled analyses was also significant (Supplemental Figure S1A). Sub-analyses by exercise modality showed significant improvements for both aerobic and combined training intervention compared to control. Sub-analyses by intervention duration showed significant improvement for the intervention when duration was less than 12 weeks and greater than 6 months compared to the control, with no significance shown for between 12 weeks and 6 months. Sub-analyses by supervision of intervention showed significance for studies using supervised and a combination of regular supervised and unsupervised sessions. Sub-analyses by frequency of intervention showed significance for 3 sessions/week in the intervention group (Supplemental Table S4).

The Six-Minute Walk Test (6MWT) was used in five studies (6 intervention groups, 392 participants)[20, 27, 31, 33, 34] (MD 54.25m, 95% CI 29.65 to 78.85; p < 0.0001) (Fig. 2B). Sub-analyses removing low-quality studies from pooled analyses was also significant (Supplemental Figure S1B). Further sub-analyses showed significant improvements with aerobic and combined training; all durations; and the supervised, and initially supervised then unsupervised intervention subgroups (Supplemental Table S4).

Other measures of functional ability

Significant improvements were seen in the pooled analyses of the Timed Up and Go Test (TUG) (four studies, 5 intervention groups, 312 participants)[20, 27, 31, 35] (SMD − 0.34, 95% CI -0.57 to -0.12; p = 0.003) (Fig. 2C); the Two-Minute Step Test (2MST) (two studies, 3 intervention groups, 139 participants)[35, 36] (MD 57.48 steps, 95% CI 27.80 to 87.16; p = 0.0001) (Fig. 2D); and the 30-second Sit to Stand Test (STS) (two studies, 3 intervention groups, 139 participants)[35, 36] (MD 6.45 repetitions, 95% CI 1.18 to 11.72; p = 0.02) (Fig. 2E). Neither TUG, 2MST, nor STS remained significant with low quality studies removed. Further sub-analyses showed significant improvements when aerobic and combined training was used at a duration > 12 weeks to ≤ 6 months with supervision (Supplemental Table S4). Handgrip Strength, (three studies, 209 participants)[25, 31, 37] was not significantly different between intervention and control (Supplemental Figure S6).

Quality of life

Included studies used comparable versions of the short form (SF)-36 questionnaire; two used the Kidney Disease Quality of Life SF-36 [29, 34], two the Health Related Quality of Life SF-36 [26, 28], one the Medical Outcomes Study SF-36 Health Survey [27], and one the RAND 36-Item SF Health Survey [33]. Analysis was completed using both mean difference (MD) and standardized mean difference (SMD). Four studies (193 participants)[26, 28, 29, 33] provided sufficient data for analysis of SF-36 General Health (GH) (MD 5.27, 95% CI 0.25 to 10.28; p = 0.04) (Fig. 3A). Three studies (136 participants)[27, 28, 34] were used for both SF-36 Physical Component Summary (PCS) (MD 1.91, 95% CI 0.25 to 3.57; p = 0.02) (Fig. 3B) and Mental Component Summary (MCS) (MD 2.40, 95% CI 0.37 to 4.42; p = 0.02) (Fig. 3C). MD analyses showed significant improvements for GH, PCS and MCS; however, with SMD only GH (SMD 0.38, 95% CI 0.09 to 0.67; p = 0.009) and PCS (SMD 0.38, 95% CI 0.04 to 0.72; p = 0.03) remained statistically significant (Table 2). Sub-analyses removing low-quality studies from pooled analyses were not significantly different between intervention and control for GH, PCS and MCS; however, both PCS and MCS analyses then contained only two studies each (Supplemental Figures S2A-C). Sub-analyses of GH showed significance for supervised subgroups; PCS and MCS showed significance for the aerobic training subgroups (Supplemental Table S4).

Renal parameters

Glomerular Filtration Rate (eGFR) (12 studies, 13 intervention groups, 467 participants)[20, 23, 39, 40, 24, 25, 27, 29, 30, 32, 35, 38] did not improve with exercise (Supplemental Figure S7A). Sub-analyses removing low-quality studies from pooled analyses indicated no change (Supplemental Figure S3A), as did sub-analyses for modality, duration, and supervision (Supplemental Table S4). Serum Creatinine (6 studies, 251 participants)[23, 31, 32, 37, 40, 41]; Serum Albumin (3 studies, 127 participants)[38, 42, 43]; Urine Albumin-to-Creatinine (UACR) (3 studies, 185 participants)[27, 31, 32]; Urine Protein-to-Creatinine ratio (UPCR) (4 studies, 213 participants)[25, 27, 31, 32]; 24-hour Urine Protein (3 studies, 4 intervention groups, 72 participants)[20, 24, 32]; and Blood Urea Nitrogen (BUN) (2 studies, 32 participants)[32, 40] all recorded no significant difference between intervention and control groups (Supplemental Figures S7B-S7G, Table S4). Sub-analyses removing low-quality studies from pooled analyses did not improve renal parameters (Supplemental Figures S3B-S3E) (note - no supplemental figure for BUN as both studies were low-quality).

Cardiovascular risk factors

Numerous outcomes related to cardiovascular risk were analysed. Resting Systolic (SBP) (10 studies, 11 interventions groups, 440 participants)[20, 23, 24, 26, 27, 32, 35, 40, 44, 45] and Diastolic (DBP) Blood Pressure (9 studies, 10 intervention groups, 408 participants)[20, 23, 24, 26, 30, 32, 35, 40, 45] did not change significantly (Supplemental Figures S8A & S8B). Sub-analyses removing low-quality studies from pooled analyses continued to show no significance (Supplemental Figures S4A & S4B). Sub-analysis of DBP by exercise modality showed a significant improvement for aerobic training (Supplemental Table S4). Resting Heart Rate (RHR) analysis (8 studies, 309 participants)[23, 29, 32, 36, 40, 44–46] and sub-analyses showed no significance (Supplemental Figures S8C & S4C, Table S4). Endothelial function was assessed via Pulse Wave Velocity (PWV) (5 studies, 207 participants)[23, 26, 29, 38, 44] and the aortic Augmentation Index (AIx) (4 studies, 163 participants)[28, 29, 38, 44] with analysis and sub-analyses of both revealing no significant results (Supplemental Figures S8D & S8E, Table S4).

Lipid Studies Exercise failed to demonstrate any statistically significant improvement in: Total Cholesterol (TC) (10 studies, 462 participants)[23, 24, 27, 29, 35, 38–40, 47, 48]; Low Density Lipoprotein (LDL-C) (9 studies, 364 participants)[23, 24, 27, 29, 32, 35, 38–40]; High Density Lipoprotein (HDL-C) (9 studies, 368 participants)[23, 24, 27, 29, 32, 35, 38–40] and Triglyceride (TG) (6 studies, 203 participants)[24, 27, 32, 38–40] (Supplemental Figures S8F-S8I). Sub-analyses removing low-quality studies from pooled analyses continued to show no significance (Supplemental Figures S4D-S4G).

Glycosylated Haemoglobin (HbA1c) (5 studies, 6 intervention groups, 163 participants)[20, 27, 32, 38, 41] and Blood Glucose (BG) (2 studies, 210 participants)[35, 47] demonstrated no statistically significant improvement from exercise compared to control (Supplemental Figure S8J & S8K); however, when low quality studies were removed a significant improvement with exercise was noted for HbA1c (MD -0.52%, 95% CI -0.94 to -0.10; p = 0.02) (Supplemental Figure S4H & S4I). Haemoglobin (4 studies, 5 intervention groups, 204 participants)[21, 32, 47, 49] analysis and sub-analyses removing low-quality studies from pooled analyses showed no significance (Supplemental Figures S8L & S4J).

Body Composition Parameters – Waist Circumference (4 studies, 5 intervention groups, 138 participants)[21, 23, 24, 38] showed a significant improvement (MD -3.17cm, 95% CI − 4.44 to -1.89; p < 0.00001) (Fig. 4); and this remained significant when low-quality studies were removed (Supplemental Figure S4K). Body Weight (7 studies, 365 participants)[23, 24, 31, 32, 35, 37, 43]; Body Mass Index (BMI) (8 studies, 9 intervention groups, 365 participants)[20, 23, 24, 26, 27, 29, 31, 43]; Body Fat (3 studies, 107 participants)[26, 27, 42]; Lean Body Mass (2 studies, 3 intervention groups, 59 participants)[21, 27] and Energy Intake (2 studies, 56 participants)[26, 32] all showed no significant change (Supplemental Figures S8M-S8Q), including when low-quality studies were removed (Supplemental Figures S4L-S4O) (note - no supplemental figure for Body Fat as all studies were high-quality).

Inflammatory Markers

Interleukin-6 (IL-6) (2 studies, 60 participants)[24, 37] and C-Reactive Protein (CRP) (9 studies, 382 participants)[23, 24, 26, 27, 29, 32, 35, 37, 49] recorded no significant results (Supplemental Figure S9A & S9B) including when low-quality studies were removed (Supplemental Figures S5A) (note - no supplemental figure for IL-6 as both studies were low-quality).

Sensitivity analysis

A significant improvement for BMI and body weight were noted upon exclusion of the Castaneda [43] study, as were haemoglobin when Howden et al. [49], and HbA1c when Gregory et al. [41] and Leehey et al. [27] were removed.

Heterogeneity and publication bias

Examination of I² values showed low to moderate heterogeneity across the majority of outcomes. Two functional ability tests (2MST and STS), as well as body weight and BMI demonstrated high heterogeneity. Egger funnel plots showed little evidence of publication bias except for 6MWT, 2MST and STS (Supplemental Figures S10-S14).

Study quality

Median TESTEX score was 10 out of 15. Blinding of assessors (6/26 studies), intention to treat (2/26 studies) and monitoring activity of the control group (3/26 studies) were the items not performed in at least 50% of studies (Supplemental Table S5). Six studies achieved a TESTEX score of less than 10/15 (Supplemental Table S5).

Exercise is not routinely recommended in the standard care of people with pre-dialysis CKD. The reasons for this are likely multifactorial including a general failure to realise the potential benefits of exercise, and difficulty obtaining funding to facilitate regular exercise, despite evidence of cost benefit [50]. This review offers the most wide-ranging meta-analyses of outcomes performed to date, with previously unreported outcomes of functional abilities including the two-minute step test (2MST), the sit to stand test (STS) and handgrip strength, as well as the physical and mental component summaries of quality-of-life questionnaires. This systematic review and meta-analyses demonstrate that exercise significantly improved functional ability (peak VO₂, 6MWT, TUG, 2MST, STS), quality of life, and waist circumference for people with pre-dialysis CKD.

Aerobic capacity has been shown to decrease gradually with increasing CKD severity [51] and is commonly measured as peak oxygen intake (peak VO2) [52] or estimated using 6MWT [53], with these tests also being predictors of all-cause-mortality and endurance [54, 55]. Our peak VO₂ analysis showed a significant improvement in the exercise when compared to the control group, similar to previous reviews [10, 56]. Our sub-analysis of exercise modality, whilst showing significant improvements in both aerobic and combined training, indicated that aerobic training exhibited a greater effect size compared to combined training. Sub-analysis of intervention duration showed that exercising over a period of six months brought the greatest gain in aerobic capacity, and a period of less than 12 weeks also increased capacity. There may be a plateau effect that is reached after beginning exercise; non-adherence over longer time periods may explain this; but a plateau could also be influenced by the absence of progressively increasing intensity or volume of exercise over time. Our sub-analyses of supervised intervention indicated either fully supervised or a combination of supervised and unsupervised exercise sessions brought the greatest changes; and starting participants with supervised training and then changing to no supervision, failed to yield significant changes at trial completion.

Our 6MWT results showed a significant improvement similar to previous reviews [10, 12]. The size of the change is above the minimum clinically important difference shown in heart failure patients, who would have similar levels of physical deconditioning to pre-dialysis patients [57]. Sub-analyses also indicated significance for supervised sessions, aerobic and combined training, duration less than 12 weeks, between 12 weeks and 6 months and, > 6 months. Our results are clinically notable as the inclusion of regular exercise for people with pre-dialysis CKD has the potential to reduce disease progression [56] and mortality risk [58] as well as increase functional ability.

Functional ability is a key measure of a person’s ability to manage everyday tasks, with reduced ability leading to a decline in quality of life and increased mortality [55]. Exercise tests mimicking regular daily movements are useful in determining functional ability. Besides the significant result of the 6MWT, results of the TUG, STS and 2MST also showed significant improvement, though heterogeneity was high for STS and 2MST likely due to low number of trials involved. We believe this to be the first review to report STS and 2MST, and previously only one other review [10] has reported TUG. Sub-analyses of STS and 2MST showed significance for each exercise modality and indicated a greater improvement in TUG with combined training compared to aerobic. These results indicate that incorporating regular exercise may enable people with pre-dialysis CKD to be functionally independent at home.

A co-relationship between reduced functional ability and poor health related quality of life (QoL) has been noted in people with pre-dialysis CKD [59]. Of the six trials reviewed investigating QoL, all used a comparable version of the short form (SF)-36 questionnaire. This is the first review to perform an RCT-only meta-analysis of the physical (PCS) and mental component summary (MCS) in people with pre-dialysis CKD compared to usual care. As different QoL questionnaires were used across included studies and to ensure robustness, analysis via MD and SMD was performed. Our analyses showed a significant improvement in the MD for PCS, MCS and the GH sections of the SF-36, and in the SMD for PCS and GH. This contradicts a previous review [9] of a within-group analysis on MCS and PCS; and also a meta-analysis [60] of observational studies; however, these authors noted MCS improved more than PCS, implying that decreased physical ability raised the risk for low QoL. Another study [61] which compared QoL in people with CKD versus those with hypertension and also found exercise has a positive impact on QoL.

Renal parameters of glomerular filtration rate (eGFR), serum creatinine and albumin, urine albumin- and urine protein-to-creatinine ratio, 24-hour urine protein and blood urea nitrogen revealed no clear benefit from regular exercise for people with pre-dialysis CKD. These results are similar to other reviews [11, 12] and yet contrary to others [56, 62]. These discrepancies may be attributed to styles of review, with some previous reviews including control groups that were not usual care, and some using the same trial data more than once within the review, hence increasing participant numbers and distorting results.

Our results showed no significant improvement from exercise in any cardiovascular risk outcomes except for waist circumference, which concurs with other studies [56, 63]. In contrast, one review [11] reported a significant decrease in SBP and DBP. Upon review, it is noted that participant numbers were included more than once for some outcomes in this review [11] which may have led to an overestimation of the training effect. A significant decrease of DBP via aerobic training was noted in our sub-analysis. In general, a trend towards an improvement was noted for systolic and diastolic blood pressure, resting heart rate, pulse wave velocity, and augmentation index. The effect of both blood pressure and other cardiac medications (e.g., statins) needs to be considered, as a high proportion of participants are medicated which may abrogate the change in blood pressure and heart rate that would normally be expected from adding an exercise routine [64]. Available publication data did not allow for further analysis with consideration of these factors.

Our analysis of C-reactive protein (CRP) and interleukin-6 (IL-6) levels demonstrated a trend for improvement following exercise intervention. With higher levels of CRP and IL-6 known to be a risk to both the cardiovascular and renal systems, these findings enhance those of a previous review [12] with an additional 6 studies included, and encourage the ongoing study of change in inflammatory markers with exercise.

We believe this to be the most comprehensive systematic review of exercise as a part of the management for pre-dialysis CKD to date and we found minimal evidence of publication bias. However, we recognise some limitations, including the small number of eligible studies for some outcomes, and the variability in terms of interventions and participants. As a result, data analysis has been limited by these factors. The exercise-based programmes varied between studies with respect to exercise intensity, duration, frequency, and modality. Accuracy in recording of intensity achieved by participants per session, and of home exercise regularity is unknown. Medication use and change during or after trial was inadequately reported. A comparison of each outcome’s pooled data to previously determined minimal clinically important differences (MCID) would be useful to determine if our statistically significant findings are in fact clinically significant [65]; however, there is a paucity of MCID values of outcomes in people at the pre-dialysis stage available currently. Comparison of MCID would also require meta-regression, which was not possible due to limited included study numbers. Future research to determine MCID values, and further randomized controlled trials of greater participant numbers, longer duration and with increased reporting details and accuracy may provide further evidence in this field.

Our review offers the most wide-ranging meta-analysis of outcomes performed to date, and our results indicate that regular exercise improves aerobic capacity, functional ability, quality of life and waist circumference in people with pre-dialysis CKD. As improvements in these outcomes may also lead to a delay of disease progression, regular exercise therapy is likely to be beneficial.

Acknowledgements

None declared.

Author contributions

All authors contributed significantly to the submitted work. NAS was the team leader, who contributed to the initial idea conception and assisted with writing and editing. GD assisted with study inclusion/exclusion, data extraction and analysis, study quality assessment, and writing and editing of both the main text and supplementary information. MJP assisted with data extraction and analysis, sub analyses and manuscript writing. AT contributed to conceptualisation, conducted the searches, data extraction and analysis, sub analyses, study quality assessment and manuscript writing.

Availability of data and materials

The data generated or analysed during this review are included in this published article and its supplementary information files.

Disclosures

The authors report no disclosures or competing interests.

Funding

This study was partially funded by the UNE School of Science and Technology Higher Degree Research allocation.

Ethics approval

Not applicable.

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No competing interests reported.

Traise2022ExerciseandPreDialysisCKDSupplementalInformation.pdf
Supplementary informationThis article contains the following supplementary information available online atSupplementary Table S1 Search strategy and results Supplementary Table S2 Excluded studies Supplementary Table S3 Detailed exercise intervention characteristics for included studies Supplementary Table S4 Summary of sub-analyses Supplementary Table S5 Assessment of study quality and reporting using the Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX) Supplementary Figures S1-S5 Sensitivity analysis of low-quality studies removed Supplementary Figures S6-S9 Forest plots of non-significant findings Supplementary Figures S10-S14 Egger funnel plots

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Clinical outcomes of exercise in people with pre-dialysis stages of chronic kidney disease: A systematic review with meta-analyses.

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Abstract

Figures

Introduction

Methods

Search strategy

Study selection

Intervention

Outcomes

Data extraction

Data synthesis

Heterogeneity and publication bias

Study Quality

Results

Characteristics

Type of intervention

*1 – same study as Aoike 2018

*2 – same study as Headley 2012

*3 – same study as Headley 2014

*4 – same study as Beetham 2018

Outcomes

Functional ability

Aerobic capacity

Other measures of functional ability

Quality of life

Renal parameters

Cardiovascular risk factors

Inflammatory Markers

Sensitivity analysis

Heterogeneity and publication bias

Study quality

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1

*¹ – same study as Aoike 2018

*² – same study as Headley 2012

*³ – same study as Headley 2014

*⁴ – same study as Beetham 2018