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Prehabilitation for the Frail Patient Approaching ESRD

Anoop Sheshadri, MD and Kirsten L. Johansen, MD

Summary: Frailty is a distinct phenotype that is highly prevalent in chronic kidney disease (CKD) and appears
to be more prevalent with decreasing glomerular filtration rate. Exercise training or intervention to increase
physical activity may ameliorate poor physical functioning and frailty, and even may improve survival in
patients with CKD. Although exercise interventions improve outcomes across the spectrum of CKD, including
patients treated with dialysis, patients treated with dialysis face barriers to exercise that patients with
predialysis CKD do not. Rehabilitation at earlier stages of CKD (or prehabilitation before dialysis) might be
more beneficial than not addressing the decreasing physical functioning and low physical activity until patients
are receiving dialysis. This review summarizes available literature on frailty in the CKD and end-stage renal
disease population, including exercise interventions and the limited evidence for prehabilitation as a strategy.
Semin Nephrol 37:159-172 Published by Elsevier Inc.
Keywords: Frailty, CKD, ESRD, prehabilitation, physical function, exercise

F
railty can result from accumulation of many significantly associated with frailty (odds ratio [OR],
small insults that lead to increasing vulnerability 1.76; 95% confidence interval [CI], 1.28-2.41).4
and lack of functional reserve over time.1 Fried Unfortunately, the majority of studies associating
et al defined frailty as a clinical syndrome in which 3 or CKD with frailty have been cross-sectional,7 but frailty
more of the following were present: unintentional weight does appear to become more prevalent with decreasing
loss (10 lbs in the past year), self-reported exhaustion, GFR. Roshanravan et al5 studied 336 patients with
weakness (grip strength), slow walking speed, and low CKD stages 1 to 4 to determine the prevalence and
physical activity. In this construct, frailty is considered a determinants of frailty in the CKD population as well
distinct phenotype in which comorbidity is a potential as its association with a composite outcome of all-cause
etiology and disability is a possible outcome.2 Frailty lies mortality or renal replacement therapy. They also found
at the intersection of numerous physiological systems that the prevalence of frailty was approximately 14%,
and is an aggregate result of decrements in function, nearly twice as high as in a reference population of
which can include immune dysfunction, inflammation, controls. The higher prevalence appeared to be driven
sarcopenia, and cognitive deficits, among others; no primarily by more physical inactivity and exhaustion
single system is responsible for frailty.3 in the patients with CKD. After multivariate adjust-
ment, an estimated glomerular filtration rate based on
cystatin (eGFR)cys of less than 30 and an eGFRcys of 30
FRAILTY IS COMMON AMONG PATIENTS WITH CKD to 44 mL/min/1.73 m2 were associated with a 2.8-fold
(95% CI, 1.3-6.3) and 2.1-fold (95% CI, 1.0-4.7) higher
Frailty is common among patients with CKD. Patients prevalence of frailty, respectively, as compared with
with chronic kidney disease (CKD) have a high patients with an eGFRcys of 60 or higher.
prevalence of frailty compared with the general pop- The prevalence has been even higher in cohorts of
ulation.4–6 Shlipak et al4 studied patients enrolled in the patients treated with dialysis. A study that examined
Cardiovascular Health Study, examining whether frailty among 2,275 incident dialysis patients enrolled in
chronic renal insufficiency (CRI) (defined as a creati- the Dialysis Morbidity and Mortality Study Wave 2 found
nine level Z 1.5 mg/dL in men and Z 1.3 mg/dL in that two-thirds were frail. Although elderly patients were
women) was associated with frailty. In this cross- more likely to be frail, 44% of patients younger than age
sectional analysis, among the 5,808 patients with 40 were frail, as well as 61.1% of patients aged 40 to 50.
measured creatinine, the prevalence of frailty was Women were more likely to be frail than men (OR, 1.55;
higher in patients with CRI (15%) than patients without 95% CI, 1.27-1.88). Patients with diabetes and a history
(6%), and after multivariate adjustment, CRI remained of stroke also were more likely to be frail, as well as
patients without permanent dialysis access. Peritoneal
Nephrology Section, San Francisco VA Medical Center and dialysis (PD) patients were less likely to be frail than
University of California, San Francisco, CA. hemodialysis (HD) patients, with an OR of 0.80 (95%
Financial disclosure and conflict of interest statements: none CI, 0.65-0.97). Despite its high prevalence, frailty was
Address reprint requests to Kirsten L. Johansen, MD, Nephrology associated with outcomes in this cohort similar to in
Section, 111J, San Francisco VA Medical Center, 4150 Clement
St, San Francisco, CA 94121. E-mail: Kirsten.johansen@ucsf.edu community-dwelling elders (hazard ratio, 2.24; 95% CI,
0270-9295/ - see front matter 1.60-3.15 for death in multivariable analysis).6
Published by Elsevier Inc. The prevalence of frailty among patients on dialysis
http://dx.doi.org/10.1016/j.semnephrol.2016.12.006 has ranged from 30% to 73%.8 It is important to note

Seminars in Nephrology, Vol 37, No 2, March 2017, pp 159–172 159


160 A. Sheshadri, K.L. Johansen

that comparison among studies of frailty in the CKD and replacement therapy, and both involved groups at high
end-stage renal disease (ESRD) populations is difficult risk for functional decline. Nevertheless, there was no
because many studies use different measurements for evidence for improvement in performance after starting
frailty, including using body mass index cut-off values dialysis, and these studies suggest that without efforts to
in place of weight loss, using different instruments to improve or preserve functioning before or after the start of
measure exhaustion or physical activity, or substituting dialysis, the trajectory is rapidly downward.15,16
patients’ self-reported physical functioning for objec-
tively measured strength and gait speed.7 Patients’ self-
reported physical functioning, as reported by the Phys- PHYSICAL INACTIVITY IN CKD
ical Function scale of the Short-Form 36 (SF-36) in
particular, is related to their performance in tests of gait Other studies have examined physical functioning or
speed and chair rising time,9 and the Physical Function physical activity directly rather than as contributors to
score has been used as a substitute for physical perform- frailty, and these also appear to decrease with worsen-
ance measures in several studies of frailty.6,7,10 How- ing kidney function.17–19 Hellberg et al found a
ever, because self-report of difficulty in physical statistically significant association between eGFR and
function and objective measurement of performance the distance walked in 6 minutes after multivariable
are fundamentally different, the specific measure of analysis, such that a 10 mL/min/1.73 m2 lower eGFR
frailty used significantly can influence the prevalence was associated with a 35-min shorter walking distance.
of frailty. In a study of 732 adult patients treated with Patients with a lower eGFR also had lower quadriceps
maintenance hemodialysis, 387 (53%) were found to be muscle strength and shorter reach, although eGFR was
frail based on self-reported function. With an objective not associated significantly with several other func-
performance-based definition of frailty, only 232 (32%) tional tests including grip strength.20 In a survey that
of the cohort met the criteria for frailty.11 included patients treated with HD and PD and patients
with CKD not on dialysis, the physical component
summary of the SF-36 score was found to be substan-
FRAILTY IS ASSOCIATED WITH OUTCOMES IN tially lower in all of these groups than for matched
PATIENTS WITH ESRD controls (36.0 versus 48.2 for patients on HD, 37.4
Frail patients may be initiated on dialysis earlier than versus 47.8 for PD patients, and 39.8 versus 46.9 for
patients who do not show the frailty phenotype, perhaps CKD patients).19 Although most studies associating
because components of frailty (eg, exhaustion) may be GFR with physical function have been cross-sectional,
perceived as symptoms of uremia, or because uremia at least one study has shown that exercise capacity in
contributes to the physical dysfunction associated with patients with stage 3 to 4 CKD decreased as estimated
creatinine clearance (Cockcroft-Gault) decreased.21
frailty.12–14 Although there are few longitudinal studies of
A cross-sectional study of self-reported physical activity
frailty or physical function before and after the initiation
in 100 patients across the spectrum of CKD and of healthy
of dialysis, available evidence suggests that elderly
controls also showed a graded association between kidney
patients experience further loss of functioning after
function and physical activity measured by a questionnaire
starting dialysis. Kurella Tamura et al15 studied patients
combining elements from the General Practice Physical
who were in nursing homes when dialysis was initiated. Activity Questionnaire and the Human Activity Profile.
They reported that only 39% of patients were able to The highest level of activity was among healthy controls
maintain predialysis functional status in the first 3 months (score, 14.7 ⫾ 4.24), with progressively lower activity
after initiation, and by 1 year 58% had died and only 13% among transplant recipients, patients with CKD stages 3 to
were alive with functional status intact. Initiation of 5, patients on home hemodialysis, peritoneal dialysis, and
dialysis was associated with a sharp decrease on the patients receiving in-center hemodialysis (11.4 ⫾ 4.20).22
Minimum Data Set Activities of Daily Living scale even The Comprehensive Dialysis study assessed physical
after accounting for the presence or absence of accelerated activity among 1,547 ambulatory patients new to dialysis
decrease in the 3 months preceding dialysis.15 Similarly, and found that physical activity was extremely low, with
Jassal et al16 studied initiation of dialysis in a cohort of 97 scores for all age and gender categories that were below
patients older than age 80. At the time of dialysis the 5th percentile for healthy individuals.23
initiation, 78% were living at home with no assistance Brenner and Brohart24 showed that among 19
required for activities of daily living. However, within patients treated with dialysis, those who reported higher
6 months, more than 30% of patients had loss of function levels of activity by questionnaire were more likely to
such that they required caregiver support or transfer to a have better quality of life and physical function
nursing home. Both of these studies were limited by not compared with those who reported less activity. A
including patients who did not initiate dialysis to compare Japanese study of 202 dialysis patients examined the
the evolution of functional status with and without renal association between habitual physical activity (as
Prehabilitation for ESRD 161

derived from accelerometer data) and mortality and In a systematic review conducted by Barcellos et al,31
showed that 93.3% of those who had physical activity of the 45 randomized controlled trials in patients
of 50 minutes or more per day (time spent with vector treated with dialysis, a total of 14 trials measured
magnitude on the accelerometer at grade 1 or higher out aerobic capacity as an outcome. All 14 reported an
of 11 total grades) survived after 7 years versus 77.2% increase in peak oxygen consumption (VO2peak) with
in patients who reported fewer than 50 minutes per day aerobic exercise. Similarly, in a meta-analysis from
of activity. After adjusting for confounders with a Heiwe and Jacobson,33 the pooled effect of aerobic
multivariate model including use of a propensity score exercise intervention in 21 studies of patients treated
for physical activity, each 10-minute/day increment of with dialysis was an improvement in aerobic capacity
physical activity was associated with a hazard ratio of (standard effect size,  0.8). The majority of these
0.78 for mortality (95% CI, 0.66-0.92).25 Two US exercise interventions were 8 to 12 weeks in duration,
cohorts of more than 1,000 patients each also showed although some lasted as long as 6 months. The
a strong link between physical activity and survival average improvement in VO2peak was approximately
among patients treated with dialysis.26,27 20%,31,33,35,36 which may be related to cardiac adapta-
Given these strikingly low levels of physical activity tion to exercise. Specifically, studies have shown better
and the links between low physical activity and poor left ventricular systolic function at rest after exercise,
physical function and higher mortality, it is logical to as well as higher cardiac output index and stroke
consider that exercise training or interventions to volume index after programs of aerobic training.37,38
increase physical activity could ameliorate poor phys- Importantly, although VO2peak improved after aerobic
ical functioning and frailty and even might improve training or combined aerobic and resistance training, it
survival in patients with CKD. We review data on the remained substantially lower than levels of age-
effects of exercise interventions, starting with studies matched controls even after training.32
conducted in the setting of hemodialysis because this is Both intradialytic and extradialytic programs can
the most-studied population. improve aerobic capacity, and in patients with very
low aerobic capacity, moderate extradialytic rather than
Exercise in Patients on Dialysis intradialytic exercise may result in greater gains.34 The
extent to which this greater degree of improvement in
Numerous studies have shown that exercise interven- aerobic capacity in extradialytic exercise as compared
tions are beneficial, feasible, and can be implemented with intradialytic exercise translates to greater functional
safely in the ESRD population.28–30 Both aerobic and changes or survival benefit is unclear. In addition,
resistance exercise interventions, administered in the intradialytic exercise programs tend to have higher
dialysis facility or outside of dialysis, have resulted in adherence than home-based or extradialytic programs.39
improvements in physical function (Fig. 1). Improvement in aerobic exercise capacity also may
be related to other functional gain in this population.
Aerobic Exercise Interventions Ouzouni et al36 randomized 35 patients to either a
There have been many studies of aerobic exercise rehabilitation program consisting of intradialytic exer-
interventions in patients treated with dialysis, as well as cise training or a control group receiving usual care.
several systematic reviews on this topic (Table 1).31–35 Both groups had measurements of baseline aerobic

Figure 1. Types of exercise intervention and expected outcomes. Increases in strength are training-specific; grip
strength will improve with grip training, leg strength will improve with exercises focusing on the legs, etc.
162
Table 1. Systematic Reviews of Exercise Interventions
Interventions by Stage of CKD

Study Study Type Total Studies Predialysis ESRD Transplant Comments


Included (n)
Cheema and Singh,102 13 RCTs, 7 uncontrolled trials, 29 29
2005 9 controlled trials
Type of intervention
Aerobic 19 19
Resistance 1 1
Combined 9 9
Koufaki et al,78 2013 Predialysis: 5 RCTs, 8 nonrandom 33 17 16 One study with pre-HD, HD, and Tx patients
controlled, 4 uncontrolled trials
Transplant: 6 RCTs, 10 uncontrolled
trials
Type of intervention One study with pre-HD and HD patients
Aerobic 24 13 3 8 One study with KTx and HD patients
Resistance 7 4 3
Combined 6 1 5
Heiwe and Jacobson,33 41 RCTs 41 6 33 3 One study enrolled patients both treated with HD and
2014 in CKD (aerobic intervention)
One study enrolled patients treated with PD alone
Type of intervention
Aerobic 33 5 25 3 One study involved an aerobic, resistance, and
combined intervention (in HD) Only one study
enrolled patients treated with both HD and CAPD
Resistance 7 1 6
Combined 4 0 4
Barcellos et al,31 2015 RCTs 59 11 46 3 One study included patients who were both on dialysis
and predialysis
Only one study included both HD and CAPD patients
One study compared aerobic training with resistance
training
Type of intervention
Aerobic 43 7 33 3

A. Sheshadri, K.L. Johansen


Resistance 8 2 6
Combined 9 2 7
Sah et al,96 2015 1 uncontrolled trial, 2 nonrandomized 11 2 8 Two reports from the same study
trials, and 8 RCTs
Type of intervention
Aerobic 1 1
Resistance 4 1 3
Combined 5 1 4
Additional unique 8 2 6
studies of exercise
Prehabilitation for ESRD 163

Abbreviations: CAPD, continuous ambulatory peritoneal dialysis; KTx, kidney transplant; Tx, transplant. Bolded numbers indicate the total number of studies included in each review.
capacity as well as a psychosocial assessment includ-
ing Beck’s Depression Inventory and questionnaires of
health-related quality of life, as well as erythropoiesis-
stimulating agents administered to achieve a target
hemoglobin level of 11 g/dL. At the 10-month follow-
up evaluation, the VO2peak in the exercise group
increased by 21.1%. The exercise group also had a
decrease of 39.4% in the depression index and
improvement in the quality-of-life index, life satisfac-
tion index, and the physical component scale of the
SF-36. The VO2peak had a positive correlation with the
quality-of-life index both at baseline and at the follow-
up evaluation. Multivariate analysis showed that the
extent of reduction of depression, increase in aerobic
capacity, and adherence to the training program were
significant predictors of the extent of improvement in
quality of life. There was no significant change in the
control group over the course of the study.36
74 (3,304) 18 (734)

Another study randomized 48 patients treated with


HD into four groups that received the following: a
6-month supervised outpatient renal rehabilitation pro-
gram with three weekly aerobic and strengthening
sessions on nondialysis days; an intradialytic exercise
program; an unsupervised moderate exercise program
4

at home; and no exercise (control group). An additional


group was composed of healthy sex- and age-matched
Total independent 26 (913)

sedentary individuals. The highest drop-out rate was


among patients assigned to the extradialytic rehabil-
1

itation program at 24%, as compared with 17% for the


or unique studies
(no. of patients)

intradialytic and home exercise groups. However, for


patients completing the program, participation in the
full supervised (extradialytic) program also resulted in
the greatest increases in VO2peak (43% compared with
24% with intradialytic exercise, 17% with home
5

exercise, and a decrease of 3% in the control group,


which was not statistically significant).40
3 uncontrolled trials, 2 nonrandomized

Although few studies followed up patients beyond


the relatively short intervention period, there is some
controlled trials, 2 randomized

evidence that exercise programs can be feasible even


on a long-term basis. A 4-year study compared 48
patients treated with hemodialysis who were assigned
Type of intervention

randomly to either a supervised outpatient exercise


controlled trials

program or an in-center, intradialytic bicycling pro-


Resistance

gram. There were a total of 8 drop-outs in the


Combined
Aerobic

extradialytic group and 5 in the intradialytic group


over the 4 years of the study, and a total of 16 and 18
patients completed the programs, respectively. At
1 year, exercise capacity, as measured by VO2peak,
increased by 47% for the extradialytic exercise group
intervention in this

and by 36% in the intradialytic exercise group. At


4 years, greater improvements were observed (70%
and 50%, respectively).41
In addition to high-intensity exercise training inter-
review

ventions, low- or moderate-intensity exercise also


appears to improve walking capacity as measured by
164 A. Sheshadri, K.L. Johansen

the 6-minute walk test (6MWT), even among patients However, there was no change in grip strength. Of
with very low levels of initial performance, and the the 6 patietns who did not complete the study, one lost
6MWT may be easier to perform than maximal tread- motivation, and one received a transplant. No patients
mill testing. Distance on the 6MWT also has been stopped because of injury.51
associated independently with survival and lower Since then, there have been several trials of pro-
risk of hospitalization in the dialysis population.42,43 gressive resistance training in patients with ESRD
A home-based exercise program of two daily designed to improve physical functioning by increasing
10-minute home walking sessions on nondialysis days strength. Of the nine trials of resistance training
at 50% below maximal treadmill speed showed included in one systematic review, all nine reported
improvements in 6-minute walking distance and an improvement in muscle strength with resistance
health-related quality of life for the exercise group training.31 Two of the larger trials examined muscle
versus the control group at the end of 6 months. A size directly using imaging of the thighs. A randomized
follow-up evaluation at 1 year after completion of the controlled trial of exercise training in 79 patients who
study showed that although the exercise group had were receiving maintenance hemodialysis by Johan-
some detraining, their 6-minute walk scores remained sen52 showed that a 12-week course of lower-extremity
above baseline, whereas the control group scores had resistance training three times per week resulted in an
decreased throughout the period of the study and the increase in quadriceps muscle cross-sectional area
follow-up period.44 Both aerobic and resistance exer- (CSA) and an improvement in self-reported physical
cise have a dose-response relationship with physical function as compared with nonexercising groups.
health such that even small doses may be more Another RCT of high-intensity, progressive resistance
beneficial than none. In one study comparing intra- training in patients treated with hemodialysis resulted
dialytic cycling with a pedometer-based intervention, in no statistically significant difference in total muscle
patients completing the intervention had similar CSA in the exercise group compared with nonexercis-
improvements in sit-to-stand and sit-and-reach testing ing controls based on computed tomography imaging
despite no significant change in VO2peak or the 6- of the thighs. However, there was significant improve-
minute walk distance between or within study groups ment in muscle attenuation, indicating a decrease in
either at 12 or 24 weeks.45 Low- and moderate-intensity intramuscular fat content (and therefore an increase in
programs also appear to result in improved control of actual muscle area) with the intervention. Strength and
blood pressure46,47 and better vascular functioning.48 midthigh and midarm circumference also increased and
However, there are no studies adequately powered to the C-reactive protein level decreased in the progres-
assess whether this translates to improved survival or sive resistance training group compared with the
decreased cardiovascular risk.34 controls.53

Resistance Training Combined Resistance and Aerobic Training


One of the key components of frailty is muscle weak- DePaul et al54 conducted a randomized, placebo-
ness. Isokinetic muscle strength has been shown to controlled trial of exercise intervention involving pro-
correlate with VO2peak,49 and muscle strength also has gressive resistance training of quadriceps and ham-
been shown to correlate with gait speed, another string as well as cycle ergometer training three times
component of frailty.50 Hellberg et al17 conducted a weekly for 12 weeks in 38 patients treated with
retrospective longitudinal study of 134 patients starting hemodialysis. Those in the control group (18 patients)
renal replacement therapy between 1998 and 2006. trained with a nonprogressive program of range-of-
Twenty-two patients died during the follow-up period. motion exercises. The exercise group (20 patients)
Better grip strength, functional reach, and standing heel experienced substantial and statistically significant
rise were associated with lower mortality in univariate improvement in scores on the submaximal exercise
analysis. In multivariate analysis adjusting for age and test and muscle strength, but not in 6MWT or physical
comorbidity, grip strength remained an independent components of the SF-36 as compared with the control
predictor, and a 50% lower grip strength was associ- group. Five months after study completion, those in the
ated with a four times higher risk of mortality.17 exercise group still were stronger, but the differences
A pioneering study of high-intensity resistance were no longer statistically significant.
training including two supervised and one unsuper- An RCT from The Netherlands involving low-
vised session per week in 16 dialysis patients (10 of moderate intensity strength training before the dialysis
whom ultimately completed the study), showed statisti- session and intradialytic cycling for a total of 12 weeks
cally significant improvements in gait speed, peak showed that participation in this exercise program
torque of leg extensors (only at 901/s), time to (60 exercising patients of a total 103 randomized)
complete sit-to-stand, and maximal walking speed. resulted in a statistically significant increase in lower-
Prehabilitation for ESRD 165

extremity muscle strength and VO2peak. Scores on the only 2 of the 17 aerobic interventions included patients
Vitality and General Health scales of the SF-36 and the on peritoneal dialysis. However, there is no evidence to
single question about health change also improved support that peritoneal dialysis patients do not also
significantly.55 benefit from exercise interventions, given that they did
Other smaller studies also have reported substantial improve their aerobic capacity in the 2 studies in which
benefit with combined interventions.56,57 A program they were included.35
involving progressive aerobic and resistance training Bohm et al63 discussed some of the methodologic
may be superior to resistance or aerobic training alone. issues with studies of exercise in patients treated with
In one study, patients were assigned randomly to either dialysis, including uncertainty about the optimal
resistance exercise alone for 10 weeks or a combined modality and dose of exercise, the best time for
program. Total exercise was the same for both groups intervention (intradialytic versus outside of dialysis),
at 30 minutes performed in the first 2 hours of lack of motivation by patients, lack of enthusiasm of
hemodialysis. Of 80 patients approached, 22 were treatment teams and providers, safety and health
excluded and 32 refused to participate, and the remain- concerns, and frequent hospitalizations and clinical
ing 26 patients were randomized with 13 in each arm. status changes in the dialysis population that can
Patients in the combined program had an improvement interrupt training. Conclusions were limited further
of 39.7 ⫾ 61.4 min in the 6MWT, whereas those in by the heterogeneity of the ESRD population, the
resistance alone actually worsened by 19.2 ⫾ 53.9 presence of multiple comorbid conditions, and diffi-
min. There was a statistically significant difference culty in implementing long-term interventions given
between the two groups in change over time. However, the high rate of drop-out in the studies to date and the
no pure strength outcomes were assessed.57 Of note, high mortality in the patient population.
those who refused to participate had longer dialysis Although most dialysis patients have reported inter-
vintage, a higher hematocrit level, and were more est in physical exercise when surveyed,64 they also
likely to be women than patients who participated in reported substantial barriers to participation. A study of
the study. 100 patients in California dialysis facilities found that
98% agreed that a sedentary lifestyle was unhealthy
and that increasing exercise would be beneficial, but
Alternatives to Exercise Interventions: Physical Therapy
only 8% reported no barriers to exercise.65 The most
There are unique challenges involved in tailoring common barriers were fatigue on dialysis days (67%)
typical physical therapy (PT) and occupational therapy and nondialysis days (40%), as well as shortness of
programs to patients with ESRD, including barriers breath (48%). In multivariate analysis, the factors most
related to health and logistics. However, use of associated with a lower activity level were the total
comprehensive PT and occupational therapy can be number of barriers endorsed, having too many medical
beneficial if the specific needs of the individual patient problems, lack of time on hemodialysis days, and lack
are kept in mind, and intradialytic therapy also is of motivation.65 In one Italian dialysis center, of 104
possible.58 A nonrandomized trial of 52 patients in patients enrolled in a study of barriers to physical
either an experimental skilled renal rehabilitation pro- activity, 96% reported at least one barrier. After
gram (including exercise, activities, and neuromuscular multivariate analysis, having too many medical prob-
re-education) or controls showed that patients enrolled lems, chest pain, and sadness all were associated with
in the program had statistically significant improve- lack of physical activity.66 An additional Canadian
ment in 6MWT, grip strength, and 20’ fast gait speed study of patients treated with maintenance hemodial-
after 12 weeks.59 There is no reason to expect that ysis reported that patients perceived symptoms such as
referral to traditional PT would not benefit patients on fatigue, health issues such as osteoporosis, time, trans-
dialysis, and a small nonrandomized study showed portation, and equipment as barriers to exercise.67
improvement in quality-of-life scores and functional Although there are barriers from patients including
performance after referral to traditional PT among lack of motivation, there also are iatrogenic barriers. A
5 patients treated with dialysis who were enrolled for survey of 505 nephrologists (55% from the United
9 weeks.60 Inpatient rehabilitation also has been shown States, and the rest from other parts of the world)
to be beneficial for patients treated with dialysis.61,62 explored provider opinions about and barriers to
exercise counseling and found that only 38% offered
exercise counseling for inactive patients either “almost
Limitations always” or “often.”68 Nephrologists who did not
The vast majority of these studies involved patients counsel patients routinely were more likely to report
receiving hemodialysis rather than peritoneal dialysis. lack of confidence in their ability to provide counseling
For example, a 2008 review of the literature on and lack of conviction that patients would respond as a
exercise interventions in dialysis patients found that barrier to offering counseling. Even among primarily
166 A. Sheshadri, K.L. Johansen

European nephrologists, exercise prescription has been


noted to be suboptimal despite better adoption of
exercise for patients treated with dialysis in many
European countries.69 An Italian study by Fiaccadori
et al66 reported that the most frequent barriers to
counseling about or prescribing exercise from the
doctors’ and nurses’ perspective were lack of time
and belief that the patients would not be adherent or
had low interest. Of note, less than half (42.3%) of the
patients expressed lack of motivation in a study that
surveyed patients directly, and lack of motivation was
not associated significantly with inactivity in multi- Figure 2. Exercise interventions may be able to blunt the impact
variate analysis. of age and decreasing GFR on loss of physical function. Physical
Taken together, the evidence from exercise studies function often deteriorates even more rapidly after initiation of
dialysis. An exercise intervention instituted predialysis may pro-
in patients on dialysis supports the idea that rehabil- vide longer time without frailty than one instituted after dialysis,
itation at earlier stages of CKD (or prehabilitation and also may be easier to perform.
before dialysis) might be more beneficial than not
addressing the decreasing physical functioning and low
physical activity until patients are receiving dialysis. three sessions a week correlated positively with exer-
Specifically, difficulty in recruitment and retention is a cise after dialysis initiation, raising the possibility that
common problem in the studies of exercise in patients increasing activity in the predialysis phases of disease
on dialysis. A higher percentage of patients with earlier could carry over into the dialysis setting.64
stages of CKD still may be capable of undertaking an
exercise program, and adherence to exercise also may
be less of a problem if patients are less debilitated. For EXERCISE INTERVENTION IMPROVES OUTCOMES IN
example, Greenwood et al70 studied the feasibility of
PREDIALYSIS CKD
an exercise program for adults including those with
CKD stage 3 to 4, on maintenance HD, and after Although comparative studies are rare, there is evi-
receiving a renal transplant. A multidisciplinary team dence that rehabilitation is beneficial among patients
conducted twice-weekly supervised exercise sessions with CKD not requiring dialysis.71–73 Gould et al74
and prescribed once-weekly home-based exercise for a published a systematic review of the effects of exercise
total of 12 weeks. Of the 263 patients referred, 131 in patients with CKD and found that aerobic exercise
commenced the program, and 77 completed it. Patients improved peak exercise capacity, and aerobic, resist-
who completed the program (attended at least 12 of the ance, and combined aerobic plus resistance exercise
supervised sessions) had improvements in anxiety, interventions improved muscle strength. Combination
depression, exercise capacity, and physical function resistance and exercise training may be superior to
(Fig. 1). A higher self-reported level of fitness at either aerobic or resistance training alone.74,75
baseline was associated with better chances of com- Exercise in the earlier stages of CKD has been
pleting the program, and hemodialysis patients had the relatively understudied compared with in the dialysis
largest percentage of noncompleters (49%). population, with fewer randomized controlled trials
In addition, the lack of complete restoration of the and significantly more heterogeneity in patient selec-
functioning that appears to be lost during predialysis tion.76–78 Many studies of exercise in CKD have
stages of CKD with exercise after dialysis initiation, as excluded patients with significant comorbidities or
well as dialysis scheduling constraints and provider known coronary artery disease.77 In general, aerobic
apathy, also suggest that prehabilitation could prevent exercise appears to improve VO2peak in patients with
some or all of the frailty and poor physical functioning CKD,78 but the effect of exercise on strength, physical
that develop during advanced CKD and initiation of function, and quality of life is less consistent in the
dialysis and lead to better functioning among incident literature.77,78 In addition, aerobic exercise need not be
and prevalent dialysis patients (Fig. 2). Few studies of high intensity to improve VO2peak.33
have addressed this possibility directly, but in one Although most exercise interventions have been of
study of 135 patients on maintenance hemodialysis, relatively short duration, one study of predialysis
patients reported that their participation in physical patients with CKD showed that a year-long aerobic
activity was limited and primarily was in the form of exercise intervention consisting of both supervised and
low-intensity recreational activities; only 10% of par- home-based exercise with individualized regimens
ticipants reported an exercise expenditure of more than resulted in improvements to VO2peak and exercise
1,000 kcal/wk. Predialysis exercise habits of at least duration as well as augmentation index (a measure of
Prehabilitation for ESRD 167

arterial stiffness), which decreased by 11.7% (95% CI, an eGFR greater than 30 mL/min/1.73 m2. The CKD
-18.79 to -4.61) in the exercise group as compared with patients tended to be older and have more cardiac risk
the controls.79 This study also showed that improve- factors and comorbidities. Although baseline self-
ment with exercise was associated with meaningful reported physical activity level and distance walked
improvement in overall quality of life as measured by in 6 minutes were lower both at baseline and after
the EuroQuol five dimensions questionnaire. Although rehabilitation in the CKD group compared with non-
studies have not adequately examined effects of CKD patients, both groups had similar relative
exercise on cardiovascular outcomes, exercise does improvement in both measures after rehabilitation.85
appear to improve lipid metabolism.80,81 Shigeta et al86 conducted a study of patients under-
There are also fewer studies of resistance training in going cardiovascular and orthopedic inpatient rehabil-
the CKD population, but in one study of 10 patients itation and found that a CKD stage higher than 3b was
with an average eGFR of 15 ⫾ 7 mL/min/1.73 m2, associated with delayed progress in physical therapy
combined aerobic and resistance training of large (length of stay, 42 SD above the mean), with an OR
muscle groups three times a week for 3 months was of 3.3 (95% CI, 1.3-9.0) for cardiovascular disease and
associated with improvement in exercise capacity on a 3.3 (95% CI, 1.3-7.9) for orthopedic disorders.
bicycle ergometer and a decrease in heart rate when Exercise interventions in CKD may be as effective
exercising at equal loads as compared with controls, as exercise interventions in healthy controls. A study
likely mediated by improvement in muscle strength by Heiwe et al87 compared the effects of a non-
and function.82 A group of nine matched controls did randomly assigned exercise intervention among 37
not show any improvement during the same period. patients with advanced CKD and 26 healthy elderly
Another study of patients randomized to a low-protein controls. The exercise program consisted of strength
diet alone or a low-protein diet plus resistance training and endurance training three times per week for
for 12 weeks showed improvement in type I and type II 12 weeks. At baseline, the patients with CKD had a
muscle fiber CSA in patients who performed resistance maximal workload that was 87% (range, 64%-113%)
training.83 of the age-expected norm, whereas the healthy controls
There has been at least one study directly comparing had a maximal workload that was 80% (range,
exercise interventions in predialysis patients with 83%-187%) of the norm. Patients with CKD had
patients treated with dialysis. Eighteen predialysis significantly lower static muscular endurance and
(expected to start dialysis in the next 6-12 mo) and performance on the 6MWT than healthy elderly
18 dialysis patients were assigned randomly to either individuals. Both groups showed similar improvements
6 months of exercise coaching and rehabilitation in muscle strength and dynamic muscular endurance
counseling or standard of care, with an additional after the intervention, as well as improvements in
6 months of follow-up evaluation after the end of the functional mobility and walking distance compared
intervention.84 Both rehabilitation groups (predialysis with their nonexercising counterparts.87
and dialysis) had increases in their general health Unfortunately, there are little data directly examin-
ratings over the time of the intervention, whereas both ing the effect of exercise before dialysis initiation on
control groups had decreases. The predialysis group patient outcomes after transitioning to dialysis. Cheng
walked farther on the 6-minute walk than the dialysis et al88 published a report of their experience with
group initially and after the 6-month intervention. a renal rehabilitation program that included pre-
Predialysis patients who did and did not exercise had dialysis education and individualized physiotherapist-
similar time to initiation of renal replacement therapy, recommended exercise as core tenets. The specifics of
but the study was underpowered for this and other the exercise program delivered within this multidisci-
comparisons. Dialysis patients who exercised did not plinary program were not discussed beyond Tai Chi
improve their physical functioning significantly com- three times a week and some of the social and group
pared with controls, and the superiority of rehabilita- interaction elements. They reported that patients who
tion in the predialysis versus dialysis setting was not completed the predialysis program were more likely to
assessed formally, presumably because of the small choose PD as their dialysis modality than those who
number of patients. Although the investigators did not did not. They also reported improvements in physical
perform a statistical comparison of the results in capacity and fewer hospital admissions, although they
predialysis and dialysis patients, they concluded that did not report numbers or magnitude.88
rehabilitation services were qualitatively more benefi-
cial in the predialysis patients.84
In one study of 376 patients with and without CKD Progression of CKD
(defined as an eGFR o60 mL/min/1.73 m2) who When considering exercise interventions in the CKD
completed cardiac rehabilitation, 115 (31%) had population, it is important to consider the theoretical
CKD. Eighty-seven percent of the CKD patients had possibility of a benefit in slowing progression
168 A. Sheshadri, K.L. Johansen

of kidney disease, which could happen through Among individuals with established CKD,
improvement in inflammation or blood pressure control. Robinson-Cohen et al91 studied a cohort of 256
Conversely, there is the possibility of risk, or more patients in the Seattle Kidney Study with an eGFR of
likely, that an increase in creatinine level related to 15 to 59 mL/min/1.73 m2 (mean, 42 mL/min/1.73 m2).
higher muscle mass could be interpreted as a decrease in During the follow-up period (median, 3.7 y), partic-
kidney function. A few small studies have reported a ipants who reported at least 150 minutes of physical
beneficial effect of exercise on progression of CKD. A activity per week had the lowest rate of eGFRcystatin c
Japanese study of patients with both cardiovascular loss (-6.2%/y versus -9.6%/y among less-active partic-
disease and CKD (19 patients; eGFR, o60 mL/min/ ipants). After adjustment, each 60-minute increment in
1.73 m2) reported that 12 weeks of exercise therapy weekly activity was associated with a 0.5% slower
resulted in statistically significant improvements in decrease in eGFR. However, after adjusting for eGFR,
anaerobic threshold VO2 during maximal exercise test- physical activity was not associated with any differ-
ing and high density lipoprotein cholesterol (HDL-C) ence in the incidence of ESRD.
levels, as well as a reduced triglyceride level. eGFR also Pechter et al92 performed a nonrandomized study
was improved, with the change in eGFR correlating examining the effects of aquatic aerobic exercise on
significantly with change in anaerobic threshold VO2 cardiorespiratory reserve and cardiovascular and
and HDL-C, and negatively with triglyceride levels.81 inflammatory markers in 26 patients with moderate
Another study of a short-term exercise program of CKD (exercise group mean eGFR, 62.9 ⫾ 5.9; control
moderate intensity in patients with type 2 diabetes group mean eGFR, 69.8 ⫾ 12.3). Seventeen patients
reported improvement in eGFR in patients with CKD were in the exercise group and 9 patients were in the
stages 2 and 3. Forty-two percent of patients with CKD control group. Patients performed aerobic exercises for
stage 3 (16 of 38), improved to CKD stage 1 or 2 after 30 minutes while immersed in a pool, with a 10-minute
the intervention.80 A third randomized controlled trial warm-up period, 10 minutes of gradually increasing
of physical training (either 30 minutes of daily bicycling exercise, and a 10-minute cool-down period and
or equivalent physical activity) versus maintenance of stretches at the end. Patients in the exercise group
usual lifestyle in 30 patients with a median eGFR of 25 had improved peak oxygen pulse, peak ventilation, and
mL/min/1.73 m2 showed improvement in maximal work peak load, as well as improved peak oxygen consump-
capacity, but did not show change in rate of progression tion at maximal load (although this last outcome did
of GFR over the 20-month follow-up period.89 not reach statistical significance). There was a statisti-
Neither delayed progression of CKD nor improve- cally significant improvement in eGFR and decrease in
ment of GFR has been shown in any large randomized proteinuria in the exercise group, but not in the control
controlled trials or in a meta-analysis, which may be group. The exercise group had improved systolic and
owing to the lack of large-scale trials with adequate diastolic blood pressures, a possible mediator of
follow-up evaluation to examine disease progres- improvement in eGFR. Pechter et al93 also reported
sion.33,74,78 According to one review, assuming a rate on the 10-year follow-up evaluation from this study.
of decline in controls of 1.47 to 3.4 mL/min/1.73 m2 Ten patients from the original study left because of a
per year, a study would require 1,870 patients to detect lack of time, and 7 patients continued with regular
a 30% improvement in eGFR with adequate conven- exercise under the supervision of a physiotherapist. At
tional statistical power, making it unlikely that RCT termination of the study, there was no significant
data will be available soon to address the question.77 difference in time to death or dialysis. However, there
However, although it is unclear whether exercise has a did appear to be a difference in occurrence of the end
significant effect on progression of renal disease, it point with the exact multinomial test. Fifty-five percent
does not appear to worsen it. of patients in the sedentary group reached the study
Nevertheless, a large population-based observational end point (three deaths and two received renal replace-
study of 63,257 Chinese men and women followed up ment therapy). However, in the exercise group, no
for a median of 15.3 years for the development of patient reached dialysis in 10 years. Among patients
incident ESRD examined risk according to level of who did not reach the end point, there was no
physical activity. Compared with patients with no significant difference in eGFR or proteinuria between
regular physical activity, patients who performed the exercisers and the controls.
moderate activity for at least 2 hours a week or
strenuous physical activity for at least 30 minutes a
DELIVERING AN INTERVENTION
week had a 24% lower adjusted risk of ESRD.
Strenuous activity was associated independently with With regard to safety, in the extensive literature on
a 42% lower adjusted risk of ESRD. Similar results exercise in patients with CKD, there have been no
were seen with a composite outcome including death serious adverse events documented related to
and ESRD.90 exercise. When considering the physical activity
Prehabilitation for ESRD 169

recommendations for elderly adults and patients with including lower baseline levels of physical functioning,
sedentary lifestyles, such as the many patients treated a higher prevalence of frailty, depression, and anxiety,
with dialysis, there are no specific recommendations and logistical barriers such as transportation. Exercise
for screening with stress testing before exercise. How- interventions may be better delivered before patients
ever, recommendations should be individualized and develop the debility that sometimes comes with the
appropriate referrals may be necessary for cardiac transition to ESRD, and recommendations for physical
rehabilitation or physical therapy. The intensity of the activity may best be delivered along with other pre-
exercise also should be tailored to the participant. ESRD care.100 Nephrologists should take an active role
Many of these studies prescribed exercise sessions of in counseling patients on exercise and physical activity
at least 30 minutes’ duration, although it is uncertain before treatment with dialysis, but also should not
whether this duration is required for either physiologic ignore exercise prescription for patients who already
or functional improvement. An ideal aerobic exercise are being treated with dialysis.101
program might include 3 to 7 days per week of
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