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ARRATIVE REVIEW
Fatigue in Patients Receiving Maintenance Dialysis: A Review ofDefinitions, Measures, and Contributing Factors
Manisha Jhamb, MD, MPH,1 Steven D. Weisbord, MD, MSc,2,3 Jennifer L. Steel, PhD,4 andMark Unruh, MD, MSc5
Fatigue is a debilitating symptom or side effect experienced by many patients on long-term dialysistherapy. Fatigue has a considerable effect on patient health-related quality of life and is viewed as beingmore important than survival by some patients. Renal providers face many challenges when attemptingto reduce fatigue in dialysis patients. The lack of a reliable, valid, and sensitive fatigue scale complicatesthe accurate identification of this symptom. Symptoms of daytime sleepiness and depression overlapwith fatigue, making it difficult to target specific therapies. Moreover, many chronic health conditionscommon in the long-term dialysis population may lead to the development of fatigue and contribute tothe day-to-day and diurnal variation in fatigue in patients. Key to improving the assessment andtreatment of fatigue is improving our understanding of potential mediators, as well as potential therapies.Cytokines have emerged as an important mediator of fatigue and have been studied extensively inpatients with cancer-related fatigue. In addition, although erythropoietin-stimulating agents have beenshown to mitigate fatigue, the recent controversy regarding erythropoietin-stimulating agent dosing inpatients with chronic kidney disease suggests that erythropoietin-stimulating agent therapy may notserve as the sole therapy to improve fatigue in this population. In conclusion, fatigue is an important andoften underrecognized symptom in the dialysis population. Possible interventions for minimizing fatiguein patients on long-term dialysis therapy should aim at improving health care provider awareness,developing improved methods of measurement, understanding the pathogenesis better, and managingknown contributing factors.Am J Kidney Dis 52:353-365. © 2008 by the National Kidney Foundation, Inc.
INDEX WORDS: Fatigue; end-stage renal disease; quality of life; psychometrics; cytokines; postdialysisfatigue.
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atigue is one of the most frequent symptomsof dialysis patients and is associated with
mpaired health-related quality of life (HRQOL).he prevalence of fatigue ranges from 60% to asigh as 97% in patients on long-term renal re-lacement therapy.1-7 The importance of fatigueo patients with kidney disease is emphasized byhe observation that 94% of hemodialysis (HD)atients endorsed a willingness to undergo morerequent dialysis if there would be an associatedncrease in energy level.8 Despite the importancef fatigue to patients, health care providers re-ain largely unaware of both the presence and
everity of fatigue in dialysis patients.9
Although clinical assessment of fatigue inialysis patients has proved difficult for physi-ians, it is important to recognize fatigue becausehere are a number of treatable causes. Recogni-ion of fatigue may be difficult because recoveryrom fatigue has great interpatient variability.10
fter recognizing fatigue and assessing its sever-ty, physicians should first consider the generalhysiological and psychological causes for fa-
igue, such as hypothyroidism and depression. Inmerican Journal of Kidney Diseases, Vol 52, No 2 (August), 2008
ddition, there are dialysis-related causes of fa-igue, and some of the factors that may lead toatigue in patients with end-stage renal diseaseESRD) include uremia, anemia, sleep disorders,nd psychosocial distress, which may be ame-able to intervention.
From the 1Western Pennsylvania Medical Center; 2Renalection and Center for Health Equity Research and Promo-ion, VA Pittsburgh Healthcare System; 3Renal-Electrolyteivision, University of Pittsburgh Medical Center; 4Univer-
ity of Pittsburgh School of Medicine, Liver Cancer Center,epartment of Surgery, Starzl Transplantation Institute; and
Renal-Electrolyte Division, University of Pittsburgh Medi-al Center, Pittsburgh, PA.
Received December 3, 2007. Accepted in revised formay 7, 2008. Originally published online as doi:
0.1053/j.ajkd.2008.05.005 on June 23, 2008.Address correspondence to Mark Unruh, MD, MSc, Uni-
ersity of Pittsburgh Medical Center, Renal-Electrolyte Divi-ion, 3550 Terrace St, A915 Scaife Hall, Pittsburgh, PA5261. E-mail: [email protected]© 2008 by the National Kidney Foundation, Inc.0272-6386/08/5202-0020$34.00/0
doi:10.1053/j.ajkd.2008.05.005: pp 353-365 353
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This report aims to examine the current defini-ions and theories of fatigue, instruments to mea-ure fatigue, underlying physiological and psy-hological correlates of fatigue, and possiblenterventions to improve fatigue in patients withSRD. This review also examines the role of
nflammation in the development of fatigue andxplores how inflammation may act as a com-on mediator of fatigue for both physiological
nd psychological causes. Finally, potential phar-acological and behavioral interventions to im-
rove fatigue in patients with ESRD are outlined.
DEFINITION OF FATIGUE
Fatigue is a subjective sense of weakness, lackf energy, and tiredness.11 Lee et al12 proposedhat it can be conceptualized as located on aontinuum of exhaustion and tiredness on onend, with energy and vitality at the opposite endf the continuum. This position has been sup-orted by the National Institutes of Health Patient-eported Outcomes Measurement Informationystem initiative, in which the items from the6-Item Short-Form Health Survey (SF-36) vital-ty scale measure fatigue and energy level acrosshe fatigue continuum.13 Ream and Richardson14
escribed fatigue as “a subjective, unpleasantymptom which incorporates total body feelingsanging from tiredness to exhaustion creating annrelenting overall condition which interferesith individuals’ ability to function to their nor-al capacity.” Similar to Lee et al,12 it is our
elief that fatigue is on a continuum with weak-ess, lack of energy, and tiredness on one endnd energy, vitality, and pep at the other extreme.
The theoretical frameworks for understandingatigue include the theories of: (1) unpleasantymptoms, (2) peripheral and central fatigue, and3) a multidimensional fatigue experience in pa-ients with ESRD. According to the theory ofnpleasant symptoms by Lenz et al,15 factorsontributing to fatigue can be categorized ashysiological, psychological, and sociodemo-raphic, all of which have multiple complex andeciprocal interactions with fatigue. There are aariety of interactions among the contributingactors and various symptoms resulting in aynergistic impact on the performance variables,hich, in turn, reciprocally influence the symp-
oms and contributing factors.15 Chaudhuri and
ehan16 introduced the concept of central versus weripheral fatigue. Central fatigue is defined asthe failure to initiate and/or sustain attentionasks (mental fatigue) and physical activitiesphysical fatigue) requiring self motivation.” Pe-ipheral or motor fatigue is caused by fatigue inither the muscle itself or brain control over theuscle.16 Lee et al17 categorized the multidimen-
ional fatigue experience of HD patients in Tai-an into 3 inextricably linked domains: physi-
al, affective, and cognitive. These theoreticalrameworks emphasize the multidimensional as-ects of fatigue and suggest that physiological,sychological, and sociodemographic factors con-ribute to fatigue.
One approach to this multidimensional symp-om has been to operationalize this complex setf symptoms by developing and subsequentlypplying criteria to identify patients with clini-ally important fatigue. Criteria proposed byella et al18 for defining cancer-related fatigueould be extrapolated to develop criteria specificor ESRD-related fatigue. Criteria for cancer-elated fatigue include the presence of significantatigue every day or nearly every day during theame 2-week period in the past month. In addi-ion, there is the presence of 5 or more of theollowing symptoms: generalized weakness orimb heaviness, diminished concentration, de-reased interest in engaging in usual activities,nsomnia or hypersomnia, unrefreshing sleep,erceived need to struggle to overcome inactiv-ty, marked emotional reactivity to feeling fa-igued, difficulty completing daily tasks, per-eived problems with short-term memory, andostexertional malaise lasting several hours.18
he use of criteria to define clinically importantatigue would help with better understanding ofhe prevalence and predictors of fatigue in theSRD population.
MEASUREMENT OF FATIGUE
There are a number of choices when selectingbrief assessment tool for fatigue in patientsith ESRD. The most widely used instrument in
he dialysis population is the vitality scale of theF-36.19,20 The SF-36 vitality subscale, whichonsists of 4 items, is considered to be at one endf a spectrum of fatigue. The vitality constructaptures a mild reduction in energy level, but failso capture the negative aspects of fatigue, such as
eakness, lack of motivation, and difficulty with
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Fatigue in Dialysis 355
oncentration. In addition to the SF-36, a numberf symptom indexes use single items to measurehe presence and severity of fatigue.7,21 Fatiguecales vary in brevity, reliability, and responsive-ess to interventions, and most have not beenalidated in the chronic kidney disease popula-ion, although the Revised-Piper Fatigue Scale,omposed of 22 items, has been shown to beeliable.22,23 The Multidimensional Fatigue In-entory has also been used to capture overallatigue.24 However, the HD population showedifficulty with comprehension of this instrument,nd there was poor internal-consistency reliabil-ty.25 Multiple aspects of fatigue and its impactn daily life are measured by using the Func-ional Assessment of Chronic Illness Therapyatigue. In patients with cancer and rheumatoidrthritis, the Functional Assessment of Chronicllness Therapy Fatigue scale has shown excel-ent reliability and strong association with theitality scales of the SF-36.26-29
Although most fatigue instruments measurehe overall experience of fatigue during a periodanging from weeks to months, dialysis patientslso experience day-to-day and diurnal variationn fatigue. Fatigue assessments using traditionalnstruments may fail to capture this variabilityecause of recall bias. Ecological momentaryssessment provides an important measurementool to assess subjective fatigue repeatedly andeliably while avoiding recall bias. Ecologicalomentary assessment incorporates repeated
eal-time measurement of such phenomena asymptoms, behaviors, or physiological processess they occur in naturalistic settings.30-32 It maye that a real-time or experiential assessment ofatigue would provide additional informationbout the experience of dialysis patients, leadingo improved treatment of severe fatigue.
CONTRIBUTORS TO FATIGUE IN ESRD
In the dialysis population, physiological, be-avioral, treatment-related, and individual char-cteristics may correlate with fatigue (Fig 1).hysiological causes include anemia, malnutri-
ion, uremia, dialysis inadequacy, hyperparathy-oidism, coexisting chronic illnesses, sleep disor-ers, depression, and side effects of medications.ietary and fluid restriction may also have a
ole.33 Physical inactivity has been associated
ith greater levels of fatigue.34 Sociodemo- braphic factors, including age, sex, race, educa-ional, marital, and vocational status, may alsoave a role in the experience of fatigue in dialy-is patients.35,36 In a study of HD patients inaiwan, greater levels of fatigue were reportedy female, older, and unemployed patients.35 Itlso is important to note that proinflammatoryytokines have emerged as potential mediatorsf fatigue, providing a common biological path-ay for physiological, behavioral, and treatment-
elated factors to cause fatigue in the dialysisopulation.
nflammation andFatigue
Multiple clinical and animal studies havehown a relationship between “sickness behav-or,” which includes a constellation of such symp-oms as fatigue, and changes in proinflammatoryytokine levels.37 ESRD is an inflammatory stateharacterized by increased circulating levels ofroinflammatory cytokines.38-41 Although theauses of increased cytokine levels in these pa-ients are not fully understood, it has been sug-ested that patients with ESRD have overproduc-ion of cytokines by peripheral-blood mononuclearells secondary to chronic activation by interactionith dialysis membranes.42-44 Moreover, in pa-
ients with this complex pathological condition,he possibility of intrinsic alterations of signalingathways and immune defects cannot be ex-luded.45 Interleukin 6 (IL-6), C-reactive pro-ein, and tumor necrosis factor � (TNF-�) have
Figure 1. Factors contributing to fatigue in ESRD.
een associated with mortality, decreased muscle
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Jhamb et al356
trength, and “vital exhaustion” in the elderlynd patients after myocardial infarction.46-49
able 1 lists a number of human studies thatinked inflammatory cytokines to fatigue in bothging patients and those with such chronic healthonditions as cancer and chronic fatigue syn-rome.55-57 Interestingly, increased levels ofroinflammatory cytokines have been linked ton increase in energy expenditure and mortalitynd lower functional status in HD patients.50,58,59
n a recent study of 30 HD patients, greater IL-6evels were associated with significantly greaterevels of resting energy expenditure,50 whichas previously associated with greater mortality
n HD and peritoneal dialysis (PD) patients.50,58-61
Cytokines might contribute to fatigue by directlyctivating the central nervous system, hypotha-amic pituitary, and adrenal axis or indirectly trig-ering multisystem deregulation caused by chronicnflammation.60 For example, interferon produceseurasthenia, a neurological fatigue suggestive ofrontal lobe changes manifesting as lack of motiva-ion.61 Cytokines, such as IL-1, IL-6, and TNF-�,uppress erythropoiesis and have been hypoth-sized to be contributing to anemia and fatigue inatients with cancer.56 Cytokines (IL-6 and TNF)rigger hyperresponsiveness of muscular ergorecep-ors, which sense fatigue or the work performed byhe muscle and thus contribute to fatigue.62 Cyto-ine-mediated malnutrition and hypoalbuminemiaay also contribute to fatigue. Animal studies sug-
est that IL-6 decreases hepatic albumin synthesis,nd serum IL-6 levels have been inversely relatedo albumin levels in patients with lymphoma.57
L-6 also induces protein catabolism, lipolysis, andnsulin resistance and has been shown to have atrong negative correlation with serum albuminevels in patients undergoing HD.42,63 Cytokinesay also mimic leptin and target hypothalamic
eurons regulating food intake and energy expendi-ure, resulting in decreased appetite and a hyper-etabolic state.56 In addition to their direct effects
n muscle and the nervous system, cytokines aressociated with sleep disorders, depression, anxi-ty, and physical inactivity and may mediate fa-igue through these conditions.64-68
nemia andFatigue
The use of erythropoietin-stimulating agentso correct anemia in dialysis patients has been
hown to improve HRQOL, fatigue, exercise polerance, and work capacity.69,70 A systematiceview of erythropoietin-stimulating agentherapy in patients with renal insufficiency andancer showed a consistently positive relation-hip between HRQOL and hematocrit, with thetrongest effect on the energy/fatigue domains.71
hese findings were confirmed by a meta-nalysis of the impact of epoetin alfa in patientsith chronic kidney disease.72 More recently, 2
tudies of predialysis patients with chronic kid-ey disease, the Correction of Hemoglobin Out-omes in Renal Insufficiency (CHOIR) Studynd the Cardiovascular Risk Reduction by Earlynemia Treatment with Epoetin Beta (CREATE)tudy, compared HRQOL in patients with higherersus lower target hemoglobin levels.73,74 TheREATE Study reported significantly improved
atigue symptoms in patients with higher hemo-lobin levels, whereas the CHOIR Study did nothow significant differences between the 2 groups.owever, the lack of association between ane-ia and fatigue in recent studies may relate to
he relatively greater targeted hemoglobin levelsor the control groups in the post-erythropoietinra.26 Although anemia resulting from reducedrythropoietin production has been cited as anmportant contributor to fatigue in both the dialy-is population and patients with other chroniconditions,75 the optimal hemoglobin target isnclear and may vary among individuals depend-ng on the severity of fatigue.
iochemicalMarkers andFatigue
Although it is believed that uremic syndromeay manifest as fatigue and weakness, the asso-
iation between fatigue and such biochemicalarkers as albumin, creatinine, Kt/V, urea reduc-
ion ratio, phosphate, and calcium has been incon-istent.25,75,76 Uremia may lead to protein andnergy malnutrition, nausea, and loss of appetite,hich can all contribute to fatigue.77 However,
tudies have shown no significant associationsmong fatigue and biochemical variables, includ-ng serum albumin level.25,75 Metabolic derange-
ents in patients with uremia may cause defi-iency of carnitine, which is required for energyeneration by skeletal muscles.78 Intravenous-carnitine supplementation has significantly im-roved fatigue in a small randomized trial of HD
atients.79
Table 1. Role of Cytokines and Inflammation in Fatigue in Populations With Chronic Health Conditions
Reference Subjects Cytokines Fatigue-Related Outcomes Results
Kamimura et al,50 2007 30 HD and 11 controls IL-6 Resting energy expenditure IL-6 is positively associated with resting energyexpenditure (which is positively associatedwith greater mortality in HD and PDpatients51)
Janszky et al,48 2005 235 Women survivors after acutemyocardial infarction
IL-6, hs-CRP, IL-1ra Self-rated health, vitalexhaustion, depression
Positive correlation between IL-6 and hs-CRPand vital exhaustion and poor self-ratedhealth
Schubert et al,52 2007 Meta-analysis of 18 studies(1,037 subjects) of cancer-related fatigue
Multiple cytokines Fatigue in cancer patients Significant positive correlation between fatigueand IL-6, IL-1ra, and neopterin; nosignificant correlation with IL-1� or TNF-�
Cesari et al,46 2004 1,020 elderly (� 65 y) enrolled inInCHIANTI Study
IL-6, IL-6sR, IL-1ra, IL-10,IL-1�, TNF-�, CRP
Physical performance andmuscle strength
High IL-6, IL-1ra, and CRP levels areassociated with poor physical performanceand muscle strength in older persons
Collado-Hidalgoet al,53 2006
50 breast cancer survivors � 2 yafter successful primarytherapy
IL-6, TNF-� production afterlipopolysaccharidestimulation, IL-1ra, sIL-6receptor
Fatigue in breast cancersurvivors
Increased production of IL-6, TNF-� afterlipopolysaccharide stimulation and higherIL-1ra and sIL-6 receptor levels in fatiguedpatients
Meyers et al,54 2005 54 patients with acutemyelogenous leukemia/myelodysplastic syndrome
IL-6, IL-1ra, IL-8, and TNF-� Cognitive function, fatigue,quality of life
Higher IL-6, IL-1ra, and TNF-� are associatedwith fatigue
Abbreviations: HD, hemodialysis; PD, peritoneal dialysis; IL-6, interleukin 6; IL-1ra, IL-1 receptor antagonist; sIL-6, soluble IL-6; hs-CRP, high-sensitivity C-reactive protein;TNF-�, tumor necrosis factor �; InCHIANTI, Invecchiare in Chianti, Aging in the Chianti area Study 1.
Fatigue
inD
ialysis357
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Jhamb et al358
The treatment of patients with uremia by meansf dialysis may also influence fatigue becausehe mode and frequency of dialysis are associ-ted with fatigue. The potential impact of dialy-is modality was shown in the Choices for Healthutcomes in Caring for ESRD Study comparingRQOL in conventional HD and PD patients.here was no significant difference in vitalitycores between HD and PD patients at the initia-ion of dialysis therapy; however, patients on PDherapy experienced significantly lower vitalityt 1 year.80 Stimuli for inflammatory response inD patients include fluid overload, decreasedytokine clearance, presence of uremia-modifiedroteins, presence of chronic infections, and met-bolic disturbances (including hyperglyce-ia).2,81,82 Last, PD patients often experience
octurnal pruritus and “difficulties finding a com-ortable sleeping position,” resulting in impairedleep quality, which contributes to daytime sleepi-ess and fatigue.83 Fatigue is an important out-ome for quotidian dialysis trials because therequency of dialysis may also affect fatigue inD patients, with some studies showing that
ompared with conventional therapy, quotidianialysis significantly improved perceived energyevel, uremic symptoms, cognitive functioning,nd overall HRQOL.84-86
ostdialysis Fatigue
Post-HD fatigue is a common, often incapaci-ating, symptom17,87,88 and may be improvedith more frequent treatment. Lindsay et al10
tudied postdialysis fatigue in 45 subjects andound a positive association between “time toecover (minutes) from HD” and fatigue; pa-ients with longer recovery time tended to havereater levels of fatigue. Also, the relationshipetween recovery time and fatigue was strongestmmediately after dialysis and weakened progres-ively during the time between sessions. In thistudy, the time to recover from HD also showedsignificant positive association with total dialy-
is stress score, which encompasses an array ofhysical signs and symptoms that can arise dur-ng the HD procedure.10 Ultrafiltration, diffu-ion, osmotic disequilibrium, changes in bloodressure, blood membrane interactions, greaterNF levels, and such psychological factors asepression have all been implicated in the patho-
enesis of postdialysis fatigue.87-89 Postdialysis iatigue has been shown to be less prevalent inaily HD patients. Lindsay et al90 reported thataily HD patients required significantly less timeo recover fully after dialysis compared withontrols (P � 0.001). In another study, minuteso recovery decreased from 397 � 395 in pa-ients undergoing conventional thrice-weekly HDo 30 � 44 in those undergoing quotidian HD at8 months of follow-up.91 Interestingly, longerostdialysis fatigue has been associated withhorter survival.92,93 This suggests that patientsith longer recovery time may have a greateregree of underlying inflammation, which couldontribute to a greater incidence of coronaryrtery disease and mortality.94 Additional studiesre needed to assess the impact of frequent andovel dialysis techniques on postdialysis fatigue.
leep andFatigue
Sleep disorders have been hypothesized to bessociated with fatigue through 2 mechanisms:he disturbance of sleep resulting in daytimeleepiness and the separate underlying biologicalathways associated with a variety of sleep disor-ers. Dialysis patients have high rates of sleeppnea, insomnia, restless legs syndrome, andxcessive daytime sleepiness.95,96 Impaired sleepnitiation, maintenance, and adequacy are associ-ted with significantly lower vitality in both HDnd PD patients.25,83,97 Sleep apnea has beenssociated with lower HRQOL in patients on HDherapy, and those without sleep apnea experi-nce significantly better vitality, social function-ng, and emotional and mental health.98 Otherymptoms, such as restless legs, which are com-on in dialysis patients and affect sleep quality,ay also impact on vitality. In a study of 894
ialysis patients, symptoms of restless legs wereignificantly associated with lower physical andental well-being, lower vitality, higher bodily
ain, and lower sleep quality.96
The relationship of sleep disorders to in-reased inflammatory cytokine levels may helpxplain the association of sleep disorders withatigue in this population. In a recent study of 57D patients, greater IL-18 levels were associatedith poor sleep quality.68 In healthy people,
dministration of TNF-� and IL-1� increasedhe amount of non–rapid eye movement sleepnd decreased rapid eye movement sleep.99 IL-6
s associated with the amount and depth of sleep,
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Fatigue in Dialysis 359
nd higher levels are associated with poorleep.100,101 IL-1� and TNF-� have also beenssociated with sleep disordered breathing inialysis patients.102 In healthy people, increasedNF-� and IL-6 levels have been associatedith circadian rhythm disruption and obstructive
leep apnea independent of obesity.100,103,104 Ad-itional research is warranted to investigate theossible shared biological mechanisms associ-ted with sleep disorders and fatigue.
epression andFatigue
Fatigue and depression are closely interre-ated, and depression may manifest as feelings ofiredness and lack of energy. Depression has alsoorrelated strongly with overall symptom burdennd severity, including fatigue in dialysis patients.7
epression is the most common psychiatric ill-ess in patients with ESRD, with prevalenceates ranging from 15% to 69%.105-107 Depres-ion has been associated with changes in cellularnd humoral immunity, including decreased T-ymphocyte proliferation, natural killer cell activ-ty, and increased production of IL-1, IL-6, andnterferon �.67,108 High levels of IL-6, IL-8, andNF-� have been associated with an increasedrevalence of major depression in older peoplend healthy women.65,67,109,110 Some anti-inflam-atory drugs, including infliximab, ameliorate
epressive symptoms and improve HRQOL.111
pecific to patients with ESRD, Lee et al112
ound that treatment with antidepressants re-ulted in decreased IL-1� levels independent ofesponse to treatment. For patients who re-ponded to treatment with selective serotonineuptake inhibitors, IL-6 levels were lower com-ared with patients who did not respond to treat-ent.112 Thus, although evidence showing a
ausal association between depression and al-ered cytokine levels is lacking, depression mayontribute to fatigue through inflammatory path-ays.
hysical Inactivity andFatigue
Physical inactivity is associated with greaterevels of fatigue in patients with ESRD.34 Inddition, obesity, which has been described as ahronic inflammatory state, may also mediatelterations in levels of certain cytokines, leadingo fatigue.113 Acute exercise results in an inflam-
atory response (eg, increases in white blood i
ell counts, IL-1 levels, and C-reactive proteinevels), whereas regular exercise has an anti-nflammatory effect and reduces proinflamma-ory cytokine levels.66,114,115 However, the effectf physical activity on the immune system maye different in HD patients than in healthydults.116 There also is evidence that muscleatabolism increases in dialysis patients, whichay be caused by insulin resistance, acidosis, or
nflammation. This may lead to muscular fatiguend further physical inactivity.117,118 Dialysisatients have severe exercise limitations thatave been attributed to muscle atrophy and weak-ess, the presence of abnormal mitochondria,nd impaired oxidative capacity.119 Muscle fa-igue, defined as the reduction in force withepeated or sustained contractions, can lead toanifestations of myopathy. Contributors to ex-
essive muscle fatigue in dialysis patients in-lude poor oxidative metabolism, greater accumu-ation of metabolic byproducts, central activationailure, and impaired neuromuscular propaga-ion.120 Endurance training has been shown toncrease muscle strength, power, peak work rate,eak oxygen consumption, fatigability, and physi-al function.121 In addition, exercise rehabilita-ion programs may have morphological and met-bolic benefits in skeletal muscles and improveork capacity.122
INTERVENTIONS TO REDUCE FATIGUE
Because of the complexity of fatigue, a multi-isciplinary approach to treatment should bedopted by nephrologists (Table 2). To addresshe level of fatigue, this symptom first needs toe recognized and accurately measured by healthare providers. All renal providers should re-eive training on identifying and addressing thessue of fatigue. Developing improved methodsf defining and measuring fatigue, includingeal-time or ecological momentary assessment,ill help identify patterns in the severity of
atigue. Because there is no widely accepted toolor screening fatigue in the ESRD population,ealth care providers should consider screeningor a sense of fatigue and tiredness that has aubstantial impact on patients’ functional abili-ies. Given the high rate of sleep disorders,ractitioners should clarify whether the patient isleepy or drowsy, rather than weak and lacking
n energy. If the patient reports that fatigue leads
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Jhamb et al360
o functional impairment, providers should ac-ively consider such common causes as worsen-ng heart failure, chronic fatigue syndrome, hypo-hyroidism, liver disease, depression, sleepisorders, and autoimmune diseases, as well ashe kidney disease–related factors outlined inhis review.
A better understanding of the pathogenesis ofatigue, particularly the role of cytokines, mayelp in designing interventions aimed at reduc-ng inflammation and fatigue. Management ofuch factors as anemia and sleep disorders isundamental. Treatment of depression, anxiety,tress, substance abuse, obesity, and malnutritionay be helpful, although studies substantiating
Table 2. Potential Multidisciplinary Approa
Targeted Area
ncrease health care provider awareness
mprove measurement of fatigue
ddress gaps in understanding pathogenesis of fatigue
est potential therapies for fatigue in patients withESRD
mprove social support for patients with fatigue
Abbreviation: ESRD, end-stage renal disease.
he role of these interventions are lacking. E
There is also a need for further research to testotential therapies for fatigue. Nonpharmacologi-al interventions targeting nutrition, sleep hy-iene, stress management, and treatment of de-ression may potentially decrease fatigue. Somemall studies indicated that acupressure mayelp improve fatigue, depression, and sleep qual-ty in dialysis patients.123,124 Exercise and yogaave also been studied as effective measures inmproving fatigue.121,125 Whether this is causedy the direct effect of muscle strengthening orndirect effect on cytokines (or both) is un-nown. Energy conservation strategies, such ashose used for patients with multiple sclerosis,ay similarly improve fatigue in patients with
Improving Fatigue in Patients With ESRD
Interventions
tion of prevalence, importance, and severity of fatigueng at identifying symptoms of fatigue
opment of criteria for defining fatigueopment of improved fatigue scales specific for thisulationf ecological momentary assessment for measurement of-to-day and diurnal variation in fatigueopment of improved survey modalities, such as telephonerview, computer-assisted interview, and proxyinistration, of interviews to reduce selection bias
ent screening for fatigue
f cytokinesof dialysisency of dialysisoneutral hemodialysis
armacologicalonal therapytherapy and sleep hygieneisemanagement
tive-behavioral treatment of depressiony conservationessureent of substance abuse and dependenceacologicaltopoieticspressants
lyticsarnitinen growth hormone
y members’ and care providers’ education and trainingssing caregiver fatigue
ches to
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NonphNutritiSleepExercStressCogniEnergAcuprTreatmPharmHemaAntideAnxioLevocHuma
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SRD.126 Overall, the bulk of evidence in the
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Fatigue in Dialysis 361
SRD population for potential nonpharmacologi-al intervention consists of small trials assessinghe impact of rehabilitation, exercise, and morerequent HD.
Among the pharmacological measures to im-rove fatigue, there is existing evidence for these of erythropoietin-stimulating agents to re-uce fatigue, as outlined.71,72 Some small trialsuggested that human growth hormone may im-rove fatigue and overall HRQOL in dialysisatients; possible mechanisms were improve-ent in nutritional status (lean body mass and
lbumin level) or changes in levels of certainnflammatory mediators (decrease in TNF-�evel).127,128 Intravenous levocarnitine infusionas also been shown to affect fatigue.79 Psycho-timulants, such as methylphenidate, have shownignificant improvement in cancer-related fa-igue and may be useful in patients with ESRD,lthough evidence supporting this is lacking.129
ecause many patients with ESRD have beenhown to have mood disorders, the physicianhould consider screening for depression andmplement treatment as appropriate.
Last, improving social support for patientsith severe fatigue is crucial and helps the pa-
ient cope with the disabling symptoms. Fatiguend tiredness may extend to the caregiver, whoay provide support for home dialysis or the
are of a child with ESRD. A recent review andeta-ethnography outlined fatigue and tiredness
s major concerns of caregivers of children withSRD.130 Therefore, care for patients with ESRD
ncludes education for the family, as well asddressing fatigue issues in the caregiver.
CONCLUSION
Fatigue is a common and complex phenom-non that significantly decreases HRQOL in di-lysis patients. Although highly prevalent, fa-igue is often an unrecognized and undertreatedymptom in the dialysis population. The lack ofdequate methods for measurement, lack of pro-ider awareness, and the complex pathogenesisf fatigue have confounded the development offfective interventions to treat fatigue. Thus, theres a strong need to develop improved assessmentethods and investigate the role of other contrib-
ting factors, especially inflammatory mediatorsf fatigue in patients with ESRD. A better appre-
iation of these may provide potential targets for dherapeutic interventions in the future. Furtheresearch is needed to evaluate the effectivenessnd impact of these interventions in the optimiza-ion of patient-centered quality of life in theialysis population.
ACKNOWLEDGEMENTSSupport: Dr Unruh was supported by Grants DK66006
nd DK77785 from the National Institute of Diabetes andigestive and Kidney Diseases, by the Paul Teschan Re-
earch Fund, and by the Fresenius Medical Care Youngnvestigator Grant of the National Kidney Foundation.
Financial Disclosure: None.
REFERENCES1. Cardenas DD, Kutner NG: The problem of fatigue in
ialysis patients. Nephron 30:336-340, 19822. Chang WK, Hung KY, Huang JW, Wu KD, Tsai TJ:
hronic fatigue in long-term peritoneal dialysis patients.m J Nephrol 21:479-485, 20013. Laupacis A, Muirhead N, Keown P, Wong C: A disease-
pecific questionnaire for assessing quality of life in patientsn hemodialysis. Nephron 60:302-306, 19924. Murtagh FE, Addington-Hall J, Higginson IJ: The
revalence of symptoms in end-stage renal disease: A system-tic review. Adv Chronic Kidney Dis 14:82-99, 2007
5. Parfrey PS, Vavasour HM, Henry S, Bullock M, GaultH: Clinical features and severity of nonspecific symptoms
n dialysis patients. Nephron 50:121-128, 19886. Unruh M, Benz R, Greene T, et al: Effects of hemodi-
lysis dose and membrane flux on health-related quality ofife in the HEMO Study. Kidney Int 66:355-366, 2004
7. Weisbord SD, Fried LF, Arnold RM, et al: Prevalence,everity, and importance of physical and emotional symp-oms in chronic hemodialysis patients. J Am Soc Nephrol6:2487-2494, 20058. Ramkumar N, Beddhu S, Eggers P, Pappas LM, Cheung
K: Patient preferences for in-center intense hemodialysis.emodial Int 9:281-295, 20059. Weisbord SD, Fried LF, Mor MK, et al: Renal provider
ecognition of symptoms in patients on maintenance hemo-ialysis. Clin J Am Soc Nephrol 2:960-967, 200710. Lindsay RM, Heidenheim PA, Nesrallah G, Garg AX,
uri R: Minutes to recovery after a hemodialysis session: Aimple health-related quality of life question that is reliable,alid, and sensitive to change. Clin J Am Soc Nephrol:952-959, 200611. Stone P, Richards M, Hardy J: Fatigue in patients
ith cancer. Eur J Cancer 34:1670-1676, 199812. Lee KA, Hicks G, Nino-Murcia G: Validity and
eliability of a scale to assess fatigue. Psychiatry Res 36:291-98, 199113. Lai JS, Chen WH: Fatigue Archival Analysis Report.
vailable at: www.nihpromis.org. Accessed March 3, 200814. Ream E, Richardson A: Fatigue: A concept analysis.
nt J Nurs Stud 33:519-529, 199615. Lenz ER, Pugh LC, Milligan RA, Gift A, Suppe F:
he middle-range theory of unpleasant symptoms: An up-
ate. ANS Adv Nurs Sci 19:14-27, 1997
J
TJ
Wt
oN
rp
tsb
Pi5
RrF
Mq3
f3
FsD
cDL
Brtge2
Kt(1
cc
st
a
c3
p
aA
s
ep
c2
oO
pd
ts2
ccK
socb
pp9
rb
LmI1
mI2
em
Adn
i
Jhamb et al362
16. Chaudhuri A, Behan PO: Fatigue and basal ganglia.Neurol Sci 179:S34-S42, 2000 (suppl 1-2)17. Lee BO, Lin CC, Chaboyer W, Chiang CL, Hung CC:
he fatigue experience of haemodialysis patients in Taiwan.Clin Nurs 16:407-413, 200718. Cella D, Peterman A, Passik S, Jacobsen P, Breitbart: Progress toward guidelines for the management of fa-
igue. Oncology (Williston Park) 12:369-377, 199819. Kalantar-Zadeh K, Unruh M: Health related quality
f life in patients with chronic kidney disease. Int Urolephrol 37:367-378, 200520. Unruh ML, Weisbord SD, Kimmel PL: Health-
elated quality of life in nephrology research and clinicalractice. Semin Dial 18:82-90, 200521. Davison SN, Jhangri GS, Johnson JA: Cross-sec-
ional validity of a modified Edmonton symptom assessmentystem in dialysis patients: A simple assessment of symptomurden. Kidney Int 69:1621-1625, 200622. Dagnelie PC, Pijls-Johannesma MC, Pijpe A, et al:
sychometric properties of the revised Piper Fatigue Scalen Dutch cancer patients were satisfactory. J Clin Epidemiol9:642-649, 200623. Piper BF, Dibble SL, Dodd MJ, Weiss MC, Slaughter
E, Paul SM: The revised Piper Fatigue Scale: Psychomet-ic evaluation in women with breast cancer. Oncol Nursorum 25:677-684, 199824. Smets EM, Garssen B, Bonke B, De Haes JC: Theultidimensional Fatigue Inventory (MFI) psychometric
ualities of an instrument to assess fatigue. J Psychosom Res9:315-325, 199525. McCann K, Boore JR: Fatigue in persons with renal
ailure who require maintenance haemodialysis. J Adv Nurs2:1132-1142, 200026. Chandran V, Bhella S, Schentag C, Gladman DD:
unctional assessment of chronic illness therapy-fatiguecale is valid in patients with psoriatic arthritis. Ann Rheumis 66:936-939, 200727. Tyring S, Gottlieb A, Papp K, et al: Etanercept and
linical outcomes, fatigue, and depression in psoriasis:ouble-blind placebo-controlled randomised phase III trial.ancet 367:29-35, 200628. Wadler S, Brain C, Catalano P, Einzig AI, Cella D,
enson AB III: Randomized phase II trial of either fluorou-acil, parenteral hydroxyurea, interferon-alpha-2a, and filgras-im or doxorubicin/docetaxel in patients with advancedastric cancer with quality-of-life assessment: Eastern Coop-rative Oncology Group Study E6296. Cancer J 8:282-286,00229. Yellen SB, Cella DF, Webster K, Blendowski C,
aplan E: Measuring fatigue and other anemia-related symp-oms with the Functional Assessment of Cancer TherapyFACT) measurement system. J Pain Symptom Manage3:63-74, 199730. Curran SL, Beacham AO, Andrykowski MA: Ecologi-
al momentary assessment of fatigue following breast can-er treatment. J Behav Med 27:425-444, 2004
31. Hacker ED, Ferrans CE: Ecological momentary as-essment of fatigue in patients receiving intensive cancerherapy. J Pain Symptom Manage 33:267-275, 2007
32. Moskowitz DS, Young SN: Ecological momentary
ssessment: What it is and why it is a method of the future in mlinical psychopharmacology. J Psychiatry Neurosci1:13-20, 200633. Pagels A, Heiwe S, Hylander B: [Nutritional status of
re-dialysis patients]. EDTNA ERCA J 32:162-166, 200634. Brunier GM, Graydon J: The influence of physical
ctivity on fatigue in patients with ESRD on hemodialysis.NNA J 20:457-461; discussion 62, 521, 1993.35. Liu HE: Fatigue and associated factors in hemodialy-
is patients in Taiwan. Res Nurs Health 29:40-50, 200636. Unruh M, Miskulin D, Yan G, et al: Racial differ-
nces in health-related quality of life among hemodialysisatients. Kidney Int 65:1482-1491, 200437. Dantzer R, Kelley KW: Twenty years of research on
ytokine-induced sickness behavior. Brain Behav Immun1:153-160, 200738. Ganz PA, Bower JE: Cancer related fatigue: A focus
n breast cancer and Hodgkin’s disease survivors. Actancol 46:474-479, 200739. Rao M, Wong C, Kanetsky P, et al: Cytokine gene
olymorphism and progression of renal and cardiovasculariseases. Kidney Int 72:549-556, 200740. Bergstrom J, Lindholm B, Lacson E Jr, et al: What are
he causes and consequences of the chronic inflammatorytate in chronic dialysis patients? Semin Dial 13:163-175,00041. Herbelin A, Nguyen AT, Zingraff J, Urena P, Des-
amps-Latscha B: Influence of uremia and hemodialysis onirculating interleukin-1 and tumor necrosis factor alpha.idney Int 37:116-125, 199042. Memoli B, Minutolo R, Bisesti V, et al: Changes of
erum albumin and C-reactive protein are related to changesf interleukin-6 release by peripheral blood mononuclearells in hemodialysis patients treated with different mem-ranes. Am J Kidney Dis 39:266-273, 200243. Girndt M, Sester U, Kaul H, Kohler H: Production of
roinflammatory and regulatory monokines in hemodialysisatients shown at a single-cell level. J Am Soc Nephrol:1689-1696, 199844. Memoli B, Libetta C, Rampino T, et al: Hemodialysis
elated induction of interleukin-6 production by peripherallood mononuclear cells. Kidney Int 42:320-326, 199245. Le Meur Y, Lorgeot V, Aldigier JC, Wijdenes J,
eroux-Robert C, Praloran V: Whole blood production ofonocytic cytokines (IL-1beta, IL-6, TNF-alpha, sIL-6R,
L-1Ra) in haemodialysed patients. Nephrol Dial Transplant4:2420-2426, 199946. Cesari M, Penninx BW, Pahor M, et al: Inflammatoryarkers and physical performance in older persons: The
nCHIANTI Study. J Gerontol A Biol Sci Med Sci 59:242-48, 200447. Harris TB, Ferrucci L, Tracy RP, et al: Associations of
levated interleukin-6 and C-reactive protein levels withortality in the elderly. Am J Med 106:506-512, 199948. Janszky I, Lekander M, Blom M, Georgiades A,
hnve S: Self-rated health and vital exhaustion, but notepression, is related to inflammation in women with coro-ary heart disease. Brain Behav Immun 19:555-563, 200549. Visser M, Pahor M, Taaffe DR, et al: Relationship of
nterleukin-6 and tumor necrosis factor-alpha with muscle
ass and muscle strength in elderly men and women: The
H5
SRp
ed
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Ib2
mmc
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km1
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RepSS
cT
JhC
er
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Bd
da
m2
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Aci1
qtN
dpI
OT
Fatigue in Dialysis 363
ealth ABC Study. J Gerontol A Biol Sci Med Sci7:M326-M332, 200250. Kamimura MA, Draibe SA, Dalboni MA, et al:
erum and cellular interleukin-6 in haemodialysis patients:elationship with energy expenditure. Nephrol Dial Trans-lant 22:839-844, 200751. Wang AY, Sea MM, Tang N, et al: Resting energy
xpenditure and subsequent mortality risk in peritonealialysis patients. J Am Soc Nephrol 15:3134-3143, 200452. Schubert C, Hong S, Natarajan L, Mills PJ, Dimsdale
E: The association between fatigue and inflammatory markerevels in cancer patients: A quantitative review. Brain Behavmmun 21:413-427, 2007
53. Collado-Hidalgo A, Bower JE, Ganz PA, Cole SW,rwin MR: Inflammatory biomarkers for persistent fatigue inreast cancer survivors. Clin Cancer Res 12:2759-2766,00654. Meyers CA, Albitar M, Estey E: Cognitive impair-ent, fatigue, and cytokine levels in patients with acuteyelogenous leukemia or myelodysplastic syndrome. Can-
er 104:788-793, 200555. Buchwald D, Wener MH, Pearlman T, Kith P: Mark-
rs of inflammation and immune activation in chronic fa-igue and chronic fatigue syndrome. J Rheumatol 24:372-76, 199756. Kurzrock R: The role of cytokines in cancer-related
atigue. Cancer 92:S1684-S1688, 2001 (suppl 6)57. Seymour JF, Talpaz M, Cabanillas F, Wetzler M,
urzrock R: Serum interleukin-6 levels correlate with prog-osis in diffuse large-cell lymphoma. J Clin Oncol 13:575-82, 199558. Balakrishnan VS, Guo D, Rao M, et al: Cytokine
ene polymorphisms in hemodialysis patients: Associationith comorbidity, functionality, and serum albumin. Kidney
nt 65:1449-1460, 200459. Kimmel PL, Phillips TM, Simmens SJ, et al: Immuno-
ogic function and survival in hemodialysis patients. Kidneynt 54:236-244, 1998
60. Hopkins SJ: Central nervous system recognition oferipheral inflammation: A neural, hormonal collaboration.cta Biomed 78:S231-S247, 2007 (suppl 1)61. Adams F, Quesada JR, Gutterman JU: Neuropsychiat-
ic manifestations of human leukocyte interferon therapy inatients with cancer. JAMA 252:938-941, 198462. Piepoli M, Clark AL, Volterrani M, Adamopoulos S,
leight P, Coats AJ: Contribution of muscle afferents to theemodynamic, autonomic, and ventilatory responses to exer-ise in patients with chronic heart failure: Effects of physicalraining. Circulation 93:940-952, 1996
63. Bologa RM, Levine DM, Parker TS, et al: Interleu-in-6 predicts hypoalbuminemia, hypocholesterolemia, andortality in hemodialysis patients. Am J Kidney Dis 32:107-
14, 199864. Brambilla F, Bellodi L, Perna G, Bertani A, Panerai
, Sacerdote P: Plasma interleukin-1 beta concentrations inanic disorder. Psychiatry Res 54:135-142, 199465. Bremmer MA, Beekman AT, Deeg DJ, et al: Inflam-atory markers in late-life depression: Results from a popu-
ation-based study. J Affect Disord 106:249-255, 200866. Kasapis C, Thompson PD: The effects of physical
ctivity on serum C-reactive protein and inflammatory mark- 2
rs: A systematic review. J Am Coll Cardiol 45:1563-1569,00567. Trzonkowski P, Mysliwska J, Godlewska B, et al:
mmune consequences of the spontaneous pro-inflammatorytatus in depressed elderly patients. Brain Behav Immun8:135-148, 200468. Yang JY, Huang JW, Chiang CK, et al: Higher plasma
nterleukin-18 levels associated with poor quality of sleep ineritoneal dialysis patients. Nephrol Dial Transplant 22:3606-609, 200769. Moreno F, Sanz-Guajardo D, Lopez-Gomez JM, Jofre
, Valderrabano F: Increasing the hematocrit has a beneficialffect on quality of life and is safe in selected hemodialysisatients. Spanish Cooperative Renal Patients Quality of Lifetudy Group of the Spanish Society of Nephrology. J Amoc Nephrol 11:335-342, 200070. Mann JF: What are the short-term and long-term
onsequences of anaemia in CRF patients? Nephrol Dialransplant 14:S29-S36, 1999 (suppl 2)71. Ross SD, Fahrbach K, Frame D, Scheye R, Connelly
E, Glaspy J: The effect of anemia treatment on selectedealth-related quality-of-life domains: A systematic review.lin Ther 25:1786-1805, 200372. Jones M, Ibels L, Schenkel B, Zagari M: Impact of
poetin alfa on clinical end points in patients with chronicenal failure: A meta-analysis. Kidney Int 65:757-767, 2004
73. Drueke TB, Locatelli F, Clyne N, et al: Normalizationf hemoglobin level in patients with chronic kidney diseasend anemia. N Engl J Med 355:2071-2084, 2006
74. Singh AK, Szczech L, Tang KL, et al: Correction ofnemia with epoetin alfa in chronic kidney disease. N EnglMed 355:2085-2098, 200675. Ossareh S, Roozbeh J, Krishnan M, Liakopoulos V,
argman JM, Oreopoulos DG: Fatigue in chronic peritonealialysis patients. Int Urol Nephrol 35:535-541, 200376. Chikotas N, Gunderman A, Oman T: Uremic syn-
rome and end-stage renal disease: Physical manifestationsnd beyond. J Am Acad Nurse Pract 18:195-202, 2006
77. Pupim LB, Cuppari L, Ikizler TA: Nutrition andetabolism in kidney disease. Semin Nephrol 26:134-157,
00678. Schreiber B: Levocarnitine and dialysis: A review.
utr Clin Pract 20:218-243, 200579. Brass EP, Adler S, Sietsema KE, Hiatt WR, Orlando
M, Amato A: Intravenous L-carnitine increases plasmaarnitine, reduces fatigue, and may preserve exercise capac-ty in hemodialysis patients. Am J Kidney Dis 37:1018-028, 200180. Wu AW, Fink NE, Marsh-Manzi JV, et al: Changes in
uality of life during hemodialysis and peritoneal dialysisreatment: Generic and disease specific measures. J Am Socephrol 15:743-753, 200481. Cueto-Manzano AM, Gonzalez-Espinoza L, Martin
el Campo F, Fortes PC, Pecoits-Filho R: Inflammation ineritoneal dialysis: A Latin-American perspective. Perit Dialnt 27:347-352, 2007
82. Pecoits-Filho R, Stenvinkel P, Wang AY, Heimburger, Lindholm B: Chronic inflammation in peritoneal dialysis:he search for the holy grail? Perit Dial Int 24:327-339,
004
sn2
S
d1
Hs
Fs
A
ba1
s
PK
pv2
Ct1
LT
pt
Pda
aN
br
Ga
sI
palE
s
Oh1
Add1
msh
Dr
Ts
aC
msB
Emat1
Sw
as3
ra
Pwo2
lC
saR
Kd
Jhamb et al364
83. Yngman-Uhlin P, Edell-Gustafsson U: Self-reportedubjective sleep quality and fatigue in patients with perito-eal dialysis treatment at home. Int J Nurs Pract 12:143-152,00684. Kutner NG: Quality of life and daily hemodialysis.
emin Dial 17:92-98, 200485. Suri RS, Nesrallah GE, Mainra R, et al: Daily hemo-
ialysis: A systematic review. Clin J Am Soc Nephrol:33-42, 200686. Suri RS, Garg AX, Chertow GM, et al: Frequent
emodialysis Network (FHN) randomized trials: Study de-ign. Kidney Int 71:349-359, 2007
87. Sklar A, Newman N, Scott R, Semenyuk L, Schultz J,iacco V: Identification of factors responsible for postdialy-is fatigue. Am J Kidney Dis 34:464-470, 1999
88. Sklar AH, Riesenberg LA, Silber AK, Ahmed W, Ali: Postdialysis fatigue. Am J Kidney Dis 28:732-736, 199689. Dreisbach AW, Hendrickson T, Beezhold D, Riesen-
erg LA, Sklar AH: Elevated levels of tumor necrosis factorlpha in postdialysis fatigue. Int J Artif Organs 21:83-86,99890. Lindsay RM, Kortas C: Hemeral (daily) hemodialy-
is. Adv Ren Replace Ther 8:236-249, 200191. Heidenheim AP, Muirhead N, Moist L, Lindsay RM:
atient quality of life on quotidian hemodialysis. Am Jidney Dis 42:S36-S41, 2003 (suppl 1)92. Kutner NG, Brogan D, Fielding B: Physical and
sychosocial resource variables related to long-term sur-ival in older dialysis patients. Geriatr Nephrol Urol 7:23-8, 199793. Kutner NG, Lin LS, Fielding B, Brogan D, Hall WD:
ontinued survival of older hemodialysis patients: Investiga-ion of psychosocial predictors. Am J Kidney Dis 24:42-49,99494. Aukrust P, Yndestad A, Smith C, Ueland T, Gullestad
, Damas JK: Chemokines in cardiovascular risk prediction.hromb Haemost 97:748-754, 200795. Merlino G, Piani A, Dolso P, et al: Sleep disorders in
atients with end-stage renal disease undergoing dialysisherapy. Nephrol Dial Transplant 21:184-190, 2006
96. Unruh ML, Levey AS, D’Ambrosio C, Fink NE,owe NR, Meyer KB: Restless legs symptoms among inci-ent dialysis patients: Association with lower quality of lifend shorter survival. Am J Kidney Dis 43:900-909, 2004
97. Unruh ML, Buysse DJ, Dew MA, et al: Sleep qualitynd its correlates in the first year of dialysis. Clin J Am Socephrol 1:802-810, 200698. Sanner BM, Tepel M, Esser M, et al: Sleep-related
reathing disorders impair quality of life in haemodialysisecipients. Nephrol Dial Transplant 17:1260-1265, 2002
99. Krueger JM, Fang J, Taishi P, Chen Z, Kushikata T,ardi J: Sleep. A physiologic role for IL-1 beta and TNF-
lpha. Ann N Y Acad Sci 856:148-159, 1998100. Mills PJ, Dimsdale JE: Sleep apnea: A model for
tudying cytokines, sleep, and sleep disruption. Brain Behavmmun 18:298-303, 2004
101. Vgontzas AN, Zoumakis M, Bixler EO, et al: Im-aired nighttime sleep in healthy old versus young adults isssociated with elevated plasma interleukin-6 and cortisolevels: Physiologic and therapeutic implications. J Clin
ndocrinol Metab 88:2087-2095, 2003 p102. Gul A, Aoun N, Trayner EM Jr: Why do patientsleep on dialysis? Semin Dial 19:152-157, 2006
103. Entzian P, Linnemann K, Schlaak M, Zabel P:bstructive sleep apnea syndrome and circadian rhythms oformones and cytokines. Am J Respir Crit Care Med 153:080-1086, 1996104. Vgontzas AN, Papanicolaou DA, Bixler EO, Kales
, Tyson K, Chrousos GP: Elevation of plasma cytokines inisorders of excessive daytime sleepiness: Role of sleepisturbance and obesity. J Clin Endocrinol Metab 82:313-1316, 1997105. Hedayati SS, Bosworth HB, Kuchibhatla M, Kim-el PL, Szczech LA: The predictive value of self-report
cales compared with physician diagnosis of depression inemodialysis patients. Kidney Int 69:1662-1668, 2006106. Kimmel PL, Cukor D, Cohen SD, Peterson RA:
epression in end-stage renal disease patients: A criticaleview. Adv Chronic Kidney Dis 14:328-334, 2007
107. Watnick S, Kirwin P, Mahnensmith R, Concato J:he prevalence and treatment of depression among patientstarting dialysis. Am J Kidney Dis 41:105-110, 2003
108. Bosker FJ, Westerink BH, Cremers TI, et al: Futurentidepressants: What is in the pipeline and what is missing?NS Drugs 18:705-732, 2004109. Penninx BW, Kritchevsky SB, Yaffe K, et al: Inflam-atory markers and depressed mood in older persons: Re-
ults from the Health, Aging and Body Composition Study.iol Psychiatry 54:566-572, 2003110. Suarez EC, Lewis JG, Krishnan RR, Young KH:
nhanced expression of cytokines and chemokines by bloodonocytes to in vitro lipopolysaccharide stimulation are
ssociated with hostility and severity of depressive symp-oms in healthy women. Psychoneuroendocrinology 29:1119-128, 2004
111. Lichtenstein GR, Bala M, Han C, DeWoody K,chaible T: Infliximab improves quality of life in patientsith Crohn’s disease. Inflamm Bowel Dis 8:237-243, 2002112. Lee SK, Lee HS, Lee TB, et al: The effects of
ntidepressant treatment on serum cytokines and nutritionaltatus in hemodialysis patients. J Korean Med Sci 19:384-89, 2004113. Vgontzas AN, Bixler EO, Chrousos GP: Obesity-
elated sleepiness and fatigue: The role of the stress systemnd cytokines. Ann N Y Acad Sci 1083:329-344, 2006
114. Nicklas BJ, Mychaleckyj J, Kritchevsky S, et al:hysical function and its response to exercise: Associationsith cytokine gene variation in older adults with kneesteoarthritis. J Gerontol A Biol Sci Med Sci 60:1292-1298,005115. Wilund KR: Is the anti-inflammatory effect of regu-
ar exercise responsible for reduced cardiovascular disease?lin Sci (Lond) 112:543-555, 2007116. Hung AM, Chertow GM, Young BS, Carey S, Johan-
en KL: Inflammatory markers are unrelated to physicalctivity, performance, and functioning in hemodialysis. Jen Nutr 12:170-176, 2002117. Lee SW, Park GH, Lee SW, Song JH, Hong KC,
im MJ: Insulin resistance and muscle wasting in non-iabetic end-stage renal disease patients. Nephrol Dial Trans-
lant 22:2554-2562, 2007
ka
P
NfR
Esmp
mS
eN
tft
mtM
Hv1
Gil
ea
Hr2
ed
Fatigue in Dialysis 365
118. Rajan JY, Mitch JW: Muscle wasting in chronicidney disease: The role of the ubiquitin proteasome systemnd its clinical impact. Pediatr Nephrol 23:527-535, 2008
119. Fitts RH: Cellular mechanisms of muscle fatigue.hysiol Rev 74:49-94, 1994120. Johansen KL, Doyle J, Sakkas GK, Kent-Braun JA:
eural and metabolic mechanisms of excessive muscleatigue in maintenance hemodialysis patients. Am J Physiolegul Integr Comp Physiol 289:R805-R813, 2005121. Storer TW, Casaburi R, Sawelson S, Kopple JD:
ndurance exercise training during haemodialysis improvestrength, power, fatigability and physical performance inaintenance haemodialysis patients. Nephrol Dial Trans-
lant 20:1429-1437, 2005122. Deligiannis A: Exercise rehabilitation and skeletaluscle benefits in hemodialysis patients. Clin Nephrol 61:46-S50, 2004 (suppl 1)123. Tsay SL: Acupressure and fatigue in patients with
nd-stage renal disease—A randomized controlled trial. Int Jurs Stud 41:99-106, 2004124. Tsay SL, Cho YC, Chen ML: Acupressure and
ranscutaneous electrical acupoint stimulation in improvingatigue, sleep quality and depression in hemodialysis pa-
ients. Am J Chin Med 32:407-416, 2004 r125. Yurtkuran M, Alp A, Yurtkuran M, Dilek K: Aodified yoga-based exercise program in hemodialysis pa-
ients: A randomized controlled study. Complement Thered 15:164-171, 2007126. Mathiowetz VG, Finlayson ML, Matuska KM, Chen
Y, Luo P: Randomized controlled trial of an energy conser-ation course for persons with multiple sclerosis. Mult Scler1:592-601, 2005
127. Feldt-Rasmussen B, Lange M, Sulowicz W, et al:rowth hormone treatment during hemodialysis in a random-
zed trial improves nutrition, quality of life, and cardiovascu-ar risk. J Am Soc Nephrol 18:2161-2171, 2007
128. Kotzmann H, Yilmaz N, Lercher P, et al: Differentialffects of growth hormone therapy in malnourished hemodi-lysis patients. Kidney Int 60:1578-1585, 2001
129. Minton O, Stone P, Richardson A, Sharpe M,otopf M: Drug therapy for the management of cancer
elated fatigue. Cochrane Database Syst Rev 1:CD006704,008130. Tong A, Lowe A, Sainsbury P, Craig JC: Experi-
nces of parents who have children with chronic kidneyisease: A systematic review of qualitative studies. Pediat-
ics 121:349-360, 2008
