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SECTION I. GUIDELINES ON EVALUATION AND
MANAGEMENT OF CARDIOVASCULAR DISEASES
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HE ASSESSMENT and treatment of bothrisk factors and end organs are essential in

he management of cardiovascular diseases. Therst section will deal with the end organs andill focus on cardiac, cerebrovascular and periph-

ral vascular diseases. Cardiac diseases haveustifiably received the most attention becausehey are by far the most common cause ofardiovascular deaths in dialysis patients. Cere-rovascular diseases and peripheral vascular dis-ases, however, also lead to substantial morbid-ty and mortality and have often been overlookedy practitioners and clinical researchers.The workgroup has faced dilemma in the

cope and depth of the coverage of end organiseases. There has been only one small random-zed trial that demonstrated beneficial effects ofpecific cardioprotective drugs (namely, carve-

© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4504-0104$30.00/0

gdoi:10.1053/j.ajkd.2005.01.019

American Journal of K16

ilol) published in dialysis patients. Therefore,ost guidelines described in this section are

eferred from published guidelines in the generalopulation. Nonetheless, there are unusual fea-ures in the dialysis patients that the practitionerseed to be aware of. For example, the pathophysi-logy and rate of progression of cardiac valvularalcification appear to be different from those inhe general population. Surveillance and treat-ent strategies should take these caveats into

onsideration. On the other hand, the implant ofissue valves is proscribed in the existing ACC/HA guidelines. More recent and stronger evi-ence, however, suggest that tissue valves aressociated with equivalent outcomes in dialysisatients. These similarities, not only differences,etween dialysis patients and the general popula-ion also need to be emphasized.

The section on end organ diseases is writtenor not only the nephrologists, but also the gen-ral practitioners, cardiologists, vascular sur-
eons and other practitioners.
idney Diseases, Vol 45, No 4, Suppl 3 (April), 2005: p S16

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GUIDELINE 1: EVALUATION OF CARDIOVASCULAR DISEASE
IN ADULT AND PEDIATRIC PATIENTS
Cardiovascular disease is prevalent in patientseceiving dialysis therapies, and it affects long-erm outcomes as well as the ability to deliverialysis in some situations. Thus, it is importanto evaluate the extent of all aspects of CVD inialysis patients. In those patients with limitedife expectancy due to severe noncardiac comor-idity, evaluation and therapy should be individu-lized.

1.1 At the initiation of dialysis, all pa-tients—regardless of symptoms—re-quire assessment for cardiovascular dis-ease (CAD, cardiomyopathy, valvularheart disease, CBVD, and PVD), as wellas screening for both traditional andnontraditional cardiovascular risk fac-tors. (C)
1.1.a Echocardiograms should be per-
merican Journal of Kidney Diseases, Vol 45, No 4, Suppl 3 (April

formed in all patients at the initia-tion of dialysis, once patients haveachieved dry weight (ideallywithin 1-3 months of dialysis ini-tiation) (A), and at 3-yearly inter-vals thereafter (see Guideline 6).(B)

1.2 Children commencing dialysis shouldbe evaluated for the presence of cardiacdisease (cardiomyopathy and valvulardisease) using echocardiography oncethe patient has achieved dry weight(ideally within 3 months of the initia-tion of dialysis therapy). (C) Childrencommencing dialysis should be screenedfor traditional cardiovascular risk fac-tors such as dyslipidemia and hyperten-
sion. (C)
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GUIDELINE 2: CORONARY ARTERY DISEASE

Ischemic heart disease (IHD) due to atheroscle-otic CAD is common in dialysis patients. Whilets evaluation and treatment are important compo-ents of the ongoing care of dialysis patients,here are special considerations for both thevaluation and treatment in dialysis patients dueo the issues of preservation of kidney function,ascular access, and bleeding tendencies.2.1 The evaluation of CAD in dialysis pa-

tients depends on individual patient sta-tus. (C)2.1.a If the patient is on the kidney

transplant waitlist and is diabetic(and initial evaluation is negativefor CAD), then evaluation for CADevery 12 months is recommended.

2.1.b If the patient is on the transplantwaitlist but is not diabetic and isclassified as “high risk,”* thenevaluation for CAD every 24months is recommended.

2.1.c If the patient is on the transplantwaitlist and is classified as nothigh risk,* then evaluation forCAD every 36 months is recom-mended.

2.1.d If the patient is on the transplantwaitlist with known CAD (andnot revascularized), evaluation forCAD should be performed every12 months.

2.1.e If the patient is on the transplantwaitlist and has a history of PTCAor coronary stent, evaluation forCAD should be performed every12 months.

2.1.f If the patient has “complete” cor-onary revascularization (i.e., allischemic coronary vascular bedsare bypassed), the first re-evalua-tion for CAD should be per-formed 3 years after coronaryartery bypass (CAB) surgery, thenevery 12 months thereafter.

* High-risk (more than 20% per 10 years cardiovascularvent rate risk) according to Framingham data includeshose with two or more “traditional” risk factors, a knownistory of coronary disease, LV ejection fraction �40%, or
VD.53
American Journal of Kidney18

2.1.g If the patient has “incomplete”coronary revascularization afterCAB surgery (i.e., not all isch-emic coronary beds are revascu-larized), then evaluation for CADshould be performed annually.

2.1.h If there is a change in symptomsrelated to IHD or clinical status(e.g., recurrent hypotension, CHFunresponsive to dry weightchanges, or inability to achievedry weight because of hypoten-sion), evaluation for CAD is rec-ommended.

2.1.i Dialysis patients with significantreduction in LV systolic function(EF<40%) should be evaluatedfor CAD.

2.1.j Evaluation for heart diseaseshould occur at initiation of dialy-sis and include a baseline electro-cardiogram (ECG) and echocar-diogram (see Cardiomyopathyguideline for echocardiographyafter dialysis initiation). Both ofthese tests provide informationpertinent to, but not restricted to,CAD evaluation. Annual ECGsare recommended after dialysisinitiation.

2.2 In patients fulfilling 2.1.a-2.1.i above,CAD evaluation should also includeexercise or pharmacological stress echo-cardiographic or nuclear imaging tests.“Automatic” CAD evaluation withstress imaging is currently not recom-mended for all dialysis patients (i.e.,patients not fulfilling 2.1.a-2.1.i). Stressimaging is appropriate (at the discre-tion of the patient’s physician) in se-lected high-risk dialysis patients forrisk stratification even in patients whoare not renal transplant candidates. (C)

2.3 Patients who are candidates for coro-nary interventions and have stress teststhat are positive for ischemia should bereferred for consideration of angio-
graphic assessment. (C)
Diseases, Vol 45, No 4, Suppl 3 (April), 2005: pp S18-S20

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GUIDELINE 2: CORONARY ARTERY DISEASE S19

2.4 Special considerations in dialysis pa-tients regarding CAD evaluation in-clude the following: (C)2.4.a To minimize the risk of potential

volume overload from the perfor-mance of angiographic studies,iso-osmolar radiocontrast media(e.g., iodixanol) should be used.

2.4.b Some dialysis patients have re-sidual renal function; there areno data on the value of “nephro-protective” strategies to reducethe potential risk of contrast ne-phropathy in these patients. Theuse of N-acetylcysteine (and io-dixanol) is appropriate in dialysispatients with residual renal func-tion, as both may offer benefitwithout known harm. Sodium bi-carbonate and hydration are notroutinely recommended, as intra-vascular volume expansion maypose risk to dialysis patients withincreased cardiac filling pressures.

2.5 In patients undergoing invasive coro-nary procedures, it is important toavoid internal jugular sites and to pre-serve brachial and radial arteries forfuture dialysis catheter and arterio-venous fistula creation, respectively. (C)

2.6 Patients undergoing planned invasiveprocedures for evaluation or treatmentof CAD should be assessed for hemor-rhagic risk and presence of anemia, asanticoagulants and/or antiplateletagents may be administered adjunc-tively for percutaneous coronary inter-vention. (C)

RATIONALEAt least a third of incident dialysis patients

ave a history of CAD.54 In some patients, theevelopment of left ventricular (LV) dysfunctionr clinically evident CHF may be a reflection ofnderlying IHD. Evaluation for CAD should beonsidered even in dialysis patients who are notandidates for kidney transplantation, since theyave high event rates for CAD, early hazard ofcute myocardial infarction (MI) after initiationf chronic dialysis, and high mortality rate follow-
ng acute MI. The purposes of using stress imag- r
ng modalities for CAD evaluation are risk strati-cation (i.e., prediction of likelihood of futurevents related to CAD), detection of obstructiveAD, and assessment of myocardial ischemicurden after coronary revascularization and/oredical therapy.

iagnostic Techniques

The optimal modality is strongly dependent onndividual institutional expertise. Exercise ECGs not recommended because of poor exerciseolerance in general, and high prevalence of leftentricular hypertrophy (LVH) in dialysis pa-ients, although published data have suggested aower accuracy for CAD detection in dialysisatients using stress nuclear or echocardio-raphic imaging techniques, compared to theeneral population.55

Stress echocardiography can be performed inifferent ways. Similar to exercise ECG, exer-ise echocardiography is, in general, unsuitableor the majority of dialysis patients due to noncar-iac exercise limitations. Echocardiography, inonjunction with stress by dobutamine, is a stan-ard method. However, it should be cautionedhat this method may be associated with approxi-ately 2%-4% risk of transient atrial fibrillation

n dialysis patients, compared to only 0.5% in theeneral population.56 Stress echocardiographyan also be performed in conjunction with aasodilator, such as adenosine or dipyridamole.he accuracy of this method in dialysis patients

s poorly defined. The combination of dobut-mine and a vasodilator has also been advocatedor stress echocardiography, but there are noublished data on this technique in the dialysisopulation. An advantage of echocardiography ishat prestress imaging can provide additionalnformation on LV ejection fraction and dimen-ions, valvular disease, pulmonary artery pres-ure, and volume status, as well as associatedericardial disease (e.g., pericardial effusion).Weak)

The same techniques of stress can be appliedo nuclear scintigraphy. Stress by exercise poseshe same problem as exercise ECG and exercisechocardiography because of the limited noncar-iac exercise tolerance in dialysis patients. Stressy adenosine and dipyridamole in conjunctionith nuclear scintigraphy is a standard method

ecommended by the American College of Cardi-

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GUIDELINE 2: CORONARY ARTERY DISEASES20

logy (ACC)/American Heart Association (AHA)uideline on imaging. Data on dobutamine-nduced stress scintigraphy in dialysis patientsre very limited. Combined stress using exercisend a vasodilator produced promising results in aingle-center study of dialysis patients,57 but itas not been well examined in diabetic dialysisatients (only 14% of Dahan’s study cohort hadiabetic CKD). For the purpose of risk stratifica-ion, the published data suggest that the accuracyf dobutamine echocardiography and vasodilator-nduced stress nuclear scintigraphy are compa-able in kidney transplant candidates. A meta-nalysis that grouped both techniques togetheround that stress imaging was predictive of fu-ure cardiac death and MI in kidney transplantandidates.58 (Weak)

For the purpose of detecting obstructive CADn dialysis patients, the available data suggesthat vasodilator-induced stress nuclear scintigra-hy is less sensitive than dobutamine echocardi-graphy. These data are predominantly derivedrom diabetic dialysis patients who were beingvaluated for kidney transplantation, as theseatients have been the focus of clinical studies ononinvasive CAD screening. This distinction maye important in monitoring patients for the detec-ion of occult re-stenosis after percutaneous cor-nary intervention.Ultrafast cardiothoracic (CT) scan or electron-

eam computerized tomography (EBCT) can de-ect calcification of the coronary arteries. Lim-ted data suggest that, while EBCT has a potentialole in risk stratification in dialysis patients, thehysiological consequences of coronary calcifi-
ation cannot be assessed by EBCT. The correla-
ion between coronary calcification and luminaliameter in dialysis patients is less certain than inhe general population, since vascular calcifica-ion in this population is often the result ofedial calcification rather than atherosclerosis.t the present time, EBCT (or other ultrafast CT)

s not recommended for the diagnosis of CAD inialysis patients. Experience with cardiac mag-etic resonance imaging (MRI) in dialysis pa-ients is very limited and the technique is notidely available. (Weak)

LIMITATIONS

Most studies deal with patients who are eli-gible for kidney transplantation. There areonly sparse data on general dialysis patients.The specific noninvasive screening method forCAD is dependent on the institution.No decision analysis has been done on thetrade-off of performing angiography versusfurther diminution of residual kidney function.

IMPLEMENTATION ISSUES

The diagnosis of obstructive CAD in patientswho do not have symptoms of myocardialischemia may raise difficult therapeutic issuesin some patients, as the choice of subsequenttreatment is predominantly opinion-based. Ad-ditional costs and potential risks of therapycould be incurred with the diagnosis of previ-ously unsuspected CAD through screening.

RESEARCH RECOMMENDATIONS

Prospective trials are needed to examine theaccuracy of noninvasive imaging in dialysis
patients and its utility for clinical management.

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GUIDELINE 3: ACUTE CORONARY SYNDROMES

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The diagnosis of acute coronary syndromesACS) in dialysis patients and in the generalopulation is usually based on the triad of symp-oms, ECG findings, and cardiac biomarkers.he outcomes of patients on dialysis with ACSre often poor, which may be related to the lackf a consistent and standard approach to thereatment of ACS.

3.1 All dialysis patients presenting withACS should be treated as in the nondi-alysis population, with the exception ofspecific attention to drugs that havealtered clearances in kidney failure (e.g.,low molecular weight heparin). Thesetherapies include percutaneous coro-nary intervention (PCI), CABG, anti-platelet agents, beta-blockers, thrombo-lytic therapy, and lipid-lowering agents.(C)3.1.a Dialysis patients with ST-segment

elevation MI should receive acutereperfusion therapy (as do pa-tients in the nondialysis popula-tion). With the potential forincreased hemorrhagic risk asso-ciated with thrombolytic therapy,emergent PCI is the preferredtreatment if it is available. (C)

3.2 The timing of dialysis in the first 48hours after ACS should take into ac-count individual risk factors. (C)

RATIONALEThere are no data regarding the safety or risk

ssociated with HD in the first 48 hours afterCS. Collaboration between nephrology teams

nd cardiology teams caring for these patientshould take into consideration volume status,lectrolyte disturbances, and bleeding potential.ialysis prescriptions should be adjusted to maxi-ize benefits while reducing the risk of hypoten-

ion during this vulnerable period.The mortality after acute MI (Fig 1) in dialysis

atients has been reported to be approximately5% in 2 years, in part due to inadequate post-MIreatment.7 Prophylactic care that is consideredo be standard in the general population maymprove upon this very poor outcome in dialysisatients. Therefore, the use of aspirin, beta-lockers, angiotensin-converting enzyme (ACE)
nhibitors, and thrombolytic therapy are recom- a

ended although controlled trials in dialysisatients are lacking. These therapies have beenound to be protective in retrospective observa-ional studies in various stages of CKD.8,59-61

bciximab and tirofiban (glycoprotein plateletGP] IIb/IIIa inhibitors) should also be consid-red as adjunctive therapy in ACS in dialysisatients. The use of adjunctive antithromboticnd antiplatelet agents during PCI presents spe-ial problems in dialysis patients, because of thencreased risk of hemorrhage. Bivalirudin is airect thrombin inhibitor specifically studied inialysis patients with dosing recommendationsnd should be preferentially considered. When aPIIb/IIIa antagonist is used, abciximab and

irofiban should be considered preferred agents,ince no dosing changes are required for abcix-mab, and dialysis-specific dosing recommenda-ions are available for tirofiban. Abciximab isypically used for PCI, as the clearance of therug is not altered in dialysis patients. There areKD—but not dialysis—patient studies dealingith this issue. One study reported safety of

bciximab for Cr �2.0 mg/dL,62 while anotherhowed no increase in bleeding for renal failureersus no renal failure for abciximab in PCI.63

owever, increased bleeding with abciximab inenal failure has been reported.64 Increased bleed-ng but reduced in-hospital mortality in CKDatients with ACS treated with IIb/IIIa antago-ists has also been shown.65 (Weak)

Fig 1. Estimated mortality of dialysis patients aftercute MI. Reproduced with permission.7

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GUIDELINE 3: ACUTE CORONARY SYNDROMESS22

LIMITATIONS

There have been very few dialysis-specificclinical trials.It is difficult to assess bleeding diathesis, andtherefore risk associated with GPIIb/IIIa inhibi-tors, in individual dialysis patients.


There may be reluctance of clinicians to
employ fibrinolytic agents for ACS in dialysis
patients due to concerns with hemorrhage. Therisk of hemorrhage in dialysis patients will behigher with fibrinolytic, antithrombotic, andantiplatelet agents.


Clinical trials of ACS treatment are requiredthat specifically target all ranges of CKD,
including dialysis patients.

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GUIDELINE 4: CHRONIC CORONARY ARTERY DISEASE

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The processes by which atherosclerotic dis-ase may be exacerbated by the uremic milieu,nd the outcomes of patients on dialysis withstablished CAD, are worse than outcomes in theeneral population.4.1 The medical management of chronic

CAD in dialysis patients should followthat of the general population. In par-ticular, patients should receive acetylsal-icylic acid (ASA), beta-blockers, nitro-glycerin, ACE inhibitors or angiotensinreceptor blockers (ARB), statins, and/orcalcium-channel blockers (CCB) as in-dicated. Dose adjustments are requiredfor medications that are renally ex-creted or dialyzed. (C)

4.2 Unique aspects of management in thedialysis population include:4.2.a Maintenance of hemodynamic dry

weight. (C)4.2.b Maintenance of hemoglobin lev-

els in accordance with K/DOQIGuidelines.52 (B)

4.2.c Modification of dosing regimensso that cardiovascular medica-tions do not adversely impact thedelivery of dialysis and ultrafiltra-tion. Nocturnal dosing of medica-tions should be considered. (C)

4.2.d Loop diuretics to increase urineoutput may be helpful for thosepatients with substantial residualrenal function. (C)

4.3 In patients with obstructive CAD le-sions, PCI and CABG are appropriaterevascularization techniques. (C)4.3.a Drug-eluting or conventional

stents should be implemented ac-cording to local practice. The inci-dence of restenosis after PCI withdrug-eluting stents is reduced inthe nondialysis population. As therisk of restenosis is higher indialysis patients, the use of drug-eluting stents is favored.

4.3.b Patients with three-vessel and/or Left main disease shouldundergo CABG as preferred
therapy. (C) g

RATIONALE

anagement of CAD (Weak)Maintenance of target dry weight is important

or the management of heart disease. Target dryeight should be periodically assessed because itay change over time. This is particularly true

or diabetic and elderly patients, since theiruscle mass may decline over time. Caution

hould be exercised when using nitrates in lowreload states (e.g., hypovolemia at the end ofD session), as these states may potentiate theypotensive effect of the drug. The hemody-amic and electrophysiological effects of CCBsre markedly different from each other, and theseifferences should be evaluated when selecting auitable therapy.

Clopidogrel is approved in the general popula-ion for the secondary prevention of atheroscle-otic cardiovascular disease (ASCVD) events,ncluding CAD. Most dialysis patients wouldheoretically be candidates for long-term clopi-ogrel therapy. It should be prescribed for allatients with coronary stents and considered inther patients with stable CAD or establishedSCVD. All dialysis patients with CAD who areot allergic to ASA should receive ASA. Thefficacy-to-risk ratio of ASA in combination withlopidogrel—compared to ASA alone—for theecondary prevention of ASCVD events is un-nown in dialysis patients; one undefined risk isemorrhage. There are data indicating a two-foldelative hemorrhagic risk with ASA�clopidogrelersus placebo alone.66 Since it may signifi-antly increase the risk of hemorrhage, clopi-ogrel should be withheld (typically for 1 week)efore major elective surgery. In contrast, with-olding ASA before surgery is usually unneces-ary. Since the use of clopidogrel is mandatoryor at least 30 days after coronary stent place-ent, elective major surgery—including renal

ransplantation—should generally be postponedo allow for discontinuation of clopidogrel be-ore surgery. For this reason, in the immediateoststent period (when clopidogrel is required),t may be appropriate to temporarily suspend thective waitlist status of patients awaiting cadav-ric renal transplantation until the clopidogrelan be discontinued. This decision should beade by consultation of the patient’s nephrolo-

ist, cardiologist, and transplant surgeon (with

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GUIDELINE 4: CHRONIC CORONARY ARTERY DISEASES24

ttention to the clinical profile of the particularatient).

oronary Revascularization (Weak)The short-term and long-term mortality after

oronary revascularization procedures in dialysisatients is considerably higher than those in theeneral population. Coronary revascularizationan be performed with either surgical or percuta-eous approaches. In diabetic dialysis patients,here is no difference in survival between percu-aneous angioplasty with and without stenting. Inontrast, stents offer better outcomes than angio-lasty without stents in nondiabetic dialysis pa-ients. In either diabetic or nondiabetic patients,he mortality at 6-9 months in retrospective stud-es is higher after PCI, compared to coronaryypass surgery, although the mortality after PCIs lower within 90 days after the procedure (seeig 2 and Table 1).55,67 Observational studiesupport the conclusion that surgical coronaryevascularization is associated with better out-omes than percutaneous coronary interventionn dialysis patients.67-69 The survival advantagef surgical coronary bypass over PCI in dialysisatients is attributable to the use of internalammary artery bypass grafts.70 Therefore, di-

lysis patients most likely to benefit from coro-ary bypass surgery are those who are suitableandidates for internal mammary graft utiliza-ion. In dialysis patients not receiving internalammary grafts, there is no apparent survival

dvantage compared to PCI, but there is still a
educed rate of repeat coronary revasculariza-
ion. There are currently no data on the impact oforonary brachytherapy or drug-eluting stents one-stenosis after PCI in dialysis patients, buthese techniques may improve the long-termutcome of dialysis patients after PCI.These general trends notwithstanding, the se-

ection of coronary artery revascularization tech-iques should also be guided by local institu-ional experience, since a wide variety of outcomeata from single centers has been reported in theiterature.

The risk of re-stenosis after percutaneous cor-nary angioplasty and stent placement is highern dialysis patients than in the general populationsee Table 1).55,71 The failure rate of variousypes of coronary grafts has not been studied inngiographic series in dialysis patients. In addi-ion, re-stenosis in dialysis patients may not belinically apparent, since dyspnea and anginaan occur in the setting of volume overload.herefore, in all dialysis patients who have under-one PCI, provocative stress imaging should beonsidered to detect clinically silent re-stenosis2-16 weeks after PCI. This latter recommenda-ion may be modified as more data on drug-luting stents in dialysis patients become avail-ble.

LIMITATIONS

All published studies are retrospective analy-ses. There are no randomized controlled trialscomparing PCI and surgical bypass of coro-

Fig 2. Estimated all-cause survival of dialy-sis patients after CABG, PTCA, and stenting.Bars indicate SEMs. Reprinted with permission(http://lww.com)67

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GUIDELINE 4: CHRONIC CORONARY ARTERY DISEASE S25

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GUIDELINE 4: CHRONIC CORONARY ARTERY DISEASES26

There have also been no studies in the dialysispopulation on the newest generation of drug-eluting stents (e.g., stents eluting sirolimus orpaclitaxel).


There is concern over the potential effects ofantianginal agents on intradialytic hemodynam-ics.The increased risk of hemorrhage associatedwith ASA�clopidogrel therapy may deter itsuse, especially before major surgery.Higher in-hospital postoperative mortality indialysis patients, compared to PCI, mightdiscourage some institutions from performing
coronary bypass surgery, although the long-
term outcome could be better with surgery.This early mortality could be a concern forquality assurance entities, as in-hospital and30-day mortality are traditionally used asbenchmarks. As in-hospital mortality for PCIis considerably less than CABG (and thebenefit of CABG is only apparent at greaterthan six months post-procedure), it is plausiblethat PCI could appear more attractive bycommonly used benchmarks. The cost fordrug-eluting stents is also a potential concern.


Randomized trials of PCI are required, usingsirolimus-eluting or paclitaxel-eluting stents
compared to coronary bypass surgery.

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GUIDELINE 5: VALVULAR HEART DISEASE

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The presence of valvular heart disease (VHD)mpacts long-term outcomes, as in the generalopulation. In addition, VHD in dialysis patientsay impair the ability to adequately deliver

ialysis, which, in turn, may limit ultrafiltrationnd toxin removal, resulting in exacerbation ofVD.5.1 Evaluation of VHD in dialysis patients:

5.1.a Patients should be evaluated forthe presence of VHD and forfollow-up of VHD in the samemanner as the general populationexcept for frequency of follow-upfor aortic stenosis. (C)

5.1.b Special considerations for echo-cardiographic evaluation in dialy-sis patients:5.1.b.i Dry weight optimization

should be achieved priorto testing, to enhance theinterpretation of results.(B)

5.1.b.ii The interpretation of re-peat echocardiographicevaluations should bedone with considerationof the relationship be-tween the echo exam andeither the HD treatmentor the presence or ab-sence of PD fluid in theperitoneal cavity. (B)

5.2 Management of VHD in dialysis pa-tients:5.2.a Published recommendations for

the management of VHD in thegeneral population should be fol-lowed. (C)

5.2.b Both mechanical and tissue valvescan be used for replacement, withsimilar outcomes, in dialysis pa-tients. (B)

5.2.c Asymptomatic dialysis patients onthe transplant waitlist with mod-erate or more severe aortic steno-sis (aortic valve area <1.0 cm2)should have annual Doppler echo-cardiograms (as aortic stenosisprogresses faster in dialysis pa-
tients than general population). g

The same frequency of follow-upis appropriate in other dialysispatients who would be suitablecandidates for aortic valve re-placement based on overall clini-cal status. (C)

5.2.d Newly or increasingly symptom-atic (e.g., displaying dyspnea, an-gina, fatigue, and unstable intra-dialytic hemodynamics) patientswith VHD should be (re)-evalu-ated for VHD severity by echocar-diography (and referred to a car-diologist for further evaluation ifthe patient is deemed suitable forintervention on clinical grounds).(C)

5.3 Children with VHD should be evalu-ated by echocardiography. Manage-ment of valvular disease should followrecommendation provided by the ACC/AHA Guidelines for the Managementof Patients With Valvular Heart Dis-ease VI.45 (C)

RATIONALE

edical Treatment

Cardiac calcification, including that of heartalves, occurs at a faster rate in dialysis patientsompared to the general population. The rate ofrogression of aortic stenosis is faster in dialysisatients.76,77 A rate of aortic stenosis progressionf 0.23 cm2/year versus 0.05-0.1 cm2/year haseen reported in the general population.77 This isresumably a complication of the metabolic mi-ieu of uremia, which includes hyperparathyroid-sm and high calcium-phosphate product (see the/DOQI Bone Metabolism and Disease Guide-

ines).78-80 It is uncertain whether pharmacologi-al agents can alter the rate of progression of thisrocess, although sevelamer has been shown toetard coronary arterial and aortic calcificationpecifically in the dialysis population, based onlinical data utilizing EBCT.81 In addition, st-tins have been suggested to inhibit calcificationnd bone formation in cardiac valves, currentlyhe subject of a proposed clinical trial in the
eneral population. (Weak)
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GUIDELINE 5: VALVULAR HEART DISEASES28

Cardiac filling pressures are greatly affectedy intravascular volume. The maintenance of dryeight is a critical part of the management ofalvular heart disease.

perative Treatment (Weak)Balloon valvuloplasty is not recommended for

ortic stenosis in the general population becausef poor long-term results due to re-stenosis, andt is also not recommended for dialysis patients.evere mitral calcification (and mitral insuffi-iency) is quite common in dialysis patients,aking mitral valvuloplasty inappropriate forany dialysis patients. Percutaneous balloon val-

uloplasty of the mitral valve in dialysis patientshould be performed only in centers with experi-nced operators.

The risk of in-hospital and long-term mortalityssociated with aortic and/or mitral valve replace-ent is considerably higher in the dialysis popu-

ation compared to the general population. In the.S., the in-hospital mortality of dialysis patientsith valvular replacement surgery is almost 20%

nd the two-year mortality is approximately0%.67

The selection of the type of prosthetic heartalve is the only practice guideline related toalvular heart disease that is at significant vari-nce from the current ACC/AHA guidelines. Theurrent ACC/AHA practice guidelines proscribehe use of bioprosthetic (i.e., tissue) heart valvesor HD patients (Class III: “conditions for whichhere is evidence and/or general agreement thathe procedure/treatment is not useful and in someases may be harmful”). This proscription isased only on four cases collected over twoecades ago, which led to the perception thatioprosthetic valves were associated with accel-rated calcification and failure in HD patients.he more recent epidemiological data on 5,825ialysis patients (4,545 were HD only, and thereas no difference in the HD subset) undergoing

ardiac valvular surgery from the USRDS foundhat approximately 900 patients had biopros-hetic valves. Similar findings are reported inmaller series on the noninferiority of biopros-hetic valves in dialysis patients (Table 2). Thereas no difference in two-year mortality (60%) inatients who received bioprosthetic valves (rela-ive risk � 1.00) and those who received me-
hanical valves (Fig 3). Therefore, both tissue

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GUIDELINE 5: VALVULAR HEART DISEASE S29

bioprosthetic) and nontissue (mechanical) pros-hetic heart valves are appropriate for dialysisatients. In dialysis patients with a history ofife-threatening hemorrhage and no other indica-ions for chronic anticoagulation, bioprostheticalves may even be preferable.

LIMITATIONS

The mortality risk of nonintervention or de-layed intervention is not known.


The current guideline provided by the AHA/

Fig 3. Estimated all-causeurvival of dialysis patientsfter heart valve replacementurgery with tissue and non-issue prosthetic valves.ars indicate standard er-

ors. Reprinted with permis-ion (http://lww.com).70

ACC task force could be a deterrent to this

new K/DOQI Guideline for the use of bio-prosthetic valves. Ideally, the ACC/AHAguideline on this particular issue would bechanged.


Observational studies of the newer generationof bioprosthetic valves (e.g., stentless valves)are required.Studies on the timing of valve replacement inrelation to survival will provide valuable infor-mation (e.g., do clinicians wait too long to
refer patients for surgery?).

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GUIDELINE 6: CARDIOMYOPATHY (SYSTOLIC OR
DIASTOLIC DYSFUNCTION)
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The prevalence of systolic or diastolic dysfunc-ion, or overt LVH, is estimated to be at least5% at dialysis initiation (see also Guideline 1).e novo and recurrent heart failure occurs in a

ubstantial proportion of patients on dialysis, andmpacts on morbidity and mortality, as well ashe ability to deliver adequate dialysis.

6.1 Evaluation of cardiomyopathy (systolicor diastolic dysfunction) in dialysis pa-tients:6.1.a Dialysis patients should be evalu-

ated for the presence of cardiomy-opathy (systolic or diastolic dys-function) in the same manner asthe general population, usingechocardiographic testing. (C)

6.1.b Patients should be re-evaluated ifthere is change in clinical status(e.g., symptoms of CHF, recur-rent hypotension on dialysis, post-cardiac events) or considered forkidney transplant. (C)

6.1.c Echocardiograms should be per-formed in all patients at the initia-tion of dialysis, once patients haveachieved dry weight (ideallywithin 1-3 months of dialysis ini-tiation) (A), and at 3-yearly inter-vals thereafter. (B)

6.1.d As in the general population, di-alysis patients identified with sig-nificant reduction in LV systolicfunction (EF <40%) should beevaluated for CAD (if not donepreviously). This evaluation mayinclude both noninvasive testing(stress imaging) and invasive test-ing (coronary angiography). Inpatients at high risk for CAD(e.g., those with diabetic CKD),coronary angiography may be ap-propriate, even in patients withnegative stress imaging tests, dueto lower diagnostic accuracy ofnoninvasive stress imaging testsin CKD patients. (C)

6.2 The treatment of cardiomyopathy inthe dialysis population is similar to that
in the nondialysis population, with the t

important exception of potential effectsof therapeutic agents (e.g., ACE inhibi-tors or beta-blockers) on intrahemodia-lytic hemodynamics. (C; B for carve-dilol)6.2.a Congestive heart failure unre-

sponsive to changes in target dryweight may also be a complica-tion of unsuspected VHD or IHD;clinical re-evaluation should beconsidered in these patients. (C)

6.2.b Dosing of therapeutic agents mayneed to be empirically individual-ized to hemodialysis schedules (inhypotensive patients). (C)

6.2.c The consistent maintenance of eu-volemia is a cornerstone of treat-ment of CHF in dialysis patients.(C)

6.3 Target “hemodynamic dry weight” mayneed to be adjusted to compensate forhemodynamic effects of therapeuticagents. (C)

6.4 Children should be evaluated for thepresence of cardiomyopathy (systolicand diastolic dysfunction) using echo-cardiographic testing. (C)

RATIONALE

iagnosis (Moderately Strong)Congestive heart failure in dialysis patients is

complex condition. It often reflects the interac-ion of hypertensive heart disease (resulting inVH and noncompliant vasculature), hypervol-mia, anemia, IHD, and—to a lesser extent—HD. In addition, there are abnormalities of theyocardial ultrastructure (e.g., fibrosis) that mayake the dialysis patient particularly vulnerable

o ischemia and, importantly, sudden cardiaceath (SCD), the single largest cause of death inhis population. Left ventricular hypertrophy, LVystolic dysfunction (decreased ejection frac-ion), and CHF are independent predictors ofoor survival in dialysis patients, as in the gen-ral population. In one prospective cohort study84

bnormal LV systolic function and LV geometryere independently associated with mortality.ther studies also suggest the prognostic impor-

ance of echocardiographically-defined LV sys-


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GUIDELINE 6: CARDIOMYOPATHY (SYSTOLIC OR DIASTOLIC DYSFUNCTION) S31

olic dysfunction85,86 and LV mass84-88 as predic-ors of cardiovascular outcome (Table 3, Table). Left ventricular hypertrophy and systolic dys-unction cannot be accurately assessed solely byistory, physical examination, or chest X-ray.eft ventricular systolic performance, however,an be accurately measured by echocardiogra-hy, gated nuclear scintigraphy, ultrafast CT,ontrast ventriculography, or cardiac MRI.

Echocardiography (M-mode, 2-D, or Doppler)rovides information on LV function, chamberimension and geometry, presence of LVH, pul-onary artery systolic pressure, VHD, and vol-

me status. No other single imaging modalityrovides this potential wealth of data in thecreening of noncoronary heart disease.

reatment (Moderately Strong)The consistent maintenance of euvolemia and

ormal blood pressure is a goal of treatment.ood volume control is a cornerstone of antihy-ertensive therapy and cardiac management. Cli-icians must be alerted to the changing lean bodyass in these patients and adjust the target dryeight accordingly, on a periodic basis. WhenHF appears to be refractory, ultrafiltration with

imultaneous direct-pressure monitoring usingight-heart catheterization (e.g., a pulmonary ar-ery catheter) may be helpful to define the opti-al intravascular volume. Echocardiography can

rovide key, noninvasive measurement of car-iac filling pressures and volume status withoppler imaging for estimation of pulmonary

rtery pressure, pulmonary vein (and diastolicransmitral), qualitative assessment of pulmo-ary venous and left atrial pressure, and inferiorena cava (IVC) imaging for estimation of righttrial pressure. Optimal blood pressure in HDatients has not been defined clearly, and shouldrobably incorporate predialysis and postdialysisystolic and diastolic blood pressures. Quotidianong-duration dialysis may be more effective inptimizing fluid volume in patients who haveifficulty attaining presumed dry weight withonventional, thrice-weekly HD.

In the general population, large multicentertudies have validated the efficacy of certaingents for the treatment of CHF in patients withmpaired LV systolic function. Agents that arenown to improve cardiovascular outcome in
linical trials (e.g., beta-blockers) are preferred.

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GUIDELINE 6: CARDIOMYOPATHY (SYSTOLIC OR DIASTOLIC DYSFUNCTION)S32

pecial dosing regimens may be necessary toacilitate the delivery of HD and ultrafiltration.mong all the medications used to treat CHF in

he general population, only carvedilol has beenhown to be effective in a randomized trial in theialysis population. In a single, small study ofialysis patients with dilated cardiomyopathies,arvedilol was found to improve LV function andecrease hospitalization, cardiovascular deathsnd total mortality.89,90 The degree of improve-ent was comparable to that observed in the

eneral population. Other beta-blockers may haveffects similar to carvedilol, but there are notudies to confirm or refute this hypothesis. Pend-ng further data, carvedilol should be the pre-erred beta-blocker for the treatment of dialysisatients with severe dilated cardiomyopathy.Moderately Strong)

Angiotensin-converting enzyme inhibitorsave been used extensively in the general popu-ation for the treatment of CHF. In randomizedlacebo-controlled trials, ACE inhibitors haveeen shown to improve survival in patients withepressed LV function and symptomatic heartailure, and to improve survival in asymptomaticatients with depressed LV function. However,inimal data exist on the use of ACE inhibitors

n dialysis patients with CHF. Nonetheless, theork Group recommends that these agents be

sed in patients with CHF and impaired LVunction. The dosing schedules may need to bendividualized for each dialysis session in ordero avoid intradialytic hypotension. One random-zed prospective study, employing a 2 � 2 designn simvastatin and enalapril, found a 30%-month drop-out rate as a result of hypotensionn the enalapril arm.91 (Weak)

Digitalis glycosides (e.g., digoxin) should beonsidered as third-line therapy for CHF. A ma-or indication for this class of agent is ventricularate control in patients with atrial fibrillation. Inost dialysis patients, diuretics are ineffective

nd not indicated for removing excess volume.here is a paucity of data on the use of spirono-

actone or eplerenone in dialysis patients withHF. Serum potassium levels have been reported

o increase in dialysis patients receiving spirono-actone and potassium loading. Pending furtherafety data, this agent should be used with great
s
caution, or not at all. (Weak)

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GUIDELINE 6: CARDIOMYOPATHY (SYSTOLIC OR DIASTOLIC DYSFUNCTION) S33

LIMITATIONS

There is only a single, small trial for carvedilolin dialysis patients.There are no data on the use of ACE inhibitorsin dialysis patients with potential hypotension.The longitudinal cohort study on echocardio-graphic changes in chronic HD patients byFoley and Parfrey was conducted in patientsrecruited from 1982-1991, mostly before theuse of erythropoietin.84 Despite the newertherapies that became available since then,cardiac events are still the major cause ofdeath and cardiac mortality increases withyears on dialysis, according to USRDSdata.2 Long-term echocardiographic surveil-lance of dialysis patients in the moderntreatment era is lacking. The appropriatetime interval for re-evaluation in chronicdialysis patients is therefore uncertain.

IMPLEMENTATION ISSUESAlthough echocardiography is widely avail-

ble, the cost is not low, and this may deter its

se. Further, the detection of cardiac abnormali-ies (such as LV dysfunction) may increase theecessity for other diagnostic tests, such as stressmaging or contrast angiography, for the assess-ent of CAD.


More clinical trials on treatment of CHF indialysis patients are required. A randomized,prospective trial on primary beta-blockertherapy to reduce the risk of CHF and deathwould be a worthwhile project in dialysispatients, especially in diabetics.Valuable information may be derived from alarge longitudinal cohort study of echocardio-graphic changes in the incident chronic HDand PD populations, in the modern era ofcardiac therapeutics.Further large cross-sectional studies are re-quired to examine the prevalence of cardio-myopathy in the chronic HD and PD popula-
tions.

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GUIDELINE 7: DYSRHYTHMIA

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Patients on maintenance dialysis are at in-reased risk for dysrhythmias, cardiac arrest, andCD. The risk of SCD or cardiac arrest increasesith age and dialysis duration.7.1 Evaluation of dialysis patients:

7.1.a All dialysis patients, regardless ofage, should undergo a routine12-lead ECG at the initiation ofdialysis. (C)

7.1.b Patients with dysrhythmiasshould be treated in the samemanner as the general populationwith regard to antiarrhythmicagents (including beta-blockers)and pacing devices (including in-ternal defibrillators). Refer toTable 5 for dosage adjustmentsand drugs to be avoided. (C)

RATIONALE

isk Factors

Patients on maintenance dialysis therapy are atncreased risk for dysrhythmias, cardiac arrest,nd SCD. Dialysis patients with underlying struc-ural or functional CVD are at much higher riskor these dysrhythmias and cardiac arrest be-ause of increased dysrhythmogenicity due toynamic changes in electrolytes, volume status,lood pressure and the use of multiple medica-ions. Even nondiabetic dialysis patients have aarkedly increased cardiac event rate and de-

reased event-free survival as compared to theeneral population.93 (Moderately Strong)Ischemic heart disease is present in many

atients even at the time of initiation of dialysis.KD Stage 5 patients with either symptomatic orsymptomatic coronary artery disease are at in-reased risk for dysrhythmias and SCD.94-97 Thisisk is potentiated with concomitant presence ofnemia98 and left ventricular hypertrophy99 orncreased left ventricular mass index, oftenresent in CKD patients at the initiation of dialy-is therapy.100,101 (Weak)

The prevalence of baseline ECG abnormalitiesnd the development of new dysrhythmias andilent myocardial ischemia is related to the con-omitant presence of CAD, and is also directly
roportional to the duration of dialysis.102-105 p

otentially life-threatening ventricular dysrhyth-ias and silent myocardial ischemia were noted

n 29% and 36%, respectively, on Holter monitorerformed 24 hours before, during HD, andontinued for 20 hours after dialysis in a smallohort of 38 HD patients.105 Furthermore, atrialysrhythmias were noted in 10% of patients in aohort of 106 maintenance HD patients106 and6% of patients demonstrated varying degrees ofentricular dysrhythmias in a cohort of 127 main-enance dialysis patients.102 The risk of newnset dysrhythmias was shown to increase inatients on peritoneal dialysis (PD), with ventric-lar dysrhythmias increasing from 30% to 43%nd supraventricular dysrhythmias (SVA) increas-ng from 40% to 57%, respectively, during aean follow-up period of 20 �4 months.107

Moderately Strong)Risk factors for increased arrhythmogenicity

nclude compromised myocardium (due to eithernderlying CAD, decreased coronary reservelood flow, or the consequences of uremia onyocardial function and structure), increasedTc interval or dispersion, electrolyte abnormali-

ies, intradialytic hypotension, concomitant pres-nce of LVH (present in almost 80% patients onialysis), and autonomic dysfunction (with orithout diabetes).108-110 (Moderately Strong)Dialysis patients have frequent electrolyte ab-

ormalities such as fluctuating levels of potas-ium, ionized calcium, magnesium, and otherivalent ions.111 Due to the intermittent nature ofhe dialysis procedure, patients on HD have wideuctuations in volume status, and potassium andicarbonate levels, in between dialysis treat-ents.97,112 These fluctuations are partly driven

y the level of potassium and calcium in theialysate fluid used during the prior session ofreatment, and wide variability in eating habitsue to varying adherence to dietary modifica-ions necessary to control the calcium-phosphateroduct.112-115 All these factors culminate in anysrhythmogenic diathesis. (Weak)Atrial fibrillation (A.fib) is perhaps the most

ommonly diagnosed dysrhythmia in the generalopulation, and also in the dialysis popula-ion.106 A historical cohort study of the USRDSMMS Wave 2 revealed that A.fib was more

ommon in dialysis patients than in the general
opulation, although the study did not show

GUIDELINE 7: DYSRHYTHMIA S35

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GUIDELINE 7: DYSRHYTHMIAS36

hether A.fib was related or unrelated to valvu-ar disease.116 (Weak)

reatment

There is strong evidence for the use of differ-nt interventions either for primary or secondaryrevention of arrhythmias and cardiac arrest inhe high-risk general population (patients withAD,117-120 CHF121,122 and near-fatal cardiacvents123-126). Since dialysis patients are at in-reased risk for CV events, it is reasonable tossume that these interventions will be effective,espite the lack of evidence in the dialysis popu-ation. Pending further research, there is pres-ntly no reason to withhold these interventions inialysis patients. (Moderately Strong)The use of beta-blockers in nondialysis pa-

ients is recommended for the primary preven-ion of SCD,127 and improves outcomes in pa-ients with CHF.128,129 Similarly, the USRDS

ave 3 and 4 study showed decreased risk ofeath in patients who were on beta-block-rs.130,131 A small study demonstrated that dialy-is patients may not tolerate sotalol due to anncreased risk of torsade de pointes.132,133 (Weak)

The use of novel agents such as Ximelagatran,irect thrombin inhibitor, fixed-dose therapy with-ut coagulation monitoring as an alternative tooumadin therapy for the prevention of strokesn patients with nonvalvular A.fib, has been dem-nstrated to be effective in the general popula-ion.134-136 However, the use of Ximelagatran in
ialysis patients has not been studied. (Weak)
LIMITATIONS

Although there is an existing and evolvingbody of evidence about the primary and sec-ondary prevention of cardiac events in theform of arrhythmias in the general population,such evidence is apparently lacking from thegrowing population of CKD and dialysis-dependent patients.Without definitive evidence from prospectivetrials in the dialysis population, there mayremain an increased concern over the safetyand efficacy of interventions.

IMPLEMENTATION ISSUESThe use of internal defibrillators may be pre-

luded due to:

lack of data in the dialysis population;invasive nature; andpotential interference with dialysis catheters.


Modifications in the CMS form are required toincrease the accuracy of data capture forarrhythmias and near-fatal cardiac arrest indialysis patients.Studies are needed to assess the outcome andthe effectiveness of different preventive andtreatment strategies to improve the dismaloutcome of near-fatal arrhythmias in dialysispatients.There is a strong need to evaluate the mecha-
nisms of sudden death in this population.

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GUIDELINE 8: EXTERNAL DEFIBRILLATION

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The capability for effective, rapid defibrilla-ion (with negligible risk of inappropriate treat-ent) is widely available with the development

f automatic external defibrillators (AEDs). Givenhe high prevalence of dysrhythmias (see Guide-ine 7), the availability of AEDs in dialysisacilities may impact the outcomes of patientsho experience cardiac events during dialysis

herapy.8.1 All dialysis units should have on-site

capability for external cardiac defibril-lation. Automatic external defibrilla-tors are the simplest, most cost-effec-tive means to achieving this guideline,as they do not require advanced lifesupport training by staff for operation,require minimal maintenance, and aredesigned for use by nonmedical person-nel. (A)8.1.a Basic life support (CPR) training

for dialysis unit staff is recom-mended as an enhancement to theeffectiveness of AEDs, as it in-cludes instruction in use of AEDs,airway and circulatory supportduring cardiorespiratory arrest,and management of noncardiacemergencies (such as choking).(B)

8.1.b Non-automatic defibrillators arealso appropriate devices for pro-viding on-site defibrillator capa-bility, but they require more main-tenance and operators certified inadvanced cardiac life support(ACLS). (B)

8.1.c All dialysis units caring for pediat-ric patients need to have on-siteexternal automatic defibrillatorsand/or appropriate pediatric equip-ment available. Automated exter-nal defibrillators may be used forchildren 1-8 years of age, andshould ideally deliver pediatricdoses and have an arrhythmia de-tection algorithm.46-48 (C)

8.1.d The goal should be the availabil-ity of AEDs in all dialysis unitswithin 12 months of the publica-
tion of these Guidelines. (C) u

RATIONALE

Sixty-one percent of all cardiac deaths in dialy-is patients have been attributed to arrhythmicechanisms.17 The rate of cardiac arrest duringD has been reported to be 7 events per 100,000ialysis sessions.95 The mortality rate immedi-tely following cardiac arrest in the general popu-ation is 7%-10% per minute, and survival isnlikely if defibrillation does not occur within 10inutes. Therefore, rapid defibrillation is essen-

ial for improving survival in dialysis patientsxperiencing cardiac arrest. The safety and effi-acy of AEDs have been validated in diverseettings, such as airports, casinos, and commer-ial aircraft. They are designed to be used eveny nonmedical personnel, and do not requiredvanced training or advanced cardiac life sup-ort (ACLS) certification. (Moderately Strong)In a study based on Emergency Medical Ser-

ices (EMS) data in Seattle and King Countyrom 1990-1996, there were 47 cardiac arrests inialysis centers, with an annual incidence perenter of 0.746.137 There were 41 witnessedvents, and bystander CPR was administered in1 patients. In 29 patients (62%) the cardiachythm was ventricular fibrillation (VF) or ven-ricular tachycardia (VT). While the overall sur-ival to hospital discharge was 30%; it was 38%or the VT/VF patients. These data reflect thexpertise of EMS crews in Seattle/King Countynd make a compelling case for on-site defibril-ator capability in all dialysis units.

Pediatric-modified, FDA-approved AEDs areow commercially available; thus the officialHA Guidelines 2000 on Resuscitation, whicho not support the use of AEDs in smallerhildren are no longer current.138 Evidence forhis recommendation is provided by studies inhildren46,48 It is anticipated that all AEDs ap-roved for sale in the U.S. will be equipped withptional modules or other electrode modifica-ions suitable for pediatric use (children �25 kgnd �8 years old) by the time these Guidelinesre published, but it is recommended that indi-idual dialysis units verify the AED capabilitiesf on-site units. The Commissioner of Health,ew York State, has issued an official advisory

effective 7/01/02) promoting the safe and effec-ive use of pediatric-modified AEDs in children
nder age 8.
), 2005: pp S37-S38 S37

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GUIDELINE 8: EXTERNAL DEFIBRILLATIONS38

Dialysis centers providing care for smallerhildren will need to establish their own proto-ols consistent with accepted pediatric practiceuidelines for pediatric resuscitation. It is recom-ended that a pediatric nephrologist helps formu-

ate center practice guidelines for this specialroup of patients. “Standard” AEDs (designedor use in patients 8 years or older) could thus besed with these removable pediatric modifica-ions. These pediatric-modified devices deliver0 Joules of electricity (compared to 200 Joulesor standard AEDs). (Moderately Strong)

LIMITATIONS

Automatic external defibrillators are easy tooperate and the operator does not requiremedical training, but AEDs need to be widely
available.

All dialysis staff should be encouraged toattempt the use of AEDs in the event of cardiacarrest, regardless of the availability of othertypes of defibrillators or certified ACLS person-nel.While an AED is available at a rather moder-ate cost, it is still an additional expense for thedialysis unit.Some units may be concerned about stafftraining and the maintenance of AEDs.


Observational studies are required to examinemortality trends after the implementation of
this guideline.

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GUIDELINE 9: CEREBROVASCULAR DISEASE

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Stroke is the third leading cause of death in theeneral population in the U.S. and many otherountries, with large economic and human bur-ens as a consequence. Patients with CKD are atncreased risk for stroke relative to the generalopulation.9.1 All dialysis patients should follow the

AHA Guidelines for the prevention,screening and evaluation, and treat-ment of stroke. A summary of theAHA guidelines with any caveats re-lated to dialysis patients is shown inTable 6. (C)

9.2 Special considerations in dialysis pa-tients include:9.2.a Anticoagulation in nonvalvular

atrial fibrillation: Dialysis pa-tients are at increased risk forbleeding and careful monitoringshould accompany intervention.(C)

9.2.b Acute stroke in dialysis patients:Given that acute stroke syn-dromes can be due to eitherthrombotic or bleeding events indialysis patients, the immediategoal of localization and cause isparticularly important in dialysispatients because of increased riskof bleeding associated with antico-agulants in this population. There-fore, imaging with establishedmethods should be undertaken.(C)

9.3 Treatment of stroke and transient isch-emic attack (TIA):9.3.a Treatment of TIAs and strokes

should follow the same principlesused in the general population forboth medical management andsurgical management, with theexception of thrombolytics in HDpatients. (C)9.3.a.i Assessment of the risk of

bleeding in patients re-cently receiving heparin ondialysis should be con-ducted when consideringthe use of thrombolytics.
(B) t

RATIONALE

revention

Few studies have identified risk factors fortroke in the dialysis population. The availableata suggest that high blood pressure, markers ofoor nutrition, age, diabetes, and ethnicity placeatients at greatest risk. Of these factors, onlylood pressure and nutrition are potentially modi-able. The largest study assessing risk factors fortroke used data from the United States Renalata System (USRDS). Several factors were

ound to be associated with stroke.139 African-mericans with a history of CVD had a lower

isk for incident stroke than Caucasians. Lowererum albumin, subjective malnutrition and lowereight were associated with a higher risk for

troke. Higher blood pressure, older age, andiabetes were also associated with a higher riskor stroke. There was no association betweenncident stroke and cholesterol, calcium, phospho-us, or parathyroid hormone. Measures of malnu-rition and diabetes were not associated withemorrhagic stroke, while polycystic kidney dis-ase, African-American race without a history ofVD, and male gender were associated with aigher risk for hemorrhagic stroke. Data fromapan identified polycystic kidney disease, higherlood pressure, higher ECG voltage, and lowerT/V as risk factors for cerebral hemorrhage.140

small study from Japan demonstrated thatypertension was a risk factor for stroke.141

actors not found to be associated with strokencluded male gender, age, diabetes, smoking,yslipidemia, and duration of dialysis. However,survival analysis was not performed and statis-

ical power was limited. The epidemiology oftroke is different in Japan and caution should besed when generalizing these data to U.S. dialy-is patients.

creening/Evaluation

There are some data to suggest that dialysisatients have higher measures of subclinical vas-ular disease142 and that these measures predictardiovascular events and death. Carotid ultra-ound measurements of elasticity or arterial stiff-ess measured in the common carotid arteryssessing incremental modulus of elasticity haveemonstrated a positive relationship between ar-
erial stiffness and cardiovascular mortality.92
), 2005: pp S39-S42 S39

GUIDELINE 9: CEREBROVASCULAR DISEASES40

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GUIDELINE 9: CEREBROVASCULAR DISEASE S41

reater carotid intimal medial thickness has alsoeen shown to be associated with a greater riskor cardiovascular events.143 Carotid artery incre-ental elastic modulus has been associated with

n increased risk for cardiovascular events. Eachne standard deviation increase was associatedith a 1.7-fold increased risk for cardiovascular

vents.92 There are no studies that have assessedhether these measures predict stroke specifi-

ally, or if screening decreases events. Routinecreening using carotid ultrasound is not recom-ended in asymptomatic patients.

LIMITATIONS

There are extensive data from the general
population regarding risk factors, screening
and treatment of stroke. However, the epidemi-ology of stroke is different in the dialysispopulation. In addition, exposures related todialysis may alter the effectiveness and compli-cations associated with treatment. All recom-mendations regarding screening and treatmentare opinion-based and should be taken withcaution.There are limited data regarding stroke that arespecific to the dialysis population. Data ad-dressing the association between risk factorsand stroke are scant. Data supporting screen-ing for stroke are based on limited and weakdata, while data addressing treatment do notexist.There are no data in the dialysis population
regarding medical or surgical management of

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GUIDELINE 9: CEREBROVASCULAR DISEASES42

stroke. However, due to the high risk ofbleeding in the CKD population, caution shouldbe used when treating with antiplatelet agents.


Altering modifiable risk factors can be imple-mented and has been shown to be effective inthe general population. Screening and treat-ment of stroke is routine in the general popula-
tion, and should therefore be possible to
implement effectively in the dialysis popula-tion.


Stroke risk is very high in the CKD popula-tion. Effective screening strategies do notexist, nor do studies assessing interventions.Studies addressing these issues are greatly
needed.

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GUIDELINE 10: PERIPHERAL VASCULAR DISEASE

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Both diabetic and nondiabetic dialysis patientsre at risk for peripheral vascular diseasePVD),144,145 with approximately 15% of inci-ent patients having a clinical diagnosis of PVD.10.1 Diagnosis of PVD:

10.1.a At the time of dialysis initia-tion, all patients should beevaluated for the presence ofPVD. (C)

10.1.b Evaluation should includephysical examination includingassessment of arterial pulse andskin integrity. (C)

10.1.c Further specialized studies,such as duplex studies or inva-sive testing, should be under-taken if abnormalities aredetected upon physical exami-nation and interventions areconsidered. (C)

10.2 Approach to therapy of PVD: (C)10.2.a Patients with PVD should be

treated in the same manner asthe general population in re-gard to smoking cessation,lipid-lowering therapy, glyce-mic control, blood pressure con-trol, and the use of ACE inhibi-tors and antiplatelet agents. Inaddition, supervised exerciseregimens and medications toincrease vasodilation should beconsidered in patients withclaudication and without criti-cal leg ischemia. Establishednational guidelines, similar tothose for stroke, are not avail-able for PVD in the generalpopulation.

RATIONALE

creening for PVD (Weak)

Ankle brachial index (ABI) (ankle systoliclood pressure divided by brachial systolic bloodressure) is a simple method of screening forVD. However, ABI might be falsely elevated in
ialysis patients because of vascular calcifica- p

ion.146 Toe brachial index (TBI) is not affectedy vascular calcification.146 Even though ABInd TBI are simple, inexpensive, noninvasiveethods, further studies are warranted to deter-ine whether screening for asymptomatic PVDith these tests improve limb survival.Checking arterial pulses and assessing skin

ntegrity should be part of a physical examina-ion, particularly in diabetic dialysis patients. AsVD is a strong predictor of cardiovascular mor-

ality in the general and dialysis population,147,148

arly diagnosis of PVD and aggressive medicalherapy (smoking cessation, lipid-loweringherapy, glycemic control, blood pressure con-rol, and the use of ACE inhibitors and antiplate-et agents) might improve cardiovascular sur-ival in dialysis patients (Table 7).

herapy of PVD (Weak)

There are no randomized, controlled trials forVD in dialysis patients that establish the effi-acy of any pharmacological agents or othernterventions. In the absence of evidence to theontrary, it might be reasonable to extend theherapy of PVD in the general population to theialysis population. The therapy of PVD dependspon the presence of claudication and critical legschemia in the general population.149

When compared to the general population,utcomes after revascularization for PVD in di-lysis patients are inferior.150,151 The problemsith revascularization in PVD in dialysis pa-

ients include: high perioperative and 1-year mor-ality; decreased wound healing; loss of limbespite patent graft; and prolonged hospital staynd poor rehabilitation.152-156 Therefore, someuthors have argued for the liberal use of primarymputation in dialysis patients.157

However, careful patient selection for revascu-arization in dialysis patients might result incceptable outcomes. A study of 44 HD patientsho underwent revascularization reported a-year survival rate of 48%, perioperative mortal-ty of 9%, primary graft patency at 1 year and 2ears of 71% and 63%, respectively and limbalvage at 1 year and 2 years of 70% and 52%,espectively.158 In this study, an aggressive ap-
roach to limb salvage was favored when pa-
), 2005: pp S43-S44 S43

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GUIDELINE 10: PERIPHERAL VASCULAR DISEASES44

ients were found to be ambulatory or able to usehe affected extremity for purposes of weightearing or transfer. Attempted limb salvage wasot advocated for patients who were chronicallyedridden, or those with uncontrolled infectionr tissue necrosis precluding a reasonable expec-ation of limb salvage.

Therefore, symptomatic PVD in dialysis pa-ients should not automatically result in amputa-ion in all patients. Revascularization (surgical orngioplasty with stent) might be the preferredethod of treatment of symptomatic PVD in

elected dialysis patients. Extensive tissue necro-is in nonweight-bearing limbs and preoperativenfection might be indications for primary ampu-
ation.
LIMITATIONS

There are no randomized, controlled trials ofany of the interventions for therapy of PVD indialysis patients.The above recommendations are based onretrospective, observational studies in dialysispatients. Further large, prospective observa-tional studies and randomized, controlled tri-als are warranted.


Further studies are warranted to examine thefeasibility and effectiveness of ankle:brachialor toe:brachial indices as screening tests forasymptomatic PVD in reducing limb amputa-
tion rates.

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SECTION II. GUIDELINES ON MANAGEMENT OF
CARDIOVASCULAR RISK FACTORS
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Traditional risk factors—such as diabetes, hy-ertension, dyslipidemia—and those specific toialysis patients (anemia and mineral metabo-ism abnormalities) require regular assessmentnd treatment as per current recommendations.he relative importance and weight of each of

hese risk factors in the dialysis population is notnown and, in the absence of controlled trials inhis population, current recommendations fromxisting organizations should be followed, with
pecial consideration given to potential risks.

Furthermore, lifestyle issues such as smoking,hysical activity, depression, and anxiety are theornerstones of therapy as in the general popula-ion. The treatment options are often similar, buthe impact of these factors is potentially morerofound in dialysis patients. These factors arell discussed in this section. Special attentionill be paid to the difference between the usual

ecommendations and those for dialysis patients.

), 2005: p S45 S45

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GUIDELINE 11: DIABETES

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11.1 All dialysis patients who have diabetesshould follow the American DiabetesAssociation guidelines.49,160 (C)

RATIONALE

lycemic Control (Weak)The rationale for this ADA recommendation is

ased on substantial evidence from the Diabetesontrol and Complications Trial (DCCT),161,162

nd the U.K. Prospective Diabetes Study (UK-DS)163,164 that the careful control of bloodlucose has a significant effect on decreasing theomplications of diabetes. Combined with sub-tantial observational evidence of the link be-ween prolonged hyperglycemia and complica-ions, the recommendation has strong evidence-ased support. However, these relationships haveot been validated specifically in dialysis pa-ients. Tight control has potential problems foratients on dialysis, and there is some evidencehat hemoglobin A1C may not be as predictive oflycemic control in patients on dialysis.The ADA recommendation indicates that ex-

remely tight control may increase the incidencef hypoglycemic events, and may produce weightain. Hypoglycemia may be worsened by nauseand the inability to eat, as well as by longeruration of drugs and increased half-life of insu-in. Therefore, care should be taken to preventypoglycemic episodes in patients on dialysisho experience significant nausea or gastrointes-

inal complaints. In addition, if excellent glyce-ic control gradually increases a patient’s solideight, it should be reflected in the adjustment ofry weight for the purpose of postdialysis weightargets.

There is evidence that hemoglobin A1C is nots representative of glycemic control in patients


n HD165 or PD.166,167 Through decreased metab-lism, anemia, and shorter life of red cells, theemoglobin A1C may under-represent glycemicontrol, and a level �7% in a dialysis patientay represent glycemic control similar to a non-

ialysis patient with a hemoglobin A1C �7%.he precise target of hemoglobin A1C that isssociated with the best outcome in dialysisatients has not been clearly established. Clini-ians are cautioned that insulin doses and oralypoglycemic doses may change substantiallyuring the transition from earlier stages of CKDo dialysis. The decrease in insulin catabolismssociated with the further loss of kidney func-ion may reduce insulin requirements. On thether hand, the glucose contained in the dialysateespecially peritoneal dialysate) may increasehe requirement of hypoglycemic agents.

The use of newer insulin regimens and insulinreparations (with properties that are closer toormal physiology) should be encouraged, possi-ly in consultation with a specialist in diabetesanagement. There are some oral hypoglycemic

gents that either should be used with caution, orot used at all, in dialysis patients (see Table 8).

utritional Therapies and Care (Weak)The rationale for metabolic and nutritionalanagement in diabetes comes primarily from a

eview by the ADA of the existing evidence,hich supports nutritional interventions in the

ontrol of diabetes and its complications.160,168

n contrast, although health and dietary habits foriabetics are generally consistent with those forialysis patients, there are special dietary consid-rations for patients on dialysis. The level ofietary protein recommended for dialysis pa-ients exceeds the ADA recommendation for pa-


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GUIDELINE 11: DIABETES S47

ients with diabetic nephropathy not requiringialysis, because the prevention of malnutritions a primary concern for dialysis patients. Inatients not requiring dialysis, the slowing ofrogression of CKD is a major concern in whichrotein restriction probably has a role. High-rotein diet may also cause more electrolytembalance and retention of nitrogenous wasteroducts in nondialysis patients. On the otherand, dietary phosphorus restriction is often nec-ssary to decrease hyperphosphatemia in dialysisatients. For more detailed recommendations,ee the K/DOQI Guidelines on Nutrition,169 andhe sections on nutrition and calcium-phospho-us product in this document.

xercise (Weak)Patients who are on dialysis may have toodify their exercise routines to match their

ialysis schedule, since postural hypotension,izziness, and washout sensations are not uncom-on, and exercise immediately after dialysisay be poorly tolerated.

ypertension Control (Weak)The rationale for these recommendations de-

ives from extensive reviews of the link betweenypertension and cardiovascular morbidity andortality for the general population and the

tatement of the Seventh Joint National Commit-ee on Prevention, Detection, Evaluation andreatment of High Blood Pressure.170 The opti-al blood pressure for dialysis patients, how-

ver, has not been firmly established (see Guide-ine 12 in this document). Although the JNC VIIecommendation for blood pressure control inatients with CKD is �130/80 mm Hg, bloodressure control in patients on HD is compli-ated by the volume and electrolyte shifts sur-
ounding dialysis procedure that acutely changes d
lood pressure. Diabetic patients on dialysis maye more prone to postural hypotension and labilelood pressure than nondiabetic dialysis patients.higher supine blood pressure may be necessary

n order to prevent symptomatic postural hypoten-ion. Individual judgment and patient evaluations required to match goals with symptoms.

ntihypertensive Therapy (Weak)The use of diuretics in patients on HD cannot

e recommended for blood pressure control, un-ess there is substantial residual kidney functionhat responds to diuretics.171,172 The choice ofnitial pharmacological therapy for hypertensionn dialysis patients is otherwise similar to thoseot on dialysis; however, the kidney-protectiveffect of ACE inhibitors and ARBs are less of aoncern. Limited data suggest that ARBs mayrotect residual kidney function for patients onhronic PD. There is weak evidence that someeta-blockers may hinder peritoneal transport inatients on PD,173,174 but this evidence is notufficient to warrant withholding the use of beta-lockers in dialysis patients when they are clearlyndicated.

Finally, as detailed in Table 9, there are somentihypertensive agents that should not be used,r should be used only with care, in dialysisatients.

ardiac Disease Screening (Weak)The NKF K/DOQI Guidelines support the

eed for cardiac screening in patients on dialysis,specially since the combination of diabetes anddvanced kidney disease substantially increaseshe likelihood of coronary disease. The tech-iques for screening and their caveats in dialysisatients are described in Guideline 2 in this
ocument.

● ●

●

GUIDELINE 11: DIABETESS48

LIMITATIONS

Many of the recommendations supported bythe ADA on the care of diabetes are based onlarge clinical studies that provide strongevidence for the particular recommendation,but those studies do not target dialysispatients.


Long-term, randomized controlled trials areneeded to strengthen the evidence for thedirect application of the ADA recommenda-tions to patients on dialysis.More research is needed on the effect of renaldietary restrictions in diabetic patients.

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GUIDELINE 12: BLOOD PRESSURE

The management of blood pressure is anmportant component of CVD risk manage-ent for all aspects of CVD: CAD, cardiomy-

pathy, VHD, CBVD, and PVD. There arenique challenges in both the measurementnd management of blood pressure in dialysisatients.

12.1 Measurement of blood pressure:12.1.a In patients who have under-

gone multiple surgical proce-dures for vascular accesses inboth arms, blood pressureshould be measured in thethighs or legs. However, health-care professionals should useappropriate cuff size and mea-sure blood pressure only in thesupine position. (B)

12.2 Predialysis and postdialysis blood pres-sure goals should be <140/90 mm Hgand <130/80 mm Hg, respectively. (C)

12.3 Management of blood pressure byadjustment of dry weight:12.3.a Management of hypertension in

dialysis patients requires atten-tion to both management of fluidstatus and adjustment of antihy-pertensive medications. This re-quires close collaboration amonghealth-care providers. (B)Excessive fluid accumulationbetween dialysis sessionsshould be managed with: (B)� Education and regular

counseling by dietitians� Low sodium intake (2-3

g/day sodium intake)� Increased ultrafiltration� Longer dialysis� More than 3 dialysis treat-

ments per week� Drugs that reduce salt

appetite12.4 Management of hypertension with

drugs in dialysis patients:12.4.a Drugs that inhibit the renin-

angiotensin system, such asACE inhibitors or angiotensin
II-receptor blockers should be

preferred because they causegreater regression of LVH, re-duce sympathetic nerve activ-ity, reduce pulse wave velocity,may improve endothelial func-tion, and may reduce oxidativestress. (C)

12.4.b Antihypertensive drugs shouldbe given preferentially at night,because it may reduce the noc-turnal surge of blood pressureand minimize intradialytic hy-potension, which may occurwhen drugs are taken themorning before a dialysis ses-sion. (C)

12.4.c In patients with difficult-to-control hypertension, the dia-lyzability of antihypertensivemedications should be consid-ered (see Table 10). (C)

12.5 Determination and management ofblood pressure in children should followrecommendations by The Fourth Re-port on the Diagnosis, Evaluation, andTreatment of High Blood Pressure inChildren and Adolescents.50 (C)12.5.a Optimal systolic and diastolic

blood pressure should be <95%for age, gender and height. (B)

12.5.b Management of hypertension ondialysis requires attention tofluid status and antihyperten-sive medications, minimizing in-tradialytic fluid accumulation by(C):� education by dietitians ev-

ery 3 months� low salt intake (2 g/day so-

dium intake)� increased ultrafiltration� longer dialysis duration� intradialytic sodium model-

ing to minimize intradia-lytic hypotension

� more than 3 dialysis treat-ments per week

� antihypertensives: considerif medications are cleared
on dialysis.
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GUIDELINE 12: BLOOD PRESSURES50

RATIONALE

efinitions

Hypertension. The Seventh Report of theoint National Committee for the Prevention,etection, Evaluation and Treatment of Highlood Pressure (JNC VII) has defined hyperten-

ion in adults in the general population as sys-olic blood pressure �140 mm Hg and diastoliclood pressure �90 mm Hg, and has definedormal blood pressure �120/80 mm Hg.170

Orthostatic Hypotension. This is defined asfall in blood pressure of at least 15 mm Hg

ystolic and 10 mm Hg diastolic after standingor at least 2 minutes. Although these levels ofecline in blood pressure are usually associatedith symptoms of cerebral anoxia, some patientsay remain asymptomatic. By contrast, some

atients may become symptomatic with lesserecreases in blood pressure. Thus, any quantita-ive definition of orthostatic hypotension may beisleading, and orthostatic hypotension should

e diagnosed whenever the patient manifests
ymptoms of brain hypoxia upon standing. Heart v
ate variability during orthostasis is impaired inany CKD patients due to the coexistence of

utonomic dysfunction. (Moderately Strong)

lood Pressure and CVD

Blood pressure and cardiovascular events. Hy-ertension is very prevalent among dialysis pa-ients (50%-60%, when hypertension is defineds blood pressure �150/90 mm Hg for HDatients). The prevalence would be even higherf we were to use the JNC VII definitions above.n a study of 2,535 HD patients, only4% were normotensive on no drugs and amonghe hypertensive patients, only 30% wereontrolled.175

Cardiovascular disease is the leading cause ofeath in patients receiving maintenance HD,specially in the first year of treatment. A historyf long-lasting arterial hypertension is associatedith an increase in cardiovascular deaths in theseatients. Hypertension is the single most impor-ant predictor of coronary artery disease in ure-ic patients, even more so than cigarette smok-

ng and hypertriglyceridemia.176 Although a directelationship between levels of blood pressurend cardiovascular events has not been clearlystablished by controlled studies, hypertensionn dialysis patients should be considered a majorardiovascular risk factor. The lack of a signifi-ant correlation between blood pressure and car-iovascular events in dialysis patients may beue to poor ventricular function, leading to lowerlood pressure in some patients, when the fol-ow-up duration is relatively short. (Weak)

It was found that, after adjusting for age,iabetes, IHD, hemoglobin and serum albumin,ach 10 mm Hg rise in mean arterial bloodressure was independently associated with arogressive increase of concentric LVH, the de-elopment of de novo cardiac failure and de novoschemic heart disease.177 Other studies how-ver, have not shown a consistent associationetween blood pressure and subsequent mortal-ty in the dialysis population. A “U-shaped”elationship between blood pressure and mortal-ty was observed, with excess mortality risk inatients with the lowest and with the highestevels of blood pressure.178 Systolic blood pres-ure �180 mm Hg was associated with poorutcomes.179-181 It has been suggested that obser-
ations longer than 5 years are required to see the

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GUIDELINE 12: BLOOD PRESSURE S51

eneficial effect of blood pressure control. In aohort study of 432 CKD patients (261 HD and71 PD) followed prospectively for an averagef 41 months, each 10 mm Hg rise in MAPncreased the relative risk of LVH by 48% onollow-up echocardiography, increased the riskf de novo CHF by 44%, and the risk of de novoHD by 39%. Interestingly, in this study lowean arterial pressure was independently associ-

ted with mortality.182 (Weak)A substantial body of evidence indicates that

ncreased pulse pressure (PP), particularly iniddle-aged and older subjects, is an indepen-

ent predictor of risk of coronary heart disease,ompared with mean arterial pressure (MAP).ulse pressure represents the pressure increaseuring systole over diastolic blood pressure. Itay be related to increased LV mass, decreased

ortic compliance, and small-vessel remodel-ng,183-185 and is associated with reduced coro-ary vasodilator capacity.186 Reducing PP inypertension may normalize small artery struc-ure.187 In a recent study of a large cohort ofondiabetic patients on chronic HD, pulse pres-ure was found to be an independent predictor ofotal mortality,188 and was superior to systolicnd diastolic blood pressure in predicting totalortality. Arterial stiffness can be measured non-

nvasively using the pulse wave velocity (PWV)echnique, which is also an independent markerf cardiovascular risk in the general popula-ion.189 Epidemiological studies have shown thatWV is increased in CKD patients and it is an

ndependent marker of cardiovascular risk inhese patients.190 Aortic stiffness depends on therterial wall structure and function, which can benfluenced by blood pressure and aging.191 Aecent prospective cohort study of 180 CKDatients on maintenance HD, followed for aean duration of 52 � 36 months, has shown

hat carotid pulse pressure and aortic PWV weretrong independent predictors of all-cause (includ-ng cardiovascular) mortality. Brachial bloodressure, including pulse pressure, had no predic-ive value for mortality.192 (Moderately Strong)

Pulse wave velocity frequently improves whenlood pressure is reduced, particularly when ACEnhibitors193 or CCBs194 are used. In CKD pa-ients, the failure of PWV to improve in responseo decreased blood pressure is associated with
orse cardiovascular outcome. Moreover, the p
se of ACE inhibitors may have a favorableffect on all-cause mortality and cardiovascularortality that is independent of blood pressure

hanges.195 (Weak)

easurement of Blood Pressuren CKD Patients

Methods. Blood pressure should be mea-ured according to existing guidelines.196-198 Theialysis personnel should be trained and regu-arly retrained. The patient must be seated qui-tly for at least 5 minutes in a chair, with feet onhe floor, and arm supported at heart level. Bloodressure should be measured at least 5 minutesefore the needles for dialysis access are placed,s this may cause substantial stress in someatients. Blood pressure should also be measuredn the standing position (at least 2 minutes) andhe arm should be supported at heart level. Bloodressure should be measured both before and athe end of dialysis. Caffeine, exercise, and smok-ng should be avoided for at least 30 minutesrior to measurement. The auscultatory methodf blood pressure measurement should be usednd the disappearance of Korotkoff sounds shouldefine diastolic blood pressure. Appropriate cuffize should be selected so that the cuff bladderncircles at least 80% of the arm. The equipmenthould be regularly inspected and validated con-idering that, in one study, automated bloodressure recordings overestimated blood pres-ure by 14/7 mm Hg before dialysis.199 (Moder-tely Strong)In patients who have undergone multiple sur-

eries for vascular accesses in both arms andlood pressure is technically not measurable inhe arms, blood pressure could be measured inhe thighs or legs. However, health-care profes-ionals need to be properly trained, and shouldse appropriate cuff size and measure bloodressure only in the supine position. It must beept in mind that blood pressure in the lowerimb does not represent blood pressure measuredn the arm. Systolic blood pressure and pulseressure are amplified from the aorta towardseripheral arteries and amplification increasesith the distance from the heart. Therefore, lower

imb blood pressure is higher than brachial pres-ure. The difference is usually expressed as ankle-rm-pressure index. In young subjects the ankle
ressure could be higher than arm pressure by as

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uch as 30%. In older subjects, ankle and armressure tend to be the same. Therefore, theeference value for systolic blood pressure of40 mm Hg is valid only for brachial pressure;he reference value for lower limb blood pressures basically unknown. (Moderately Strong)

In patients with severe vascular calcifications,ndirect measurements of blood pressure may benaccurate. Intra-arterial measurements of bloodressure could provide true blood pressure, buthis is not feasible in most dialysis units. (Weak)

Predialysis vs. postdialysis blood pressure.Weak) It is unclear which blood pressure read-ng should be used as the guide for therapy andontrol of CVD. Some data suggest that predialy-is systolic blood pressure correlates best withVH.200 Another report suggests that postdialy-is blood pressure is the most representativef mean interdialytic blood pressure measuredy ambulatory blood pressure monitoringABPM).201 Others have suggested that an aver-ge of predialysis and postdialysis blood pres-ure may be a better predictor of mean interdialy-is blood pressure.202 In reality, neither is aarticularly good predictor of interdialytic bloodressure.203 This issue is complicated by thenown fall in blood pressure during dialysis in aarge number (40%-50%) of patients, and by theact that this fall is short-lived (12-24 hours).hus, perhaps ABPM or self-measured homelood pressure are better markers of interdialyticlood pressure load; however, for practical andnancial reasons, these tools cannot be applied to

he totality of dialysis patients.Circadian blood pressure variability and car-

iovascular risk. (Weak) Ambulatory bloodressure monitoring has improved the existingnowledge of the relationship between circadianariability of arterial blood pressure and end-rgan damage. Normally, blood pressure tends toe the highest during the morning, and graduallyecreases during the course of the day to reachhe lowest levels at night.204-207 Some hyperten-ive patients (approximately 10%-25% of pa-ients with essential hypertension) fail to mani-est this normal nocturnal dipping of bloodressure, defined as a night-time blood pressureall of �10%. These patients are called “nondip-ers,”208,209 whereas those with a normal circa-ian rhythm are called “dippers.” Among pa-
ients with advanced renal disease,210 and those d
n maintenance HD,211-214 the lack of diurnalariation in blood pressure and of the nocturnalipping of blood pressure can affect as many as4%-82% of patients. At times, in these patients,octurnal blood pressure can be greater thanlood pressure measured during the day. Be-ause blood pressure is usually measured duringhe day, this may lead to the erroneous impres-ion of good antihypertensive control.215 UsingBPM, it was observed that, in HD patients,lood pressure decreased after dialysis and dur-ng the first night, but by the next morningeached predialysis levels and it did not decreaseuring the second night.216

The phenomenon of nondipping can be im-roved with volume depletion and, perhaps, byosing drugs at night rather than in the morning.The mechanisms responsible for the abnormal

ircadian rhythm of blood pressure in patientsith renal failure remain elusive. Autonomicysfunction,217 reduced physical activity,218 sleepisordered breathing219,220 and volume over-oad221 have all been implicated. Since the phe-omenon of nondipping is more prevalent amongalt-sensitive patients with essential hyperten-ion, and since this disturbance improves withalt restriction,222,223 one would predict that vol-me expansion would play a major role in HDatients. However, not all evidence supports arimary role of volume expansion in the phenom-non of blood pressure nondipping.224-226

The correlation between blood pressure mea-ured in the physician’s office and cardiovascu-ar end-points is usually weak. A large body ofvidence from subjects with essential hyperten-ion has shown that average 24-hour ambulatorylood pressure correlates with incident cardiovas-ular events227-231 better than office blood pres-ure. Ambulatory blood pressure monitoring hasetter long-term reproducibility than casual bloodressure measurement in HD patients.232

A relationship also seems to exist between thebsence of nocturnal dipping of blood pressurend the severity of cardiovascular target organamage.209 In a study of 57 treated hypertensiveD patients, it was observed that after an aver-

ge follow-up of 34.4 � 20.4 months and afterdjusting for age, gender, and previous cardiovas-ular events, an elevated nocturnal and 24-hourP, and low office diastolic blood pressure pre-
ict cardiovascular mortality.233 However, one

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as to remember that among HD patients there issubstantial day-to-day variability in the day-

ight blood pressure profile.212 Moreover, noctur-al blood pressure measurements predict cardio-ascular outcome only in patients witheproducible blood pressure profiles.234

athophysiology of Hypertensionn Dialysis Patients

The pathogenesis of hypertension in CKDatients is complex and multifactorial. (Table1).

Role of sodium and volume status. (Moder-tely Strong) Excessive intravascular volumes a major pathogenic factor of hypertension inatients with CRF. However, the relationshipetween weight gain during two dialyses andypertension is unclear. Some studies have estab-ished that volume gain affects interdialytic bloodressure, whereas other studies have not shownuch a relationship.235

The HEMO study observed that volume statusnfluenced both predialysis and postdialysis bloodressure.236 However, the intradialytic reductionn body weight (or interdialytic fluid gain) iselpful but insufficient to describe volume statusnd to predict blood pressure changes in HDatients.The strongest evidence supporting a role for

xtracellular volume expansion derives from ob-ervations that, when excessive body fluids areemoved with slow dialysis (8 hours � 3 timeseekly) and “dry-weight” is achieved, blood
ressure normalizes in more than 90% of dialysis- w
ependent patients.237 It is of interest that whilsthe normalization of the extra-cellular volumeas achieved in the first month of dialysis treat-ent, blood pressure continued to decrease for

nother 8 months, despite the withdrawal ofntihypertensive medication. The reasons forong, slow dialysis achieving a more effectivelood pressure control may be due to moreffective control of the ECV expansion with aow rate of hypotension episodes. Moreover, dryeight is probably more difficult to achieve with

hort dialysis than with long, slow HD.In dialysis patients, normal blood pressure can

e achieved independently of the duration andose of dialysis, provided that the control of theostdialysis ECV is adequate. Decreased ECFxpansion is responsible for a significant portionf HTN control in HD regardless of modality,ut variability in achieved ECV is significant.238

Longer and more frequent dialysis. (Weak)ong, slow dialysis was shown to achieve aetter blood pressure control and survival.239

ther investigators have also shown better regres-ion of LVH with slow dialysis.240 Several stud-es have shown that short, daily HD treatmentay be associated with a significant reduction

f blood pressure, reduced use of antihyperten-ive medications, and lowered LV mass in-ex.226,241,242 In other studies, daily dialysisshort diurnal or nocturnal) improved blood pres-ure control, but only short daily HD resulted inower ECV.243

The improvement of blood pressure observed
ith short, daily HD is not necessarily due to less

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ostdialysis ECFV. Unchanged postdialysisCFV has been reported after the conversion toocturnal HD and after excellent blood pressureontrol was achieved.244 Some have suggestedhat short daily HD may decrease SNS activity.

In patients who remain hypertensive despitentense ultrafiltration, sodium and volume excessay play only a secondary role. The lack of

orrelation between exchangeable sodium and/orxtracellular volume and blood pressure in theseatients supports this notion.245,246

Role of CAPD. (Weak) Since CAPD allowsor more consistent control of extracellular fluidolume than HD, it has been suggested thatAPD may provide better control of blood pres-

ure than HD. Within 12 months of startingAPD, between 40%-60% of hypertensive pa-

ients no longer required antihypertensiverugs.247

Better blood pressure control achieved duringhe first 2 months appears to be volume-related.fter the initial 6 months of CAPD treatment,

he sustained reduction in blood pressure doesot correlate any longer with changes in volumend it is more likely related to removal of pressorormones, although precise measurements oflood volume have not been performed.248 After-2 years of CAPD treatment, blood pressureay rise again, and so does the need for antihy-

ertensive drugs, presumably due to fluid reten-ion related to sclerosis of the peritoneum, de-reased efficiency of the peritoneal membrane inemoving fluids, and reduced kidney function.

Role of erythropoietin. (Moderatelytrong) The advent of recombinant humanrythropoietin (rhEPO) has substantially im-roved the management of anemia and the qual-ty of life in patients with chronic renal failure.owever, increasing the hematocrit with rhEPO

an lead to several adverse side effects, includingorsening of hypertension.During studies in dialysis and pre-phase IIIulticenter trials of rhEPO in dialysis patients,

n increase in diastolic blood pressure of morehan 10 mm Hg and/or a need to increase antihy-ertensive therapy occurred in 88 of 251 (35%)f previously hypertensive patients. A similarncrease in blood pressure was noted in 31 of 7144%) of normotensive patients; in 32% of theseatients, antihypertensive therapy had to be insti-
uted.249,250 This adverse rise in blood pressure m
as not been noted in patients receiving rhEPOor other reasons, suggesting that renal diseaseay confer a particular susceptibility251 to the

ypertensive action of rhEPO. The rise in bloodressure during rhEPO administration usuallyccurs within 2-16 weeks, although some pa-ients may experience a rise in blood pressureeveral months after the initiation of therapy.

Patients who are at greater risk for developingypertension during rhEPO therapy are thoseith severe anemia, those in whom anemia is

orrected too rapidly, and those with pre-existingypertension.

anagement of Blood Pressuren Dialysis Patients

Target blood pressures. Despite the obviousmportance of defining an ideal goal blood pres-ure for HD patients, this issue has not beenesolved. According to JNC VII recommenda-ions, normal blood pressure is �120/80 mmg.170 In patients with essential hypertension,

eceiving antihypertensive therapy, the recom-ended goal blood pressure is �135/85 mm Hg.his recommendation is largely based on theOT study.252 The same study indicated that, iniabetic patients, the goal blood pressure shoulde set lower and should probably be below30/80 mm Hg.In patients with renal disease, particularly those

ith proteinuria greater than 1 g per 24 hours, aoal blood pressure of 125/75 mm Hg providesaximum protection against progression of re-

al disease.253 This recommendation, however,oes not apply to African-Americans with hyper-ension and renal disease in whom no differencen progression of renal disease was observedetween MAP of 107 and 92 mm Hg.254 Further-ore, these studies did not address the effect of

ifferent levels of blood pressure control onVD.It has been suggested that blood pressure of

ess than 150/90 mm Hg is a reasonable goal forost patients undergoing HD. The Work Group

n chronic renal failure and renovascular hyper-ension, however, recommended a goal bloodressure of �130/85 mm Hg.255 In the onlyrospective study so far performed in the dialysisopulation, a blood pressure of 140/90 mm Hg
inimized the occurrence of LVH and death.182

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It is the opinion of this Work Group that, inD patients, a reasonable goal is predialysislood pressure �140/90 mm Hg (measured inhe sitting position), provided there is no substan-ial orthostatic hypotension and these levels areot associated with substantial and symptomaticntradialytic hypotension. (Weak)

Treatment algorithm. (Weak) The manage-ent of hypertension in dialysis patients is

requently challenging and it requires the knowl-dge of the pharmacokinetic and pharmacody-amic properties of all the agents used. Weropose an algorithmic approach to the manage-ent of hypertension in dialysis patients (Fig 4).Lifestyle modifications should be an integral

art of the management of hypertensive CKDatients. The importance of salt restriction shoulde continuously emphasized. Achievement ofry weight and reduction of ECFV should beursued, although this is not easy to monitor orccomplish, and it may not be effective in every

Fig 4. Hypertension treatm

atient. c

If those measures are unsuccessful (and fre-uently they are), antihypertensive drugs shoulde initiated. As a first line of treatment in theajority of patients, we propose the use of ACE

nhibitors or ARBs. The latter also reduce LVHn HD patients, and may be more potent thanCE inhibitors.195,256-258 In an observational

tudy, the use of an ACE inhibitor has beenssociated with decreased mortality in cohorts ofKD Stage 5 patients.259

Table 12 describes some of the criteria to besed in the selection of antihypertensive drugs inialysis patients based on compelling indications.

In patients with previous myocardial infarc-ion or with well-established coronary arteryisease, �-blockers should be preferred. Expo-ure to beta-blockers is associated with de-reased mortality in CKD (see also Guideline).130 Calcium channel antagonists and anti–lpha-adrenergic drugs should be an integral partf the management of hypertension to achieve

orithm in dialysis patients.

ontrol if necessary. Observational studies sug-

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est that CCBs are associated with decreasedotal and cardiovascular mortality.260 In the mostevere forms of hypertension, multiple antihyper-ensive drugs are needed, including minoxidil. Ifull doses of one agent are ineffective, a secondr a third drug should be added. If blood pressures not controlled with dialysis and three antihyper-ensive agents of different classes, the patienthould be evaluated for potential secondaryauses of resistant hypertension. If no evidentause for resistant hypertension is found, and theatient remains hypertensive after a trial withinoxidil, one should consider treating the pa-

ient with continuous ambulatory peritoneal dialy-is (CAPD). If CAPD proves ineffective, surgi-al or embolic nephrectomy should be considered.

Resistant hypertension. (Weak) In dialysisatients, hypertension is considered resistant iflood pressure in a compliant patient remainsbove 140/90 mm Hg after achieving dry weight,nd after an adequate and appropriate triple-drugegimen. In elderly patients with isolated systolicypertension, resistant hypertension is defined ashe failure of an adequate regimen to reduceystolic blood pressure to less than 140-150 mmg. The regimen should include nearly maximaloses of at least three different pharmacologicalgents selected from ACE inhibitors, calciumntagonists, �-blockers, antiadrenergic agents,r direct vasodilators, such as hydralazine or
inoxidil. i
Several factors can cause resistant hyperten-ion, including patient noncompliance, inad-quate regime, drug-to-drug interactions, pseu-oresistance, secondary hypertension, andnrecognized pressor mechanisms (Table 13).Paradoxical rise of blood pressure during

ialysis. (Weak) Hypertension induced by HDs a topic that has received little attention. Itccurs in a small number of patients during HD.he causes of this phenomenon have not beenell worked out. Sometimes it is precipitated by

emoval of certain antihypertensive drugs duringialysis.Hemodialysis reduces blood levels of some

CE inhibitors (enalapril, ramipril) but not oth-rs (benazepril, fosinopril, methyldopa, atenolol,cebutolol, nadolol, minoxidil and nitroprus-ide); by contrast, levels of clonidine, carvedilol,abetalol, CCBs and ARBs do not change signifi-antly (see Table 12). At times, excessive volumeepletion may result in hypertension rather thann hypotension. This has been attributed to exces-ive stimulation of the renin-angiotensin systemrecipitated by the decrease in blood volume. Anlternative possibility, which has not been prop-rly investigated, is that this might be the resultf excessive activation of the sympathetic ner-ous system and resulting vasoconstriction.In a recent study of seven patients with this

haracteristic, all with marked cardiac dilation,
ntense ultrafiltration reduced blood pressure and

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ardiac dilation and eliminated the paradoxical el-vation of blood pressure during dialysis.261 Thexplanation of this phenomenon remains elusive.

LIMITATIONS

One major limitation of these guidelines is thelack of large-scale clinical trials correlatinglevels of blood pressure with cardiovasculardisease events. Particularly puzzling is theU-shaped relationship between systolic bloodpressure and cardiovascular morbidity andmortality, and the apparent lack of high bloodpressure effects on cardiovascular diseaseevents until systolic blood pressure reachesapproximately 180 mm Hg. The increase mor-tality in patients with lower blood pressurecould be related to poor ventricular function.The lack of effects of blood pressure oncardiovascular events over a wide range ofblood pressure between 100-180 mm Hg couldbe related to variable ventricular function, andto “survival bias,” whereby high-risk patientswith higher blood pressure may not havesurvived to be entered into the study.Another limitation of these guidelines is relatedto the great variability of blood pressure withdialysis and the lack of firm criteria on definitionof hypertension in this patient population.Another major limitation of these guidelinesis the lack of controlled studies on the effectof different blood pressure goal and differ-ent therapeutic intervention on CVD events.Most of the recommendations are based oninference from studies performed in thegeneral population with normal renal func-tion. Other studies were performed in pa-tients with various degrees of kidney dis-
ease, but not on dialysis therapy, and the
outcomes were deterioration of renal func-tion but not CVD.


Measurement and recording of blood pressureis already implemented in most HD programs.Not all dialysis programs, however, routinelymeasure blood pressure in the sitting andupright position both before and after dialysis.Further definition and evaluation of the associ-ated costs and benefits are required to deter-mine the need for and implementation of24-hour ABPM.Longer and/or more frequent short dialysismay be necessary to achieve control of bloodpressure and fluid/volume status in manypatients. However, current Medicare reim-bursement policies, and patient resistance tomore frequent and/or longer dialysis rendersthe implementation of these recommendationsdifficult.


More studies are necessary to better determinegoal blood pressures in dialysis patients.Studies are needed to determine which antihy-pertensive drugs are best suited for dialysispatients.More studies are necessary to determine opti-mal dosing (dose and time of administration)of antihypertensive drugs in dialysis patients.Further studies are needed to ascertain thepotential advantage of daily dialysis overdialysis performed 3 times weekly to achievebetter blood pressure control and better cardio-
vascular outcomes.

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GUIDELINE 13: DYSLIPIDEMIA

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Since the NKF K/DOQI Clinical Practiceuidelines for Managing Dyslipidemia inhronic Kidney Disease Patients were estab-

ished only recently,51 we refer to those guide-ines. However, we add the information on fourecent studies that provide some new insights onhe inverse association between cholesterol levelnd mortality, as well as further indirect evidencef the beneficial effects of lipid-lowering therapy.urthermore, unpublished results of the recentlyompleted “4D Trial” on the effect of statins inhronic HD patients recently became availablend will be discussed.

Management of dyslipidemias for prepubertalhildren with CKD and CKD Stage 5 shouldollow recommendations by National Choles-erol Expert Panel in Children and Adolescents.ostpubertal children or adolescents with CKDtages 4 and 5 should follow the recommenda-

ions provided in the K/DOQI Clinical Practiceuidelines for Managing Dyslipidemias inhronic Kidney Disease.51

RATIONALE

ssociation between Dyslipidemia and CVD inialysis Patients (Weak)The previous guidelines listed the studies,

hich investigated an association between cho-esterol levels and CVD, and discussed the often-bserved “paradoxical association” between dys-ipidemia and CVD in HD patients, i.e., thatigher cholesterol levels are apparently associ-ted with better outcomes in HD patients. As onef several explanations it was mentioned thatone of the previous studies was a long-term,rospective cohort study and that illness, inflam-ation, and poor nutrition might have con-

ounded the relationship between dyslipidemiand CVD. This was recently observed in a studynvestigating the association of cholesterol levelsith all-cause and CVD mortality in a prospec-

ively followed cohort of 823 patients who initi-ted dialysis treatment.262 During a median fol-ow-up of 2.4 years, 324 deaths (including 159VD deaths) occurred. Average serum choles-

erol level was lower in the presence of inflamma-ion/malnutrition than in its absence. A higheraseline total serum cholesterol level was associ-ted with a decreased risk of all-cause mortality
verall and in the presence of inflammation/ f

alnutrition. In contrast, a higher serum choles-erol level was associated with an increased riskn the absence of inflammation/malnutrition. ForVD mortality, an inverse trend was not statisti-ally significant in the presence of inflammation/alnutrition, and a positive association was evi-

ent in the absence of inflammation/malnutrition.he authors concluded that the inverse associa-

ion of total cholesterol level with mortality inialysis patients is likely due to the cholesterol-owering effect of systemic inflammation andalnutrition, not to a protective effect of high

holesterol concentrations. These findings wouldupport the treatment of hypercholesterolemia inialysis patients.

ndirect Evidence for Lipid-Lowering Therapyn Kidney Disease (Weak)

Even if the present guidelines focus on dialy-is patients, further indirect evidence for theeneficial effect of lipid-lowering interventionomes from three additional studies. A multi-enter, randomized, double-blind, placebo-con-rolled trial of 40-80 mg fluvastatin was con-ucted in 2,102 kidney transplant recipientsollowed for 5-6 years.263 Fluvastatin reducedDL cholesterol concentrations by 32%. Risk

eduction for the composite primary endpointncluding myocardial infarction, cardiac deathnd cardiac interventions did not reach signifi-ance although the fluvastastin group experi-nced a third fewer cardiac death and nonfatalI than the placebo group. Coronary interven-

ion procedures and other secondary endpointsere not significantly different between the tworoups.Another study was performed in more than

9,000 hypertensive patients with at least threether CVD risk factors.264 Patients with non-asting cholesterol concentrations of 6.5 mmol/Lr less were randomly assigned additional atorva-tatin 10 mg or placebo. A prespecified subgroupnalysis in 6517 patients with kidney dysfunc-ion revealed a significantly lower risk for therimary endpoint (nonfatal MI or cardiac death)n the atorvastatin group when compared to pla-ebo.

A randomized trial of pravastatin versus pla-ebo in 4,159 patients with previous MI and totallasma cholesterol level �6.21 mmol/L per-
ormed a post hoc analysis in 1,711 patients with

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KD.265 After a median follow-up of almost 5ears, the incidence of the primary end pointcoronary death or nonfatal MI) was lower inatients receiving pravastatin than in those receiv-ng placebo, suggesting that pravastatin is effec-ive for secondary prevention of cardiovascularvents in persons with mild chronic kidney insuf-ciency.

D Trial

Together with the Heart Protection Study,266

ll four studies support the hypothesis that lipid-owering intervention might be beneficial in pa-ients with kidney insufficiency.

The latest results came from the “4D Trial”Deutsche Diabetes Dialyse Studie) which haveot yet been published. It was a randomized,lacebo-controlled study in 1,255 type 2 diabeticatients on chronic HD.267 Out of those patients,19 were treated with 20 mg atorvastatin com-ared to 636 matched controls treated with pla-ebo for a median of 4 years. The statin was safend effective in reducing the median serum LDLholesterol level by 42% throughout the studyeriod. However, the primary endpoint—defineds the composite of cardiac death, nonfatal MI,nd fatal or nonfatal stroke—was only reducedy 8% which was not statistically significantChristoph Wanner for the 4D Study investiga-ors, American Society Nephrology 37th Annual

eeting, October 2004). This was in distinctontrast to the recently published CARDS trialCollaborative Atorvastatin Diabetes Study) inype 2 diabetic patients who had not yet devel-ped significant kidney disease.268 In that study,
torvastatin reduced the rate of acute coronary c
vents by 36%, coronary revascularization by1%, stroke by 48%, and death by 27%. The 4Dnvestigators concluded that the negative resultsight have been due to the advanced cardiovas-

ular diseases in the chronic HD patients, andecause statin therapy was initiated too late.herapy might better be started during the earlytages of disease progression as demonstrated byhe CARDS study. There are, of course, otherotential explanations for these results, whichould warrant further studies. Whether the effectf statin reported in the 4D Trial on diabeticialysis patients is different in nondiabetic dialy-is patients or chronic PD patients needs to beurther investigated.

ecent NCEP Report on ATP III Guidelines

A recent report from the National Cholesterolducation Program (NCEP) discussed the impli-ations of clinical trials on the Adult Treatmentanel III (ATP III) guidelines.269 Results from

he Heart Protection Study and the PROVE ITtudy suggested that additional benefit may bebtained by reducing LDL cholesterol levels toubstantially below 100 mg/dL. Since other stud-es are underway to prove the efficacy of lower-ng LDL to very low levels, the NCEP reporttated that “until these trials are completed, pru-ence requires that setting an LDL-C goal of70 mg/dL for high-risk patients must be left astherapeutic option on the basis of clinical trial

vidence, whereas a goal of �100 mg/dL can beetained as a strong recommendation. Factorshat favor a decision to reduce LDL-C levels to

70 mg/dL are those that place patients in the
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GUIDELINE 14: SMOKING, PHYSICAL ACTIVITY,
AND PSYCHOLOGICAL FACTORS
While there are few data specific to CVD inialysis patients regarding smoking, physical ac-ivity, and psychological factors (depression, anxi-ty, and hostility), the evidence in the generalopulation is clearly in favor of addressing eachf these issues. In order to ensure that cliniciansaring for dialysis patients do not overlook themportance of each of these factors, we haveedicated an entire guideline to them.14.1 All dialysis patients should be coun-

seled and regularly encouraged to stopsmoking. (A) Referral to smoking ces-sation specialists is recommended. (C)14.1.a Special consideration should be

given to cessation of smoking indepressed individuals with littleability to engage in physicalactivity. (C)

14.2 All dialysis patients should be coun-seled and regularly encouraged bynephrology and dialysis staff to in-crease their level of physical activity.(B)14.2.a Unique challenges to exercise

in dialysis patients need to beidentified in order to refer pa-tients appropriately (e.g., tophysical therapy or cardiac re-habilitation) and to enable thepatients to follow regimens suc-cessfully. Such challenges in-clude orthopedic/musculoskel-etal limitations, cardiovascularconcerns, and motivational is-sues. (C)

14.3 Measurement of physical functioning:14.3.a Evaluation of physical function-

ing and re-evaluation of thephysical activity programshould be done at least every 6months. (C)

14.3.b Physical functioning can bemeasured using physical per-formance testing or question-naires (e.g., SF-36). (C)

14.3.c Potential barriers to participa-tion in physical activity shouldbe assessed in every patient.
(C)

14.4 Physical activity recommendations:14.4.a Many dialysis patients are se-

verely deconditioned and there-fore may need a referral forphysical therapy to increasestrength and endurance to thepoint where they are able toadopt the recommended levelsof physical activity.14.4.a.i Patients who qualify

for cardiac rehabilita-tion should be referredto a specialist. (C)

14.4.a.ii The goal for activityshould be for cardio-vascular exercise at amoderate intensity for30 minutes most, if notall, days per week. Pa-tients who are not cur-rently physically ac-tive should start atvery low levels and du-rations, and graduallyprogress to this recom-mended level. (C)

14.4.b Follow-up:14.4.b.i Physical functioning

assessment and en-couragement for par-ticipation in physicalactivity should be partof the routine patientcare plan. Regular re-view should includeassessment of changesin activity and physi-cal functioning. (C)

14.5 Depression, anxiety, and hostilityshould be identified and treated indialysis patients. (B)14.5.a Every dialysis patient should

be seen by the dialysis socialworker at initiation of dialysis,and at least biannually thereaf-ter, to assess the patient’s psy-chological state, with specificfocus on the presence of depres-
sion, anxiety, and hostility. (C)

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14.5.b Dialysis patients should betreated for depression, anxiety,and hostility if they are experi-encing these psychologicalstates. (C)

RATIONALE

efinitions

Physical activity. Bodily movement that isroduced by the contraction of skeletal musclend that substantially increases energy expendi-ure.

Regular physical activity. Accumulation of ateast 30 minutes of moderate-intensity physicalctivity on most—and preferably all—days ofhe week. Moderate intensity is at levels appropri-te to the capacity, needs, and interest of thendividual.

Physical functioning. Ability of the indi-idual to participate in required activities ofiving.

Physical capacity. Measured ability to per-orm specific tasks, such as performance testingnd exercise testing.

Major Depression is typically characterizedy having a depressed mood and a significantoss of interest in all activities that persists for ainimum of 2 weeks and is accompanied by ainimum of four of the following symptoms:

ppetite or sleep disturbances; psychomotor retar-ation or agitation; fatigue; feeling guilty ororthless; problems with concentration; or sui-

idal ideation.270 Because many of the somaticymptoms associated with depression are alsoymptoms of uremia, the cognitive symptomsay be better used when assessing depression in

ialysis patients.Anxiety has both physiological and psychologi-

al symptoms. The psychological aspects, whichay be more relevant when assessing those with

re-existing medical problems, include: feelingsf powerlessness; a sense of impending danger;xhaustive alertness; self-absorption that inter-eres with ability to effectively problem-solve;nd extreme doubts about a threatening occur-ence and one’s ability to deal with it; andorries that are difficult to control and may

nterfere with functioning. The concerns may beith or without cause, are pervasive, and last

onger than would be expected.271 c

Hostility involves negative behavior and feel-ngs, often directed at interpersonal relation-hips. It includes such characteristics as anger,ynicism, and lack of trust.270

moking (Moderately Strong)Cigarette smoking is universally recognized

s an independent risk factor for CVD. Smoking,herefore, should also be discouraged in patientsith CKD. However, this recommendation is

ven more compelling, considering the relation-hip between smoking and poor outcomes inialysis and transplant patients (Table 14). Therequency and duration of contact with dialysisealth-care providers should facilitate concertednd serious efforts directed towards assistingatients to discontinue smoking.

hysical Activity (Weak)Dialysis patients have extremely low levels of

hysical functioning and exercise capacity, andre often physically inactive. Physical inactivitys known to be a risk factor for CVD and overallortality272 as well as increasing risk for devel-

ping several chronic conditions, including dia-etes273,274 and hypertension.275 In the generalopulation, regular physical activity: reduces highlood pressure in persons with hypertension;educes depression and anxiety; helps to controleight; helps to maintain healthy bones, muscles,

nd joints; helps older adults become strongernd better able to move about without falling;nd promotes psychological well-being. This evi-ence is clearly documented in the U.S. Surgeoneneral’s Report on Physical Activity andealth.276 Several other national guidelines rec-mmend regular physical activity as part of treat-ent for cardiovascular-related risk factors, spe-

ifically, the Sixth Report of the Joint Nationalommittee on Prevention, Detection, Evalua-

ion, and Treatment of High Blood Pressure277

nd the National Cholesterol Education Projectdult Treatment Guidelines III.278 In fact, inoth of these documents, lifestyle change (whichncludes regular physical activity) is the firstecommendation.

Data in dialysis patients indicate that self-eported physical functioning is highly predic-ive of outcomes such as hospitalizations andeath, even when corrected for case mix and
omorbidity.279 Likewise, a recent study has

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GUIDELINE 14: SMOKING, PHYSICAL ACTIVITY, AND PSYCHOLOGICAL FACTORSS62

hown that objective laboratory measures ofhysical fitness are independently predictive ofortality, with patients with low maximal oxy-

en uptake (�17 mL/kg/min) showing signifi-antly higher mortality.280 It is not known whethermproving exercise capacity and/or increasinghysical activity will result in reduction in hospi-alizations or death in dialysis patients.

Although no randomized clinical trials haveeen performed to assess the effects of physicalctivity on cardiovascular risk in patients withenal failure, the preponderance of evidence andxisting guidelines for physical activity for otheropulations at high risk for CVD suggest similarmplementation of physical activity for patientsith renal failure. The well-documented litera-

ure on low levels of physical functioning in this
opulation, and evidence that it can be improved w
ith exercise training, warrants attention to thisifestyle issue.281-297

sychological Factors (Moderately Strong)The purpose of this guideline is to identify

hose individuals at increased risk for developingr worsening CVD due to their psychologicaltate. There is a strong association between de-ression, anxiety, and hostility, and CVD in theeneral population. No research was identifiedhat addressed the association of psychologicaltate per se with CVD in dialysis patients. How-ver, since there is a high prevalence of depres-ion and anxiety, as well as documented hostility,n this population, it is reasonable to recommendssessment and treatment of these conditions thatre known elsewhere to be highly associated
ith CVD.

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Depression. In the 1980s, two meta-analy-es of the research literature evaluating psycho-ogical functioning and CVD found conflictingesults. One strongly suggested that depressionelates to CAD, including its development, whilehe other found that depression did not predicthe occurrence of CAD.298,299 Another study of98 men found that depression was only slightlyssociated with incidence of CHD.300 However,ecent evidence from 13 rigorously designedesearch studies linking patients exhibiting de-ressive symptoms or experiencing major depres-ion with higher cardiovascular morbidity andortality suggests depression may be an indepen-

ent risk factor in CVD progression.270,301 Aeta-analysis of 11 epidemiological studies found

hat the relative risk for developing CHD was.64 in depressed individuals.300 Multiple stud-es that followed patients with coronary heartisease for up to 2 years found that depressionredicted the occurrence of angina pectoris, MI,nd angioplasty and/or coronary artery bypassurgery.302 Depression also resulted in more thanfourfold increased independent risk of mortal-

ty, giving it the same prognostic value as a prioristory of MI.302

Rates of depression of 30%-50% have beeneported in dialysis patients who use self-eported measures of depressive symptoms,lthough lower rates have been reported whenSM III-R criteria are used to assess for majorepression.303 HD patients’ mean depressioncore has been documented to be significantlyigher than that of normal subjects.304 In onetudy of 128 dialysis patients, 25.7% exhibitedymptoms of depression and 26.6% scoredithin the range of clinical depression. Ap-roximately 50% of participants scored withinhe range that indicated a potentially clinicallyignificant depression.305 A more recent studyound that approximately 25% of the 1,000 HDatients studied were depressed.279 Forty-hree percent of 9,382 hemodialysis patientscored within the depressed range of the Cen-er for Epidemiological Studies Depressioncreening Index.306 Multiple studies have dem-nstrated that depression is associated withecreased overall survival in dialysis patients.t has not been established whether depression
s an independent risk factor or if depression I
ffects other variables, such as adherence, thatay impact survival.303

Anxiety. Most early studies suggested thatnxiety was, at the most, only slightly related toVD.298,299 An exception was a 5-year prospec-

ive study of 10,000 adult men which found thatot only was anxiety an independent contributoro the development of angina pectoris, but theikelihood of developing angina increased as theevel of anxiety rose.307 Later evidence fromhree research studies, one involving 34,000ealthy subjects, further documented a signifi-ant association between anxiety and the devel-pment of cardiac events and SCDs.270 Othersave shown that social anxiety both significantlyredicts CHD development as well as increasests incidence.300 Multiple studies have estab-ished that those who experienced both depres-ion and anxiety had a compounded cardiacisk.270 Other research has documented the rela-ionship between anxiety and cardiac events,ncluding MI302,308,309 and SCD.310

Approximately 45% of 128 dialysis patients inne study exhibited clinical anxiety.305 As withepression, the mean anxiety score of HD pa-ients has been found to be significantly higherhan that of normal subjects.304

Hostility. Research evaluating the relation-hip of hostility with CVD has shown mixedesults in the general population. Three prospec-ive, controlled studies representing 1,250 sub-ects in the general population, which used theook-Medley Hostility Inventory as a measuref hostility, demonstrated that the presence ofostility predicted CAD events and overall mor-ality.298 Further support for hostility being anndependent risk factor for CAD comes from aeta-analysis of 45 research studies.311 Data

rom the Western Collaborative Group Studyhowed that potential for hostility was a signifi-ant predictor for developing CHD.299 Addi-ional studies revealed that hostility was indepen-ently related to coronary atherosclerosis andignificantly predicted the development ofHD.299 It was found that patients with docu-ented hostility had a 1.9 risk ratio for experienc-

ng MI, angina, and cardiac death after control-ing for other traditional risk factors.302

The intensity of anger, which is a componentf hostility, has also been associated with CVD.
n a prospective study of 1,305 individuals, those

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ho experienced a higher level of anger wereound to have a 3.2 times higher risk of having aatal or nonfatal coronary event compared tohose who reported the lowest level of anger.310

nother study documented that the relative riskf experiencing another MI was 2.3 within 2ours of an anger episode in 1,623 post-MIatients.302

The Kellner Symptom Questionnaire, whichas administered to female subjects, showed

hat not only were dialysis patients more de-ressed, they were also more hostile than theealthy control group.312 A study of dialysisatients and their partners documented that thosen dialysis experienced a variety of psychologi-al reactions, including anger.313

Physiological factors associated with depres-ion, anxiety, and hostility. (Weak) Depres-ion, anxiety, and hostility may be associatedith CVD through several mechanisms. For

xample, these factors may lead to nonadher-nce with the dialysis or diet regimen, whichay impair cardiovascular functioning. In ad-

ition, a patient who is experiencing any ofhese psychological states may be more proneo engage in high-risk behaviors, such as smok-ng, that could have a negative impact onardiovascular health.

Additionally, there are pathophysiological ef-ects when a person experiences depression, anxi-ty, or hostility. Depression has been associatedith impaired platelet functioning, hypercortisol-

mia, heightened plasma and urinary cat-cholamines, increased heart rate, altered vagalontrol, and a reduction in the variability of theeart rate. Each of these may have a negativempact on the prognosis of CHD.301 Patientsxperiencing depression have exhibited sympa-hoadrenal hyperactivity, and it has been sug-ested that this may contribute to the develop-ent of CVD due to the cathecholamines’ effects

n cardiac functioning and platelets.301 Depres-ion has also been associated with the inflamma-ory response, and consequent CAD progres-ion.302 Other physiological changes associatedith depression that negatively impact cardiovas-

ular function are hypercoagulability, systemicnd localized inflammation, and cardiac rhythmlterations.314

Some patients with anxiety have exhibited
ecreased heart rate variability, which may result T
n pathological alterations in cardiac autono-ous tone. This could involve either increased

ympathetic stimulation or impaired vagal con-rol, both of which have been linked to mortal-ty.270 Sympathetic-adrenal medullary and adre-al cortical activity are higher when anxiety isresent, and this may also be a contributor toVD.307 Anxiety may also result in coronaryasospasm that can cause atherosclerotic plaqueso rupture.302

People who exhibit hostility and are exposedo certain stimuli, such as mental tasks, haveeen shown to have higher blood pressure andeart rates than those who are not hostile,270,298

s well as other physiological changes that areinked to CVD.270,302

Assessment and suggested treatment of depres-ion, anxiety, and hostility. (Weak) Althoughhere are no studies specifically addressing theelationship between psychological factors andVD in dialysis patients, the prevalence of these

actors, as discussed earlier, makes treatment anmportant issue. There is documented evidencehat psychological and social interventions, inddition to standard cardiac rehabilitation, canignificantly reduce mortality and morbidity andave positive influences on cholesterol, bloodressure, and heart rate.302

Adequate dialysis and anemia control are im-ortant contributors to overall well-being anduality of life for dialysis patients. These factors,ombined with an assessment of the patient’shysical health and potential side effects of medi-ation, should first be evaluated as possible con-ributors to depression and anxiety.

Typically, referral to a psychologist may beecessary for psychometric testing, although qual-ty-of-life assessments, which include depres-ion, have become routine in many dialysis facili-ies. Several instruments measure levels ofepression, anxiety, and hostility (Table 15). Theeck Depression Inventory (BDI), which is used

requently, is a well-validated instrument.303 TheDI Fast Screen is a self-report instrument thatas developed specifically to measure depres-

ion in patients who have medical illness.315 Theognitive Depression Index, a subset of the BDI,ontrols for the possible impact of somatic symp-oms, which may artificially inflate depressionates when assessing the dialysis population.303

he SF-36 has also been established as a good

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creening tool for depression with center HDatients.279 The World Health Organization Qual-ty of Life-100 (WHOQOL-100) and its abbrevi-ted version, WHOQOL-BREF, were developedor use throughout the world in a variety ofultures. These instruments contain a psychologi-al domain that assesses depression and anxi-ty.316 The State-Trait Anxiety Inventory (STAI)as been commonly used and is considered to bene of the best standardized tests to measurenxiety.317 Similarly, the State-Trait Anger Ex-ression Scale (STAXI) has also been used exten-ively. It has predictive validity and vast norma-ive data, and distinguishes between theuppression and the expression of anger.318 An-ther measure of hostility is the Cook-Medleyostility Inventory, which is taken from theinnesota Multiphasic Personality Inventory

MMPI). This instrument has been found toredict CAD events, CHD mortality and overallortality.298,319

Social support has been shown to lower depres-ion in the general population.303 Poor socialupport has also been associated with an in-reased incidence of CAD.270 Group counselinghat focused specifically on modifying Type Aersonality traits, such as hostility, was found notnly to reduce Type A characteristics, but also toignificantly reduce cardiac deaths in a con-rolled study of over 800 post-MI participants.
roup instruction that included stress reduction m
echniques was also found to lower hostility, asell as cardiac deaths.270

The use of cognitive-behavioral therapy wasound to lower anxiety and reduce depression inhe general population,311 and has also effec-ively reduced hypertension and the morbiditynd mortality from CVD that is associated withypertension.318 Relaxation techniques were alsoqual to or more effective than other psychologi-al interventions in lowering physiologicalrousal in persons with CVD. Biofeedback, oneorm of relaxation, lowered hypertension in 60%f study participants with CVD.318 Other tech-iques, such as controlled breathing, have beenound to be significantly associated with reduc-ion in MIs, as well as all-cause mortality.270

hronic HD patients who were taught simplerogressive relaxation exercises had signifi-antly lowered anxiety levels, while a controlroup remained unchanged.317 Multiple studiesith the general population have documented

hat anger is also treatable using a variety ofifferent interventions.311,318

Patient education has been documented tompact psychological state. Patients who partici-ated in an educational program about CKDwhich included information on its treatmentsnd potential impact on quality of life) prior toeginning dialysis were found to have signifi-antly lower levels of anxiety and improved
oods compared to a control group. This differ-

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nce remained for the first six months afternitiating dialysis.320 As discussed earlier in thisuideline, physical activity can also significantlympact the dialysis patient’s well-being.

If patients exhibit depressive or anxiety symp-oms that do not respond to other treatments,sychotropic medication should be considered.elective serotonin reuptake inhibitors or atypi-al antidepressants, such as nefazodone or bupro-rion, may be considered for use in CVD pa-ients who are depressed. These antidepressantedications may have fewer potential negative

ardiovascular effects than many other antidepres-ants.301 Studies have documented that pharma-ological intervention has had positive effects onhe psychological functioning of patients withKD.321

LIMITATIONS

moking

Cessation of smoking in dialysis patients maybe difficult to achieve, as in the generalpopulation.There are no comprehensive studies of the useof the pharmacotherapies recommended forsmoking cessation in dialysis patients.

hysical Activity

There are no randomized trials in dialysispatients of the effects of exercise on cardiovas-cular risk profile; however, there are random-ized trials in dialysis patients that demonstratethe effects of exercise training on physicalfunctioning. Many patients are severely debili-tated and will require lower levels of rehabili-tation efforts. These levels may not be suffi-cient to modify cardiovascular risks; however,they will prove adequate to improve physicalfunctioning.

sychological Factors

Research studies have produced conflictingdata that may be due to using different defini-tions of the constructs, examining componentswithin a construct rather than using the entireconstruct, or using varying methods of measur-ing psychological constructs. Additional prob-lems in some studies included small sample
sizes, large percentages of a study population
lost to follow-up, and not controlling forvariables that could affect the outcome.This guideline is largely based upon observa-tional studies, meta-analyses, and review ar-ticles. No research could be found that evalu-ated the association between psychologicalfactors and CVD in dialysis patients.



In the U.S., regulations governing dialysisfacilities mandate that Masters-prepared socialworkers with clinical specialization perform apsychological and social assessment of pa-tients when they begin dialysis. Social work-ers, as part of the multidisciplinary team, arealso mandated to reassess stable patients everysix months and unstable patients as part ofteam care planning.Nephrologists and other dialysis health-careproviders may not routinely assess dialysispatients’ psychological functioning. They maynot feel confident in assessing psychologicalfunction and may think that this task fallsoutside their area of expertise. They may alsonot be aware of the prevalence of thesepsychological traits in the dialysis population,the positive associations between these traitsand CVD, or the interventions that have beenshown to reduce psychological distress.The various interventive techniques discussedfor psychological factors could be imple-mented by the dialysis facility social worker orby referral to an outside mental health profes-sional. Medicare will cover 50% of the chargesfor outpatient mental health treatment, after adeductible is met, if it is provided by anapproved Medicare provider.


moking

Studies are required in CKD patients to exam-ine the pharmacokinetics/safety of pharmaco-therapies known to be effective in smokingcessation.Randomized trials are needed to determine themost effective interventions for smoking cessa-
tion in dialysis patients.

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Randomized, controlled trials are needed todetermine the effects of smoking cessation oncardiovascular and all-cause outcomes in dialy-sis patients.

hysical Activity

Randomized clinical trials are needed to studythe effects of exercise training on cardiovascu-lar risk in dialysis patients.Studies are required to determine the optimalexercise prescription and to develop practicalways of incorporating physical activity andassessment of physical functioning into theroutine care of dialysis patients.Studies are needed to define the barriers toexercise in dialysis patients and to developmotivational strategies to increase participa-
tion in regular physical activity.
Studies are required to determine how toeffectively incorporate physical activity intothe routine care of dialysis patients.


Research is needed to study the presence ofpsychological distress in dialysis patients.Further studies are required to examine theimpact of psychological distress on cardiovas-cular functioning and outcomes in dialysispatients.Studies are required in dialysis patients toexamine the impact of therapeutic interven-tions, which are used to treat psychologicalconditions associated with CVD, on psycho-
logical states and cardiovascular events.

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GUIDELINE 15: ANEMIA

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The impact of anemia on CVD (specifically,VH) and exacerbation of CAD is well describedn the dialysis population. Given the prevalencef anemia in the dialysis population, and itsssociation with poor outcomes, anemia is con-idered a “uremia-specific” CVD risk factor.

15.1. All dialysis patients with anemiashould follow the K/DOQI Guidelinesfor Treatment of Anemia.52

RATIONALE (Weak)

Anemia results in decreased peripheral vascu-ar resistance and plasma viscosity, and in-reased venous return. A reduced hemoglobinevel lowers oxygen delivery, resulting in in-reased heart rate and venous tone. These factorsause increased cardiac output, which increasesrterial volume and LV wall tension. The cumu-ative effect is LVH, arterial hypertrophy, andrteriosclerosis. Guidelines have been previ-usly developed by the K/DOQI Anemia Workroup.52

Observational studies have demonstrated anssociation between anemia and adverse cardio-ascular outcomes in CKD patients. One suchtudy demonstrated that a hemoglobin level �8.8/dL was independently associated with LV dila-ion, cardiac failure, and total mortality.331 Othertudies have supported these findings, and areeviewed in the previous anemia guidelines.52

It is not known if treatment of anemia preventsardiovascular events in CKD patients. The Nor-al Hematocrit Trial randomized 1,200 patientsith heart failure or ischemic heart disease to a

arget hematocrit of 30% or 42%, and assessedime to first myocardial infarction or death.332

lthough there was no significant difference in

American Journal of K68

utcome between groups, the trial was stoppedarly due to a trend suggesting poorer outcomesmong those with higher hematocrit levels.

The Canadian Normalization of Hemoglobinrial randomized 146 CKD patients with eitheroncentric LV hypertrophy or LV dilation333 toeceive doses of erythropoietin to achieve a he-oglobin of either 10 or 13 g/dL (100 or 130

/L). In the patients with concentric LVH, changesn LV mass index were similar between groups.n the patients with LV dilation, changes inolume index were also similar between groups.owever, those with concentric LVH were less

ikely to develop progressive LV dilation if theyere assigned to the high hemoglobin group.

LIMITATIONS

There is a clear association between pooroutcomes and low hemoglobin, but there arelittle data to suggest that hemoglobin levels�13 g/dL are associated with improved out-comes. The data supporting an associationbetween anemia treatment and improvementsin CVD are limited.


Identification and treatment of anemia can beeasily implemented, making it readily ame-nable to intervention. The use of erythropoi-etin to treat anemia is currently a standard carepractice and is feasible.


Studies are needed to determine the mostappropriate hemoglobin value to reduce the
risk of nonatherosclerotic heart disease.
idney Diseases, Vol 45, No 4, Suppl 3 (April), 2005: p S68

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GUIDELINE 16: ARTERIAL STIFFNESS, VASCULARAND VALVULAR CALCIFICATION, CALCIUM,

PHOSPHORUS AND PTH

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The role of abnormalities of calcium, phospho-us, and PTH in contributing to arteriosclerosis,ubsequent arterial stiffness, calcification andardiac valve calcification is an area of intenseesearch. The importance of these parameters toVD outcomes and the biological plausibility of

hese variables in CVD processes require atten-ion to them as “uremia-related” risk factors.

16.1 All dialysis patients should have pulsepressure (PP) determined monthly be-fore dialysis.16.1.a For PP >60 mm Hg and sys-

tolic blood pressure >135 mmHg, it is recommended that PPbe reduced by achieving idealbody weight and the use ofantihypertensive medicationwith the target PP being 40 mmHg. (B)

16.2 Identification and treatment of calcifi-cation:16.2.a If arterial calcification is identi-

fied by plain radiography inany of the following sites (ab-dominal aorta, carotid arteries,ileo-femoral axis or femoro-popliteal axis), identification ofcalcification at another siteshould be sought. (C)

16.2.b If vascular calcification ispresent in two or more sites,consideration should be givento prescription of a non-cal-cium-containing phosphatebinder. (B)

16.3 All dialysis patients should follow cur-rent K/DOQI Guidelines for treatmentof calcium, phosphate, and PTH.78

16.3.a Serum phosphorus should bemaintained between 3.5-5.5mg/dL (1.13-1.78 mmol/L). (B)

16.3.b PTH should be measured every3 months using an intact PTHassay (first-generation immuno-radiometric assay). (C)16.3.b.i. For prevention of

CVD, the target PTH
value should be be- W

tween 150-300 pg/mL(16.5-33.0 pmol/L). (B)

16.3.b.ii. Treatment strategiesfor PTH values <150pg/mL (16.5 pmol/L)and >300 pg/mL (33.0pmol/L) should be de-veloped according tothe K/DOQI Bone Dis-ease Guidelines.78 (B)

RATIONALE

rterial Stiffness (Weak)Increased arterial stiffness in dialysis patients

s the result of chronic flow/volume overload,remia-induced endothelial dysfunction, fibro-lastic intimal thickening, increased extracellu-ar matrix, and medial calcification.334 Arterialtiffness may cause CVD because it increases LVfter-load and decreases the diastolic pressure,esulting in a decrease in coronary perfusion.rterial stiffness can be assessed by measure-ent of PWV using B-mode ultrasonography.owever, pulse wave velocity is not easily mea-

ured in clinical practice. In contrast, PP can beasily measured and is an attractive surrogate forWV. Pulse pressure, the difference betweenystolic and diastolic blood pressure, reflects LVjection and aortic elasticity. Similar to PWV,ncreased PP has been associated with increasedll-cause mortality in nondiabetic HD patients.188

thers have reported that pre- and post-dialysislood pressures have independent associationsith mortality in a manner that implicates wideulse pressures.130 (Moderately Strong)

Patients who had a decrease in PWV with aecrease in blood pressure also had regression inVH.335 Further, it has been shown that patientshose PWV could be decreased by correctingypertension had better survival rates than thosehose PWV did not change with blood pressureecrease.195 Whether a decrease in PP wouldlso identify those with better survival is notnown. In a study of 22 HD patients with type 2iabetes, there was an improvement in PWVmong patients treated with fluvastatin.336

hether the improved PWV associated with

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tatins would improve cardiovascular outcomesequires further study. (Weak)

The evidence supporting an association be-ween arterial stiffness and increased risk ofeath in dialysis patients is derived from prospec-ive cohort studies using PWV as the estimate forrterial stiffness. A study of 243 chronic HDatients with a PWV �12.0 mL/sec compared to9.4 mL/sec had an odds ratio of 5.4 for all-

ause mortality and 5.9 for cardiovascular mortal-ty.190 The evidence supporting an associationetween pulse pressure and mortality in dialysisatients is based on two prospective cohort stud-es. The first study cohort consisted of 1,243hronic HD patients followed for 9 years.188

uring the mean follow-up of 76 months, theortality rate among those with PP �59 mm Hgas 28%, compared to 38%, 46%, and 60% for

hose with PP 60-79, 80-99 and �100 mm Hgespectively. Using multivariate analysis for non-iabetic patients, there was an 8% increase in theelative risk for all-cause mortality associatedith each 10 mm Hg increase in pulse pressure.he second study cohort consisted of a randomample of 11,142 subjects followed from 1994-000.130 Higher systolic and lower diastolic bloodressure were associated, in a multivariate analy-is, with an increased risk of death. The associa-ions are strong and consistent. (Moderatelytrong)

ascular Calcification

The calcium content in coronary arteries ofialysis patients is much higher than that foundn age-gender-matched controls and in nonure-ic patients with CAD.337 Moreover, there is an

ssociation between the Agatston338 score andhe prevalence of atherosclerotic disease in HDatients.339 However, the ACC/AHA did notecommend EBCT for the diagnosis of obstruc-ive coronary disease due to the low specificity ofhis test.340 However, EBCT remains a valuableurrogate outcome when used in the tightly con-rolled environment of the randomized clinicalrial. For clinical practice, spiral CT may be aeasible alternative341 but there are insufficientata to recommend routine use of this technique.Weak)

A valid and reproducible estimate of vascularalcification that is easily applied in clinical
ractice is required. The method of Guerin342 t
ses ultrasound and soft-tissue radiographs tostimate arterial calcification in the commonarotid arteries, abdominal aorta, iliofemoral axisnd femoro-popliteal axis. The overall scoreanges from 0-4 based on the number of calcifiedites. Good inter-observer reproducibility haseen reported. It is a valid predictor of all-causeortality and cardiovascular mortality.343 How-

ver, the Work Group felt that the experienceith this technique was limited, and that thereould be major barriers to its acceptance and

mplementation. (Weak)The recommendation made by the K/DOQI

linical Practice Guidelines for Bone Metabo-ism and Disease in CKD was that a non-calcium-ased binder be used if there was evidence forevere vascular calcification.78 While the diagno-is is based on an incidental finding of vascularalcification on plain radiography, no suggestions made for frequency of diagnostic evaluationor is there a definition for severe vascular calci-cation.Young dialysis patients with detectable coro-

ary artery calcification had a mean daily cal-ium carbonate dose of 6,456 mg compared to,325 mg among those who had no detectablealcium.32 Older age, male gender, diabetes, di-lysis vintage, higher serum calcium, and highererum phosphorus have been associated withigher coronary artery calcification scores.339

revention of hyperphosphatemia is critical, butietary phosphorus restriction and conventionalD are often not adequate. An orally adminis-

ered phosphate binder is required. An alterna-ive to calcium-based phosphate binders is desir-ble. One currently available alternative isevelamer hydrochloride. In a randomized clini-al trial, subjects treated with sevelamer for 12onths did not have a statistically significant

ncrease in the coronary artery or in the aorticalcification scores while those treated with cal-ium carbonate or calcium acetate had a contin-ed increase.81 The serum phosphorus valuesere well controlled in both groups. The inci-ence of hypercalcemia (16% vs. 5%) and therevalence of an undesirable suppression of PTHt the end of the study (57% vs. 30%) werereater in the calcium-treated group. (Moder-tely Strong)The calcification score at which to initiate

reatment with a non-calcium-based phosphate

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inder is unclear. Ideally, calcium-based bindershould be avoided entirely, but there are costonsiderations as the currently available non-alcium-based binder (sevelamer hydrochloride)s considerably more expensive. The Work Groupecommends that, if vascular calcification is notedn one part of the vascular tree (either carotids,orta, ileo-femoral or femoropopiteal) and thealcium-phosphorus product exceeds 55, plainadiographs of the other areas should be made. Ifositive in one other area, a non-calcium-basedhosphate binder should be considered. It isecognized that vascular calcification on plainadiographs does not disqualify arteriosclerosiswhich may respond to reduction in calcium-hosphorus product) from atherosclerosis (whichs unlikely to respond). (Weak) (Table 16)

Lanthanum carbonate is a non-calcium-basedhosphate binder but there are insufficient pub-ished data on its efficacy and safety.344

alvular Calcification

Valvular calcification was found to be muchore common in CKD patients treated with HD

han in age-matched and gender-matched con-rols.345 There is an increased prevalence ofalvular insufficiency with calcification of theitral (29% vs. 6%) and aortic valves (22% vs.

%). Using EBCT, calcification was reported in5% of the mitral and 34% of the aortic valves inD patients, compared to an expected 3%-5% in

ontrols.339 Others found significant increases inalvular calcium estimated by EBCT over a2-month period.337 There is no convincing evi-ence linking valvular calcification to abnormali-ies in serum calcium, phosphorus, or PTH. Val-ular calcification is associated with a worseurvival, perhaps mediated by increased LVH,or those with aortic valve calcification. There islso an increased risk for death among PD pa-ients with valvular calcification (Table 17).346

Weak)

erum Phosphorus

Observational studies in HD patients show atatistically significant increase in the risk forll-cause and cardiovascular mortality with se-um phosphorus �6.5-6.6 mg/dL (2.10-2.13mol/L) (Table 18).347,348 The evidence linking

ncreased serum phosphorus to vascular calcifica-
ion is based on the observation that vascular

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alcification is an active process of ossifica-ion.349 Prior to the deposition of calcium inedial smooth muscle cells, bone matrix proteins

re detectable. The linkage of hyperphosphatemiao development of vascular calcification is basedn the observation that phosphorus can inducehe production of bone-forming proteins in theascular smooth muscle.350 The in vitro evidenceor the role of inorganic phosphorus in the patho-enesis of vascular calcification has been re-iewed.351 Exposure of cultured human aorticmooth muscle cells to concentrations of phos-horus similar to those found in CKD patientsncreased the expression of osteogenic factors.n additional mechanism by which hyperphos-hatemia might cause cardiac disease is in-reased cardiac fibrosis.352 The progression of vas-ular calcification in coronary arteries has beenssociated with high doses of calcium-based phos-hate binders32 and there is progression in patientsrescribed a mean dose of 1,500 mg elementalalcium daily.81 (Moderately Strong)

The strategies to treat hyperphosphatemia andhe evidence for the use of non-calcium-basedhosphate binders are described in the K/DOQIone Disease Guidelines.78

TH

It is common to consider hyperparathyroidisms a traditional risk factor for CVD (Table 19).he relative risk for all-cause mortality was 1.18

n the quintile with PTH values �511 pg/mL56.2 pmol/L) compared to the referent quintilef PTH values 34-91 pg/mL (3.7-10.0 pmol/L) inn observational study.347 In another study, theelative risk for sudden death was 1.06 in theuintile with PTH values �496 pg/mL (54.6mol/L) compared to the reference quintile withTH values 91-197 pg/mL (10.0-21.7 pmol/).348 (Weak)Patients with histological evidence for adynamic

one disease have decreased ability to buffer exog-nous calcium loads than do patients with high-urnover bone disease or those with mixed uremicsteodystrophy.353 Intact PTH has been used as aurrogate marker for bone metabolic activity. In PDatients, a prevalence of 63.2% for biopsy-provenow-turnover bone disease was reported.354 Anntact PTH value �200 pg/mL (22.0 pmol/L) haseen used to define relative hypoparathyroidism in
b
HD patients.355 (Weak)

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Factors suppressing PTH include hypercalce-ia, increased vitamin D levels, diabetes melli-

us and increasing age. Despite being associatedith these risk factors for CVD, hypoparathyroid-

sm was found to be an independent predictor ofortality.355 In several studies, low PTH levels

o not show a convincing association with aariety of markers of cardiovascular outcomes.There are several intact PTH assays available,

he most frequently used currently being the Ni-hols assay. This assay measures both active PTHnd PTH fragments which might be either inactiver inhibitory. This assay has been used in theajority of studies reported in the literature. Theeasurement of serum PTH and the target values

or CKD patients are discussed in the K/DOQIone Disease Guidelines.78

LIMITATIONS

rterial Stiffness

The data addressing the relationship betweenincreased PP and increased mortality rates arerobust, while data relating high pulse pressurewith medial calcification are less robust. Thedata supporting the efficacy of interventions todecrease the pulse pressure and to improveclinical outcomes are relatively weak. Earlierinterventions that prevent the development ofnoncompliant blood vessels might be moreeffective than the treatment of establishedvascular stiffness in dialysis patients.

erum Phosphorus

The evidence linking hyperphosphatemia to anincreased risk of all-cause and cardiovascularmortality is based on observational data. Theevidence linking hyperphosphatemia with vascu-lar calcification is based on empirical data thatare consistent with clinical observations. Therandomized clinical trial comparing sevelamerto calcium-containing phosphate binders showeda convincing decrease in the rate of vascularcalcification.81 However, the demonstration ofimproved clinical outcomes awaits longer-termstudies.The mechanisms by which vascular calcifica-tion leads to specific cardiovascular events are
not clear, and further studies are required.

rterial Stiffness

Measurement and recording of PP can beeasily implemented. Therefore, PP could beidentified as a risk factor amenable to interven-tion. The interventions (targeted ideal bodyweight, lowering of blood pressure and use ofstatins) are also feasible.

erum Phosphorus

The regular measurement of serum phospho-rus and the prescription of diets containing800-1,000 mg phosphorus are common prac-tices in most dialysis units. The limitation onthe dose of oral calcium-containing phosphatebinders is new and will require a change inprescribing habits. There may be fiscal barriersto the use of sevelamer. This might be allevi-ated by the use of a combination of calcium-based binders and sevelamer.356

TH

The discussion of hypoparathyroidism is basedon relatively new concepts from a small numberof articles published since 2001. The credibilityof aggressive therapy for treating relative hypo-parathyroidism will be greeted with skepticism,given the long-term focus on hyperparathyroid-ism. The association of relative hypoparathyroid-ism with worse outcomes may be confounded bythe relationship with age and diabetes. There willbe continued reliance on PTH as a surrogate forbone turnover but this may be clarified with theintroduction of intact PTH assays.


Further studies are required to examine the useof statins in patients with PP �60 mm Hg.Evaluation of interventions is needed that mightprevent or reverse the decrease of vascularcompliance in patients with increased PP.The validity of the semi-quantitative estima-tion of vascular calcification as a predictor ofsurvival requires confirmation in other centers.Evaluation of alternative methods for estima-tion of coronary artery calcification (e.g.,
multislice CT) is needed.

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SECTION III. STATE OF THE SCIENCE: NOVEL AND
CONTROVERSIAL TOPICS IN CARDIOVASCULAR DISEASES
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The following sections have been prepared tonsure that the state of the art and science relatedo CVD includes novel concepts, therapeutictrategies, and emerging areas of pathophysiologi-al and practical importance to the care of dialy-is patients.

The reader will notice that the format of thisection is different, reflecting its different perspec-ive: namely, the relative lack of evidence onhich to base plausible guideline statements.he evidence that does exist, and is cited in thisection, is either completely in nondialysis popu-ations, or is purely associative information, witho intervention in any population yet tested.hus, it would be a problem to include guidelinetatements or recommendations.

Nonetheless, this section describes the currenttatus of knowledge with respect to risk factorsnd biomarkers, and represents an overview ofey areas for future clinical trials. The reader isncouraged to review this section, and examineis or her current understanding and practiceithin the context of these highlights.The literature review has been conducted us-

ng the same systematic strategy as for the previ-us guidelines in this document. The reviewsresented here have been thoughtfully con-tructed so that clinicians can adopt differentractices based on them. However, for reasonsited above, the ability to truly recommend oruggest changes in practice would be prematuret this time.

INTRADIALYTIC HYPOTENSION

ntroduction

Intradialytic hypotension (IDH) is defined as aecrease in systolic blood pressure by �20 mmg or a decrease in MAP by 10 mm Hg associ-

ted with symptoms that include: abdominal dis-omfort; yawning; sighing; nausea; vomiting;uscle cramps; restlessness; dizziness or faint-

ng; and anxiety. It impairs the patient’s well-eing, can induce cardiac arrhythmias, predis-oses to coronary and/or cerebral ischemic events.n addition, IDH precludes the delivery of andequate dose of dialysis, as hypotension epi-odes lead to the compartment effect and result
n suboptimal Kt/Vurea. t

Cardiovascular complications of IDH include:schemic (cardiac or neurological) events; vascu-ar access thrombosis; dysrhythmias; and mesen-eric venous infarction.364 Long-term effects ofDH include: volume overload due to suboptimalltrafiltration and use of fluid boluses for resusci-ation; LVH, with its associated morbidity andortality; and interdialytic hypertension.

iscussion

Evaluation of risk. During the past 10 years,espite improvements in dialysis technology, therequency of IDH has remained unchanged atbout 25% of all HD sessions.365 In addition, thencidence of IDH will continue to increase as anncreasing number of elderly patients will de-elop CKD, and also due to the progressivencrease in the number of diabetic patients withKD. Patient subgroups most likely to have IDH

nclude those with diabetic CKD, CVD, poorutritional status and hypoalbuminemia, uremiceuropathy or autonomic dysfunction, severe ane-ia, age �65, and predialysis systolic blood

ressure �100 mm Hg.There are no large-scale, epidemiological stud-

es to define the risk factors that are associatedith the risk of developing IDH, although IDH

ppears to be more common in patients withiabetes and predialysis hypotension. Both nor-otensive or hypertensive dialysis patients can

evelop IDH. The degree of IDH in the sameatient may vary from time to time or may haveeasonal variations.

A small group of patients (5%-10%) may haveow systolic blood pressure (�100 mm Hg) athe initiation of dialysis.364 This group includesnephric patients, those who are on dialysis for aonger period, and diabetic patients with persis-ent orthostatic hypotension due to autonomicysfunction. Patients on dialysis with autonomicysfunction show an exaggerated drop in sys-olic and diastolic blood pressures and MAP,ompared to those without underlying auto-omic dysfunction.366 Other risk factors includelder age (�60 years), female sex, diabetes mel-itus, presence of CAD, and the use of nitratesefore a dialysis session.Patients with CKD have defective reactivity of

he resistance vessels as well as the capacitance


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STATE OF THE SCIENCE S77

essels during the HD sessions.367,368 The exactechanism of this poor vascular responsiveness

s not known; however, recent data from isolatedltrafiltration and hemodiafiltration have shownhat vascular responses remained intact as theseodalities are not associated with increase in

ore body temperature.369

The following subgroups of chronic HD pa-ients should be evaluated carefully for the riskf developing IDH:

Patients with diabetic CKD Stage 5Patients with CVD:

LVH and diastolic dysfunction with or with-out CHFLV systolic dysfunction and CHFPatients with valvular heart diseasePatients with pericardial disease (constric-tive pericarditis or pericardial effusion)

Patients with poor nutritional status and hy-poalbuminemiaPatients with uremic neuropathy or autonomicdysfunction due to other causesPatients with severe anemiaPatients requiring high volume ultrafiltration;more than expected interdialytic weight gainPatients with predialysis SBP of �100 mm HgPatients 65 years or older age.

Routine measures for the treatment of IDHnclude the use of Trendenlenburg’s positionnd saline boluses to increase the systoliclood pressure to 100-110 mm Hg. In addition,t is advisable to assess for the signs of ortho-tatic hypotension before the patient is dis-
harged from the dialysis unit. Additional fac- t
ors relating to IDH treatment are presented inable 20.

ialysis Interventions

Dialysate temperature modeling. Duringtandard dialysis, an increase in core body tem-erature is usual and increases the risk for IDH.he increase in body temperature is either re-

ated to heat load from the extracorporeal sys-em, or secondary to volume removal. Volumeemoval is associated with increased metabolicate with decreased thermal losses either directly,r secondary to peripheral vasoconstriction370

nd impaired convective mechanisms of heatoss.

Temperature monitoring is difficult in dialysisatients due to variability in room, core body,nd dialysate temperatures, as well as the lack ofensitive equipment to monitor the dialysate-lood temperature gradient. The use of low-emperature dialysate (i.e., lower than the pa-ient’s core temperature) compared with standardialysate-temperature (37-38°C)371,372 decreaseshe frequency and intensity of symptomatic hypo-ension. Low-temperature dialysis improves theeactivity of capacitance and resistance vessels,nd is associated with improvement in cardiacontractility.373,374

Isothermic dialysis. Maintenance of isother-ic dialysis involves keeping the temperature

onstant during the dialysis treatment. Each per-ent change in ultrafiltration-induced body weightequires removal of 6% heat to prevent an in-rease in core body temperature.370 It was shown
hat differences in vascular reactivity in patients

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STATE OF THE SCIENCES78

ith standard HD, hemodiafiltration, or isolatedltrafiltration remained unchanged if energy trans-er was similar.369,375

In a recent multicenter analysis, the impact ofhermoneutral dialysis (preventing any transferf thermal energy between dialysate and extracor-oreal circulation) on hemodynamic stability inelected hypotension-prone patients was com-ared to isothermic dialysis (keeping the predialy-is body temperature unchanged) by using blood-emperature monitoring. The frequency ofntradialytic morbid events decreased by 25%ith isothermic HD.376 During isothermic treat-ents, body temperature was maintained at pre-

ialysis temperature settings and was toleratedithout adverse effects, as compared to a simpleecrease in dialysate temperature that often leadso rigors and shivering.377

Dialysate calcium modeling. The long-termemodynamic and osseous consequences associ-ted with the use of different levels of dialysatealcium need careful evaluation. The use ofow-calcium dialysate has been associated withecreased LV contractility and a correspondingecrease in blood pressure.378,379 It was furtherssociated with a significant intradialytic de-rease in blood pressure in both healthy andardiac-compromised HD patients and patientsith decreased LV ejection fraction.378,380 Sig-ificant changes in blood pressure,380 myocar-ial contractility378,380,381 and changes in intra-ialytic blood pressure in cardiac compromisedatients382 have been associated with the changeshen dialysate calcium concentration is �2.5Eq/L. A dialysate Ca of 3.5 mEq/L may lead to

ypercalcemia and decreased bone turnover.78

urthermore, limited studies have shown onlyarginal benefit on the frequency of IDH epi-

odes with the use of dialysate Ca �3.0 mEq/L.Dialysate sodium modeling. Sodium profil-

ng is based on the principle that there is a linearelationship between the changes in plasma so-ium concentration and blood volume (BV). Thentradialytic decrease in plasma volume can bes much as three-fold greater with dialysateodium of 134 mEq/L than with a dialysateodium of 144 mEq/L.383-386 In this technique,he dialysate sodium concentration at the begin-ing of treatment is hypertonic, and during the
nal hours of dialysis is progressively reduced, M
eaching almost normal levels before the end ofialysis.Sodium modeling prevents the development

f IDH by: a) an increased ECF sodium level athe time of peak UF rate improves shift of waterrom ICF to the ECF compartment with im-roved venous refill and prevention of the Bezold-arisch reflex;387,388 and b) hypertonic dialy-ate—to a greater extent—accelerates ureaquilibration between ICF and ECF while ureaemoval is at its peak during the first hour ofialysis.389

Limitations of dialysate sodium modeling in-lude the following: a) there is poor temporalorrelation between the time of onset of IDH andn antecedent decrease in blood volume;390 b)here is a significant interdialysis and interindi-idual variation in serum sodium, and for anyiven level of serum sodium, the amount ofiffusible plasma water varies based on totalody water, serum proteins and other nondiffus-ble elements in the plasma;391 and c) the devel-pment of postdialysis hypernatremia can bessociated with thirst, dysphoria, hypertension,nd increased interdialytic weight gain.384 Inome instances, a reverse sodium profile is pre-cribed, in which the dialysate sodium concentra-ion increases toward the end of the session whenlasma volume is lowest. Various profiles ofltrafiltration modeling can also be used to de-rease the incidence of hypernatremia.

harmacological Interventions

Midodrine. Midodrine prevents IDH byaintaining the central blood volume (CBV) and

ardiac output, and a marginal increase in periph-ral vascular resistance (PVR). A single dose ofidodrine (5 mg) administered 30 minutes be-

ore the dialysis session was associated with anmprovement in intradialytic and postdialytic sys-olic and diastolic blood pressures and MAP,ompared to dialysis sessions without the use ofidodrine.392 Others have reported the contin-

ed efficacy of midodrine use for more than 8onths without development of adverse

vents.393

Midodrine is effectively cleared by HD and itsalf-life is reduced to 1.4 hours by HD.394 Suchharmacokinetic data are not available in PDatients at the time of writing these guidelines.
idodrine has minimal cardiac and central ner-

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ous system effects, due to its specificity for �1eceptors, and it does not cross the blood-brainarrier. The most frequent side effects of mido-rine are piloerection, scalp itching or tingling,ausea and heartburn, urinary urgency, head-che, nervousness, and sleep disturbance. Long-erm use has been associated with supine systolicypertension in less than 10% of patients; thiside effect warrants cessation of therapy.395 Pa-ients should also be monitored for bradycardia,s midodrine is associated with reflex parasympa-hetic stimulation.396 Since midodrine is admin-stered on the days of dialysis, both prodrug andctive metabolite are removed effectively byD; therefore, the risk of developing supineypertension is possible, but very rare.Midodrine should be used cautiously in pa-

ients with CHF and in those using other negativehronotropic agents such as beta-blockers,igoxin and nondihdropyridine CCBs. Concomi-ant use with other �-adrenergic agents—such asphedrine, pseudoephedrine and phenylpropanol-mine—should be avoided, as this may aggra-ate supine hypertension. Midodrine can alsontagonize the actions of �-adrenergic blockerssuch as terazosin, prazosin and doxazosine) andould result in urinary retention.

The combination of cool dialysate and predi-lysis doses of midodrine may lead to decreasedrequency and intensity of symptoms of IDHithout side effects.Carnitine. Hemodialysis therapy for more

han 6 months is associated with reduction oflasma and tissue levels of carnitine and carni-ine esters. Carnitine deficiency is associatedith several metabolic defects, defined as dialy-

is-related carnitine disorders, including IDH.397

multicenter trial of intravenous L-carnitineherapy at 20 mg/kg into the dialysis venous portith each session of dialysis was associated with

educed frequency of IDH and muscle cramps44% versus 18% and 36% versus 13%, respec-ively), as compared with the placebo group.397-399

he reasons for this beneficial effect are not clear,ut could be due to improvement in vascular smoothuscle and cardiac muscle function.Sertraline. Sertraline is a selective serotonin

euptake inhibitor and has been shown to im-rove symptoms in patients with neurocardio-enic syncope,400 idiopathic orthostatic hypoten-
ion,401 and IDH.402 These disorders share a c
ommon pathogenic mechanism with IDH: aaradoxical withdrawal of central sympatheticutflow, resulting in sudden decrease in bloodressure with bradycardia. Both retrospectivend prospective studies in small number of pa-ients demonstrated that treatment with sertralineydrochloride was associated with an improve-ent in the hemodynamic parameters in patientsith IDH.402-404 Side effects of sertraline in-

lude dizziness, insomnia, fatigue, somnolence,nd headache.

Resistant IDH. Resistant cases of IDHhould be treated with a combination of modali-ies, such as combination of midodrine and dialy-ate temperature profiling, combination of dialy-ate temperature profiling and 3 mEq/L dialysatealcium, or combination of dialysate temperatureodeling and sodium modeling. Such patients

hould also be offered alternative measures torevent and treat IDH. For example, isolatedltrafiltration and other techniques providing aigh convective solute transport (such as hemo-ltration and hemodiafiltration) are associatedith decreased incidence of IDH and improvedemodynamic stability compared to conven-ional HD, due to improved plasma refill andppropriate neurohormonal response to loss ofntravascular volume.236,405-407

There are limited data to make any recommen-ation about the benefit of extended daily dialy-is or nocturnal HD to prevent the developmentf IDH. However, these two modalities of dialy-is therapy have the advantage of slow ultrafiltra-ion rate and the possibility to prevent the activa-ion of Bezold-Jarisch reflex and subsequentardiodepressor response. However, more clini-al studies are needed to prove the efficacy andost-effectiveness of these two modalities in thereatment of IDH.408-410

Limitations. It is unclear if episodes of IDH,er se, are associated with increased morbiditynd mortality. The data supporting the effective-ess of various therapeutic options for the treat-ent of IDH are available in the form of case

eries and case reports. Very few multicenterandomized studies have been published.

Objective assessment of dry weight using suchethods as IVC sonography, or bioimpedance or

issue impedance techniques, have not been rig-rously tested in relation to IDH and long-term
linical outcomes.

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esearch Recommendations

A randomized study in patients with IDH iseeded to assess the safety, efficacy, and cost-ffectiveness of automated feedback systems thatontinuously adjust ultrafiltration rate, dialysateodium, and dialysate temperature. Controlledtudies are also needed to examine the use ofontinuous on-line hematocrit monitoring to cal-ulate the rate of ultrafiltration and blood volumend impedance measurements in the assessmentf actual dry weight and desired goal for ultrafil-ration.

onclusions

Patients with CKD who are at risk for IDHay require evaluation for the presence of under-

ying cardiovascular and autonomic function.
he patients’ medications list should be verified n
ery carefully to avoid the use of short-actingnti-hypertensive medications and peripheral va-odilators immediately before the dialysis ses-ion.

Hemodialysis patients at risk for, or predis-osed to, IDH may benefit from lowering dialy-ate temperature, dialysate sodium modeling,nd maintaining dialysate calcium at 3 mEq/L.urther benefits may be derived from treatmentith pharmacological agents that prevent theevelopment of IDH.If modifications in dialysis prescription and

djustments in antihypertensive medications doot improve IDH, these patients should be consid-red for extended daily dialysis or nocturnal HD.f no improvement is seen after these measures,atients may be counseled for living-donor kid-
ey transplantation.

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BIOMARKERS

TROPONIN

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The diagnosis of acute coronary syndromes inialysis patients and the general population issually based on the triad of symptoms, electro-ardiographic findings, and cardiac biomarkers.he presence of a time-dependent elevation inerum cardiac troponin T or I levels in the settingf acute coronary syndromes is associated withncreased cardiovascular morbidity and mortal-ty.

iscussion

An emerging indication for the measurementf cardiac troponins is risk stratification in asymp-omatic HD patients, in the absence of otherigns and laboratory tests suggestive of acuteoronary syndromes (Table 21,Table 22). Sev-ral published studies have demonstrated that theresence of elevated serum cardiac troponin T,nd—to a lesser extent—troponin I, is a power-ul predictor of mortality in HD patients. In arospective study of 733 asymptomatic outpa-ients on chronic HD, serum troponin was highlyredictive of all-cause mortality (Fig 5).411 Pa-ients without detectible troponin T had a 2-year% mortality, with progressively higher mortal-ty predicted by increasing ranges of the biomar-er. Patients with troponin T �0.1 �g/L had a-year mortality of approximately 50%. Anothertudy found a significant correlation between thencrease in serum troponin T levels and theeverity of CAD in a subset of asymptomatic HDatients.412 It is plausible that the elevation inerum cardiac troponins in asymptomatic dialy-is patients is a reflection of silent IHD andonischemic cardiomyopathy, and troponin lev-ls have been related to LV mass.413 Troponinlevation (as seen in dialysis patients, i.e., notollowing a time-appropriate rise and fall after anndex ischemic event) has been reported in pa-ients with severe nonischemic cardiomyopathy.egardless, it is clear that these elevations inardiac troponin levels in dialysis patients areot spurious findings. The clearance of troponinsay be altered in dialysis patients, but the source

s cardiac.The potential clinical duality of troponin test-

ng in dialysis patients needs to be recognized. d


he diagnosis of acute coronary syndromes andisk stratification in nonischemic settings areiscrete, but complementary tasks. It is a keyssue that a time-appropriate rise and fall of theardiac biomarker occurs in acute coronary syn-romes; as serum troponin elevation is prognos-ically important, but not necessarily indicativef acute coronary syndrome. The operationalharacteristics of different-generation troponinssays vary widely and—unfortunately, as newssays become available—nullify conclusions at-ributable even to recent data. Although troponinmay “currently” be the best cardiac biomarker

or diagnosis of acute coronary syndrome (seeig 5B; only 45 of 733 [6%] asymptomaticialysis patients had any detectible troponin I),ased on “specificity” criteria, this may not nec-ssarily be correct for the next generation ofroponin I and T assays.


A prospective, randomized clinical trial onroponin testing and clinical decision-makingould provide valuable information. There is aeed for prospective cohort studies on the corre-ation between troponin levels and the burden ofAD, as well as fatal and nonfatal CAD-relatednd non–CAD-related events.

onclusions

Therefore, serum troponin T levels should beonsidered for risk stratification in chronic dialy-is patients. In HD patients, the blood sampleshould be collected before dialysis. The utility ofroponin T for risk stratification in PD patientsas not been reported, but there is no obviouseason to suspect that these patients differ fromD patients in this regard. The assay for tropo-in T is widely available. However, it is currentlynclear how this information can be utilized. Forxample, should an elevated serum troponin Tevel be followed by another diagnostic test (e.g.,tress imaging) or therapeutic intervention (e.g.,he administration of beta-blockers)? To deter-ine the appropriate therapeutic consequences,

nderstanding of the precise causes of death in
ialysis patients with elevated serum troponin
), 2005: pp S81-S89 S81

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evels, and the underlying pathophysiologicalechanisms, must be improved.A credible case can be made for recommend-

ng the measurement of serum cardiac troponinsn dialysis patients for the purpose of risk stratifi-ation (distinct from the diagnosis of acute coro-ary syndrome). Indeed, in May 2004 the U.S.ood and Drug Administration approved the mea-urement of troponin T in patients with chronicenal failure (i.e., dialysis) for the express pur-ose of risk stratification (i.e., prediction of mor-ality). The K/DOQI Work Group has not desig-ated this as a practice guideline, however,ecause of uncertainty at the present time regard-ng appropriate clinical strategies using this infor-

ation.

INFLAMMATION

ntroduction

Patients arrive at CKD Stage 5 with significantardiovascular risk factors and, once on dialysis,hey die at a more rapid rate than would beredicted by their Framingham risk factors alone.ecently, much interest has focused on the rolef nontraditional risk factors for atherosclerosis,uch as an excessive inflammatory response.lthough the concept that inflammation plays a

entral role in the pathophysiology of atheroscle-osis has gained a lot of recent interest, we do notnow yet whether inflammation reflects vascularnjury or is instead a cause of vascular injury.owever, recent data suggest that inflammatoryiomarkers, such as interleukin-6 (IL-6) and therchetypal acute phase reactant C-reactive pro-ein (CRP), are not only markers but also media-ors of atherothrombotic disease in man. In theeneral population, high-sensitive C-reactive pro-ein (hs-CRP) appears to be the best inflamma-ory biomarker employed to detect enhancedbsolute risk of CVD. Moreover, there is evi-ence supporting the use of CRP in primaryrevention of CVD; in fact, CRP may be atronger predictor of cardiovascular events thanhe LDL-cholesterol level. It has been speculatedhat a persistent inflammatory response may me-iate malnutrition (i.e., wasting) and progressivetherosclerotic CVD by a number of pathogenic

mechanisms.


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iscussion

Whereas chronic inflammation is a commonhenomenon in European420 and North Ameri-an421,422 CKD patients, the prevalence of inflam-ation seems to be lower in Asian CKD patients

Table 23).423,424 This suggests that genetic fac-ors and/or cultural habits (such as food intake)ay affect the inflammatory response in dialysis

atients. Recent studies suggest that a reductionf kidney function per se may be associated withn inflammatory response, both in mild CKD425

nd advanced kidney failure.426,427 Factors com-on in dialysis patients, such as clotted access

rafts,428 failed kidney grafts429 atherosclero-is,430 and persistent infections431,432 may con-ribute to an acute-phase response, thus elevatingnflammatory biomarkers such as CRP and IL-6.

A recent evaluation of a historical cohort of93,451 U.S. dialysis patients demonstrated thatepticemia was associated with increased cardio-ascular death risk.433 Although the associationetween CVD and inflammation is well docu-ented in CKD patients,434,435 we do not know

f the acute-phase response merely reflects estab-ished atherosclerosis or if acute-phase reactantsre actually involved in the initiation and progres-ion of atherosclerosis. However, an increasing

Fig 5. Kaplan-Meier survival curves by baselineroponin levels. The number of patients at risk ataseline, 1 year, 2 years, and 2.5 years for each cutoff

s shown at the bottom of the graph. The 99th percen-ile refers to the normal reference limit. The 10% CVefers to the lowest concentration that demonstrates a0% total precision. The ROC cutoff refers to concen-rations optimized for the sensitive and specific detec-ion of MI. Reproduced with permission (http://lww-com).411

ody of evidence suggests that CRP may be t

irectly involved in atherothrombogenesis thatxtends beyond its previously accepted role as annflammatory marker. Thus, CRP and other bi-markers of inflammation, such as IL-6, TNF-�,nd fibrinogen, may contribute to atherogen-sis.436 The circulating calcification inhibitor,etuin-A, has recently attracted interest as itsevel decreases during chronic inflammation, andatients with low serum fetuin-A levels showed aignificantly poorer survival rate compared tohose with normal or high-normal values.437 Sev-ral studies have shown that elevated CRP pre-icts all-cause and cardiovascular mortality inoth HD322,422,424 and PD423,438,439 patients.oreover, in PD patients, elevated CRP was

ndependently shown to predict nonfatal myocar-ial infarction440 and increased incidence ofVD.438 Also, recent data from the MDRD study

n�801) showed that, after adjusting for tradi-ional CVD risk factors, the odds of CVD were.73 times greater in patients with high CRPevels.421 Further support for linking inflamma-ion to poor outcomes is evident from two recentarge studies of 7,719441 and 25,661442 HD pa-ients, respectively, showing a direct associationetween neutrophil counts and mortality.In the current evaluation (Table 23), we have

efined inflammation as elevated CRP (usuallyefined as a serum level �5-10 mg/L). In sometudies, other inflammatory markers such as IL-6,ave been used to assess the presence of inflam-ation. Most studies with high applicability did

how that elevated CRP predicted all-cause mor-ality in dialysis patients.322,359,422,438,439 Nota-ly, in the only study in which no significantelationship was observed between the odds riskf death and CRP,362 the observation period wasnly 6 months. Most studies with high applicabil-ty322,422,439 also showed that elevated CRP pre-icted cardiovascular mortality in CKD. Theajority of papers with a lower level of applica-

ility also show that elevated CRP predicts all-ause mortality and/or are associated with cardio-ascular disease. Taken together, the presence ofnflammation predicts both all-cause and cardio-ascular mortality in CKD patients.

imitations

There is no consensus in the literature withegard to the optimal “cut-off” point of CRP used
o define the presence of inflammation in CKD


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atients. Moreover, most studies have used onlysingle determination of CRP (or IL-6), whichay be problematic since inflammatory biomar-

ers vary with time in dialysis patients.443 Diffi-ulties and differences in the definition of cardio-ascular mortality may also limit the applicabilityf the present studies. Also, there are no con-rolled studies in which the effects of variousnti-inflammatory treatment strategies have beenvaluated in this patient population. Finally, theost-effectiveness of CRP screening in dialysisatients has not been evaluated.


Future research should aim at finding the opti-al “cut-off” point at which elevated CRP pre-

icts outcome in CKD. Studies are needed tonvestigate the possible interactions between theresence of inflammation and both traditionalisk factors (such as dyslipidemia) and nontradi-ional risk factors (such as oxidative stress, vas-ular calcification, advanced glycation end-roducts and endothelial dysfunction) fortherosclerosis. Research is also required to in-estigate the impact of age, gender, physicalctivity, diet, race and genetic factors on therevalence of inflammation in CKD. Nonpharma-ological and pharmacological interventions foratients with signs of inflammation should beeveloped and evaluated for efficacy in reducingnflammation and improving clinical outcomesn this patient group. The independent role ofotential proatherogenic inflammatory biomark-rs such as CRP, fetuin-A, and IL-6, in therocesses of atherogenesis and progression, needo be tested in the uremic milieu.

onclusions

Based on the studies reviewed, CRP predictsutcomes and improves risk prediction. There-ore, it would be beneficial to assess CRP levelsn dialysis patients on a regular basis, and to seekources of infection or inflammation. A highlyensitive method for measuring CRP is recom-ended. Various causes of inflammation may be

dentified in dialysis patients. Overt and occultnfectious processes (such as clotted arterio-enous grafts) require appropriate treatment. Fac-ors associated with dialysis treatments that mayrovoke an inflammatory response include im-
ure dialysate (due to endotoxin or bacterial o
ontamination), back-filtration, and bioincompat-ble dialysis membranes.

OXIDATIVE STRESS

ntroduction

Oxidative stress is defined as the tissue dam-ge resulting from the imbalance between anxcessive generation of oxidant compounds andntioxidant defense mechanisms. It should beecognized that the generation of oxidative com-ounds is an important mechanism of normalhysiology, playing a role in both inflammationnd tissue repair processes. Thus, oxidative stressepresents part of the defense mechanisms againstnvading micro-organisms and malignant cells,s well as a signal for tissue healing and remodel-ng. However, in a pathological situation, chronicctivation of oxidative processes may contributeo cell and tissue injury.

As oxidants are highly reactive species with aalf-life of only seconds, in vivo determination isenerally not feasible. However, some lipids,roteins, carbohydrates and nucleic acids areodified by oxy-radicals and have lifetimes rang-

ng from hours to weeks. Therefore, these mark-rs may serve as clinical surrogate markers ofxidative stress (Table 24). As oxidative stressccurs when the production of oxidants exceedsocal anti-oxidant capacity, the prevention of thearmful effects of reactive oxygen systems—byoth enzymatic and nonenzymatic antioxidantystems—are of major importance.447,448 Sev-ral deficiencies in different components of anti-xidant defense mechanisms have been demon-trated in CKD. These include reduced levels ofitamin C, increased levels of oxidized vitamin, reduced intracellular levels of vitamin E,

educed selenium concentrations, and deficiencyn the glutathione scavenging system.448

iscussion

Increased generation of oxidants in CKD. Inhe human body, oxidative activity is generatedn the mitochondrial respiratory chain and in thehagocyte NADPH oxidase system.447,448 Amonghagocyte-derived oxidants, chlorinating reac-ions catalyzed by myeloperoxidase (MPO) maye the most important. Activation of polymorpho-uclear cells and secretion of MPO may link
xidative stress to both inflammation and endo-

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helial dysfunction in CKD patients.449 The clini-al importance of MPO activation is furthernderscored by the fact that both elevated leuko-yte and blood MPO levels are associated, in theeneral population, with signs of CAD.450 Fur-hermore, in patients with acute coronary syn-romes, MPO serum levels predicted subsequentardiovascular events451 and identified patientst risk for cardiac events.452

Available evidence suggests that the balanceetween pro- and anti-oxidant capacities is shiftedowards an increased oxidative stress in ure-ia.447,448 Factors contributing to increased pro-

xidant activity in CKD may include typicalharacteristics of the CKD patient population,uch as advanced age and diabetes, uremia,hronic inflammation, malnutrition and factorsssociated with the dialysis treatment per se.ndeed, several recent studies have shown thatarious indicators of oxidative stress are in-reased in patients with CKD.453-455 Althoughome groups have reported a normal lipid peroxi-ation,456 most investigators457-459 have re-orted increased lipid peroxidation in CKD. Pro-eins and amino acids may also be elective targetsf oxidant-mediated injury, and an increasedormation of 3-chlortyrosine (a specific markerf MPO-catalyzed oxidation) has been demon-
trated in HD patients.460 Moreover, increased a
evels of advanced oxidation protein productsAOPP) in CKD patients have been demon-trated.461 Oxidative compounds may also inter-ct with nucleic acids to form 8-hydroxy-2=-eoxyguanosine, which has been used to evaluateeukocyte DNA damage. Significantly elevatedevels of this marker of oxidative stress haveeen documented in CKD.462

Consequences of increased oxidative stressn CKD. In the general population, increasedascular oxidative stress was shown to predictardiovascular events in those with CAD.463

everal recent studies indicate that increasedxidative stress may contribute to the excessiveurden of cardiovascular morbidity and mortal-ty also in CKD. It was shown that the serumnti-oxLDL antibody titer is an independent pre-ictor of cardiovascular mortality in CKD pa-ients.464 An association between AOPP and ca-otid arteriosclerosis was reported in HDatients.465 This finding was corroborated by aecent study showing that AOPP was an indepen-ent risk factor for CAD in the general popula-ion.466 Moreover, whereas oxidative stress waselated to impaired endothelial function in aroup of 37 CKD patients with moderate renalysfunction,467 another group found that endothe-ial dysfunction is unrelated to LDL oxidation in

cross-sectional analysis of 23 dialysis and 16

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ondialysis CKD patients.468 Clearly, the relation-hip between oxidative stress and endothelialysfunction in CKD needs to be addressed inarger patient groups. The relationship betweenalonyldialdehyde (MDA) levels as an indicator

f oxidative stress and the development of athero-clerosis was recently demonstrated in a cross-ectional study of 76 HD patients.469 Finally, twoecent studies have demonstrated that two surro-ate markers of oxidative stress, oxLDL470 andlasmalogen471 were associated with increasedardiovascular mortality in patients with ad-anced CKD. It is also notable that other compli-ations in dialysis patients, such as amyloidosis,nemia, hypertension and malnutrition may beinked to increased oxidative stress.447,448 Al-hough increased oxidative stress seems to bessociated with many complications of CKD, noarge, prospective epidemiological studies haveet demonstrated a link between oxidative stressnd patient outcome.

Linking oxidative stress to inflammation andalnutrition. As increased oxidative stress, in-ammation, and malnutrition all are commoneatures of CKD, it has been speculated thathere may be significant associations betweenhem.449 Indeed, several recent clinical studiesuggest links between oxidative stress, inflamma-ion and malnutrition. The presence of inflamma-ion and the duration of dialysis are the mostmportant determinants of oxidative stress in HDatients.472 Associations between F2-isopros-anes and CRP levels have been reported in HDatients.453,454 A significant positive correlations found between acute-phase proteins and mark-rs of oxidative stress in a group of 64 predialy-is patients.473 It has also been demonstrated thatOPPs act as mediators of oxidative stress andonocyte respiratory burst, which points toonocytes as both targets and actors in the

mmune deregulation associated with CKD.461

ifferent isoforms of vitamin E may have differ-nt activities. Thus, the administration of �-to-opherol (in contrast to �-tocopherol) to patientsith CKD results in a decrease in circulating

evels of CRP.474 Finally, evidence suggests thatalnourished CKD patients have increased oxi-

ative stress compared to well-nourished pa-ients,475 which is of interest as S-albumin canct as a binding protein for products of oxidation
f carbohydrates, lipids and proteins,476 and re- a
ox active metals. Thus, it could be speculatedhat malnutrition, which is interrelated to chronicnflammation,434 may further contribute to cardio-ascular morbidity and mortality by reducingoth antioxidant defenses due to poor nutritionalntake. Taken together, these observations mayrovide one explanation why hypoalbuminemiand inflammation so strongly correlate with car-iovascular mortality in both the general popula-ion477,478 and CKD patients.322,479

Treatment strategies for increased oxidativetress in CKD. Although epidemiological datauggest that the intake of vitamin E is inverselyelated to the development of CVD, large, pro-pective, randomized controlled trials all haveailed to show that vitamin E supplementationmproves cardiovascular outcomes in the generalopulation.480 Moreover, a recent study showedhat, whereas vitamin E supplementation dideduce circulating oxidized LDL, it did not re-uce the progression of atherosclerosis in theeneral population.481 On the other hand, a studyas shown positive results of vitamin E supple-entation on outcome482 and the combination of

itamin E and C slowed the progression of ca-otid artery lesions in another study.483 As dis-ussed elsewhere484 there may be a number ofeasons why vitamin E supplementation failed tomprove survival in these patient groups. In CKDatients, oral vitamin E supplementation haseen shown to reduce the oxidative susceptibilityf LDL,485 and to prevent the oxidative stressssociated with anemia therapy or improve eryth-opoietin responsiveness.486 The SPACE trialested the effect of vitamin E (800 IU/day) on aombined cardiovascular endpoint in 196 HDatients with pre-existing CVD, and showed aignificant benefit from vitamin E supplementa-ion.487 In contrast, a recent study reported nourvival benefit of vitamin E in patients withild to moderate CKD.488 In another recent

tudy, treatment with the antioxidant acetylcys-eine was associated with a reduced number ofardiovascular events in patients undergoingD.489 Moreover, vitamin C supplementation in

hronic HD patients can reduce the lymphocyte-OHdG levels and the production of intracellu-ar reactive oxygen species.490 Based on theseesults, larger trials that are sufficiently poweredo assess the effects of antioxidants on mortality
ppear highly desirable in CKD patients.

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As the interaction between dialysis mem-ranes and blood neutrophils can trigger oxida-ive stress491 direct scavenging at the membraneite is another attractive therapeutic approach.hus, specific dialysis techniques (such as vita-in E-modified cellulose membranes) have been

ntroduced in an attempt to reduce oxidativetress. However, although some studies haveemonstrated beneficial effects of vitamin E-oated dialyzers on markers of oxidative stress,492

ndothelial dysfunction,493 and cytokine induc-ion,494 no study yet has, to the best of ournowledge, demonstrated any benefit of thesexpensive dialyzers on cardiovascular morbidityr mortality. Other modifications of the dialysisrocedure may also reduce oxidative stress. Re-ently, it was shown that high-flux HD wasssociated with an improvement in some mea-ures of protein oxidation.495 Another aspect ofhe management of CKD with potential clinicalmplications for oxidative stress is the treatmentf anemia. As red blood cells contain high levelsf antioxidants (in particular, reduced gluta-hione), it is possible that a rise in red cell massay increase the total antioxidative capacity.496

n the other hand, the intravenous injection ofron may induce an increase in protein oxida-ion465,497 and carotid atherosclerosis.465 There-ore the relationship between anemia manage-ent and oxidative stress may be complicated.


Studies are needed to determine which surro-ate marker of oxidative stress best predicts
utcome in CKD patients. Further research is p
equired to investigate the possible interactionsetween the presence of oxidative stress andoth traditional risk factors (such as dyslipide-ia) and non-traditional risk factors (such as

nflammation, vascular calcification, advancedlycation end-products and endothelial dysfunc-ion) for atherosclerosis. Studies are also neededo determine which oxidative stress pathwayi.e., nitrosative, chlorinated or carbonyl stress)s quantitatively the most important in CKDatients. Nonpharmacological (such as diet) andharmacological (such as vitamin E and acetyl-ysteine) interventions for CKD patients withigns of increased oxidative stress should beeveloped and evaluated for efficacy in reducingxidative stress and improving clinical outcomesn this patient group.

onclusions

Oxidative stress, which is an important part ofhe host defense mechanism, may play a crucialole in the pathogenesis of atherosclerosis inKD. Associations exist between increased oxi-ative stress, inflammation and endothelial dys-unction, which may contribute to increased riskf cardiovascular disease. As oxidants have veryhort half-lives they cannot be reliably evaluatedn the clinical situation. Thus, the determinationf oxidative stress relies on the use of moretable surrogate markers. Oxidative stress ap-ears to play an important part in the pathogene-is of CVD in CKD patients. However, the ben-fit of antioxidant treatment strategies in this
atient group remains undefined.

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NUTRITIONAL AND METABOLIC FACTORS

BODY WEIGHT AND MANAGEMENT

ntroduction

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The Clinical Guidelines on the Identification,valuation, and Treatment of Overweight andbesity in Adults were published in 1998 to

ddress the increasing problem of overweightnd obesity in the United States.498 This docu-ent reports strong evidence that overweight

nd obesity increases morbidity from hyperten-ion, dyslipidemia, type 2 diabetes, CHD, stroke,all bladder disease, osteoarthritis, sleep apneand respiratory problems, and endometrial, breast,rostate and colon cancers. Overweight and obe-ity also increase all-cause mortality.

There is strong evidence that weight loss inverweight and obese individuals reduces riskactors for diabetes and CVD. Weight loss haseen associated with reductions in blood pres-ure, reductions in triglycerides, total choles-erol and LDL cholesterol, increases in HDLholesterol, reductions in blood glucose inverweight and obese persons without diabe-es, and reductions in blood glucose and HbA1c

n some patients with type 2 diabetes. Norospective trials exist to show that weightoss changes mortality.

In the NIH Guidelines, the definition of over-eight is a body mass index (BMI) of 25-29.9g/m2 and obesity as a BMI of �30 Kg/m2. Theanel also suggested that waist circumferencehould be used as a marker of abdominal fat,ith measurements of �102 cm in men and �88

m in women indicating high risk. These mea-urements are not direct measures of body com-osition (i.e., fat mass and lean body mass),hich are more accurately measured using totalody water, total body potassium, bioelectricalmpedance, dual energy X-ray absorptiometryDEXA) (see the chapter on Malnutrition in thisocument), MRI, and computed tomography. Inpidemiological studies, BMI is the favored mea-ure of excess weight to estimate relative risk ofisease, since it is a simple, rapid and inexpen-ive measure that can be applied generally todults. Likewise, CT and MRI are more accurateeasures of abdominal fat, but impractical for

linical use; thus, the recommendation for mea-
urement of waist circumference. c
American Journal of Kidney D90

iscussion

In contrast to the general population, higherMI is associated with better outcomes in dialy-

is patients, even when overall health status isonsidered. The preponderance of associativevidence suggests this BMI paradox in dialysisatients confers a survival advantage.499-502

However, BMI may be an inappropriate mea-ure of body composition in patients with renalailure, since it is complicated by excess fluideight and muscle wasting, and may be related

o malnutrition. A recent study measured leanody mass and thus was able to evaluate thessociation of body composition (i.e., muscleass as indicated by 24-hour urinary creatinine

xcretion) in addition to BMI, and cardiovascu-ar and overall outcomes.503 This study showedhat, as in other studies, patients with high BMI�27 Kg/m2) had lower all-cause and cardiovas-ular death rates than those with normal BMI.owever, the survival advantage of a high BMIas only confined to those with low body fat;

ven in the low BMI group, high body fat andow muscle mass were associated with increasedisk of death.

Thus, in terms of body composition, it appearshat maintenance of muscle mass and loweringf body fat are important in reducing cardiovas-ular risk. Evidence suggests that exercise train-ng (aerobic exercise and resistance training)ncreases muscle mass, as does nandrolone de-anoate in dialysis patients.504 There are no ran-omized clinical trials to determine the effects ofither of these interventions, or caloric restric-ion to lower body fat, on cardiovascular orll-cause mortality in dialysis patients.

linical Applications

The following considerations are based on theIH Clinical Practice Guidelines.498 Clearly spe-

ial attention related to nutritional status is neces-ary for patients with renal failure. The BMI datahat have established the theory of the “BMIaradox” in dialysis patients have resulted inew, if any, interventions for weight managementn dialysis patients. Certainly, no randomized
linical trials have been conducted to test stan-
iseases, Vol 45, No 4, Suppl 3 (April), 2005: pp S90-S106

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ardized approaches to weight management inialysis patients. Likewise, the confounding fac-ors of nutritional deficiency and those of deter-ining lean body mass, fat mass, and fluid weight

omplicate goal setting and monitoring of anyrograms. Nonetheless, reduction in fat mass andaintenance of muscle mass may be important

n dialysis patients.Weight loss. While the recommended weight

oss goal for the general population is to reduceody weight by approximately 10% from base-ine, the safety and efficacy of weight loss in theverweight dialysis patient is unknown, as is theotential benefit to CVD outcomes. Therefore,eight loss in the dialysis patient should be

pproached with close monitoring by a regis-ered dietitian and physician. Further weight lossan be attempted, if indicated, through furtherssessment to ensure fat loss and not muscle loss.ntil weight loss studies are completed in dialy-

is patients, rates of weight loss should be indi-idually determined.Dietary therapy. For the general population,

owering caloric intake and increasing exercisere recommended for weight loss in overweightnd obese persons. Reducing fat as part of aow-calorie diet is a practical way to reducealories. Weight loss for the dialysis patient re-uires an individualized meal plan that is deter-ined by a registered dietitian working with the

atient. Such a diet plan would need to meet theutritional recommendations for dialysis patientsn regards to micro- and macro-nutrients (see theKF-K/DOQI Nutrition Guidelines169) while de-

reasing total calories appropriately. Monitoringf laboratory values and food intake during aeight loss diet is critical due to the paucity of

nformation regarding weight loss in dialysisatients. It is important to avoid the popular dietshat could induce adverse metabolic complica-ions. Examples include high protein types, food-ombining diets, and diets that encourage unusu-lly large portion sizes of fruits and vegetables.

Physical Activity. Exercise is recommendeds part of a comprehensive weight loss therapynd weight control program because it 1) mod-stly contributes to weight loss in overweightnd obese adults; 2) may decrease abdominal fat;) increases cardiorespiratory fitness; and 4) mayelp with maintenance of weight loss. Physical
ctivity should be an integral part of weight-loss i
herapy and weight maintenance, and should bendertaken in combination with behavioralherapy that assesses the patient’s motivationevels and other factors that contribute to theuccess of an exercise program. For additionalnformation, see Guideline 12.

pecial Treatment Groups

Smokers. All smokers, regardless of theireight status, are likely to benefit from smoking

essation while minimizing weight gain. If weightain does occur, it may be treated through dietaryherapy, physical activity, and behavioral therapy,

aintaining the primary emphasis on the impor-ance of abstinence from smoking.

Older adults. A clinical decision to foregobesity treatment in older adults should be guidedy an evaluation of the potential benefits ofeight reduction for day-to-day functioning and

eduction of the risk of future cardiovascularvents, as well as the patient’s motivation foreight reduction. Care must be taken to ensure

hat any weight reduction program minimizes theikelihood of adverse effects on bone health orther aspects of nutritional status.

ConclusionsStrong evidence in the general population has

hown that overweight and obesity are associ-ted with increasing risks of a variety of cardio-ascular complications, and with higher all-ause mortality. However, no studies havexamined standardized approaches to weightanagement in dialysis patients. Overweight or

bese patients are likely to benefit from weighteduction, but plans will need to be carefullyndividualized and monitored for each patient.

OMEGA-3 FATTY ACIDS

ntroduction

Fatty acid biochemistry. There are four fami-ies of polyunsaturated fatty acids in mammalianissue: �-3, �-6, �-7 and �-9 (Fig 6). The fattycids that are considered to be essential to humanealth belong to the first two families: 18:3, �-3;8:2, �-6; and arachidonic acid (20:4, �-6).505

he main dietary sources of �-3 fatty acids areold-water fish, canola oil, soybeans, walnuts,axseeds, and their products. Omega-6 fatty ac-

ds are found predominantly in all other veg-

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table oils and foods prepared with them, while-9 fatty acids are predominantly found in olivesnd olive oil.

Inter-relationship between �-3 fatty acid bio-hemistry and CVD. The beneficial effects of-3 fatty acids on CVD risk appear to be related

o their impact on several risk factors identifiedo have a role in the development of CVD. Thesenclude: systemic inflammation, thrombotic ten-ency, lipid levels, endothelial function, reduc-ion of proinflammatory responses, cardiachythm, and—to a lesser extent—hyperten-ion.506-509 Mechanisms thought to be respon-ible for the beneficial effects of �-3 fatty acidsn CVD risk and treatment are listed in Table 25.he results from these studies have been ana-

yzed and summarized for review elsewhere (1,, 7, 11, 12).506-508,510,511

The effect of �-3 fatty acids on some of theseisk factors has been demonstrated by partial

Fig 6. Desaturation and elongation of the majorermission.8

d

ubstitution of �-3 fatty acids for arachidoniccid in the sn-2 position of cell membrane phos-holipids. The replacement of the �-3 fatty acidicosapentaenoic acid (20:5, �-3) for the 20:4,-6 arachidonic fatty acid alters the proinflamma-

ory thromboxane-prostanoid balance by attenu-ting the rate of dienoic eicosanoid production,esults in a decrease in triglyceride levels, andonfers antithrombotic and anti-inflammatoryroperties.505,509,512 Omega-3 fatty acids haveeen reported to decrease platelet activation, andmprove vascular tone513 and endothelium-ediated vasodilation.511,514 Recent studies indi-

ate that �-3 fatty acids also impact the metabo-ism of adhesion molecules and cytokines (seeable 25).515,516

Hypotheses regarding the role of �-3 fattycids on decreasing sudden death and arrhyth-ias relate to inhibition of the fast, voltage-

ependent sodium current and the L-type cal-ium channels, inhibition of thromboxaneroduction, and beneficial effects on factors thatffect heart-rate variability.517,518

Diet and risk reduction. The role of diet inisk reduction of CVD in the general populationas been debated for over 100 years. Early ani-al studies demonstrated that diets high in cho-

esterol and saturated fat resulted in atherosclero-is. Human studies in the 1950s showed that

s of polyunsaturated fatty acids. Reproduced with

iets high in cholesterol and saturated fatty acids

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ncreased serum cholesterol levels. Epidemiologi-al data indicated that elevated serum cholesterolevels predicted the risk of CHD.507,509 As aesult of these studies, initial dietary recommen-ations focused on lowering dietary cholesterolntake to 300 mg or less, decreasing saturatedatty acids to �10% of fat calories and total fat to30% of total caloric intake.519 The application

f these guidelines to the diet were accomplishedy cutting back on animal fat intake, replacingutter with margarine, and using corn and otheregetable oils in food preparation and saladsather then partially hydrogenated fats and lard.

Advancing research over the years has nowdentified that CVD has many metabolic compo-ents, of which several are modifiable by dietaryatty acids. In addition to affecting serum lipidevels (Table 26),269 dietary fatty acids—specifi-ally those of the �-3 class—attenuate proinflam-atory mediators and mechanisms that have

een identified to have a role in the developmentf CVD.506,508,520

As a result of the growing abundance of litera-ure including epidemiological and randomizedlinical trials evaluating omega-3 fatty acids, themerican Heart Association (AHA) and the Insti-

ute of Medicine (IOM) have recently included aecommendation for inclusion of �-3 fatty acidsn the diets of Americans for the purpose ofrevention and treatment of cardiovascular dis-ase.506,508 Prudent application of these newuidelines should be considered for the potentialf prevention and treatment of CVD for theidney patient on renal replacement therapy untilata specific for this patient population becomevailable.

iscussion

While there is an abundance of literature on-3 fatty acids and kidney disease,521-530 no

andomized clinical trials have been completed
hat evaluate the effectiveness of �-3 fatty acids p
n CVD risk factors and surrogate markers inialysis patients.One recent study reports the effect of fish

ntake in dialysis patients.531 In a cohort of 216ncident dialysis patients, those who reportedsh consumption were 50% less likely to dieompared to those who did not report fish intakeuring the study interval (p�0.02). Multivariatenalysis indicated that younger age, black race,nd high mental health scores at baseline werelso associated with a lower mortality risk.mega-3 fatty acid substitution was not objec-

ively documented in this study. Despite thisimitation, the results suggest a beneficial effectf �-3 fatty acids via fish consumption andurther studies are warranted.

Fatty acid guidelines for general health main-enance. The IOM recently published Accept-ble Macronutrient Distribution Ranges (AM-Rs) that have been established for protein,

arbohydrate, fat, �-6 and �-3 fatty acids.506

he AMDRs are based on the results of epidemio-ogical studies and a literature review that evalu-ted associations between diet intake and risk ofhronic disease. The AMDR for fat is 20%-35%f calories, 5-10% of calories for linoleic acid�-6 polyunsaturated fatty acids, PUFAs) and.6%-1.2% of energy for alpha-linolenic acid�-3 PUFAs). Up to 10% of the AMDR for �-3atty acids can be consumed as eicosapentaenoiccid (EPA) and/or docosahexenoic acid (DHA);.06%-0.12% of energy. It is important to avoidxcessive intake of �-3 fatty acids as there haveeen reports of adverse effects on immune func-ion and a potentially increased risk of excessiveleeding and hemorrhagic stroke.506 An intake of3 g/day is unlikely to cause clinically signifi-

ant bleeding.508

The IOM also has introduced a new referencealue, Adequate Intake (AI), for the general
opulation. It is defined as the recommended

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verage daily intake level based on observed orxperimentally determined approximations or es-imates of nutrient intake by a group (or groups)f apparently healthy people that are assumed toe adequate. This value is used when the Recom-ended Dietary Allowance (RDA) cannot be

etermined.506

The AI for alpha-linolenic acid is 1.6 g and.1 g for men and women, respectively. Up to0% can be consumed as EPA and/or DHA. Thismount of �-3 fatty acid can be obtained byating at least two servings of fatty fish per weekr by taking supplements. For linoleic acid, theI is 17 g/day for adult men and 12 g/day for

dult women. Table 27 identifies amounts of �-3atty acids provided by selected food sources andupplements.


Overall approach. The AHA Guidelines forVD prevention include encouraging the intakef fruits, vegetables, grains, low-fat or nonfatairy products, fish, legumes, poultry, and leaneats. Food choices should be modified to re-

uce saturated fats (�10% of calories), choles-erol (�300 mg/dL) and trans-fatty acids byubstituting grains and unsaturated fatty acidsrom fish, vegetables, legumes, and nuts. Saltntake should be limited to �6 g/day. Alcoholntake should also be limited (�2 drinks per dayn men and women) among those who drink.508

Response to therapy. Routine review of di-tary intake and laboratory values should beufficient to monitor tolerance to the inclusion ofoods enriched in �-3 fatty acid at least twice pereek.For patients with documented CHD, initial

imonthly check of bleeding times would berudent, followed by monthly check with routineaboratory values once stable. Lipid levels, includ-ng triglycerides, should be monitored.

Patients taking 2-4 g of EPA�DHA supple-ents should maintain bimonthly checks of

leeding times with triglyceride monitoring asart of routine monthly laboratory values.Follow-up. For those patients taking thera-

eutic doses of �-3 fatty acids for hypertriglycer-demia, supplementation can be modified to aower dose of 1 g/day upon normalization of theipid profile and/or inclusion of foods enriched in
-3 fatty acids 1-2 times per week. f
Limitations. There are more questions thannswers regarding essential fatty acid metabo-ism, oxidative stress, CVD, and diet in theialysis patient. The lack of evidence in theialysis population makes extrapolation of guide-ines for the general population to the dialysisatient questionable. However, the abundance ofvidence suggesting a beneficial effect of �-3atty acids, fresh fruits and vegetables, the ongo-ng data that saturated and trans-fatty acids areot heart-healthy, and the continued high preva-ence of CVD morbidity and mortality in thisatient population justifies prudent applicationf healthy eating guidelines until hard data forhis patient population become available.

Incorporation of fruits, vegetables, grains, andonfat dairy products can be problematic forany dialysis patients due to the need to restrict

ietary potassium intake to (on average) 2 g/day.n addition, foods enriched in alpha-linoleniccid (flaxseed, walnuts, soy) are high in potas-ium, and contribute dietary protein and phospho-us (Table 28). Therefore, these foods are un-ikely to be a reliable source of �-3 fatty acidsor the dialysis patient. Alternatively, the oils ofhese foods (walnut and flaxseeds) as well asanola oil can be safely incorporated into the dietor dialysis patients.


Studies are required to identify the essentialatty acid status of CKD patients, both progres-ive and for those on renal replacement therapy.tudies should also evaluate the interrelation-hips among �-3 fatty acid supplementation,xidative stress, CVD and dialysis therapy. Clini-al trials are needed to evaluate the role ofietary fatty acid modification on CVD risk andutcomes in CKD patients on renal replacementherapy. Further clinical trials should evaluateurrent nutrition recommendations for the gen-ral population modified to the diet recommenda-ions for CKD patients.

onclusions

Based on the available evidence, it is benefi-ial for well-nourished, stable dialysis patients,ho have no evidence of CVD, early CVD, or

stablished CVD, to include food sources of �-3
atty acids in their diet at least twice weekly.

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HOMOCYSTEINE

ntroduction

Homocysteine is the demethylation product ofhe amino acid methionine. Once degraded, ho-ocysteine enters the cysteine biosynthetic path-
ay (transulfuration), or is remethylated to me- h
hionine (activated methyl cycle). The controllingnzymes in these two pathways are cystathionineynthase (CBS), methionine synthase (MS) and,10-methylene tetrahydrofolate reductaseMTHFR), the latter of which supplies the methylroup required by MS in the methylation of
omocysteine. Each enzyme requires a member

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f the B vitamin family as a co-factor. A second-ry pathway for the remethylation of homocys-eine is by betaine methyltransferase, a pathwayhat occurs in the kidney and liver. The kidneysccount for approximately 70% of plasma clear-nce of homocysteine. The majority of plasmaomocysteine is in the protein-bound form. Theormal plasma concentration of homocysteine ispproximately 5-10 �mol/L. Degrees of hyperho-ocysteinemia (HHCY) approximately defined

s mild are 15 �mol/L, as moderate are 25mol/L, as intermediate are 50 �mol/L, and as

evere are �50 �mol/L.532-536

In the general population, HHCY has beenuggested by many studies to be a risk factor forVD, including atherosclerosis and arterial andenous thrombosis.537-547 It is not entirely clearhether a mild increase in plasma homocysteine

ontributes to the pathogenesis of vascular dis-ase or is a marker for increased risk.537-539

athogenic mechanisms that have been postu-ated include activation of the coagulation cas-ade, damage to endothelial cells either directlyr through an oxidative stress response, and lipideroxidation.540-544 The association betweenHCY and CVD has not yet been proven to be

ausal. Clarification of the interrelationships be-ween HHCY and CVD will require completionf prospective, randomized intervention trials,everal of which are in progress.546 Despite the
ack of a solid relationship, there is significant a
esearch activity exploring interventions for thereatment of HHCY for the prevention of CVD inoth the general population and in CKD patientseceiving renal replacement therapy.

iscussion

Association data. Whether the associationetween HHCY and CVD applies to patientseceiving renal replacement therapy is unclear.everal studies have demonstrated that HHCY isn independent risk factor for CVD or a CVDutcome in HD patients.159,327,357,435,548-561 Oth-rs have found negative or inconclusive re-ults.562-566 A recent study reports that in 94 HDatients taking a multivitamin, lipid peroxidationnd inflammation—but not HHCY—were theain risk factors for mortality.470

Summaries of data pertaining to the associa-ion of HHCY and CVD in the general popula-ion are available. A literature review of 33rospective cohort studies evaluated MI, stroke,V morbidity, CV death, and/or all-cause mortal-

ty.537,547 In 73% of the studies, there was aignificant association between elevated homocys-eine and the aforementioned outcomes; 27% of thetudies were inconclusive. In CKD patients receiv-ng maintenance dialysis, 19 studies suggested anssociation between elevated plasma homocysteineevels and CVD.159,327,357,435,470,552-566 However,
causal relationship between HHCY and CVD has

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ot been established in either the general or CKDopulation.

Treatment of HHCY in the general popula-ion. Intervention studies in the general popula-ion have demonstrated that dietary supplementa-ion with folic acid, vitamin B12 and/or vitamin B6,owers plasma homocysteine levels.546,547,567-570 A

eta-analysis of randomized trials of homocys-eine-lowering vitamin supplements concludedhat daily supplementation with 0.5-5.0 mg fo-ate and 0.5 mg vitamin B12 would be expectedo reduce homocysteine levels by 12 �mol/L topproximately 8-9 �mol/L.567 Interventionaltudies designed to reduce plasma homocysteineevels and determine if this reduction modifiesardiovascular outcomes need to be completed.

Observations of HHCY in dialysis patients.yperhomocysteinemia is a common observa-

ion in the CKD population.551 The prevalencef HHCY in HD patients has been reported in theange of 85%-100%, with the higher end ob-erved in patients who were not receiving atandard multivitamin supplement.551 Concentra-ions of homocysteine range from 20.4-68.0mol/L.551 Mildly elevated levels of homocys-

eine occur in approximately 5%-7% of theeneral population, while severe HHCY isare.533,537,567 Patients without kidney failureith mild HHCY are described as asymptomaticntil the third or fourth decade, when CAD andecurrent arterial and venous thrombosis de-elop.533 The severe elevations of homocysteineeen in patients on maintenance dialysis therapyould be one of the nontraditional risk factors forhe 50% mortality rate from CVD observed inhis patient population.

Plasma homocysteine levels in HD patientsave been reported to be lowered by dietaryupplementation with folic acid that is givenith or without vitamin B12 and B6.571-581 Other

herapies that have been examined include intra-enous folinic acid and MTHF. Doses of orallydministered nutrients in these studies rangedrom 1 mg-60 mg folic acid, with or without upo 110 mg vitamin B6 and with or without up to 1

g vitamin B12. The higher doses of oral folateid not have a better result compared to the loweroses in terms of the post treatment plasmaomocysteine levels.These studies demonstrate that, while plasma

omocysteine levels can be reduced by these a

utrients, they are not normalized, and remain inhe range of 15.9-29.9 �mol/L. Possible reasonsor this resistance include impaired folic acidetabolism and impaired folate absorption.551

upplementation with betaine or serine, and withhe addition of betaine to folic acid, has notemonstrated a reduction in elevated plasmaomocysteine levels.569 Results from interven-ional studies designed to determine whetherodifying plasma homocysteine levels affect

ardiovascular outcomes in dialysis patients areot available at this time.


Existing guidelines for the general popula-ion. The Canadian Task Force on Preventiveealth Care completed an evidence-based re-iew of the literature regarding both the associa-ion of elevated homocysteine levels and CAD,nd the effect of lowering homocysteine levelsith vitamin supplementation or diet.546 This

valuative process yielded several results show-ng associations between total homocysteine lev-ls and CAD risk, but there was insufficientvidence to make therapeutic recommendationsegarding screening for, or management of,HCY.Applicability to the dialysis patient. There is

strong inverse correlation between serum folateevels and plasma homocysteine levels, and aeaker correlation between homocysteine levels

nd plasma levels of vitamins B6 and B12.532 Inhe general population, administration of theeficient nutrient will correct the defi-iency.568,570,582 In the dialysis patient, the admin-stration of folate, and vitamins B6 and B12 haveeen reported to lower, but not normalize, plasmaomocysteine levels.567-577 It has been observedhat patients who are not receiving a multivita-in supplement have higher levels of plasma

omocysteine.553 As a result, routine vitaminupplementation for the dialysis patient becomesmportant not only for adequate nutritional sta-us. B vitamin supplementation is necessary toeplace the losses from dialysis, and to preventn independent, additive elevation in serum ho-ocysteine levels that could be due to deficient

r marginal intake of folate, riboflavin (vitamin2),583 pyridoxine (vitamin B6) and/or cobal-
min (vitamin B12).578

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onclusions

As in the general population, the literature forialysis patients is inconclusive regarding HHCYnd CVD. Current studies indicate that normal-zation of the plasma homocysteine levels in theidney patient population cannot be effectivelybtained through folate, B6, or vitamin B12upplementation. In addition, any lowering ofhe plasma homocysteine level that has beeneported, has not been shown to effect CVDutcomes. However, the evidence does show thatitamin deficiency, particularly that of vitamins2, B6, B12 and folic acid, contribute to HHCY.Current opinion and evidence suggests that it

s prudent to supplement, rather than risk defi-iency, especially when supplementation is safet the recommended levels. Therefore, dialysisatients are likely to benefit from a daily vitaminupplement that provides the recommended pub-ished vitamin profile for dialysis patients, withpecial attention to the inclusion of folic acid,nd vitamins B2, B6 and B12.

LIPOPROTEIN(A) ANDAPOLIPOPROTEIN(A) POLYMORPHISM

ntroduction

Lipoprotein(a) [Lp(a)] is an LDL-like lipopro-ein, consisting of an LDL particle to which thelycoprotein apolipoprotein(a) [apo(a)] is at-ached. Apolipoprotein(a) shows a high homol-gy with plasminogen and competes with it forinding on plasminogen receptors, fibrinogen,nd fibrin.584 This apolipoprotein contains a heri-able number of so-called kringle-IV (K-IV) re-eats, providing the basis for the apo(a) K-IVepeat polymorphism.585 The molecular weightf apo(a) increases with the number of K-IVepeats (300 kDa to �800 kDa) and is inverselyelated to the Lp(a) plasma concentrations. Thateans that individuals with high molecular-eight (HMW) or large apo(a) isoforms have, on

verage, low Lp(a) concentrations, and thoseith low molecular-weight (LMW) or small iso-

orms exhibit usually high concentrations of p

p(a). Depending on the population under inves-igation, this association explains between 30%-0% of the variability in Lp(a) levels.Since most studies showed that lipids were not

seful for atherosclerosis risk assessment in dialy-is patients, many studies during the last decadeocused on nontraditional lipid abnormalities.p(a) was a promising candidate because of thetrong evidence from the general population thatp(a) is a risk factor for CVD.586-589

The NKF-K/DOQI Clinical Practice Guide-ines for Managing Dyslipidemias in CKD Pa-ients51 focused primarily on lipids, and less onhose abnormalities that cannot be intervention-lly influenced at present. Due to the strongnterest in Lp(a), this review examines the litera-ure relating Lp(a) and/or the apo(a) polymor-hism to CVD.

iscussion

Lp(a) concentrations and apo(a) size polymor-hism in renal disease. In the early stages ofenal disease, Lp(a) starts to increase, often longefore glomerular filtration rate is de-reased.590,591 This holds true mostly for patientsith HMW apo(a) isoforms and not for thoseith LMW apo(a) isoforms when compared to

po(a) isoform-matched controls.322,590,592-595

his isoform-specific increase was observed ineveral—but not all—studies in non-nephroticenal disease and HD patients, but not in patientsith nephrotic syndrome596,597 or in PD pa-

ients.594 Those treatment groups showed an in-rease in Lp(a) in all apo(a) isoform groups,robably as a consequence of the pronouncedrotein loss they experience. In support of thisssumption, a decrease of Lp(a) following auccessful kidney transplantation can be ob-erved in HD patients with HMW apo(a) iso-orms598,599 and in CAPD patients with all apo(a)soform groups.600

There is evidence that malnutrition and/ornflammation have an Lp(a)-increasing ef-ect.322,434,601,602 However, the elevation of Lp(a)an be observed already in the earliest stages ofenal impairment590 as well as in HD patients322

ith HMW apo(a) phenotypes and normal CRPnd/or normal serum amyloid A levels. Theseesults suggest that CRP only modifies Lp(a)oncentrations, but they fail to explain the apo(a)
henotype-specific elevation of Lp(a).

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Association of Lp(a) concentrations withVD. The association of Lp(a) with atheroscle-

otic complications was investigated in numeroustudies in dialysis patients. The results, however,ere ambiguous in prospective as well as in retro-

pective studies.143,159,322,325,357,419,555,561,603-633

ost of the retrospective studies, including thoseith the largest patient numbers, found no associa-

ion between Lp(a) levels and cardiovascular com-lications. The same holds true for prospectivetudies (Table 29). A study of 129 HD patientseported significantly higher Lp(a) concentrationsn those who suffered a CVD complication duringhe 4-year observation period.610 The two largestrospective studies, however, did not observe anssociation between high Lp(a) concentrations andAD events603 or total mortality,605 respectively.Association of the apo(a) size polymorphism

ith CVD. Almost all studies that did not onlyeasure Lp(a) concentrations but also per-

ormed apo(a) phenotyping consistently showedn association between the apo(a) K-IV repeatolymorphism and CVD complications (Table0).357,603-605,613,617-619,624,630 A study of 167D patients reported the apo(a) phenotype to bebetter predictor for the prevalence and the

egree of carotid atherosclerosis than the Lp(a)lasma concentration.618 Similarly, others foundMW apo(a) isoforms (besides age and oxidizedDL) to be predictive for the presence of carotidlaques in 109 predialysis patients with terminalhronic renal failure.434 A doubling of the fre-uency of LMW apo(a) phenotypes was ob-erved in those CAPD patients who had sufferedCAD event.630 A large cross-sectional study in07 HD patients described an association ofMW apo(a) phenotypes with CAD events.604

nother study of 440 HD patients prospectivelyollowed for a period of 5 years found a strongssociation between the LMW apo(a) phenotypend CAD events defined by stringent criteriadefinite myocardial infarction, percutaneousransluminal coronary angioplasty, aortocoro-ary bypass or a stenosis �50% in the coronaryngiography) (Fig 7).603 Patients with LMWpo(a) isoforms had, on average, twice the num-er of coronary events per 100 patient-years.603

imilarly, the CHOICE study recently reportedhat LMW apo(a) isoforms were associated withotal mortality in an inception cohort of 864
ncident dialysis patients who were followed for d
median of 33.7 months; again, Lp(a) concentra-ions were not associated with total mortality.605

n the other hand, when prevalent atheroscle-otic CVD at the start of renal replacement therapyas investigated in the same cohort, Lp(a) con-

entrations were associated with prevalent dis-ase in whites younger than 60 years, but notmong blacks or those older than 60 years. Inddition, apo(a) isoforms were not associatedith prevalent atherosclerotic CVD.606


Considering all these studies, it seems thatp(a) concentrations might not be very fruitful

or risk prediction. However, from two prospec-ive studies (total of 1,300 patients) and most ofhe cross-sectional studies (including more than,000 patients) the evidence is strong that thepo(a) size polymorphism is associated with vari-us endpoints. The diverging results for Lp(a)oncentrations might be caused, at least in part,y the methodological problems with the Lp(a)easurement, which is not standardized. The

po(a) polymorphism might be a better predictors discussed previously.603,634 This fact is basedn the above-described apo(a) isoform-specificlevation of Lp(a).592,594 In hemodialysis pa-ients with only large apo(a) isoforms, Lp(a)oncentrations increase and come closer to theoncentrations usually seen in patients with smallsoforms. Therefore, the risk for atheroscleroticomplications can no longer be discriminated byeans of Lp(a) concentrations. The apo(a) phe-

otype, however, gives approximate informationbout the prior contribution of Lp(a) to the riskor atherosclerosis. This is probably more impor-ant, since the predisease period (with its specifictherosclerosis risk) lasted longer in most of theatients than did the present situation. It is further-ore conceivable that patients with a LMW

po(a) phenotype and a more pronounced athero-clerosis preload develop a more rapidly-pro-ressing atherosclerosis after commencement ofenal insufficiency or hemodialysis treatment.

At present, no easily practicable method forowering Lp(a) is available and sufficient proofs lacking that lowering Lp(a) is favorable. Thisolds true for the general population, as well asialysis patients. The question remains whetherhe apo(a) K-IV repeat polymorphism should be
etermined in dialysis patients.



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Further large dialysis cohorts should investi-ate the value of Lp(a) concentrations and Apo(a)henotypes for risk assessment. This questionhould especially be addressed in PD patients asell as in various ethnicities. A possible interac-

ion of various apo(a) isoforms with lipids andther cardiovascular risk factors should be inves-igated. Experimental therapeutic strategies toower Lp(a) should be examined in randomized,ontrolled clinical trials, especially in high-riskopulations such as dialysis patients.

onclusions

Although Lp(a) levels are not a suitable factoror CVD risk prediction in dialysis patients, theres strong evidence that the apo(a) size polymor-hism is associated with various clinical end-oints.

MALNUTRITION

ntroduction

Protein-energy malnutrition (PEM) and wast-ng are common among CKD patients,635-637 andre associated with higher rates of morbidity andortality.169,441,635,638,639 Although various fac-

ors associated with the dialysis procedure, pere (such as dialyzer membrane bio-incompatibil-ty, and nutrient losses), may contribute to PEM,

Fig 7. Coronary event-free survival and apo(a) phe-otypes. Adjusted results are obtained from a multipleox proportional hazards regression analysis. Num-ers near the survival curves represent the number ofatients with HMW and LMW apo(a) phenotypes at riskt the times 0, 12, 24, 36, 48 and 60 months. Repro-uced with permission (http://lww.com).603

ecent studies have shown that malnutrition is p

lso common before the start of dialysis.434,638

arious factors contributing to malnutrition inKD patients are presented in Table 31. Theecline in nutritional status during the course ofrogressive kidney failure may be caused byisturbances in protein and energy metabolism,ormonal derangement, as well as by spontane-us reductions in dietary energy and proteinntake.640 However, as it has been demonstratedhat patients treated with HD for a long timeecome malnourished despite adequate dialysisose and protein intake,641 several co-morbidonditions may also contribute to PEM amongialysis patients. In particular, chronic inflamma-ion, CVD, diabetes mellitus, and other superim-osed illnesses may produce anorexia and malnu-rition. It was recently reported that diminishedppetite (anorexia) was associated with higheroncentrations of proinflammatory cytokines.642

vidence suggests that the presence of PEM isssociated with inflammation in CKD pa-ients.421,434,643,644 Moreover, both PEM at base-ine and worsening of PEM over time are associ-ted with a greater risk for cardiovascular deathn dialysis patients328,645 and strong associationsetween the presence of malnutrition and CVDave been documented both in predialysis434 andialysis643 populations. On the other hand, aecent study646 documented no association be-ween BMI and hospitalized acute coronary syn-romes in a large group of incident Medicareialysis patients. The exact mechanism(s) byhich PEM may increase the risk of CVD areot known. However, as PEM and low BMIecently have been associated with both in-reased oxidative stress475,647 and impaired endo-helium-dependent vasodilation with reduced bio-vailability of nitric oxide,647 these may beechanisms that contribute to the high preva-

ence of CVD in malnourished CKD patients. Asutritional status is so strongly associated withutcome, it is important to define which nutri-ional indicators to use in the clinical setting.owever, the optimal protocol to diagnose andonitor the response to nutrition intervention

as not yet been defined. Therefore, the currentpproach is to integrate parameters that haveeen shown to have nutritional relevance; i.e.,linical assessment, food intake, biochemical as-essment, body weight, body composition, and
sychosocial evaluation.

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iscussion

Validity of serum albumin as a nutritionalarker. Over the past few years, the process of

utrition assessment and management of the CKDatients has been presented with new challengesegarding validity and reliability. This is largelyue to the fact that parameters previously reliedpon for visceral stores assessment, predomi-antly serum albumin (and, to a lesser extent,realbumin), are independently altered by sys-emic inflammation. Several studies have demon-trated that a low serum albumin concentra-ion is strongly associated with both mortal-ty181,362,441,479,649 and cardiac disease479 in CKDatients maintained on either PD or HD. More-ver, among 1,411 HD patients enrolled in theEMO study, patients in the low albumin groupad significantly greater prevalence of CHD.650

owever, in studies in which the effect of inflam- i

ation (measured by CRP levels) is also ac-ounted for in multiple-regression analysis, lowerum albumin levels tend to lose predictiveower,322,422,445suggesting that inflammation maye a more powerful predictor of poor outcome.ndeed, in two recent studies of 7,719441 and5,661442 HD patients, respectively, the risk ofortality was directly associated with the neutro-

hil count. The interactions between inflamma-ion and nutritional status may be complex, asnflammation and dietary protein intake exertompeting effects on serum albumin levels.651 Inact, inflammation may cause the same changesn serum protein levels and body composition asEM, even with adequate calorie and protein

ntake. Recent studies have shown that inflamma-ory cytokines, such as TNF-� and IL-6, aressociated with protein synthesis and catabolism
n the body, and downregulate albumin synthe-

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is.652 The poor correlation documented betweenerum albumin and other nutritional parame-ers445,653 implies that non-nutritional factors ac-ually may be more important in determiningerum albumin levels than dietary intake andutritional status per se in CKD patients. Indeed,number of factors other than protein intake andutritional status may affect the serum albuminoncentration in CKD patients (Table 32). Be-ide inflammation, age and co-morbidities, suchs CVD and diabetes, have been shown to betrongly associated with serum albumin levels in

KD patients.445,654,655 Moreover, external albu-in losses, such as albuminuria and losses in

ialysate, may significantly contribute to hy-oalbuminemia in CKD.655 Finally, over-hydra-ion, which is a common feature in dialysisatients, may also contribute to low serum albu-in levels.Among a number of other available biochemi-

al nutritional indicators, prealbumin and serumreatinine may have unique validity, when re-earchers reach a more detailed mechanistic un-erstanding of their functions. Prealbumin is

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uriously misnamed, as it is not structurallyelated to albumin in any way, but is in fact thehyroxin-binding protein, transthyretin. Transthy-etin levels are more sensitive to nutritional sta-us than serum albumin levels. Both are sup-ressed when hepatic protein synthesis switcheso the production of acute-phase proteins, butransthyretin levels change more rapidly. There-ore, transthyretin represents a good index ofiver anabolic protein synthesis. However, thelinical picture is complicated, because transthy-etin is reabsorbed and/or metabolized by theroximal tubule.656 Therefore, serum levels ofransthyretin rise as kidney function declines.442

onetheless, transthyretin levels correlatetrongly with serum albumin and have beenhown to provide prognostic value independentf albumin in HD patients.657 Because serumreatinine concentration reflects muscle mass,omatic protein stores, and dietary protein in-ake, and also predicts outcome in CKD,181 it

ay be another useful marker of nutritionaltatus in CKD. However, creatinine levels arelso affected by inflammation and other factorsuch as age, sex, race, residual kidney function,ariation in creatinine metabolism, and dialysisose.441,651

Other potentially useful nutrition markers.learly, other nutritional indices are needed tossess nutritional status in CKD. Ideally, a nutri-ional marker should not only predict outcome,ut it should also be an inexpensive, reproduc-ble, and easily performed test that is not affectedy such factors as inflammation, gender, age, andystemic diseases. Unfortunately, no such idealutritional marker is available at present. Thus,he use of a broad panel of putative indicatorsay best facilitate the epidemiological and clini-

al assessment of nutritional status (Table 33).he assessment of dietary intake has been com-only used to assess nutritional status. In particu-

ar, the normalized protein catabolic rate (nPCR)as been widely used as a measure of dietaryrotein intake, assuming a state of protein bal-nce. Indeed, nPCR is much simpler to deter-ine than dietary protein intake from diet diaries

r interviews.658 However, a recent study ob-erved no relationship between mortality andither baseline or 6-month follow-up measure-
e
ments of nPCR in 7,719 U.S. adult HD pa-

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ients,441 raising doubt about the clinical useful-ess of this nutritional parameter.Several methods have been used to monitor

ean body mass in CKD, e.g., anthropometrics,reatinine kinetics, multifrequency bioimped-nce (BIA) and DEXA. Of these, DEXA seemso be the most reliable, especially if serial mea-urements are made.659 However, to the best ofur knowledge, no studies have yet evaluatedhether lean body mass (by DEXA) predictsutcomes and/or is associated with CVD. Bysing DEXA, a reliable estimation of the amountf body fat mass can also be done. However, asEXA is not widely available, other nutritional

ndicators are needed.660 Although measures suchs BIA and handgrip muscle strength (HGS) areractical and convenient, they, too, suffer fromimitations.661-663

Subjective global assessment (SGA), on thether hand, is widely available and seems to be aeliable predictor of poor outcome in both sexesTable 34).445 It is a combined subjective andbjective test of the patient’s medical history andhysical examination, including recent weightoss, dietary intake, gastrointestinal symptomsnd visual assessment of subcutaneous fat.664,665

n addition, several large prospective studiesave demonstrated that SGA is a reliable predic-or of poor outcome in dialysis patients, suggest-ng that it provides a meaningful assessment ofutritional status.441,635 Although SGA has sev-ral advantages, such as its low cost, rapid perfor-ance, and strong predictive value for mortality,

t should be appreciated that visceral proteins areot assessed and that the sensitivity, precisionnd reproducibility over time of SGA have noteen well studied. In a recent study, it was foundhat whereas SGA may not be a reliable predictorf degree of protein malnutrition (as assessed by
otal body nitrogen), it may differentiate severely n
alnourished patients from those with normalutrition.666


Studies are needed to identify the incidence ofypoalbuminemia due to visceral protein storeepletion vs. hypoalbuminemia due to chronicnflammation. Effective nutrition and medicalanagement interventions need to be identified

hat are specific for malnutrition vs. inflamma-ion vs. metabolic challenges. Studies are alsoequired to examine how long-term nutritionalntervention affects cardiovascular risk and spe-ific risk factors for accelerated atherosclerosis,uch as oxidative stress and endothelial dysfunc-ion, in CKD patients.

onclusions

Protein-energy malnutrition and wasting aretrong predictors of mortality among CKD pa-ients. Although several biochemical and anthro-ometric measurements correlate with nutri-ional status, there is not a single measurementhat provides complete and unambiguous assess-ent. While serum albumin is a robust andell-documented indicator of mortality risk inKD patients, its value as a nutritional markeras been questioned because levels are affectedy a number of non-nutritional factors. As SGAs a simple and inexpensive indicator that pre-icts outcome, this test could be useful in identi-ying malnourished CKD patients at high risk.he utility of the SGA for nutrition assessmentnd management of this patient population re-uires further verification. At present, the use ofbroad panel of nutritional indicators, such asMI, SGA, handgrip strength (or other measuref muscle mass), waist circumference, serumlbumin, and serum creatinine may be the bestpproach to provide useful information about the
utritional status in any given clinical situation.

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RISK STRATIFICATION

OVERVIEW OF RISK STRATIFICATION

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Risk stratification is the categorization of pa-ients with a special disease into risk strata thateflect the probability to develop a certain eventr an exacerbation of the disease. The categoriza-ion is based on several factors, e.g., demo-raphic variables, comorbidities, or conditionshat are already known to be associated with anncreased risk for the endpoints of interest. It is,herefore, the goal of risk stratification to identifyhose patients who have the highest risk to de-elop an endpoint. The most important task ofisk stratification is to improve the health statusy slowing or preventing complications througharly detection or appropriate intervention be-ore a fatal or nonfatal event occurs. One oppor-unity to do so is to offer the patients diseaseanagement programs.It is important to distinguish between two

ifferent kinds of stratifiers. The first kind in-ludes those conditions that can be detected andhanged by avoidance (e.g., smoking) or interven-ion (e.g., high blood pressure or hypercholester-lemia). Data from the general population showhat these changes are associated with a lowerncidence of cardiovascular events. In CKD pa-ients, data are often rare and it is necessary toxtrapolate results from the general population.n the other hand, many of these conditions are

eported to show paradoxical associations in di-lysis patients. For example, many studies showhigher BMI to be associated with a higherortality risk in CKD patients, which is com-

letely opposite to what is observed in the gen-ral population.668-672 This association is evenndependent of serum albumin, clinical assess-ent of nutritional status, and comorbid condi-

ions. Similar associations with mortality, whichre opposite to those in the general population,ere reported for cholesterol and homocys-

eine.181,562,673-677 Studies that described associa-ions opposite to what is known from the generalopulation resulted in a discussion of a so-calledeverse epidemiology in dialysis patients.678,679

n many cases, there is an explanation for thispparent paradox on further examination of theata, as was recently shown for the reversessociation between cholesterol and mortality in
ialysis patients.262 c

The second kind of risk stratifiers is that that isfixed” and cannot usually be changed. Ex-mples are age, gender, and—in particular—enetically determined conditions. Biomarkerslso belong to this category, since they cannot behanged, but they point to an already damagedardiovascular system or to a cardiovascular sys-em which is at high risk of future damage.ypical examples discussed earlier include tro-onins411,412,414,419,680 or particular genetic vari-nts of the apo(a) gene, the so-called LMW (ormall) apo(a) isoforms.603-605,613,617-619,624,630 Al-hough age, gender, or special genetic variantsre fixed stratifiers, they should be considered inny decision regarding intervention. For ex-mple, patients with adverse conditions shoulde followed more closely by noninvasive testse.g., ultrasound of the carotid arteries) and inhorter time intervals, since cardiovascularhanges often develop rapidly. If an invasive teste.g., coronary angiography) is indicated, thesedverse conditions might support its use. How-ver, at present, no randomized controlled stud-es in CKD patients are available that have inves-igated whether risk stratification by these fixedtratifiers is beneficial, when it is either followedy a “forced” structured disease managementrogram or by “routine” care.

FAMILY HISTORY AND GENETICS

ntroduction

Family history (Table 35) is a strong predictorf CVD in the general population. It remainsredictive for CVD even after correction foreasured familial risk factors such as hyperten-

ion, cholesterol, obesity and diabetes.681-685 Theamilial aggregation of genes and shared environ-ent strongly contribute to the increased fre-

uency of a positive family history. A study ofore than 120,000 families from the Healthamily Tree Study and the Family Heart Studybserved that 14% of the families that had aositive family history of CHD accounted for2% of persons with early CHD (onset beforege 55 for men and age 65 for women) and 48%f CHD at all ages. For strokes, 11% of familiesith a positive family history for stroke ac-

ounted for 86% of early strokes (before age 75)

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nd 68% of all strokes.681 Family history collec-ion is therefore a validated and inexpensive toolor family-based preventive medicine and medi-al research in the general population. However,here are no sufficiently powered studies in theKD population that have investigated the valuef this tool for risk assessment. Instead, severaltudies have examined a handful of candidateenes for CVD in dialysis patients.

iscussion

The studies on candidate genes can be strati-ed into three groups. Two groups were already

nvestigated in more than three patient cohortsnd showed, in the majority of the studies, eitherstatistically significant association with CVD

ndpoints in dialysis patients (e.g., the apo(a)ize polymorphism and the MTHFR polymor-hism) or rejected such an association (ApoEnd ACE polymorphism). The third group inves-igated candidates mostly in one cohort, and itsesults need to be confirmed by further studies.

ositive Genetic Association Studies

Apo(a) size polymorphism. There is clearvidence that the apo(a) K-IV repeat polymor-hism is associated with CVD in the generalopulation, as well as in dialysis patients [seeection on Lp(a) and apo(a) size polymorphism].n brief, almost all studies found an associationetween LMW apo(a) phenotypes and atheroscle-otic complications or total mortality (see Table0).677C3T polymorphism of the MTHFR

nzyme. A recent meta-analysis suggested thatlevated homocysteine is, at most, a modestndependent predictor of IHD and stroke in theeneral population.686 Interestingly, moderate in-reases of homocysteine are reported in subjectsho are carriers of a variant of the MTHFR gene.
hose with a C-to-T substitution at position (
77687 have a reduced enzyme activity and about0% higher homocysteine concentrations,688 es-ecially when associated with low folate in-ake.689 A meta-analysis of all case-control obser-ational studies from the general populationevealed that the TT genotype was associatedith 16% higher odds of CHD compared to

ndividuals with the CC genotype.690 Five stud-es, mostly in HD patients, investigated thisolymorphism in relation to various cardiovascu-ar endpoints (Table 36).562,565,691-693 Four of theve studies found an association with outcome innivariate and/or in multivariate analysis562,691-693

hich was not confirmed by another largetudy.565 Recently, a prospective follow-uptudy694 of earlier reported cross-sectional analy-is in 459 patients was published.562 In contrasto the earlier findings, the prospective follow-uptudy did not show an association of this muta-ion with CVD.694 Taken together, it seems thathere might exist an association between thisutation and CVD; however, the association is

ncertain (Table 36).

egative Genetic Association Studies

Apolipoprotein E polymorphism. The ApoEolymorphism is significantly associated withntermediate phenotypes (e.g., concentrations ofpoE, ApoB, total and LDL cholesterol)695 andisease endpoints (coronary or peri-heral atherosclerosis) in the general popula-ion.696,697 Only a few studies have investigatedhe ApoE polymorphism in relation to atheroscle-osis in CKD patients and reported contrastingesults.614,628,698,699 Thus, it appears that thepoE polymorphism is not helpful for atheroscle-

osis risk stratification in dialysis patients (Table7).ACE polymorphism. A common ACE gene

ariant is known, with an insertion (I) or deletion
D) of a 287-bp fragment within intron 16. The D


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llele is associated with increased ACE levelsnd the polymorphism explains about half of theariation in plasma and tissue levels of ACE. Anssociation between the DD genotype and CADn the general population is controversial.700 Inialysis patients, most studies (especially thearger ones) did not reveal an association withlinical endpoints of cardiovascular disease (Table8).691,701-707

Interesting candidates under investigation.he anti-inflammatory cytokine interleukin-10

IL-10) counteracts the cascade of inflammatoryactors leading to an acute-phase reaction.708 Annteresting observation was recently reported for

polymorphism in the promoter of the IL-10ene.709 This polymorphism, at position -1082,eads to low production of IL-10 (-1082Allele)710and the AA genotype is associated withhigher cardiovascular morbidity709 compared

o the GG genotype. This reflects the reducedbility of the -1082 AA genotype to downregu-ate inflammatory processes as compared to the1082 GG genotype.

Myeloperoxidase is an abundant enzyme inhe production of free radicals. A functionalenetic variant of this enzyme in position -463G3A) is associated with a lower myeloperoxi-ase expression and a lower prevalence of CVDn HD patients.711


The predictive value of family history of CVDhould be investigated in patients with renalisease. Further large dialysis cohorts shouldnvestigate the value of Lp(a) concentrations andpo(a) phenotypes for risk assessment. This ques-ion should especially be addressed in PD pa-ients as well as in various ethnicities. Arisingandidate genes for CVD should be investigatedn dialysis patients.

onclusions

Family history and/or genetic testing are poten-ial tools for CVD risk assessment or risk stratifi-ation, since they examine factors that cannot behanged by intervention. At the moment, insuffi-ient data are available to determine whetheramily history is as predictive for CVD in dialy-is patients as it is in the general population.

Laboratory testing for genetic factors may be
onsidered for the apo(a) K-IV repeat polymor- w
hism. This test can be done at any time, but theime of first presentation is preferred for an earlytratification. Patients with LMW apo(a) pheno-ypes are exposed to an increased risk for mortal-ty and CVD. Testing for MTHFR variants doesot add significant information to that alreadybtained by measuring homocysteine levels. Fur-her genetic testing is not indicated at the mo-ent.Patients with a positive family history and/or a

MW apo(a) phenotype may be considered highisk, and they may benefit from intensive riskactor assessment and interventional manage-ent.

MENOPAUSE

ntroduction

The mean age of women with CKD Stage 5uggests that the majority of these women areostmenopausal.17 Different patterns of abnor-alities may be seen in women with CKD before

nd after menopause. The primary hormonalefect observed in premenopausal women withKD is due to hypothalamic dysfunction. Inomen of reproductive age and normal renal

unction, a sustained midcycle increase in estra-iol causes an increase in hypothalamic secretionf gonadotropin-releasing hormone (GnRH). Thisormone then stimulates the pituitary gland toncrease leutinizing hormone (LH) secretion and,ith an increase in progesterone and estradiol,

ollicle-stimulating hormone (FSH) levels in-rease. This hormonal pattern leads to normalvulation and menstruation. In the majority ofremenopausal uremic women, the positive feed-ack mechanism of estradiol on the hypothala-us is blunted. The midcycle increase of proges-

erone, LH, and FSH is impaired, and anovulatoryenstrual patterns predominate.712-714 Estradiol

evels in uremic women are comparable to nor-al in the follicular phase, but a reduced mid-

ycle peak has been documented.713 Hyperpro-actinemia is present in approximately 70% ofomen with CKD due to reduced renal clear-

nce, increased secretion by the anterior pitu-tary, and anterior pituitary resistance due to theownregulatory effects of dopamine.715 Meno-ause occurs at a younger age among women
ith CKD; the median age of menopause is


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0-51 years in normal women and 47 yearsmong women with CKD.716

iscussion

Menopause and cardiovascular risk. In theeneral population, the risk of CVD increasesfter menopause. This is thought to be due to lossf the protective effect of estrogen on lipids andascular function. The role menopause plays inhe accelerated CVD that is characteristic ofKD is not known.

ormone Replacement Therapy

Prevalence. Although appropriate indica-ions for estrogen replacement therapy are contro-ersial, 5%-11% of women with CKD over 45ears of age are treated with hormone-replace-ent therapy (HRT).716,717 Younger, better-

ducated Caucasians are more likely to receiveRT.717 It is not known whether reports from theomen’s Health Initiative (WHI), indicating a

ack of cardioprotective effect associated withRT in healthy women, has impacted the use ofRT.Cardioprotection. There are few reports that

ave assessed the impact of HRT on cardiovascu-ar outcomes among CKD patients. In the gen-ral population, HRT is known to lower LDLholesterol and Lp(a), and increase HDL andriglycerides. The most common lipoprotein ab-ormalities in CKD include reduced HDL andlevated LDL, triglycerides, and Lp(a). Since thenly lipoprotein abnormality that has been asso-iated with CVD in dialysis patients is Lp(a), it isossible that HRT has positive cardiovascularffects in CKD patients.610

One small study in women with CKD demon-trated an increase in HDL and ApoA-I with nohange in total cholesterol, LDL, Lp(a), or trig-ycerides after 8 weeks of treatment.718 Estrogenlso modifies vascular function and atherosclero-is among women without CKD. In the generalopulation, estrogen increases stroke volume,eart rate and contractility, and reduces periph-ral vascular resistance in postmenopausalomen.719-721 Regression of atheroscleroticlaques has been shown to occur among womenollowing institution of HRT.722 Although this
ay, in part, be due to alterations in lipid metab- t
lism, estrogen also inhibits vascular smoothuscle cell proliferation in vitro, a process that

ontributes to atherogenesis.723

The use of HRT in the general population hasecome increasingly controversial. Reports fromhe WHI have documented significant reductionsn hip fracture and colorectal cancer rates amongostmenopausal women treated with HRT.724

lthough estrogens have been reported to im-rove the lipid profile by increasing high-densityipoprotein and decreasing low density lipopro-ein,725 the WHI did not find an overall benefitmong those receiving both estrogen and proges-erone.724 In addition, studies have demonstratedn increased risk of venous thrombosis amongomen who use estrogen.724,725 Patients withKD have an increased risk for pulmonary embo-

us and are at risk for vascular access thrombosis.he association between HRT and venous throm-osis, particularly vascular access thrombosis,mong women with CKD remains unstudied.

Dosing. Previous reports have suggested thatenal failure may alter the pharmacokinetics ofstrogen, and that dose adjustments are neces-ary in patients with CKD. One study reportedhat, after a single dose of estradiol, serum con-entrations of estradiol and estrone were 2-3imes that of the controls,726 while another re-orted that urinary excretion of estradiol in menith normal renal function was 78%-83% over 4ays compared to 1.4% in men with CKD.727

ther potential risks of estrogen, such as breastancer, coagulopathy, or CAD, may be dose-ependent. A recent study found that estradiolerum concentrations among post-menopausalomen with CKD requiring maintenance HDere over 20% greater than those among womenith normal renal function, in spite of reducing

he dose of �-estradiol by 50%. These datauggest that women with CKD should receive a0%-70% lower dose of �-estradiol to achievequivalent concentrations. Measurement of estra-iol levels (and possibly FSH levels) may be ofalue in selected postmenopausal women withKD receiving HRT. It is likely that any benefitould be relative to the blood concentration andot the actual dose, and there may be potentialarm in having excessively high blood concentra-
ions.

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Little is known regarding cardiovascular out-omes associated with menopause. Observa-ional studies should assess the impact of meno-ause on CVD risk. Given that there are over0,000 women with CKD treated with HRT,tudies should assess if the use of HRT is associ-ted with improved CVD outcomes.

onclusions

Given the lack of data from the CKD popula-ion, it may be prudent to follow the recentlyublished guidelines from North American Meno-ause Society, which state that the treatment ofenopause symptoms remains the primary indi-

ation for HRT, and that HRT not be used solelyor primary or secondary prevention of CHD.728

or those women with CKD on HRT, doses ofstrogen replacement that are 50%-70% lowerhan those among women with normal renalunction would have an equivalent effect.

REVENTIVE FOOT CARE IN DIABETES

ntroduction

In 1994, the annualized rate of amputationmong Medicare diabetic and nondiabetic pa-ients on dialysis was 11.8 and 2.3 per 100espectively.144 Compared to dialysis patientsith glomerulonephritis as the cause of kidney

ailure, diabetic dialysis patients had 8.9-foldigher odds of undergoing amputation.144 The0-day perioperative mortality in dialysis pa-ients who underwent amputation was 16%.729

hus, there is an exceedingly high risk of ampu-ation in diabetic dialysis patients, with its atten-ant loss of quality of life and high perioperativeortality. Hence, it is imperative to implementeasures to decrease the amputation rates in

iabetic dialysis patients. Adoption of preventiveare of the diabetic foot has been outlined in themerican Diabetic Association (ADA) Positiontatement,730 and these recommendations, withertain modifications, may be applied to CKDatients.

iscussion

Several clinical studies in the nondialysis dia-etic population have shown that coordinatedrograms to screen for high-risk feet and to
rovide regular foot care decreased lower extrem- t
ty amputation rates.731,732 In a controlled study,5 HD patients were assigned to intensive educa-ion and care management that included preven-ive foot care and 38 HD patients were assignedo usual care.733 Over the 12-month follow-uperiod, there were no amputations in the studyroup while there were five lower extremitymputations and two finger amputations in theontrol group.


The ADA Position Statement has discussedeveral measures that can be implemented forreventive foot care in diabetic patients.730 Footxamination at the initiation of dialysis is likelyo reveal high-risk foot conditions, such as periph-ral neuropathy, altered biomechanics, PVD, ul-ers, and severe nail pathology. Identification ofny of these risk factors may necessitate furtheregular examinations. Minor conditions may bereatable to prevent complications; however, otheronditions (e.g., increased plantar pressure) mayequire referral to a foot-care specialist.

A major issue will be raising the awareness ofreventive foot care in diabetic dialysis patients,nd patient education in preventive foot careeasures is desirable as part of routine care.ducation of dialysis health-care professionals islso important.


Long-term studies are warranted to examinehe effectiveness of screening with ABI, andarly diagnosis of PVD, on reducing the develop-ent of critical limb ischemia and the rates of

mputation. Randomized, controlled trials areeeded to study the effects of antiplatelet agentsnd statins in asymptomatic and symptomaticVD on the development of critical limb isch-mia and the rates of amputation.

onclusions

There are no randomized controlled trials ofntensive education and care management versussual care of feet in diabetic dialysis patients.onetheless, diabetic dialysis patients are likely

o benefit from examination of the foot as part ofhe routine dialysis care. In this regard, recom-endations made by the ADA are applicable to

he care of diabetic dialysis patients.

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ASPIRIN

ntroduction

There are no randomized controlled trials inialysis patients that establish the safety andfficacy of aspirin for primary or secondaryrevention of atherosclerotic events. However,ince CKD patients are among the highest-riskroups for atherosclerotic events, it might beeasonable to use aspirin in dialysis patientsithout contraindications for aspirin therapy.

iscussion

There are no data on use of aspirin in primaryrevention of CVD in dialysis patients. In anbservational study of 3,374 incident dialysisatients with and without CAD in the USRDSialysis Morbidity Mortality Study Wave II,atients on aspirin had 2.9-fold higher hazard ofcute coronary syndrome in unadjusted analy-is.734 However, this result was nonsignificant inultivariate analysis. Even though this study

sed Medicare data to track acute coronary syn-romes, not all of the study patients were onedicare.In an analysis of the Cooperative Cardiovascu-

ar Project, dialysis patients who received aspirinollowing MI had 43% lower odds of dyingithin 30 days in a multivariate analysis.735

nother observational retrospective study found t

hat the use of aspirin and beta-blockers follow-ng MI was associated with lower mortality inatients with CKD.61 Thus, there are reasonableata to support the use of aspirin following MI.The major risk of aspirin therapy is gastrointes-

inal (GI) bleeding. A randomized controlled trialf aspirin plus clopidrogel versus placebo torevent AV graft thrombosis was terminated earlyecause of GI bleeding.66 However, a retrospec-ive observational study of USRDS data did notnd increased risk of GI bleeding with aspi-in.736


Randomized controlled trials of aspirin asprimary or secondary prophylaxis in prevent-ing cardiovascular events with attention to GIbleeding are warranted.The cost-effectiveness of aspirin (risk of GIbleeding versus reduction in cardiovascularevents) needs to be studied.

onclusions

Aspirin may be useful for primary preventionf atherosclerotic disease in dialysis patients,ith careful monitoring for bleeding complica-

ions. Its use following MI is warranted, based onhe available evidence. Further large, prospec-ive, observational studies and randomized con-
rolled trials are required.

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METHODS FOR REVIEW OF ARTICLES

AIMS

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The overall aim of the project was to developlinical practice guidelines for the evaluation andanagement of CVD in CKD patients who re-

uire either HD or PD.The Work Group sought to develop the guide-

ines using an evidence-based approach. Evi-ence regarding the guideline topics was derivedrom a systematic summary of the availablecientific literature on the epidemiology of CVDmong dialysis patients, the evaluation and man-gement of cardiac, cerebrovascular, and periph-ral vascular disease among dialysis patients, thevaluation and management of specific risk fac-ors for CVD among dialysis patients, and cardio-ascular risk stratification among dialysis pa-ients.

OVERVIEW OF PROCESSDevelopment of the guideline and evidence

eport required many concurrent steps to:

Form the Work Group and Evidence ReviewTeam that were to be responsible for differentaspects of the processHold meetings to discuss processes, methods,and resultsDevelop and refine topicsDefine population of interestCreate draft guideline statements and ration-alesCreate draft summary tablesCreate data extraction formsCreate and standardize quality assessment andapplicability metricsDevelop literature search strategiesPerform literature searchesScreen abstracts and retrieve full articlesReview literatureExtract data and perform critical appraisal ofthe literatureGrade the evidenceTabulate data from articles into summarytablesGrade the strength of the recommendationsWrite guideline statements and rationales basedon literature.

reation of Groups

The Co-Chairs of the K/DOQI Advisory Board
elected the Work Group Co-Chairs and Director r

f the Evidence Review Team, who then as-embled groups to be responsible for the develop-ent of the guidelines and the evidence report,

espectively. These groups collaborated closelyhroughout the project.

The Work Group consisted of “domain ex-erts,” including individuals with expertise inephrology, epidemiology, cardiology, nutrition,ocial work, pediatrics, and internal medicine. Inddition, the Work Group had a liaison memberrom the Renal Physicians Association. The firstask of the Work Group members was to definehe overall topic and goals, including specifyinghe target condition, target population, and targetudience. They then further developed and re-ned each topic, literature search strategy, andata extraction form (described below). The Workroup members were the principal reviewers of

he literature, and from these detailed reviews,hey summarized the available evidence and tookhe primary roles of writing the guidelines andationale statements.

The Evidence Review Team consisted of neph-ologists (two senior nephrologists and a nephrol-gy fellow) and methodologists from Tufts-Newngland Medical Center with expertise in system-tic review of the medical literature. They wereesponsible for coordinating the project, includ-ng coordination of meetings, refinement of goalsnd topics, creation of the format of the evidenceeport, development of literature search strate-ies, initial review and assessment of literature,nd coordination of all partners. The Evidenceeview Team also coordinated the methodologi-al and analytical process of the report, coordi-ated the meetings, and defined and standardizedhe methodology of performing literatureearches, of data extraction and of summarizinghe evidence in the report. They performed litera-ure searches, retrieved and screened abstractsnd articles, created forms to extract relevantata from articles, and tabulated results. Through-ut the project, and especially at meetings, thevidence Review Team led discussions on sys-

ematic review, literature searches, data extrac-ion, assessment of quality and applicability ofrticles and the body of evidence, and summary
eporting.
), 2005: pp S115-S120 S115

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evelopment of Topics

The goals of the Work Group targeted a di-erse group range of topics, which would haveeen too large for a comprehensive review of theiterature. Based on their expertise, members ofhe Work Group focused on the specific ques-ions, and employed a selective review of evi-ence: a summary of reviews for establishedoncepts (review of textbooks, reviews, guide-ines and selected original articles familiar tohem as domain experts); and a review of pri-ary articles and data for new concepts.

efinement of Topics and Developmentf Materials

The Work Group and Evidence Review Teameveloped a) draft guideline statements; b) draftationale statements that summarized the ex-ected pertinent evidence; and c) data extractionorms requesting the data elements to be re-rieved from the primary articles. The topic refine-

ent process began prior to literature retrievalnd continued through the process of reviewingndividual articles.

Data extraction forms were designed to cap-ure information on various aspects of the pri-ary articles. Forms for all topics included study

etting and demographics, eligibility criteria,auses of kidney disease, numbers of subjects,tudy design, study funding source, dialysis char-cteristics, comorbid conditions, descriptions ofelevant risk factors and cardiovascular out-omes, statistical methods, results, study qualitybased on criteria appropriate for each studyesign, see below), study applicability (see be-ow), and sections for comments and assessmentf biases.Training of the Work Group members to ex-

ract data from primary articles occurred at meet-ngs, and subsequently by e-mail and duringeleconferences.

iterature Search

The Work Group and Evidence Review Teamecided in advance that a systematic processould be followed to obtain information on

opics that relied on primary articles. Only fullournal articles of original data were included.ditorials, letters and abstracts were not in-luded. Selected review articles were included
or background material. Though reports of for- u
al studies were preferred, case series were alsoncluded. No systematic process was followed tobtain textbooks and review articles.Studies for the literature review were identi-

ed through MEDLINE searches of English lan-uage literature conducted between March andctober 2002. These searches were supple-ented by relevant articles known to the domain

xperts and reviewers through December 2003.The MEDLINE literature searches were con-

ucted to identify clinical studies published from966 through the search dates. The primary searchas designed to capture studies pertaining to all

opics. Supplemental searches were made toaximize retrieval of studies pertaining to spe-

ific topics, including: anxiety and hostility,arnitine, diet, hormone replacement therapy,ediatrics, and peripheral vascular disease. Devel-pment of the search strategies was an iterativerocess that included input from all members ofhe Work Group. The text words or MeSH head-ngs for all topics included “renal replacementherapy,” end-stage renal disease and relatederms. The searches were limited to studies onumans and published in English, and focusedn either adults or children, as relevant.MEDLINE search results were screened byembers of the Evidence Review Team. Poten-

ial papers for retrieval were identified fromrinted abstracts and titles, based on study popu-ation, relevance to topics, and study size. Fortudies of risk factors and treatments, those withewer than 10 subjects were excluded; for epide-iology studies, those with fewer than 30 sub-

ects were excluded. Studies of risk factors hado evaluate a cardiovascular outcome to be in-luded. Studies of risk factor or cardiovascularreatments, including surgery, had to be compara-ive; thus single-cohort case series were ex-luded. After retrieval, each paper was read toerify relevance and appropriateness for review,ased primarily on study design and ascertain-ent of necessary variables. Some articles were

elevant for two or more topics. Domain expertsade the final decision for inclusion or exclusion

f articles. All articles included were extractednd are contained in the summary tables. Numer-us additional articles that did not meet thepecific criteria necessary to qualify for inclusionere reviewed, with or without extraction, for
se as background material.

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In an iterative process, the topics for whichrticles would be analyzed in depth and summa-ized were restricted to those topics that had noteen sufficiently summarized previously by other/DOQI Work Groups or others and provided

vidence for the specific guidelines. For mostopics, given the small number of available stud-es, all comparative studies with at least 10ialysis patients per arm were included. Forertain topics with relatively large numbers oftudies, stricter criteria were used. For studies oferum calcium, phosphorus, and PTH as predic-ors of CVD, only studies that reported that theyere sufficiently powered for these predictorsere included. Studies that evaluated tobaccose as a risk factor for CVD had to both definemoking use categories a priori and have ainimum of 100 subjects. Studies of both Lp(a)

nd genetic markers were required to have ateast 10 subjects with CVD outcomes. For predic-ors with sufficient numbers of studies, onlyssociations with CVD event outcomes werencluded. These included: C-reactive protein, ran-om serum troponin levels, smoking, echocardio-ram measurements, and surgical interventionsor coronary artery disease. Intermediate out-omes, including vascular calcification, intima-edia thickness, and ventricular arrhythmia were

ncluded for other predictors analyzed. For cer-ain predictors, studies were also included thateported prevalent (as opposed to future) CVD.hese included genetic markers and ankle-armrachial index.Overall, 16,691 citations were screened (9,078

rom the primary search; 7,613 from supplemen-al searches), from which 396 articles were re-rieved and reviewed. An additional 151 articles,dded by Work Group members and domainxperts, were reviewed. Of these, a total of 86rticles met sufficient criteria to be included inummary tables.

ormat for Evidence Tables

Two types of evidence tables were prepared.etailed tables contain data from each field of

he components of the data extraction forms.hese tables were used to efficiently track and

ransmit data about all extracted studies. Theyere completed by the Evidence Review Team

rom extraction forms filled out by Work Group
embers. They were then given to the Work

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roup members, but are not included in theeport.

Summary tables describe the strength of evi-ence according to four dimensions: study sizeof both HD and PD patients) and duration, studypplicability, results and methodological quality.ithin each table, the studies are first grouped by

utcome type. Outcomes are ordered by all-ause death, CVD death, and CVD events. Stud-es with intermediate and prevalent outcomes arehaded at the bottom of the tables. Within eachutcome, studies are ordered first by methodologi-al quality (best to worst), then by applicabilitymost to least) and then by study size (largest tomallest). When relevant, outcome thresholdse.g., of troponin I levels) or definitions of predic-ors (for genetic predictors) are included. Resultsre presented using summary symbols, as de-ned below. An example of an evidence table ishown in Table 39.

Study size and duration. The study (sample)ize is used as a measure of the weight of thevidence. In general, large studies provide morerecise estimates of prevalence and associations.n addition, large studies are more likely to beeneralizable; however, large size alone does notuarantee applicability. A study that enrolled aarge number of selected patients may be lesseneralizable than several smaller studies thatncluded a broad spectrum of patient popula-ions. Similarly, longer duration studies may bef better quality and more applicable, dependingn other factors.Applicability. Applicability (also known as

eneralizability or external validity) addresseshe issue of whether the study population isufficiently broad so that the results can be gener-lized to the population of interest at large. Thetudy population is typically defined primarilyy the inclusion and exclusion criteria. The tar-et population was defined to include patientsith end stage renal disease (primarily those onialysis). A designation for applicability wasssigned to each article, according to a three-evel scale. In making this assessment, sociode-ographic characteristics were considered, asere the stated causes of chronic kidney disease,

nd prior treatments. Applicability referred toither the HD population or the PD population,
s appropriate. a
Sample is representative of the targetpopulation, or results are definitely applicable todialysis population irrespective of study sample.Sample is representative of a relevant sub-groupof the target population. For example, sample isonly representative of people with a narrowrange of GFR, or only a specific relevantsubgroup, such as elderly individuals or patientswith diabetic kidney disease.Sample is representative of a narrow subgroupof patients only, and not well generalizable toother subgroups. For example, the studyincludes only patients with a rare disease.Studies of such narrow subgroups may beextremely valuable for demonstrating“exceptions to the rule.”

Results. In general, the result is summarizedy both the direction and strength of the associa-ion. Depending on the study type, the resultsay refer either to dichotomous outcomes, such

s the presence of a specific genotype or aaboratory test above or below a threshold value,r to the association of continuous variables withutcomes, such as serum laboratory tests. Theagnitude of the association and both the clini-

al and statistical significance of the associationsere considered. Criteria for indicating the pres-

nce of an association varied among predictorsepending on their clinical significance. Bothnivariate and multivariate associations are pre-ented. Associations are generally representedccording to the following symbols:

Positive association (positive predictor predictsa clinically meaningful increase in CVD orworsening of intermediate CVD outcome)No association (predictor is not associated withCVD outcomes)Negative association (positive predictor predictsa decrease in CVD outcomes)Statistically significant association (generally P� 0.05)

For studies of troponin I and T, sensitivity andpecificity data are included when reported. Forlarity, the results for studies of surgical interven-ions for coronary artery disease are presented asABG, Stent, or Tissue to indicate studies forhich the intervention had significantly betterutcomes, or CABG for studies where there wastrend toward better outcomes with coronary

rtery bypass graft.

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Quality. Methodological quality (or internalalidity) refers to the design, conduct, and report-ng of the clinical study. Because studies with aariety of types of design were evaluated, a three-evel classification of study quality was devised:

Least bias; results are valid. A study that mostlyadheres to the commonly held concepts of highquality, including the following: a formal study;clear description of the population and setting;clear description of an appropriate referencestandard; proper measurement techniques;appropriate statistical and analytic methods; noreporting errors; and no obvious bias. Notretrospective studies or case series.Susceptible to some bias, but not sufficient toinvalidate the results. A study that does notmeet all the criteria in category above. It hassome deficiencies but none likely to causemajor bias.Significant bias that may invalidate the results.A study with serious errors in design orreporting. These studies may have largeamounts of missing information ordiscrepancies in reporting.

ummarizing Reviews and Selectedriginal Articles

Work Group members had wide latitude inummarizing reviews and selected original ar-icles for topics that were determined not toequire a systemic review of the literature.

ranslation of Evidence to Guidelines

Format. This document contains 14 guide-ines. The format for each guideline is outlined inable 40. Each guideline contains one or morepecific “guideline statements,” which are pre-ented as “bullets” that represent recommendationso the target audience. Each guideline containsackground information, which is generally suffi-ient to interpret the guideline. A discussion of theroad concepts that frame the guidelines is pro-ided in the preceding section of this report. Theationale for each guideline contains a discussion ofpecific topics that support the guideline state-ents, together with a classification of the strength

f evidence. The guideline concludes with a discus-ion of limitations of the evidence review and arief discussion of implementation issues and re-earch recommendations regarding the topic.

Strength of evidence. The overall guideline
s, in general, graded according to the strength of c
vidence supporting the individual topics ad-ressed by the guideline statements. Strength ofvidence was assessed by assigning either “A,”B,” or “C” (Table 41). An “A” rating indicatesit is strongly recommended that clinicians rou-inely follow the guideline for eligible patients.here is strong evidence that the practice im-roves health outcomes, and benefits substan-ially outweigh harms.” The “B” rating indicatesit is recommended that clinicians routinely fol-ow the guideline for eligible patients. There isoderate evidence that the practice improves

ealth outcomes.” A “C” rating indicates “it isecommended that clinicians consider followinghe guideline for eligible patients. This recom-endation is based on either weak evidence, or

n the opinions of the Work Group and review-rs, that the practice might improve healthutcomes.”The strength of evidence was graded using a

ating system that takes into account: 1) method-logical quality of the studies; 2) whether or not thetudy was carried out in the target population, i.e.,atients with CKD on dialysis, or in other popula-ions; and 3) whether the studies examined healthutcomes directly, or examined surrogate measuresor those outcomes, e.g., valve calcification insteadf CVD death (Table 42). These three separatetudy characteristics were combined in rating thetrength of a body of evidence provided by the
omposite of the pertinent studies.

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WORK GROUP BIOGRAPHIESS120

In addition, the Work Group adopted a conven-ion for using existing expert guidelines issuedor populations other than the target population.rades assigned by the guideline-issuing bodies

or the strength of evidence were adopted. Whenhe guideline or the evidence was not graded, this

ork Group assumed that the guideline woulde based on at least moderately strong evidence.he extrapolation of ungraded guideline recom-endations from the general populations to the

arget population was considered to support graderecommendations.

imitations of Approach

While the literature searches were intended toe comprehensive, they were not exhaustive.EDLINE was the only database searched, and

earches were limited to English language publi-ations. Hand searches of journals were not per-ormed, and review articles and textbook chap-

ers were not systematically searched. However,mportant studies known to the domain expertshat were missed by the literature search werencluded in the review.

Exhaustive literature searches were hamperedy limitations in available time and resourceshat were judged appropriate for the task. Theensitive search strategies required to capturevery article that may have had data on each ofhe questions frequently yielded upwards of0,000 articles. Given the large number of top-cs, this approach was not feasible. The difficultyf finding all potentially relevant studies wasompounded by the fact that in many studies, thenformation of interest for this report was aecondary finding for the original studies. Wesed our best judgment in developing searchtrategies to balance the yield of potentiallyseful articles and feasibility.

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WORK GROUP BIOGRAPHIES

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Kline Bolton, MD, FACP, is Professor ofedicine at University of Virginia in Charlottes-

ille, where he is Chief of the Division of Ne-hrology and Director of the Nephrology Clini-al Research Center, Kidney Center and Renalperations. He has received special honors fromrganizations ranging from the American Soci-ty for Clinical Investigation to the Internationalociety of Nephrology. He has published manyrticles in journals ranging from American Jour-al of Kidney Diseases and Kidney Internationalo Immunologic Renal Diseases, and contributedo numerous textbooks, including the Textbook ofhe Autoimmune Diseases and the Textbook ofephrology. Dr. Bolton is Chairman of the Renalhysicians Association Work Group on Appropri-te Preparation of Patients for Renal Replace-ent Therapy. In addition, Dr. Bolton serves on

he Advisory Boards for Amgen and Ortho-iotech. His research interests are in refining thepitope(s) involved in causing Goodpasture’syndrome, treating glomerulonephritis, and dis-ase management of CKD and ESRD.

Srinivasan Beddhu, MD, is Assistant Profes-or of Medicine at the University of Utah andirector, End-Stage Renal Disease Program, Saltake VA Healthcare System, Salt Lake City, UT.e received his medical degree from Madrasniversity, Madras, India and completed his ne-hrology fellowship at the University of Pitts-urgh, Pittsburgh, PA. His major area of researchnterest is atherosclerosis, inflammation and nu-rition in chronic kidney disease. He has pub-ished several peer-reviewed articles in this arean journals such as the Journal of Americanociety of Nephrology, Kidney International,merican Journal of Medicine and Americanournal of Kidney Disease. He has receivedunding from several sources including thegency for Healthcare Research and Quality

AHRQ). He has been a reviewer for many ne-hrology journals and reviewed abstracts for themerican Society of Nephrology meetings. He

s a member of the American Society of Nephrol-gy, National Kidney Foundation, and Interna-ional Society of Nephrology.

Vito M. Campese, MD, is Professor of Medi-ine, Physiology and Biophysics at the Keckchool of Medicine, University of Southern Cali-
ornia in Los Angeles, where he is Chief of the c

ivision of Nephrology and Hypertension Cen-er. Dr. Campese received his M.D. from theniversity of Bari in Italy. In 1974 he came to

he United States via the University of Southernalifornia for a fellowship in hypertension andas subsequently promoted to full Professor ofedicine with tenure in 1985. His main research

nterests are neurogenic factors in renal hyperten-ion and salt-sensitivity in hypertension. He ishe author or co-author of more than 235 scien-ific publications. Dr. Campese has been active inany professional societies, including the Na-

ional Kidney Foundation, the American Societyf Nephrology, and the American Society ofypertension. He is a member of the Leadershipommittee of the Council for High Blood Pres-

ure. He has served or is serving on the editorialoard of several renal and hypertension journals.Blanche M. Chavers, MD, is Professor of

ediatrics at the University of Minnesota. She ismember of the American Society of Nephrol-

gy, the American Society of Pediatric Nephrol-gy, the American Society of Transplantation,he International Society of Nephrology, and thenternational Society of Pediatric Nephrology.r. Chavers is Deputy Director of the Cardiovas-

ular Special Studies Center at the United Statesenal Data System, NIH. Dr. Chavers is on theublic Policy Committee of the American Soci-ty of Pediatric Nephrology, she is the Americanociety of Nephrology’s representative to UNOS,nd she is a member of the American Society ofransplantation’s Kidney and Pancreas Trans-lant Committee. Dr. Chavers is Co-editor of themerican Journal of Kidney Diseases. She haseen published numerous times in a variety ofournals and books. Her areas of research andpecial interest include cardiovascular disease inhildren with kidney disease, pediatric kidneyransplant outcomes, and diabetic nephropathy.r. Chavers has received grants from the Depart-ent of Health and Human Services for theational Health and Nutrition Survey IV

NHANES) and the United States Renal Dataystem.Alfred K. Cheung, MD, is a Professor ofedicine in the Division of Nephrology & Hyper-

ension and the Executive Director of the Dialy-is Program at the University of Utah. He re-
eived his Nephrology fellowship training at the
), 2005: pp S121-S126 S121

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niversity of California, San Diego, under theesearch mentorship of Dr. Lee Henderson. Hisesearch interest has focused on chronic kidneyisease and HD. In addition to serving as aember of the editorial board of several jour-

als, he has served as an Associate Editor of theour editions of the National Kidney Foundationrimer on Kidney Diseases, and the Journal ofmerican Society of Nephrology. Dr. Cheung is

he principle investigator of grants from theational Institutes of Health and the Departmentf Veterans Affairs for the study of novel strate-ies to prevent vascular access stenosis. He islso the Chair of the Kidney Disease Researchonsortium, which was formed in 2003 for theurpose of performing multicenter studies re-ated to chronic kidney disease and dialysis. Inhe last 15 years, he has served on a number ofommittees in the National Kidney Foundationnd the American Society of Nephrology, andas lectured frequently in national meetings ofhose organizations. He is currently the Chair ofhe D-Subcommittee in the National Institute ofiabetes and Digestive and Kidney Diseases forrant reviews. Dr. Cheung has co-authored over00 papers and book chapters. He is activelynvolved in the care of patients with chronicidney disease and the training of fellows forlinical nephrology and research.

David N. Churchill MSc, MD, FRCPC,ACP, is Professor of Medicine in the Faculty ofealth Sciences at McMaster University, Hamil-

on, Ontario. He was the Director of the Divisionf Nephrology from 1989-1999. Currently, heas a cross-appointment in the Department oflinical Epidemiology and Biostatistics at Mc-aster University. He has been a member of the

cientific Advisory Board of the Kidney Founda-ion of Canada for 3 terms since 1987 and theational Kidney Foundation Research Reviewommittee since 2002. From 1995-1998, he washair of the ISPD Committee on Internationaltudies. Dr. Churchill was the Vice-Chair of theriginal DOQI Peritoneal Dialysis Work Groupnd is currently a member of the KDOQI Advi-ory Board. He was also the Chair for the Cana-ian Society of Nephrology Committee on Clini-al Practice Guidelines from 2000-2003. He is anssociate Editor for the Journal of the Americanociety of Nephrology and is a member of the
ditorial Boards for Nephrology, Dialysis and M
ransplantation; Peritoneal Dialysis Interna-ional and the Hong Kong Journal of Nephrol-gy. Dr. Churchill’s research interests includedequacy of dialysis (Co-Principal Investigatoror the CANUSA group), anemia of renal dis-ase, quality of life in ESRD, vascular access andconomic analysis. He has 140 peer-reviewedublications and 9 book chapters. He is the Chairf the Amgen Canada Scientific Advisory Boardnd has received research funding from Amgen.e has also been a consultant for Genzymeorporation.Jordi Goldstein-Fuchs, DSc, RD, is Clinical

ssistant Professor at the University of Nevadachool of Medicine, Department of Internaledicine and is completing a second term as

ditor-in-Chief of the Journal of Renal Nutri-ion. She also works with DaVita, Inc. as aesearcher and clinical dietitian in Reno, NV. Dr.oldstein first became interested in kidney dis-

ase while studying for her Master’s degree athe MGH Institute of Health Professions. Heresearch thesis was in the area of urea kineticodeling. The resulting publication was awarded

he Mary P. Huddleson Award by the Americanietetic Association. After working as a renalietitian for several years, Dr. Goldstein returnedo graduate school and received her Doctor ofcience degree in Nutritional Sciences from Bos-

on University. Her doctorate work was in therea of essential fatty acids and experimentalidney disease. She is the author or co-author ofver 25 scientific publications and book chap-ers. Dr. Goldstein is now participating in re-earch in chronic kidney disease and energyxpenditure, and essential fatty acids with theomprehensive Dialysis Study. She is the recipi-nt of the 2003 Service Award from the Nationalidney Foundation Council on Renal Nutrition.he is a member of several nutrition and kidneyocieties including the International Society ofenal Nutrition & Metabolism, the Council onenal Nutrition of the National Kidney Founda-

ion, and the American Dietetic Association. Dr.oldstein is a reviewer for several nutrition andephrology journals.Charles A. Herzog, MD, is Director of the

ardiovascular Studies Center, United States Re-al Data System. He has been a cardiologist atennepin County Medical Center (HCMC) in
inneapolis and a University of Minnesota fac-

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WORK GROUP BIOGRAPHIES S123

lty member for 20 years; he recently becamerofessor of Medicine at the University of Min-esota. Since 1985 he has been the cardiologyonsultant to the ESRD program at HCMC (dialy-is and renal transplantation). He founded therogram in interventional cardiology and serveds the director of the cardiac catheterizationaboratory at HCMC from 1985 to 1991. Since997 he has been the director of the cardiacltrasound laboratory at HCMC. Dr. Herzog is aellow of the American College of Cardiology.is areas of research or special interest include

ardiac disease and ESRD and echocardiogra-hy. Dr. Herzog has received research supportrom Amgen, Astra-Zeneca, Medtronic, and theational Institutes of Health (NIDDK). He haseen a consultant for Amgen, Bayer Ag (Chair-an, Critical Event Committee, CHORUS trial),amtel Medical (Minntech), Ortho-Biotech/

ohnson & Johnson (Critical Event Committee,HOIR trial), Guidant, and NIH (memberSMB, FAVORIT trial). He has received lectureonoraria from Bayer, Ortho-Biotech/Johnson &ohnson, and First Nuclear. He recently wasppointed trustee of the Roche Foundation fornemia Research (ROFAR).William Henrich, MD, is the Theodore E.oodward Professor and Chairman of Medicine

t the University of Maryland School of Medi-ine. He also serves as Physician-in-Chief of theniversity of Maryland Medical Center. Dr. Hen-

ich joined the Department as Chairman in Feb-uary of 1999. A nephrologist with special inter-sts in end stage renal disease and analgesic-elated renal disease, he received his M.D. fromhe Baylor College of Medicine in Houston,exas. He then served his internship and resi-ency in medicine at the University of Oregonedical School Hospitals and Clinics, and fellow-

hip in renal diseases at the University of Colo-ado Medical School. He is the author or co-uthor of over 200 scientific publications. He islso the editor of the popular dialysis textbookhe Principles and Practice of Dialysis, justeleased in its third edition. Dr. Henrich hasaintained an active investigative interest in

eart disease in dialysis patients, hemodynamictability during dialysis, analgesic nephropathynd the intrarenal renin-angiotensin system. Heurrently leads a NIH-sponsored multicenter
tudy of the effect of analgesics on the kidney o
nd has a leadership role as Co-Chair in a NIHulticenter trial on renal artery stenosis. Over

he years he has been active in many professionalocieties including the American Society of Ne-hrology and National Kidney Foundation, ande is the recipient of the President’s and Distin-uished Service Awards from the National Kid-ey Foundation. Dr. Henrich is an elected coun-ilor of the American Society of Nephrology ands slated to serve as President of the Society in006-2007. He is a member of several presti-ious scientific societies including the Associa-ion of American Physicians, American Societyf Clinical Investigation, the International Soci-ty of Nephrology, and the American Clinicalnd Climatological Association. Dr. Henrich is aeviewer and editorial board member for severalenal and internal medicine journals.

Karren King, MSW, ACSW, LCSW, is aidney disease social work consultant. She serveds president of the National Kidney Foundation’sNKF) Council of Nephrology Social WorkersCNSW). She also served on the NKF Executiveommittee and Board of Directors, as Chair of

he NKF Patient Services Committee and onumerous other NKF committees both nationallynd within the NKF affiliate. She was a memberf the NKF’s Dialysis Outcomes Quality Initia-ive, HD Adequacy Work Group, as well as theenal Physicians Association / American Soci-ty of Nephrology Workgroup that developed thelinical Practice Guideline on Shared Decisionaking in the Appropriate Initiation of and With-

rawal from Dialysis. She is a past member ofhe Life Options Rehabilitation Advisory Coun-il, the Missouri Kidney Program Advisory Coun-il and the Robert Wood Johnson Foundation,romoting Excellence in End-of-Life Care, Endtage Renal Disease Peer Workgroup. She cur-ently serves on the Executive Committee andoard of Directors of the Center for Practicalioethics. She was also appointed by Secretaryonna Shalala to serve as a member of theecretary of Health and Human Services Advi-ory Committee on Xenotransplantation. She ishe editor of the NKF’s Family Focus patientewspaper. She also served on the editorial boardf Geriatric Nephrology and Urology and was anssociate Editor of Advances in Renal Replace-ent Therapy. Ms. King is co-author of a chapter
n kidney disease in the Encyclopedia of Disabil-

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ty and Rehabilitation. She has also published 19apers and made over 60 presentations, bothationally and internationally, on the psychologi-al and social aspects of kidney disease. She haseen the recipient of the National CNSW Meritward and its President’s Award, the NationalKF’s Distinguished Service Award, the Chair-an’s Award and the Martin Wagner Memorialward, and was the first recipient of the Univer-ity of Missouri School of Social Work Outstand-ng Alumni Award.

Florian Kronenberg, MD, is Professor ofenetic Epidemiology in the Department ofedical Genetics, Molecular and Clinical Phar-acology at the Innsbruck Medical University,ustria. He is Head of the Division of Geneticpidemiology as well as of the Genotyping Unitf the “Gene Discovery Core Facility.” Dr. Kro-enberg received his M.D. from the Universityf Innsbruck, Austria. After specializing in Medi-al Biology and Human Genetics he joined theniversity of Utah, Salt Lake City for a two-year

esearch stay. He then headed the research unitGenetic Epidemiology” at the Institute of Epide-iology at the GSF (National Research Center

or Environment and Health, Munich, Germany)or two years. Recently he became Full Professort the Innsbruck Medical University. Dr. Kronen-erg served as principal investigator in severaltudies on genetic risk factors for atherosclerosisnd disturbances in lipid metabolism especiallyn high-risk populations such as patients withidney diseases or patients with peripheral arte-ial disease. He contributed several publicationsn the association of lipoprotein(a), the apoli-oprotein(a) phenotype as well as lipoproteinsot only in kidney patients but also in the generalopulation. He has published about 75 peer-eviewed articles, and about 20 reviews and bookhapters. Besides other awards he has been theecipient of the Bernd-Tersteegen Award of theerman Dialysis Society as well as the Knollilliam Harvey Prize. Dr. Kronenberg is on the

ditorial Board of the Journal of Renal Nutritionnd Experimental Gerontology and Current Wom-n’s Health Review.

B. Sandra Miholics, RN, CNN, is an Indepen-ent Nephrology Nurse Consultant for Nephrol-gy Outsourcing, providing Clinical Support Ser-ices to the nephrology community. Sandy
eceived her nursing diploma from Charles E. S
regory School of Nursing, Perth Amboy, NJ.he has been in nephrology since 1967 and haserved in most HD roles. She is an acute careialysis nurse at Robert Wood Johnson Univer-ity Hospital. She was Research and Vascularccess Coordinator at Dialysis Clinics Inc. inorth Brunswick, NJ, coordinating clinical trials

or the Vasca Lifesite Device, a new antibiotic,efazolin dosing in HD and a new method for

insing dialyzers. She co-authored several ar-icles on vascular access. In 1999, she wrote anbstract and did a survey on practice variationsf heparinization for HD and the basis for theractices. It was published in the Nephrologyursing Journal and presented as a poster at aational ANNA Symposium. Her interests haveeen urea kinetics, anticoagulation for HD, vas-ular access, nephrology specific quality assur-nce in hospital settings, regulatory support, andurrently, infection control. Sandy has main-ained membership in the American Nephrologyurses Association (ANNA) since 1969. She

ounded the Garden State Chapter of ANNA inJ and currently serves as its conference man-

ger. While president of the chapter, she foundedeach Out for Children with Kidney Disease

ROCK), a fundraising project for pediatric kid-ey patients. She has also held various local,egional, and national positions with ANNA andoes numerous presentations for nephrology pro-essionals. As a volunteer she strives to promotehe goals of ANNA within the workplace. Sheaintains membership in the American Nursesssociation and the NJ State Nurses’ Associa-

ion. Sandy is also a member of the Associationor Professionals in Infection Control and Epide-iology (APIC). She is currently preparing for

oard certification to enable her to practice as annfection control professional.

Patricia L. Painter, PhD, is an Adjunct Asso-iate Professor in the Department of Physiologicursing at the University of California, Sanrancisco. She also manages the Exercise Physi-logy Laboratory at UCSF. Dr. Painter has pub-ished many articles in journals such as Trans-lantation, Kidney International, Journal oflinical Investigation, and Journal of Cardiovas-ular Physical Therapy. She was a member ofhe Board of Trustees for the American Collegef Sports Medicine and received a Distinguished
ervice Award from the National Kidney Founda-

toaid

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WORK GROUP BIOGRAPHIES S125

ion. Dr. Painter has also received grants fromrganizations such as Satellite Healthcare, Amgen,nd the National Institute of Health. Her areas ofnterest are exercise physiology in end stage renalisease and after organ transplantation.

Rulan Parekh, MD, MS, is an Assistant Pro-essor of Pediatrics and Internal Medicine at theohns Hopkins University. She is a previousecipient of the American Kidney Fund clinicalcientist fellowship and the Carl W. GottshalkSN Award for clinical investigation. In addi-

ion, Dr. Parekh has received research fundingrom the Child Health Center of the Nationalnstitutes of Health, NIDDK-NIH, the Thomas

ilson Sanitarium, and the National Kidneyoundation of Maryland, to study cardiovascularisease in children with end stage renal disease.he is also participating in an NIDDK-NIH spon-ored multicenter collaborative study, the Familynvestigation of Nephropathy in Diabetes (FIND).he is a scientific reviewer of grants for theational Kidney Foundation of Maryland, and

he Clinical Scientist Selection Committee of themerican Kidney Fund, and abstract reviewer

or the American Society of Nephrology meet-ngs. Dr. Parekh was also a work group memberor the Kidney Disease Outcomes Quality Initia-ive (K/DOQI) Clinical Practice Guidelines for

anaging Dyslipidemias and is a current mem-er of the K/DOQI Advisory Board. She is aember of the advisory committee on obesity

nd minority children of the International Soci-ty on Hypertension in Blacks (ISHIB).

Mark S. Roberts, MD, MPP, is a practicingnternist and Associate Professor of Medicine andealth Policy and Management and Chief of theection of Decision Sciences and Clinical Systemsodeling in the Division of General Medicine at

he University of Pittsburgh. A nationally recog-ized expert in modeling and decision sciences, hes an Associate Editor for Medical Decision Mak-ng, and is Chair of the Healthcare Technology andecision Sciences study section of the Agency forealthcare Research and Quality (AHRQ). He is a

ore faculty member of the Center for Research onealth Care, a multidisciplinary health services

esearch center at the University of Pittsburgh, ando-Director of the NHLBI-funded Clinical Re-

earch Training Program. He is funded as a prin-iple investigator or co-investigator on multiple
IH grants from the HHLBI, NIDDK, NIGMS a
nd the NSF. His research interests include theathematical modeling of disease, cost effective-

ess and decision analytic modeling, health ser-ices research and clinical information systems/uality improvement.

Catherine Stehman-Breen, MD, MS, re-eived her medical degree from the University ofhicago in 1990. She received her residency and

ellowship training at the University of Washing-on where she also received a Masters of Scienceegree in Epidemiology. She spent six years as aaculty member in the Division of Nephrology athe University of Washington. Her primary re-ponsibilities included managing the Clinical Re-earch Training Program and the development ofhe Epidemiology and Clinical Trials Researchrogram. Her research focused on bone andardiovascular disease in renal disease patients.r. Stehman-Breen was also active in a variety ofational programs including participation as a mem-er of the Data Safety and Monitoring Board forhe NIH sponsored Vascular Access Trials Consor-ium. She is currently an Associate Director oflinical Research at Amgen.Peter Stenvinkel, MD, PhD, is an Associate

rofessor at the Karolinska Institute, Stockholm,weden and a senior lecturer at the Karolinskaniversity Hospital, Stockholm. He was a visit-

ng Associate Professor at the University of Cali-ornia at Davis, California from 2000 to 2001.is main research interest is various aspects of

nflammation, malnutrition and metabolism inSRD patients. He has published about 110riginal papers and contributed to 11 book chap-ers. Dr. Stenvinkel was a Baxter Extramuralrant awardee in 1996 and a Söderbergs Founda-

ion awardee in 2003 from which he has receivedesearch grants. He has been a member of theaxter Medical Advisory Board since 2002. He

s a member of the Editorial Boards for theournal of American Society of Nephrology andephrology Dialysis Transplantation. Dr. Sten-inkel is a member of American Society ofephrology, International Society of Nephrol-gy, Society of Nutrition and Metabolism, Swed-sh Society of Nephrology and Swedish Societyf Hypertension. Dr. Stenvinkel is on the Advi-ory Board for Amgen from which he also re-eives a research grant. He has given about 70nvited lectures at various international meetings
nd congresses.

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Ravinder Wali, MD, is Assistant Professor ofedicine in the Division of Nephrology at theniversity of Maryland School of Medicine. Dr.ali received his M.D. from the Kashmir Medi-

al College in India, and an MRCP from theoyal College of Physicians, Great Britain. Heompleted his internship and residency at theeorgetown Medical School and VA Medicalenter in Washington, D.C., followed by a fellow-

hip in Nephrology and Transplantation at theniversity of Maryland School of Medicine in

uly 1999. Following this he was offered a fac-lty position, which he accepted. His areas ofnterest are cardiovascular disease in patientsith chronic kidney disease and following kid-ey transplantation, renal failure and chronicllograft nephropathy. His faculty positions in-lude Staff Physician at the VA Baltimore, Assis-
ant Instructor in the Division of Nephrology at a
MSOM, and Registrar at the University oflasgow School of Medicine, NHS Trust, Royal

nfirmary, Glasgow, Great Britain. He has au-hored several scientific papers, and is a profes-ional member of several scientific societies,ncluding the American Society of Nephrology,he American Society of Transplantation and theational Kidney Foundation.Miriam F. Weiss, MD, FACP, is Professor ofedicine at Case Western Reserve University.

he is a member of the Division of Nephrology,epartment of Medicine at University Hospitalsf Cleveland, and founding Medical Director ofhe Home Dialysis Program at UH. As a clinicalranslational researcher, she has published on theanagement of complications of peritoneal dialy-

is. In the laboratory she is investigating the rolef advanced glycation end products in uremia
nd in diabetic nephropathy.

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ACKNOWLEDGMENTS

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The Work Group appreciates the careful reviewf the draft guidelines and suggestions for improve-ent by external reviewers. Each comment was

arefully considered and, whenever possible, sug-estions for change were incorporated into the finaleport. As a result, the K/DOQI Cardiovascularisease in Dialysis Patients guidelines is the prod-ct of the Work Group, the Evidence Review Team,he NKF, and all those who contributed their efforto improve the Guidelines.

The following individuals provided writteneview of the draft guidelines: Mahmoud Abu-andil, MD; Olufemi Adeleye, MD; Jane Alder-

ice, MD; Harith Aljebory, MD; Gerard Ames,D; Nayle Araguez, MD; Koichi Asahi, MD;eorge Bailie, PharmD, PhD; Vinod Bansal,D; Paul Barre, MD, FRCP (C); Rashad Bar-

oum, MD; Gavin Becker, MD, FRACP; Bryanecker, MD; Jeffrey Berns, MD; Mary Bethallahan, ACSW, LMSW, ACP; Josefa Borregoinojosa, MD; Davide Bottalico, MD; Deborahrommage, MS, RD, CSR, CDN; Rafael Burgos-alderon, MD; Vallorie Clarke-Bates; Mariaoco, MD; Giorgio Coen; Maire Cole; Allanollins, MD, FACP; Leesa Conley, BSN; Joanneooke, MS, RD, CSR; Helen Currier, RN, CNN;uca De Nicola, MD; Thomas Depner, MD; Paulombrower, MD; Neval Duman, MD; Rowlandlwell, PharmD; Sebastiao Ferreira, MD; Pauline, MD; Frederic Finkelstein, MD; Daniloliser, MD; Michael Fredericks, MD; Linda Fried,D; Paula Frost, RD, CSR, LD; Masafumi Fuka-

awa, MD; Jessica Funes, RN; Sana Ghaddar,D, PhD; Carlos Gomez-Alamillo, MD; Jocelynoss; Darren Grabe, BS, PharmD; Jane Greene,D, CSR, LDN; Pradeep Gupta, MD; Seongyun Kim, MD; Gunnar Heine, MD; Alan Hull,D; Adriana Hung, MD; Atul Ingale, MD; Areef

shani, MD; Takahito Ito, MD; Sushamma Jo-eph, RD; Serkan Kahraman, MD; Lynetteartechner; Markus Ketteler, MD; Shikha Kho-

la, MD; Janice Knouff, RN, BS; Nelson Kopyt,O, FACP; Harvey Kramer, MD; Craig Lang-an, MD; Edgar Lerma, MD, FACP, FASN;erard London, MD; Alison MacLeod, MD;
enise Mafra; Harold Manley, PharmD, BCPS; z

eter McCullough, MD, MPH; Sue McManus,CNP; Sherry Meadows, RN; Gary Myrthil,D; Benjamin Navarro, MD; Martin Neff, MD;

auline Nelson, RD; Marianne Neumann, RN,NN; Keith Norris, MD; David Parra, PharmD,CPS; Uptal Patel, MD; Thakor Patel, MD;

orge Patino, MD; F Pizarelli, MD; Velvie Pogue,D; Sally Rice, LCSW, DCSW; Patricia Rob-

rts, MS, RN, CNN; Michele Root, CNS; Sylviaosas, MD; Jocelyne Saikali, MD; Isidro Sa-

usky, MD; Augusto Sam, MD; Ruth Sardeson;ristine Schonder, PharmD; Anton Schoolwerth,D, FAHA; Stephen Seliger, MD; Ranjit Shail,D; Alexander Shutov, MD; Israel Silva; Bh-

pinder Singh, MD; Yolanda Solis, RN, CCRN;ita Solomon-Dimmitt, RD, LDN, CSR; Sand-ep Soman, MD; Diane Soulliard; Leslie Spry,D, FACP; Peter Thomson, MD; Hung-Bin Tsai,D; Wai Tse, MD; Allen Vander, MD; Raymond

anholder, PhD, MD; David VanWyck, MD;nitha Vijayan, MD; Johannes Wagner, MD;oberta Wagner; Rowan Walker, MBBS, FRACP,D; Fang Wang, RD; Jean-Pierre Wauters, MD;

ynne Weiss, MD; Anthony Wierzbicki, MD,Phil; Elaine Williams, DO; Elizabeth Witten,SW, ACSW, LSCSW; Jang Won Seo, MD.Organizations that took part in the review

rocess include: American Association of Kid-ey Patients; American Federation for Medicalesearch; American Nephrology Nurses Associa-

ion; Bard Peripheral Vascular; Biovail Pharma-euticals, Inc.; Bone Care International; ESRDetwork #6; NIDDK of the National Institutes ofealth; The University of Kansas; UCLA Medi-

al Center.Participation in the review does not necessar-

ly constitute endorsement of the content of theeport by the individuals or the organization ornstitution they represent.

The National Kidney Foundation, as well as theork Group, would like to recognize the support of

atellite Healthcare for the development of theuidelines. The National Kidney Foundation isroud to partner with Satellite Healthcare and Gen-
yme Therapeutics on this important initiative.
), 2005: p S124 S127

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REFERENCES

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eport, in, Bethesda, MD, The National Institutes of Health,ational Institute of Diabetes and Digestive Diseases, 20023. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger

E, Agodoa LY, Held PJ, Port FK: Comparison of mortalityn all patients on dialysis, patients on dialysis awaitingransplantation, and recipients of a first cadaveric transplant.

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5. Lindner A, Charra B, Sherrard DJ, Scribner BH: Accel-rated atherosclerosis in prolonged maintenance hemodialy-is. N Engl J Med 290:697-701, 1974

6. Rostand SG, Gretes JC, Kirk KA, Rutsky EA, An-reoli TE: Ischemic heart disease in patients with uremiandergoing maintenance hemodialysis. Kidney Int 16:600-11, 19797. Herzog CA, Ma JZ, Collins AJ: Poor long-term sur-

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