s 0272638606005543

Hemodialysis Adequacy 2006

Work Group Membership

Work Group Co-Chairs

Thomas A. Depner, MDUniversity of California, Davis

Sacramento, CA

Work G

Kaiser Permanente Medical Group, Los Angeles, CA

Hemodialysis and Perito

Christina Kwack Yuhan, MD

John T. Daugirdas, MDUniversity of Illinois Medical Center

Chicago, IL

roup

Stuart Goldstein, MDBaylor College of MedicineTexas Children’s Hospital

Houston, TX

Todd S. Ing, MDHines VA/Loyola University Medical Center

Wilmette, IL

Victoria Kumar, MDUniversity of California, Davis

Klemens B. Meyer, MDTufts University School of Medicine-

New England Medical CenterBoston, MA

Keith Norris, MDDean of Research

Charles R. Drew UniversityLynwood, CA

Evidence Review TeamNational Kidney Foundation Center for Guideline Development and Implementation at Tufts-New England

Medical Center, Boston, MA

Ethan Balk, MD, MPH, Project Director, Hemodialysis and Peritoneal Dialysis AdequacyKatrin Uhlig, MD, Project Director, Vascular Access

George Fares, MD, Assistant Project Director, Hemodialysis and Peritoneal Dialysis AdequacyAshish Mahajan, MD, MPH, Assistant Project Director, Vascular Access,

neal Dialysis Adequacy

Amy Earley, BSRebecca Persson, BAGowri Raman, MD

Priscilla Chew, MPHStanley Ip, MD

Mei Chung, MPH

In addition, oversight was provided by:

Joseph Lau, MD, Program Director, Evidence Based MedicineAndrew S. Levey, MD, Center Director

TTTTTTTTTT

TTT

TTTTTTT

FFFFFF

A

Tables

able 1. Validated GFR-Estimating Equations................................................................................ S14able 2. Causes of Unusually Low or High Endogenous Creatinine Generation............................ S14able 3. Causes of Unusually Low or High Kidney Tubular Creatinine Secretion ......................... S15able 4. Methods for Calculating eKt/V ......................................................................................... S20able 4A. Preferred Measures of the Delivered Dose (in Order of Preference)................................. S23able 5. Recommended Predialysis Blood-Drawing Procedure ..................................................... S25able 6. Slow-Blood-Flow Method for Obtaining the Postdialysis Sample.................................... S26able 7. Stop-Dialysate-Flow Method of Obtaining the Postdialysis Sample ................................ S26able 8. Effect of HD Dose on Mortality ........................................................................................ S30able 9. Fraction of Treatments With an spKt/V Greater Than 1.2 When Targeting 1.2

to 1.4 per Dialysis .............................................................................................................. S31able 10. Effect of Residual Kidney Function on Mortality ............................................................. S41able 11. Complications That May Prompt Initiation of Kidney Replacement Therapy .................. S49able 12. Effect of High Flux Dialysis on Mortality, Cardiovascular Mortality and

�2 Microglobulin (�2M)................................................................................................... S55able 13. Minimum spKt/V Values Corresponding to a stdKt/V of Approximately 2.0 per Week ... S58able 14. Effect of Dialyzer Reuse on Mortality............................................................................... S64able 15. Efforts to Protect RKF....................................................................................................... S69able 16. Potential Insults to RKF .................................................................................................... S69able 17. Effect of Pharmacologic Interventions on Loss of Residual Kidney Function.................. S70able 18. Values for k at Different Dialysis Frequencies and BUN Targets...................................... S76
able 19. Minimum spKt/V Required to Achieve a stdKt/V of 2.0 per Week................................... S76
Figures

igure 1. Impact of Ultrafiltration on Delivered Dose of HD Measured By Using spKt/V and URR. ... S19igure 2. eKt/V as a Function of Dialysis Treatment Time. .............................................................. S21igure 3. Components of Postdialysis Urea (BUN) Rebound........................................................... S25igure 4. Stop-dialysate Method for Postdialysis Blood Sampling................................................... S27igure 5. Illustration of the “Lag Phenomenon” ............................................................................... S34igure 6. Effect of Residual Native Kidney Clearance (Kr).............................................................. S75

merican Journal of Kidney Diseases, Vol 48, No 1, Suppl 1 (July), 2006: p S3 S3

S

Abbreviations and Acronyms� Standardized coefficient

�2M �2-microglobulinAAMI Association for the Advancement of Medical Instrumentation

ACE Angiotensin-converting enzymeADMA Asymmetric dimethylarginine

AR Access recirculationARB Angiotensin receptor blocker

AV ArteriovenousBMI Body mass indexBSA Body surface areaBUN Blood urea nitrogenBW Body weight

C ConcentrationC0/C Predialysis to postdialysis concentration ratio

CANUSA Canada-USA StudyCAPD Continuous ambulatory peritoneal dialysisCAPR Cardiopulmonary recirculation

Cav Average concentrationCFU Colony-forming unit

CI Confidence intervalCKD Chronic kidney diseaseCMS Centers for Medicare and Medicaid Services

COX-2 Cyclooxygenase-2CPG Clinical Practice GuidelineCPR Clinical Practice RecommendationCQI Continuous quality improvement

CVD Cardiovascular diseaseDOPPS Dialysis Outcomes and Practice Patterns Study

DOQI Dialysis Outcomes Quality InitiativeeKt/V Urea-equilibrated Kt/V

ECF Extracellular fluidECV Extracellular volumeEKR Equivalent renal clearance

G Urea generation rateGFR Glomerular filtration rate

HbA1c Hemoglobin A1c

HD HemodialysisHEMO Study Kidney Disease Clinical Studies Initiative Hemodialysis Study

HMG 3-Hydroxy-3-methylglutarylHR Hazard ratio

HRQOL Health-related quality of lifeIDEAL Initiating Dialysis Early And Late

JNC Joint National CommitteeKce Continuous equivalent clearanceKd Dialyzer clearance

KDOQI Kidney Disease Outcomes Quality InitiativeKDQOL-SF™ Kidney Disease and Quality of Life Short Form

Kecn Dialyzer clearance estimated by conductivityKLS Kidney Learning System
K0A Dialyzer mass transfer area coefficient
American Journal of Kidney Diseases, Vol 48, No 1, Suppl 1 (July), 2006: pp S4-S54

ABBREVIATIONS AND ACRONYMS S5

Kr Residual native kidney urea clearanceKRT Kidney replacement therapyKt/V Clearance expressed as a fraction of urea or body water volume

Kt/Vurea Urea clearance expressed as Kt/VKuf Ultrafiltration coefficient

Kurea Effective (delivered) dialyzer urea clearanceLVH Left ventricular hypertrophy

MDRD Modification of Diet in Renal DiseaseNCDS National Cooperative Dialysis Study

nd No data reportednEKR Equivalent renal clearance normalized to body size

NIH National Institutes of HealthNIVM Noninvasive monitoring

NKF National Kidney FoundationnPCR Normalized protein catabolic ratenPNA Normalized protein nitrogen appearance rate

NS Not significantOR Odds ratioPD Peritoneal dialysis

p38MAPK p38 mitogen-activated protein kinaseQOL Quality of life

rKt/V Residual Kt/VRC Remote compartment

RCT Randomized controlled trialRKF Residual kidney function

RR Relative riskSD Standard deviation

spKt/V Single-pool delivered Kt/V (by dialysis only, exclusive of RKF)stdKt/V Standard Kt/V

SRI Solute removal indext Treatment time

td Time from beginning to end of dialysisTAC Time-averaged concentrationTCV Total cell volumeTMP Transmembrane pressureUFR Ultrafiltration rateURR Urea reduction ratio

USRDS United States Renal Data SystemV Volume, usually of body urea distribution or total body water

Vurea Patient’s volume of urea distribution

TCHttgipvcgtlmpd

tasSarfllatftemts

VOL 48, NO 1, SUPPL 1, JULY 2006

AJKD American Journal ofKidney Diseases

S

Foreword

assbpaciscecdhmsftgrcaisaft

GasWpascw

he publication of the second update of theClinical Practice Guidelines (CPGs) and

linical Practice Recommendations (CPRs) foremodialysis represents the second update of

hese guidelines since the first guideline on thisopic was published in 1997. The first set ofuidelines established the importance of measur-ng the dose of dialysis in all long-term dialysisatients and the benefits of placing an arterio-enous fistula in a timely manner to reduce theomplications that can occur from using either aortex graft or a permanent catheter for long-erm hemodialysis access. Several of these guide-ines have been selected as clinical performanceeasures by regulatory agencies to drive the

rocess of quality improvement in long-termialysis patients.A number of important randomized clinical

rials have been performed in long-term hemodi-lysis patients since the publication of the firstet of guidelines. The Kidney Disease Clinicaltudies Initiative Hemodialysis (HEMO) Study,National Institutes of Health (NIH)-sponsored

andomized clinical trial of dialysis dose andux, is the largest study to date performed in

ong-term hemodialysis patients. Results of thesend other studies of long-term hemodialysis pa-ients have been included in the literature reviewor this updated set of guidelines. In addition,his update includes new guidelines on the pres-rvation of residual kidney function, the manage-ent of volume status and blood pressure, and

he importance of patient education on all dialy-is modalities.

© 2006 by the National Kidney Foundation, Inc.0272-6386/06/4801-0101$32.00/0

idoi:10.1053/j.ajkd.2006.04/063

American Journal of Kidn6

This document has been divided into 3 majorreas. The first section consists of guidelinetatements that are evidence based. The secondection is a new section that consists of opinion-ased statements that we are calling “clinicalractice recommendations” or CPRs. These CPRsre opinion based and are based on the expertonsensus of the Work Group members. It is thentention of the Work Group that the guidelinetatements in Section I can be considered forlinical performance measures because of thevidence that supports them. Conversely, be-ause the CPRs are opinion based, and not evi-ence based, they should not be considered toave sufficient evidence to support the develop-ent of clinical performance measures. The third

ection consists of research recommendationsor these guidelines and CPRs. We have decidedo combine all research recommendations for theuidelines into 1 major section and also haveanked these recommendations into 3 categories:ritical importance, high importance, and moder-te importance. Our intended effect of this changen how the research recommendations are pre-ented is to provide a guidepost for fundinggencies and investigators to target research ef-orts in areas that will provide important informa-ion to benefit patient outcomes.

This final version of the Clinical Practiceuidelines and Recommendations for Hemodi-

lysis has undergone extensive revision in re-ponse to comments during the public review.

hereas considerable effort has gone into theirreparation during the past 2 years and everyttention has been paid to their detail andcientific rigor, no set of guidelines and clini-al practice recommendations, no matter howell developed, achieves its purpose unless it

s implemented and translated into clinical

ey Diseases, Vol 48, No 1, Suppl 1 (July), 2006: pp S6-S7

pntLtms

tmytot

dWdantd

FOREWORD S7

ractice. Implementation is an integral compo-ent of the KDOQI process and accounts forhe success of its past guidelines. The Kidneyearning System (KLS) component of the Na-

ional Kidney Foundation is developing imple-entation tools that will be essential to the

uccess of these guidelines.In a voluntary and multidisciplinary under-

aking of this magnitude, many individualsake contributions to the final product now in

our hands. It is impossible to acknowledgehem individually here, but to each and everyne of them, we extend our sincerest apprecia-
ion. This limitation notwithstanding, a special
ebt of gratitude is due to the members of theork Group and their co-chairs, John Daugir-

as of The University of Illinois at Chicagond Tom Depner at the University of Califor-ia at Davis. It is their commitment and dedica-ion to the KDOQI process that has made thisocument possible.

Adeera Levin, MD, FACPKDOQI Chair

Michael Rocco, MD, MSCE
KDOQI Vice-Chair

apEIctspct(1ts(suotriwQ

dltpmflbwm(Hhidaaboce

S

Introduction

ctitPdfshJtwSrD&tc

icdipqoobpiccuatscet

(wafCmec

Nephrologists in the United States in generalre savvy physicians who respond quickly toublic information about care of their patients.ven before the Kidney Disease Clinical Studies

nitiative Hemodialysis (HEMO) Study was con-luded, average dialysis doses were increasing inhe United States, perhaps stimulated by thetudy itself, which was widely publicized toromote enrollment among the 72 participatinglinics.1,2 The original National Kidney Founda-ion (NKF)-Dialysis Outcomes Quality InitiativeDOQI) guidelines for hemodialysis (HD) in997 probably also fueled the dose increase. Athe time the study was completed, the averageingle-pool fractional urea clearance Kt/VspKt/V) in the United States was 1.52 per dialy-is given 3 times per week.3 This was and contin-es to be significantly greater than the minimumf 1.2 established originally in 1994 by a consor-ium of nephrologists.4,5 The original minimumecommended dose was based mostly on opin-ons generated from observational studies andas reiterated by the Kidney Disease Outcomesuality Initiative (KDOQI) in 2001.6

The HEMO Study showed that the minimumose established by the previous KDOQI guide-ines is appropriate when dialysis is performed 3imes per week for 2.5 to 4.5 hours.1 Dialysisroviders no longer need to focus on providingore dialysis by using bigger dialyzers and higherow rates, but they cannot sit back and relaxecause the yearly mortality rate for patientsith chronic kidney disease (CKD) stage 5 re-ains unacceptably high in the United States

�20% per year in 2002, and 17% per year in theEMO Study). This ongoing high mortality rateas served as an incentive for investigators seek-ng better alternative solutions for dialysis-ependent patients and has spurred interest inlternative therapies and modes of therapy, suchs hemofiltration, daily dialysis, sorbent therapy,etter volume control, use of ultrapure water, andther interventions. Mortality differences amongountries are now explained partially by differ-nces in patient selection and comorbidity, but a

© 2006 by the National Kidney Foundation, Inc.0272-6386/06/4801-0102$32.00/0

edoi:10.1053/j.ajkd.2006.03.055

American Journal of Kidne8

onsiderable gap remains, especially when statis-ics in the United States are compared with thosen Japan, where annual mortality rates are lesshan 10%. The Dialysis Outcomes and Practiceatterns Study (DOPPS) analyses show that theseifferences are not caused by different methodsor gathering statistics.7 The HEMO Studyhowed that the differences are not caused byigher doses in Japan.1 Better survival in theapanese may be caused by genetic differenceshat enhance survival of Asian dialysis patients,hether treated in the United States or Japan.8,9

ome consolation can be gained from the mostecent data published by the United States Renalata System (USRDS) and Centers for MedicareMedicaid Services (CMS) that show a reduc-

ion in mortality rates during the past 2 de-ades.10

The HEMO Study broadened the scope ofnterest and opened the eyes of the dialysis healthare industry to the issue of dialysis adequacy. Itid not settle the question of small-solute toxic-ty, but it served to redirect attention to otherossible causes of morbidity, mortality, and pooruality of life (QOL). These include retentionf solutes that are poorly removed by diffusionr convection because of their large size orinding to serum proteins, solute sequestration,hysiological stress caused by either the dialysistself or the intermittent schedule of dialyses thatauses fluctuations in fluid balance and soluteoncentrations, or accumulation of such non–remia-associated toxins as drug metabolites thatre known to accumulate in dialyzed patients. Inhe latter case, reducing or stopping antihyperten-ive drug therapy may have hidden benefits. Thearegiver can be a source of the problem, asvidenced by past experience with aluminumoxicity.

The enormous risk for cardiovascular diseaseCVD) in patients with CKD stage 5 comparedith patients with normal renal function suggeststoxic phenomenon. Perhaps alternate pathways

or toxin removal are damaged in patients withKD, causing accumulation of toxins not nor-ally eliminated by the kidneys. Other possible

xplanations for the high risk for CVD anderebrovascular disease include a yet to be discov-
red renal effect that may protect the vascular
y Diseases, Vol 48, No 1, Suppl 1 (July), 2006: pp S8-S11

etsittisspw

tcsetrsljb

ltVpeltir

tastcsstf

uadwcttW

blcwpfaciaacaciacsietbIei(mdidwmebpe

mrQvsHairIS

t

INTRODUCTION S9

ndothelium. This role of kidney disease in pa-ients with heart failure and the “cardiorenalyndrome” may be related to cardiovascular risksn patients with renal disease.11 It is worth notinghat the loss of hormones normally produced byhe kidney is a well-established cause of disabil-ty and mortality that is not responsive to dialy-is. The strong association of survival with re-idual native kidney function in both HD anderitoneal dialysis (PD) patients is consistentith such an effect.The potential for inflammation caused by con-

aminated dialysate or soft-tissue reactions toalcium deposits may contribute to the observedtrong relationship among inflammatory mark-rs, CVD, and renal disease. It is possible thathe high morbidity and mortality rates are notelated to dialysis at all. If so, more attentionhould be given to comorbidity and QOL andess attention to the adequacy of dialysis. At thisuncture in the search for answers and solutions,oth imagination and science are needed.New issues addressed in these updated guide-

ines include the timeline for initiation of dialysisherapy, which also is addressed by the PD andascular Access Work Groups. Emphasis waslaced on patients destined for HD therapy, butfforts also were made to coordinate these guide-ines with the initiation guidelines generated byhe other work groups that recommended steppedncreases in the prescribed dialysis dose, earlyeferral, and early access placement.

Predialysis blood urea nitrogen (BUN) is easyo measure, but the postdialysis concentration is

moving target. Its decrease during dialysis isharply reversed when the treatment ceases; thus,iming of the postdialysis blood sample is criti-al. The Work Group determined that markedlylowing blood flow at the end of dialysis beforeampling the blood is the safest and simplestechnique for achieving the uniformity neededor reliable and reproducible values of Kt/V.

The delivered Kt/V determined by single-poolrea kinetic modeling continues to be preferreds the most precise and accurate measure ofialysis. Simplified formulas are acceptableithin limits, and urea reduction ratio (URR)

ontinues to be viable, but with pitfalls. Conduc-ivity (ionic) clearance also is accepted, but tendso underestimate dialyzer urea clearance. The

ork Group believed that more attention should m

e given to residual kidney function (RKF) inight of recent evidence linking outcomes morelosely to RKF than to dialysis dose. Althoughe do not recognize a state of “overdialysis,”atient QOL is compromised by dialysis; there-ore, giving unnecessary treatment should bevoided, especially now that we recognize aeiling dose above which morbidity and mortal-ty are not improved. Pitfalls and controversiesbout methods for adding RKF to dialyzer clear-nce were reviewed, but were considered tooomplex for the average dialysis clinic to man-ge. Implementation was simplified by setting autoff urea clearance of 2 mL/min, above whichnclusion of residual native kidney urea clear-nce (Kr) is recommended and below which itan be ignored. Although the cutoff value isomewhat arbitrary, it serves to separate patientsnto 2 groups: 1 group in which the trouble andxpense of measuring RKF can be avoided, andhe other group in which more attention shoulde focused on RKF to potentially improve QOL.n the latter group are patients for whom recov-ry of renal function may be anticipated. Patientsn the group with RKF greater than 2 mL/min�10% to 30%) should have regular measure-ents of native kidney clearance to avoid under-

ialysis as function is lost and to avoid prolong-ng dialysis if function recovers. Twice-weeklyialysis may be permissible in a few patientsithin the group with RKF greater than 2 mL/in who have stable function and do not have

xcessive fluid gains. Because RKF is preservedetter in current HD patients compared with theast, a separate guideline was established toncourage preservation of RKF.

More frequent dialysis is becoming more com-on; thus, methods for measuring the dose are

equired. Partially controlled studies suggest thatOL improves, hypertension is alleviated, leftentricular hypertrophy (LVH) regresses, andleep disturbances abate with daily or nocturnalD. The Work Group reviewed current methods

nd gave practice recommendations for measur-ng the dose in these patients. More definitiveecommendations may come from the Nationalnstitutes of Health (NIH) Frequent HD Networktudy that currently is enrolling patients.The Work Group focused more intently on the

arget dose and its relationship with the mini-
um dose which, in light of HEMO Study find-

iptvKwd11podflvdmflddsiSbt

miffiitvuedlobtennttetta

wi

tspWPftlettamuTh

wAlmctaghv

dchcmdwMcaaHipa

pflssd

GUIDELINES FOR HEMODIALYSIS ADEQUACYS10

ngs, remains 1.2 Kt/V units per dialysis foratients dialyzed 3 times per week. Data fromhe HEMO Study also revealed a coefficient ofariation within patients of approximately 0.1t/V units; therefore, the previous target of 1.3as considered too low. To grant 95% confi-ence that the dose will not decrease to less than.2 per dialysis, the target dose was increased to.4 per dialysis. This is in keeping with currentractice and is consistent with the target spKt/Vf approximately 1.4 set by the European Stan-ards Group.12 The Work Group favored high-ux membranes. The HEMO Study did not pro-ide definitive answers, but data suggested thatialysis vintage and flux are related and CVDight be affected favorably by the use of high-ux dialysis.1 The issue of sex also was ad-ressed by the Work Group, which believed thatialysis doses and targets should remain theame in women compared with men. However,n light of suggestive findings from the HEMOtudy and observational studies, clinicians shoulde aware of a possible increased responsivenesso dialysis in females compared with males.13

Concern was raised by the Work Group aboutalnourished patients with respect to both the

nitiation and adequacy of HD. Initiation is con-ounded by errors in calculation of glomerularltration rate (GFR) for patients with diminish-

ng muscle mass, and adequacy is confounded byhe effect of malnutrition on patients’ waterolume (V), the denominator of the integratedrea clearance expression (Kt/V). Estimationquations for calculating GFR before startingialysis therapy are based on serum creatinineevel, but are adjusted for sex, size, race, andther factors that tend to alter the relationshipetween concentration and clearance. Most ofhese factors either increase or decrease the gen-ration of creatinine, but the patient’s state ofutrition—which is well known to affect creati-ine generation—is not a variable in this equa-ion. The consequent error in malnourished pa-ients would tend to underestimate GFR and thusndanger the patient from the ill consequences ofhe delayed initiation of dialysis therapy. In addi-ion, if the patient is malnourished, dialysis prob-bly is better started early.

After a patient starts dialysis therapy, loss ofeight because of malnutrition will decrease V,

ncreasing the Kt/V, potentially to values higher m

han the desired target range. Reducing the dialy-is dose (Kt/V) in such patients may lead tootential harm from inadequate dialysis. Theork Group addressed this problem in Clinical

ractice Recommendation (CPR) 4.6, which callsor an increase in Kt/V when signs of malnutri-ion are present. The magnitude of the increase iseft to the clinician, who might take into consid-ration the absolute level of Kt/V and cause ofhe malnutrition. If Kt/V is already much greaterhan the minimum, an additional increase prob-bly would not benefit the patient. Similarly, ifalnutrition is caused by a condition other than

remia, increasing the dose may have no effect.his issue will require revisiting in the future,opefully with more available hard data.The importance of missed dialysis treatments

as emphasized repeatedly by the Work Group.lthough difficult to quantify in terms of a guide-

ine, patient cooperation and compliance is aajor determinant of survival.14-16 To ensure

ompliance, efforts should be made to maintainhe patient’s confidence in the health care systemt all levels. However, patient satisfaction ineneral and patient encounters with physiciansave not shown a strong correlation with sur-ival.17

Other aspects of dialysis adequacy were ad-ressed, including fluid balance, blood pressureontrol, and membrane biocompatibility. Reuseas moved to the background among issues ofoncern in dialysis clinics for 2 reasons: (1)any clinics in the United States no longer reuse

ialyzers, and (2) risks associated with reuseere examined and found to be very small.onitoring outcome goals within each dialysis

linic is vitally important for quality assurancend quality improvement, and this issue beendded as a Clinical Practice Guideline (CPG) forD and PD adequacy. This outcomes-monitor-

ng guideline is not intended to guide individualatient care, but is intended for the dialysis clinics a whole.

More data are available regarding adequacy inediatric HD patients, but the numbers thank-ully remain small, so definitive evidence isacking. The greater metabolic rate per unit ofurface area in children has been invoked byome to justify a higher dose. Use of V as aenominator (see previous discussion of V) also
ay endanger smaller patients. In other respects,

fdt

lngmcms(p1trua

wpa

pNbsldCswtldtfrrbdoRv

INTRODUCTION S11

or younger smaller patients, we have little evi-ence to support a different dosing regimen thanhat delivered to adults.

Since the last issuance of the KDOQI Guide-ines, the Standards Group of the European Re-al Association in 2002 published adequacyuidelines for HD measurement, dosing, andinimum standards.12 The HD adequacy group

hose urea-equilibrated Kt/V (eKt/V), recom-ending the Daugirdas method69 for converting

pKt/V to eKt/V, with a target of 1.2 per dialysisspKt/V � 1.4). The target was higher than thatreviously recommended by KDOQI (spKt/V �.3 per dialysis), but the rationale for increasinghe target was not clearly delineated. The groupecommended using the mean of creatinine andrea clearance as a measure of RKF and discour-ged twice-weekly dialysis.

In the United States, we have come a longay, from marveling about how HD can snatchatients from the jaws of death and keep them
live indefinitely to coping with 0.1% of the i
opulation depending on HD for life support.ephrologists have learned that, although num-ering more than 300,000, these patients repre-ent a small segment of approximately 20 mil-ion people in the United States with kidneyisease who have survived tremendous risks forVD and other morbid diseases to develop CKD

tage 5. They often arrive in the dialysis clinicith a legacy of diabetes, CVD, and inflamma-

ory diseases that continue to progress. The chal-enge for today’s health care workers and theialysis industry is to provide an opportunity forhese patients to live long and comfortably withreedom to pursue their dreams, even if for only aelatively short length of time in those at highisk. We need to be all things for these patients,ut first and foremost, we must deliver the bestialysis therapy we can with available technol-gy. These new KDOQI HD CPGs, CPRs, andesearch Recommendations are designed to pro-ide a clearer pathway and help everyone move
n that direction.

I. CLINICAL PRACTICE GUIDELINES FOR
HEMODIALYSIS ADEQUACY

1

1

1

Cisrcktcsfcaatspt

A

GUIDELINE 1. INITIATION OF DIALYSIS

imaa

oohacacddNpnv

PT

cPtaosfksttaktsdabtaod(hi

.1 Preparation for kidney failure:Patients who reach CKD stage 4 (esti-mated GFR < 30 mL/min/1.73 m2) shouldreceive timely education about kidneyfailure and options for its treatment, in-cluding kidney transplantation, PD, HDin the home or in-center, and conservativetreatment. Patients’ family members andcaregivers also should be educated abouttreatment choices for kidney failure. (B)

.2 Estimation of kidney function:Estimation of GFR should guide decisionmaking regarding dialysis therapy initia-tion. GFR should be estimated by using avalidated estimating equation (Table 1) orby measurement of creatinine and ureaclearances, not simply by measurement ofserum creatinine and urea nitrogen. Table2 and Table 3 summarize special circum-stances in which GFR estimates should beinterpreted with particular care. (B)

.3 Timing of therapy:When patients reach stage 5 CKD (esti-mated GFR < 15 mL/min/1.73 m2), neph-rologists should evaluate the benefits, risks,and disadvantages of beginning kidneyreplacement therapy. Particular clinicalconsiderations and certain characteristiccomplications of kidney failure may promptinitiation of therapy before stage 5. (B)

BACKGROUND

Optimum timing of treatment for patients withKD prevents serious and uremic complications,

ncluding malnutrition, fluid overload, bleeding,erositis, depression, cognitive impairment, pe-ipheral neuropathy, infertility, and increased sus-eptibility to infection. However, all forms ofidney replacement therapy entail importantrade-offs. As GFR decreases, patients and physi-ians must weigh many risks and benefits. Deci-ion making is more complex for older and moreragile patients. Together, patients and physi-ians must continually reconsider whether thenticipated physiological benefits of solute clear-nce and extracellular fluid (ECF) volume con-rol now outweigh the physical risks and psycho-ocial toll of therapy. In some cases, social andsychological factors may lead to earlier dialysis
herapy initiation, and in some cases, to later (
merican Journal of Kidney Diseases, Vol 48, No 1, Suppl 1 (July)

nitiation. The initiation of dialysis therapy re-ains a decision informed by clinical art, as well

s by science and the constraints of regulationnd reimbursement.

For some patients, conservative therapy, with-ut dialysis or transplantation, is the appropriateption.27-29 If the patient makes this choice, theealth care team should strive to maximize QOLnd length of life by using dietary and pharma-ological therapy to minimize uremic symptomsnd maintain volume homeostasis. These in-lude, but are not limited to, use of low-proteiniets, ketoanalogs of essential amino acids, loopiuretics, and sodium polystyrene sulfonate.ephrologists also should be familiar with therinciples of palliative care30 and should noteglect hospice referral for patients with ad-anced kidney failure.

RATIONALE

reparation for Kidney Failure (CPG 1.1)imely Education in Stage 4 CKDTimely patient education as CKD advances

an both improve outcomes and reduce cost.31

lanning for dialysis therapy allows for the initia-ion of dialysis therapy at the appropriate timend with a permanent access in place at the startf dialysis therapy. Planning for kidney failurehould begin when patients reach CKD stage 4or several reasons. The rate of progression ofidney disease may not be predictable. There isubstantial variability in the level of kidney func-ion at which uremic symptoms or other indica-ions for dialysis appear. Patients vary in theirbility to assimilate and act on information aboutidney failure. Local health care systems vary inhe delays associated with patient education andcheduling of consultations, tests, and proce-ures. Results of access creation procedures vary,nd the success or failure of a procedure may note certain for weeks or months. Timely educa-ion will: (1) allow patients and families time tossimilate the information and weigh treatmentptions, (2) allow evaluation of recipients andonors for preemptive kidney transplantation,3) allow staff time to train patients who chooseome dialysis, (4) ensure that uremic cognitivempairment does not cloud the decision, and
5) maximize the probability of orderly and
, 2006: pp S13-S16 S13

pa

sodapiihwmphhfnhd

C

mavttkPt

tc4lbftpperqC

EM

foofstotPlp

EUCG

palmeae


lanned treatment initiation using the permanentccess.

Predialysis education to inform the patient andupport persons about the relative value of vari-us renal replacement modalities offers a free-om of choice that must be honored. Educationnd choice of modality also are vital to the timelylacement of vascular or peritoneal access, train-ng for home dialysis, and actual timing of thenitiation of the selected first modality. A compre-ensive preemptive discussion of these issuesill enable patients and their support groups toake rational decisions and will serve to involve

atients as active participants in their personalealth care. Playing an active role in one’s ownealth care, although thwarting the natural de-ense mechanism of denial, reduces risks fromegligence and psychological depression thatave been associated with poor outcomes afterialysis therapy is started.32

ontingency PlansOptimal timing of vascular access creationay depend on plans regarding transplantation

nd/or PD treatment. Early attempts at nativeein arteriovenous (AV) fistula creation are par-icularly important in patients who are: (1) notransplant candidates or (2) lack potential livingidney donors and also seem unlikely to performD. For patients hoping to undergo “preemptive”

ransplantation, thus avoiding dialysis treatment,

Table 2. Causes of Unusually Low or Condition Vegetarian diet 22 Muscle wasting 22 Amputation 22 Spinal cord injury 23 Advanced liver disease 24,

Muscular habitus 22
Asian race 26
he decision about whether to attempt AV fistulareation at CKD stage 4 (and, if so, when in stage) depends on the nephrologist’s estimate of theikelihood that preemptive transplantation wille accomplished. For patients interested in per-orming PD, the decision about whether to at-empt AV fistula creation at CKD stage 4 de-ends on the nephrologist’s estimate of therobability that PD will be successful. The ben-fits of planning for kidney failure treatment areeflected in the literature comparing the conse-uences of early and late referral of patients withKD to nephrologists.33-36

ducation of Health Care Providers and FamilyembersOptimally, education in preparation for kidney

ailure will include not only the patient, but alsother individuals who are likely to influence hisr her decisions. These may include family, closeriends, and primary care providers. Their under-tanding of such issues as the impact of interven-ions designed to slow progression, the absencef symptoms despite underlying kidney disease,ransplantation eligibility, the choice betweenD and HD, and the choice and timing of vascu-

ar access may have critical consequences for theatient.

stimation of Kidney Function (CPG 1.2)se of GFR-Estimating Equations andlearances Rather Than Serum Creatinine touide Dialysis InitiationVariability in creatinine generation across the

opulation makes serum creatinine level alonen inaccurate test for patients with kidney failureikely to benefit from dialysis treatment. Forost patients in CKD stages 4 and 5, estimating

quations based on values of serum creatininend other variables approximate GFR with ad-quate accuracy. For most patients, measured

Endogenous Creatinine Generation eatinine Generation

Low Low

woLLow Low High

HighCr

25

woL

co

V

moatnmttnhim

V

cltseoenhmG

TI

oBpofiak

stnHo

ididsttpghncdmdstrcm1itmtcq

omtGt1v

INTRODUCTION S15

learance does not offer a more accurate estimatef GFR than prediction equations.37

ariation in Creatinine GenerationIt is well established that creatinine generationay be unusually low in patients with a number

f conditions and may be increased in individu-ls of unusually muscular habitus (Table 2). Inhese situations, GFR estimated by using creati-ine and urea clearances may be substantiallyore accurate (compared with radionuclide GFR)

han results of creatinine-based estimating equa-ions. In patients for whom endogenous creati-ine generation is likely to be unusually low origh, GFR should be estimated by using methodsndependent of creatinine generation, such aseasurement of creatinine and urea clearances.

ariation in Tubular Creatinine SecretionSeveral drugs are known to compete with

reatinine for tubular secretion, and advancediver disease has been associated with increasedubular creatinine secretion (Table 3). Decreasedecretion will result in artifactually low GFRstimates, and increased secretion will result inverestimation of GFR by means of estimatingquations. In patients for whom tubular creati-ine secretion is likely to be unusually low origh, the consequent bias to all creatinine-basedeasures should be considered in interpretingFR estimates.

iming of Therapy (CPG 1.3)nitiation of Kidney Replacement Therapy

This guideline is based on the assumption thatverall kidney function correlates with GFR.ecause the kidney has many functions, it isossible that 1 or more functions will decreaseut of proportion to the decrease in GFR. There-ore, caregivers should be alert to signs of declin-ng health that might be directly or indirectlyttributable to loss of kidney function and initiate

Table 3. Causes of Unusually Low or HDrug or Condition KTrimethoprim 22 Cimetidine 22 Fibrates (except gemfibrozil) 22 Advanced liver disease 25

idney replacement therapy (KRT) earlier in m

uch patients. However, they should considerhat dialysis therapy is not innocuous and doesot replace all functions of the kidney and thatD-related hypotension may accelerate the lossf RKF. This may particularly be true of HD.Individual factors—such as dialysis accessibil-

ty, transplantation option, PD eligibility, homeialysis eligibility, vascular access, age, declin-ng health, fluid balance, and compliance withiet and medications—often influence the deci-ion about the timing of when to start dialysisherapy. It may be optimal to perform kidneyransplantation or begin home dialysis beforeatients reach CKD stage 5. Even when GFR isreater than 15 mL/min/1.73 m2, patients mayave a milder version of uremia that may affectutrition, acid-base and bone metabolism, cal-ium-phosphorus balance, and potassium, so-ium, and volume homeostasis. Conversely,aintenance dialysis imposes a significant bur-

en on the patient, family, society, and healthystem. This is complicated further by the poten-ial risks of dialysis therapy, especially thoseelated to dialysis access and dialysate. Theseonsiderations necessitate conservative manage-ent until GFR decreases to less than 15 mL/min/

.73 m2, unless there are specific indications tonitiate dialysis therapy. Thus, the recommendediming of dialysis therapy initiation is a compro-ise designed to maximize patient QOL by ex-

ending the dialysis-free period while avoidingomplications that will decrease the length anduality of dialysis-assisted life.Theoretical considerations support initiation

f dialysis therapy at a GFR of approximately 10L/min/1.73 m2, and this was the recommenda-

ion of the 1997 NKF KDOQI HD Adequacyuideline.38-40 In 2003, mean estimated GFR at

he initiation of dialysis therapy was 9.8 mL/min/.73 m2. This mean value reflects lower averagealues (�7 to 9 mL/min/1.73 m2) for young and

Kidney Tubular Creatinine Secretion Tubular Creatinine Secretion

woL woL

Low High

igh idney

iddle-aged adults and higher average values

(eii

iGsfsgKmltpd

tawhseiattcaslattprtfs

iNmtsG

iawippeiFfiw

lmctvwrsvtoitput


�10 to 10.5 mL/min/1.73 m2) for children andlderly patients. Average GFR at initiation hasncreased in all age groups since 1995; it hasncreased most in the oldest patients.41

It is difficult to make a recommendation fornitiating KRT based solely on a specific level ofFR. Several studies concluded that there is no

tatistically significant association between renalunction at the time of initiation of KRT andubsequent mortality.42-45 However, others sug-ested that worse kidney function at initiation ofRT is associated with increased mortality ororbidity.40-46 When corrections are made for

ead-time bias, there is no clear survival advan-age to starting dialysis therapy earlier in com-arative outcome studies of patients initiatingialysis therapy at higher versus lower GFRs.47,48

Furthermore, it now is clear from observa-ional registry data from the United States, Can-da, and the United Kingdom48A that patientsith comorbidities initiate dialysis therapy atigher levels of estimated GFR.41,49,50 It is rea-onable to assume that this practice is based onxperience and the speculation, hope, and/ormpression that dialysis therapy may alleviate orttenuate symptoms attributed to the combina-ion of the comorbidity plus CKD. Because symp-oms of early uremia are fairly nonspecific, onean expect that patients with symptoms associ-ted with their comorbidities would initiate dialy-is therapy early. Healthy and hardy patients withess comorbidity likely will develop symptoms atlater stage than a frailer, early-starting compara-

ive group. Frail patients who start dialysisherapy earlier do not live as long as hardyatients who start dialysis later. However, thisemains merely an interpretation of observa-ional data. A more definitive answer may emergerom properly designed prospective trials. One
uch trial expects to report in 2008. The Initiat- c
ng Dialysis Early and Late (IDEAL) Study fromew Zealand and Australia is a prospective,ulticenter, randomized, controlled trial (RCT)

o compare a broad range of outcomes in patientstarting dialysis therapy with a Cockcroft-GaultFR of 10 to 14 versus 5 to 7 mL/min/1.73 m2.51

In 2000, the NKF KDOQI CPG on Nutritionn CKD advocated that—in patients with CKDnd estimated GFR less than 15 mL/min/1.73 m2

ho are not undergoing maintenance dialysis—f: (1) protein-energy malnutrition develops orersists despite vigorous attempts to optimizerotein-energy intake, and (2) there is no appar-nt cause for it other than low nutrient intake,nitiation of KRT should be recommended.52

urthermore, those guidelines set forth measuresor monitoring nutritional status and identifyingts deterioration. Those guidelines are consistentith the present recommendations.

LIMITATIONS

Individuals vary tremendously in the physio-ogical response to uremia and dialysis treat-ent. Patients expected to experience uremic

omplications often survive much longer thanhe physician anticipates, without apparent ad-erse consequences. Patients also vary in theirillingness and ability to adhere to a medical

egimen intended to forestall the need for dialy-is treatment. Health care systems and providersary greatly in their capability to monitor pa-ients with advanced kidney failure safely with-ut dialysis treatment. At best, the decision tonitiate dialysis treatment or perform preemptiveransplantation represents a joint decision byatient and physician, reflecting their mutualnderstanding of the compromises and uncertain-ies. It requires clinical judgment based on clini-
al experience.

aits

2

2

2

2

2

slosbmsmdb(

A

GUIDELINE 2. METHODS FOR MEASURING AND
EXPRESSING THE HEMODIALYSIS DOSE
ptrtdoitdndcestg

F

cpGCmsriHoqndimtidoc

D

Heas

Quantifying HD is the first step towardssessment of its adequacy. Fortunately, thentermittent rapid decrease in urea concentra-ion during HD allows a relatively easy mea-urement of the dose.

.1 The delivered dose of HD should be mea-sured at regular intervals no less thanmonthly. (A)

.2 The frequency of treatments should beincluded in the expression of dose. (A)

.3 The dose of HD should be expressed as(Kurea � Td)/Vurea (abbreviated as Kt/V),where Kurea is the effective (delivered)dialyzer urea clearance in milliliters perminute integrated over the entire dialysis,Td is the time in minutes measured frombeginning to end of dialysis, and Vurea isthe patient’s volume of urea distributionin milliliters. (B)

.4 The preferred method for measurementof the delivered dose is formal urea ki-netic modeling. Other methods may beused provided they give similar resultsand do not significantly overestimate themodeled dose. (A)

.5 Methods described in Appendix can beused to add the continuous component ofresidual urea clearance to the intermit-tent dialysis spKt/V to compute an ad-justed intermittent Kt/V. Laboratories re-porting adjusted session Kt/V valuesshould clearly identify such measure-ments by a different name (eg, “adjusted”Kt/V or “total” Kt/V). (B)

BACKGROUND

HD is a process that removes accumulatedolute from a patient who has total or near-totaloss of kidney function. The process is diffusionf solute from the blood into a physiological saltolution (dialysate) that is separated from thelood by a thin semipermeable membrane, theajor component of the dialyzer. The rate of

olute diffusion is a vital part of any measure-ent of dialysis or its adequacy, but the rate of

iffusion across the dialyzer membrane is driveny blood concentration and is proportional to it
following first-order kinetics). This linear pro- d

ortionality for simple diffusion (and convec-ion) allows expression of the dialysis effect as aatio of the diffusional removal rate (eg, mg/mL)o blood concentration (eg, mg/mL). This ratio,efined as “clearance,” is a fundamental measuref dialysis that tends to remain constant duringntermittent treatments as both blood concentra-ions of small solutes and solute removal ratesecrease. Clearance can be measured instanta-eously by sampling blood on both sides of theialyzer or, more appropriately for clinical appli-ations, as an average measurement during thentire duration of a single dialysis treatment byampling blood at the beginning and end ofreatment. This latter approach is simpler andives a measure of the true delivered dose of HD.

RATIONALE

requency of Measurements (CPG 2.1)

Numerous outcome studies have shown aorrelation between delivered dose of HD andatient mortality and morbidity (see Table 8,uideline 4).14,53-58 To ensure that patients withKD treated with HD receive adequate treat-ents, delivered dose of dialysis must be mea-

ured. Clinical signs and symptoms alone are noteliable indicators of dialysis adequacy. In stud-es of the relationship between delivered doses ofD and patient outcomes, the typical frequencyf measurement was monthly.1,54-56,58 Less fre-uent measurements may compromise the timeli-ess with which deficiencies in the deliveredose of HD are detected and hence may delaymplementation of corrective action. Monthlyeasurements also are pragmatic because pa-

ients undergo blood testing on a monthly basisn nearly all dialysis clinics. Alternatively, theose can be measured more frequently by usingn-line methods (see the discussion of on-linelearance that follows).

uration and Frequency of HD (CPG 2.2)

Because—as currently applied—therapeuticD is nearly always delivered intermittently,

xpression of the dialysis dose as a clearance isdvantageous because clearance is relatively con-tant throughout the treatment despite a marked
ecrease in blood concentrations of easily dia-
, 2006: pp S17-S23 S17

ldsfctsptidontanpmaitdbadpBefem(mfC

VC

mpcrsrltifas

cso

TV

jstiiomwdfcarcKfitnIcapu

U

btpmsTtcb


yzed solutes. To account for variations in theuration and schedule of treatments, dose expres-ion must include factors for both duration andrequency. This contrasts with measurements ofontinuous kidney function and continuous (peri-oneal) dialysis for which a simple clearance rateuffices. To account for the variable time eachatient spends on dialysis (treatment time or “t”),he clearance rate can be expressed per dialysisnstead of per unit of time. Expression of theose as a volume processed per dialysis insteadf volume flow (volume per unit of time) elimi-ates the need to measure “t” when calculatinghe dose (see calculation of clearance next). Toccount for differences in frequency, either theumber of treatments per week must be ap-ended to the expression of dose (eg, 3 treat-ents per week) or the dose can be expressed asfunction of repeating intervals (eg, per week

nstead of per dialysis). To compare doses amongreatments given at different frequencies, theose for a single treatment typically is multipliedy the number of treatments per week. For ex-mple, a target dose of 1.3 urea volumes perialysis would equate to a target of 3.9 volumeser week for patients treated 3 times per week.ecause a more frequent schedule also is morefficient, additional adjustments are required forrequency. The Work Group believed that dosesxpressed per dialysis should include an ele-ent for the number of treatments per week

eg, spKt/V[3] for 3 treatments per week). Aore detailed discussion of these effects can be

ound under “Effects of Dialysis Frequency” inPR 4, Minimally Adequate Hemodialysis.

alue of Urea as a Marker of Dialyzerlearance (CPG 2.3)

While the ultimate goal of dialysis treat-ents is a decrease in solute levels in the

atient, measurement of isolated solute levelsan be misleading if the solute measured is notepresentative of all uremic toxins. Because noolute probably qualifies in this respect, it iseasonable to pick as a marker an easily dia-yzed solute, such as urea, for which concentra-ions in the patient decrease significantly dur-ng the treatment. Urea clearance determinedrom a ratio of concentrations, rather than fromn absolute value, is a sensitive marker of
mall-solute diffusion across the dialyzer. Be-
ause dialysis most effectively removes smallolutes, urea Kt/V is a sensitive measure of theverall dialysis dose.

he Denominator Is the Patient’s Waterolume (CPG 2.3)

Native kidney clearance traditionally is ad-usted to body size and specifically to bodyurface area (BSA). This adjustment normalizeshe clearance effect among larger and smallerndividuals and among species of widely differ-ng size.59,60 However, for intermittent dialysisf solutes that distribute in body water, it isathematically more convenient to use bodyater volume as the denominator because byoing so, the clearance expression is reducedrom a flow to a fractional removal rate (the rateonstant). The product of the rate constant (K/V)nd time (t) can be determined easily as a loga-ithmic function of the predialysis to postdialysisoncentration ratio (C0/C): Kt/V � ln(C0/C).61,62

t/V is a measure of clearance per dialysisactored for patient size, measured as V. Express-ng clearance in this manner eliminates the needo specifically measure the individual compo-ents of Kt/V (clearance, time, and body size).nstead, predialysis and postdialysis solute con-entrations (C0 and C) provide a measure ofverage clearance per dialysis factored for theatient’s size in this simplified setting with noltrafiltration or urea generation.

ltrafiltration and Other Components (CPG 2.4)

However, enhancement of clearance causedy ultrafiltration that almost always occurs simul-aneously with diffusional clearance during thera-eutic dialysis adds a significant component thatust be included along with the simultaneous

olute generation rate in the Kt/V calculation.he more complex mathematical expressions

hat incorporate these vital components requireomputer programs to precisely calculate Kt/Vy iterating the following equation363:

wuncueemdmmmetco

S

dcwuami

wpaoocwweirepsvlm(

tsm

sm

AprUet

UferirKoeWeaok

HakvrB

METHODS FOR MEASURING AND EXPRESSING THE HEMODIALYSIS DOSE S19

here V is postdialysis urea distribution vol-me, G is urea generation rate, Kr is residualative kidney urea clearance, B is rate ofhange in V during dialysis, and Kd is dialyzerrea clearance. Despite the complexities of thequation and the iterative computer model, thexpression of clearance simulates solute re-oval from only a single compartment. Finite

iffusion rates among multiple body compart-ents add complexities that require additionalathematical adjustments, usually requiring nu-erical analysis for a solution. Fortunately, the

rrors encountered when applying the simpler modelo the usual thrice-weekly dialysis schedule tend toancel one another, allowing accurate assessmentf dose with the single-compartment model.63,64

impler Methods (CPG 2.4)

The arguments discussed show that the majoreterminants of Kt/V are the decrease in ureaoncentration during dialysis, contraction of bodyater volume during dialysis, and generation ofrea during the treatment. Use of these 3 vari-bles in an empirical formula allows an approxi-ation of Kt/V from a single equation, bypass-

ng the need for formal modeling65:

here R is the ratio of postdialysis BUN toredialysis BUN, t is time on dialysis in hours,nd BW is body weight. Although this andther similar methods give an approximationf the true spKt/V, calculated Kt/V matches theomputer-derived modeled Kt/V fairly closelyhen applied to dialysis given 3 times pereek for 2.5 to 5 hours. Disadvantages of this

quation when used alone to measure Kt/Vnclude no measure of the net protein catabolicate (PCR) that urea modeling generates andrrors when applied to short, frequent, orrolonged dialysis.65 However, additionalimplified equations that include the absolutealue of predialysis BUN can be used to calcu-ate normalized PCR (nPCR), also called nor-

alized protein nitrogen appearance ratenPNA).66

Because the relative decrease in urea concen-ration during therapeutic dialysis is the mostignificant determinant of Kt/V, direct measure-
ent of URR has been proposed as a simpler i
ubstitute for complex equations or formal ureaodeling to calculate dialysis dose.

URR = (C0 – C)/C0

lthough URR correlates well with spKt/V inopulation studies, significant variability in cor-elation in individual patients occurs becauseRR fails to include both the contraction in

xtracellular volume (ECV) and the urea genera-ion that typically occur during routine HD.

Fig 1 shows that for a given value of Kt/V,RR may vary considerably depending on the

raction of weight lost during dialysis. How-ver, when outcomes, including death, are cor-elated with either URR or Kt/V, no differencen degree of correlation is detectable. Theeason for this lack of a better correlation witht/V probably results from the narrow rangef doses achieved during HD and the curvilin-ar relationship between the 2 parameters.hen level of kidney replacement increases,

specially when treatment is given daily, URRpproaches zero. URR also is zero in continu-usly dialyzed patients or patients with normalidney function. Other disadvantages of URR

Fig 1. Impact of ultrafiltration on delivered dose ofD measured by using spKt/V and URR. The curvesre derived from formal single-pool modeling of ureainetics assuming a 3-hour dialysis, no RKF, and aolume of urea distribution that is 58% of BW. �Wtefers to net ultrafiltration losses as a fraction of finalW. Reprinted with permission.67

nclude the inability to adjust the prescription

aaRi

N

pcpofiwQc“tvsvksrtFtE

E

isit

cirrefcrmsTcbaas

wssrd(Ktttosidf


ccurately when the value is off target (bydjusting K or t), inability to add the effect ofKF, and inability to troubleshoot by compar-

ng prescribed with delivered dose.

ative Kidney Function (CPG 2.5)

The Canada-USA (CANUSA) Study of PDatients suggested that native kidney functionontributed more than dialysis function to im-rove outcomes at each level of total creatininer urea clearance.68 In view of the HEMO Studyndings that prolonging HD in the current thrice-eekly model does not improve outcome orOL1, failure to include residual clearance in

alculation of the required dose could lead toexcessive” dialysis that would compromise pa-ient QOL. The reduction in quality years mayary from patient to patient, who consider timepent on dialysis of variable quality. These obser-ations strongly support the notion that nativeidney function should be included in any expres-ion of overall kidney function (both native andeplacement). However, omission will protecthe patient from underdialysis when RKF is lost.or further discussion and practice recommenda-

ions, see CPR 2, Methods for Measuring andxpressing the HD Dose.

quilibrated Kt/V (eKt/V)(CPG 2.3)

When the time is shortened and dialysis isntensified, the treatment is less efficient becauseolute disequilibrium is enhanced and more times available for solutes to accumulate between
reatments. Allowance for solute disequilibrium p
an be made by adjusting spKt/V for the reboundn urea concentration at the end of dialysis. Theesulting eKt/V has a time-dependent factor thateflects the intensity of dialysis for a given deliv-red dose (spKt/V), as shown in Table 4. The firstormula by Daugirdas shown in Table 4, oftenalled the “rate equation,” was derived fromegression data that showed a tight fit with valueseasured by using the rebounded BUN mea-

ured 30 or 60 minutes after dialysis.69 Theattersall equation was derived from theoreticalonsiderations of disequilibrium and rebound,ut the coefficient was derived from fitting toctual data.70 The Leypoldt equation is a recentddition, also based on empirical fitting of mea-ured data.71

Many, including our European colleagues,12

ould like to convert the dose benchmark frompKt/V to eKt/V for HD (for PD, eKt/V andpKt/V are identical). Concern is raised aboutapid dialysis in small patients, for whom theifference between spKt/V and eKt/V is largerFig 2). After debating this issue in depth, theDOQI HD Work Group unanimously decided

o disallow shortened dialysis for treatments 3imes per week, but to do this explicitly ratherhan as a modification of Kt/V (see CPG 4). Usef eKt/V as a benchmark does not prohibit ultra-hort dialysis provided the clearance can bencreased, for example, by increasing blood andialysate flow rates or increasing dialyzer sur-ace area. For such highly sequestered solutes as
hosphate, this would not improve removal and

tflatdPDdcsOlsmdqrwrsc

O

oabdmaeK

itceufteltscdti

dmmmpuetrdtCedbbmaapoaof

mmcscbmKa

Tdc(L


he shortened dialysis time would compromiseuid removal, as noted in CPG 5. For pediatricnd small adult patients, the size-associated mor-ality risk may be related in part to the shortenedialysis time often prescribed for small patients.revious reports and recent evidence from theOPPS showing a positive correlation betweenialysis treatment time and mortality support theoncept that ultrashort dialysis (�3 hours), de-pite an adequate spKt/V, should be avoided.72,72A

f note, eKt/V determined by using all the formu-as in Table 4 first requires measurement ofpKt/V, and if the prescribed dose requires adjust-ent, conversion back to spKt/V is required to

etermine the change in dialyzer K that is re-uired. Equilibrated K cannot be adjusted di-ectly. In the absence of more evidence thatould favor the additional effort and target-

ange adjustment required to substitute eKt/V forpKt/V, the Work Group elected to stay with theurrently established standard.

n-line Clearance (CPG 2.4)

The requirement for monthly measurementsf HD adequacy is a compromise between costnd the utility of the measurement. The dose cane assessed more frequently by measuring con-uctivity (or ionic) clearance across the dialyzerembrane. This method does not require consum-

bles or blood sampling and can be used withach dialysis treatment to predict the delivered

0.8

0.9

1.0

1.1

1.2

1.3

1.4

0.0 2.0 4.0 6.0 8.0 10.0

time (hours)

Kt/

V

Fig 2. eKt/V as a function of dialysis treatment time.he rate equations for eKt/V (lower 3 lines) predict thatialysis efficiency decreases as time is shortened,reating a larger difference between eKt/V and spKt/V.— spKt/V, – – Daugirdas,69 ---- Tattersall et al,70 – - –eypoldt et al71 )

t/V in real time before the treatment is fin- p

shed.73-76 The method is based on the assump-ion that changes in dialysate conductivity areaused by transmembrane movement of smalllectrolytes, mostly sodium, that behave likerea. A step up in dialysate sodium concentrationollowed by a step down while measuring conduc-ivity changes in the effluent dialysate tends toliminate the effect of cardiopulmonary recircu-ation (CAPR) and provides a sodium clearancehat is similar to or only slightly less than theimultaneously measured cross-dialyzer urealearance.76 When applied in this fashion, con-uctivity clearance can be used safely as a substi-ute for the blood-side urea method for measur-ng dialysis dose.

To avoid errors from changes in clearanceuring dialysis, multiple ionic clearance measure-ents must be performed throughout the treat-ent. To calculate Kt/V, time on dialysis and Vust be determined accurately. The latter is a

otential problem if anthropometric formulas aresed to estimate V because these formulas arestimates that often differ significantly from therue value. Discrepancies between anthropomet-ic estimates of BSA and apparent need forialysis have similarly confounded interpreta-ions of creatinine clearance and GFR duringKD stages 1 to 4. Conversely, errors in mod-led V do not translate directly to errors inialysis dose because they are caused most ofteny errors in estimated K. The dose, which isased on the ratio K/V, which, in turn, is derivedostly from the log ratio of predialysis to postdi-

lysis BUN (see previous discussion), is moreccurate and patient specific. In addition, anthro-ometric formulas for V recently were shown toverestimate V in HD patients on average bypproximately 15%.77 However, this systematicverestimation of V tends to protect the patientrom underdialysis.

Instead of estimating V, one approach usesodeled V, measured monthly from urea kineticodeling, as the denominator.76 If conductivity

learance is measured during the modeled dialy-is, it can be used in place of the predictedlearance, eliminating the necessity to recordlood flow, dialysate flow, and dialyzer ureaass transfer-area coefficient (K0A) to calculateand V. This approach reduces the variance

ssociated with anthropometric V, as discussed;
reserves the value of V as a patient-specific

ml

oodetcdsta

dlljigpivvnsobeom

S

mmeoVmbotmmimrBat

KSt

ibm(seqK

bpetpdbdwgiiat

arrpttcpmatatnmestnp


easure of body composition; and allows calcu-ation of the patient’s G and nPCR.

Another suggested approach uses BSA insteadf V as the denominator (see previous discussionf the denominator and V).78 This measure ofialysis dose is appealing because it tends toquate dialyzer function with native kidney func-ion by using the same denominator, which isloser than V to the universal scaling factoriscussed. However, it sacrifices the individualpecificity of V and G, relying instead on popula-ion averages to calculate BSA from body heightnd weight.

Although these approaches to measuring theialysis dose are intriguing and increasingly popu-ar, the HD Work Group believed that compel-ing evidence for an improvement that wouldustify changing the current methods for measur-ng dialysis is lacking. Measurement of the inte-rated clearance as Kt/V from a simple ratio ofredialysis to postdialysis BUN is possible onlyn patients dialyzed intermittently for whom BUNalues fluctuate greatly. These fluctuations pro-ide an opportunity to measure adequacy, V, andPCR that is unparalleled in other therapeuticettings. The suggested newer methods usingn-line clearance and/or a different denominatoreg for research that could, in the future, providevidence for superior performance as a measuref dialysis adequacy (see HD Research Recom-endations).

ummary of Methods

Table 4A lists the expressions of dose andethods currently used in clinical practice toeasure the delivered dose of dialysis. Prefer-

nce continues to be given (similar to the previ-us KDOQI recommendations) to delivered Kt/urea as the best outcome correlate and to theethod of single-pool urea kinetic modeling

ecause of its simplicity, accuracy, and targetingf small-solute clearance, the principal therapeu-ic effect of HD. While eKt/V theoretically isore indicative of the true dialysis effect, itsajor advantage is seen during short treatments;

t cannot be adjusted directly and it requireseasurement of spKt/V for estimation from the

egression-based formulas shown in Table 4.ecause CPR 4 now limits shortened dialysisnd for lack of standards, as well as evidence,
hat eKt/V correlates better with outcome, the p
DOQI Work Group, in contrast to the Europeantandards Group,12 did not strongly recommend

his expression of dose.

LIMITATIONS

To accurately measure Kt/V from the decreasen BUN levels during dialysis, the decrease muste significant, ie, the 2 concentrations (C0 and C)ust be significantly different from one another

ratio � �1.5). This means that the dialysischedule must be truly intermittent to avoidxcessive mathematical variance. As the fre-uency and duration increase, measurement oft/V becomes less precise.Measurement of HD dose and adequacy can

e anticipated by both the dialysis staff and theatient. Even if unannounced in advance, mod-led or measured dialysis may differ from theypical dialysis because staff are alerted by theredialysis BUN sampling. This issue was ad-ressed by a study that found a higher averagelood volume processed during the measuredialysis.79 In 20% of their patients, the differenceas clinically relevant. Quality assurance pro-rams should take this into account by examin-ng elements of the dialysis prescription, includ-ng blood volume processed, time on dialysis,nd average flow rates during the nonmeasuredreatments.

The ideal denominator for dialysis dosagemong patients of varying size is the generationate of uremic toxins because in a steady state ofegular dialysis treatments, levels of toxins in theatient are likely to be directly proportional toheir generation rates (and inversely proportionalo clearance). Therefore, the increase in Kt/Vaused by weight loss (lower V) in a dialysisatient with malnutrition likely is a false improve-ent in dialysis dose. No universally accepted

djustments currently are available to eliminatehis potential error, but nephrologists should beware of the pitfall and consider offering addi-ional dialysis for patients with evidence of mal-utrition. Because V is a measure of lean bodyass and although using V as the denominator

liminates potential errors that might result fromubstituting weight in obese patients (presuminghat fat is not a source of uremic toxins), it doesot eliminate the potential error in malnourishedatients. Similarly, an increase in edema fluid or
ossibly even muscle mass (if edema and muscle

dilsdisHgf

tcmra

it


o not influence the generation of uremic toxins)s expected to decrease Kt/V, although toxinevels in the patient are not affected. Althoughome experts are opposed to the notion thatelivered dialysis dose be scaled to patient size,80

t seems intuitive that a one-sized dialysis pre-cription does not fit all patient ages and sizes.owever, it also is possible that the rate of toxineneration has more to do with diet or other

Table 4A. Preferred Measures of the Del

For 2 or 3 dialysis treatments per wkSingle pool Kt/Vurea determined by:

Urea kinetic modeling Simplified multivariable equation

Equilibrated Kt/V (eKt/V) Bloodless measurements of dialyzer clearURRDouble pool Kt/Vurea by formal kinetic moSolute removal index (SRI) from dialysate

For more frequent dialysis: a continuStandard Kt/Vurea

Normalized Kt/Vurea

actors than body size. d

The patient’s native kidneys provide functionshat cannot be duplicated by the dialyzer and thatontribute to patient survival.81 These benefits,ost of which are poorly understood, are not

eflected in small-solute clearances, even whendjusted for intermittence.

As dialysis frequency is increased, fluctuationsn solute concentration are diminished, reducinghe power of urea kinetic modeling and favoring

Dose (in Order of Preference)

ing ionic conductance or dialysate urea monitoring

(used only for research purposes) ions quivalent of kidney clearance

ivered

ance us

deling collectous e

ialysate methods for measuring the dose.

pmu

3

3

3

3

S

uwpe32supdpim

3

S

GUIDELINE 3. METHODS FOR POSTDIALYSIS
BLOOD SAMPLING
bwsrsucmt

lstr(c1llebs3tdabbidmtP3

bfomsddt

P3

When dialysis adequacy is assessed by usingredialysis and postdialysis BUN measure-ents, blood samples should be drawn by

sing certain acceptable procedures.

.1 Both samples (predialysis and postdialy-sis) should be drawn during the sametreatment session. (A)

.2 The risk of underestimating predialysisBUN level because of saline dilution or bysampling the blood after treatment hasbegun should be avoided. (A)

.3 The risk of underestimating the postdialy-sis BUN level because of access recircula-tion (AR) should be avoided by firstslowing the blood flow through the dia-lyzer to a rate at which AR is expected tobe minimal (100 mL/min) for a periodlong enough to ensure that unrecirculatedblood has advanced to below the samplingport (usually 15 seconds). (A)

.4 An alternative method is to stop thedialysate flow for a period long enough toincrease the dialysate outlet BUN levelclose to that of the blood inlet BUN level(3 minutes) before obtaining the postdialy-sis sample. (A)

BACKGROUND

ummary of Updated Changes

The proper methods of sampling blood forrea nitrogen before and after an HD treatmentere detailed in Guidelines 7 through 9 of thereviously published KDOQI 2000 HD Ad-quacy Guidelines.6 These updated guidelines,.1, 3.2, and 3.3, are largely unchanged from the000 guidelines, except for minor details. Whenampling blood from venous catheters, the vol-me of the initial aspirate is specified morerecisely, and a recommendation is made toiscard—instead of routinely reinfusing—the as-irated blood sample. Guideline 3.4, acknowledg-ng the alternative use of the dialysate-stop-flowethod, is new.

RATIONALE

As reviewed in the 2000 guidelines,6 there are
components of postdialysis urea nitrogen re- s
American Journal of Kidney24

ound (see Fig 3). The first is caused by AR,hich resolves within seconds after stopping dialy-

is (point B), the second is caused by CAPR, whichesolves within 1 to 2 minutes after stopping dialy-is (point C), and the third is caused by entry ofrea from relatively undialyzed tissues and bodyompartments, which we term remote-compart-ent (RC) rebound. The latter resolves within 30

o 60 minutes after stopping dialysis (point D).The first focus of these blood-drawing guide-

ines is to limit the effect of AR on the postdialy-is BUN sample because AR causes large overes-imations of the true delivered dose and canesult in true delivered Kt/V values less than 0.8at which level mortality risk is strongly in-reased) in patients with apparent Kt/V values of.4 or greater.83 Since the KDOQI 2000 guide-ines were published, it has become clear that theater rebound caused by CAPR is small84 andffects of RC rebound are relatively predictableased on the rate of dialysis.84,85 In addition,ome studies showed that sampling blood about0 minutes before the end of dialysis can predicthe BUN level 30 minutes after the end ofialysis.86 This method is not recommended indults because of its relative complexity andecause RC rebound is relatively predictableased on the rate of dialysis,84,85 and—mostmportantly—because in the presence of AR, theialysis dose can still be markedly underesti-ated unless a slow-flow method is used to draw

he sample 30 minutes before the end of dialysis.redialysis Blood Sampling Procedure (CPG.1 and 3.2, see Table 5)

The predialysis BUN sample must be drawnefore dialysis is started to prevent this samplerom reflecting any impact of dialysis. Dilutionf the predialysis sample with saline or heparinust be avoided. Underestimating the predialy-

is BUN level will result in underestimation ofelivered Kt/V or URR, which is not particularlyangerous; however, nPCR then will be underes-imated.

ostdialysis Blood-Sampling Procedure (CPG.3, see Table 6)

Proper timing for acquisition of the postdialy-
is BUN sample is critical.6,83 Immediately upon
Diseases, Vol 48, No 1, Suppl 1 (July), 2006: pp S24-S27

ctrbtrTfeo

mTtpuatsb

aaCtnpuvritrowdfllmCt

t(R

METHODS FOR POSTDIALYSIS BLOOD SAMPLING S25

ompletion of HD, if AR was present, some ofhe blood remaining in the access and extracorpo-eal circuit actually is recirculated blood. If thelood sample is drawn immediately upon comple-ion of dialysis, just-dialyzed blood that hasecirculated into the access will dilute the sample.he consequence of sampling this admixture is a

alsely decreased BUN value and artificially el-vated Kt/V and URR.6,83 Therefore, the amountf dialysis delivered will be overestimated.Early urea rebound (�3 minutes after dialysis)ay be viewed as a 2-component process.89-91

he first component is caused by blood recircula-ion within the access or catheter and is notresent in patients without AR. If AR is present,rea rebound from recirculation begins immedi-tely upon completion of HD and resolves in lesshan 1 minute, usually within 20 seconds. Theecond component of early urea rebound is causedy CAPR that begins approximately 20 seconds

-41 6

2 0

2 4

2 8

3 2

3 6

BU

N (m

g/d

l)Fig 3. Components of postdialysis urea

BUN) rebound. See text for explanation.eprinted with permission.82

fter stopping HD and is completed 2 to 3 minutesfter slowing or stopping the blood pump.90

APR refers to the routing of just-dialyzed bloodhrough the veins to the heart, through the pulmo-ary circuit, and back to the access without theassage of the just-dialyzed blood through anyrea-rich tissues.90-93 It should not occur with aenous access because venous (rather than arte-ial) blood is sampled; however, some increasen urea concentration during the initial 3-minuteime frame may occur because of mixing of ureaeturning from different organs. The late phasef urea rebound (�3 minutes) is completedithin 30 to 60 minutes after the cessation ofialysis. The late phase is a consequence ofow-volume disequilibrium (perfusion or paral-

el-flow model)94 and/or delayed transcellularovement of urea (diffusion model)92,95 (seePG 2, Methods of Measuring and Expressing

he HD Dose).

-2 0 0 2 0 4 0 6 0

ime (minutes postdialysis)

AR

CAPR

RC rebound

0

WS

tswsnmwsri1mtp

c1alibbibb

fbDets


hy the Blood Pump Should Be Slowed BeforeamplingDecreasing blood flow to 100 mL/min reduces

he entry of cleared blood into the access andtops AR (unless there is needle reversal, inhich case it still greatly reduces AR). The dead

pace of the blood tubing attached to the accesseedle usually is about 3 mL. The dead space inost venous catheters is similar, albeit some-hat less, in the range of 1 to 2 mL. The dead

pace between the tip of the dialyzer inlet (arte-ial) blood tubing and sampling port area usuallys about 7 to 12 mL, giving a total dead space of0 to 15 mL, although this should always beeasured and known for a given set of blood

ubing because in some blood tubing, the sam-ling port is farther removed from the patient

onnection. A flow rate of 100 mL/min is about.6 mL/s. Therefore, waiting 15 seconds at suchflow rate will ensure that the column of undi-

uted blood will have moved 1.6 � 15 � 24 mLnto the blood tubing during the time of reducedlood flow. As long as the volume of tubingetween the patient connection and sampling sites substantially less than this 24 mL, the sampledlood should not be contaminated with outflowlood.In situations in which the blood is drawn not

rom a sampling port on the inflow blood tubing,ut by attaching a Luer-Lock connector (Bectonickinson and Co., Franklin Lakes, NJ, USA) to

ither the venous catheter or arterial needle bloodubing, the dead-space volume to the samplingite is only 2 to 3 mL. However, for simplicity,

tflw

S

iuWobpbTtnpaboesbh

dsbidurs

2Badcs

vdrs

avsftTpflim

METHODS FOR POSTDIALYSIS BLOOD SAMPLING S27

he Work Group recommended keeping the slow-ow period the same regardless of the site fromhich blood is sampled.

topping Dialysate Flow Before SamplingA new method for postdialysis blood sampling

ntroduced since the KDOQI 2000 Guidelinepdate was reviewed by the Work Group.96,97

hen dialysate flow is stopped, the dialysateutlet urea concentration starts to approach thelood inlet level, and AR (if present) has arogressively lower dilutional effect on inletlood flow. With this method, as outlined inable 7, blood flow must not be reduced because

he dialysate, now “trapped” in the dialyzer,eeds to equilibrate with blood as quickly asossible. Two studies showed that 5 minutes wasdequate to equilibrate the arterial and venouslood tubing samples.96,97 The Work Group rec-mmendation is to follow the method of Geddest al.96 It should be realized that 3 minutes aftertopping dialysis, the CAPR component of re-ound will be complete and RC rebound will

Fig 4. Stop-dialysate method for postdi-lysis blood sampling. Mean arterial andenous blood urea concentrations aftertopping dialysate flow are expressed as araction of the blood urea concentration inhe contralateral arm at time zero (n � 10).he data suggest that, for practical pur-oses, 3 minutes after stopping dialysateow, equilibration has occurred between

nlet and outlet blood. Reprinted with per-ission.96

ave begun. Hence, a postdialysis BUN sample b

rawn by using this dialysate method will belightly higher than that obtained when using thelood method because with the latter, the samples obtained only 15 seconds after the end ofialysis. This means that the spKt/V obtained bysing the stop-dialysate-flow method will (theo-etically) be slightly lower in comparison to thelow-the-blood-flow method.

Use of a 5-minute waiting period resulted in a% decrease in measured value for URR (Fig 4).96

ecause of the rebound considerations discussednd based on data in Fig 4, the Work Groupecided that a 3-minute waiting period was suffi-ient. By that time, dialyzer inlet and outletamples have nearly equilibrated.

LIMITATIONS

The stop-dialysate-flow method has not beenalidated during pediatric dialysis. If a largeialyzer is used at a relatively lower blood flowate, the dialyzer outlet blood may still have aubstantially lower urea concentration than inlet
lood after 3 minutes of stopping dialysate flow.

4

4

4

4

M

aogcrShSgTbacpssbetoa

S

GUIDELINE 4. MINIMALLY ADEQUATE HEMODIALYSIS

vMs

H(

rv6virttptchmoilftHrodeWEhmg

H

amofiplTteHh

.1 Minimally adequate dose:The minimally adequate dose of HD given 3times per week to patients with Kr less than2 mL/min/1.73 m2 should be an spKt/V(excluding RKF) of 1.2 per dialysis. Fortreatment times less than 5 hours, an alter-native minimum dose is a URR of 65%. (A)

.2 Target dose:The target dose for HD given 3 times perweek with Kr less than 2 mL/min/1.73 m2

should be an spKt/V of 1.4 per dialysis notincluding RKF, or URR of 70%. (A)

.3 In patients with residual urea clearance(Kr) greater than or equal to 2 mL/min/1.73m2, the minimum session spKt/V can bereduced. One method of minimum dosereduction is described in CPR 4.4. In suchpatients, the target spKt/V should be atleast 15% greater than the minimum dose.(B)

.4 Missed and shortened treatments:Efforts should be made to monitor andminimize the occurrence of missed orshortened treatments. (B)

RATIONALE

inimally Adequate Dose (CPG 4.1)

The present adequacy guideline for a minimallydequate dose remains unchanged from the previ-us (2000) guidelines.6 In deciding whether thisuideline needed to be changed, the committeeonsidered 3 lines of evidence. The first wasesults of the primary analysis of the NIH HEMOtudy, published in 2002.1 The committee alsoad access to as-treated results of the HEMOtudy, which were published at the time the draftuidelines were released in November 2005.98

his report was judged to be of some importanceecause it identified a dose-targeting bias in thenalysis of delivered therapy versus mortality inross-sectional data sets, which potentially im-acts on the weight of evidence derived fromuch data sets. The second was a series of articlesuggesting that dosing of dialysis should not beased on URR or its derivative, Kt/V (whichssentially is volume of blood cleared divided byhe modeled urea volume, V), but on the volumef blood cleared (Kt) only.78,99-101 The third was
series of analyses of delivered dose (ie, URR) t

ersus mortality based on either the USRDS-edicare data set or the Fresenius Medical Care

ubset of these data.102-104

EMO Clinical Study: PrimaryRandomized) Results

Primary results of the HEMO Study, whichandomized patients to a delivered eKt/V of 1.16ersus 1.53, equivalent to URR values of about3% versus 75% or spKt/V values of about 1.3ersus 1.7, revealed little evidence to supportncreasing the dose of dialysis beyond the cur-ent (2000) KDOQI recommendations, respec-ively.6 The lack of benefit, without even a trendhat was close to statistical significance, ap-eared not only in the primary outcome of mor-ality, but also in a variety of main secondaryomposite outcomes relating to various causes ofospitalization combined with mortality. Further-ore, analysis of minor secondary composite

utcomes dealing with nutritional measures—ncluding changes in weight and serum albuminevels,105 as well as QOL measures106—alsoailed to support a beneficial effect of increasinghe dose of dialysis. Of all trials evaluated, theEMO Study was by far the largest, and its

andomized design and measurement of hardutcomes were given an enormous weight inetermining whether the 2000 KDOQI HD Ad-quacy Guidelines needed to be changed. Theork Group realized that the recently published

uropean guidelines recommended substantiallyigher minimal doses of HD based on an eKt/Veasure, corresponding to spKt/V minimum tar-

ets of about 1.4 to 1.5.12

EMO Clinical Study: As-Treated ResultsThe HEMO dose-versus-mortality question

lso was assessed within each treatment arm,easuring the effects of actual delivered dose

ver time versus mortality.98 This study identi-ed a dose-targeting bias and suggested thatatients in a cross-sectional analysis receivingess dialysis are also at greater risk for death.his increased death risk was of a high magni-

ude and was incompatible with a biologicalffect of dose. Although conditions of the 2EMO Study arms were not representative ofow dialysis is prescribed in the field, documen-
ation of such a strong potential dose-targeting

bsWdoo

SU

CteiFtsaKmamodiaosrtls2aoeCibccsdtm

mtpwU

wta(ecGceumfldcaptb

molrmVtwwVwBcpt

DD

licdoeirmtc

MINIMALLY ADEQUATE HEMODIALYSIS S29

ias (which may be operative in cross-sectionaltudies, albeit to a lesser degree) convinced theork Group members to place less weight on

ose-versus-mortality relationships derived frombservational studies despite the large numbersf patients included in such studies.

tudies Advocating Alternate Measures ofrea-Based AdequacyThese studies are discussed in more detail in

PG 2, Methods for Measuring and Expressinghe HD Dose. Since the 2000 KDOQI HD Ad-quacy Guidelines were published, 1 group ofnvestigators in particular, using data derived fromresenius Medical Care North America patients in

he United States, argued that dose of dialysishould not be factored by modeled V.78,100,101 Therguments against using URR or its derivativet/V fall into 2 general categories: (1) doing soay result in relative underdialysis of women

nd small patients of both sexes, and (2) becauseodeled V is itself a predictor of mortality, use

f dialysis dose factored by V may confoundialysis dose-versus-mortality relationships foundn cross-sectional studies in complex and notlways predictable ways. A secondary analysisf the intent-to-treat results of the HEMO Studyuggested that the higher dose of dialysis mayesult in better survival in women, who alsoended to be smaller than the men in that particu-ar trial.13 The Work Group decided, based onuggestive evidence, that more dialysis (beyond000 KDOQI levels) may be better for womennd, perhaps, smaller patients, but that the levelf evidence did not reach a point at which thexisting guideline should be changed. Hence, 2PRs were derived suggesting that more dialysis

n women and/or in smaller patients might beeneficial (see Section II). Despite the theoreti-al arguments, as well as attempts to addressonfounding effects of V in cross-sectional dataets, the committee believed that, at present, theata are not compelling enough to depart fromhe 2000 recommendation to follow small-olecule clearance using Kt/V.Given the increased use of conductivity toeasure clearance during the dialysis session,

he Work Group also considered using an anthro-ometric volume as the clearance denominatorhen clearance was measured by conductivity.
sing an anthropometric volume as denominator l
as speculated to result in a more stable denomina-or, less affected by errors in predialysis and postdi-lysis urea nitrogen determinations. For example,Kecn � T/Vant, where Vant � anthropometrically-stimated total body water distribution volume)ould be used instead of Kt/V urea. The Workroup’s conclusion was that there were not suffi-

ient data comparing sequential dialysis ad-quacy measures by using both conductivity andrea kinetics in the same patients to make such aajor revision, although it was recognized that

rom a quality-assurance perspective, it would beess challenging to ensure a constant dialysisose given a more constant denominator. Con-erns also were raised about altered modeled tonthropometric urea volume ratios in individualatients, although given the relative flatness ofhe adequacy to mortality curve, this issue maye of secondary importance.Another potential strategy discussed was to nor-alize the dialysis amount to a denominator based

n BSA as opposed to urea volume, whether theatter was derived from modeling or anthropomet-ics. For example, this is accomplished easily byultiplying the target Kt/V value by 3.27 �/V0.667 (V raised to the 2/3 power). Such a correc-

ion method (developed by the Frequent HD Net-ork investigators) gives the same dialysis dosehen V � 35 L, but then augments the dose whenis less than this amount and reduces the dose

hen V is larger, giving, in effect, a dose based onSA instead of V. Again, for lack of definitivelinical outcomes evidence supporting this ap-roach, it was left for perhaps a future revision ofhe guidelines when more data might be available.

ose-Related Mortality in Large Observationalata SetsSince the KDOQI 2000 HD Adequacy guide-

ines were published, a number of studies, includ-ng analyses of USRDS Annual Data Reports,ontinued to examine the relationship betweenose of dialysis and mortality. Most, but not all,bservational studies reported dose in terms ofither spKt/V or URR. The dose-versus-mortal-ty relationship was examined as a function oface and sex57,104 and as influenced by variouseasures of body size102,103 and nutritional sta-

us.99 Because the general median spKt/V in-reased over time, these analyses included much
arger samples of patients receiving higher doses


oirtSblrctrap

RG

w5tIcsrmsKmamwcdRAsoi

T

sapoturfca

dob12ttgiaott1tgb

A

iahd

T

ngress o


f dialysis. Most of these analyses suggested thatncreasing the dose of dialysis above the targetecommended in the 2000 guidelines to levelsargeted in the high-dose arm of the HEMOtudy (spKt/V � 1.7) should decrease mortalityy a substantial amount (Table 8). However, theack of concordance between these observationalesults and negative results of the HEMO Study,oupled with the dose-targeting bias identified inhe as-treated analysis of HEMO Study patients,estrained the Work Group from recommending

global increase in recommended spKt/V foratients dialyzed 3 times per week.

enal Clearance Compared With the 2000uidelinesThe 2000 KDOQI HD Adequacy Guidelines

ere applied to patients with a Kr less thanmL/min/1.73 m2, for which Kr is defined as

he average of urea and creatinine clearances.n the present guidelines, the committee de-ided to use urea clearances for the purpose ofpecifying minimally adequate urea fractionalemoval. This allows more accurate measure-ent of protein catabolism in patients with

ignificant Kr and an opportunity to combiner with Kd (see CPG 2). Urea clearance of 3L/min corresponds approximately to an aver-

ge of urea and creatinine clearances of 5L/min. In the present guidelines, this numberas reduced to 2 mL/min of normalized urea

learance to enable some decrease in dialysisose for patients with moderate degrees ofKF, as discussed in the accompanying CPR.more complete discussion of why this “step”

trategy was adopted, rather than the additionf residual clearance as a continuous function,

able 9. Fraction of Treatments With an spKper

Achieved KTarget Kt/V k = 1 k = 21.20 0.51 0.481.25 0.66 0.681.30 0.79 0.821.35 0.87 0.901.40 0.92 0.95Data shown for a single treatment (k = 1) and for avera*Greene et al. Proceedings of the XVth International Co

s detailed in the accompanying CPR. l

arget Dose (CPG 4.2)

The KDOQI 2000 HD Adequacy Guidelinespecified a target spKt/V of 1.3, with a minimallydequate dose of 1.2 per dialysis given 3 timeser week. During the course of measuring the dosef therapy many times in each patient enrolled inhe HEMO Study, the variability of modeled vol-me and hence of spKt/V was determined accu-ately. The within-patient coefficient of variationor single-pool V in the HEMO patient data set waslose to 10%. The relationship between target Kt/Vnd subsequent achieved Kt/V is shown in Table 9.

As shown in Table 9, the previous recommen-ations to target 1.3 would result in about 21%f treatments at any given time apparentlyeing less than the Kt/V minimum target of.21 (the fraction � 1.2 is 0.79, so 0.21, or1%, would be � 1.2). Thus, it appears thatargeting 1.3 would result in needless prescrip-ion modifications and/or troubleshooting. Tar-eting therapy at an spKt/V of 1.4 and averag-ng results from 3 monthly measurements ofdequacy results in a much greater proportionf treatments (in the range of 97%), greaterhan the minimum 1.2 adequacy target. Settinghe target dose of dialysis to 1.4, rather than.3, also seemed to be justified given sugges-ive results (not yet qualifying for guideline-enerating status) that subsets of patients mightenefit from higher doses of dialysis.

voiding Missed Treatments (CPG 4.3)

Measurement of fractional urea removal dur-ng a single dialysis treatment obviously is not

monthly average of dialysis adequacy andas validity only if dialysis treatments areelivered reliably 3 times per week on a regu-

reater Than 1.2 When Targeting 1.2 to 1.4 sis eraged over k treatments*

k = 3 k = 4 0.47 0.47 0.68 0.69 0.84 0.84 0.93 0.93 0.97 0.97

r k treatments. f Nephrology, Buenos Aires, Argentina, May 2 through 6, 1999.106A

t/V GDialyt/V av ging ove

ar basis. A number of studies document that

tsmncKgKfnmtpndtdma

dwdisotig1pspms


he number of missed and/or shortened dialy-is treatments in US dialysis patients (4%issed treatments per month) is more than the

umber missed by their counterparts in otherountries, such as Japan.107 Whereas theDOQI 2000 HD Adequacy Guidelines sug-ested increasing the frequency of measuringt/V or URR in patients for whom treatments

requently were shortened or missed, they didot address the issue of monitoring and mini-izing the occurrence of missed and shortened

reatments. A number of studies suggested thatoor compliance in HD, especially in terms ofumber of missed treatments, is an important pre-ictor of mortality and hospitalizations.14-16 Forhis reason, the Work Group believed that everyialysis center should have a mechanism in place toonitor and minimize the occurrence of missed

nd shortened dialysis treatments. K

LIMITATIONS

The main limitation to recommending adequateosing of dialysis in patients following a thrice-eekly schedule is the difficulty performing ran-omized studies, as well as multiple confoundingssues related to analysis of dose-mortality relation-hips in observational studies. In the Work Group’spinion, data from the HEMO Study suggested thathe dose-benefit relationship for values of spKt/Vn the current clinical setting are relatively flat atreater than the recommended minimum value of.2 thrice weekly. Many patient subgroups anderhaps all patients might benefit from more dialy-is, but it seems that benefits would be derivedrimarily from extending dialysis treatment timearkedly or moving to a more frequent dialysis

chedule, as opposed to simply increasing urea
t/V.

pstoVide

5

5

5

pwflcttcspicipsus

scrw3

A

GUIDELINE 5. CONTROL OF VOLUME AND
BLOOD PRESSURE
t4ewdplhdos

A(

wdrmcmpprbterdvarcttipbt“fisobeFd

There is ample evidence in the non-CKDopulation that optimal control of blood pres-ure influences mortality. In the HD popula-ion, available evidence indicates that controlf a patient’s fluid volume influences outcome.olume and blood pressure are linked; thus, it

s important to optimize ultrafiltration andry weight to control blood pressure in anffort to improve patient outcome.

.1 The ultrafiltration component of the HDprescription should be optimized with agoal to render the patient euvolemic andnormotensive. This includes counselingthe patient on sodium and fluid restric-tion, adequate ultrafiltration, and the useof diuretics in patients with RKF. (A)

.2 Daily dietary sodium intake should be re-stricted to no more than 5 g of sodiumchloride (2.0 g or 85 mmol of sodium). (A)

.3 Increasing positive sodium balance by“sodium profiling” or using a high dialy-sate sodium concentration should beavoided. (B)

RATIONALE

The volume status of a maintenance dialysisatient is mainly a function of sodium intake,ater intake, urine output, and removal of excessuid by ultrafiltration during dialysis. Becauseellular membranes are freely permeable to wa-er, the osmotic gradient generated by the addi-ion of dietary sodium to the ECF compartmentauses water to move from cells into the ECFpace, thus expanding ECF volume at the ex-ense of the intracellular fluid compartment. Thencrease in ECF osmolality stimulates the thirstenter of the hypothalamus, increasing waterntake. Thus, the combined influence of bothositive sodium and water balances causes expan-ion, primarily of the ECF volume.108 Such vol-me expansion can be especially marked in dialy-is patients with poor RKF.

Poor volume control can exacerbate hyperten-ion and its myriad detrimental effects on theardiovascular system.109-112 Early reports ofisks associated with excessive sodium and waterere inconclusive, but analysis of USRDS Waves
and 4, when adjusted for comorbidity, showed a

hat weight gain between dialyses of more than.8% (ie, 3.4 kg in a 70 kg person), a reflection ofxcessive sodium and water intake, is associatedith increased mortality.113 Although a preciseefinition of dry weight is not possible in eachatient, methods have been described for control-ing volume and blood pressure and are reviewedere. A thorough examination of the approach toeriving a true “dry” weight is beyond the scopef the Work Group. The reader is referred totandard dialysis texts for detailed information.

chievement of Optimal “Dry” WeightCPG 5.1)

A patient’s true dry weight, defined as theeight when fluid volume is optimal, can beetermined accurately, but the method is noteadily available in clinical settings (eg, use ofultiple-frequency bioimpedance spectros-

opy).114 Instead, dry weight usually is deter-ined clinically by evaluating level of blood

ressure, evidence of fluid overload, and theatient’s tolerance of ultrafiltration aimed to ar-ive at the estimated target weight.115 It shoulde noted that a patient can have fluid excess inhe absence of gross clinical evidence of volumexpansion,116 a phenomenon termed “silent ove-hydration.”117 During dialysis, as the patient’sry weight is approached, the rate at which theascular compartment refills from fluid in thedjacent tissue spaces is reduced.118 If UFR iseduced toward the end of dialysis, the reducedompensatory refilling process may be adequateo support the patient’s depleted blood volume,hereby avoiding hypotension and muscle cramp-ng. When the blood volume is refilled and bloodressure improves, more rapid ultrafiltration cane resumed. For a fluid-overloaded dialysis pa-ient, this step-by-step process of identifying, orprobing,” for the true dry weight through ultra-ltration—but without inducing hypotension—hould be accomplished gradually over a numberf dialysis treatments (usually over 4 to 12 weeks,ut it may require as long as 6 to 12 months) untilvidence of fluid overload is in abeyance.119-121

or patients with diabetes mellitus (autonomicysfunction) or cardiomyopathy, this process of
pproaching the dry weight may take longer
, 2006: pp S33-S39 S33

bp

csdfipsibtIpbeadAsmd

twptuplimh

tsfdq

eqpHtpisdssdtpecmipa

Ha

Hss

u


ecause plasma refilling can be low even in theresence of an expanded volume.From the very beginning of the dialysis therapy,

oncomitant with ultrafiltration probing, dietaryodium should be restricted and use of a highialysate sodium concentration and sodium pro-ling should be avoided. While decreasing theatient’s fluid volume, net fluid losses ideallyhould not exceed 1 to 2 kg/wk, and by restrict-ng dietary sodium and fluid intake, weight gainetween dialyses should not exceed 1 kg duringhe week and 1.5 to 2 kg during the weekend.121

t should be noted that during this dry weight–robing stage, in 90% of patients, ECF volumeecomes normal within a few weeks, but thelevated blood pressure continues to decrease fornother 8 months or longer. See Fig 5 for aescription of this “lag phenomenon.”122-125

s patients lose excess fluid and their hyperten-ion improves, therapy with antihypertensiveedications can be systematically tapered or

iscontinued.121

Tolerance to ultrafiltration varies among pa-ients. The slow approach to achievement of dryeight is appropriate for most patients, but foratients with cardiac failure or severe complica-ion-associated hypertension, more aggressiveltrafiltration may be required acutely.126 Someatients may require slow ultrafiltration during aonger time than 4 hours 3 times weekly.115 Tomprove fluid removal during dialysis and reduceorbidity, monitoring blood volume during HD

as been recommended. However, use of moni-

Fig 5. Illustration of the “lag phenomenon.” The seconnassociated with a change in ECV was observed in all 8 pati

oring devices has met with varying degrees ofuccess; some investigators have obtained satis-actory results,127-130 whereas other have hadisappointing results.131 Further studies are re-uired to clarify this important issue.Hypotension during dialysis has many adverse

ffects and potential life-threatening conse-uences. By impairing tissue perfusion, low bloodressures can compromise dialysis adequacy.132

ypotension induced by overzealous ultrafiltra-ion also may contribute to loss of RKF and, inredisposed patients, coronary and/or cerebralschemia.121 To avoid hypotension, dry weighthould be systematically reevaluated after eachialysis treatment. It was suggested that a dialy-is log summarizing the relevant information,uch as body weights, blood pressures, and intra-ialytic incidents, is essential to provide a longi-udinal dynamic view of ECF volume and bloodressure changes.133 Dry weight may change, forxample, when a newly dialyzed patient be-omes less uremic, regains appetite, and gainsuscle and nonfluid weight (reflected by an

ncrease in serum creatinine level), or when aatient has an intercurrent illness and loses musclend tissue weight.

ypertension: Prevalence, Pathogenesis,nd Risks (CPG 5.1)

It is noteworthy that 60% to 90% of maintenanceD patients have hypertension.41,109,134-138 De-

pite the use of multiple medications, hyperten-ion in these patients often is poorly con-

dary decrease in blood pressure seen at 5 monthsents studied. Reprinted with permission.125

tfiHtNoptpe

rpotssslhemoppCcwCvnpotprlpw

tmatfscnnew

sop

clphfnsSosnlsvelpchdbtaVptthdsdsRdtnIsptbt

pnS

CONTROL OF VOLUME AND BLOOD PRESSURE S35

rolled.109,111,124,136,139 For example, among therst 1,238 maintenance HD patients enrolled in theEMO Study, less than 30% had blood pressures

hat were considered normotensive by the Jointational Committee (JNC) VI standards.111 In an-ther study of 2,535 clinically stable adult HDatients, 86% were found to be hypertensive. Withinhis hypertensive group, only 30% had their bloodressure under adequate control, 58% were inad-quately treated, and 12% were not treated at all.109

With regard to the pathogenesis, it generally isecognized that the majority of hypertensive HDatients develop hypertension because of fluidverload secondary to sodium and water reten-ion.123,133,140-142 A high predialysis or interdialy-is blood pressure may be related to excessiveodium and water ingestion during the interdialy-is period,126,136 a high dialysate sodiumevel,143,144 or sodium profiling,145 whereas aigh postdialysis blood pressure may reflect inad-quate achievement of dry weight.113,146 Thereay be exceptions to these simple explanations

f the effects of sodium and water retention on aatient’s blood pressure. For example, bloodressures in a small number of patients withKD stage 5 were found to respond less readilyompared with the majority when challengedith similar degrees of fluid retention.112,134

onversely, reduction of fluid excess in a hyper-olemic and hypertensive dialysis patient mayot bring about a prompt decrease in bloodressure until ECV is less than a certain thresh-ld value. These clinical observations suggesthat the relationship between ECV and bloodressure in some patients may be sigmoidal,ather than linear, and that volume overloadeads to an increase in blood pressure only whenhysiological autoregulation can no longer copeith the fluid excess.147

For some patients, the conventional dialysisime is too short for their ultrafiltration require-ents to be readily fulfilled. Attempts to acceler-

te ultrafiltration in these patients may precipi-ate hypovolemia and hypotension. Normal salinerequently is administered and ultrafiltration islowed or discontinued, at least temporarily. As aonsequence, at the end of the dialysis session,ot only has the originally targeted fluid excessot been removed, but the infused saline also hasxpanded ECV further. More sodium and water
ill accumulate during the succeeding interdialy- s
is period, contributing further to a chronic statef baseline volume expansion in association withersistent hypertension.It should be noted that each 10 mm Hg in-

rease in mean arterial blood pressure is corre-ated independently with the development ofrogressive concentric LVH, de novo ischemiceart disease, and de novo congestive cardiacailure.148 The leading cause of death in mainte-ance HD patients is CVD,149 which is respon-ible for at least 50% of HD deaths in the Unitedtates.112 Apart from fluid overload, there arether significant pathogenic factors for hyperten-ion in dialysis patients,150 such as arterial stiff-ess151,152 caused by arteriosclerosis, salt-re-ated reduction in nitric oxide formation,153-155

ympathetic nervous system overactivity,156 acti-ation of the renin-angiotensin system,157 pres-nce of other vasoconstrictors,126 lack of vasodi-ators,126 erythropoietin therapy,158 geneticredisposition,112 and other as yet poorly definedauses. Although it is generally recognized thatypertension requires control in hypertensiveialysis patients,110,147,159,160 the ideal targetlood pressure is unknown at present.161 In pa-ients with reduced vascular and cardiac compli-nce, blood pressure goals may need to be higher.igorous contraction of plasma volume in suchatients should be avoided to allow adequateissue perfusion during ultrafiltration when hypo-ension is prone to occur.161 However, someave recommended that attempts be made toecrease these high pressures as much as pos-ible to achieve optimal survival.162 Finally, someialysis patients with low predialysis blood pres-ures also have a high mortality rate.148,163,164

isk for death in these patients may reflect car-iac failure, coronary artery disease, malnutri-ion, inadequate dialysis, or other serious ill-esses that can decrease blood pressure.110,161,165

t is likely that the cardiovascular problems inome of these patients result from poorly treatedrior hypertension. Thus, there is every incentiveo control blood pressure as early as possibleefore cardiac damage leads to permanent hypo-ension and an almost certain early death.166

In a small number of patients, blood pressurearadoxically increases after dialysis. The mecha-ism of this elevation is not fully understood.147

ome hypertensive patients for whom blood pres-
ure increases while fluid is removed during

dbscfls

R

t6bIamtcvctttpto5fnlwa

gtcbezbdpdwbrr1rtce

fiamiaspptcbaiq

tiaAfaatfidt

SC

hckcCdpstmiad

aheti


ialysis may respond to still more fluid removaly undergoing repeated isolated ultrafiltrationessions, with eventual better blood pressureontrol.167 However, attempts to remove excessuid from these patients by using ultrafiltrationhould be conducted with special care.147

ecommended Sodium Intake (CPG 5.2)

The normal daily sodium chloride intake inhe United States varies from 5.8 to 17.4 g (2.3 to.9 g [100 to 300 mmol] of sodium),168 whileoth the American Heart Association169,170 andnstitute of Medicine171 recommend a daily toler-ble upper intake level for sodium chloride of noore than 5.8 g (2.3 g [100 mmol] of sodium) for

he average healthy adult. The Institute of Medi-ine also recommends that because older indi-iduals, African Americans, and people withhronic diseases, including hypertension, diabe-es, and kidney diseases, are especially sensitiveo the blood pressure–increasing effects of salt,hey should consume less than the tolerable up-er intake level. The European Society of Hyper-ension and European Society of Cardiology rec-mmend a daily sodium chloride intake of 4.7 to.8 g (1.8 to 2.3 g [80 to 100 mmol] of sodium)or patients with arterial hypertension.172 Fi-ally, use of a low-sodium chloride diet, namely,ess than 5.8 g (2.3 g [100 mmol] of sodium) alsoas found to decrease blood pressure in individu-

ls without hypertension.173

Thus, the daily sodium chloride intake sug-ested for dialysis patients (namely, no morehan 5 g [ie, 2.0 g [85 mmol] of sodium]) isonsistent with recommendations for healthy adultsy US health research groups and for patients withssential hypertension by European health organi-ations. It also is recommended for dialysis patientsy various investigators.133,141,174-176 A 5-g so-ium chloride diet in a 70 kg anuric compliantatient should bring about a 1.5-kg average inter-ialysis weight gain on a conventional thrice-eekly regimen.141 Most dialysis patients shoulde able to tolerate this degree of ultrafiltrationequirement. A more stringent daily sodium chlo-ide limitation amounting to 2.5 to 3.8 g (1 to.5 g [43 to 65 mmol] of sodium) has beenecommended for hypertensive dialysis pa-ients.121,126 In patients who happen to lose appre-iable amounts of sodium through either RKF or
xtrarenal routes, sodium restriction can be modi- r
ed and tailored to those losses. Patients who areccustomed to a more liberal sodium intakeight lose their appetites and become malnour-

shed if sodium restriction is instituted toobruptly and too strenuously. In such patients,odium limitation can be introduced gradually torovide ample time for taste adjustments. Mostatients find that they do not miss the sodium ifhey cut back gradually.176A For patients whoannot tolerate sodium restriction at all, to com-at sodium and water excess, more prolongednd/or more frequent dialysis treatments (includ-ng periodic isolated ultrafiltration) may be re-uired (see Prolonging Dialysis Treatments).When observing a low-sodium diet, in addi-

ion to refraining from adding salt during cook-ng and at the dining table, canned, processed,nd salty-tasting food should be avoided.172,175

low-sodium diet does not equate to tastelessood. Many varieties of flavor enhancers arevailable to make food more appealing and palat-ble.143 Moreover, after exposure to salt restric-ion for 8 to 12 weeks, the appeal of low-sodiumoods in both normotensive and hypertensivendividuals is enhanced.177 Sodium restrictionoes not require a reduced intake of other essen-ial nutrients.178

odium Restriction and Blood Pressureontrol (CPG 5.2)

That excessive sodium intake can aggravateypertension and adequate sodium restrictionan prevent or ameliorate hypertension is wellnown.169 As early as the middle of the lastentury, limiting daily sodium intake of non-KD hypertensive patients with a rice and fruitiet was shown to reduce ECF volume and bloodressure during a period of weeks as excessodium was excreted in urine.179 This observa-ion pertaining to the benefit of sodium limitationay relate to the rarity of hypertension among

ndividuals of populations living in very remotereas who consume a low-sodium diet (medianaily intake, 17 to 51 mmol).180

Among dialysis patients, myriad observationalnd interventional studies of patients with CKDave shown that restricting sodium intake is anssential tool for volume and blood-pressure con-rol.124,125,140,141,165,175,181-192 Apart from its effectn nonuremic hypertensive patients, a sodium-poor
ice and fruit diet also was shown to improve the

hTwto

cntcaaptdm

P

stpufidspt1lmtmihsdrclrbmpmftms

bdaaststat

ssudt(wfwms(sapsos

D

iwadRpEswgictrtto


ypertension of patients with renal failure.193,194

hese observations echo those in PD patients, forhom decreasing sodium in the diet is crucial for

he achievement of dry weight and effective controlf blood pressure.195

Since infancy, most of us are accustomed toonsuming a larger quantity of salt than weeed.196 Restricting salt intake in HD patients isantamount to requiring them to change theirustomary lifestyle. Changing one’s lifestyle islways a difficult undertaking. However, moder-ting one’s sodium intake is a small price for aatient with CKD to pay if one wishes to avoidhe devastating effects of relentless excess so-ium and water accumulation on morbidity andortality.

rolonging Dialysis TreatmentsElevated blood pressures can be decreased

atisfactorily with aggressive ECF volume con-rol, achieved by limiting sodium intake anderforming adequate ultrafiltration.182 Successsing this strategy has been reported in studiesrom Tassin, France, showing that hypertensions improved substantially with a combination ofietary sodium limitation (85 to 100 mmol/d ofodium) and dialyzing slowly for 8 hours 3 timeser week.197 Sodium limitation decreased pa-ients’ average weight gain between dialyses to.7 kg, less than 3% of mean BW.133 Both theimited weight gain (ie, ultrafiltration require-ent) and long period of ultrafiltration combined

o ensure that symptoms during dialysis wereinimized and dry weight was achieved.133 Upon

nitiation of HD treatments, 89% of patients wereypertensive despite therapy with antihyperten-ive medications. However, after 3 months of theescribed strategy, only 5% of those patients stillequired the use of such medications.197 Ofourse, because the Tassin patients were dialyzedonger than patients treated with a conventionalegimen, it could be argued that these patients faredetter because they had better removal of small andiddle molecules, improved nutrition, and better

hosphate control. However, a comparison study ofortality rates in conventionally dialyzed patients

rom Nottingham, United Kingdom, concluded thathe improved control of blood pressure was theost likely and predominant cause of better results

hown by the Tassin patients.198 i

It should be noted that adequate control oflood pressure as a consequence of dietary so-ium restriction (�100 mmol/d of sodium) andppropriate ultrafiltration with175 or without185,199

low-sodium dialysate (135 mmol/L) also washown in patients treated with a conventionalhrice-weekly (4 to 5 hours per treatment) dialy-is regimen. In addition to blood pressure con-rol, patients also showed regression of LVH anddecrease in left atrial and left ventricular sys-

olic and diastolic pressures.185,199

For conventionally dialyzed patients (3 ses-ions per week, �4 hours per session) who aretill overloaded despite maximally tolerableltrafiltration, the recently proposed: (1) short-aily (2 to 3 hours for each treatment, 6 or 7reatments per week) regimen;200-202 (2) long8 hours for each session) nocturnal thrice-eekly regimen;197,203 and (3) long (8 hours

or each session) nocturnal (6 to 7 nights pereek) regimen204,205 all were reported to re-ove excess fluid and improve hypertension

atisfactorily.110 A longer weekly treatment time5 hours per session, 3 times per week) also washown to cause less hypotension during dialysisnd less postdialysis postural hypotension com-ared with its shorter counterpart (4 hours peression, 3 times per week).206 Alternatively, peri-ds of isolated ultrafiltration can be added to atandard treatment regimen.199

ietary Water RestrictionWhen a patient is advised to restrict sodium

ntake, does he or she need to be advised to limitater intake too? It was suggested that attempts

t water restriction commonly are futile if so-ium limitation is not observed simultaneously.educing a patient’s water intake alone is notrudent most of the time because the increasedCF osmolality brought about by the excessiveodium ingestion stimulates thirst, followed byater consumption and hence isotonic fluidain.207,208 Advising patients to limit their waterntake without curtailing their sodium intake willause suffering from unnecessary thirst. Some ofhese patients may even feel guilty if they fail toesist the urge to drink in the face of markedhirst.143 However, although excessive water in-ake accompanies the ingestion of excess salt,ther factors can have a role in stimulating drink-
ng. Such factors include hyperglycemia, el-

esptt

P

lsttmmpatpshcfnfIwisahtinicvrTvtfvhtt

U

dic

te1niipost

D

radsmtwrdncisidhwicm(1sstlltettpad


vated blood angiotensin levels, and ingestion ofuch drugs as clonidine.209 Thus, to ensure com-lete safety, patients should be watched carefullyo make sure they do not accumulate more fluidhan recommended.

athogenesis of the Lag PhenomenonThe exact mechanism responsible for the

ag phenomenon is still not fully under-tood.122,125,174 Its occurrence may be related tohe appearance of lower peripheral vascular resis-ance caused by relaxation of endothelial smoothuscle.174 In this regard, it was shown that p38itogen-activated protein kinase (p38MAPK)

romotes the formation of asymmetric dimethyl-rginine (ADMA). The latter, in turn, can inhibithe action of nitric oxide synthase and hence theroduction of nitric oxide. Sodium chloride wasuggested to bring about p38MAPK release andence ADMA synthesis.153 The consequent de-rease in endothelial nitric oxide formation leads toailure of arteriolar muscle to relax. It should beoted that high ADMA concentrations have beenound in plasma of patients with CKD stage 5.154,155

n recent studies involving experimental animalsith chronic renal failure, high sodium chloride

ntake decreased nitric oxide synthase expres-ion in certain areas of the brain, resulting inctivation of the sympathetic nervous system andypertension.210 In addition, there is evidencehat sodium overload may cause reversal of thenhibition of Na�, K�-ATPase through endoge-ous ouabain. This step would bring about anncrease in intracellular sodium and calcium con-entrations, subsequently causing an increase inascular tone and blood pressure.211 Sodiumestriction should lead to the opposite effects.he contention that sodium limitation can causeascular relaxation is consistent with the observa-ion that long-term dialysis patients maintainedor years on a low-salt diet have peripheralascular resistance that is lower than that ofealthy controls.212 Thus, it is entirely possiblehat sodium restriction may work in ways otherhan that of simple ECF volume contraction.

se of DiureticsTo promote loss of sodium and water from

ialysis patients, large doses of potent loop diuret-cs, such as furosemide, bumetanide, or torsemide,
an be administered.213-216 However, diuretic d
herapy is effective only when RKF is highnough to provide daily urine output of at least00 mL.217 The effectiveness of this therapy mayot last long,209 possibly because of a furthernevitable decline in renal function. Loop diuret-cs should be used with caution because of theossibility of ototoxicity.218,219 The incidencef ototoxicity appears to be greater with furo-emide and much less with bumetanide ororsemide.213,214

ialysate Sodium Concentration (CPG 5.3)

High concentrations of sodium in dialysateeduce the removal of sodium during dialysisnd ultrafiltration.143,144 In the 1960s, when aialysis treatment typically lasted 6 hours, dialy-ate sodium levels were in the realm of 135mol/L.144 However, since the early 1970s, with

he advent of shorter treatments (3 times pereek for �4 hours per treatment), removal of the

equired amount of excess fluid became moreifficult. To overcome this difficulty, it becameecessary to increase dialysate sodium to a greateroncentration (eg, to the region of �140 mmol/Ln the 1990s).143,220 Although increasing dialy-ate sodium concentration can decrease morbid-ty both during and between treatments, suchialysates can aggravate thirst, fluid gain, andypertension.143,144,220,221 Similar consequencesere found in patients treated with sodium profil-

ng, a technique that increases dialysate sodiumoncentration early in treatment (eg, 145 to 155mol/L), followed by a progressive decrease

linear, step, or logarithmic) to a lower value (eg,35 to 140 mmol/L) at the end of dialysis.145 Ithould be noted that the patient’s postdialysiserum sodium concentration is a function of theime-averaged dialysate level, not the terminalevel of sodium in dialysate.222 Reviews of thearge volume of literature on this topic showedhat sodium profiling is of uncertain ben-fit.144,145,223 Some investigators had satisfac-ory experiences with a dialysate sodium concen-ration of 138 mmol/L in a large number ofatients. During these studies, the dosage ofntihypertensive medications often had to beecreased or discontinued.

CONCLUSIONUse of appropriate ultrafiltration techniques,

ietary sodium restriction, and lower dialysate

stotftpvdhnnnahs

dfi

tsmcbcbfetac


odium concentrations160,224 has been instrumen-al in attaining a true dry weight and ameliorationf hypertension in many maintenance HD pa-ients.133 Reembracing the time-honored and use-ul, yet inexpensive, tool of dietary salt restric-ion should serve to promote the health of HDatients. During the process of controlling ECFolume and decreasing predialysis weight, theevelopment of hypotension during dialysis orypertension between dialysis treatments shouldot be construed as a failure of volume control toormalize blood pressure. The lag phenomenonoted previously should be taken into consider-tion when evaluating patients with persistentypertension.112 To more easily control hyperten-
ion in most dialysis patients, use of a high s
ialysate sodium concentration and sodium pro-ling should be discouraged.Finally, application of appropriate ultrafiltra-

ion with every dialysis treatment, the inces-ant vigilance to target and subsequently toaintain a true dry weight (which is subject to

hange because of loss or gain of nonfluidody tissue), and confirmation that a patient isompliant with a sodium-restricted diet com-ine to demand a considerable amount of timerom members of the health care team. How-ver, to obtain favorable results, an intense,otally committed, and prolonged effort—withhigh degree of motivation—is required from

aregivers, as well as from the patients them-
elves.112

tep

6

6

tlhpttddivuslpis

oscpettPlpodbopt

S

GUIDELINE 6. PRESERVATION OF RESIDUAL
KIDNEY FUNCTION
psamcpttaiputhddtci

arlpieanaiqciptkvaaedwedtf

Prospective randomized trials and observa-ional studies have confirmed that the pres-nce of RKF is one of the most importantredictors of a patient’s survival.

.1 One should strive to preserve RKF in HDpatients. (A)

.2 Methods for preserving RKF differ amongpatients (see CPR 6). (B)

BACKGROUND

When HD therapy is first initiated, most pa-ients have small and significant (but inadequate)evels of RKF, and many have normal or evenigh rates of urine output. This level of RKF mayersist for many months and years, adding con-inuous solute clearance and other kidney func-ions to the intermittent clearances provided byialysis treatments. The volume of urine pro-uced each day allows more fluid intake, reduc-ng the otherwise larger fluctuations in body fluidolumes between dialysis treatments that contrib-te to volume overload syndromes, hyperten-ion, and cardiac hypertrophy. Unlike hemodia-yzer clearance, RKF is subject to temporary orermanent reduction caused by numerous toxicnsults that often confront patients with CKDtage 5.

RATIONALE

The impact of residual function on durationf life and QOL has been evaluated exten-ively in PD patients,68,225-227 but only re-ently has attention been given to it in HDatients (see Table 10).81 This difference isspecially striking because the number of long-erm HD patients in the United States is morehan 10 times as large as the number receivingD. Possible reasons for ignoring RKF include a

ack of RKF measurements in HD patients, com-lacency because of confidence in the larger dosef dialysis possible with HD, previous rapidecrease in urine output after HD therapy isegun, and the added inconvenience and expensef collecting urine. Measurement of RKF in HDatients also likely was ignored because, in con-
rast to PD, nearly all KRT is managed for the t

atient by nurses and technicians. Selecting aubgroup of patients who prefer self-care (PD)lso selects for willingness to perform self-easurements of RKF. There also has been con-

ern that PD is minimally adequate; thus, RKF maylay a more essential role. Earlier studies showedhat RKF decreased more rapidly in patients ini-ially treated with HD compared with continuousmbulatory PD (CAPD).228 However, recent stud-es showed that RKF is preserved better in HDatients than in the past, possibly because of these of more biocompatible membranes, discon-inuation of acetate as a bicarbonate precursor,igh-flux dialysis, and the earlier initiation ofialysis therapy, especially in patients withiabetes.81,229-231 More recent studies suggesthat with the use of ultrapure water to diluteoncentrated dialysate, RKF decreases at a ratendistinguishable from that in CAPD patients.232

The protective role of RKF for preserving lifend extending longevity in PD patients is wellecognized68,226,227; previous KDOQI guide-ines promoted the preservation of RKF in thisopulation.233 More recent data show that RKFn HD patients affords many of the same ben-fits, including a lower dialysis dose requirementnd improved patient survival.234 The reducedeed for dietary potassium and fluid restrictionnd reduced requirement for fluid removal dur-ng HD can enhance QOL and reduce the fre-uency of hospitalizations. In HD patients, theontinuous nature of RKF contrasts with thentermittent schedule of dialysis, whereas for PDatients, both are nearly continuous. Evidencehat includes mathematical analysis of soluteinetics and comparison of outcomes in PDersus HD patients suggests that continuous clear-nce is more efficient than intermittent clear-nce.235 Such arguments have been used, forxample, to explain the much lower weeklyialysis clearance requirement in PD comparedith HD patients despite nearly equal outcomes,

specially in the first year of treatment. If thisifference in efficiency is accepted, the contribu-ion of RKF to overall kidney plus dialyzerunction is greater than the simple addition of
ime-averaged clearances would suggest.

eruatl

t

iaHsiafdwfip

poeurmyarbtwcmomrasa

PRESERVATION OF RESIDUAL KIDNEY FUNCTION S41

Because it appears that RKF can be preserved,very effort should be made to protect existingenal function in HD patients, especially if dailyrine volume exceeds 100 mL. When measuresre taken to protect RKF after initiation of HDherapy, patients may continue to experienceong-term benefits, even at very low GFRs.

Suggested methods to protect RKF are de-ailed in CPR 6.

LIMITATIONS

Data that support reducing the dose of dialysisn patients with significant residual function arell observational. The recent randomized trial ofD dose1 intentionally excluded patients with

ignificant residual function; therefore, little dos-ng information for patients with RKF is avail-ble. It is possible that patients with residualunction can derive more benefit from doses ofialysis targeted for anephric patients comparedith the downward adjusted dose; therefore, arm recommendation to reduce the dose is notossible at this time.In rare cases, persistence of nephrotic-range

roteinuria may necessitate renal embolizationr removal of the kidneys. Occasionally, renalndocrine function (eg, renin secretion) contrib-tes to hypertension, necessitating ablation oremoval of the native kidneys. This scenario isuch less common today compared with 40

ears ago because potent antihypertensive agentsre readily available. Occasionally, removal ofesidual kidney mass may be required to manageacterial pyelonephritis. Before transplanta-ion, removal of obstructed kidneys or kidneysith stones or cysts causing infections that

annot be completely eradicated with antibioticsay be warranted. In these cases, careful timing

f the transplantation and nephrectomy can maxi-ize benefit from RKF while also reducing the

isk of transplantation. In some cases, removal oftransplanted kidney is warranted to eliminate

ymptomatic inflammation caused by continuedllograft rejection.

poIl

7

7

7

pps

gfaoptoota

fltt

S

GUIDELINE 7. QUALITY IMPROVEMENT PROGRAMS

apcrtdsfmlpidi

(sc

●

●

●

●

easocpCtiiH

micttadumpo

The continuous quality improvement (CQI)rocess has been shown to improve clinicalutcomes in many disciplines, including CKD.t presently is conducted at both the facilityevel and local network level.

.1 For HD adequacy, each dialysis clinicshould continue to monitor the processesrelated to the delivery of dialysis, such asKt/V, reuse standards, etc. (A)

.2 Consideration should be given to provid-ing resources and training for expandingthe assessment of clinical outcomes be-yond mortality to include hospitalizationrates, QOL, patient satisfaction, and trans-plantation rates, recognizing that withoutadequate resources and training, theseoutcomes are unlikely to be valid, and theefforts to collect such information mayadversely affect patient care. (B)

.3 Quality improvement programs shouldinclude representatives of all disciplinesinvolved in the care of HD patients, includ-ing physicians, physician assistants, nursepractitioners, nurses, social workers, dieti-tians, and administrative staff. (B)

BACKGROUND

The CQI process has been shown to improverocess and clinical outcomes in many disci-lines, including CKD and particularly CKDtage 5.236

Improvement in both QOL and longevity areoals of Healthy People 2010, the strategic planor the nation’s health (www.healthypeople.gov;ccessed May 1, 2006).236A Kidney disease is 1f 18 focus areas for Healthy People 2010. Foratients with CKD stage 5 receiving dialysisherapy, the ongoing process to improve clinicalutcomes is linked inextricably to the assessmentf dialysis adequacy, and the need for programso continuously assess and improve care remainss great as ever.237

RATIONALE

With regard to HD adequacy guidelines, datarom the HEMO Study support a plateau at theevel of the existing recommended HD adequacyargets for the current practice of thrice-weekly
reatments. There is no compelling evidence that l

dditional increases in dialysis dose within theresently recommended range improve such clini-al outcomes as patient mortality, hospitalizationates, QOL, patient satisfaction, and/or transplan-ation rates.1 However, as the global care forialysis patients evolves, it is reasonable to as-ume that so may the most effective thresholdsor delivery of dialysis. Therefore, continuingonitoring of outcomes—including not only de-

ivered dose of dialysis, but also other key as-ects of established and emerging factors thatmpact on both QOL and longevity of life forialysis patients—will be critical for the continu-ng improvement of care for the dialysis patient.

Domains of clinical outcomes to be monitoredin addition to mortality) when sufficient re-ources exist and validated standards have beenreated might include:

Hospitalization ratesQOLPatient satisfactionTransplantation rates

Key to this process is the commitment to anvidence-based approach that will build upon,nd not detract from, the existing limited re-ources.237 This would contribute to the creationf a system in which clinical outcome trendsould be tracked and then meaningfully com-ared with regional outcome data (eg, from theKD Stage 5 Network), national data, interna-

ional data, and historical data from the facilitytself. These findings could build upon the exist-ng evidence-based recommendations for PD andD, anemia management, and vascular access.Comparison with regional or national dataay be difficult because of limitations in adjust-

ng for the case-mix of patients at individualenters and variations in quality of data collec-ion to capture the adequate case-mix descrip-ion. Thus, facilities that have fewer resourcesnd less trained staff and/or more linguisticallyiverse patient populations are more likely to benable to capture a complete clinical profile andore likely to underestimate case-mix severity,

roviding an overestimate of adjusted mortalityr hospitalization rates.For the overall care of dialysis patients, there

ikely will be value in tracking selected associ-


asqfipNTalowc

s

●

●

●

●

●

●

●

H

mtofgTa

Q

awQTcdtatmKcvbb

tcaino

P

Strdvictts

mpwdpsact

T

drttptisats

ch“K

QUALITY IMPROVEMENT PROGRAMS S43

ted clinical outcomes to assess the role of HD,uch as those related to reuse systems and fre-uent dialysis strategies. Many investigators andacilities already assess the former (eg, mortal-ty) and the NIH is assessing the latter in arospective study (www.clinicaltrials.gov/show/CT00264758; accessed May 1, 2006).237A-239

he establishment of highly functional systemsnd well-trained dedicated staff (including thoseisted next) to ensure the quality and uniformityf data collection, as well as the ability to extracthich component(s) contribute to clinical out-

omes, will be critical to this process.Quality improvement program representatives

hould include:

PhysiciansPhysician assistantsNurse practitionersNursesSocial workersDietitiansAdministrative staff

ospitalization Rates

The large number of patients hospitalized atultiple facilities creates a tremendous task in

he collection of accurate and valid data. More-ver, differences in similar procedures per-ormed in an inpatient and outpatient setting varyeographically and across health care systems.his information would need to be clarified and/orppropriately adjusted to capture meaningful data.

uality of Life

One of the more commonly used tools tossess health-related QOL (HRQOL) for patientsith CKD stage 5 is the Kidney Disease anduality of Life Short Form™ (KDQOL-SF).240

here is evidence that the physical, psychologi-al, and/or mental components of HRQOL pre-ict death and hospitalization among HD pa-ients.32,241-243 Unfortunately, the area of QOLssessment is still limited by the use of multipleools, challenging attempts at maintaining unifor-

ity in QOL data collection. Although theDQOL-SF has been translated and used in

ulturally, geographically, and linguistically di-erse populations, it does not appear to haveeen validated in these settings. This is critical
ecause there may be significant sex, genera- t
ional, and/or racial/ethnic variations in per-eived—and therefore, reported—QOL.244-247 Inddition, many of the interventions shown tomprove QOL have not been validated simulta-eously to decrease the risk for adverse clinicalutcomes.

atient Satisfaction

Multiple factors influence patient satisfaction.pecific to HD, one key factor influencing pa-

ient satisfaction, time on dialysis therapy, iselated inversely to achieving a higher dose ofialysis, higher phosphate clearance, less rapidolume removal, and other factors linked tomproved clinical outcomes. This may place fa-ilities in the situation in which patient satisfac-ion and clinical outcomes are in conflict, andhere are no national standards for arbitrating thisituation.248

Similar to QOL assessments, there also areultiple tools actively being used for assessing

atient satisfaction that vary across and evenithin facilities. Without standard tools and vali-ation of the tools, the utility of such surveys atresent is insufficient to meet a clinical guidelinetandard. However, the continuing developmentnd refinement of these tools is crucial to theontinued improvement of care and the founda-ion of future guidelines.

ransplantation Rates

There are no data linking the delivery ofialysis doses within the recommended range toenal transplantation. Multiple factors influenceransplantation rates, including, but not limitedo, case-mix, geography, insurance status, andatient and provider bias.249,250 While the moni-oring of trends is valuable, assessment of thempact of these factors needs to be isolated,tandardized, and validated into an appropriatenalytical model before including dialysis transi-ion rates to renal transplantation as a potentialtandard.

LIMITATIONS

These guidelines for achieving the broad clini-al outcome goals of improved QOL and en-anced longevity are a summation of ongoingbest practices” that supplement the existingDOQI HD Guidelines. These best practices and

he robust evidence required to support the rigor

omdtafgimeoo

laantcidcvl


f a CPG are still evolving. This will require aethodologically sound foundation with stan-

ards that are generalizable. Future data collec-ion will require assessments using prespecifiedpproaches to data analysis that include all theseactors and other related confounders (eg, demo-raphics, case-mix, and medical therapeutics)nto a clinically valid multivariable statisticalodel. Otherwise, the ability to ascertain the

vidence of the contribution of existing clinicalutcome best practices versus the achievement
f recommended guidelines becomes a statistical/ s
ogistical impossibility. Such a consideration isn intense undertaking and should not be initi-ted without total commitment to the resourceseeded to address each of these issues and createhe valid models needed to monitor improvedare in a meaningful way. If this is not done,nterpretation of partially collected or invalidata would: (1) be unable to determine the rootause of changes in clinical outcomes, (2) not bealid across and/or within facilities, and (3) addimited value above the present outcome analy-
es.

A

GUIDELINE 8. PEDIATRIC HEMODIALYSIS PRESCRIPTION
AND ADEQUACY
eertmmncptHstpracmdnbHCa

Gptlmiunc

8.1 Initiation of HD:8.1.1 Dialysis initiation considerations

for the pediatric patient shouldfollow the adult patient guide-line of a GFR less than 15 mL/min/1.73 m2. (A)

8.1.2 For pediatric patients, GFR can beestimated by using either a timedurine collection or the Schwartzformula. (A)

8.1.3 Dialysis therapy initiation shouldbe considered at higher estimatedGFRs when the patient’s clinicalcourse is complicated by the pres-ence of the signs and symptomslisted in Table 11, CPR 1 for adultpatients, as well as malnutritionor growth failure for pediatric pa-tients. Before dialysis is undertaken,these conditions should be shownto be refractory to medicationand/or dietary management. (A)

8.2 Measurement of HD adequacy:8.2.1 spKt/V, calculated by either for-

mal urea kinetic modeling or thesecond-generation natural loga-rithm formula, should be used formonth-to-month assessment of de-livered HD dose. (B)

8.2.2 Assessment of nutrition status is anessential component of HD ad-equacy measurement. nPCR shouldbe measured monthly by using ei-ther formal urea kinetic modelingor algebraic approximation. (B)

8.2.3 Principles and statements regard-ing slow-flow methods for postdi-alysis sampling and inclusion ofRKF (or lack thereof) outlined inthe adult guidelines also pertainto pediatric patients. (B)

8.3 Prescription of adequate HD:8.3.1 Children should receive at least the

delivered dialysis dose as recom-mended for the adult population. (A)

8.3.2 For younger pediatric patients, pre-scription of higher dialysis doses
and higher protein intakes at 150% s

of the recommended nutrient in-take for age may be important. (B)

8.4 Non–dose-related components of ad-equacy:

Accurate assessment of patient in-travascular volume during the HDtreatment should be provided tooptimize ultrafiltration. (B)

BACKGROUND

Provision of evidence-based pediatric HD ad-quacy guidelines is hampered by a number ofpidemiological issues. Stage 5 CKD remains aelatively uncommon disease, and renal transplan-ation is still the predominant and preferred KRTodality for children. In addition, PD is a viableodality option for many pediatric patients. Fi-

ally, children with CKD stage 5 show signifi-antly better survival rates compared with adultatients. As a result of these factors, no long-erm pediatric outcome study comparable to theEMO Study or the National Cooperative Dialy-

is Study (NCDS) would be adequately poweredo detect an effect of delivered HD dose onediatric patient outcome. Nevertheless, someecent pediatric data exist to describe the mostccurate methods for quantifying urea removal,orrelate delivered dose of dialysis with inflam-ation, and examine other components of the

ialysis prescription, including ultrafiltration andutrition provision. These data can serve as theasis for CPRs in caring for children receivingD. For areas in which no pediatric data exist,PGs and CPRs for adult patients should serves a minimum standard for pediatric patients.

RATIONALE

Although the Schwartz formula overestimatesFR, especially at lower GFR levels, recentediatric data show that GFR estimated by usinghe Schwartz formula of 15 mL/min/1.73 m2 oress had excellent negative predictive value for a

easured GFR of 20 mL/min/1.73 m2 byothalamate clearance.21,251 Because 24-hourrine collections often are not possible for smalleron–toilet-trained children, reliance on serumreatinine–based formulas is essential in this
ubset. As with the MDRD equation, use of the
, 2006: pp S45-S47 S45

Sufpl

fcarksttgttepawdotpp

tsotaatdcdbemretsaen

spm

Cgpmswdcnmtomlmgloteatacipp

itawplGsyfrodtcsaflrNdt


chwartz formula is simple and does not dependpon collection of urine samples. The Schwartzormula contains a cofactor that accounts foratient sex and age to incorporate estimates ofean muscle mass.

Modality choice is governed by a number ofactors, including patient size, availability of aaregiver to competently perform home dialysis,nd the expected length of waiting time for aenal allograft. Children weighing less than 10g are better suited for PD because HD in verymall children requires extensive nursing exper-ise. Also, because infants require greater nutri-ional needs to promote growth on a per-kilo-ram basis, thrice-weekly HD often is insufficiento maintain acceptable fluid, potassium, and elec-rolyte balances. HD should be strongly consid-red for patients who do not have one, andreferably two, caregivers who are competentnd motivated to provide home PD. For patientsho have a consenting living renal allograftonor available and who have substantial urineutput and electrolyte control, initiation of main-enance dialysis therapy may be avoided if areemptive transplantation can be scheduled ex-editiously.Monthly solute clearance and nutrition sta-

us measurement using urea as the surrogatemall molecule are essential to assess the dosef dialysis in pediatric patients because pa-ients receiving optimal dialysis should grownd gain weight through adolescence. Thus,ssessment of Kt/V will guide the practitionero increase dialyzer size, blood flow rates, orialysis treatment time as patients grow. Single-enter pediatric data exist that show the Daugir-as formula reliably estimates spKt/V derivedy using formal urea kinetic modeling.252 Anssential component of adequacy measure-ent is nutrition status assessment because

ecent pediatric data show that increased deliv-red dialysis dose does not in and of itself leado improved nutritional intake.253 Pediatric datahow that nPCR is more sensitive than serumlbumin concentration as a marker of protein-nergy malnutrition in a small group of mal-ourished children receiving HD.254,255

No large-scale studies exist to validate a targetpKt/V or eKt/V as adequate for the pediatric HDopulation, although methods for accurate measure-
ent of each have been validated in children.254,256 a
ertainly, because infants and young children havereater nutritional requirements to support growth,ediatric patients should receive at least the mini-um dialysis dose as prescribed for adults. A study

howed that pediatric patients who receive a thrice-eekly Kt/V of 2.0 and 150% of the recommendedaily allowance of protein were able to showatch-up linear growth without the use of recombi-ant growth hormone.257 Chronic inflammatoryediator levels seem to be inversely proportional

o eKt/V in pediatric HD patients,258 although anptimal eKt/V level has not been established toitigate chronic inflammation, which is related in

arge part to dialysis vintage. Thus, a case can beade for providing pediatric patients with a Kt/V

reater than the adult-based guideline of 1.2, but aarger scale study is warranted to determine anptimal Kt/V target. Such a strategy will ensurehat smaller growing pediatric patients receivenough nutrition and adequate waste product clear-nce. Observational pediatric data exist showinghat older, larger, and African-American childrenre less likely to receive an spKt/V greater than 1.2onsistently259; therefore, practitioners should benformed to make specific efforts to ensure therovision of adequate dialysis in these vulnerableopulations.

Management of pediatric HD patient fluid statuss especially difficult because children are expectedo grow and gain weight from infancy throughdolescence. Thus, distinguishing between realeight accretion versus fluid overload is critical torevent a chronic fluid-overloaded state that canead to chronic hypertension and resultant CVD.iven the relative high ultrafiltration rate to dialy-

is treatment time ratio and the relative inability ofounger patients to accurately verbalize symptomsrom overly rapid ultrafiltration, the means to accu-ately assess patient intravascular volume can helpptimize ultrafiltration to attain patient true targetry weight while minimizing intradialytic symp-oms. Noninvasive monitoring (NIVM) of hemato-rit during the dialysis treatment uses an in-lineensor to reflect the change in patient blood volumes an inverse change in patient hematocrit duringuid removal. Ultrafiltration guided by NIVM algo-ithms that adjust UFRs and targets based on hourlyIVM blood volume changes have been shown toecrease patient symptoms, hospitalization, extrareatments for fluid overload and hypertension,
ntihypertensive medication requirements, and

fr

e

phpHC

PEDIATRIC HEMODIALYSIS PRESCRIPTION AND ADEQUACY S47

ourth weekly HD treatments for pediatric patientseceiving HD.260-262

LIMITATIONS

Any pediatric study to determine either an ad-
quate or optimal delivered dialysis dose requires u
ractical end points to be valid. Whereas death andospitalization rates are easily measurable endoints, their relative infrequency in the pediatricD population and the low prevalence of pediatricKD stage 5 make an adequately powered study
sing these end points a virtual impossibility.

II. CLINICAL PRACTICE RECOMMENDATIONS
FOR HEMODIALYSIS ADEQUACY

t

A

CLINICAL PRACTICE RECOMMENDATION FOR
GUIDELINE 1: INITIATION OF DIALYSIS
fc

Certain complications of kidney failure jus-ify initiation of dialysis treatment in patients

Table 11. Complications That May Prom

Intractable ECV overload HyperkalemiaMetabolic acidosis HyperphosphatemiaHypercalcemia or hypocalcemia AnemiaNeurological dysfunction (eg, neuropPleuritis or pericarditis Otherwise unexplained decline in funGastrointestinal dysfunction (eg, nauWeight loss or other evidence of maln
Hypertension

or whom estimated GFR has not yet de-reased to 15 mL/min/1.73 m2 (Table 11).

tiation of Kidney Replacement Therapy

ncephalopathy)

g or well-being miting, diarrhea, gastroduodenitis) n

pt Ini

athy, e

ctioninsea, voutritio

, 2006: p S49 S49

lsrp

2

2

kdasosarstioedabtodwdsdsd

A

it

S

CLINICAL PRACTICE RECOMMENDATIONS FORGUIDELINE 2: METHODS FOR MEASURING AND

EXPRESSING THE HEMODIALYSIS DOSE

iIapqdo1RdapsRlppw

Rmwcadrt

●

●

●

●

obt

For patients managed with HD, both dia-yzer and native kidney function can be mea-ured periodically to assess the adequacy ofeplacement therapy. Urea clearance is thereferred measure of both (see Guideline 2).

.1 Residual kidney urea clearance (Kr) ismeasured best from a timed urine collec-tion.

.2 For purposes of quality assurance, thedelivered dose should be measured andcompared with the prescribed dose eachmonth.

BACKGROUND

Failure to include Kr in the model of ureainetics will not harm the patient provided theose of dialysis is adequate. Inclusion of Kr isdvantageous because it allows accurate mea-urement of G and nPCR (or nPNA), whichtherwise are underestimated in patients withignificant RKF and are helpful to assess dietarydequacy. Inclusion of Kr also allows a potentialeduction in the duration and frequency of dialy-is as a means of improving QOL by extendingime off dialysis. Limiting time and reducing thentensity of dialysis may benefit some more thanthers, depending on lifestyle and treatment tol-rance. Mathematical analysis of solute kineticsuring and between HD treatments shows thatverage and peak solute levels are controlledetter by continuous (compared with intermit-ent) clearance, and that increasing the frequencyf a given weekly clearance also lowers levels ofialyzable solutes. Comparison of delivered doseith prescribed dose of dialysis adds anotherimension to the analysis of adequacy that canpot problems with the blood access device andialysis equipment, including blood and dialy-ate pumps. This function is independent of theetermination of adequacy.

RATIONALE

dding RKF to Dialyzer Clearance

If Kr is included in the dialysis prescription,t becomes important to measure Kr frequently
o avoid prolonged periods of underdialysis as Kr a

s lost. The rate of loss may vary among patients.n some patients, monthly measurements aredvised, whereas in others with good urine out-ut, quarterly measurements will suffice. If infre-uent measurements are chosen, the patient andialysis staff must be alert to changes in urineutput and exposure to toxic insults (see Table6, CPR 6). Urine output roughly correlates withKF, but it should not be used as the soleeterminant because it does not predict RKFccurately in individual patients.81 Patients withotentially recoverable renal function represent apecial group in whom regular measurements ofKF are especially advantageous. Failure to fol-

ow up RKF closely may lead to unnecessaryrolongation or perpetuation of dialysis in aatient with adequate native kidney functionho does not require dialysis.For both PD and HD, the preferred measure of

KF is urea clearance. This differs from recom-ended measures of kidney function in patientsith CKD stages 1 to 4, for whom creatinine

learance has been the traditional index, as wells the serum creatinine–based estimate of GFRerived from the MDRD Study.263 Reasons forecommending urea clearance as opposed to otherechniques include the following:

Unlike creatinine clearances, measurements ofurea clearance are not confounded by renaltubular secretion.Native kidney urea clearances are lower thanthe kidney’s GFR, so the patient is protected.Conversely, creatinine clearances are alwayshigher than GFR.MDRD estimates of GFR based on serumcreatinine level are not valid in patients man-aged with dialysis.Inclusion of native kidney urea clearances inkinetic modeling programs allows accuratecalculation of G and nPCR as an aid to dietassessment.

When Kr is included in the expression ofverall excretory function, the method for com-ining intermittent dialyzer clearance with con-inuous Kr requires some effort. Methods for
dding Kr to Kd should take into account the

adoaKeivbco(wC

dtuo

dtctatpciW

H

ddmclgdvsrdiltusor

dtccmmctwe

addaaaaraasre

bbttctpsteaoi“asdti


dditional clearance that RKF provides betweenialysis treatments and the increased efficiencyf continuous (compared with intermittent) clear-nce. Suggested methods for combining Kr withd can be found in Appendix. Caution must be

xercised when using any of the methods foundn the Appendix to adjust the dialysis dose for Kr

alues above 2 mL/min. Other potentially vitalenefits of dialysis must be considered whenontemplating a reduction in dose based solelyn urea kinetics. An alternative simplified methodusing a table) for adjusting spKt/V in patientsith Kr � 2 mL/min/1.73 m2 can be found inPR 4, Minimally Adequate Hemodialysis.It is important to note that the adequacy stan-

ards described in these guidelines and CPRshat refer to dialysis-session-based spKt/V val-es do not include an adjustment for the continu-us component of residual urea clearance.One of the disadvantages of adjusting the HD

ose according to RKF is the patient’s percep-ion of worsening health when the ultimate de-rease in native kidney function requires longerreatment times. Successive prolongations of di-lysis can contribute to psychological depressionhat further compromises the patient’s QOL and,ossibly, survival.32 Incremental dosing whileounseling the patient to anticipate the increasen treatment time as renal function is lost is the

ork Group’s preferred approach.

ow to Measure More Frequent Dialysis

The correction for rebound at the end ofialysis (see previous discussion of eKt/V) re-uces, but does not eliminate, the effect of inter-ittence and disequilibrium on dialysis effi-

iency. Efficiency is defined as the effect ofowering solute concentration achieved for aiven level of dialysis dose. Because the dose isefined as a clearance, the solute level is in-ersely proportional to the dose and the relation-hip between the 2 is curvilinear, eventuallyeaching a plateau of effectiveness as dialysisose is increased. Intermittent dialysis therefore,n contrast to continuous dialysis, has a self-imiting aspect that diminishes its efficiency. Ifhe efficiency of continuous dialysis is defined asnity, then the efficiency of thrice-weekly dialy-is has been estimated as 0.7 or less, dependingn the solute. The greater the solute disequilib-
ium, the lower the efficiency of intermittent r
ialysis. Increasing the frequency, ie, movingoward a more continuous pattern, increases effi-iency. An adjustment in dose therefore theoreti-ally is necessary to account for the improve-ent in efficiency for dialysis schedules that areore frequent than 3 times per week. This con-

ept is inherent in the already accepted dictumhat the same weekly dose given once or twiceeekly will not suffice to maintain HD ad-

quacy.The recommended method for normalizing

nd expressing the dose of dialysis indepen-ent of frequency is to reduce the expressedelivered dose to a continuous equivalent clear-nce.202,264,265 This method relies on calculatedverage or peak concentrations of the index solutend assumes a weekly steady state of generationnd removal. Under such conditions, the soluteemoval rate will equal the generation rate. Inddition, the well-known relationship between clear-nce and concentration dictates that the averageolute level will be proportional to the generationate and inversely proportional to the continuousquivalent clearance (Kce):

Cav = G/Kce

Kce = G/Cav

where Cav is average concentration

The value of Kce for urea is calculated easilyy using formal urea modeling that producesoth G and time-averaged C (TAC).264 However,he resulting clearance is significantly higherhan a consensus-derived continuous equivalentlearance for PD. This observation led 2 groupso propose using the average peak or averageredialysis urea concentrations as the target in-tead of mean concentration.265,266 This substitu-ion of a higher concentration than Cav in thexpressions resulted in a lower average clear-nce, more in keeping with the accepted continu-us peritoneal clearances for CAPD. The result-ng quasiclearance was called “standard K” andstandard Kt/V” (stdKt/V).265 Another proposedpproach is to model the kinetics of otherolutes because almost all other small and largeialyzable solutes have greater disequilibriumhan urea.267,268 As noted, the inefficiency ofntermittent dialysis is accentuated by disequilib-
ium. All these methods produced a set of curves

rtwcaskNfa

paswr

weesseiuw

qpaldomMmlrtm3gttd

watcsepaKl

Q

camseoadsibscduuIecipsfiKlesdtpifob

RECOMMENDATIONS FOR HEMODIALYSIS ADEQUACYS52

elating spKt/V to stdKt/V or normalized Kt/Vhat were similar, partially because parametersere chosen in each case to “force” the resulting

ontinuous equivalent clearance to match theccepted values for continuous PD (CAPD).tdKt/V is calculated easily by using formal ureainetic modeling and has been chosen by theIH-sponsored Frequent HD Network as the

requency-normalized expression to monitor di-lysis doses in their study of daily HD outcomes.

Conversion of spKt/V to stdKt/V can be ap-roximated by using an explicit equation thatssumes a symmetric weekly schedule of dialy-es, no Kr, and a fixed volume (V). This methodas presented first by Gotch in 1998 and later

efined by Leypoldt in 200471:

1Nt

10080

Kt/V

1t

110080

Kt/V

sp

eKt/V

eKt/V

std

−+−

−

= −

−

e

e

here N is number of treatments per week andKt/V is derived from spKt/V by using 1 of thexpressions in Table 4. It should be noted thattdKt/V calculated using this equation may differlightly from stdKt/V calculated using the morexact method described previously that takesnto account other variables, such as ECF vol-me expansion/contraction, asymmetry of theeekly schedule, and Kr.The complexities of normalizing more fre-

uent HD to a continuous equivalent clearanceerhaps have contributed to a lack of consensusbout dose expressions for the increasingly popu-ar schedule of 4 treatments per week. The extraialysis treatment often helps with managementf larger patients, patients with refractory ane-ia, and patients with excessive fluid gains.ost of these methods require formal kineticodeling and modeling programs that are not

ocked into 3 treatments per week. In addition,egulatory agencies have not caught up withhese concepts and continue to demand a mini-um Kt/V of 1.2 per dialysis as if they are giventimes per week. If an extra dialysis treatment isiven, a simple mathematical calculation showshat the minimum dose per dialysis required ifhe minimum for 3 times per week is 1.2 per
ialysis is 0.9 per dialysis to achieve the same r
eekly clearance. This calculation assumes thatll dialysis treatments are equal and the extrareatment produces no gain in efficiency. Thisonservative calculation will provide more dialy-is for the patient than is apparent from thexpressed dose, which effectively protects theatient from underdialysis. Alternatively, the di-lysis clinic can simply multiply the measuredt/V by 4 and divide by 3 to obtain the equiva-

ent of Kt/V for 3 treatments per week.

uality Assurance

The Work Group continues to recommendomparisons of prescribed with delivered dosess a quality assurance aid. Guideline 4 provides ainimum Kt/V threshold below which action

hould be taken to prevent underdialysis. How-ver, even if the dose is adequate, comparisonf prescribed with delivered dose has potentialdditional benefit for the patient. If significantlyifferent (�15% difference), troubleshootinghould be done to detect other problems that maympact on future dosing, such as AR or a faultylood pump. In practice, comparison of pre-cribed with delivered dose is accomplished byomparing modeled V with real V. The latter isetermined preferably by averaging previous val-es of modeled V, but also can be determined bysing an anthropometric formula, eg, Watson.269

f a problem exists with delivery, usually mod-led V is significantly greater than real V. Be-ause urea modeling provides a ratio of K/V, thenflated V is caused by an inordinately highrescribed K compared with delivered K. Pre-cribed K is determined from the dialyzer speci-cation, K0A, and flow rates, whereas modeled/V is determined mainly from changes in BUN

evels during the dialysis. Comparison of mod-led V with a previously determined patient-pecific value for V is equivalent to comparingelivered with prescribed clearance. When V isoo high, efforts should be made to detect suchroblems as AR, an error in dialysis timing,nadequate blood pump occlusion or calibration,aulty dialysate pump, error in blood sampling,r inadequate performance of the dialyzer (eg,ecause of clotting during dialysis or excessive
euse).

C

4

4

4

4

A

LINICAL PRACTICE RECOMMENDATIONS FOR GUIDELINE 4:
MINIMALLYADEQUATE HEMODIALYSIS
4

4

4

4

.1 High-Flux Membrane:When methods to achieve good dialy-sate water quality are available, high-flux HD membranes should be used,defined as those providing �2-micro-globulin (�2M) clearance of at least20 mL/min under conditions of actualuse.

.2 Minimum dose with hemofiltration orhemodiafiltration:

The recommended minimum de-livered dose target, measured byusing pretreatment and posttreat-ment BUN levels, is the same as thatfor HD.

.3 Minimum spKt/V levels for different dialy-sis schedules:4.3.1 Two to 6 treatments per week are

appropriate for certain patients.4.3.2 Twice-weekly HD is not appropriate

for patients with Kr less than 2mL/min/1.73 m2.

4.3.3 Minimum spKt/V targets for 2-, 4-,and 6-times-per-week dialysis sched-ules logically should be differentfrom that for the thrice-weeklyschedule. In the absence of dose-ranging outcomes data, minimumspKt/V targets for different sched-ules can be based on achieving aminimum stdKt/V of 2.0 per week.

4.3.4 The target spKt/V dose should be atleast 15% higher than the listedminimum dose because of the vari-ability in measuring Kt/V, as dis-cussed in Guideline 4.

.4 RKF (measured by Kr):4.4.1 The minimally adequate dose of dialy-

sis can be reduced in patients with Kr

greater than 2 mL/min/1.73 m2.4.4.2 In the absence of dose-ranging out-

comes data, the minimum spKt/Vtarget for patients with substantialRKF can be reduced, but the re-duced target should be no lowerthan 60% of the minimum targetfor patients with no residual renal
function (the reduction depends on

dialysis frequency), per values pro-vided in Table 13.

4.4.3 When the minimally adequate doseis reduced because of substantialRKF, Kr should be monitored atleast quarterly and as soon as pos-sible after any event that mighthave acutely reduced RKF.

.5 Increase in minimally adequate dose forwomen and smaller patients:

An increase in the minimally ad-equate dose of dialysis should beconsidered for the following groupsof patients:4.5.1 Women of any body size.4.5.2 Smaller patients, for example,

patients with values for an-thropometric or modeled V of25 L or lower.

.6 Dialysis adequacy for patients who are mal-nourished and/or losing weight:

An increase in the minimally ad-equate dose of dialysis and/or achange to a more frequent dialysisschedule should be considered forthe following groups of patients:4.6.1 Patients whose weights are

20% less or lower than theirpeer body weights.

4.6.2 Patients with recent otherwiseunexplained and unplannedweight loss.

.7 Dialysis adequacy for patients with hyper-phosphatemia or chronic fluid overload andother categories of patients who mightbenefit from more frequent dialysis:

A change to a more frequent dialy-sis schedule should be consideredfor the following groups of pa-tients:4.7.1 Patients with hyperphos-

phatemia.4.7.2 Patients with chronic fluid

overload with or without re-fractory hypertension.

.8 A change to a more frequent dialysisschedule may be beneficial to a broader
group of patients in terms of improving
, 2006: pp S53-S62 S53

4

H

twbAbooishpohlrdcetcdymwvtadbsfvg

2et

sa�(i

td1ryta0timbj

ucutrepcsgg

lhdamdCams

eubapWm


QOL and quality of sleep, reducing sleepapnea, and improving sensitivity to eryth-ropoietin.

.9 Minimum dialysis treatment time forthrice-weekly schedules:

The minimum HD treatment timefor thrice-weekly dialysis in patientswith Kr less than 2 mL/min shouldbe at least 3 hours.

RATIONALE

igh-Flux Membrane (CPR 4.1)

The �2M molecule has an important role inhe pathogenesis of dialysis-related amyloidosis,hich is seen primarily in HD patients who haveeen dialysis dependent for more than 5 years.n important question is whether use of mem-ranes that clear �2M gives rise to superiorutcomes over shorter periods, especially in termsf such hard outcomes as mortality and hospital-zation. The primary results of the HEMO Studyuggested that assignment to dialysis using aigh-flux membrane had no significant effect onatient mortality or a variety of main secondaryutcomes that combined mortality with eitherospitalization or decrease in serum albuminevels.1 However, in contrast to results of doseandomization (for which the mean effect size ofose on mortality or secondary outcomes waslose to zero) in the flux analyses, the meanffect size for mortality, as well as for several ofhe secondary outcomes, was fairly consistentlylose to a 10% benefit, although the 95% confi-ence intervals (CIs) included zero. Further anal-sis of the HEMO Study data showed that assign-ent to high-flux dialysis improved mortality (asell as main secondary outcomes) in higherintage patients, ie, those dialyzed longer thanhe median time of 3.7 years at baseline.270 Thisnalysis in higher vintage patients was pre-efined at the outset of the HEMO Study beforeeginning the trial. Furthermore, some of theecondary outcomes—in particular, compositesocusing on cardiovascular death and/or cardio-ascular hospitalizations—were improved in theroup assigned to high-flux therapy.271

During the KDOQI HD update period, 2000 to005, no other randomized trials assessing hardnd points (mortality and/or hospitalization) in pa-
ients undergoing high-flux versus low-flux dialy- C
is were published. Several randomized trials lookedt the effects of high-flux dialysis on predialysis2M levels, and all found a measurable effect

reduction in level with high-flux dialysis), includ-ng the HEMO Study (see Table 12).270,272,273

Additional observational studies suggested thathe mortality rate might be decreased in patientsialyzing with high-flux membranes (see Leypoldt,999,274 and Woods, 2000275 in Table 12). Afteresults of the HEMO Study were disclosed, anal-sis of mortality versus flux data from the 1999o 2000 USRDS, published in abstract form, foundsmall mortality risk reduction (relative risk [RR],.972; 95% CI, 0.950 to 0.995) in prevalent pa-ients, and an RR of 0.951 (CI, 0.937 to 0.966) inncident patients dialyzed with high-fluxembranes.277A However, this abstract has not

een published as an article in a peer-reviewedournal.

In a large European cohort of patients makingp the Lombardi registry, mortality and risk forarpal tunnel surgery were compared in patientsndergoing (mostly low-flux) HD, hemodiafiltra-ion, and hemofiltration.278 A 10% mortality riskeduction was found in patients treated withither hemodiafiltration or hemofiltration com-ared with mostly low-flux HD, but the CI in-luded zero. However, the investigators found aignificant risk reduction for carpal tunnel sur-ery in the hemodiafiltration/hemofiltrationroups.The most recent European Best Practice Guide-

ines include recommendations for the use ofigh-flux membranes, supported by level B evi-ence (Guideline II.2.1) and also recommend theddition of a convective component to enhanceiddle-molecule removal, also with level B evi-

ence (Guideline II.2.2).279 However, a recentochrane group review, looking at a meta-nalysis of RCTs studying the effect of dialysisembrane on outcome, concluded that it was too

oon to make a definitive recommendation.273

The Work Group ultimately decided that thevidence for benefits of high-flux membranese in terms of hard outcomes was suggestive,ut not definitive enough to be formulated asguideline, taking a more conservative ap-

roach than the European group. However, theork Group decided that the evidence forortality reduction was strong enough for a
PR encouraging high-flux dialysis. The evi-


ds(lt�bi

hcaa(if�agit2bom

MH

mtmaamrtatglfioIGmbtusm

iltmGaawma

MS

gwiiwbtpGmBWtt

stotmcd(mctndwdd

Rope


ence is incontrovertible that high-flux dialy-is decreases predialysis serum �2M levelsTable 12),270,272,273 and lower predialysis �2Mevels were linked to improved outcome. Fur-hermore, reduced long-term consequences of2-amyloidosis with the use of high-flux mem-ranes was reported by 2 groups,280,281 confirm-ng a much earlier report.282

The Work Group also specified a definition ofigh-flux dialysis. In the HEMO Study, �2Mlearances were measured in vivo, and a clear-nce of at least 20 mL/min was defined asdequate for a dialyzer to be considered high fluxthe low-flux dialyzers used had �2M clearancendistinguishable from zero). Because the manu-acturing industry has learned how to expand2M clearances while minimizing albumin leak-ge, current dialyzers are available with muchreater �2M clearances, and the clearance can bencreased still further by the use of hemodiafiltra-ion and/or novel dialyzer designs. The value of0 mL/min was adopted for these guidelinesecause it corresponded to the minimum levelbtained in the HEMO Study, which provideduch of the evidence for this CPR.

inimum Dose With Hemofiltration oremodiafiltration (CPR 4.2)

Urea is a surrogate adequacy molecule foreasuring clearance of a large family of uremic

oxins, some of which may have a much higherolecular weight. Because convective removal

ccelerates removal of larger (�5 kd), yet perme-ble, solutes during extracorporeal therapy, itight be argued that with hemofiltration, the

atio of removal of these larger molecular-weightoxins to urea removal is higher; hence, minimaldequacy parameters based on urea removal ei-her do not apply or existing minimal adequacyuidelines based on urea removal should beower when hemofiltration is used. No dose-nding studies of hemofiltration that report hardutcomes could be identified by the Work Group.n the absence of data to the contrary, the Workroup decided to maintain recommended mini-um adequacy standards for urea removal for

oth hemofiltration- and hemodiafiltration-basedherapies. With hemodiafiltration, urea removalsually is unchanged or slightly enhanced by theupplemental filtration, so this was a somewhat
oot issue. However, for some forms of primar- d
ly hemofiltration-based dialysis therapy (in whichimited amounts of replacement fluid are used),he recommended minimum levels of urea re-oval may be difficult to achieve. The Workroup decided, on the basis of current evidence

nd lack of an interaction between urea-baseddequacy and flux in the HEMO Study, that itould be prudent to recommend the same mini-um levels of spKt/V for HD, hemofiltration,

nd hemodiafiltration.

inimum spKt/V Levels for Different Dialysischedules (CPR 4.3)

The KDOQI 2000 HD Adequacy Guidelinesave adequacy recommendations only for thrice-eekly HD schedules. Since the last update, 1

mportant cross-sectional study appeared suggest-ng that survival in patients treated with twice-eekly HD was no worse (and was possiblyetter) in a USRDS patient sample.234 Givenhese data and with earlier initiation of dialysis inatients with higher levels of RKF, the Workroup decided that thrice-weekly HD as a mini-um frequency level was no longer appropriate.ased on solute kinetics (discussed later), theork Group was comfortable recommending a

wice-weekly dialysis schedule, but only for pa-ients with substantial RKF.

Also, since the KDOQI 2000 update, a largeet of studies was published regarding the poten-ial advantages of giving dialysis treatments moreften than 3 times per week. The number ofreatments ranges from an additional fourth treat-ent per week in patients who have problems

ontrolling volume283 to offering short “daily”ialysis treatments ranging from 1.5 to 3 hoursor longer) 4 to 6 times per week. An alternativeethod of extending therapy is to greatly in-

rease dialysis treatment time (from the usual 2.5o 5 hours) to 7 to 10 hours by giving dialysis atight. Various frequency schedules for nocturnalialysis have been reported, from 3 to 6 times pereek.284 Simple avoidance of the 2-day inter-ialysis interval by giving dialysis every otheray also has been advocated.285

At the time of the present guideline update, noCTs have been conducted to measure hardutcomes (mortality and/or hospitalization) com-aring conventional thrice-weekly dialysis withither short-daily or nocturnal HD. Also, no
ose-finding RCTs have appeared comparing fre-

qms

iftgiq

tbdruimcpcamm4stn

udovmnlldnsmdcTsaepstt

tstqdspsr

clttm

rstrfbttTm

mctuttp

dntflWmt

TM

wasd


uent short dialysis with longer nocturnal regi-ens in an effort to achieve varying degrees of

olute removal.Given the lack of maturity of the research data

n this field, the Work Group decided to refrainrom making specific recommendations abouthe usefulness of these therapies in terms of auideline or from proposing guidelines regard-ng minimally adequate therapy given more fre-uently than 3 times per week.How to measure adequacy of more frequent

herapies is not established. One of the mainenefits of more frequent therapies may be rid-ing the body of solutes that are difficult toemove, such as phosphate, �2M, or some stillnknown uremic toxins. Another benefit may ben better control of salt and water balance, whichay impact on patient survival as much as solute

ontrol. In particular, the Work Group was im-ressed with observational data linking hard out-omes to calcium-phosphorus product,286 as wells better control of serum phosphorus levels withore intensive daily dialysis schedules200 andost nocturnal dialysis schedules.284 Because 2,

, 5, and 6 treatments per week (nocturnal and/orhort-daily therapies) increasingly are prescribed,he Work Group decided that some guidance waseeded in terms of minimally adequate doses.Although an argument could be made that

rea is not the only solute to use for measuringoses in a more frequent dialysis setting, controlf small-solute levels in patients is vital to sur-ival, so the Work Group decided to base recom-endations for this CPR on urea. Potential alter-

ative solutes, such as �2M, are not as clearlyinked to outcome. Phosphate, while clearlyinked to outcome, has complex and as yet poorlyefined kinetics, and serum levels are affectedot only by dialysis, but also by diet and con-umption of phosphorus binders. One of theajor disadvantages of urea is the rapidity of its

iffusion among body compartments (high inter-ompartmental mass transfer area coefficient).his limitation can be minimized by using thetdKt/V construct, as described in detail in CPR 2nd in the Appendix. When the dialysis dose isxpressed as stdKt/V, it seeks to control the meanre-dialysis BUN, but, alternatively, it can be con-idered to model a well-cleared, but highly seques-ered, solute with a low intercompartmental mass
ransfer area coefficient. Because highly seques- t
ered solutes will have a large rebound after dialy-is, the time-averaged blood level will be close tohe mean predialysis level. stdKt/V also has theuality of reflecting advantages of a more frequentialysis schedule that more efficiently removesequestered solutes, such as phosphorus, but alsoossibly including a whole range of dialyzableolutes in the 100 to 1,000 d molecular-weightange.

In developing this CPR, the Work Group de-ided to target a minimum dialysis dose equiva-ent to an stdKt/V level of 2.0 per week. This ishe level obtained when one dialyzes using ahrice-weekly schedule to an spKt/V of approxi-ately 1.2 per treatment over 3.5 hours (Table 19).In the absence of RKF, it is not possible to

each an stdKt/V of 2.0 by using a twice-weeklychedule. Kinetic modeling was used to examinehe levels of spKt/V per treatment that would beequired to reach a weekly stdKt/V value of 2.0or twice-weekly to 7-times-weekly schedulesy using dialysis treatment times ranging from 2o 8 hours. The simulation was performed both inhe absence of RKF and when Kr was 2 mL/min.his simulation was used to arrive at the recom-ended minimum values in Table 13.These spKt/V values should be consideredinimum values, not target values. It is espe-

ially important to note that extending dialysisime is much more effective for controlling sol-te levels when frequency is increased to 4 to 7reatments per week. Particularly in short-dailyherapies, longer treatment times markedly im-rove phosphate removal.From Table 19, similar spKt/V values can be

etermined for 8-hour treatments more typical ofocturnal HD. Usually the Kt/V for an 8-hourreatment, even at reduced dialysate and blood-ow rates, will be greater than 1.0; hence, theork Group did not believe that adequacy deter-ined by predialysis or postdialysis BUN moni-

oring is appropriate for nocturnal HD schedules.

arget spKt/V Values per Treatment forore-Frequent TherapiesIn contrast to thrice-weekly schedules, for

hich there are good data regarding the vari-nce in Kt/V on repeated measurements, nouch data have been published for short-dailyialysis, although there is no reason to assume
hat it would be much different from the 10%

vritT

R

lfmprsplsiai�woowpvcmvlsat

tba

u2wKtvmwfc

fmwTfcsccpmhfrtsiwtlhamcdt


ariance found in the HEMO Study. For thiseason, the Work Group recommended target-ng an spKt/V value that is about 15% higherhan the recommended minimum targets inable 19 in the Appendix.

esidual Kidney Function (CPR 4.4)

The KDOQI 2000 HD Adequacy Guidelineseft unspecified any adequacy recommendationsor patients with substantial RKF (GFR � 5.0L/min/1.73 m2, defined as the average of urea

lus creatinine clearance). Given the trends andecommendations for earlier institution of dialy-is therapy and perhaps the more successfulreservation of RKF in the past several years, aarge number of currently dialyzed patients haveubstantial RKF. A consideration of solute kinet-cs shows that even low levels of RKF canccount for removal of large amounts of solute,ncluding such large-molecular-weight solutes as2M, in addition to helping maintain salt andater balance. Although there are no reliableutcome data suggesting that the delivered dosef dialysis might safely be reduced in patientsith substantial RKF, reduction of the extracor-oreal dose makes sense from a solute-kineticsiewpoint. The HEMO Study deliberately ex-luded patients with Kr for urea greater than 1.5L/min and hence cannot be of guidance. Obser-

ational studies suggested a benefit of even smallevels of RKF in terms of survival and otherecondary outcome measures, so it is clear thatll possible efforts should be expended to main-ain RKF (see Guideline 6).

The Work Group was of the opinion that, athe present state of incomplete knowledge, theest way to adjust for residual renal urea clear-
nce is to add it to the weekly stdKt/V. Residual l
rea clearance of 2 mL/min is approximately0 L/wk of clearance; accordingly, in a patientith V � 30 L, it represents about a 0.67 weeklyt/V unit. Table 13 shows spKt/V values per

reatment corresponding to a weekly stdKt/Value of 2.0 in patients undergoing 2 to 6 treat-ents per week after adjusting (or not) for aeekly Kr of 2 mL/min. In discussing adjustments

or Kr, the Work Group had 2 broad areas ofoncern.

First, the kinetic effect of RKF is so power-ul that in patients with Kr greater than 2L/min, an equivalent reduction in spKt/Vould result in very low recommended values.he Work Group believed this was undesirable

or 2 reasons: (1) very low Kt/V values, espe-ially for the twice-weekly or thrice-weeklychedules, would limit other potential benefi-ial effects of dialysis, including salt and waterontrol; and (2) RKF sometimes can decreaserecipitously. Patients who were receiving aarkedly reduced dose of dialysis because of a

igher Kr then might be underdialyzed for aew months until the reduction in Kr wasecognized and acted upon. For these reasons,he Work Group developed an alternativecheme that limited the downward adjustmentn spKt/V for Kr to 2 mL/min, even for patientsith higher levels of Kr. The decision to “cap”

he reduction in session Kt/V was based on theack of outcomes data in patients who haveigher levels of RKF and receive very lowmounts of dialysis Kt/V. Maintaining a mini-um “total Kt/V” value of 1.2, using an exact

alculation of the required dialysis spKt/V asescribed in the Appendix, would allow reduc-ion of the dialysis dose down to near zero at
evels of RKF that are below the threshold for

iitdrgcicurr

foqscdfdt

IS

lmHipcSsmsg

W

ttohhownmat

ctdwWeaat

(pmnitbgbfhmwser

B

psmvawmwaswwptWw

npto


nitiating dialysis. The wisdom of recommend-ng this fully incremental approach was in-ensely debated in the Work Group. Opinionsiffered, so it was decided to leave furthereductions in dialysis dose, below values sug-ested in Table 13, to the discretion of thelinician. One single study81, addressed thisssue but there are few other studies of out-omes in patients with RKF hemodialyzedsing an incremental dialysis schedule. Thisemains a critical area where more research isecommended.

Second, it was recommended that in patientsor whom treatments are reduced because of Kr

f 2.0 or greater, Kr should be rechecked at leastuarterly (every 3 months) and after any eventuspected to be associated with a sudden de-rease in Kr. However, because the Work Groupid not want to impose a burden of verifying Kr

or all patients in a dialysis clinic, the recommen-ation is to verify it only in patients for whomhe target dialysis dose is reduced.

ncrease in Minimally Adequate Dose forpecial Populations (CPR 4.5)

One potential area of concern relates to se-ected subgroups of patients who may requireore dialysis. During the design phase of theEMO Study, 7 such subgroups were postulated,

ncluding patients with high comorbidity scores,atients with diabetes, high-vintage patients, Cau-asian patients, and women. Based on HEMOtudy results plus results from subsequent cross-ectional studies plus clinical judgment and “com-on sense,” the Work Group recommended pos-

ibly increasing the target dose of dialysis in 2roups of patients: women and small patients.

omenOf the 7 “high-risk” groups identified during

he design phase in the HEMO Study, an interac-ion with dose group assignment was present fornly women (Table 8).13 Women assigned to theigher dose of dialysis (URR �75%, on average)ad better survival than those assigned to URRf about 63%. The overall benefit for men andomen was close to zero because an oppositeonsignificant trend for increased mortality inen assigned to the higher dose of dialysis

lso was found. As best could be determined,
he sex-dose-mortality interaction was not o
aused by body size, although most women inhe HEMO Study had a smaller body size,etermined by using a variety of measures,ith little overlap with the men in the study.hile the HEMO Study was in progress, oth-

rs identified a similar sex-dose interaction,57

nd after HEMO Study results were reported,nother group reported a similar association inhe USRDS-Medicare database.104

To complicate matters, the dose-targeting biasdiscussed in more detail in Guideline 4) ap-eared to be enhanced in women compared withen.98 This means that observational data should

ot necessarily be considered confirmatory of thentent-to-treat sex-dose-mortality interaction iden-ified in the HEMO Study. However, becauseoth randomized and observational data sug-ested that a higher dose of dialysis might beeneficial for women, the Work Group was com-ortable with issuing a CPR for considering aigher dialysis target dose in women. For theost part, this happens naturally because mostomen have a smaller value for V; thus, the

ame prescription applied to a man and a woman,ven considering patients of equal weight, willesult in a higher Kt/V in the woman.

ody SizeThere are, of course, multiple reasons why a

atient can be “small.” A patient can be short,mall boned, or simply thin, all without beingalnourished. Most data examining body size

ersus dose versus mortality interactions lookedt anthropometric measures in which body sizeas derived from weight and height—eg, bodyass index (BMI)—and, in some studies (inhich Watson V was used), sex, and age. It

ppears that most of the mortality effect in thesetudies is related to BW because the Work Groupas not able to find data in which patient heightas a predictor of mortality (nor was height aredictor of mortality in the HEMO Study). It ishen presumed that patients with lower BMI or

atson V primarily are underweight patientsho are malnourished.A separate issue is whether smaller nonunder-

ourished patients who are at or near their ex-ected weight might require more dialysis. Here,he argument has to do with sizing delivered dosef therapy based on body water, which is a factor
f BW to the 1.0 power (usually V � some factor

muf(sttaKsbsqAsn

bsMi

sHbdnsmotffiaUo

wdltt

●

●

●

scist

DM

rtmhtSimrlpsrttcB

pcwmaeopina

DHVPFP

pad


ultiplied times the postdialysis weight). GFRsually is sized according to BSA, which is aactor multiplied times BW raised to the 0.6672/3) power. If Kt was normalized to BSA orome factor multiplied by V0.667 and a singlearget value was assigned for all values of weight,he result would be that more dialysis would bessigned to smaller patients than with the currentt/V strategy, and less dialysis would be as-

igned to very large patients. The argument haseen made that V is determined substantially bykeletal muscle mass, which may be relativelyuiescent in terms of generation of uremic toxins.lthough women or less muscular men may have a

maller V than similar-height controls, it does notecessarily mean they require less dialysis.

The Work Group noted and reviewed a num-er of studies in this field, examining the relation-hip of Kt and various measures of body size.ost of these analyzed the Fresenius North Amer-

ca patient data set.78,101

The Work Group also looked at an analysis ofurvival by various body size parameters in theEMO Study,13 in which various measures ofody size were not found to interact with deliveredose. The Work Group concluded that there wasot sufficient evidence to abandon the concept ofizing of dialysis dose according to V for theoment because cross-sectional survival analyses

f dose versus mortality have so many biaseshat—at present—the effects of individual con-ounding factors have not been completely clari-ed. Furthermore, there is great simplicity in beingble to monitor delivered dialysis dose based onRR and then combine this with weight loss andther information to compute a delivered Kt/V.

The compromise solution for the present updateas to keep the dose as spKt/V and the minimumose unchanged, as per the KDOQI 2000 guide-ines, but to issue this CPR, which recommendshat one consider increasing minimum dialysis doseargets in both women and small patients.

Several logical questions arise:

By how much should the targets be increased?Should targets be increased for both largewomen and small women?In small women who also are “small” in termsof their size, should the increase in dose be
greater than the increase for small men? p
The Work Group decided to leave these deci-ions up to the practitioner, although an in-reased minimum dose of 25% was the range ofncrease in dose envisaged for either women ormall patients (eg, to an spKt/V of 1.5 for ahrice-weekly schedule with Kr � 2).

ialysis Adequacy for Patients Who Arealnourished and/or Losing Weight (CPR 4.6)

Because nutrition tends to deteriorate even atelatively well-preserved levels of renal func-ion,288 the notion is prevalent in the dialysis com-unity that increasing the amount of dialysis may

elp improve nutritional status. A variety of nutri-ional parameters were measured in the HEMOtudy, and the higher-dose group did not show

mprovement in any of the nutritional parameterseasured, including serum albumin, anthropomet-

ics, or food intake. However, patients treated withonger (8-hour) periods of dialysis given 3 timeser week or patients following 6-times-per-weekhort-daily dialysis regimens or nocturnal-dialysisegimens sometimes reported marked benefits inerms of food intake, serum albumin level (al-hough this is confounded by blood volume changesaused by hemoconcentration), and increase in dryW.284

For these reasons, the Work Group issued theresent CPR, which recommends that practitionersonsider increasing the dose of dialysis in a thrice-eekly framework in patients who are judged to bealnourished by BW criteria, subjective global

ssessment, or other means. The lack of a beneficialffect on nutritional parameters in the HEMO Studyf increasing spKt/V from 1.3 to 1.7 suggests thaterhaps a more useful strategy in such patients is toncrease dialysis frequency, although it is recog-ized that such therapies are not uniformly avail-ble at all centers.

ialysis Adequacy for Patients Who Areyperphosphatemic or With Refractoryolume Overload and Other Categories ofatients Who Might Benefit From Morerequent Dialysis (CPR 4.7)atients With HyperphosphatemiaSerum phosphorus level appears to be a robust

redictor of mortality in dialysis patients, as wells patients with CKD.286 Phosphorus control isependent on phosphorus intake, compliance with
hosphorus-binder intake, and HD prescription.

Bltmrchpsmsh(sowsAtaetop

pltp2lpaetsrepph

V

atratww

hosmn

OF

tatptpuiais

TTm

Tsa21saweiteSpmtc

gottwI


ecause serum phosphorus level decreases to aow level early in dialysis, increases in Kt/V in ahrice-weekly framework while holding treat-ent time constant (eg, by increasing blood flow

ate or dialyzer urea clearance) or slight in-reases in dialysis treatment time are expected toave only a mild to negligible effect on serumhosphorus levels. With short-daily dialysischedules, the initial 30 minutes of each treat-ent occurs while serum phosphorus levels are

till high, but overall serum phosphorus controlas been disappointing, especially using short1.5- to 2-hour) treatments. Patients undergoinghort-daily dialysis sometimes increase their foodr protein (and therefore phosphorus) intake,hich may compensate or even override the

mall additional amount of phosphorus removal.recent nonrandomized study in which 3-hour

reatments were given 6 times per week showeddecrease in serum phosphorus levels.200 How-

ver, it is not clear to what extent patients wouldolerate 3-hour treatments given 6 days per weekr if alternative measures to control serum phos-horus might be equally or more effective.An increase in total weekly hours of dialysis,

robably more than 24 h/wk, distributed over ateast 3 treatments per week appears to be neededo control phosphorus levels in most dialysisatients. In the Tassin experience (8 h/wk � 3 �4 h), approximately one third of patients noonger required phosphate binders (B. Charra,ersonal communication, February 2005). Usingn “every-other-night” nocturnal dialysis strat-gy (�28 h/wk) should give results similar tohose in the Tassin experience. Nocturnal dialy-is given 5 to 6 times per week appears toemove the need for phosphorus binders, ad-quately controls phosphorus levels in almost allatients, and often requires the addition of phos-horus to the dialysate to preventypophosphatemia.284

olume-Overloaded PatientsControl of patient volume and blood pressure

re reviewed in detail in Guideline 5. In additiono the recommendations discussed in Guideline 5egarding sodium balance, one of the most reli-ble methods to help achieve volume control iso extend total weekly dialysis time. In cases inhich this cannot be done practically in a thrice-
eekly framework, a 4-times-per-week schedule t
as proved useful. Additional benefits may bebtained by moving to a short-daily or not-so-hort daily 6-times-per-week schedule, and ulti-ate control would be expected using a noctur-

al HD schedule.

ther Categories of Patients for Whom Morerequent Dialysis May Be BeneficialAt the present time, other patient subgroups

hat might benefit from more frequent dialysisre not as clearly identified. It remains possiblehat almost all patients might benefit, althoughractical and reimbursement issues, as well ashe present incomplete state of knowledge, clearlyreclude such a recommendation. Small largelyncontrolled studies suggest that—in addition tomproved nutritional status, serum phosphorus,nd volume control—more frequent dialysis maymprove erythropoietin sensitivity, quality ofleep, and sleep apnea, as well as overall QOL.

he Minimum Dialysis Treatment Time for 3reatments per Week With Kr Less Than 2L/min Should Be 3 Hours (CPR 4.8)

This guideline evolved from 2 considerations.he first is the concept of attempting to maintaintdKt/V close to 2.0 per week as a minimummount of dialysis across all schedules. For a-hour dialysis treatment, an spKt/V of at least.4 is required to achieve an stdKt/V of 2.0. Theecond consideration is that it is difficult tochieve good control of salt and water balanceith very short treatment times. The outcomes

vidence for this CPR is not particularly strong;n the HEMO Study, the minimum treatmentime was 2.5 hours and there was no randomizedvaluation of treatment time; thus, the HEMOtudy is not applicable here. A study that com-ared conventional dialysis (3- to 4-hour treat-ents) with ultrashort high-efficiency hemodiafil-

ration found no difference in level of blood pressureontrol.289

Very recent studies, including 1 RCT, sug-ested that dialysis treatment time has an impactn outcomes.72A Cross-sectional data showedhat dialysis treatment time was related inverselyo mortality, but much of this effect disappearedhen patient BSA was included in the model.101

t was the Work Group’s belief that a minimum
reatment time of 3 hours reflects clinical prac-

ta

Hbttdmt

wtmhaH

t

aaasaoisifta

Wiecai


ice and was especially important in patients withlow Kr (�2 mL/min).

LIMITATIONS

Given the difficulty conducting RCTs in theD population, many of the questions addressedy the present CPRs will not be answered defini-ively with Level A evidence for many years. Itakes approximately 2,000 patients to run a ran-omized trial powered to detect a change inortality (eg, the HEMO trial), and even then,

he power to detect smaller effects is limited.The level of �2M clearance in the HEMO Study

as modest, and it is unclear whether more defini-ive benefits of convective and/or high-flux treat-ent might be seen with high-substitution volume

emodiafiltration, in which levels of �2M clear-nce substantially greater than those obtained in theEMO Study can be achieved.The Work Group believes that given the dose-

argeting bias identified in the HEMO database98 d

nd the multiple confounding factors present inssignment of dialysis dose, modeled volume,nd different survival effects caused by bodyize, it is difficult to draw valid conclusionsbout how best to target dialysis therapy basedn body size. The present guidelines address thessue of increasing the amount of minimal dialy-is for smaller patients. They do not address thessue of reducing the amount of minimal dialysisor very large patients, for which technical andime issues become burdensome for both staffnd patient.

With regard to more frequent therapies, theork Group understands that their use is grow-

ng markedly. The present time should be one ofxperimentation in terms of finding the bestombination of schedules and treatment times,nd the Work Group was accordingly restrainedn terms of its recommendations for how best to
eliver such therapies.

popQ

5

5

5

H(

twGt

paatcsUUdpptr

dhfct

A

CLINICAL PRACTICE RECOMMENDATION 5: DIALYZER
MEMBRANES AND REUSE
stlmba

asrpmpcmaetptvoysaaitiodtcti

1ri1mctpsmb

Selection of dialyzer membranes and reuseractices are not included in the prescriptionf small-solute clearance, yet they can be im-ortant determinants of patient survival andOL.

.1 When dialyzers are reused, they should bereprocessed following the Association forthe Advancement of Medical Instrumenta-tion (AAMI) Standards and RecommendedPractices for reuse of hemodialyzers.291

.2 Dialyzers intended for reuse should have ablood compartment volume not less than80% of the original measured volume or aurea (or ionic) clearance not less than 90%of the original measured clearance.

.3 The use of poorly biocompatible, unmodi-fied cellulose dialyzer membranes for HDis discouraged.

RATIONALE

emodialyzer Reprocessing and ReuseCPR 5.1)

Thorough examination of data pertaining tohe impact of reused dialyzers on patient safetyas beyond the scope of the HD Adequacy Workroup. Therefore, the Work Group takes no posi-

ion for or against the practice of dialyzer reuse.Reprocessing dialyzers for reuse in the same

atient was popularized 2 to 3 decades ago tollow widespread use of the more biocompatiblend higher flux dialyzers that are more expensivehan their less biocompatible and lower fluxounterparts. Reuse of the former more expen-ive dialyzers remains a common practice in thenited States today.41,292-297 In 2002 in thenited States, 78% of HD clinics reprocessedialyzers,41 but—largely as a result of decliningrices and the recent decision of a major dialysisrovider (Fresenius Medical Care, US) to discon-inue reuse—fewer US dialysis patients are en-olled in reuse programs today.

Reprocessing of disposable medical devicesesigned for single use as a cost-saving measureas been debated, not only for dialyzers, but alsoor sundry and other medical devices.297 In thease of dialyzer reuse, the main concern has been
he risk to life, but other issues have been raised, s

uch as risk for infection and pyrogenic reac-ions, toxicity from disinfectants, reduced dia-yzer performance,297 impaired removal of large

olecules,294 and the validity of the dialyzerlood volume measurement as a criterion forssessing dialyzer function.292,298

Over the years, a plethora of publications haveddressed the possible cause-and-effect relation-hip between reuse and mortality. Conclusionseported in earlier publications were conflicting,ossibly because reuse-related morbidity andortality is a moving target (Table 14). Practice

atterns, reuse procedures, dialyzer membranes,omorbidity, age difference, nature of the pri-ary disease, disease severity, ethnic make-up,

nd other potentially confounding influences havevolved over time. For example, high-flux syn-hetic membranes have almost completely re-laced low-flux cellulosic membranes. Whereashe number of times that a dialyzer is reusedaries from clinic to clinic, the average numberf reuses per dialyzer is higher (�15) in recentears compared with earlier years (�10).294 Theterilant used also has varied from clinic to clinicnd over time. During 1983 to 2002, the percent-ge of centers using formaldehyde for reprocess-ng dialyzers decreased from 94% to 20%, whereashe percentage using a peracetic acid preparationncreased from 5% to 72%. In 2002, a total of 4%f centers used heat or glutaraldehyde to disinfectialyzers between reuses.295 Also, the number ofimes that a dialyzer is reused varies from clinic tolinic. Because of these various confounding fac-ors, research data obtained from decades-old stud-es may have less present-day clinical relevance.

In one of the largest retrospective analyses,- to 2-year follow-up data were examined in aepresentative sample of 12,791 patients treatedn 1,394 dialysis facilities from 1994 through995.297 After adjustment for other risks, RR forortality did not differ for patients treated in

linics that reused dialyzers compared with pa-ients from single-use clinics. In addition, amongatients at clinics that reused dialyzers, high-fluxynthetic membranes were associated with lowerortality risk, particularly when exposed to

leach.297 However, a recent study found a patient
urvival advantage when the patient was switched
, 2006: pp S63-S67 S63

fbhspcmppcs

pewubaMfaraUencr

aWaodpga1bmtdaaFerth

f


rom reuse to single use.299 It was suggested thatecause the cost of biocompatible membranesas decreased of late, it might be time for dialy-is clinics to consider abolition of the reuseractice.300 However, the cost of single-use bio-ompatible dialyzers is still considerable, andost investigators continue to maintain that the

ractice of reuse is safe,301,302 provided it iserformed according to recognized reuse proto-ols, including the dialyzer manufacturer’s in-tructions.292,295,296,303

In an analysis of 49,273 incident Medicareatients from 1998 to 1999, no significant differ-nces in mortality or first hospitalization riskere found among patients treated with single-se dialyzers compared with dialyzers cleansedy using different reprocessing techniques.238 Inrecent review of published reports, adjustededicare and Centers for Disease Control data

rom the early to mid-1990s showed no measur-ble mortality risk from reuse.239 In accordance,ecent Medicare data also showed no survivaldvantage associated with single use in incidentS patients during 2001.304 In addition, no differ-

nces in mortality were found among for-profit,ot-for-profit, hospital-based, and free-standinglinics. To date, no prospective RCTs of dialyzereuse have been carried out.

The delivered dose of dialysis may decrease asresult of dialyzer reuse.306-310 The previousork Group was particularly concerned by the

pparent dialysis center–specific effect of reusen delivered Kt/V, suggesting that the process ofialyzer reuse and/or its monitoring may beroblematic. Recently, more encouraging resultsenerated by the HEMO Study showed that aver-ge loss of urea clearance was only 1% to 2% per0 reuses for both low-flux and high-flux mem-ranes reprocessed with different germicidal regi-ens.310 Focusing on larger molecule removal,

he same study showed that reuse of high-fluxialyzers made of different membrane materialsnd reprocessed with different germicides broughtbout widely disparate clearances of �2M.310

or example, �2M clearances increased mark-dly by using high-flux polysulfone dialyzerseprocessed with bleach, whereas reprocessinghe same dialyzer with peracetic acid appeared toave the opposite effect.310

The Work Group recommends that dialysis
acilities choosing to reuse dialyzers follow the

ArasbpfTa

M

fttadv(maerbprmucpaAliifiofrqdnds

ldratT

dca

dccecodpnTTbr

ltaitciTsusairSott

ardspdnanl“m

DIALYZER MEMBRANES AND REUSE S65

AMI recommendations for reprocessing whileemaining alert to the possibility that reuse maydversely affect adequacy of the delivered dialy-is dose. AAMI recommendations were preparedy a panel of experts and offer practical reuserocedures that have been adopted by the CMS,ormerly Health Care Financing Administration.hese recommendations represent the best guid-nce available on dialyzer reuse procedures.

onitoring Reuse (CPRs 5.1 and 5.2)

Because small-solute clearance is the majorunction of the dialyzer and clot formation withinhe blood compartment reduces clearance, some-imes irreversibly, a method for monitoring clear-nce with each reuse is required to avoid under-ialyzing the patient. Dialyzer blood compartmentolume, sometimes called “total cell volume”TCV) or “fiber bundle volume,” is an indirecteasure of the total membrane surface area

vailable for diffusive transport. It is measuredasily by displacement of air or water during theeprocessing procedure.291 As surface area is lostecause of clotting, solute clearances decrease,utting the patient at risk for underdialysis. Thisisk would go undetected in a clinic that does noteasure clearances or TCV with each re-

se.306,308-311 Changes in TCV were shown toorrelate well with changes in small-solute trans-ort characteristics of hollow-fiber dialyzers,lthough the relationship is not linear.307,312,313

20% loss of TCV correlates with only a 10%oss of clearance because the (now) higher veloc-ty in the remaining functioning fibers leads to anncrease in average diffusion rate within eachber.291,313,314 To allow accurate measurementf these changes, TCV should be measured be-ore the first use and during each subsequenteuse processing. The first measurement is re-uired because of possible variability amongialyzers and dialyzer lots. The Work Group didot consider using the average volume amongialyzers of a given model or lot as an acceptableubstitute for this measurement before first use.

In vitro determination of TCV may not detectoss of surface area caused by clotting duringialysis.315 However, during routine dialysis in aepresentative group of patients who underwentdequate anticoagulation during each dialysisreatment, no differences were found between
CV values measured by using an ultrasound i
etection method applied during dialysis andonventional volume displacement measurementfter dialysis.316

In the place of TCV as an indirect yardstick ofialyzer function, direct measurements of ioniclearance (also known as conductivity or sodiumlearance) or urea clearances also can be used tovaluate dialyzer function because results of theselearance values correlate closely with one an-ther and TCV results.74,291,317-323 A variety ofialysate delivery systems have the capacity toerform noninvasive, automated, on-line determi-ation of a dialyzer’s ionic clearance.318,319,323

he Work Group agrees with the AAMI thatCV, ionic clearance, and urea clearance can alle used to assess the function of either fresh oreused dialyzers.76,317

Because a 10% decrease in urea clearance couldead to inadequate dialysis if the dialysis prescrip-ion was marginal to begin with, the Work Groupgrees with the position of the AAMI that a changen urea clearance of �10% is acceptable as long ashe patient’s dialysis prescription takes into ac-ount the 10% loss in such clearance (20% lossn TCV) that may occur with dialyzer reuse.291

his criterion of �10% clearance change alsohould apply to ionic clearances when they aresed as yardsticks because ionic clearance washown to correlate closely with urea clear-nce.291 Finally, monitoring relevant patient datas recommended to ensure that all parameterselating to dialyzer clearance are being met.pecifically, examination of Kt/V and/or URRver time is needed. The failure of these resultso meet the expectations of the dialysis prescrip-ion should be investigated.291

When TCV measurements are used to evalu-te dialyzer function before the first use, theinsing associated with the reprocessing proce-ure may help remove undesirable dialyzer re-iduals (such as ethylene oxide,324 bore fluids,otting compound [eg, polyurethane] fragments,ialyzer membrane fragments, plastic compo-ents, and other noxious substances remainingfter dialyzer manufacture). In this regard, it isow a not-uncommon practice for centers (regard-ess of whether practicing dialyzer reuse) topreprocess” dialyzers before their first use toinimize the introduction of harmful manufactur-

ng residuals into the bloodstream.300

D

flucbbc1hthwam

cmyrt

pwchfiiawiuafacaaonemboispdbo

bsm

omifltaodccfibcaimevcrpnch(aumdhtetdc

sFamvmcmb


ialyzer Membranes (CPR 5.3)

Dialyzer membranes can be classified into low-ux or high-flux varieties in accordance with theirltrafiltration coefficient (Kuf) and large-moleculelearance. The HEMO Study suggested that mem-ranes with �2M clearance less than 10 mL/mine regarded as low flux, whereas those with �2Mlearance greater than 20 mL/min and Kuf of4 mL/h/mm Hg or greater may be classified asigh flux.270 Another classification recommendedhat dialyzers with Kuf between 4 and 8 mL//mm Hg be regarded as low flux, whereas thoseith Kuf greater than 20 mL/h/mm Hg be regarded

s as high flux.325 Both cellulose and syntheticembranes can be either low flux or high flux.A thorough examination of all available data

oncerning the pros and cons of the use of theyriad varieties of dialyzer membranes was be-

ond the scope of the Work Group. The reader iseferred to standard texts and relevant publica-ions for more information.

In the past, most cellulose membranes wererimarily hydrophilic and synthetic membranesere primarily hydrophobic. However, more re-

ent synthetic membranes can possess mixedydrophobic-hydrophilic structures.325 Unmodi-ed cellulose dialyzers had enormous popularity

n the past, mainly because of their availabilitynd low cost, but their use has been associatedith a variety of abnormal biochemical changes

n the blood.326 One of the main causes for thesenfavorable changes centers on activation of thelternate complement pathway with the resultantormation of detrimental anaphylatoxins.327 Otherdverse effects involve impairment of granulo-yte function, including phagocytosis, adhesion,nd formation of reactive oxygen species,328

nd, in the presence of other factors, facilitationf cytokine production by peripheral-blood mono-uclear cells. An example of the latter phenom-non is depicted as follows: unmodified celluloseembranes and certain modified cellulose mem-

ranes allow, by diffusion, more ready passagef pyrogens (eg, endotoxins and their fragments)nto the blood from contaminated dialysate thanuch synthetic high-flux membranes as those ofolyamide, polyacrylonitrile, and polysulfone—espite the larger pore size of the high-flux mem-ranes.329,330 Pyrogens can promote the formation
f deleterious cytokines by circulating peripheral- c
lood mononuclear cells that previously weretimulated by exposure to unmodified celluloseembranes.331,332

With regard to the possible impact of the usef unmodified cellulose membranes on patientorbidity and mortality, suffice it to say that

nvestigations carried out to date provided con-icting results.333 A number of studies suggested

hat low-flux unmodified cellulose membranesre inferior to high-flux synthetic ones in termsf patient mortality.297,328,334,335 Conversely, noifferences in mortality were found in certainomparative studies.280,336 Furthermore, the Co-hrane Database of Systematic Reviews did notnd evidence of benefit when synthetic mem-ranes were compared with cellulose or modifiedellulose membranes with regard to mortalitynd dialysis-related adverse effects.273 Finally,n patients dialyzed with unmodified celluloseembranes, no acute clinically detectable ill

ffects that could be related to complement acti-ation were observed.337,338 Investigations thatontrol for the confounding influences of age, sex,ace, duration of renal failure, duration and type ofrior dialysis treatments, primary disease, RKF,utrition status, degree of fluid overload, cal-ium � phosphorus product, hyperparathyroidism,yperlipidemia, acidosis, anemia, comorbiditiessuch as diabetes, hypertension, heart failure,nd other cardiovascular ailments), dialyzer singlese or reuse (if reuse, method of sterilization),embrane flux, dialysis adequacy, and so on are

ifficult to perform. Such confounders mightelp explain the conflicting results encounteredo date. In summary, to date, no unequivocalvidence has come forward supporting the no-ion that biocompatible synthetic membranes areefinitely superior to their less biocompatibleellulose-derived counterparts.

Not all cellulose membranes behave in theame manner when interacting with the body.or example, unmodified cellulose membranesctivate complement to a greater extent thanodified cellulose membranes, such as those of

arious cellulose acetates, whereas some of theodified cellulose membranes tend to activate

omplement to a greater extent than syntheticembranes.339,340 Because of differences in the

iological behavior of the various categories of
ellulose membranes, data derived from the use

oa

ttpbmbpbeas(gatli�i

modlhw

oplaasib

nomaipcgowkblodBpc

DIALYZER MEMBRANES AND REUSE S67

f functionally diverse dialyzers should be evalu-ted separately.

Many synthetic membranes have the capacityo adsorb endotoxins and �2M to various ex-ents. Adsorption of endotoxins is related to therovision of binding sites for bacterial productsy the hydrophobic domains of the syntheticembranes.329 Adsorption of �2M by mem-

ranes made of polysulfone, polyacrylonitrile,olyamide, polymethylmethacrylate, and polycar-onate279 is believed to be a function of thelectrical charges distributed both at the surfacend in the substance of the membrane.341,342 Ithould be noted that high-flux membraneswhether cellulose or synthetic), because of theirreater porosity, remove such large moleculess �2M (molecular weight, 11,815 d)o a greater extent than low-flux cellulose orow-flux synthetic membranes, often decreas-ng serum levels.277,280,343-346 Accumulation of2M in high concentrations promotes its polymer-

zation to cause �2M amyloidosis.Use of high-flux synthetic polyacrylonitrileembranes has brought about a lesser incidence

f the amyloid-associated carpal tunnel syn-rome and cystic bone lesions than the use ofow-flux cellulose membranes.282 Furthermore,igh-flux dialysis using polysulfone membranes
as reported to postpone clinical manifestations f
f dialysis-related amyloidosis.347 In 1 study,rolonged use of high-flux synthetic membranesed to improvement in carpal tunnel syndromend patient mortality.348 In the HEMO Study,lthough high-flux membranes did not cause atatistically significant improvement in mortal-ty, predialysis serum �2M levels were found toe a good predictor of mortality.349

Because unmodified cellulose membranes haveo known advantages over synthetic membranesther than lower cost, and unmodified celluloseembranes can markedly activate complement

nd bring about other potentially adverse effectsn the blood, it would seem prudent to dialyzeatients with the more biocompatible and lessomplement-activating membranes.279 This sug-estion is strengthened because long-term effectsf intense complement activation and other unto-ard interactions with blood are largely un-nown. However, it equally could be argued thatecause of their lower costs, unmodified cellu-ose dialyzers would allow the implementationf otherwise cost-prohibitive, but life-saving,ialysis therapy in some developing countries.350

ecause synthetic membranes are more biocom-atible, cause less complement activation, andan adsorb endotoxins and �2M, their use is
avored.

m

6

6

6

iPHgestst

amscsippiflssph

S

CLINICAL PRACTICE RECOMMENDATIONS FOR GUIDELINE
6: PRESERVATION OF RESIDUAL KIDNEY FUNCTION
ad

2ftioap

waiaapvPo

tutritidtaaiitCrd

Hbmbiapd

Several actions and precautions are recom-ended to preserve and enhance RKF.

.1 Angiotensin-converting enzyme (ACE) in-hibitors and/or angiotensin receptor block-ers (ARBs) are agents of choice in HDpatients with significant RKF and whoneed antihypertensive medication. Othermeasures to protect native kidneys arelisted in Table 15.

.2 Insults known to be nephrotoxic (eg, seeTable 16) in patients with normal orimpaired kidney function should be as-sumed, in the absence of direct evidence,to be nephrotoxic for the remnant kidneyin HD patients and therefore should beavoided.

.3 Prerenal and postrenal causes of decreasein RKF should be considered in the appro-priate clinical setting.

BACKGROUND

Although the contribution of RKF to survivals well documented for patients managed withD, the impact is less clear for those requiringD. Most studies assumed that RKF is negli-ible and report survival as a function of deliv-red Kt/Vurea, ignoring the potential benefits as-ociated with RKF. However, recent data supporthe notion that RKF is an important predictor ofurvival and delivered Kt/Vurea can be adjustedo reflect the presence of renal function.81,230

RATIONALE

RKF is an important contributor to dialysisdequacy, and adequacy was shown to impact onorbidity and mortality in patients with CKD

tage 5.53 In contrast to HD, RKF providesontinuous clearance of both small and largeolutes and helps attenuate the large fluctuationsn fluid balance and blood pressure that are moreronounced in anuric patients. Urine volumeermits more fluid and potassium intake, relax-ng overall dietary restrictions and reducing theuctuations in body fluid volumes between dialy-is treatments that contribute to volume overloadyndromes, hypertension, and cardiac hypertro-hy.351 Preservation of residual renal mass also
as the potential to provide beneficial endocrine c

nd potentially other functions that are not yetiscovered.To measure RKF, Kr can be calculated from a

4-hour urine collection for urea clearance. Asor PD, 24-hour urine collections should be ob-ained at least every 4 months or when a decreasen RKF is suspected (eg, decreasing urine outputr recent exposure to a nephrotoxin). Precautionsnd actions that have been recommended toreserve RKF are listed in Table 15.The nephrotoxic insults listed in Table 16 are

ell known to cause injury to normal kidneysnd kidneys damaged by a variety of diseases. Its reasonable to presume that these insults alsore harmful to the remnant kidney and should bevoided if RKF is to be preserved for as long asossible. Please refer to the Guideline for Preser-ation of RKF in PD patients in the NKF KDOQID Adequacy Guidelines for further discussionf this topic.Episodes of intravascular volume depletion

hat frequently occur during HD probably contrib-te to more rapid loss of RKF; therefore, effortso maintain hemodynamic stability should beoutine. Strategies to minimize hypotension dur-ng HD include avoidance of excessive ultrafiltra-ion, maintaining the target hematocrit, reductionn dialysate temperature, increasing dialysate so-ium concentration, and predialysis administra-ion of an � agonist, such as midodrine. Avoid-nce of hypotension also helps ensure delivery ofdequate dialysis and minimize symptoms dur-ng HD. Paradoxically, loop diuretics, which aremplicated as a cause of worsening renal func-ion when used overzealously in patients withKD, probably benefit HD patients because they

educe the requirement for fluid removal duringialysis.The more prolonged preservation of RKF in

D patients observed in more recent years haseen attributed to numerous factors, includingore widespread use of biocompatible mem-

ranes, high-flux dialysis, and use of bicarbonatenstead of acetate buffers. There is general dis-greement about which of these factors, if any,lays a role (Table 17). A recent prospective ran-omized study suggested that ultrapure water, when
ombined with high-flux dialysis, may benefit

nhbcgedl

igfApHcatbot

naymtm

phpiictala

creidHcit

1mrdt

PRESERVATION OF RESIDUAL KIDNEY FUNCTION S69

ative kidney function.232,352 Another study ofigh-flux biocompatible membranes with bicar-onate buffer and ultrapure water showed a de-rease in RKF similar to that in a contemporaryroup of CAPD patients.229 The more prolongedxposure to membranes during nocturnal andaily-dialysis regimens hopefully will shed moreight on membrane contributions.

Despite some early concerns about irrevers-ble drug-induced renal disease,353 it is nowenerally accepted that the decrease in renalunction observed in most patients treated withCE inhibitors and ARBs is reversible and reno-rotective, even in patients with CKD stage 5.230

owever, the drug-induced decrease in GFRauses an increase in levels of BUN, creatinine,nd other solutes and may decrease urine output;hus, consequences in HD patients are not allenign. Irreversible loss of renal function mayccur in patients with ischemic renal diseasereated with ACE inhibitors.

Severe hypertension is well known to damageormal kidneys acutely (malignant hypertension)nd can cause ongoing damage over a period ofears (hypertensive nephrosclerosis). In addition,ost kidney diseases, especially those like diabe-

es that target the kidney vasculature or glo-

atients initiating HD therapy, the kidneys mayave been damaged more acutely by severe hy-ertension. Control of hypertension after initiat-ng dialysis therapy has been associated withmprovement in RKF, sometimes allowing dis-ontinuation of dialysis therapy.354 These pa-ients should be identified from the beginning,nd special attention should be given to control-ing blood pressure for the purpose of preservingnd possibly improving RKF.

The Work Group encourages PD as a firsthoice of modality for patients initiating KRT foreasons outlined in the NKF KDOQI PD Ad-quacy Guidelines, but also as a means of preserv-ng RKF. However, most patients are not candi-ates for self-dialysis outside of a clinic; thus,D remains the most common initial modality

hoice for new patients. The same attention thats given to RKF in PD patients should be directedo this much larger group of HD patients.

LIMITATIONS

Use of the nephrotoxic agents listed in Table6 is not always contraindicated because theyay be required in special circumstances to

elieve pain (eg, nonsteroidal anti-inflammatoryrugs), treat a difficult problem (eg, ultrafiltra-ion during dialysis), or complete a vital diagnos-

eruli, are exacerbated by hypertension. In some tic test (eg, coronary angiogram).


irweaCrc

G

poehcedtipnpuctHrispdpfipeu

lptnwv

A

III. RESEARCH RECOMMENDATIONS

kv

tqcbcirTetvuGrtapse

GE

vtIQpb

ndtltabtt

GS

dic

RANKING OF RECOMMENDATIONS

Research recommendations have been groupednto 3 categories: critical research, importantesearch, and research of interest. These rankingsere made by the Work Group based on current

vidence and the need for research to providedditional evidence for the current CPGs andPRs. No attempt was made to rank research

ecommendations within each of the 3 researchategories.

CRITICAL RESEARCHRECOMMENDATIONS

uideline 1: Initiation of HDIt has been well shown that education and

lanning for kidney failure can improve patientutcomes, but optimal approaches have not beenstablished. Answers to certain questions couldelp improve clinical outcomes while reducingosts. These questions include the approaches toducation and planning for kidney failure inifferent demographic and cultural groups andheir relative costs. How effective are video andnternet-based educational materials? Are com-uter-interactive programs helpful? How canephrologists, nurses, social workers, dietitians,harmacists, other professionals, and patient vol-nteers work together most effectively to edu-ate new kidney patients and families? What ishe best training for kidney patient educators?ow much of the educational role should neph-

ologists delegate? For example, can earlier teach-ng about dietary potassium allow more exten-ive treatment with ACE inhibitors and ARBs inatients with CKD? Can new approaches to earlyietary education yield improved volume andhosphorus control when patients reach kidneyailure? What are the psychological and behav-oral consequences of early education about therospect of eventual organ failure and the short-ned life expectancy associated with kidney fail-re?Estimation equations for GFR (Table 1, Guide-

ine 1) should be examined in patients whoroduce unusually little creatinine, in particular,he elderly and patients with other chronic ill-esses. A second important clinical group forhich current estimating equations have not been
alidated is those with significantly decreased c

idney perfusion, as occurs in patients with ad-anced heart failure.Studies of the time to initiate replacement

herapy are needed to determine the conse-uences of timing on survival, morbidity, andost. Results of the IDEAL Study will be critical,ut it seems unlikely to be definitive for alllinical subgroups. In view of racial differencesn dialysis mortality rates, it seems plausible thatesponse to early treatment might vary by race.he HEMO Study finding of differential doseffects in women also suggests the possibilityhat the response to early initiation also mightary by sex. Because of longer exposure toremia, do patients with a slower decrease inFR benefit from earlier initiation of kidney

eplacement therapy? Do patients with primaryubular disorders benefit from initiation of KRTt a higher level of GFR than patients withrimary glomerular disorders? These questionshould be addressed in particular groups of inter-st, including children and the elderly.

uideline 2: Methods for Measuring andxpressing HD DoseThe ongoing Frequent HD Network will pro-

ide data that should be used to evaluate poten-ial benefits of short-daily or nocturnal dialysis.f published uncontrolled studies showing betterOL are confirmed, efforts must be directed torovide more frequent dialysis in a less encum-ering manner.The conductivity method promises to elimi-

ate the need for drawing blood before and afterialysis and can be applied to each dialysisreatment. Objective studies are needed to corre-ate the delivered dose measured by using conduc-ivity (ionic) dialysate methods with both eKt/Vnd spKt/V determined by using classic blood-ased methods. Testing is needed to show whetherhis method is a reliable substitute for the presentechnique.

uideline 3: Methods for Postdialysis BloodamplingBecause the amount of blood drawn from

ialysis patients should always be minimized, its desirable to minimize the volume of the dis-ard sample when drawing blood from a venous
atheter. Studies of how the ratio of discarded
, 2006: pp S71-S74 S71

vc

poflc

G

tsifm(tlivr

uwcpmiveiswfsuo

espbsse

GC

hp

acsa

etnmtw

G

ptmscmbsw

oosRnuwct

di

ooepptds

dof

HEMODIALYSIS ADEQUACYS72

olume to catheter lumen volume affects BUNoncentration would be of practical interest.

Because timing may be different in smalleratients with shorter circuit pathways, validationf the stop-blood-flow method and stop-dialysate-ow method for determining dialysis dose inhildren requires future research.

uideline 4: Minimally Adequate HDThere are no reliable data regarding mortality

hat are not extremely susceptible to patientelection, and no RCT comparing mortality ratess foreseen in the near future. Whether morerequent dialysis reduces hospitalization ratesay be answered by an RCT currently in progress

NIH Frequent HD Network trial), although thisrial is underpowered to detect other than a veryarge reduction. However, it is powered to detectmprovements in both QOL measures and leftentricular mass index; the latter is stronglyelated to “hard” cardiovascular outcomes.

An alternative measure of dialysis dose innits measuring conductivity is Kecn � T/Vant,here Kecn is the conductivity-derived dialyzer

learance, T � session length, and Vant � anthro-ometric volume. Studies are needed to deter-ine whether adequacy determined serially us-

ng a conductivity standard is more or lessariable, and more or less reliable, than ad-quacy determined based on classical urea kinet-cs with predialysis vs. postdialysis BUN mea-urements. Studies are also needed to determinehether much of the same information gleaned

rom monthly pre- and postdialysis BUN mea-urements in terms of PCR could be obtainedsing monthly predialysis BUN measurementsnly, and quarterly pre/post BUN values.Further study would look at the ratio of mod-

led to anthropometric volume, both cross-ectionally, and serially in large numbers ofatients, and the possibility of dosing dialysisased on Kecn � T/BSA, where BSA is bodyurface area multiplied by a correction factoruch that it would vary to the 2/3 power and inffect, reflect dosing based on body surface area.

uideline 5: Volume and Blood PressureontrolThe cost of dialyzer and blood tubing disposal

as a direct impact on reuse, which reduces this
rovider burden. Aside from the biological haz- m
rd, recycling of dialyzer and tubing materialsould reduce the requirement for disposal sitepace. Studies of the potential economic benefitsre needed.

Reuse of dialyzers and blood tubing may influ-nce patient exposure to spallated particles, plas-icizers, bore fluid, ethylene oxide, and otheroxious manufacturing residuals from newlyanufactured dialyzers. Studies should compare

hese exposures with the single-use situationhen dialyzers and tubing are reused.

uideline 6: Preservation of RKFAdditional comparative studies of outcome in

atients with and without RKF are needed.355 Athe present time, many dialysis clinics do noteasure RKF routinely and some do not mea-

ure it at all. Such studies would help resolve theritical question about the importance of RKFeasurements. Perhaps even more helpful would

e a controlled clinical trial in which the pre-cribed dialysis dose is adjusted or not in patientsith significant RKF.Some studies have implicated contamination

f the water used to prepare dialysate as a causef dialysis morbidity and mortality. Other studiesuggested that ultrapure dialysate helps preserveKF.232 Additional confirmatory studies areeeded to determine whether introduction ofltrapure dialysate into routine clinical practiceould help preserve RKF and improve such

linical outcomes as blood pressure control, nu-ritional status, and QOL.

A trial of ACE inhibitors or ARBs should beone to evaluate the effectiveness of such agentsn preserving RKF.

After dialysis therapy has started, diureticsften are prescribed for patients with good urineutput to help with potassium balance and avoidxcessive fluctuations in ECF volume and bloodressure. This practice may or may not helpreserve RKF. Studies should address the effec-iveness of various diuretic doses and whetheriuretics should be advocated in patients withignificant urine output to help preserve RKF.

For patients in whom the targeted prescribedialysis dose is based on RKF, there is an obvi-us need to measure RKF, but the optimumrequency of measurements has not been deter-
ined. The optimum frequency may depend on

th

G

tslpmtadtirt

GA

cppisrapypssudpdWtHep

G

ourb

cnoesti

GE

smbatrmbsasadtatpb

GS

cseia

GC

ibcaa

G

d

RESEARCH RECOMMENDATIONS S73

he type of kidney disease and the patient’sistory of its progression.

uideline 7: Clinical Outcome GoalsAdditional studies are needed to validate the

ools currently used to measure QOL and patientatisfaction within the diverse CKD stage 5 popu-ation. Interventions used to improve QOL andatient satisfaction should be evaluated to deter-ine success in improving QOL, patient satisfac-

ion, and clinical outcome. As standards of carere modified and new care strategies are intro-uced, there is need for periodic reassessment ofhe presently recommended dose of dialysis andts effect on patient mortality, hospitalizationates, QOL, patient satisfaction, and transplanta-ion rates.

uideline 8: Pediatric HD Prescription anddequacyThe high rates of young adult HD patient

ardiovascular mortality and morbidity,356,357

sychological illness, and unemployment358 com-el pediatric HD patient study in the areas ofnflammation, cardiovascular fitness, nutrition as-essment and malnutrition treatment, and health-elated QOL. Because many young adult patientsre treated in pediatric programs and have theotential to develop morbidities in their pediatricears, there is a need to study these areas inediatric patients. Measurement of HD small-olute clearance, preferably using either mea-ured or validated estimated eKt/V, and nutrition,sing nPCR, are critical to control for the dose ofelivered dialysis and nutrition status in anyediatric HD outcome study. Recent recommen-ations from the European Pediatric Dialysisorking Group359 provide an excellent basis in

erms of the current state of the art in pediatricD practice, from which future research should

manate to improve the care of pediatric HDatients.

IMPORTANT RESEARCHRECOMMENDATIONS

uideline 1: Initiation of HDLess critical questions include measurement

f patients’ preferences (in the technical sense oftility) for the states of education vs. ignoranceegarding prognosis and choices. It also would
e important to understand demographic and t
ultural determinants of preference variation. Fi-ally, work is needed on the ethical implicationsf therapeutic attempts to influence patient pref-rences. These issues are all less critical as re-earch priorities, not because they are less impor-ant, but because the findings are less likely tonfluence practice and policy in the short term.

uideline 2: Methods for Measuring andxpressing the HD DoseTests of variance are needed for Kt/V mea-

ured in patients receiving daily dialysis treat-ents. Theoretically, the variance will be larger

ecause measured BUN values will be consider-bly lower and excursions from predialysis BUNo postdialysis BUN also will be lower, whicheduces the power of kinetic modeling. Howuch lower and how much variance have not

een determined in an experimental setting. Thistudy can be done simply by drawing predialysisnd postdialysis blood samples several days inuccession. If blood-based measurements of Kt/Vre found to be less reliable in these patients,ialysate methods may be required to measurehe delivered dose. However, dialysate methodsre intrinsically less accurate for measuring Kt/Vhan blood-based methods,364 so additional com-arative studies will be required if the blood-ased methods are found to be inadequate.

uideline 3: Methods for Postdialysis BloodamplingA study of needlestick injuries in dialysis

linics might help promote the use of blood-ampling procedures that do not involve use ofxposed needles. This is an area of obviousmportance and interest for which very few datare available.

uideline 5: Volume and Blood PressureontrolMore research should be devoted to reprocess-

ng techniques for various types of dialyzer mem-ranes made by different manufacturers, espe-ially with regard to approaches involving heatnd more biocompatible chemicals, such as citriccid.

uideline 6: Preservation of RKFObservational studies should include data to

etermine whether RKF serves to reduce fluctua-
ions in serum potassium and bicarbonate concen-

ts

dftwRtg

tpps

G

cwyasaioatac

GA

s

dst

pto

ot

wom

lwi

Ttqsto

mch


rations and reduce ECF volume and blood pres-ure fluctuations.

Some patients with slowly progressive kidneyisease might benefit from incremental dialysisrequency (initiation of HD at a frequency � 3imes per week). Studies are needed to determinehether such a practice would help preserveKF in patients with significant urine output and

hose with a marginally functional renal allo-raft.RKF imparts a stronger survival advantage

han dose of dialysis. Investigations should ex-lore potential kidney synthetic functions that, ifreserved in the remnant kidney, may provideurvival benefits not explained by level of GFR.

uideline 7: Clinical Outcome GoalsThere is a need for analysis of data linking

linical outcomes to recommended processesithin the target goals. This would include anal-sis of the impact of specific KDOQI processesdjusting for established factors (eg, blood pres-ure control, hemoglobin A1c [HbA1c], lipid man-gement, pharmacological therapy) that stronglynfluence clinical outcomes of HD patients. Peri-dically, there is a need for refining case-mixdjustments over time to reflect changes in rela-ive contribution of traditional, nontraditional,nd emerging risk factors as standards of carehange.

uideline 8: Pediatric HD Prescription anddequacyRecent data from a small pediatric study

howed benefits of daily nocturnal HD in chil- m

ren. Additional study of daily HD treatmentchedules and technologies should be under-aken in children.

RESEARCH RECOMMENDATIONSOF INTEREST

Less critical issues include the development ofrediction instruments to allow estimation ofime to symptomatic kidney failure on the basisf serial GFR estimates.Less critical questions include measurement

f patient preferences about the tradeoffs be-ween the burdens and benefits of earlier therapy.

Investigation of dialysis creatinine kineticsould help assess the effect of muscle mass onutcome and compare somatic with visceral bodyass as risk factors for survival.Studies of large patient populations to corre-

ate urine output with RKF would help determinehether urine volume-related cutoff values for

gnoring RKF are useful.Although the potential insults listed in CPR

able 16 are known to injure normal and par-ially damaged native kidneys, studies are re-uired to indict each insult in patients with CKDtage 5. It is unlikely that controlled clinicalrials will appear in the near future; therefore,bservational studies are encouraged.The benefits of RKF may relate more to renalass than urine volume. This possibility should be

onsidered in outcome studies. Also, it would beelpful to correlate kidney size with RKF to deter-
ine whether RKF is predictable based on size.

idedssrflicst

viucKokdsfssp

(lstt

A

APPENDIX. METHODS FOR ADDING RESIDUAL CLEARANCE
TO HEMODIALYZER CLEARANCE
Km

bdBKwicah(ertk

wi

bvefipct

bwtb

E

3u

bsnp

Because the duration is short and the clearances relatively low, RKF contributes little to theecrease in BUN levels during dialysis. Theffect of residual urea clearance (Kr) is seenuring the long interdialysis interval when iterves to decrease the predialysis BUN level, ashown in Fig 6. When Kr is zero, the interdialysisise in the BUN level is linear in the absence ofuid gain. If Kr is greater than zero, the increase

n BUN level between dialyses is curvilinear andoncave downward, resulting in a lower predialy-is BUN level, so less HD is required to maintainhe same average BUN level.

In addition, the continuous nature of Kr pro-ides a more efficient clearance, so simply add-ng the time-averaged Kr to time-averaged Kd

nderestimates the contribution of Kr to overalllearance. A quantitative relationship betweenr, Kd, and overall urea clearance can be devel-ped by applying a mathematical model of ureainetics. The goal is to determine how much of aecrease in Kd can be allowed to achieve theame level of BUN when Kr is added. Theollowing simplified formula depicts the relation-hip between dialyzer clearance (Kd) in the ab-ence of Kr, and lower dialyzer clearance (Kd=)ermitted in the presence of Kr.

360,361

kKr = Kdt – Kd t

Fig 6. Effect of residual native kidney clearanceKr). The increase in BUN levels from the post-BUNevel to the next pre-BUN level is modulated by Kr, ashown in the lower curve. The result is a pre-BUN level

bhat is lower when compared to the pre-BUN level inhe absence of Kr (upper line).


r, Kd and Kd= are expressed in milliliters perinute; t is the duration of HD in minutes.In this formula, k relates Kr to the difference

etween Kd and Kd=, or the decrease in dialysisose that is possible while still achieving the sameUN level that would be expected when there is nor. The parameter k has units of mL/(mL/min) andhen multiplied by Kr permits an expression of Kr

n equivalent dialysis units than can be spared. Itan also be considered as a time or duration of Kr

nalogous to dialysis duration (t), but always isigher than the average interval between dialysesti) because Kr is more efficient than Kd. Whenxpressed per dialysis, the relationship among theeduced dialysis dose (Kd=t/V), the required dose inhe absence of Kr (Kdt/V), and the residual nativeidney clearance (kKr/V), is expressed by:

t/V = K d t/V kK r /V K _d

here V is the patient’s volume of urea distributionn milliliters.

In the absence of kinetic modeling, Kd=t/V cane solved by substituting the interdialysis inter-al (10,080 min per wk/frequency) for k in thisxpression. Note that this approach, shown in therst data column in Table 18, ignores the im-roved efficiency of the continuous RKF, but it isonsidered safe for the patient because it underes-imates the effect of Kr.

Another method to incorporate Kr into Kt/V isased on the equivalent clearance (EKR),264

hich represents the continuous equivalent ofhe patient’s intermittent urea clearance and cane calculated as follows:

(G = urea generation rate; TAC = time-averaged BUN)

KR = G/TAC

The result can be normalized to a typical V of5 L and expressed in terms of nPCR and TACsing the equation for nPCR.362

nEKR = [35 · (nPCR – 0.17)]/(5.42 · TAC)

EKR is a total clearance that includes RKF,ut the dialyzer component can be extracted byubtracting Kr. EKR is the continuous clearanceecessary to maintain the equivalent TAC at theatient’s nPCR. The EKR of intermittent HD can
e directly compared to the EKR of patients
, 2006: pp S75-S77 S75

dotc

feaAttpft

pt

idbaotkcaBc

remaind


ialyzed at any frequency or with the clearancef continuously functioning native kidneys. Rou-inely solving these equations requires the use ofomputational software.

The use of EKR has been criticized because itails to fully account for the improvement infficiency associated with the continuous clear-nce of native kidneys or continuous dialysis. 267

pparently, equating average urea concentra-ions ignores other more toxic solutes for whichhe difference in removal by continuous com-ared with intermittent clearance is greater thanor urea. Equating “standard clearances” usinghe average peak BUN instead of TAC in the

Table 18. Values for k at Differen Frequency using Ti alone

2 5040 3 3360 4 2520 5 2016 6 1680 7 1440

* The underlined numbers have been published.360,362 The

Table 19. Minimum spKt/Va RequiredK

No. per Week 2.0

2 -- 3 -- 4 0.87 5 0.64 6 0.51 7 0.42

Kr = 2 m

No. per Week 2.0

2 ---- 3 0.94 4 0.62 5 0.46 6 0.37 7 0.31

a. Dialyzer clearance only, expressed pe b. Calculated using a 2-compartment ma

not matter); Td is constant; Kd varies; umatter); dialyzed compartment is 1/3 o

It is important to note that the minimum vreported improvements in outcome fromthan 3x/week.

.

revious equation has been offered as a solutiono this apparent problem.265

Instead of inflating Kr to match the relativelynefficient non-continuous dialyzer clearance asescribed above, an alternative method, favoredy the Work Group, reduces the dialyzer clear-nce to a continuous equivalent clearance, basedn normalizing the predialysis BUN. This con-inuous equivalent of a dialyzer clearance, alsonown as “standard clearance”265 (stdK) is theontinuous clearance that maintains the BUN atconstant value equal to the average predialysisUN achieved during intermittent dialysis. Be-ause the pre-dialysis BUN is targeted, this ap-

ysis Frequencies and BUN Targets tnatsnoc dloh ot NUB detegra

Averaged* Average Predialysis* 6500 95004000 55002850 3700 2200 2700 1780 2100 1500 1700 er were derived from urea kinetic modeling.

chieve a stdKt/Vb of 2.0 per Week

Td (hr) 3.5 8.0 -- 3.00

1.22 1.06 0.77 0.68 0.57 0.51 0.45 0.40 0.38 0.34

.73 m2

Td (hr) 3.5 8.0 1.93 1.68 0.85 0.77 0.56 0.52 0.42 0.39 0.34 0.31 0.28 0.26

s al model. Assumptions: Patient with V = 35 L (should

tion rate is 7 L/wk; nPCR is 1 g/kg/d (should not ; Kr(urea) is 0 or 2 mL/min; symmetric schedule. r spKt/V shown in this table do not take into account ng Kt/V when dialysis frequency is increase to more

t DialT

Time-

To A

r = 0

L/min/1

r dialysithematicltrafiltraf total Values fo

increasi

ptise(v

tfT2ns

APPENDIX. METHODS FOR ADDING RESIDUAL CLEARANCE TO HEMODIALYZER CLEARANCE S77

roach gives results similar to that depicted inhe third data column of Table 18. After normal-zing the dialyzer clearance to stdK, Kr canimply be added to it because both can be consid-red continuous clearances. Dialyzer clearancesspKt/V) required to achieve a stdKt/V of 2.0
olumes per week are shown in Table 19 for C
reatment times that vary from 2 to 8 hours andor schedules from 2 to 7 treatments per week.hese values were determined using a formal-compartment mathematical model of urea ki-etics but similar results are obtained using theimplified equation for stdKt/V shown in section
PR2.

CoihSctwCanNdHtafpnA

PItMiSUilgsaadopIIiHNwbApt

S

WORK GROUP BIOGRAPHIES

So

scttSHepANoattIsAPGatHuBatgPtLU

AUayeDtetdtc

John T. Daugirdas, MD (Co-Chair), is alinical Professor of Medicine at the Universityf Illinois College of Medicine. His areas ofnterest include dialysis adequacy and dialysisypotension. He is a member of the Americanociety of Nephrology and the International So-iety of Nephrology and a founding member ofhe International Society of Hemodialysis. Heas the Principal Investigator of one of the 15linical Centers participating in the HEMO Studynd currently is a Consultant to the Data Coordi-ating Center for the Frequent Hemodialysisetwork trial of short-daily and nocturnal hemo-ialysis. Dr Daugirdas is one of the editors of theandbook of Dialysis and is founding editor of

he electronic journal, Hypertension, Dialysis,nd Clinical Nephrology. He has received grantsrom Watson, American Regent, Aksys, Ne-hros, RRI, HDC Medical, Advanced Renal Tech-ologies, Amgen, Ortho Biotech, Shire, Roche,stra Zeneca, and Neurochem.Thomas A. Depner, MD (Co-Chair), is a

rofessor of Medicine in the Department ofnternal Medicine, Division of Nephrology, athe University of California, Davis School of

edicine. He trained at the University of Portlandn Oregon, at Johns Hopkins University Medicalchool in Baltimore, and at Case Western Reserveniversity, where he completed his residency in

nternal medicine at University Hospitals in Cleve-and. He is a practicing board-certified nephrolo-ist with a long-standing interest in hemodialy-is. He currently is the director of dialysis servicest the University of California, Davis, and hasuthored a textbook on the prescription of hemo-ialysis. He is a member of the American Societyf Nephrology, the International Society of Ne-hrology, the American Society for Artificialnternal Organs, and a founding member of thenternational Society of Hemodialysis. He wasnvolved as a Principal Investigator during theEMO Study and similarly is involved in theIH-Clinical Trial: Frequent Hemodialysis Net-ork clinical trial. He has been a member of theoard of trustees for the American Society forrtificial Internal Organs since 1997 and is a pastresident of that organization. He has served on
he dialysis advisory council for the American L

ociety of Nephrology and on the editorial boardf NephSAP.Stuart Goldstein, MD, is an Associate Profes-

or of Pediatrics at the Baylor College of Medi-ine in Houston, TX. He is Medical Director ofhe Dialysis Unit at the Texas Children’s Hospi-al and Administrative Director of the Pheresiservice at the Texas Children’s Hospital, both ofouston. He is a member of the American Acad-

my of Pediatrics, the American Society of Ne-hrology, the International Pediatric Nephrologyssociation, the American Society of Pediatricephrology, the International Society of Nephrol-gy, and the Society for Pediatric Research. Inddition, he is on the Medical Review Board forhe End-Stage Renal Disease Network of Texas,he Pediatric Nephrologist Representative for thenternational Society of Nephrology Commis-ion of Acute Renal Failure, on the Clinicalffairs Committee for the American Society ofediatric Nephrology, on the Dialysis Advisoryroup for the American Society of Nephrology,

nd on the Training/Certification Committee ofhe American Society of Pediatric Nephrology.e has received grants from Gambro Renal Prod-cts, Dialysis Solutions Inc, Baxter Healthcare,. Braun Inc, Amgen Inc, Abbott Laboratories,nd Toray Inc. He has also lectured for Genen-ech. Dr Goldstein has received research funds,rants, or contracts from American Academy ofediatrics, Baxter Healthcare, Dialysis Solu-

ions, Inc., Gambro Renal Products, Genentech,uitpold Pharmaceuticals, NxStage Inc., and Theniversity of Missouri.Todd S. Ing, MD, joined the Hines Veterans

ffairs Hospital as a nephrologist and the Loyolaniversity Chicago Stritch School of Medicine

s a faculty member in 1976, after a number ofears in private practice. Committed to medicalducation, he is an editor of the Handbook ofialysis. Topics of special interest to him include

he formulation of dialysates, bicarbonate-buff-red peritoneal dialysis, first-use syndrome, peri-oneal sclerosis, peritoneal fluid eosinophilia,ialysis ascites, and dialysis-associated pericardi-is. Dr Ing has received research funds, grants, orontracts from Abbott Laboratories and Aksys
td.

oDDwCK

sMSmafMccBNeiaii

paefCSC

nhCUlPqsaiccrL

WORK GROUP BIOGRAPHIES S79

Victoria Kumar, MD, is Associate Professorf Medicine, Department of Internal Medicine,ivision of Nephrology, University of Californiaavis Medical Center. Dr Kumar’s fellowshipas at University of California Davis Medicalenter. Dr Kumar also is staff physician at theaiser Permanente Medical Group.Klemens B. Meyer, MD, is Associate Profes-

or of Medicine at Tufts University School ofedicine. He serves as Director of Dialysis

ervices, Chair of the Health Information Com-ittee, and Division of Nephrology Webmaster

t Tufts-New England Medical Center. Heounded Dialysis Clinic Inc’s (DCI’s) Outcomes

onitoring Program and serves as DCI’s Medi-al Director for Information Technology. He hashaired both the Medical Review Board and theoard of Directors for End-Stage Renal Diseaseetwork 1. He participated in the design and

xecution of the HEMO and CHOICE Studies. Hes an active participant in the NKF KEEP programsnd other regional chronic kidney disease screen-ng and education programs. Dr Meyer’s particular
nterests include informatics and decision sup- n
ort in chronic kidney disease stages IV and Vnd clinical applications of measures of patientxperience. Dr Meyers has received researchunds, grants, or contracts from Primary Insightontributor Network, MEDA Corp/Leerinkwann & Co., and Gerson Lehram Healthcareouncil.Keith Norris, MD, is board certified in inter-

al medicine and nephrology and is a certifiedypertension specialist. He is the director of thelinical Research Center at the Charles R. Drewniversity of Medicine and Science in Los Ange-

es, CA, where he also serves as the Vice-resident of Research. He serves as a continuinguality improvement and quality assurance advi-or to industry and has published more than 100rticles and book chapters. He is the principalnvestigator for a National Institutes of Healthomprehensive center for health disparities inhronic kidney disease. Dr Norris has receivedesearch funds, grants, or contracts from Abbottaboratories, Amgen, Genzyme/Bone Care Inter-
ational, Merck, and Pfizer.

ds

sS

Am(

ic

lP

tK

LrK

tP3

vp

fD

c

HHS

aH

h1

Na

NhI

oa

c

R

S

REFERENCES

fieG

Mr2

crA

f

Fs

Abo

fK

ar1

nd

ddt1

b“

c

pos

ps6

pt

nC

aA

1. Eknoyan G, Beck GJ, Cheung AK, et al: Effect ofialysis dose and membrane flux in maintenance hemodialy-is. N Engl J Med 347:2010-2019, 2002

2. Eknoyan G, Levey AS, Beck GJ, et al: The Hemodialy-is (HEMO) Study: Rationale for selection of interventions.emin Dial 9:24-33, 1996

3. Centers for Medicare & Medicaid Services. 2003nnual Report: End Stage Renal Disease Clinical Perfor-ance Measures Project. Am J Kidney Dis 44:S1-S92, 2004

suppl 1)4. Consensus Development Conference Panel: Morbid-

ty and mortality of renal dialysis: An NIH consensusonference statement. Ann Intern Med 121:62-70, 1994

5. Renal Physicians Association: Clinical Practice Guide-ine on Adequacy of Hemodialysis. Washington, DC, Renalhysicians Association, 1993

6. National Kidney Foundation: K/DOQI Clinical Prac-ice Guidelines for Hemodialysis Adequacy, 2000. Am Jidney Dis 37:S7-S64, 2001 (suppl 1)

7. Goodkin DA, Young EW, Kurokawa K, Prutz KG,evin NW: Mortality among hemodialysis patients in Eu-

ope, Japan, and the United States: Case-mix effects. Am Jidney Dis 44:16-21, 2004

8. Hall YN, Sugihara JG, Go AS, Chertow GM: Differen-ial mortality and transplantation rates among Asians andacific Islanders with ESRD. J Am Soc Nephrol 16:3461-463, 2005

9. Wong JS, Port FK, Hulbert-Shearon TE, et al: Sur-ival advantage in Asian American end-stage renal diseaseatients. Kidney Int 55:2515-2523, 1999

10. Collins AJ, Kasiske B, Herzog C, et al: Excerptsrom the United States Renal Data System 2004 Annualata Report. Am J Kidney Dis 45, 2005 (suppl 1)

11. Shlipak MG, Massie BM: The clinical challenge ofardiorenal syndrome. Circulation 110:1514-1517, 2004

12. European Best Practice Guidelines Expert Group onemodialysis, European Renal Association: Section II.aemodialysis adequacy. Nephrol Dial Transplant 17:S16-31, 2002 (suppl 7)

13. Depner T, Daugirdas J, Greene T, et al: Dialysis dosend the effect of gender and body size on outcome in theEMO Study. Kidney Int 65:1386-1394, 2004

14. Held PJ, Port FK, Wolfe RA, et al: The dose ofemodialysis and patient mortality. Kidney Int 50:550-556,996

15. Leggat JE Jr, Orzol SM, Hulbert-Shearon TE, et al:oncompliance in hemodialysis: Predictors and survival

nalysis. Am J Kidney Dis 32:139-145, 199816. Saran R, Bragg-Gresham JL, Rayner HC, et al:

onadherence in hemodialysis: Associations with mortality,ospitalization, and practice patterns in the DOPPS. Kidneynt 64:254-262, 2003

17. Plantinga LC, Fink NE, Sadler JH, et al: Frequencyf patient-physician contact and patient outcomes in hemodi-lysis care. J Am Soc Nephrol 15:210-218, 2004

18. Cockcroft DW, Gault MH: Prediction of creatininelearance from serum creatinine. Nephron 16:31-41, 1976

19. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N,
oth D: A more accurate method to estimate glomerular n

ltration rate from serum creatinine: A new predictionquation. Modification of Diet in Renal Disease Studyroup. Ann Intern Med 130:461-470, 1999

20. Levey AS, Greene T, Kusek JW, Beck GJ, GroupS: A simplified equation to predict glomerular filtration

ate from serum creatinine. J Am Soc Nephrol 11:155A,000 (abstr)

21. Schwartz GJ, Brion LP, Spitzer A: The use of plasmareatinine concentration for estimating glomerular filtrationate in infants, children, and adolescents. Pediatr Clin Northm 34:571-590, 1987

22. Stevens LA, Levey AS: Measurement of kidneyunction. Med Clin North Am 89:457-473, 2005

23. Mohler JL, Barton SD, Blouin RA, Cowen DL,lanigan RC: The evaluation of creatinine clearance inpinal cord injury patients. J Urol 136:366-369, 1986

24. Gonwa TA, Jennings L, Mai ML, Stark PC, LeveyS, Klintmalm GB: Estimation of glomerular filtration ratesefore and after orthotopic liver transplantation: Evaluationf current equations. Liver Transpl 10:301-309, 2004

25. Sherman DS, Fish DN, Teitelbaum I: Assessing renalunction in cirrhotic patients: Problems and pitfalls. Am Jidney Dis 41:269-278, 2003

26. Jafar TH, Schmid CH, Levey AS: Serum creatinines marker of kidney function in South Asians: A study ofeduced GFR in adults in Pakistan. J Am Soc Nephrol6:1413-1419, 2005

27. Moss AH: Shared decision-making in dialysis: Theew RPA/ASN guideline on appropriate initiation and with-rawal of treatment. Am J Kidney Dis 37:1081-1091, 2001

28. Galla JH: Clinical practice guideline on sharedecision-making in the appropriate initiation of and with-rawal from dialysis. The Renal Physicians Association andhe American Society of Nephrology. J Am Soc Nephrol1:1340-1342, 2000

29. Moss AH: Too many patients who are too sick toenefit start chronic dialysis: Nephrologists need to learn tojust say no.” Am J Kidney Dis 41:723-727, 2003

30. Moss AH, Holley JL, Davison SN, et al: Palliativeare. Am J Kidney Dis 43:172-173, 2004

31. Levin A, Lewis M, Mortiboy P, et al: Multidisci-linary predialysis programs: Quantification and limitationsf their impact on patient outcomes in two Canadianettings. Am J Kidney Dis 29:533-540, 1997

32. Lopes AA, Bragg J, Young E, et al: Depression as aredictor of mortality and hospitalization among hemodialy-is patients in the United States and Europe. Kidney Int2:199-207, 2002

33. Arora P, Obrador GT, Ruthazer R, et al: Prevalence,redictors, and consequences of late nephrology referral at aertiary care center. J Am Soc Nephrol 10:1281-1286, 1999

34. Astor BC, Eustace JA, Powe NR, et al: Timing ofephrologist referral and arteriovenous access use: TheHOICE Study. Am J Kidney Dis 38:494-501, 2001

35. Avorn J, Bohn RL, Levy E, et al: Nephrologist carend mortality in patients with chronic renal insufficiency.rch Intern Med 162:2002-2006, 2002

36. Avorn J, Winkelmayer WC, Bohn RL, et al: Delayed
ephrologist referral and inadequate vascular access in

pE

FE1

iD

wD

k1

RoM

o

op

nA

fT

sp

is

Fi1

Ac2

RoM

sm2

Ir

tK

o

f3

Jtd

oD

EiD

Ds

iA

ORS

c

tT2

iK

R(1

iK

me

ph1

vS

caS

K2

Ri

REFERENCES S81

atients with advanced chronic kidney failure. J Clinpidemiol 55:711-716, 2002

37. Levey AS, Coresh J, Balk E, et al: National Kidneyoundation practice guidelines for chronic kidney disease:valuation, classification, and stratification. Ann Intern Med39:137-147, 2003

38. Keshaviah PR, Emerson PF, Nolph KD: Timelynitiation of dialysis: A urea kinetic approach. Am J Kidneyis 33:344-348, 1999

39. Nolph KD: Rationale for early incremental dialysisith continuous ambulatory peritoneal dialysis. Nephrolial Transplant 13:S117-S119, 1998 (suppl 6)

40. Tattersall J, Greenwood R, Farrington K: Ureainetics and when to commence dialysis. Am J Nephrol5:283-289, 1995

41. US Renal Data System: USRDS 2004 Annual Dataeport. The National Institutes of Health, National Institutef Diabetes and Digestive and Kidney Diseases, Bethesda,D, 200442. Ellis PA, Reddy V, Bari N, Cairns HS: Late referral

f end-stage renal failure. QJM 91:727-732, 199843. Ifudu O, Dawood M, Homel P, Friedman EA: Timing

f initiation of uremia therapy and survival in patients withrogressive renal disease. Am J Nephrol 18:193-198, 1998

44. Roubicek C, Brunet P, Huiart L, et al: Timing ofephrology referral: Influence on mortality and morbidity.m J Kidney Dis 36:35-41, 2000

45. Sesso R, Belasco AG: Late diagnosis of chronic renalailure and mortality on maintenance dialysis. Nephrol Dialransplant 11:2417-2420, 1996

46. Fink JC, Burdick RA, Kurth SJ, et al: Significance oferum creatinine values in new end-stage renal diseaseatients. Am J Kidney Dis 34:694-701, 1999

47. Korevaar JC, Jansen MA, Dekker FW, et al: When tonitiate dialysis: Effect of proposed US guidelines onurvival. Lancet 358:1046-1050, 2001

48. Traynor JP, Simpson K, Geddes CC, Deighan CJ,ox JG: Early initiation of dialysis fails to prolong survival

n patients with end-stage renal failure. J Am Soc Nephrol3:2125-2132, 2002

48A. The Renal Association UK Renal Registry. The Sixthnnual Report, Dec. 2003. Available at: www.renalreg.

om/Report%202003/Cover3_Frames.htm. Accessed May 1,006

49. US Renal Data System: USRDS 2003 Annual Dataeport. The National Institutes of Health, National Institutef Diabetes and Digestive and Kidney Diseases, Bethesda,D, 200350. Curtis BM, Barret BJ, Jindal K, et al: Canadian

urvey of clinical status at dialysis initiation 1998-1999: Aulticenter prospective survey. Clin Nephrol 58:282-288,

00251. Cooper BA, Branley P, Bulfone L, et al: The

nitiating Dialysis Early and Late (IDEAL) Study: Studyationale and design. Perit Dial Int 24:176-181, 2004

52. National Kidney Foundation: K/DOQI Clinical Prac-ice Guidelines for Nutrition in Chronic Renal Failure. Am Jidney Dis 35:S1-S140, 2000 (suppl 2)

53. Lowrie EG, Laird NM, Parker TF, Sargent JA: Effect
f the hemodialysis prescription of patient morbidity: report 2
rom the National Cooperative Dialysis Study. N Engl J Med05:1176-1181, 1981

54. Owen WF Jr, Lew NL, Liu Y, Lowrie EG, LazarusM: The urea reduction ratio and serum albumin concentra-ion as predictors of mortality in patients undergoing hemo-ialysis. N Engl J Med 329:1001-1006, 1993

55. Hakim RM, Breyer J, Ismail N, Schulman G: Effectsf dose of dialysis on morbidity and mortality. Am J Kidneyis 23:661-669, 1994

56. Parker TF III, Husni L, Huang W, Lew N, LowrieG: Survival of hemodialysis patients in the United States is

mproved with a greater quantity of dialysis. Am J Kidneyis 23:670-680, 1994

57. Owen WF Jr, Chertow GM, Lazarus JM, Lowrie EG:ose of hemodialysis and survival: Differences by race and

ex. JAMA 280:1764-1768, 199858. Collins AJ, Ma JZ, Umen A, Keshaviah P: Urea

ndex and other predictors of hemodialysis patient survival.m J Kidney Dis 23:272-282, 1994

59. Renkin EM, Gilmore JP: Glomerular filtration, inrloff J, Berliner RW (eds): Handbook of Physiology—enal Physiology. Washington, DC, American Physiologyociety, 1973, pp 185-248

60. Singer MA, Morton AR: Mouse to elephant: Biologi-al scaling and Kt/V. Am J Kidney Dis 35:306-309, 2000

61. Colton CK, Lowrie EG: Physical principles andechnical considerations, in Brenner BM, Rector FC (eds):he Kidney. Philadelphia, PA, Saunders, 1981, pp 2425-489

62. Depner TA: Single-compartment model, in Prescrib-ng Hemodialysis: A Guide to Urea Modeling. Boston, MA,luwer, 1991, pp 65-89

63. Daugirdas JT, Greene T, Depner TA, Gotch FA, StarA: Relationship between apparent (single-pool) and true

double-pool) urea distribution volume. Kidney Int 56:1928-933, 1999

64. Depner TA: Multi-compartment model, in Prescrib-ng Hemodialysis: A Guide to Urea Modeling. Boston, MA,luwer, 1991, pp 91-126

65. Daugirdas JT: Second generation logarithmic esti-ates of single-pool variable volume Kt/V: An analysis of

rror. J Am Soc Nephrol 4:1205-1213, 199366. Depner TA, Daugirdas JT: Equations for normalized

rotein catabolic rate based on two-point modeling ofemodialysis urea kinetics. J Am Soc Nephrol 7:780-785,996

67. Depner TA: Estimation of Kt/V from the URR forarying levels of dialytic weight loss: A bedside graphic aid.emin Dial 6:242, 1993

68. Bargman JM, Thorpe KE, Churchill DN: Relativeontribution of residual renal function and peritoneal clear-nce to adequacy of dialysis: A reanalysis of the CANUSAtudy. J Am Soc Nephrol 12:2158-2162, 2001

69. Daugirdas JT: Simplified equations for monitoringt/V, PCRn, eKt/V, and ePCRn. Adv Ren Replace Ther:295-304, 1995

70. Tattersall JE, DeTakats D, Chamney P, GreenwoodN, Farrington K: The post-hemodialysis rebound: Predict-

ng and quantifying its effect on Kt/V. Kidney Int 50:2094-
102, 1996
http://www.renalreg.com/Report%202003/Cover3_Frames.htm

http://www.renalreg.com/Report%202003/Cover3_Frames.htm

tS

Dm

LaK

faO

c

Pac

Fc8

Rtvr

ma2

Cas

OaI

eoetD2

U

Muip

tiS

sP

pd

st

Rci2

h

Nh

Cn

CuO

4

bu

cK

RT1

Ai2

oSN

Lu1

sh

md2

Ra


71. Leypoldt JK, Jaber BL, Zimmerman DL: Predictingreatment dose for novel therapies using urea standard Kt/V.emin Dial 17:142-145, 2004

72. Held PJ, Levin NW, Bovbjerg RR, Pauly MV,iamond LH: Mortality and duration of hemodialysis treat-ent. JAMA 265:871-875, 199172A. Saran R, Bragg-Gresham JL, Levin NW, et al:

onger treatment time and slower ultrafiltration in hemodi-lysis: associations with reduced mortality in the DOPPS.idney Int 69:1222-1228, 2006

73. Petitclerc T, Goux N, Reynier AL, Bene B: A modelor non-invasive estimation of in vivo dialyzer performancesnd patient’s conductivity during hemodialysis. Int J Artifrgans 16:585-591, 1993

74. Polaschegg HD: On-line dialyser clearance usingonductivity. Pediatr Nephrol 9:S9-S11, 1995 (suppl)

75. Di Filippo S, Pozzoni P, Manzoni C, Andrulli S,ontoriero G, Locatelli F: Relationship between urea clear-nce and ionic dialysance determined using a single-steponductivity profile. Kidney Int 68:2389-2395, 2005

76. Gotch FA, Panlilio FM, Buyaki RA, Wang EX,olden TI, Levin NW: Mechanisms determining the ratio ofonductivity clearance to urea clearance. Kidney Int Suppl9:S3-S24, 2004

77. Daugirdas JT, Greene T, Depner TA, Chumlea C,occo MJ, Chertow GM: Anthropometrically estimated

otal body water volumes are larger than modeled ureaolume in chronic hemodialysis patients: Effects of age,ace, and gender. Kidney Int 64:1108-1119, 2003

78. Lowrie EG, Li Z, Ofsthun N, Lazarus JM: The onlineeasurement of hemodialysis dose (Kt): Clinical outcome

s a function of body surface area. Kidney Int 68:1344-1354,005

79. Brimble KS, Onge JS, Treleaven DJ, Carlisle EJ:omparison of volume of blood processed on haemodialysisdequacy measurement sessions vs regular non-adequacyessions. Nephrol Dial Transplant 17:1470-1474, 2002

80. Lowrie EG, Chertow GM, Lew NL, Lazarus JM,wen WF: The urea [clearance x dialysis time] product (Kt)

s an outcome-based measure of hemodialysis dose. Kidneynt 56:729-737, 1999

81. Termorshuizen F, Dekker FW, van Manen JG, Kor-vaar JC, Boeschoten EW, Krediet RT: Relative contributionf residual renal function and different measures of ad-quacy to survival in hemodialysis patients: An analysis ofhe Netherlands Cooperative Study on the Adequacy ofialysis (NECOSAD)-2. J Am Soc Nephrol 15:1061-1070,004

82. Depner TA: Assessing adequacy of hemodialysis:rea modeling. Kidney Int 45:1522-1535, 1994

83. Daugirdas JT, Burke MS, Balter P, Priester-Coary A,ajka T: Screening for extreme postdialysis urea rebound

sing the Smye method: Patients with access recirculationdentified when a slow flow method is not used to draw theostdialysis blood. Am J Kidney Dis 28:727-731, 1996

84. Daugirdas JT, Greene T, Depner TA, et al: Factorshat affect postdialysis rebound in serum urea concentration,ncluding the rate of dialysis: Results from the HEMO
tudy. J Am Soc Nephrol 15:194-203, 2004 N
85. Daugirdas JT, Depner TA, Gotch FA, et al: Compari-on of methods to predict equilibrated Kt/V in the HEMOilot Study. Kidney Int 52:1395-1405, 1997

86. Jean G, Charra B, Chazot C, Laurent G: Quest forostdialysis urea rebound-equilibrated Kt/V with only intra-ialytic urea samples. Kidney Int 56:1149-1153, 1999

87. Lew JK, Hutchinson R, Lin ES: Intra-arterial bloodampling for clotting studies. Effects of heparin contamina-ion. Anaesthesia 46:719-721, 1991

88. McLaren G, Hanna C, Mills L, Bourdeau J, Cowin: Comparison of sampling methods for obtaining accurateoagulation values in hemodialysis patients with heparin-zed central venous catheters. Nephrol Nurs J 28:632-636,001

89. Hakim RM, Depner TA, Parker TF III: Adequacy ofemodialysis. Am J Kidney Dis 20:107-123, 1992

90. Schneditz D, Kaufman AM, Polaschegg HD, LevinW, Daugirdas JT: Cardiopulmonary recirculation duringemodialysis. Kidney Int 42:1450-1456, 1992

91. Schneditz D, Polaschegg HD, Levin NW, et al:ardiopulmonary recirculation in dialysis. An underrecog-ized phenomenon. ASAIO J 38:M194-M196, 1992

92. Cappello A, Grandi F, Lamberti C, Santoro A:omparative evaluation of different methods to estimaterea distribution volume and generation rate. Int J Artifrgans 17:322-330, 1994

93. Sherman RA: Recirculation revisited. Semin Dial:221-223, 1991

94. Schneditz D, Van Stone JC, Daugirdas JT: A regionallood circulation alternative to in-series two compartmentrea kinetic modeling. ASAIO J 39:M573-M577, 1993

95. Pedrini LA, Zereik S, Rasmy S: Causes, kinetics andlinical implications of post-hemodialysis urea rebound.idney Int 34:817-824, 1988

96. Geddes CC, Traynor J, Walbaum D, Fox JG, MactierA: A new method of post-dialysis blood urea sampling:he ‘stop dialysate flow’ method. Nephrol Dial Transplant5:517-523, 2000

97. Wu MJ, Feng YF, Shu KH, Cheng CH, Lian JD:nother simpler bypassing dialysate technique for measur-

ng post-haemodialysis BUN. Nephrol Dial Transplant 12:124-2127, 1997

98. Greene T, Daugirdas J, Depner T, et al: Associationf achieved dialysis dose with mortality in the Hemodialysistudy: An example of “dose-targeting bias.” J Am Socephrol 16:3371-3380, 2005

99. Chertow GM, Owen WF, Lazarus JM, Lew NL,owrie EG: Exploring the reverse J-shaped curve betweenrea reduction ratio and mortality. Kidney Int 56:1872-1878,999

100. Lowrie EG, Li Z, Ofsthun N, Lazarus JM: Bodyize, dialysis dose and death risk relationships amongemodialysis patients. Kidney Int 62:1891-1897, 2002

101. Lowrie EG, Li Z, Ofsthun N, Lazarus JM: Measure-ent of dialyzer clearance, dialysis time, and body size:

eath risk relationships among patients. Kidney Int 66:2077-084, 2004

102. Port FK, Ashby VB, Dhingra RK, Roys EC, WolfeA: Dialysis dose and body mass index are stronglyssociated with survival in hemodialysis patients. J Am Soc
ephrol 13:1061-1066, 2002

Jm

KlK

diK

hq2

SSmNC4

t2

sSp

ToU

t3

Rt2

aa

ap1

PaP

rS

s7

co

rf

f1

cN

s(2

sp

P

i

ci1

sDW

dcM

CcJ

Av6

Ph(p

Id1

Eh9

wO

t

REFERENCES S83

103. Wolfe RA, Ashby VB, Daugirdas JT, Agodoa LY,ones CA, Port FK: Body size, dose of hemodialysis, andortality. Am J Kidney Dis 35:80-88, 2000104. Port FK, Wolfe RA, Hulbert-Shearon TE, McCullough

P, Ashby VB, Held PJ: High dialysis dose is associated withower mortality among women but not among men. Am Jidney Dis 43:1014-1023, 2004

105. Rocco MV, Dwyer JT, Larive B, et al: The effect ofialysis dose and membrane flux on nutritional parametersn hemodialysis patients: Results of the HEMO Study.idney Int 65:2321-2334, 2004

106. Unruh M, Benz R, Greene T, et al: Effects ofemodialysis dose and membrane flux on health-relateduality of life in the HEMO Study. Kidney Int 66:355-366,004

106A. Greene T, Daugirdas J, Beck G, Depner T, Ornt D,chulman G, Star R, Eknoyan G, and the HEMO Study:tatistical basis for performance standards for achieving ainimum spKt/V goal based on variability observed in theIH HEMO Study. Proceedings of the XVth Internationalongress of Nephrology, Buenos Aires, Argentina, 1999, p19

107. Bleyer AJ, Hylander B, Sudo H, et al: An interna-ional study of patient compliance with hemodialysis. JAMA81:1211-1213, 1999

108. Schrier RW, Gurevich AK, Abraham WT: Renalodium excretion, edematous disorders, and diuretic use, inchrier RW (ed): Renal and Electrolyte Disorders. Philadel-hia, PA, Lippincott Williams & Wilkins, 2003, pp 64-114

109. Agarwal R, Nissenson AR, Batlle D, Coyne DW,rout JR, Warnock DG: Prevalence, treatment, and controlf hypertension in chronic hemodialysis patients in thenited States. Am J Med 115:291-297, 2003

110. Horl MP, Horl WH: Hemodialysis-associated hyper-ension: Pathophysiology and therapy. Am J Kidney Dis9:227-244, 2002

111. Rocco MV, Yan G, Heyka RJ, Benz R, Cheung AK:isk factors for hypertension in chronic hemodialysis pa-

ients: Baseline data from the HEMO Study. Am J Nephrol1:280-288, 2001

112. Wilson J, Shah T, Nissenson AR: Role of sodiumnd volume in the pathogenesis of hypertension in hemodi-lysis. Semin Dial 17:260-264, 2004

113. Foley RN, Herzog CA, Collins AJ: Blood pressurend long-term mortality in United States hemodialysisatients: USRDS Waves 3 and 4 Study. Kidney Int 62:1784-790, 2002

114. De Lorenzo A, Deurenberg P, Andreoli A, Sasso GF,alestini M, Docimo R: Multifrequency impedance in thessessment of body water losses during dialysis. Renhysiol Biochem 17:326-332, 1994

115. Sherman RA: Modifying the dialysis prescription toeduce intradialytic hypotension. Am J Kidney Dis 38:S18-25, 2001 (suppl 4)

116. Mitch WE, Wilcox CS: Disorders of body fluids,odium and potassium in chronic renal failure. Am J Med2:536-550, 1982

117. Dorhout Mees EJ, Ozbash C, Akcicek F: Cardiovas-ular disturbances in hemodialysis patients: The importance
f volume overload. J Nephrol 8:71-78, 1995 1
118. Koomans HA, Geers AB, Mees EJ: Plasma volumeecovery after ultrafiltration in patients with chronic renalailure. Kidney Int 26:848-854, 1984

119. Chazot C, Charra B, Vo Van C, et al: The Janus-aced aspect of ‘dry weight.’ Nephrol Dial Transplant4:121-124, 1999

120. Zucchelli P, Santoro A, Zuccala A: Genesis andontrol of hypertension in hemodialysis patients. Seminephrol 8:163-168, 1988

121. Mailloux LU, Fields S, Campese VM: Hyperten-ion in chronic dialysis patients, in Nissenson AR, Fine RNeds): Dialysis Therapy. Philadelphia, PA, Hanley & Belfus,002, pp 341-358

122. Charra B, Bergstrom J, Scribner BH: Blood pres-ure control in dialysis patients: Importance of the laghenomenon. Am J Kidney Dis 32:720-724, 1998

123. D’Amico M, Locatelli F: Hypertension in dialysis:athophysiology and treatment. J Nephrol 15:438-445, 2002

124. Fishbane SA, Scribner BH: Blood pressure controln dialysis patients. Semin Dial 15:144-145, 2002

125. Comty C, Rottka H, Shaldon S: Blood pressureontrol in patients with end-stage renal failure treated byntermittent haemodialysis. Proc Eur Dial Transplant Assoc:209-213, 1964

126. Campese VM, Tanasescu A: Hypertension in dialy-is patients, in Henrich WL (ed): Principles and Practice ofialysis (ed 3). Philadelphia, PA, Lippincott Williams &ilkins, 2004, pp 227-256127. Jabara AE, Mehta RL: Determination of fluid shifts

uring chronic hemodialysis using bioimpedance spectros-opy and an in-line hematocrit monitor. ASAIO J 41:M682-687, 1995128. Leypoldt JK, Cheung AK, Steuer RR, Harris DH,

onis JM: Determination of circulating blood volume byontinuously monitoring hematocrit during hemodialysis.Am Soc Nephrol 6:214-219, 1995

129. Rodriguez HJ, Domenici R, Diroll A, Goykhman I:ssessment of dry weight by monitoring changes in bloodolume during hemodialysis using Crit-Line. Kidney Int8:854-861, 2005

130. Goldstein SL, Patel HP, Mahan JD, Flynn JT:rospective evaluation of a non-invasive monitoring ofematocrit (NIVM) algorithm to improve cardiovascularCV) parameters in pediatric (ped) hemodialysis (HD)atients (Pt). J Am Soc Nephrol 16:725A, 2005 (abstr)

131. Reddan DN, Szczech LA, Hasselblad V, et al:ntradialytic blood volume monitoring in ambulatory hemo-ialysis patients: A randomized trial. J Am Soc Nephrol6:2162-2169, 2005

132. Schneditz D, Zaluska WT, Morris AT, Levin NW:ffect of ultrafiltration on peripheral urea sequestration inaemodialysis patients. Nephrol Dial Transplant 16:994-98, 2001

133. Charra B, Terrat JC, Vanel T, et al: Long thriceeekly hemodialysis: The Tassin experience. Int J Artifrgans 27:265-283, 2004

134. Salem M: Hypertension in the hemodialysis popula-ion? High time for answers. Am J Kidney Dis 33:592-594,
999

o1

Nht

c1

o5

Ks

h

d1

d

t7

s

bp

sY

Jp

MoK

r

ir

Me

tg2

hphi

l

L

f

Ss

Sf

pe

he

ht

csRK

oH

obD

apI

PsD

cD

Bd2

rp

cJ

EhH

ghc

d


135. Raine AE, Margreiter R, Brunner FP, et al: Reportn management of renal failure in Europe, XXII,991. Nephrol Dial Transplant 7:S7-S35, 1992 (suppl 2)

136. Grekas D, Bamichas G, Bacharaki D, Goutzaridis, Kasimatis E, Tourkantonis A: Hypertension in chronicemodialysis patients: Current view on pathophysiology andreatment. Clin Nephrol 53:164-168, 2000

137. Levey AS, Eknoyan G: Cardiovascular disease inhronic renal disease. Nephrol Dial Transplant 14:828-833,999

138. Mittal SK, Kowalski E, Trenkle J, et al: Prevalencef hypertension in a hemodialysis population. Clin Nephrol1:77-82, 1999

139. Cheigh JS, Milite C, Sullivan JF, Rubin AL, StenzelH: Hypertension is not adequately controlled in hemodialy-

is patients. Am J Kidney Dis 19:453-459, 1992140. Scribner BH: A personalized history of chronic

emodialysis. Am J Kidney Dis 16:511-519, 1990141. Shaldon S: What clinical insights from the early

ays of dialysis are being overlooked today? Semin Dial8:18-19, 2005

142. Cohen EP: Dialysis hypertension: Dry weight andialysis time. Nephrol Dial Transplant 13:554-555, 1998

143. Charra B, Chazot C: The neglect of sodium restric-ion in dialysis patients: A short review. Hemodial Int:342-347, 2003

144. Flanigan M: Dialysate composition and hemodialy-is hypertension. Semin Dial 17:279-283, 2004

145. Stiller S, Bonnie-Schorn E, Grassmann A, Uhlen-usch-Korwer I, Mann H: A critical review of sodiumrofiling for hemodialysis. Semin Dial 14:337-347, 2001

146. Agarwal R: Hypertension in hemodialysis, in Nis-enson AR, Fine RN (eds): Clinical Dialysis (ed 4). Nework, NY, McGraw-Hill, 2005, pp 755-769

147. Zoccali C, Dunea G: Hypertension, in DaugirdasT, Blake PG, Ing TS (eds): Handbook of Dialysis. Philadel-hia, PA, Lippincott Williams & Wilkins, 2001, pp 466-476

148. Foley RN, Parfrey PS, Harnett JD, Kent GM,urray DC, Barre PE: Impact of hypertension on cardiomy-

pathy, morbidity and mortality in end-stage renal disease.idney Int 49:1379-1385, 1996

149. Collins AJ: Cardiovascular mortality in end-stageenal disease. Am J Med Sci 325:163-167, 2003

150. Luik AJ, Kooman JP, Leunissen KM: Hypertensionn haemodialysis patients: Is it only hypervolaemia? Neph-ol Dial Transplant 12:1557-1560, 1997

151. Blacher J, Guerin AP, Pannier B, Marchais SJ, SafarE, London GM: Impact of aortic stiffness on survival in

nd-stage renal disease. Circulation 99:2434-2439, 1999152. Klassen PS, Lowrie EG, Reddan DN, et al: Associa-

ion between pulse pressure and mortality in patients under-oing maintenance hemodialysis. JAMA 287:1548-1555,002

153. Fujiwara N, Osanai T, Kamada T, Katoh T, Taka-ashi K, Okumura K: Study on the relationship betweenlasma nitrite and nitrate level and salt sensitivity in humanypertension: Modulation of nitric oxide synthesis by saltntake. Circulation 101:856-861, 2000

154. MacAllister RJ, Rambausek MH, Vallance P, Wil-
iams D, Hoffmann KH, Ritz E: Concentration of dimethyl- M
-arginine in the plasma of patients with end-stage renalailure. Nephrol Dial Transplant 11:2449-2452, 1996

155. Vallance P, Leone A, Calver A, Collier J, Moncada: Accumulation of an endogenous inhibitor of nitric oxideynthesis in chronic renal failure. Lancet 339:572-575, 1992

156. Converse RL Jr, Jacobsen TN, Toto RD, et al:ympathetic overactivity in patients with chronic renalailure. N Engl J Med 327:1912-1918, 1992

157. Agarwal R, Lewis R, Davis JL, Becker B: Lisino-ril therapy for hemodialysis hypertension: Hemodynamic andndocrine responses. Am J Kidney Dis 38:1245-1250, 2001

158. Abraham PA, Macres MG: Blood pressure inemodialysis patients during amelioration of anemia withrythropoietin. J Am Soc Nephrol 2:927-936, 1991

159. Agarwal R: Hypertension and survival in chronicemodialysis patients—Past lessons and future opportuni-ies. Kidney Int 67:1-13, 2005

160. London G, Marchais S, Guerin AP: Blood pressureontrol in chronic hemodialysis patients, in Jacob C, Kjell-trand CM, Koch KM, Winchester JF (eds): Replacement ofenal Function by Dialysis. Dordrecht, The Netherlands,luwer, 1996, pp 966-989

161. Agarwal R: Exploring the paradoxical relationshipf hypertension with mortality in chronic hemodialysis.emodial Int 8:207-213, 2004

162. Schomig M, Eisenhardt A, Ritz E: Controversy onptimal blood pressure on haemodialysis: Normotensivelood pressure values are essential for survival. Nephrolial Transplant 16:469-474, 2001

163. Zager PG, Nikolic J, Brown RH, et al: “U” Curvessociation of blood pressure and mortality in hemodialysisatients. Medical Directors of Dialysis Clinic, Inc. Kidneynt 54:561-569, 1998

164. Port FK, Hulbert-Shearon TE, Wolfe RA, et al:redialysis blood pressure and mortality risk in a nationalample of maintenance hemodialysis patients. Am J Kidneyis 33:507-517, 1999

165. Scribner BH: Can antihypertensive medicationsontrol BP in haemodialysis patients: Yes or no? Nephrolial Transplant 14:2599-2601, 1999

166. Levin NW, Blagg CR, Twardowski ZJ, Shaldon S,ower JD: What clinical insights from the early days ofialysis are being overlooked today? Semin Dial 18:13-15,005

167. Cirit M, Akcicek F, Terzioglu E, et al: ‘Paradoxical’ise in blood pressure during ultrafiltration in dialysisatients. Nephrol Dial Transplant 10:1417-1420, 1995

168. Eaton SB, Konner M: Paleolithic nutrition. Aonsideration of its nature and current implications. N EnglMed 312:283-289, 1985

169. Appel LJ, Brands MW, Daniels SR, Karanja N,lmer PJ, Sacks FM: Dietary approaches to prevent and treatypertension: A scientific statement from the Americaneart Association. Hypertension 47:296-308, 2006

170. Krauss RM, Deckelbaum RJ, Ernst N, et al: Dietaryuidelines for healthy American adults. A statement forealth professionals from the Nutrition Committee, Ameri-an Heart Association. Circulation 94:1795-1800, 1996

171. Dietary Reference Intakes: Water, Potassium, So-ium, Chloride and Sulfate. Washington, DC, Institute of
edicine, National Academy Press, 2004

Sa

oAS3

hin

Sss

pC6

aW

N

io

d

pS

s

BdL

t

pT

vp

ta2

ip

tO

SaI

Rcp

p

c3

h1

aw

vs

pr

a1

rs

vtd

GhtN

e1

S

L

NR

NN

RrN

fle1

fl

REFERENCES S85

172. 2003 European Society of Hypertension-Europeanociety of Cardiology: Guidelines for the management ofrterial hypertension. J Hypertens 21:1011-1053, 2003

173. Sacks FM, Svetkey LP, Vollmer WM, et al: Effectsn blood pressure of reduced dietary sodium and the Dietarypproaches to Stop Hypertension (DASH) diet. DASH-odium Collaborative Research Group. N Engl J Med44:3-10, 2001

174. Khosla UM, Johnson RJ: Hypertension in theemodialysis patient and the “lag phenomenon”: Insightsnto pathophysiology and clinical management. Am J Kid-ey Dis 43:739-751, 2004

175. Krautzig S, Janssen U, Koch KM, Granolleras C,haldon S: Dietary salt restriction and reduction of dialysateodium to control hypertension in maintenance haemodialy-is patients. Nephrol Dial Transplant 13:552-553, 1998

176. Rostand SG, Rutsky EA: Cardiac disease in dialysisatients, in Nissenson AR, Fine RN, Gentile DE (eds):linical Dialysis. Norwalk, CT, Appleton & Lange, 1995, pp52-698

176A. Kaplan NM: Patient information. Hypertensionnd diet and weight. UpToDate, version 13.3, UptoDate Inc.,altham, MA, September 2005177. Mattes RD: The taste for salt in humans. Am J Clin

utr 65:S692-S697, 1997 (suppl 2)178. Korhonen MH, Jarvinen RM, Sarkkinen ES, Uus-

tupa MI: Effects of a salt-restricted diet on the intake ofther nutrients. Am J Clin Nutr 72:414-420, 2000

179. Kempner W: Treatment of hypertensive vascularisease with rice diet. Am J Med 8:545-577, 1948

180. Carvalho JJ, Baruzzi RG, Howard PF, et al: Bloodressure in four remote populations in the INTERSALTtudy. Hypertension 14:238-246, 1989

181. Ahmad S: Dietary sodium restriction for hyperten-ion in dialysis patients. Semin Dial 17:284-287, 2004

182. Blumberg A, Nelp WB, Hegstrom RM, ScribnerH: Extracellular volume in patients with chronic renalisease treated for hypertension by sodium restriction.ancet 2:69-73, 1967

183. Mailloux LU: The overlooked role of salt restric-ion in dialysis patients. Semin Dial 13:150-151, 2000

184. Maduell F, Navarro V: Dietary salt intake and bloodressure control in haemodialysis patients. Nephrol Dialransplant 15:2063, 2000

185. Ozkahya M, Toz H, Qzerkan F, et al: Impact ofolume control on left ventricular hypertrophy in dialysisatients. J Nephrol 15:655-660, 2002

186. Shaldon S: Dietary salt restriction and drug-freereatment of hypertension in ESRD patients: A largelybandoned therapy. Nephrol Dial Transplant 17:1163-1165,002

187. Shaldon S: Salt restriction and not length of dialysiss the key to drug free blood pressure control in ESRDatients. J Nephrol 16:159, 2003

188. Shaldon S: Is salt restriction more important thanhe length of dialysis in the miracle of Tassin? Int J Artifrgans 27:813-814; author reply 27:815, 2004

189. Hegstrom RM, Murray JS, Pendras JP, Burnell JM,cribner BH: Two year’s experience with periodic hemodi-lysis in the treatment of chronic uremia. Trans Am Soc Artif
ntern Organs 8:266-280, 1962 I
190. Shaldon S, Rae AI, Rosen SM, Silva H, Oakley J:efrigerated femoral venous-venous haemodialysis withoil preservation for rehabilitation of terminal uraemicatients. Br Med J 5347:1716-1717, 1963

191. Scribner BH: Adequate control of blood pressure inatients on chronic hemodialysis. Kidney Int 41:1286, 1992

192. Abuelo JG: Large interdialytic weight gain. Causes,onsequences and corrective measures. Semin Dial 11:25-2, 1998

193. Kempner W: Treatment of kidney disease andypertensive disease with rice diet. N C Med J 5:125-133,944

194. Kempner W: Treatment of heart and kidney diseasend of hypertensive and arteriosclerotic vascular diseaseith the rice diet. Ann Intern Med 31:821-856, 1949

195. Gunal AI, Duman S, Ozkahya M, et al: Strictolume control normalizes hypertension in peritoneal dialy-is patients. Am J Kidney Dis 37:588-593, 2001

196. Ritz E: Salt—Friend or foe? Nephrol Dial Trans-lant [Epub ahead of print, http://ndt.oxfordjournals.org/cgi/eprint/gfi256v1] Dec 29, 2005

197. Charra B, Calemard E, Ruffet M, et al: Survival asn index of adequacy of dialysis. Kidney Int 41:1286-1291,992

198. Innes A, Charra B, Burden RP, Morgan AG, Lau-ent G: The effect of long, slow haemodialysis on patienturvival. Nephrol Dial Transplant 14:919-922, 1999

199. Ozkahya M, Ok E, Cirit M, et al: Regression of leftentricular hypertrophy in haemodialysis patients by ultrafil-ration and reduced salt intake without antihypertensiverugs. Nephrol Dial Transplant 13:1489-1493, 1998

200. Ayus JC, Mizani MR, Achinger SG, Thadhani R,o AS, Lee S: Effects of short daily versus conventionalemodialysis on left ventricular hypertrophy and inflamma-ory markers: A prospective, controlled study. J Am Socephrol 16:2778-2788, 2005

201. Buoncristiani U: Fifteen years of clinical experi-nce with daily haemodialysis. Nephrol Dial Transplant3:S148-S151, 1998 (suppl 6)

202. Depner TA: Why daily hemodialysis is better:olute kinetics. Semin Dial 12:462-471, 1999

203. Alloatti S, Molino A, Manes M, Bonfant G, Pellu V:ong nocturnal dialysis. Blood Purif 20:525-530, 2002

204. Lockridge RS Jr, Spencer M, Craft V, et al:octurnal home hemodialysis in North America. Adv Reneplace Ther 8:250-256, 2001

205. Pierratos A, Ouwendyk M, Francoeur R, et al:octurnal hemodialysis: Three-year experience. J Am Socephrol 9:859-868, 1998

206. Brunet P, Saingra Y, Leonetti F, Vacher-Coponat H,amananarivo P, Berland Y: Tolerance of haemodialysis: A

andomized cross-over trial of 5-h versus 4-h treatment time.ephrol Dial Transplant 11:S46-S51, 1996 (suppl 8)

207. Tomson CR: Advising dialysis patients to restrictuid intake without restricting sodium intake is not based onvidence and is a waste of time. Nephrol Dial Transplant6:1538-1542, 2001

208. Rigby AJ, Scribner BH, Ahmad S: Sodium, notuid, controls interdialytic weight gain. Nephrol News
ssues 14:21-22, 2000
http://ndt.oxfordjournals.org/cgi/reprint/gfi256v1

http://ndt.oxfordjournals.org/cgi/reprint/gfi256v1

hT2

HaN

oh

pl

ue

p“

tc1

p1

lA

RJ

n

dvcn

eCT

i1

Ca

i

Ocr2

io1

Vff

ir

wfK

lJ

er4

flp

PA

PA

a2

OmIa

h

ci2

N

aMT

p1

W(

tt3

ps


209. Feinstein EI: Nutritional therapy in maintenanceemodialysis, in Nissenson AR, Fine RN (eds): Dialysisherapy. Philadelphia, PA, Hanley & Belfus, 2002, pp81-285

210. Campese VM, Mozayeni P, Ye S, Gumbard M:igh salt intake inhibits nitric oxide synthase expression and

ggravates hypertension in rats with chronic renal failure. Jephrol 15:407-413, 2002

211. Hamlyn JM, Hamilton BP, Manunta P: Endogenousuabain, sodium balance and blood pressure: A review and aypothesis. J Hypertens 14:151-167, 1996

212. Luik AJ, Charra B, Katzarski K, et al: Bloodressure control and hemodynamic changes in patients onong time dialysis treatment. Blood Purif 16:197-209, 1998

213. Dunn CJ, Fitton A, Brogden RN: Torasemide. Anpdate of its pharmacological properties and therapeuticfficacy. Drugs 49:121-142, 1995

214. Flamenbaum W, Friedman R: Pharmacology, thera-eutic efficacy, and adverse effects of bumetanide, a newloop” diuretic. Pharmacotherapy 2:213-222, 1982

215. Medcalf JF, Harris KP, Walls J: Role of diuretics inhe preservation of residual renal function in patients onontinuous ambulatory peritoneal dialysis. Kidney Int 59:128-1133, 2001

216. Wilcox CS: New insights into diuretic use inatients with chronic renal disease. J Am Soc Nephrol3:798-805, 2002

217. Khandelwal M, Oreopoulos DG: Is there a need forow sodium dialysis solution for peritoneal dialysis patients?dv Perit Dial 20:156-162, 2004

218. Schwartz GH, David DS, Riggio RR, Stenzel KH,ubin AL: Ototoxicity induced by furosemide. N EnglMed 282:1413-1414, 1970

219. Humes HD: Insights into ototoxicity. Analogies toephrotoxicity. Ann N Y Acad Sci 884:15-18, 1999

220. Van Stone JC, Bauer J, Carey J: The effect ofialysate sodium concentration on body fluid compartmentolume, plasma renin activity and plasma aldosteroneoncentration in chronic hemodialysis patients. Am J Kid-ey Dis 2:58-64, 1982

221. Locatelli F, Di Filippo S, Pontoriero G: Fluid andlectrolyte balance during extracorporeal therapies, in Ronco, Bellomo R (eds): Critical Care Nephrology. Dordrecht,he Netherlands, Kluwer, 1998, pp 249-259

222. Mann H, Stiller S: Urea, sodium, and water changesn profiling dialysis. Nephrol Dial Transplant 11:S10-S15,996 (suppl 8)

223. Sang GL, Kovithavongs C, Ulan R, KjellstrandM: Sodium ramping in hemodialysis: A study of beneficialnd adverse effects. Am J Kidney Dis 29:669-677, 1997

224. Horl MP, Horl WH: Drug therapy for hypertensionn hemodialysis patients. Semin Dial 17:288-294, 2004

225. Menon MK, Naimark DM, Bargman JM, Vas SI,reopoulos DG: Long-term blood pressure control in a

ohort of peritoneal dialysis patients and its association withesidual renal function. Nephrol Dial Transplant 16:2207-213, 2001

226. Shin SK, Noh H, Kang SW, et al: Risk factorsnfluencing the decline of residual renal function in continu-us ambulatory peritoneal dialysis patients. Perit Dial Int
9:138-142, 1999 a
227. Singhal MK, Bhaskaran S, Vidgen E, Bargman JM,as SI, Oreopoulos DG: Rate of decline of residual renal

unction in patients on continuous peritoneal dialysis andactors affecting it. Perit Dial Int 20:429-438, 2000

228. Lysaght MJ, Vonesh EF, Gotch F, et al: Thenfluence of dialysis treatment modality on the decline ofemaining renal function. ASAIO Trans 37:598-604, 1991

229. McKane W, Chandna SM, Tattersall JE, Green-ood RN, Farrington K: Identical decline of residual renal

unction in high-flux biocompatible hemodialysis and CAPD.idney Int 61:256-265, 2002

230. Moist LM, Port FK, Orzol SM, et al: Predictors ofoss of residual renal function among new dialysis patients.Am Soc Nephrol 11:556-564, 2000

231. Van Stone JC: The effect of dialyzer membrane andtiology of kidney disease on the preservation of residualenal function in chronic hemodialysis patients. ASAIO J1:M713-M716, 1995

232. Schiffl H, Lang SM, Fischer R: Ultrapure dialysisuid slows loss of residual renal function in new dialysisatients. Nephrol Dial Transplant 17:1814-1818, 2002

233. National Kidney Foundation: K/DOQI Clinicalractice Guidelines for Peritoneal Dialysis Adequacy, 2000.m J Kidney Dis 37:S65-S136, 2001 (suppl 1)

234. Hanson JA, Hulbert-Shearon TE, Ojo AO, et al:rescription of twice-weekly hemodialysis in the USA.m J Nephrol 19:625-633, 1999

235. Depner TA: Daily hemodialysis efficiency: Annalysis of solute kinetics. Adv Ren Replace Ther 8:227-35, 2001

236. Sugarman JR, Frederick PR, Frankenfield DL,wen WF Jr, McClellan WM: Developing clinical perfor-ance measures based on the Dialysis Outcomes Quality

nitiative Clinical Practice Guidelines: Process, outcomes,nd implications. Am J Kidney Dis 42:806-812, 2003

236A. Healthy People 2010. Available at: www.ealthypeople.gov. Accessed May 1, 2006

237. Owen WF Jr: Patterns of care for patients withhronic kidney disease in the United States: Dying formprovement. J Am Soc Nephrol 14:S76-S80, 2003 (suppl)

237A. Available at: www.clinicaltrials.gov/show/CT00264758. Accessed May 1, 2006

238. Collins AJ, Liu J, Ebben JP: Dialyser reuse-ssociated mortality and hospitalization risk in incidentedicare haemodialysis patients, 1998-1999. Nephrol Dial

ransplant 19:1245-1251, 2004239. Robinson BM, Feldman HI: Dialyzer reuse and

atient outcomes: What do we know now? Semin Dial8:175-179, 2005

240. Hays RD, Kallich JD, Mapes DL, Coons SJ, CarterB: Development of the Kidney Disease Quality of Life

KDQOL) instrument. Qual Life Res 3:329-338, 1994241. DeOreo PB: Hemodialysis patient-assessed func-

ional health status predicts continued survival, hospitaliza-ion, and dialysis-attendance compliance. Am J Kidney Dis0:204-212, 1997

242. Kalantar-Zadeh K, Kopple JD, Block G, Hum-hreys MH: Association among SF36 quality of life mea-ures and nutrition, hospitalization, and mortality in hemodi-
lysis. J Am Soc Nephrol 12:2797-2806, 2001
http://www.healthypeople.gov

http://www.healthypeople.gov

http://www.clinicaltrials.gov/show/NCT00264758

http://www.clinicaltrials.gov/show/NCT00264758

rht

edp

Dpr

Br3

ep

pa

DrK

Ta1

Va8

t2

dh

Bt5

Imn

tBh

ma

Sp6

S

rP

icN

Nd

vh

utCN

cD

lD

ci(

L1

s

va1

hH

dt

h[2

CtC

oc3

hN

m

REFERENCES S87

243. Mapes DL, Lopes AA, Satayathum S, et al: Health-elated quality of life as a predictor of mortality andospitalization: The Dialysis Outcomes and Practice Pat-erns Study (DOPPS). Kidney Int 64:339-349, 2003

244. Bakewell AB, Higgins RM, Edmunds ME: Doesthnicity influence perceived quality of life of patients onialysis and following renal transplant? Nephrol Dial Trans-lant 16:1395-1401, 2001

245. Hicks LS, Cleary PD, Epstein AM, Ayanian JZ:ifferences in health-related quality of life and treatmentreferences among black and white patients with end-stageenal disease. Qual Life Res 13:1129-1137, 2004

246. Kutner NG, Brogan D, Fielding B, Hall WD:lack/white differences in symptoms and health satisfaction

eported by older hemodialysis patients. Ethn Dis 10:328-33, 2000

247. Unruh M, Miskulin D, Yan G, et al: Racial differ-nces in health-related quality of life among hemodialysisatients. Kidney Int 65:1482-1491, 2004

248. Bass EB, Wills S, Fink NE, et al: How strong areatients’ preferences in choices between dialysis modalitiesnd doses? Am J Kidney Dis 44:695-705, 2004

249. Ayanian JZ, Cleary PD, Keogh JH, Noonan SJ,avid-Kasdan JA, Epstein AM: Physicians’ beliefs about

acial differences in referral for renal transplantation. Am Jidney Dis 43:350-357, 2004

250. Ayanian JZ, Cleary PD, Weissman JS, Epstein AM:he effect of patients’ preferences on racial differences inccess to renal transplantation. N Engl J Med 341:1661-669, 1999

251. Seikaly MG, Loleh S, Rosenblum A, Browne R:alidation of the Center for Medicare and Medicaid Serviceslgorithm for eligibility for dialysis. Pediatr Nephrol 19:893-97, 2004

252. Goldstein SL: Hemodialysis in the pediatric pa-ient: State of the art. Adv Ren Replace Ther 8:173-179,001

253. Marsenic O, Peco-Antic A, Jovanovic O: Effect ofialysis dose on nutritional status of children on chronicemodialysis. Nephron 88:273-275, 2001

254. Goldstein SL, Baronette S, Gambrell TV, Currier H,rewer ED: nPCR assessment and IDPN treatment of malnutri-

ion in pediatric hemodialysis patients. Pediatr Nephrol 17:531-34, 2002

255. Orellana P, Juarez-Congelosi M, Goldstein SL:ntradialytic parenteral nutrition treatment and biochemicalarker assessment for malnutrition in adolescent mainte-

ance hemodialysis patients. J Ren Nutr 15:312-317, 2005256. Goldstein SL, Brewer ED: Logarithmic extrapola-

ion of a 15-minute postdialysis BUN to predict equilibratedUN and calculate double-pool Kt/V in the pediatricemodialysis population. Am J Kidney Dis 36:98-104, 2000

257. Tom A, McCauley L, Bell L, et al: Growth duringaintenance hemodialysis: Impact of enhanced nutrition

nd clearance. J Pediatr 134:464-471, 1999258. Goldstein SL, Currier H, Watters L, Hempe JM,

heth RD, Silverstein D: Acute and chronic inflammation inediatric patients receiving hemodialysis. J Pediatr 143:653-57, 2003

259. Frankenfield DL, Neu AM, Warady BA, Watkins
L, Friedman AL, Fivush BA: Adolescent hemodialysis: i
esults of the 2000 ESRD Clinical Performance Measuresroject. Pediatr Nephrol 17:10-15, 2002

260. Goldstein SL, Smith CM, Currier H: Noninvasiventerventions to decrease hospitalization and associatedosts for pediatric patients receiving hemodialysis. J Am Socephrol 14:2127-2131, 2003

261. Jain SR, Smith L, Brewer ED, Goldstein SL:on-invasive intravascular monitoring in the pediatric hemo-ialysis population. Pediatr Nephrol 16:15-18, 2001

262. Michael M, Brewer ED, Goldstein SL: Bloodolume monitoring to achieve target weight in pediatricemodialysis patients. Pediatr Nephrol 19:432-437, 2004

263. Levey AS, Greene T, Schluchter MD, et al: Glomer-lar filtration rate measurements in clinical trials. Modifica-ion of Diet in Renal Disease Study Group and the Diabetesontrol and Complications Trial Research Group. J Am Socephrol 4:1159-1171, 1993

264. Casino FG, Lopez T: The equivalent renal urealearance: A new parameter to assess dialysis dose. Nephrolial Transplant 11:1574-1581, 1996

265. Gotch FA: The current place of urea kinetic model-ing with respect to different dialysis modalities. Nephrolial Transplant 13:S10-S14, 1998 (suppl 6)

266. Keshaviah PR, Nolph KD, Van Stone JC: The peakoncentration hypothesis: A urea kinetic approach to compar-ng the adequacy of continuous ambulatory peritoneal dialysisCAPD) and hemodialysis. Perit Dial Int 9:257-260, 1989

267. Depner TA: Benefits of more frequent dialysis:ower TAC at the same Kt/V. Nephrol Dial Transplant3:S20-S24, 1998 (suppl 6)

268. Depner TA, Bhat A: Quantifying daily hemodialy-is. Semin Dial 17:79-84, 2004

269. Watson PE, Watson ID, Batt RD: Total body waterolumes for adult males and females estimated from simplenthropometric measurements. Am J Clin Nutr 33:27-39,980

270. Cheung AK, Levin NW, Greene T, et al: Effects ofigh-flux hemodialysis on clinical outcomes: Results of theEMO Study. J Am Soc Nephrol 14:3251-3263, 2003

271. Cheung AK, Sarnak MJ, Yan G, et al: Cardiaciseases in maintenance hemodialysis patients: Results ofhe HEMO Study. Kidney Int 65:2380-2389, 2004

272. Locatelli F, Andrulli S, Pecchini F, et al: Effect ofigh-flux dialysis on the anaemia of haemodialysis patientssee comment]. Nephrol Dial Transplant 15:1399-1409,000

273. MacLeod AM, Campbell M, Cody JD, et al:ellulose, modified cellulose and synthetic membranes in

he haemodialysis of patients with end-stage renal disease.ochrane Database Syst Rev CD003234, 2005

274. Leypoldt JK, Cheung AK, Carroll CE, et al: Effectf dialysis membranes and middle molecule removal onhronic hemodialysis patient survival. Am J Kidney Dis3:349-355, 1999

275. Woods HF, Nandakumar M: Improved outcome foraemodialysis patients treated with high-flux membranes.ephrol Dial Transplant 15:S36-S42, 2000 (suppl 1)

276. Schiffl H, Fischer R, Lang SM, Mangel E: Clinicalanifestations of AB-amyloidosis: Effects of biocompatibil-

ty and flux. Nephrol Dial Transplant 15:840-845, 2000

kI

mJ

boR2

sT

otC1

hA

MpW1

fct1

d1

s

LaN

hs

sr1

GEc1

(N

td2

rD3

a3

dNp

Mt

cPW

Mms3

F

cr2

r(

g3p

f

f

aU2

Dr9

TK

Hd

BA

M


277. Leypoldt JK, Cheung AK, Deeter RB: Reboundinetics of beta2-microglobulin after hemodialysis. Kidneynt 56:1571-1577, 1999

277A. Ebben JP, Liu J, Collins AJ: Membrane associatedorbidity in incident and prevalent hemodialysis patients.Am Soc Nephrol 13:614A, 2002 (abstr)

278. Locatelli F, Marcelli D, Conte F, Limido A, Mal-erti F, Spotti D: Comparison of mortality in ESRD patientsn convective and diffusive extracorporeal treatments. Theegistro Lombardo Dialisi E Trapianto. Kidney Int 55:286-93, 1999

279. European Best Practice Guidelines for Haemodialy-is (Part 1): Section III. Biocompatibility. Nephrol Dialransplant 17:S32-S44, 2002 (suppl 7)

280. Locatelli F, Mastrangelo F, Redaelli B, et al: Effectsf different membranes and dialysis technologies on patientreatment tolerance and nutritional parameters. The Italianooperative Dialysis Study Group. Kidney Int 50:1293-302, 1996

281. Nakai S, Iseki K, Tabei K, et al: Outcomes ofemodiafiltration based on Japanese dialysis patient registry.m J Kidney Dis 38:S212-S216, 2001 (suppl 1)

282. van Ypersele de Strihou C, Jadoul M, Malghem J,aldague B, Jamart J: Effect of dialysis membrane and

atient’s age on signs of dialysis-related amyloidosis. Theorking Party on Dialysis Amyloidosis. Kidney Int 39:1012-

019, 1991283. Twardowski Z: Effect of long-term increase in the

requence and/or prolongation of dialysis duration on certainlinical manifestations and results of laboratory investiga-ions in patients with chronic renal failure. Acta Med Pol6:31-44, 1975

284. Pierratos A, McFarlane P, Chan CT: Quotidianialysis—Update 2005. Curr Opin Nephrol Hypertens 14:19-124, 2005

285. Diaz-Buxo JA: Beyond thrice-weekly hemodialy-is. Hemodial Int 9:309-313, 2005

286. Block GA, Klassen PS, Lazarus JM, Ofsthun N,owrie EG, Chertow GM: Mineral metabolism, mortality,nd morbidity in maintenance hemodialysis. J Am Socephrol 15:2208-2218, 2004

287. Salahudeen AK, Dykes P, May W: Risk factors forigher mortality at the highest levels of spKt/V in hemodialy-is patients. Nephrol Dial Transplant 18:1339-1344, 2003

288. Kopple JD, Greene T, Chumlea WC, et al: Relation-hip between nutritional status and the glomerular filtrationate: Results from the MDRD Study. Kidney Int 57:1688-703, 2000

289. Velasquez MT, von Albertini B, Lew SQ, MishkinJ, Bosch JP: Equal levels of blood pressure control inSRD patients receiving high-efficiency hemodialysis andonventional hemodialysis. Am J Kidney Dis 31:618-623,998

290. Kurella M, Chertow GM: Dialysis session length“t”) as a determinant of the adequacy of dialysis. Seminephrol 25:90-95, 2005

291. Association for Advancement of Medical Informa-ion (AAMI): American National Standard. Reuse of Hemo-ialyzers (ANSI/AAMI RD47:2002 & RD47:2002/A1:
003). Arlington, VA, AAMI, 2003 r
292. National Kidney Foundation: Report on dialyzereuse. Task Force on Reuse of Dialyzers, Council onialysis, National Kidney Foundation. Am J Kidney Dis0:859-871, 1997

293. Agodoa LY, Wolfe RA, Port FK: Reuse of dialyzersnd clinical outcomes: Fact or fiction. Am J Kidney Dis2:S88-S92, 1998 (suppl 4)

294. Clark WR, Scott MK, Leypoldt JK: Reuse ofialyzers: Methods and complications of dialyzer reuse, inissenson AR, Fine RN (eds): Dialysis Therapy. Philadel-hia, PA, Hanley & Belfus, 2002, pp 199-203

295. Finelli L, Miller JT, Tokars JI, Alter MJ, ArduinoJ: National surveillance of dialysis-associated diseases in

he United States, 2002. Semin Dial 18:52-61, 2005296. Light PD: Reuse of hemodialysis membranes in

hronic dialysis therapy, in Henrich WL (ed): Principles andractice of Dialysis (ed 3). Philadelphia, PA, Lippincottilliams & Wilkins, 2004, pp 16-27297. Port FK, Wolfe RA, Hulbert-Shearon TE, et al:

ortality risk by hemodialyzer reuse practice and dialyzerembrane characteristics: Results from the USRDS Dialy-

is Morbidity and Mortality Study. Am J Kidney Dis7:276-286, 2001

298. Vinhas J, Pinto dos Santos J: Haemodialyser reuse:acts and fiction. Nephrol Dial Transplant 15:5-8, 2000

299. Lowrie EG, Li Z, Ofsthun N, Lazarus JM: Repro-essing dialysers for multiple uses: Recent analysis of deathisks for patients. Nephrol Dial Transplant 19:2823-2830,004

300. Robinson BM, Feldman HI, Kobrin SM: Dialyzereuse, in Nissenson AR, Fine RN (eds): Clinical Dialysised 4). New York, NY, McGraw-Hill, 2005, pp 274-291

301. Kaufman AM, Levin NW: Dialyzer reuse, in Dau-irdas J, Blake PG, Ing TS (eds): Handbook of Dialysis (ed). Philadelphia, PA, Lippincott Williams & Wilkins, 2001,p 169-181

302. Murthy BV, Pereira BJ: Effects of reuse on dialyzerunction. Semin Dial 13:282-286, 2000

303. Petersen J, Jani A: Effects of reuse on dialyzerunction. Semin Dial 13:289-290, 2000

304. Fan Q, Liu J, Ebben JP, Collins AJ: Reuse-ssociated mortality in incident hemodialysis patients in thenited States, 2000 to 2001. Am J Kidney Dis 46:661-668,005

305. Collins AJ, Ma JZ, Constantini EG, Everson SE:ialysis unit and patient characteristics associated with

euse practices and mortality: 1989-1993. J Am Soc Nephrol:2108-2117, 1998

306. Sherman RA, Cody RP, Rogers ME, Solanchick JC:he effect of dialyzer reuse on dialysis delivery. Am Jidney Dis 24:924-926, 1994

307. Farrell PC, Eschbach JW, Vizzo JE, Babb AL:emodialyzer reuse: Estimation of area loss from clearanceata. Kidney Int 5:446-450, 1974

308. Garred LJ, Canaud B, Flavier JL, Poux C, Polito-ouloux C, Mion C: Effect of reuse on dialyzer efficacy.rtif Organs 14:80-84, 1990

309. Murthy BV, Sundaram S, Jaber BL, Perrella C,eyer KB, Pereira BJ: Effect of formaldehyde/bleach

eprocessing on in vivo performances of high-efficiency

cN

EbG

Dr

eDK

rBB

tAN

vT

i

dd

PvM

LdA

Po

Ndp

ct

oLl

fo

p(B

bp

Jkc

rT

d

Mh(

ad(

GK

daS

tp

Aw

tA

ip

Cia

ha

Sw

T

1u

2A

Ma9

2

REFERENCES S89

ellulose and high-flux polysulfone dialyzers. J Am Socephrol 9:464-472, 1998

310. Cheung AK, Agodoa LY, Daugirdas JT, et al:ffects of hemodialyzer reuse on clearances of urea andeta2-microglobulin. The Hemodialysis (HEMO) Studyroup. J Am Soc Nephrol 10:117-127, 1999

311. Delmez JA, Weerts CA, Hasamear PD, WindusW: Severe dialyzer dysfunction undetectable by standard

eprocessing validation tests. Kidney Int 36:478-484, 1989312. Deane N, Bemis JA: Multiple Use of Hemodialyz-

rs (a report to the National Institute of Arthritis, Diabetes,igestive and Kidney Disease). New York, NY, Manhattanidney Center, 1981

313. Gotch FA: Solute and water transport and sterilantemoval in reused dialyzers, in Deane N, Wineman RJ,emis JA (eds): Guide to Reprocessing of Hemodialyzers.oston, MA, Nijhoff, 1986, pp 39-61

314. Dialyzers transport properties and germicidal elu-ion, in Seminar on the Reuse of Hemodialyzers andutomated and Manual Methods. New York, NY, Nationalephrology Foundation, 1984

315. Krivitski NM, Kislukhin VV, Snyder JW, et al: Inivo measurement of hemodialyzer fiber bundle volume:heory and validation. Kidney Int 54:1751-1758, 1998

316. Narsipur SS: Measurement of fiber bundle volumen reprocessed dialyzers. Clin Nephrol 61:130-133, 2004

317. Di Filippo S, Manzoni C, Andrulli S, et al: How toetermine ionic dialysance for the online assessment ofelivered dialysis dose. Kidney Int 59:774-782, 2001

318. Steil H, Kaufman AM, Morris AT, Levin NW,olaschegg HD: In vivo verification of an automatic nonin-asive system for real time Kt evaluation. ASAIO J 39:M348-352, 1993319. Lindsay RM, Bene B, Goux N, Heidenheim AP,

andgren C, Sternby J: Relationship between effective ionicialysance and in vivo urea clearance during hemodialysis.m J Kidney Dis 38:565-574, 2001

320. Mercadal L, Ridel C, Petitclerc T: Ionic dialysance:rinciple and review of its clinical relevance for quantificationf hemodialysis efficiency. Hemodial Int 9:111-119, 2005

321. Petitclerc T, Bene B, Jacobs C, Jaudon MC, Goux: Non-invasive monitoring of effective dialysis doseelivered to the haemodialysis patient. Nephrol Dial Trans-lant 10:212-216, 1995

322. Rahmati MA, Rahmati S, Hoenich N, et al: On-linelearance: A useful tool for monitoring the effectiveness ofhe reuse procedure. ASAIO J 49:543-546, 2003

323. Gotch FA: On-line clearance: Advanced methodol-gy to monitor adequacy of dialysis at no cost, in Ronco C,a Greca G (eds): Hemodialysis Technology. Basel, Switzer-

and, Karger, 2002, pp 268-271324. Ing TS, Daugirdas JT: Extractable ethylene oxide

rom cuprammonium cellulose plate dialyzers: Importancef potting compound. ASAIO Trans 32:108-110, 1986

325. Ronco C, Levin NW, Polaschegg HD: Technicalroblems during hemodialysis, in Nissenson AR, Fine RNeds): Dialysis Therapy (ed 3). Philadelphia, PA, Hanley &elfus, 2002, pp 156-165

326. Cheung AK, Leypoldt JK: The hemodialysis mem-ranes: A historical perspective, current state and future
rospect. Semin Nephrol 17:196-213, 1997 b
327. Craddock PR, Fehr J, Dalmasso AP, Brighan KL,acob HS: Hemodialysis leukopenia. Pulmonary vascular leu-ostasis resulting from complement activation by dialyzerellophane membranes. J Clin Invest 59:879-888, 1977

328. Himmelfarb J, Hakim RM: Biocompatibility andisk of infection in haemodialysis patients. Nephrol Dialransplant 9:S138-S144, 1994 (suppl 2)

329. Lonnemann G: Should ultra-pure dialysate be man-atory? Nephrol Dial Transplant 15:S55-S59, 2000 (suppl 1)

330. Smollich BP, Falkenhagen D, Schneidewind J,itzner S, Klinkmann H: Importance of endotoxins in

igh-flux dialysis. Nephrol Dial Transplant 6:S83-S85, 1991suppl 3)

331. Lonnemann G, Koch KM: Beta(2)-microglobulinmyloidosis: Effects of ultrapure dialysate and type ofialyzer membrane. J Am Soc Nephrol 13:S72-S77, 2002suppl 1)

332. Schindler R, Linnenweber S, Schulze M, et al:ene expression of interleukin-1 beta during hemodialysis.idney Int 43:712-721, 1993

333. Churchill DN: Clinical impact of biocompatibleialysis membranes on patient morbidity and mortality: Anppraisal of the evidence. Nephrol Dial Transplant 10:S52-56, 1995 (suppl 10)

334. Hakim RM, Held PJ, Stannard DC, et al: Effect ofhe dialysis membrane on mortality of chronic hemodialysisatients. Kidney Int 50:566-570, 1996

335. Hornberger JC, Chernew M, Petersen J, Garber AM:multivariate analysis of mortality and hospital admissions

ith high-flux dialysis. J Am Soc Nephrol 3:1227-1237, 1992336. Bonomini V, Coli L, Scolari MP, Stefoni S: Struc-

ure of dialysis membranes and long-term clinical outcome.m J Nephrol 15:455-462, 1995

337. Bergamo Collaborative Dialysis Study Group: Acutentradialytic well-being: Results of a clinical trial comparingolysulfone with cuprophan. Kidney Int 40:714-719, 1991

338. Skroeder NR, Jacobson SH, Lins LE, KjellstrandM: Biocompatibility of dialysis membranes is of no

mportance for objective or subjective symptoms during orfter hemodialysis. ASAIO Trans 36:M637-M639, 1990

339. Chenoweth DE: Complement activation duringemodialysis: Clinical observations, proposed mechanisms,nd theoretical implications. Artif Organs 8:281-290, 1984

340. Ivanovich P, Chenoweth DE, Schmidt R, et al:ymptoms and activation of granulocytes and complementith two dialysis membranes. Kidney Int 24:758-763, 1983

341. Chanard J: [Membrane biocompatibility in dialysis:he role of absorption]. Nephrologie 24:359-365, 2003

342. Chanard J, Caudwell V, Valeire J, et al: Kinetics of31I-beta2 microglobulin in hemodialysis patients:Assessmentsing total body counting. Artif Organs 22:574-580, 1998

343. Acchiardo S, Kraus AP Jr, Jennings BR: Beta-microglobulin levels in patients with renal insufficiency.m J Kidney Dis 13:70-74, 1989

344. Hoenich NA, Woffindin C, Matthews JN, GoldfinchE, Turnbull J: Clinical comparison of high-flux cellulose

cetate and synthetic membranes. Nephrol Dial Transplant:60-66, 1994

345. Mrowka C, Schiffl H: Comparative evaluation of beta-microglobulin removal by different hemodialysis mem-
ranes: A six-year follow-up. Nephron 63:368-369, 1993

hI3

hr

ccp

mR2

b

td

4

Waa

reN

id

vn

c3

woC

HP

NN

PDE

U

d

Kd


346. Zingraff J, Beyne P, Urena P, et al: Influence ofaemodialysis membranes on beta 2-microglobulin kinetics:n vivo and in vitro studies. Nephrol Dial Transplant:284-290, 1988

347. Kuchle C, Fricke H, Held E, Schiffl H: High-fluxemodialysis postpones clinical manifestation of dialysis-elated amyloidosis. Am J Nephrol 16:484-488, 1996

348. Koda Y, Nishi S, Miyazaki S, et al: Switch fromonventional to high-flux membrane reduces the risk ofarpal tunnel syndrome and mortality of hemodialysisatients. Kidney Int 52:1096-1101, 1997

349. Cheung AK, Rocco MV, Yan G, et al: Serum beta-2icroglobulin levels predict mortality in dialysis patients:esults of the HEMO Study. J Am Soc Nephrol 17:546-555,006

350. Ivanovich P, Rosner K: A case for cellulosic mem-rane hemodialyzers. Semin Dial 13:409-411, 2000

351. Chandna SM, Farrington K: Residual renal func-ion: Considerations on its importance and preservation inialysis patients. Semin Dial 17:196-201, 2004

352. Ward RA: Ultrapure dialysate. Semin Dial 17:489-97, 2004

353. Devoy MA, Tomson CR, Edmunds ME, Feehally J,alls J: Deterioration in renal function associated with

ngiotensin converting enzyme inhibitor therapy is notlways reversible. J Intern Med 232:493-498, 1992

354. James SH, MeyersAM, Milne FJ, Reinach SG: Partialecovery of renal function in black patients with apparentnd-stage renal failure due to primary malignant hypertension.
ephron 71:29-34, 1995 s
355. Kuno T, Matsumoto K: Clinical benefit of preserv-ng residual renal function in patients after initiation ofialysis. Blood Purif 22:S67-S71, 2004 (suppl 2)

356. Chavers BM, Li S, Collins AJ, Herzog CA: Cardio-ascular disease in pediatric chronic dialysis patients. Kid-ey Int 62:648-653, 2002

357. Sarnak MJ, Levey AS: Cardiovascular disease andhronic renal disease: A new paradigm. Am J Kidney Dis5:S117-S131, 2000 (suppl 1)

358. Reynolds JM, Morton MJ, Garralda ME, Postleth-aite RJ, Goh D: Psychosocial adjustment of adult survivorsf a paediatric dialysis and transplant programme. Arch Dishild 68:104-110, 1993

359. Fischbach M, Edefonti A, Schroder C, Watson A:emodialysis in children: General practical guidelines.ediatr Nephrol 20:1054-1066, 2005

360. Gotch FA: Kinetic modeling in hemodialysis, inissenson AR, Fine RN, Gentile DE (eds): Clinical Dialysis.orwalk, CT, Appleton and Lange, 1995, pp 156-188

361. Yeun JY, Depner TA: Principles of hemodialysis, inereira BJ, Sayegh MH, Blake P (eds): Chronic Kidneyisease, Dialysis, and Transplantation. Philadelphia, PA,lsevier Saunders, 2005, pp 307-340

362. Depner TA: Prescribing Hemodialysis: A Guide torea Modeling. Boston, MA, Kluwer, 1991

363. Sargent JA, Gotch FA: Mathematic modeling ofialysis therapy. Kidney Int 18:S2-10, 1980 (suppl 10)

364. Depner TA, Greene T, Gotch FA, Daugirdas JT,eshaviah PR, Star RA: Imprecision of the hemodialysisose when measured directly from urea removal. Hemodialy-
is Study Group. Kidney Int 55:635-647, 1999

Documents

s 0272638606005543