IV. NKF-K/DOQI CLINICAL PRACTICE GUIDELINES FOR
`ANEMIA OF CHRONIC KIDNEY DISEASE:
`UPDATE 2000
`
`NOTE: The citation for these guidelines should read as follows: National Kidney Foundation. K/DOQI
`Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis 37:S182-S238,
`2001 (suppl 1)
`
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`Acronyms and Abbreviations
`
`Abbreviation
`AIDS
`BSA
`CAPD
`CBC
`CKD
`CRF
`EPO
`ESRD
`FDA
`Fe
`GFR
`HCFA
`Hct
`Hgb
`IP
`IV
`LVH
`PD
`PET
`PMMA
`PTFE
`RBC
`SC
`SLE
`TIBC
`TSAT
`USRDS
`
`Term
`acquired immune deficiency syndrome
`body surface area
`continuous ambulatory peritoneal dialysis
`complete blood count
`chronic kidney disease
`chronic renal failure
`erythropoietin
`end-stage renal disease
`Food and Drug Administration
`iron
`glomerular filtration rate
`Health Care Financing Administration
`hematocrit
`hemoglobin
`intraperitoneal
`intravenous
`left ventricular hypertrophy
`peritoneal dialysis
`positron-emission tomography
`polymethylmethacrylate
`polytetrafluoroethylene
`red blood cell
`subcutaneous
`systemic lupus erythematosus
`total iron binding capacity
`transferrin saturation
`United States Renal Data System
`
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`Introduction
`
`ANORMOCYTIC, normochromic anemia is
`
`present in the majority of patients who
`have a reduction in kidney function.3 The same
`pathophysiology underlies this anemia in all such
`patients. In these guidelines, the term “chronic
`kidney disease” (CKD) is used to describe pa-
`tients with chronically reduced kidney function,
`including those with chronic allograft dysfunc-
`tion, and those in kidney failure who are dialysis
`dependent (administratively termed ESRD).
`When untreated, the anemia of CKD is associ-
`ated with a number of physiologic abnormalities,
`including decreased tissue oxygen delivery and
`utilization,4-8 increased cardiac output, cardiac
`enlargement, ventricular hypertrophy, angina,
`congestive heart failure,9-14 decreased cognition
`and mental acuity,15 altered menstrual cycles,16-18
`decreased nocturnal penile tumescence,19 and
`impaired immune responsiveness.20,21 In addi-
`tion, anemia may play a role in growth retarda-
`tion and decreased intellectual performance in
`pediatric patients.22,23 These abnormalities re-
`duce quality of life24 and opportunities for reha-
`bilitation of CKD patients and decrease patient
`survival.25
`The primary cause of anemia in patients with
`CKD is insufficient production of erythropoietin
`(EPO) by the diseased kidneys.26 Additional fac-
`tors which may cause or contribute to the anemia
`include: iron deficiency,27 either related to or
`independent of blood loss from repeated labora-
`tory testing, needle punctures, blood retention in
`the dialyzer and tubing, or gastrointestinal bleed-
`ing; severe hyperparathyroidism28; acute and
`chronic inflammatory conditions29; aluminum
`toxicity30; folate deficiency31; shortened red blood
`cell survival32; hypothyroidism33; and hemoglo-
`binopathies such as ␣-thalassemia.33 These poten-
`tial contributing factors, if relevant, should be
`considered and addressed.
`Recombinant human erythropoietin (rHuEPO)
`has been used in the treatment of the anemia of
`CKD since 1986.34,35 This recombinant hormone
`has been referred to by several names, including
`rHuEPO, EPO, Epoetin, Epoetin alfa, Epoetin
`beta, and erythropoietin. Epoetin alfa (manufac-
`
`© 2001 by the National Kidney Foundation, Inc.
`0272-6386/01/3701-0105$3.00/0
`doi:10.1053/ajkd.2001.20787
`
`tured by Amgen Inc, Thousand Oaks, CA; distrib-
`uted in the United States as Epogen by Amgen,
`Inc, and as Procrit by Ortho Biotech, Johnson &
`Johnson) is the only approved recombinant hu-
`man erythropoietin (rHuEPO) product available
`in the United States. In addition to Epoetin alfa,
`Epoetin beta, another rHuEPO product with simi-
`lar pharmacologic effects, is available in other
`countries but not the United States. Clinical trials
`with both Epoetin alfa and Epoetin beta have
`been performed within and outside of the United
`States, and the clinical response to both has been
`similar. These guidelines for the management of
`anemia are based upon available literature for
`both products. Since these guidelines may be
`used outside as well as within the United States,
`the term “Epoetin,” when used throughout the
`guidelines, should be assumed to apply to both
`Epoetin alfa and beta. Situations that apply only
`to Epoetin alfa are clearly indicated.
`A new erythropoietin-like molecule, called
`NESP, or novel erythropoietic stimulating pro-
`tein (manufactured by Amgen, Inc), is being
`used in clinical trials and as of July 2000 is being
`reviewed by the FDA. NESP is a glycoprotein
`similar to erythropoietin, but has 5 additional
`amino acids in its primary sequence and two
`extra N-linked carbohydrate side chains, giving
`it a longer plasma half-life. There have been no
`peer-reviewed clinical studies published about
`this molecularly engineered hormone prior to
`January 2000 when the structured literature re-
`view of this update was closed.
`Iron is also essential for hemoglobin forma-
`tion. The iron status of the patient with CKD
`must be assessed and adequate iron stores should
`be available before Epoetin therapy is initiated.
`Iron supplementation usually is essential to as-
`sure an adequate response to Epoetin in patients
`with CKD because the demands for iron by the
`erythroid marrow frequently exceed the amount
`of iron that is immediately available for erythro-
`poiesis (as measured by percent transferrin satu-
`ration) as well as iron stores (as measured by
`serum ferritin). In most cases, intravenous iron
`will be required to achieve and/or maintain ad-
`equate iron stores. In the United States as of July
`1999, the commercially available intravenous
`iron preparations consist of iron dextran, manu-
`
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`INTRODUCTION
`
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`factured as INFeD by Watson Pharmaceutical,
`Inc, Nephrology Division (formerly Schein Phar-
`maceutical, Inc.) and as Dexferrum by American
`Regent Laboratories Inc and sodium ferric glu-
`conate complex in sucrose (referred to in this text
`as iron gluconate), manufactured as Ferrlecit by
`R & D Laboratories and marketed by Watson
`Pharmaceutical, Inc, Nephrology Division (for-
`merly Schein Pharmaceutical, Inc.). An addi-
`tional intravenous iron preparation, iron sucrose
`(Venofer, manufactured by American Regent Lab-
`oratories, Inc), was approved by the FDA in
`November 2000. The molecular weights of the
`two iron dextran compounds differ, and they will
`be considered different compounds.
`Effective treatment of the anemia of CKD
`improves survival,36 decreases morbidity,37,38 and
`increases quality of life.24,39 These 27 clinical
`practice guidelines, which cover the diagnosis,
`work-up, and management of the anemia of
`CKD, as well as possible sequelae related to its
`therapy, provide information that will help care-
`givers accomplish these goals. Unless otherwise
`specified, these guidelines, and their rationales,
`apply to all age groups.
`The potential impact of these guidelines on
`aggregate use of Epoetin is unknown. For ex-
`ample,
`these guidelines recommend a higher
`target Hgb/Hct than is used in current practice
`and than has been recommended on the basis of
`an evaluation of evidence performed by Cana-
`dian nephrologists.40 All other things being equal,
`this recommendation would increase the amount
`of Epoetin required. On the other hand,
`the
`guidelines also have recommended maintenance
`
`of iron stores for the support of erythropoiesis
`that are greater than those maintained in current
`practice. This recommendation should produce
`an Epoetin-sparing effect. In addition, the guide-
`lines recommend that Epoetin be administered
`by the subcutaneous (SC) route to most patients.
`This should provide an improved Hgb/Hct re-
`sponse for the same Epoetin dose, again produc-
`ing an Epoetin-sparing effect. The likely net
`impact of these different effects is difficult to
`predict.
`Some of the practices recommended in these
`guidelines are at variance with current policy of
`the Health Care Financing Administration
`(HCFA) and with information contained in the
`package inserts for Epoetin (Guideline 25) and
`iron dextran (Guideline 9). In these instances, the
`Anemia Work Group believes there is sufficient
`published scientific data to justify its recommen-
`dations. In most circumstances, recommenda-
`tions contained in this document are based on
`evidence from the medical literature.
`When recommendations are based on evi-
`dence, a rationale and supporting literature refer-
`ences are indicated. When recommendations are
`based on opinion in the absence of published
`evidence, the rationales for the recommendations
`are described. In some instances, however, recom-
`mendations are based in whole or in part on the
`opinion of the Work Group members. The eviden-
`tiary basis (published evidence, opinion, or both)
`for all recommendations is clearly indicated,
`along with the rationale (chain of reasoning) for
`each recommendation.
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`I. Anemia Work-Up
`
`GUIDELINE 1
`
`When to Initiate the Work-Up of Anemia
`
`An anemia work-up should be initiated in
`patients with chronic kidney disease (CKD) when
`the:
`● Hgb ⬍11g/dL (Hct is ⬍33%) in pre-meno-
`pausal females and pre-pubertal patients
`(Evidence)
`● Hgb ⬍12g/dL (Hct is ⬍37%) in adult males
`and post-menopausal females (Evidence)
`Rationale Anemia is defined in terms of the
`Hgb or Hct concentration. In this guideline, we
`recommend that a work-up of anemia be initiated
`when the Hgb/ Hct level declines to approxi-
`mately 80% of the mean level for defined healthy,
`normal subgroups (see Table IV-1: eg, in fe-
`males, 80% of Hct 41 ⫽ Hct 33; in males, 80%
`of Hct 47 ⫽ Hct 37). Differences in average
`Hgb/Hct levels between adult men and women
`are likely due to differences in estrogen and
`testosterone production that emerge at puberty,
`but subside after menopause. Anemia is likely to
`be present in individuals when Hgb/ Hct concen-
`trations are below these levels. However, the
`mean Hgb/ Hct in the general population is only
`a statistical benchmark and may not be the best
`indication of anemia in every individual. For
`example, there is a 75% likelihood of anemia in
`an adult female with a Hct of 34% or a Hgb of 11
`g/dL, or in a male with a Hct of 39% or a Hgb of
`12.5 g/dL. Moreover, many individuals have
`Hgb/Hct concentrations which are physiologi-
`cally normal for them, but which would be
`defined as anemia in terms of the general popula-
`tion data. Others have a Hgb/Hct level that may
`be physiologically inadequate for them (eg, pa-
`tients with chronic obstructive pulmonary dis-
`ease), even though it falls within the range con-
`sidered normal for the general population.
`In hemodialysis patients, blood samples to
`document and monitor anemia should be ob-
`tained prior to or immediately upon initiation of
`the dialysis procedure (predialysis). While a Hgb/
`Hct obtained at the end of the dialysis procedure
`(postdialysis) may relate better to a patient’s
`estimated dry weight, experience and data re-
`ported in the literature universally refer to predi-
`alysis Hct and Hgb levels; hence the need to
`
`relate these guidelines to predialysis blood
`samples.
`An automated cell counter should be used to
`determine RBC indices, Hct, and Hgb because
`the results are more easily standardized. Auto-
`mated cell counters also have the advantage of
`providing a total white blood cell count and,
`often, a platelet count.
`Outside of the United States, Hgb, rather than
`Hct, is used to quantify the level of anemia in
`patients with CKD. There are several reasons
`why Hgb is a more accurate, and hence better
`measure of anemia than is Hct. First, whereas
`Hgb is stable when a blood sample is stored at
`room temperature, Hct is not. Specifically, MCV
`(from which Hct is calculated: MCV ⫻ erythro-
`cyte count ⫽ Hct) is stable at room temperature
`for only 8 hours and is stable for only 24 hours
`when a blood sample is refrigerated.41 When a
`blood sample is stored for longer periods of time,
`MCV increases, resulting in increases in calcu-
`lated Hct by as much as 2% to 4%.42 In contrast,
`Hgb remains unchanged when a blood sample is
`stored for the same amount of time under the
`same conditions.42 The sensitivity of Hct to blood
`sample storage conditions is particularly impor-
`tant in light of increased consolidation in the
`dialysis industry in the United States and the
`resulting tendency for dialysis centers that com-
`prise a given dialysis chain to ship blood samples
`over variable distances, under poorly controlled
`conditions, to centralized laboratories.
`A second reason why Hgb is a more accurate
`measure than Hct is that in the presence of
`hyperglycemia, MCV (but not Hgb) is falsely
`elevated, resulting in a false elevation of calcu-
`lated Hct.43,44 Finally, there is greater variability
`across automated analyzers in estimation of the
`number and size of erythrocytes that are in a
`blood sample (and hence in calculation of Hct)
`than there is in measurement of Hgb.45 Data
`comparing the within-run and between-run coef-
`ficient of variation (CV) in automated analyzer
`measurements have shown that these CVs for
`measurement of Hgb are one half and one third
`those for Hct, respectively.46
`For all these reasons, Hgb is a better measure
`to use to monitor and manage anemia in patients
`with CKD than is Hct, particularly given the
`
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`ANEMIA WORK-UP
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`Table IV-1. Mean Normal Values of Hemoglobin and
`Hematocrit for the Healthy, Normal Population47
`
`Age/Gender
`
`Birth
`1 month
`2 to 6 months
`6 months to 2 years
`2 to 6 years
`6 to 12 years
`12 to 18 years (male)
`Menstruating female
`Adult male/post-menopausal
`female
`
`Hemoglobin
`(g/dL)
`
`Hematocrit
`(%)
`
`16.5 ⫾ 3.0
`14.0 ⫾ 4.0
`11.5 ⫾ 2.5
`12.0 ⫾ 1.5
`12.5 ⫾ 1.0
`13.5 ⫾ 2.0
`14.5 ⫾ 1.5
`14.0 ⫾ 2.0
`15.5 ⫾ 2.0
`
`51 ⫾ 9
`43 ⫾ 6
`35 ⫾ 7
`36 ⫾ 3
`37 ⫾ 3
`40 ⫾ 5
`43 ⫾ 6
`41 ⫾ 5
`47 ⫾ 6
`
`growing tendency for dialysis centers to send
`blood samples to outside laboratories, rather than
`measuring Hgb or Hct in-house. In addition, use
`of hemoglobin will allow better comparison of
`anemia management between countries, since
`most other countries use measurement of hemo-
`globin as the standard. Therefore, the Anemia
`Work Group strongly urges that hemoglobin be
`the primary means of quantifying the level of
`anemia in patients with CKD.
`
`GUIDELINE 2
`Anemia Evaluation
`A. Evaluation of anemia should consist of mea-
`the following: (Evi-
`surement of at
`least
`dence)
`
`● Hemoglobin (Hgb) and/or Hematocrit (Hct)
`● Red blood cell (RBC) indices
`● Reticulocyte count
`● Iron parameters:
`—Serum iron
`—Total Iron Binding Capacity (TIBC)
`—Percent transferrin saturation (serum iron ⫻
`100 divided by TIBC) [TSAT]
`—Serum ferritin
`● A test for occult blood in stool
`● B. This work-up should be performed before
`Epoetin therapy is begun. (Opinion)
`Rationale The red blood cell indices, reticulo-
`cyte count (an index of new red blood cell
`formation), and iron parameters are helpful to
`detect the cause of many anemias which are not
`due to EPO deficiency.48 The anemia of CKD is
`generally normocytic and normochromic. Micro-
`cytosis may reflect iron deficiency, aluminum
`
`excess, or certain hemoglobinopathies; macrocy-
`tosis may be associated with vitamin B12 or
`folate deficiency. Macrocytosis can also be asso-
`ciated with iron excess49 and/or Epoetin therapy
`that shifts immature, larger reticulocytes into
`circulation. An elevated reticulocyte count (cor-
`rected for the degree of anemia) suggests that
`active hemolysis may be present, such as in acute
`renal failure due to the hemolytic uremic syn-
`drome. An abnormal white blood cell count and/or
`platelet count may reflect a more generalized
`disturbance of bone marrow function, such as
`that due to malignancy or vasculitis.
`Iron is critical for Hgb synthesis. Conse-
`quently, patients should be carefully evaluated
`for the availability of iron, by measuring the
`serum iron and the TIBC. The serum iron and the
`percent TSAT reflect the amount of iron immedi-
`ately available for hemoglobin synthesis. The
`serum ferritin reflects total body iron stores. A
`low level of either of these indices may indicate
`the need for supplemental iron to support eryth-
`ropoiesis. Iron deficiency has been shown to be
`present in as many as 25% to 37.5% of patients
`presenting with the anemia of CKD50,51 and, if
`treated, can at least temporarily improve or cor-
`rect the anemia52 (Endnote a). Absolute iron
`deficiency in the general population is indicated
`by a TSAT of less than 16%53 and/or a serum
`ferritin value of less than 12 ng/mL.54 However,
`higher values of TSAT and serum ferritin may be
`necessary to achieve an erythropoietic response
`prior to initiation of Epoetin therapy (Endnote a)
`and higher values for these parameters will be
`required to support accelerated erythropoiesis
`stimulated by pharmacological administration of
`Epoetin (see Guideline 6: Target Iron Level). The
`presence of iron deficiency requires a search for
`the cause, which is usually blood loss. A stool
`guaiac test for occult blood is recommended to
`test for gastrointestinal bleeding in patients with
`iron deficiency. Another test for early iron defi-
`ciency is an increase in the number of hypochro-
`mic red blood cells determined by certain auto-
`analyzers,
`ie, Technicon H-1, H-2, and H-3
`Autoanalyzers (Bayer Diagnostics). A hypochro-
`mic red blood cell is defined as an individual cell
`with an Hgb concentration of ⬍28 g/dL. Nor-
`mally, less than 2.5% of red blood cells are
`hypochromic. Although the autoanalyzer used to
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`S188
`
`GUIDELINES FOR ANEMIA OF CHRONIC KIDNEY DISEASE
`
`Fig IV-1. Anemia work-up
`for CKD patients. Asterisk in-
`dicates that laboratory val-
`ues are consistent with un-
`complicated iron deficiency.
`
`perform this test is available in Europe,55,56 it is
`not readily available in the United States at this
`time. Because of the limited availability of these
`autoanalyzers in the United States, this test has
`not been included as part of the guideline. How-
`ever, if such technology becomes routinely avail-
`able in the United States, this test should be
`considered in the work-up of the anemia of
`CKD, particularly since Epoetin therapy may
`increase the likelihood of functional iron defi-
`ciency.
`In CKD patients without iron deficiency, it is
`prudent to screen for common causes of anemia
`other than EPO deficiency (see Guideline 3:
`Erythropoietin Deficiency). Correcting an easily
`reversible cause of anemia makes both clinical
`and economic sense. An example is hypothyroid-
`ism, which is common in the general population,
`
`and can cause a normochromic, normocytic ane-
`mia that can mimic the anemia due to EPO
`deficiency.33 If a reversible cause of anemia is
`not present or has been corrected, and EPO
`deficiency is the likely primary cause of the
`anemia, then anemia should be treated with Epo-
`etin to improve patient quality of life,24 to im-
`prove the various physiological abnormalities
`associated with anemia, to decrease morbidity,37
`to decrease hospitalization,57 and to improve
`patient survival.36
`
`GUIDELINE 3
`
`Erythropoietin Deficiency
`
`If no cause for anemia other than CKD is
`detected, based on the work-up outlined in Guide-
`line 2: Anemia Evaluation, and the serum creati-
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`ANEMIA WORK-UP
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`S189
`
`nine is ⱖ2 mg/dL, anemia is most likely due to
`EPO deficiency. Measurement of serum EPO
`levels usually is not indicated. Fig IV-1 provides
`a guideline for the work-up of anemia in patients
`with a serum creatinine ⱖ2 mg/dL, and for those
`occasional patients with a lower serum creatinine
`and impaired kidney function who have a normo-
`cytic, normochromic anemia. (Evidence)
`Rationale As kidney function declines, the
`likelihood of anemia associated with EPO defi-
`ciency increases because the diseased kidneys
`are unable to produce sufficient quantities of
`EPO. Anemia can develop relatively early in the
`course of CKD, however, and has been associ-
`ated with a serum creatinine as low as 2.0 mg/
`dL,58 and occasionally even lower, particularly
`in individuals with a reduced muscle mass. On
`the other hand, there is a wide range of Hgb/Hct
`levels for any degree of kidney dysfunction. Two
`studies have found a linear relationship between
`Hct and creatinine clearance in pediatric pa-
`tients. A linear relationship between GFR and
`Hct was observed in 48 pediatric patients in one
`study,59 and in 31 CKD pediatric patients in
`another study when the GFR was estimated from
`
`the serum creatinine.60 In these two studies,
`significant anemia was noted when the GFR was
`less than 20 and 35 mL/min/1.73 m2, respec-
`tively.
`The anemia of CKD should not be confused
`with the anemia of chronic disease. In the latter,
`inflammatory cytokines suppress the endoge-
`nous production of EPO and erythropoiesis di-
`rectly.61,62 Measurable levels of circulating cyto-
`kines may be found in stable dialysis patients,
`but,
`in the absence of inflammation, do not
`appear to adversely affect the action of Epo-
`etin63,64 (see Guideline 20: Causes for Inadequate
`Response to Epoetin).
`In patients with non-renal anemia, serum EPO
`levels are usually elevated in an effort to compen-
`sate for the anemia. In patients with impaired
`kidney function and a normochromic, normo-
`cytic anemia, it is rare for the serum EPO level to
`be elevated. Therefore, measurement of EPO
`levels in such patients is not likely to guide
`clinical decision-making or Epoetin therapy.
`Figure IV-1 suggests an approach for evaluat-
`ing anemia in CKD patients who do not have
`gastrointestinal bleeding.
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`II. Target Hemoglobin/Hematocrit
`
`BACKGROUND
`
`The initial patient experience with Epoetin
`came in a Phase I-II clinical trial in hemodialysis
`patients with the anemia of CKD. The target
`maintenance Hct for these patients was 35% to
`40%, ie, at the lower range of normal.35 When
`investigators met to design the Phase III multi-
`center clinical trial, hematologists argued that the
`target Hct should be a normal Hct, while neph-
`rologists proposed a lower level. A compromise
`target Hct of 35% was used in the trial. The final
`Hct levels for the more than 300 patients treated
`with Epoetin in the Phase III trial ranged from
`33% to 38%. The results of this study,65 together
`with those of the Phase I-II clinical trial, were
`submitted to the FDA. The FDA approved Epo-
`etin therapy in June, 1989, but the target Hct
`range recommended by the FDA was only 30%
`to 33%, for reasons that have never been clear.
`The FDA recommendation is probably respon-
`sible for the previously held belief that a target
`Hct of 30% to 33% is medically appropriate. In
`spite of the FDA’s decision in June 1994 to
`widen the target hematocrit range to 30% to
`36%, the USRDS data derived from practice in
`1993 (United States Renal Data System 1996
`Annual Data Report)66 showed that the mean Hct
`for Epoetin-treated dialysis patients in the United
`States was still in the lower end of this target
`range (30.2%), with 43% of patients having Hct
`values ⬍30%. By the end of 1997 the mean Hct
`increased to 32.4% (USRDS 1999 Annual Data
`Report).67
`Most of the initial physiologic and quality of
`life studies of anemic predialysis and dialysis
`patients treated with Epoetin in the United States
`had target Hct values of ⱖ36%. Virtually all
`studies have shown that, with increased Hct,
`there is marked improvement in various physi-
`ologic measures—oxygen utilization [VO2]4-8;
`muscle strength and function68; cognitive and
`brain electrophysiological function15; cardiac
`function9,12-14,69,70; sexual function18; or quality
`of life.24 While two reports have cautioned that a
`target Hct greater than 30% could result in clot-
`ting of various arteries, as well as underdialy-
`sis,71,72 these predictions have failed to material-
`ize or be substantiated. Two other groups of
`investigators reported that there were no differ-
`
`ences in various physiologic and quality of life
`measures between hemodialysis patients with
`Hct (or Hgb) levels of 30% (9 to 10 g/dL) versus
`36% (11 to 12 g/dL).73-75 However, a re-examina-
`tion of these data allows for a different conclu-
`sion: the data are difficult to interpret in one
`study, and some physiological parameters were
`better at the higher Hgb/Hct in the other study
`(Endnote b). The authors of one of these studies
`have recently completed various physiological
`and quality of life studies in a small number of
`hemodialysis patients and have clearly shown
`that a normal Hgb (14 g/dL) is superior to a Hgb
`of 10 g/dL.76-79
`Since 1989, when the FDA established its
`guidelines for the target Hct, and the Health Care
`Financing Administration (HCFA) established a
`policy under which it would not reimburse dialy-
`sis centers for the use of Epoetin when the Hct
`was above 36%, there have been few studies
`published in the United States which examine
`whether a Hct higher than 36% is more beneficial
`than a Hct of 30% in dialysis patients. While
`there are many studies that have shown the
`benefits of Hct values ⱖ36%, in most cases the
`comparison was made to outcomes of patients
`with an Hct level of ⬍25% (see above). In order
`to formulate our recommendations regarding the
`target Hgb/Hct, the Anemia Work Group re-
`viewed only peer-reviewed studies that com-
`pared baseline Hgb/Hct levels of 10 to 11 g/dL/
`30% to 33% (which is the current target level in
`the United States and most other countries) to
`higher values. Review of the literature which
`involved predialysis and dialysis patients within
`and outside the United States showed that, com-
`pared to higher Hgb/Hct values, Hgb/Hct values
`11 g/dL/⬍33% are associated with increased
`morbidity and mortality. In addition, a number of
`recent United States and non-United States stud-
`ies reported in abstracts indicate that patients
`with CKD function better at Hct levels that are
`near normal or normal and that improvement is
`continuous as the Hgb/Hct increases above 10
`g/dL/30% to normal levels. The only exception
`to this has been a study sponsored by Amgen that
`involved more than 1,200 hemodialysis patients
`with documented heart disease. This study was
`discontinued when it appeared that those patients
`
`S190
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`TARGET HEMOGLOBIN/HEMATOCRIT
`
`S191
`
`randomized to a target Hct in the normal range
`(42% ⫾ 3%) were experiencing a greater inci-
`dence (30%, with a confidence interval of 0.9 to
`1.9) of non-fatal myocardial infarctions or death
`than did the control group randomized to a target
`Hct of 30% ⫾ 3%.80 The difference was not
`statistically significant at the time the study was
`terminated, however. Additional studies are
`needed to clarify the relationship between Hgb/
`Hct and outcomes in CKD patients, particularly
`those with heart disease. Such studies should be
`designed to determine the highest Hgb/Hct that
`provides incremental benefits without serious
`side effects. Several multicenter studies address-
`ing this question are in progress outside the
`United States. A study determining whether the
`“prevention” of anemia and its associated ad-
`verse effects could also be of value, since one of
`the aims of treating anemia is to prevent or retard
`the development of heart disease.
`
`GUIDELINE 4
`Target Hemoglobin/Hematocrit for
`Epoetin Therapy
`
`The target range for hemoglobin (hematocrit)
`should be Hgb 11 g/dL (33%) to Hgb 12 g/dL
`(36%). (Evidence) This target is for Epoetin
`therapy and is not an indication for blood transfu-
`sion therapy. (Opinion)
`Rationale A Hgb of 11 g/dL (Hct 33%) is at
`the lower limit of the normal range for pre-
`menopausal females and pre-pubertal patients; a
`Hgb of 12 g/dL (Hct 36%) is just below the lower
`limit of the normal range for adult males and
`post-menopausal females (see Guideline 1: When
`to Initiate the Work-up of Anemia). Because the
`anemia literature in CKD patients does not distin-
`guish between sexes, subsequent Hgb/Hct levels
`will apply to both males and females.
`There are several pieces of evidence suggest-
`ing that patient outcomes are worse when the
`Hgb is ⱕ10 g/dL (Hct ⱕ30%):
`1. Survival of dialysis patients declines as the
`Hct decreases below a range of 30% to 33%.25,81
`Survival was also shorter in dialysis patients
`with chronic glomerulonephritis whose mean
`Hgb level was 9.9 g/dL, compared to patients
`with polycystic kidney disease whose mean Hgb
`level was 11.3 g/dL.82 Whereas one study failed
`to note any improved survival at a Hgb ⬎11 g/dL
`
`compared to an Hgb 10 to 11 g/dL,83 several
`other reports have shown improved survival at
`higher Hgb/Hct levels. Survival was improved in
`Italian hemodialysis patients when the Hct ex-
`ceeded 32%, either spontaneously or following
`Epoetin therapy, when compared to Hct ⬍32%,84
`and in the United States an Hct of 33% to 36%
`reduced the risk of death from any cause by 10%
`when compared to patients whose mean Hct was
`30% to 33%.85 Survival has been noted in one
`study to be better in patients with cardiac disease
`who attained and maintained a normal Hct com-
`pared to similar patients who did not attain and
`maintain a normal Hct.80 In fact, within both the
`normal Hct group and the control group, the
`mortality decreased at higher Hct levels.80 In
`those 200 patients who achieved and maintained
`a normal Hct for 6 months, mortality decreased
`to approximately 15% per year, versus 40% per
`year in those maintained at an Hct of 30%. There
`were no convincing factors that appeared to
`explain why those patients that did not achieve
`and stabilize at a normal Hct had a greater
`incidence of non-fatal myocardial infarctions or
`death than did the control group.80
`2. Left ventricular hypertrophy (LVH) is more
`likely in CKD patients with anemia (Hct
`ⱕ33%)86-88 and in patients with ESRD89; in such
`patients the risk of death is increased 2.9-fold
`(Endnote c).90 Partial correction of anemia (Hgb
`6.3 ⫾ 0.8 to 11.4 ⫾ 1.5 g/dL) with Epoetin
`resulted in partial regression of LVH in dialysis-
`dependent patients.91 Angina was significantly
`decreased in patients with progressive CKD when
`Epoetin therapy increased the Hct to 31% ⫾ 4%
`versus 23% ⫾ 4%.92
`3. Quality of life either is not improved, or
`improved only slightly, when the Hgb/Hct is
`increased from 8 g/dL/25% to a level no higher
`than 9 to 10 g/dL/28% to 30%.93-95 However,
`quality of life of dialysis patients, as assessed by
`standardized patient questionnaires, increases as
`the Hgb/Hct increases above 10 to ⬎12 g/dL and
`30% to ⬎36%.96-98 When the results of the Am-
`gen Phase III (mean Hct 35%) and Phase IV
`(mean Hct 30%) studies were compared, it was
`concluded that patients with Hct levels of 35%
`had better quality of life as measured by Karnof-
`sky scores than those maintained at a Hct of
`30%.99 Both quality of life and various physiolog-
`
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`S192
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`GUIDELINES FOR ANEMIA OF CHRONIC KIDNEY DISEASE
`
`ical parameters in predialysis patients have been
`shown to be significantly better at a Hct of 36%
`to 39% than at 27% to 29%.100-107
`4. In hemodialysis patients, exercise capacity
`(VO2) increased when the Hct increased from
`30% to 35% to 40%.108
`5. In hemodialysis patients, the incidence of
`hospitalization was lower when the Hct was 33%
`to 36% in comparison to patients with lower Hct
`values.109
`6. There are a number of studies in dialysis
`patients (reported initially only in abstracts) that
`indicate that quality of life, maximum exercise
`capacity, number of meters walked in 6 minutes,
`cardiac output, cognitive function, amino acid
`levels, sleep dysfunction with daytime sleepi-
`ness, insulin resistance with hyperlipidemia, and
`survival
`improved when a normal Hct was
`achieved,76-78,110-118 and that there were no ad-
`verse effects observed at a normal Hct.110,111
`Several of these studies have now been pub-
`lished in peer review journals, and demonstrate
`that a normal Hgb/Hct is associated with better
`physical performance,79 better cognitive func-
`tion,119 improved brain oxygen supply,120 and
`improved sleep patterns121 compared to lower
`Hgb/Hct levels.
`Studies in patients with anemia due to condi-
`tions other than CKD als