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American Journal of Kidney Diseases

IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000

        Acronyms and abbreviations

        Tabled 1
        AbbreviationTerm
        AIDSacquired immune deficiency syndrome
        BSAbody surface area
        CAPDcontinuous ambulatory peritoneal dialysis
        CBCcomplete blood count
        CKDchronic kidney disease
        CRFchronic renal failure
        EPOerythropoietin
        ESRDend-stage renal disease
        FDAFood and Drug Administration
        Feiron
        GFRglomerular filtration rate
        HCFAHealth Care Financing Administration
        Hcthematocrit
        Hgbhemoglobin
        IPintraperitoneal
        IVintravenous
        LVHleft ventricular hypertrophy
        PDperitoneal dialysis
        PETpositron-emission tomography
        PMMApolymethylmethacrylate
        PTFEpolytetrafluoroethylene
        RBCred blood cell
        SCsubcutaneous
        SLEsystemic lupus erythematosus
        TIBCtotal iron binding capacity
        TSATtransferrin saturation
        USRDSUnited States Renal Data System

        Introduction

        A normocytic, normochromic anemia is present in the majority of patients who have a reduction in kidney function.
        • Eschbach JW
        • Adamson JW
        Anemia of end-stage renal disease (ESRD).
        The same pathophysiology underlies this anemia in all such patients. In these guidelines, the term “chronic kidney disease” (CKD) is used to describe patients with chronically reduced kidney function, including those with chronic allograft dysfunction, and those in kidney failure who are dialysis dependent (administratively termed ESRD). When untreated, the anemia of CKD is associated with a number of physiologic abnormalities, including decreased tissue oxygen delivery and utilization,
        • Horina JH
        • Schwaberger G
        • Brussee H
        • Sauseng-Fellegger G
        • Holzer H
        • Krejs GJ
        Increased red cell 2,3-diphosphoglycerate levels in haemodialysis patients treated with erythropoietin.
        • Robertson HT
        • Haley NR
        • Guthrie M
        • Cardenas D
        • Eschbach JW
        • Adamson JW
        Recombinant erythropoietin improves exercise capacity in anemic hemodialysis patients.
        • Braumann KM
        • Nonnast-Daniel B
        • Boning D
        • Bocker A
        • Frei U
        Improved physical performance after treatment of renal anemia with recombinant human erythropoietin.
        • Teehan B
        • Sigler MH
        • Brown JM
        • Benz RL
        • Gilgore GS
        • Schleifer CR
        • Morgan CM
        • Gabuzda TG
        • Kelly JJ
        • Figueroa WG
        • Peterson DD
        Hematologic and physiologic studies during correction of anemia with recombinant human erythropoietin in predialysis patients.
        • Mayer G
        • Thum J
        • Cada EM
        • Stummvoll HK
        • Graf H
        Working capacity is increased following recombinant human erythropoietin treatment.
        increased cardiac output, cardiac enlargement, ventricular hypertrophy, angina, congestive heart failure,
        • Wizemann V
        • Schafer R
        • Kramer W
        Follow-up of cardiac changes induced by anemia compensation in normotensive hemodialysis patients with left-ventricular hypertrophy.
        • Harnett JD
        • Foley RN
        • Kent GM
        • Barre PE
        • Murray D
        • Parfrey PS
        Congestive heart failure in dialysis patients: Prevalence, incidence, prognosis and risk factors.
        • Wizemann V
        • Kaufmann J
        • Kramer W
        Effect of erythropoietin on ischemia tolerance in anemic hemodialysis patients with confirmed coronary artery disease.
        • Cannella G
        • La Canna G
        • Sandrini M
        • Gaggiotti M
        • Nordio G
        • Movilli E
        • Maiorca R
        Renormalization of high cardiac output and of left ventricular size following long-term recombinant human erythropoietin treatment of anemic dialyzed uremic patients.
        • Macdougall IC
        • Lewis NP
        • Saunders MJ
        • Cochlin DL
        • Davies ME
        • Hutton RD
        • Fox KAA
        • Coles GA
        • Williams JD
        Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin.
        • Pascual J
        • Teruel JL
        • Moya JL
        • Liano F
        • Jimenez-Mena M
        • Ortuno J
        Regression of left ventricular hypertrophy after partial correction of anemia with erythropoietin in patients on hemodialysis: A prospective study.
        decreased cognition and mental acuity,
        • Wolcott DL
        • Marsh JT
        • La Rue A
        • Carr C
        • Nissenson AR
        Recombinant human erythropoietin treatment may improve quality of life and cognitive function in chronic hemodialysis patients.
        altered menstrual cycles,
        • Eschbach JW
        • Adamson JW
        Recombinant human erythropoietin: Implications for nephrology.
        • Ramirez G
        • Bittle PA
        • Sanders H
        • Rabb HAA
        • Bercu BB
        The effects of corticotropin and growth hormone releasing hormones on their respective secretory axes in chronic hemodialysis patients before and after correction of anemia with recombinant human erythropoietin.
        • Schaefer RM
        • Kokot F
        • Heidland A
        Impact of recombinant erythropoietin on sexual function in hemodialysis patients.
        decreased nocturnal penile tumescence,
        • Sobh MA
        • Abd el Hamid IA
        • Atta MG
        • Refaie AF
        Effect of erythropoietin on sexual potency in chronic haemodialysis patients: A preliminary study.
        and impaired immune responsiveness.
        • Gafter U
        • Kalechman Y
        • Orlin JB
        • Levi J
        • Sredni B
        Anemia of uremia is associated with reduced in vitro cytokine secretion: Immunopotentiating activity of red blood cells.
        • Vanholder R
        • Van Biesen W
        • Ringoir S
        Contributing factors to the inhibition of phagocytosis in hemodialyzed patients.
        In addition, anemia may play a role in growth retardation and decreased intellectual performance in pediatric patients.
        • Scigalla P
        • Bonzel KE
        • Bulla M
        • Burghard R
        • Dippel J
        • Geisert J
        • Leumann E
        • von Lilien T
        • Muller-Wiefel DE
        • Offner G
        • Pistor K
        • Zoellner K
        Therapy of renal anemia with recombinant human erythropoietin in children with end-stage renal disease.
        • Burke JR
        Low-dose subcutaneous recombinant erythropoietin in children with chronic renal failure.
        These abnormalities reduce quality of life
        • Evans RW
        • Rader B
        • Manninen DL
        • Cooperative Multicenter EPO
        • Clinical Trial Group
        The quality of life of hemodialysis recipients treated with recombinant human erythropoietin.
        and opportunities for rehabilitation of CKD patients and decrease patient survival.
        • Lowrie EG
        • Ling J
        • Lew NL
        • Yiu Y
        The relative contribution of measured variables to death risk among hemodialysis patients.
        The primary cause of anemia in patients with CKD is insufficient production of erythropoietin (EPO) by the diseased kidneys.
        • Eschbach JW
        The anemia of chronic renal failure: Pathophysiology and the effects of recombinant erythropoietin.
        Additional factors which may cause or contribute to the anemia include: iron deficiency,
        • Parker PA
        • Izard MW
        • Maher JF
        Therapy of iron deficiency anemia in patients on maintenance dialysis.
        either related to or independent of blood loss from repeated laboratory testing, needle punctures, blood retention in the dialyzer and tubing, or gastrointestinal bleeding; severe hyperparathyroidism
        • Potasman I
        • Better OS
        The role of secondary hyperparathyroidism in the anemia of chronic renal failure.
        ; acute and chronic inflammatory conditions
        • Adamson JW
        • Eschbach JW
        Management of the anaemia of chronic renal failure with recombinant erythropoietin.
        ; aluminum toxicity
        • Kaiser L
        • Schwartz KA
        Aluminum-induced anemia.
        ; folate deficiency
        • Hampers CL
        • Streiff R
        • Nathan DG
        • Snyder D
        • Merrill JP
        Megaloblastic hematopoiesis in uremia and in patients on long-term hemodialysis.
        ; shortened red blood cell survival
        • Eschbach JW
        • Funk DD
        • Adamson J
        • Kuhn K
        • Scribner BH
        • Finch CA
        Erythropoiesis in patients with renal failure undergoing chronic dialysis.
        ; hypothyroidism
        • Eschbach JW
        The future of r-HuEPO.
        ; and hemoglobinopathies such as α-thalassemia.
        • Eschbach JW
        The future of r-HuEPO.
        These potential 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.
        • Winearls CG
        • Oliver DO
        • Pippard MJ
        • Reid C
        • Downing MR
        • Cotes PM
        Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis.
        • Eschbach JW
        • Egrie JC
        • Downing MR
        • Browne JK
        • Adamson JW
        Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: Results of a combined phase I and II clinical trial.
        This recombinant hormone has been referred to by several names, including rHuEPO, EPO, Epoetin, Epoetin alfa, Epoetin beta, and erythropoietin. Epoetin alfa (manufactured by Amgen Inc, Thousand Oaks, CA; distributed in the United States as Epogen by Amgen, Inc, and as Procrit by Ortho Biotech, Johnson & Johnson) is the only approved recombinant human erythropoietin (rHuEPO) product available in the United States. In addition to Epoetin alfa, Epoetin beta, another rHuEPO product with similar 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 protein (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 review of this update was closed.
        Iron is also essential for hemoglobin formation. 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 assure 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 erythropoiesis (as measured by percent transferrin saturation) as well as iron stores (as measured by serum ferritin). In most cases, intravenous iron will be required to achieve and/or maintain adequate iron stores. In the United States as of July 1999, the commercially available intravenous iron preparations consist of iron dextran, manufactured as INFeD by Watson Pharmaceutical, Inc, Nephrology Division (formerly Schein Pharmaceutical, Inc.) and as Dexferrum by American Regent Laboratories Inc and sodium ferric gluconate 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 (formerly Schein Pharmaceutical, Inc.). An additional intravenous iron preparation, iron sucrose (Venofer, manufactured by American Regent Laboratories, 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,
        • Mocks J
        • Franke W
        • Ehmer B
        • Scigalla P
        • Quarder O
        Analysis of safety database for long-term epoetin-beta treatment. A meta-analysis covering 3697 patients.
        decreases morbidity,
        • Consensus Development Conference Panel
        Morbidity and mortality of renal dialysis: An NIH consensus conference statement.
        • Grutzmacher P
        • Scheuermann E
        • Low I
        • Bergmann M
        • Rauber K
        • Baum R
        • Heuser J
        • Schoeppe W
        Correction of renal anaemia by recombinant human erythropoietin: Effects on myocardial function.
        and increases quality of life.
        • Evans RW
        • Rader B
        • Manninen DL
        • Cooperative Multicenter EPO
        • Clinical Trial Group
        The quality of life of hemodialysis recipients treated with recombinant human erythropoietin.
        • Delano BG
        Improvements in quality of life following treatment with r-HuEPO in anemic hemodialysis patients.
        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 caregivers 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 example, 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 Canadian nephrologists.
        • Muirhead N
        • Bargman J
        • Burgess E
        • Jindal KK
        • Levin A
        • Nolin L
        • Parfrey P
        Evidence-based recommendations for the clinical use of recombinant human erythropoietin.
        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 guidelines recommend that Epoetin be administered by the subcutaneous (SC) route to most patients. This should provide an improved Hgb/Hct response for the same Epoetin dose, again producing 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 recommendations. In most circumstances, recommendations contained in this document are based on evidence from the medical literature.
        When recommendations are based on evidence, a rationale and supporting literature references 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, recommendations are based in whole or in part on the opinion of the Work Group members. The evidentiary basis (published evidence, opinion, or both) for all recommendations is clearly indicated, along with the rationale (chain of reasoning) for each recommendation.

        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:
        • 1.
          Hgb <11g/dL (Hct is <33%) in pre-menopausal females and pre-pubertal patients (Evidence )
        • 2.
          Hgb <12g/dL (Hct is <37%) in adult males and post-menopausal females (Evidence )
        Table IV1. Mean Normal Values of Hemoglobin and Hematocrit for the Healthy, Normal Population
        Age/GenderHemoglobin (g/dL)Hematocrit (%)
        Birth16.5 ± 3.051 ± 9
        1 month14.0 ± 4.043 ± 6
        2 to 6 months11.5 ± 2.535 ± 7
        6 months to 2 years12.0 ± 1.536 ± 3
        2 to 6 years12.5 ± 1.037 ± 3
        6 to 12 years13.5 ± 2.040 ± 5
        12 to 18 years (male)14.5 ± 1.543 ± 6
        Menstruating female14.0 ± 2.041 ± 5
        Adult male/post-menopausal female15.5 ± 2.047 ± 6
        In hemodialysis patients, blood samples to document and monitor anemia should be obtained 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 reported in the literature universally refer to predialysis 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. Automated 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 × erythrocyte count = Hct) is stable at room temperature for only 8 hours and is stable for only 24 hours when a blood sample is refrigerated.
        • Henry JB
        Methods Hematology: Basic Methodology.
        When a blood sample is stored for longer periods of time, MCV increases, resulting in increases in calculated Hct by as much as 2% to 4%.
        • Britten GM
        • Brecher G
        • Johnson CA
        • Elashoff RM
        Stability of blood in commonly used anticoagulants.
        In contrast, Hgb remains unchanged when a blood sample is stored for the same amount of time under the same conditions.
        • Britten GM
        • Brecher G
        • Johnson CA
        • Elashoff RM
        Stability of blood in commonly used anticoagulants.
        The sensitivity of Hct to blood sample storage conditions is particularly important in light of increased consolidation in the dialysis industry in the United States and the resulting tendency for dialysis centers that comprise 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 calculated Hct.
        • Holt JT
        • DeWandler MJ
        • Aevan DA
        Spurious elevation of electronically determined mean corpuscular volume and hematocrit caused by hyperglycemia.
        • Van Duijniioven HLP
        • Treskes M
        Marked interference of hyperglycemia in measurements of mean (red) cell volume by Technicon H analyzers.
        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.
        • Paterakis GS
        • Laoutaris NP
        • Alexia SV
        • Siourounis PV
        • Stamulakatou AK
        • Premetis EE
        • Sakollariou CH
        • Terzoglou GN
        • Papassotiriou IG
        • Loukopoulos D
        The effect of red cell shape on the measurement of red cell volume. A proposed method for the comparative assessment of this effect among various haematology analysers.
        Data comparing the within-run and between-run coefficient 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.
        • Fraser CG
        • Wilkinson SP
        • Neville RG
        • Knox JDE
        • King JF
        • MacWalters RS
        Biologic variation of common hematologic laboratory quantities in the elderly.
        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 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 hemoglobin 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 measurement of at least the following: (Evidence )
        • 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, reticulocyte 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.
        • Hillman RS
        • Finch CA
        Clinical approach—Anemia.
        The anemia of CKD is generally normocytic and normochromic. Microcytosis may reflect iron deficiency, aluminum excess, or certain hemoglobinopathies; macrocytosis may be associated with vitamin B12 or folate deficiency. Macrocytosis can also be associated with iron excess
        • Gokal R
        • Weatherall DJ
        • Bunch C
        Iron induced increase in red cell size in haemodialysis patients.
        and/or Epoetin therapy that shifts immature, larger reticulocytes into circulation. An elevated reticulocyte count (corrected for the degree of anemia) suggests that active hemolysis may be present, such as in acute renal failure due to the hemolytic uremic syndrome. 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. Consequently, 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 immediately 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 erythropoiesis. Iron deficiency has been shown to be present in as many as 25% to 37.5% of patients presenting with the anemia of CKD
        • Hutchinson F
        • Jones WJ
        A cost-effectiveness analysis of anemia screening before erythropoietin in patients with end-stage renal disease.
        • Loge JP
        • Lange RD
        • Moore CV
        Characterization of the anemia associated with chronic renal insufficiency.
        and, if treated, can at least temporarily improve or correct the anemia
        • Silverberg DS
        • Iaina A
        • Peer G
        • Kaplan E
        • Levi BA
        • Frank N
        • Steinbruch S
        • Blum M
        Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.
        (Endnote a). Absolute iron deficiency in the general population is indicated by a TSAT of less than 16%
        • Bainton DF
        • Finch CA
        The diagnosis of iron deficiency anemia.
        and/or a serum ferritin value of less than 12 ng/mL.
        • Jacobs A
        • Worwood M
        Ferritin in serum: Clinical and biochemical implications.
        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 deficiency is an increase in the number of hypochromic red blood cells determined by certain autoanalyzers, ie, Technicon H-1, H-2, and H-3 Autoanalyzers (Bayer Diagnostics). A hypochromic red blood cell is defined as an individual cell with an Hgb concentration of <28 g/dL. Normally, less than 2.5% of red blood cells are hypochromic. Although the autoanalyzer used to perform this test is available in Europe,
        • Macdougall IC
        • Cavill I
        • Hulme B
        • Bain B
        • McGregor E
        • McKay P
        • Sanders E
        • Coles GA
        • Williams JD
        Detection of functional iron deficiency during erythropoietin treatment: A new approach.
        • Schaefer RM
        • Schaefer L
        The hypochromic red cell: A new parameter for monitoring of iron supplementation during rhEPO therapy.
        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. However, if such technology becomes routinely available 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 deficiency.
        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 hypothyroidism, which is common in the general population, and can cause a normochromic, normocytic anemia that can mimic the anemia due to EPO deficiency.
        • Eschbach JW
        The future of r-HuEPO.
        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 Epoetin to improve patient quality of life,
        • Evans RW
        • Rader B
        • Manninen DL
        • Cooperative Multicenter EPO
        • Clinical Trial Group
        The quality of life of hemodialysis recipients treated with recombinant human erythropoietin.
        to improve the various physiological abnormalities associated with anemia, to decrease morbidity,
        • Consensus Development Conference Panel
        Morbidity and mortality of renal dialysis: An NIH consensus conference statement.
        to decrease hospitalization,
        • Churchill DN
        • Muirhead N
        • Goldstein M
        • Posen G
        • Fay W
        • Beecroft ML
        • Gorman J
        • Wayne Taylor D
        Effect of recombinant human erythropoietin on hospitalization of hemodialysis patients.
        and to improve patient survival.
        • Mocks J
        • Franke W
        • Ehmer B
        • Scigalla P
        • Quarder O
        Analysis of safety database for long-term epoetin-beta treatment. A meta-analysis covering 3697 patients.

        Guideline 3: Erythropoietin deficiency

        Figure thumbnail gr1
        Fig IV1. Anemia work-up for CKD patients. Asterisk indicates that laboratory values are consistent with uncomplicated iron deficiency.
        Rationale As kidney function declines, the likelihood of anemia associated with EPO deficiency 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 associated with a serum creatinine as low as 2.0 mg/dL,
        • Hakim RM
        • Lazarus JM
        Biochemical parameters in chronic renal failure.
        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 patients. A linear relationship between GFR and Hct was observed in 48 pediatric patients in one study,
        • Chandra M
        • Clemons GK
        • McVicar MI
        Relation of serum erythropoietin levels to renal excretory function: Evidence for lowered set point for erythropoietin production in chronic renal failure.
        and in 31 CKD pediatric patients in another study when the GFR was estimated from the serum creatinine.
        • McGonigle RJS
        • Boineau FG
        • Beckman B
        • Ohene-Frempong K
        • Lewy JE
        • Shadduck RK
        Erythropoietin and inhibitors of in vitro erythropoiesis in the development of anemia in children with renal disease.
        In these two studies, significant anemia was noted when the GFR was less than 20 and 35 mL/min/1.73 m2, respectively.
        The anemia of CKD should not be confused with the anemia of chronic disease. In the latter, inflammatory cytokines suppress the endogenous production of EPO and erythropoiesis directly.
        • Cleaveland CR
        Anemia of chronic disease: A misnomer.
        • Krantz SB
        Pathogenesis and treatment of anemia of chronic disease.
        Measurable levels of circulating cytokines may be found in stable dialysis patients, but, in the absence of inflammation, do not appear to adversely affect the action of Epoetin
        • Pereira BJG
        Balance between pro-inflammantory cytokines and their specific inhibitors in patients on dialysis.
        • Eschbach JW
        • Haley NR
        • Egrie JC
        • Adamson JW
        A comparison of the responses to recombinant human erythropoietin in normal and uremic subjects.
        (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 compensate for the anemia. In patients with impaired kidney function and a normochromic, normocytic 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 evaluating anemia in CKD patients who do not have gastrointestinal bleeding.

        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.
        • Eschbach JW
        • Egrie JC
        • Downing MR
        • Browne JK
        • Adamson JW
        Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: Results of a combined phase I and II clinical trial.
        When investigators met to design the Phase III multicenter clinical trial, hematologists argued that the target Hct should be a normal Hct, while nephrologists 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,
        • Eschbach JW
        • Abdulhadi MH
        • Browne JK
        • Delano BG
        • Downing MR
        • Egrie JC
        • Evans RW
        • Friedman EA
        • Graber SE
        • Haley NR
        • Korbet S
        • Krantz SB
        • Lundin AP
        • Nissenson AR
        • Ogden DA
        • Paganini EP
        • Rader B
        • Rutsky EA
        • Stivelman J
        • Stone WJ
        • Teschan P
        • Van Stone JC
        • Van Wyck DB
        • Zuckerman K
        • Adamson J
        Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial.
        together with those of the Phase I-II clinical trial, were submitted to the FDA. The FDA approved Epoetin 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 responsible 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)
        • US Renal Data System
        The USRDS Dialysis Morbidity and Mortality Study (Wave 1).
        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).
        • Wolfe R
        • Port F
        • Wess R
        • Bloembergen W
        • Hirth R
        • Young E
        • Ojo A
        • Strawderman R
        • Parekh R
        • Stack A
        • Tedeschi P
        • Hulbert-Shearon T
        • Ashby V
        • Callard S
        • Hanson J
        • Jain A
        • Meyers-Purkiss A
        • Roys E
        • Brown P
        • Wheeler J
        • Jones C
        • Greer J
        • Agoda L
        Introduction to the Excerpts From the United States Renal Data System 1999 Annual Data Report.
        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 ≥36%. Virtually all studies have shown that, with increased Hct, there is marked improvement in various physiologic measures—oxygen utilization [VO2 ]
        • Horina JH
        • Schwaberger G
        • Brussee H
        • Sauseng-Fellegger G
        • Holzer H
        • Krejs GJ
        Increased red cell 2,3-diphosphoglycerate levels in haemodialysis patients treated with erythropoietin.
        • Robertson HT
        • Haley NR
        • Guthrie M
        • Cardenas D
        • Eschbach JW
        • Adamson JW
        Recombinant erythropoietin improves exercise capacity in anemic hemodialysis patients.
        • Braumann KM
        • Nonnast-Daniel B
        • Boning D
        • Bocker A
        • Frei U
        Improved physical performance after treatment of renal anemia with recombinant human erythropoietin.
        • Teehan B
        • Sigler MH
        • Brown JM
        • Benz RL
        • Gilgore GS
        • Schleifer CR
        • Morgan CM
        • Gabuzda TG
        • Kelly JJ
        • Figueroa WG
        • Peterson DD
        Hematologic and physiologic studies during correction of anemia with recombinant human erythropoietin in predialysis patients.
        • Mayer G
        • Thum J
        • Cada EM
        • Stummvoll HK
        • Graf H
        Working capacity is increased following recombinant human erythropoietin treatment.
        ; muscle strength and function
        • Guthrie M
        • Cardenas D
        • Eschbach JW
        • Haley NR
        • Robertson HT
        • Evans RW
        Effects of erythropoietin on strength and functional status of patients on hemodialysis.
        ; cognitive and brain electrophysiological function
        • Wolcott DL
        • Marsh JT
        • La Rue A
        • Carr C
        • Nissenson AR
        Recombinant human erythropoietin treatment may improve quality of life and cognitive function in chronic hemodialysis patients.
        ; cardiac function
        • Wizemann V
        • Schafer R
        • Kramer W
        Follow-up of cardiac changes induced by anemia compensation in normotensive hemodialysis patients with left-ventricular hypertrophy.
        • Cannella G
        • La Canna G
        • Sandrini M
        • Gaggiotti M
        • Nordio G
        • Movilli E
        • Maiorca R
        Renormalization of high cardiac output and of left ventricular size following long-term recombinant human erythropoietin treatment of anemic dialyzed uremic patients.
        • Macdougall IC
        • Lewis NP
        • Saunders MJ
        • Cochlin DL
        • Davies ME
        • Hutton RD
        • Fox KAA
        • Coles GA
        • Williams JD
        Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin.
        • Pascual J
        • Teruel JL
        • Moya JL
        • Liano F
        • Jimenez-Mena M
        • Ortuno J
        Regression of left ventricular hypertrophy after partial correction of anemia with erythropoietin in patients on hemodialysis: A prospective study.
        • Fellner SK
        • Lang RM
        • Neumann A
        • Korcarz C
        • Borow KM
        Cardiovascular consequences of correction of the anemia of renal failure with erythropoietin.
        • Low-Friedrich I
        • Grutzmacher P
        • Marz W
        • Bergmann M
        • Schoeppe W
        Long-term echocardiographic examinations in chronic hemodialysis patients substituted with recombinant human erythropoietin.
        ; sexual function
        • Schaefer RM
        • Kokot F
        • Heidland A
        Impact of recombinant erythropoietin on sexual function in hemodialysis patients.
        ; or quality of life.
        • Evans RW
        • Rader B
        • Manninen DL
        • Cooperative Multicenter EPO
        • Clinical Trial Group
        The quality of life of hemodialysis recipients treated with recombinant human erythropoietin.
        While two reports have cautioned that a target Hct greater than 30% could result in clotting of various arteries, as well as underdialysis,
        • Junor BJR
        Hematocrit above 30% in continuous ambulatory peritoneal dialysis patients treated with erythropoietin is harmful.
        • Shinaberger JH
        • Miller JH
        • Gardner PW
        Erythropoietin alert: Risks of high hematocrit hemodialysis.
        these predictions have failed to materialize or be substantiated. Two other groups of investigators reported that there were no differences 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).
        • Canadian Erythropoietin Study Group
        Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis.
        • McMahon LP
        • Johns JA
        • McKenzie A
        • Austin M
        • Fowler R
        • Dawborn JK
        Haemodynamic changes and physical performance at comparative levels of haemoglobin after long-term treatment with recombinant erythropoietin.
        • McMahon LP
        • Dawborn JK
        Subjective quality of life assessment in hemodialysis patients at different levels of hemoglobin following use of recombinant human erythropoietin.
        However, a re-examination of these data allows for a different conclusion: 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.
        • Sangkabutra T
        • McKenna MJ
        • Mason K
        • Crankshaw DP
        • McMahon LP
        Effects of K+, pH, and different haemoglobin levels on maximal exercise performanace in haemodialysis patients.
        • Mason K
        • Skinner S
        • Sangkabutra T
        • Burge C
        • McMahon L
        Effects of erythropoietin on cardiac mass and function, ambulatory blood pressure and blood volumes at comparative levels of haemoglobin.
        • Mason K
        • McMahon LP
        Normalization of haemoglobin in haemodialysis patients: A comparative study.
        • McMahon LP
        • McKenna MJ
        • Sangkabutra T
        • Mason K
        • Sostaric S
        • Skinner SL
        • Burge C
        • Murphy B
        • Crankshaw D
        Physical performance and associated electrolyte changes after haemoglobin normalization: A comparative study in haemodialysis patients.
        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 dialysis 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 ≥36%, 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 reviewed only peer-reviewed studies that compared 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, compared 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 studies 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 randomized to a target Hct in the normal range (42% ± 3%) were experiencing a greater incidence (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%.
        • Besarab A
        • Bolton WK
        • Browne JK
        • Egrie JC
        • Nissenson AR
        • Okamoto DM
        • Schwab SJ
        • Goodkin DA
        The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and Epoetin.
        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 addressing this question are in progress outside the United States. A study determining whether the “prevention” of anemia and its associated adverse 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 transfusion 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 distinguish between sexes, subsequent Hgb/Hct levels will apply to both males and females.
        There are several pieces of evidence suggesting that patient outcomes are worse when the Hgb is ≤10 g/dL (Hct ≤30%):
        • 1.
          Survival of dialysis patients declines as the Hct decreases below a range of 30% to 33%.
          • Lowrie EG
          • Ling J
          • Lew NL
          • Yiu Y
          The relative contribution of measured variables to death risk among hemodialysis patients.
          • Foley RN
          • Parfrey PS
          • Harnett JD
          • Kent GM
          • Murray DC
          • Barre PE
          The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease.
          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.
          • Ritz E
          • Zeier M
          • Schneider P
          • Jones E
          Cardiovascular mortality of patients with polycystic kidney disease on dialysis: Is there a lesson to learn?.
          Whereas one study failed to note any improved survival at a Hgb >11 g/dL compared to an Hgb 10 to 11 g/dL,
          • Madore F
          • Lowrie EG
          • Brugnara C
          • Lew NL
          • Lazarus JM
          • Bridges K
          • Owen WF
          Anemia in hemodialysis patients: Variables affecting this outcome predictor.
          several other reports have shown improved survival at higher Hgb/Hct levels. Survival was improved in Italian hemodialysis patients when the Hct exceeded 32%, either spontaneously or following Epoetin therapy, when compared to Hct <32%,
          • Locatelli F
          • Conte F
          • Marcelli D
          The impact of haematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity—The experience of the Lombardy Dialysis Registry [news].
          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%.
          • Ma JZ
          • Ebben J
          • Xia H
          • Collins AJ
          Hematocrit level and associated mortality in hemodialysis patients.
          Survival has been noted in one study to be better in patients with cardiac disease who attained and maintained a normal Hct compared to similar patients who did not attain and maintain a normal Hct.
          • Besarab A
          • Bolton WK
          • Browne JK
          • Egrie JC
          • Nissenson AR
          • Okamoto DM
          • Schwab SJ
          • Goodkin DA
          The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and Epoetin.
          In fact, within both the normal Hct group and the control group, the mortality decreased at higher Hct levels.
          • Besarab A
          • Bolton WK
          • Browne JK
          • Egrie JC
          • Nissenson AR
          • Okamoto DM
          • Schwab SJ
          • Goodkin DA
          The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and Epoetin.
          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.
          • Besarab A
          • Bolton WK
          • Browne JK
          • Egrie JC
          • Nissenson AR
          • Okamoto DM
          • Schwab SJ
          • Goodkin DA
          The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and Epoetin.
        • 2.
          Left ventricular hypertrophy (LVH) is more likely in CKD patients with anemia (Hct ≤33%)
          • Levin A
          • Singer J
          • Thompson CR
          • Ross H
          • Lewis M
          Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention.
          • Greaves SG
          • Gamble GD
          • Collins JF
          • Whalley GA
          • Sharpe DN
          Determinants of left ventricular hypertrophy and systolic dysfunction in chronic renal failure.
          • London GM
          • Fabiani F
          • Marchais SJ
          • De Vernejoul M
          • Guerin AP
          • Safar ME
          • Metivier F
          • Llach F
          Uremic cardiomyopathy: An inadequate left ventricular hypertrophy.
          and in patients with ESRD
          • Silberberg JS
          • Rahal DP
          • Patton DR
          • Sniderman AD
          Role of anemia in the pathogenesis of left ventricular hypertrophy in end-stage renal disease.
          ; in such patients the risk of death is increased 2.9-fold (Endnote c).
          • Silberberg JS
          • Barre PE
          • Prichard SS
          • Sniderman AD
          Impact of left ventricular hyperytrophy on survival in end-stage renal disease.
          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.
          • Silberberg J
          • Racine N
          • Barre P
          • Sniderman AD
          Regression of left ventricular hypertrophy in dialysis patients following correction of anemia with recombinant human erythropoietin.
          Angina was significantly decreased in patients with progressive CKD when Epoetin therapy increased the Hct to 31% ± 4% versus 23% ± 4%.
          • Nagao K
          • Tsuchihashi K
          • Ura N
          • Nakata T
          • Shimamoto K
          Appropriate hematocrit levels of erythropoietin supplementary therapy in end-stage renal failure complicated by coronary artery disease.
        • 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%.
          • Levin NW
          • Lazarus JM
          • Nissenson AR
          Maximizing patient benefits with epoetin alfa therapy. National Cooperative rHu Erythropoietin Study in patients with chronic renal failure—An interim report.
          • Ifudu O
          • Paul H
          • Mayers JD
          • Cohen LS
          • Brezsnyak WF
          • Herman AI
          • Avram MM
          • Friedman EA
          Pervasive failed rehabilitations in center-based maintenance hemodialysis patients.
          Erythropoietin.
          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%.
          • Auer J
          • Simon G
          • Stevens J
          • Griffiths P
          • Howarth D
          • Anastassiades E
          • Gokal R
          • Oliver D
          Quality of life improvements in CAPD patients treated with subcutaneously administered erythropoietin for anemia.
          • Valderrabano F
          Erythropoetin in chronic renal failure.
          • Walls J
          Haemoglobin—Is more better?.
          When the results of the Amgen 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 Karnofsky scores than those maintained at a Hct of 30%.
          • Paganini EP
          In search of an optimal hematocrit level in dialysis patients: Rehabilitation and quality-of-life implications.
          Both quality of life and various physiological parameters in predialysis patients have been shown to be significantly better at a Hct of 36% to 39% than at 27% to 29%.
          • Revicki DA
          • Brown RE
          • Feeny DH
          • Henry D
          • Teehan BP
          • Rudnick MR
          • Benz RL
          Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients.
          • Brown CD
          • Friedman EA
          Clinical and blood rheologic stability in erythropoietin-treated predialysis patients.
          • Abraham PA
          • Opsahl JA
          • Rachael KM
          • Asinger R
          • Halstenson CE
          Renal function during erythropoietin therapy for anemia in predialysis chronic renal failure patients.
          • Eschbach JW
          • Kelly MR
          • Haley NR
          • Abels RI
          • Adamson JW
          Treatment of the anemia of progressive renal failure with recombinant human erythropoietin.
          • Lim VS
          • DeGowin RL
          • Zavala D
          • Kirchner PT
          • Abels R
          • Perry P
          • Fangman J
          Recombinant human erythropoietin treatment in pre-dialysis patients: A double-blind placebo-controlled trial.
          • Kleinman KS
          • Schweitzer SU
          • Perdue ST
          • Bleifer KH
          • Abels RI
          The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: A double-blind, placebo-controlled trial.
          • Koch KM
          • Koene RAP
          • Messinger D
          • Quarder O
          • Scigalla P
          The use of epoetin beta in anemic predialysis patients with chronic renal failure.
          • Clyne N
          • Jogestrand T
          Effect of erythropoeitin treatment on physical exercise capacity and renal function in predialytic uremic patients.
        • 4.
          In hemodialysis patients, exercise capacity (VO2 ) increased when the Hct increased from 30% to 35% to 40%.
          • Suzuki M
          • Tsutsui M
          • Yokoyama A
          • Hirasawa Y
          Normalization of hematocrit with recombinant human erythropoietin in chronic hemodialysis patients does not fully improve their exercise tolerance abilities.
        • 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.
          • Xia H
          • Ebben J
          • Ma JZ
          • Collins AJ
          Hematocrit levels and hospitalization risks in hemodialysis patients.
        • 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 sleepiness, insulin resistance with hyperlipidemia, and survival improved when a normal Hct was achieved,
          • Sangkabutra T
          • McKenna MJ
          • Mason K
          • Crankshaw DP
          • McMahon LP
          Effects of K+, pH, and different haemoglobin levels on maximal exercise performanace in haemodialysis patients.
          • Mason K
          • Skinner S
          • Sangkabutra T
          • Burge C
          • McMahon L
          Effects of erythropoietin on cardiac mass and function, ambulatory blood pressure and blood volumes at comparative levels of haemoglobin.
          • Mason K
          • McMahon LP
          Normalization of haemoglobin in haemodialysis patients: A comparative study.
          • Bonelli C
          • Alvarez S
          • Alsina M
          • Brana D
          Search of a good hematocrit (H) for patients (P) with a chronic renal insuffiency in hemodialysis.
          • Eschbach JW
          • Glenny R
          • Robertson T
          • Guthrie M
          • Rader B
          • Evans R
          • Chandler W
          • Davidson R
          • Easterling T
          • Denney J
          • Schneider G
          Normalizing the hematocrit (HCT) in hemodialysis patients (HDP) with EPO improves quality of life (Q/L) and is safe.
          • Riedel E
          • Hampl H
          • Nundel M
          • Bosch J
          Total correction of renal anemia improves malnutrition and amino acid (AA) metabolism in hemodialysis (HD) patients.
          • Barany P
          • Svedenhag J
          • Katzarski K
          • Divino Filho J
          • Norman R
          • Freyschiuss U
          • Bergstrom J
          Physiological effects of correcting anemia in hemodialysis patients to a normal HB.
          • Benz RL
          • Pressman MR
          • Hovick ET
          • Peterson DD
          Relationship between anemia of chronic renal failure (ACRF) and sleep, sleep disorders, and daytime alertness: Benefits if normalizing hematocrit (The Sleepo Trial).
          • Mak HK
          Human recombinant erythropoietin (EPO) corrects insulin resistance and hyperlipidemia in patients on peritoneal dialysis(PD).
          • Nissenson AR
          • Pickett JL
          • Theberge DC
          • Brown WS
          • Schweitzer SV
          Brain function is better in hemodialysis (HD) patients (PTS) when hematocrit (HCT) is normalized with erythropoeitin (rHuEPO).
          • Avram MM
          • Sreedhara R
          • Batish R
          • Chattopadhyay J
          • Mittman N
          Characteristics of very long-term survivors on hemodialysis (HD); survival up to 30 years.
          • Hayashi T
          • Shoji T
          • Okada N
          • Nakanishi T
          • Tsubakihara Y
          To see the effect on circadian blood pressure variation and cardiac function in predialysis patients when hematocrit is normalized to 40% following recombinant human erythropoietin.
          and that there were no adverse effects observed at a normal Hct.
          • Bonelli C
          • Alvarez S
          • Alsina M
          • Brana D
          Search of a good hematocrit (H) for patients (P) with a chronic renal insuffiency in hemodialysis.
          • Eschbach JW
          • Glenny R
          • Robertson T
          • Guthrie M
          • Rader B
          • Evans R
          • Chandler W
          • Davidson R
          • Easterling T
          • Denney J
          • Schneider G
          Normalizing the hematocrit (HCT) in hemodialysis patients (HDP) with EPO improves quality of life (Q/L) and is safe.
          Several of these studies have now been published in peer review journals, and demonstrate that a normal Hgb/Hct is associated with better physical performance,
          • McMahon LP
          • McKenna MJ
          • Sangkabutra T
          • Mason K
          • Sostaric S
          • Skinner SL
          • Burge C
          • Murphy B
          • Crankshaw D
          Physical performance and associated electrolyte changes after haemoglobin normalization: A comparative study in haemodialysis patients.
          better cognitive function,
          • Picket JL
          • Theberge DC
          • Brown WS
          • Schweitzer SU
          • Nissenson AR
          Normalizing hematocrit in dialysis patients improves brain function.
          improved brain oxygen supply,
          • Metry G
          • Wikstrom B
          • Valind S
          • Sandhagen B
          • Linde T
          • Beshara S
          • Langstrom B
          • Danielson BG
          Effect of normalization of hematocrit on brain circulation and metabolism in hemodialysis patients.
          and improved sleep patterns
          • Benz R
          • Pressman M
          • Hovick E
          • Peterson D
          A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients: The SLEEPO Study.
          compared to lower Hgb/Hct levels.
        Studies in patients with anemia due to conditions other than CKD also indicate that an Hct of ≤30% is harmful. Patients undergoing peripheral vascular surgery had more cardiac ischemia when their Hct decreased from 39% to 27% to 30% compared to others whose Hct decreased only to 32%.
        • Christopherson R
        • Frank S
        • Norris E
        • Rock P
        • Gottlieb S
        • Beattie C
        Low postoperative hematocrit is associated with cardiac ischemia in high-risk patients.
        Patients with lupus nephritis have increased mortality, unrelated to kidney dysfunction, as Hgb decreases to below 11 g/dL.
        • Donadio Jr, JV
        • Hart GM
        • Bergstralh EJ
        • Holley KE
        Prognostic determinants in lupus nephritis: A long-term clinicopathologic study.
        Patients with anemia related to cancer have improved quality of life when Hct is increased from 29% to >35% with Epoetin.
        • Abels RI
        Use of recombinant human erythropoietin in the treatment of anemia in patients who have cancer.
        Finally, an Hgb <10 g/dL increases prematurity rates to almost twice normal in otherwise healthy pregnant women.
        • Klein L
        Premature birth and maternal prenatal anemia.
        Since anemia is treated in these conditions to improve patient well-being and survival, patients with CKD should not be deprived of the same therapeutic goal.
        Despite this plethora of data, there has been much controversy as to what Hgb/Hct is best in CKD patients. Prior to the availability of Epoetin, evidence was provided that, during neurosurgical procedures, relative oxygen transport capacity for the human brain was optimal at an Hct of 30% to 33%, as achieved by hemodilution (usually phlebotomy combined with dextran infusion).
        • Wood JH
        • Kee DB
        Hemorrheology of the cerebral circulation in stroke.
        This was based on in vitro hemodilution studies involving blood flow through glass capillaries.
        • Crowell JW
        • Smith EE
        Determinant of the optimal hematocrit.
        This long-standing belief among anesthesiologists, neurologists, and neurosurgeons was supported by data showing that hemodilution increased cerebral blood flow. This belief has been challenged by more recent studies, which indicate that, while there is an inverse relationship between Hct and cerebral blood flow, there is a linear relationship between Hct and oxygen delivery to brain tissue, with the maximal level of oxygen delivery occurring within an Hct range of 40% to 45% (Endnote d).
        • Kusunoki M
        • Kimura K
        • Nakamura M
        • Isaka Y
        • Yoneda S
        • Abe H
        Effects of hematocrit variations on cerebral blood flow and oxygen transport on ischemic cerebrovascular disease.
        There also was concern during the early experience with Epoetin about possible adverse effects when the Hct was increased above 30%. These adverse effects are not, in fact, seen today, except for an increase in the need for antihypertensive medications in 23% of patients with CKD, whose blood pressure can be controlled with appropriate clinical care (see Guideline 24: Possible Adverse Effects Related to Epoetin Therapy: Hypertension). Two studies of small numbers of unselected dialysis patients found no adverse effects when target Hct was increased to a mean of 38.3%
        • Bonelli C
        • Alvarez S
        • Alsina M
        • Brana D
        Search of a good hematocrit (H) for patients (P) with a chronic renal insuffiency in hemodialysis.
        and 42%.
        • Eschbach JW
        • Glenny R
        • Robertson T
        • Guthrie M
        • Rader B
        • Evans R
        • Chandler W
        • Davidson R
        • Easterling T
        • Denney J
        • Schneider G
        Normalizing the hematocrit (HCT) in hemodialysis patients (HDP) with EPO improves quality of life (Q/L) and is safe.
        Hypertension was no more frequent in those cardiac patients who attained a normal Hct than patients maintained at an Hct of 30.4%.
        • Berns J
        • Rudnick M
        • Cohen R
        • Bower J
        • Wood B
        Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac disease.
        In a large multicenter study of 1,200 hemodialysis patients with documented cardiac disease (congestive heart failure or ischemic heart disease), hypertension was no more frequent at a normal Hct (42% ± 3%) than at an Hct of 30% ± 3%.
        • Besarab A
        • Bolton WK
        • Browne JK
        • Egrie JC
        • Nissenson AR
        • Okamoto DM
        • Schwab SJ
        • Goodkin DA
        The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and Epoetin.
        There was no association between adverse outcomes and either (a) the average Hct during the study or (b) the Epoetin dose administered. No conclusions can be drawn from the results of this trial with regard to CKD patients who do not have heart disease (as defined in the Amgen study).
        The only published investigation relating Epoetin therapy to increased cardiovascular disease is from Okinawa, Japan.
        • Iseki K
        • Nishime K
        • Uehara H
        • Tokuyama K
        • Toma S
        • Yoshihara K
        • Kowatari T
        • Terukina S
        • Osawa A
        • Fukiyama K
        Increased risk of cardiovascular disease with erythropoietin in chronic dialysis patients.
        The authors reported that the annual incidence of stroke and acute myocardial infarction increased following the use of Epoetin in CKD patients (Endnote e). However, these findings differ from recent European data, in which cardiovascular morbidity and mortality were decreased by 15% to 20% after 2 years of Epoetin therapy in CKD patients.
        • Mocks J
        • Franke W
        • Ehmer B
        • Scigalla P
        • Quarder O
        Analysis of safety database for long-term epoetin-beta treatment. A meta-analysis covering 3697 patients.
        Clinicians should bear in mind that approximately 5% of hemodialysis patients attain an Hct ≥40%
        • Charles G
        • Lundin III, AP
        • Delano BG
        • Brown C
        • Friedman EA
        Absence of anemia in maintenance hemodialysis.
        without receiving Epoetin. In addition, some Epoetin-treated patients may have a spontaneous increase in Hct to above 36% after Epoetin therapy has been discontinued. There have been no published reports of an increased incidence of deaths and/or non-fatal myocardial infarctions in such patients. In view of recent abstracts
        • Sangkabutra T
        • McKenna MJ
        • Mason K
        • Crankshaw DP
        • McMahon LP
        Effects of K+, pH, and different haemoglobin levels on maximal exercise performanace in haemodialysis patients.
        • Mason K
        • Skinner S
        • Sangkabutra T
        • Burge C
        • McMahon L
        Effects of erythropoietin on cardiac mass and function, ambulatory blood pressure and blood volumes at comparative levels of haemoglobin.
        • Mason K
        • McMahon LP
        Normalization of haemoglobin in haemodialysis patients: A comparative study.
        • Eschbach JW
        • Glenny R
        • Robertson T
        • Guthrie M
        • Rader B
        • Evans R
        • Chandler W
        • Davidson R
        • Easterling T
        • Denney J
        • Schneider G
        Normalizing the hematocrit (HCT) in hemodialysis patients (HDP) with EPO improves quality of life (Q/L) and is safe.
        • Riedel E
        • Hampl H
        • Nundel M
        • Bosch J
        Total correction of renal anemia improves malnutrition and amino acid (AA) metabolism in hemodialysis (HD) patients.
        • Barany P
        • Svedenhag J
        • Katzarski K
        • Divino Filho J
        • Norman R
        • Freyschiuss U
        • Bergstrom J
        Physiological effects of correcting anemia in hemodialysis patients to a normal HB.
        • Benz RL
        • Pressman MR
        • Hovick ET
        • Peterson DD
        Relationship between anemia of chronic renal failure (ACRF) and sleep, sleep disorders, and daytime alertness: Benefits if normalizing hematocrit (The Sleepo Trial).
        • Mak HK
        Human recombinant erythropoietin (EPO) corrects insulin resistance and hyperlipidemia in patients on peritoneal dialysis(PD).
        • Nissenson AR
        • Pickett JL
        • Theberge DC
        • Brown WS
        • Schweitzer SV
        Brain function is better in hemodialysis (HD) patients (PTS) when hematocrit (HCT) is normalized with erythropoeitin (rHuEPO).
        • Avram MM
        • Sreedhara R
        • Batish R
        • Chattopadhyay J
        • Mittman N
        Characteristics of very long-term survivors on hemodialysis (HD); survival up to 30 years.
        • Hayashi T
        • Shoji T
        • Okada N
        • Nakanishi T
        • Tsubakihara Y
        To see the effect on circadian blood pressure variation and cardiac function in predialysis patients when hematocrit is normalized to 40% following recombinant human erythropoietin.
        and peer-reviewed articles
        • McMahon LP
        • McKenna MJ
        • Sangkabutra T
        • Mason K
        • Sostaric S
        • Skinner SL
        • Burge C
        • Murphy B
        • Crankshaw D
        Physical performance and associated electrolyte changes after haemoglobin normalization: A comparative study in haemodialysis patients.
        • Picket JL
        • Theberge DC
        • Brown WS
        • Schweitzer SU
        • Nissenson AR
        Normalizing hematocrit in dialysis patients improves brain function.
        • Metry G
        • Wikstrom B
        • Valind S
        • Sandhagen B
        • Linde T
        • Beshara S
        • Langstrom B
        • Danielson BG
        Effect of normalization of hematocrit on brain circulation and metabolism in hemodialysis patients.
        • Christopherson R
        • Frank S
        • Norris E
        • Rock P
        • Gottlieb S
        • Beattie C
        Low postoperative hematocrit is associated with cardiac ischemia in high-risk patients.
        showing beneficial effects from raising the Hgb/Hct to normal, it is possible that a target Hgb/Hct higher than what the Anemia Work Group recommends now may ultimately prove to be appropriate.
        In summary, based on currently available data, the Anemia Work Group recommends that the Hgb/Hct be maintained between 11 and 12 g/dL (33% and 36%). In striving to maintain the Hgb/Hct within this target range, the Hgb/Hct will likely rise above this range. The reasons why some patients will temporarily exceed an Hgb/Hct of 12 g/dL (36%) is that the response to Epoetin varies amongst patients, the interplay between IV iron supplementation and epoetin dosing may be unpredictable, and it is impossible for the bell-shaped distribution of Hgb/Hct for all patients be limited to between 11 and 12 g/dL or 33% and 36%, respectively. As of January 2000, HCFA will continue to provide reimbursement for the cost of Epoetin alfa even if the Hgb/Hct temporarily rises above their target range, as long as the rolling 3-month average Hgb/Hct is <12.5 g/dL (37.5%). Medical justification is needed for maintaining the Hgb (Hct) above 12 g/dL (36%).

        III. Iron support

        Background

        Iron is essential for hemoglobin formation, as is erythropoietin. Several important issues related to iron deficiency and its management in the CKD patient, particularly in patients receiving Epoetin therapy should be considered:
        • 1.
          Iron (blood) losses are high, particularly in the hemodialysis patient.
        • 2.
          Oral iron usually cannot maintain adequate iron stores, particularly in the hemodialysis patient treated with Epoetin.
        • 3.
          Epoetin, by stimulating erythropoiesis to greater than normal levels, often leads to functional iron deficiency.
        • 4.
          Prevention of functional (and absolute) iron deficiency by regular use of intravenous iron (ie, small doses, weekly, to replace predicted blood losses) improves erythropoiesis.
        • 5.
          The serum iron, total iron binding capacity, and serum ferritin are the best indicators of iron available for erythropoiesis and iron stores, but they do not provide absolute criteria for either iron deficiency or iron overload.These guidelines suggest that the regular use of small doses of IV iron, particularly in the hemodialysis patient, will prevent iron deficiency and promote better erythropoiesis than can oral iron therapy.
        • 6.
          Prior to July 1999, the only IV iron preparation available in the United States was iron dextran. The doses recommended for iron dextran are detailed in these Guidelines. Since July 1999, iron gluconate and iron sucrose have become available for IV use in the United States. Since the amount of iron gluconate per vial differs from that of iron dextran, the Work Group recommends that the substitution of iron gluconate for iron dextran would be 8 doses of 125 mg of iron gluconate (over 8 weeks per quarter), or 8 doses of 62.5 mg of iron gluconate over 8 weeks instead of 10 doses of 50 mg of iron dextran over 10 weeks. Doses of iron gluconate larger than 125 mg given at one time are not recommended by the manufacturer, whereas iron dextran can be given at one time at doses of 250, 500, and/or 1,000 mg doses, if indicated. Iron sucrose can be given in doses of 100 mg or less.

        Guideline 5: Assessment of iron status

        Iron status should be monitored by the percent transferrin saturation (TSAT) and the serum ferritin. (Evidence )

        Guideline 6: Target iron level

        • 1.
          A. CKD patients should have sufficient iron to achieve and maintain an Hgb/Hct of 11 to 12 g/dL/33% to 36%. (Evidence )
        • 2.
          B. To achieve and maintain this target Hgb/Hct, sufficient iron should be administered to maintain a TSAT of ≥20%, and a serum ferritin level of ≥100 ng/mL (Evidence ).
        • 3.
          C. In hemodialysis patients in whom TSAT is ≥20% and the serum ferritin is ≥100 ng/mL, yet the Hgb/Hct is 11 g/dL/<33%, as well as in patients requiring comparatively large doses of Epoetin to maintain an Hgb/Hct of 11 to 12 g/dL/33% to 36%, the patient’s response to 1.0 g of IV iron given over 8 to 10 weeks should be observed. (Opinion ) If in response to this course of iron, there is no increase in Hgb/Hct and no increase in serum ferritin and TSAT level, at the same dose of Epoetin, a second course of IV iron should be tried. (Opinion ) If, in response to this second course of IV iron, there still is no increase in Hgb/Hct, but either the TSAT or serum ferritin level increases, then the weekly dose of IV iron should be reduced to the lowest amount required to maintain the TSAT ≥20% and serum ferritin at ≥100 ng/mL. (Opinion ) If, on the other hand, in response to either of these courses of IV iron, there is an increase in Hgb/Hct at a constant dose of Epoetin, or a stable Hct at a decreased dose of Epoetin, then it is reasonable to administer 1.0 g of iron IV over 8 to 10 weeks again in an effort to achieve and maintain the Hgb/Hct at 11 to 12 g/dL/33% to 36%. (Opinion )
        • 4.
          D. CKD patients are unlikely to respond with a further increase in Hgb/Hct and/or a further reduction in Epoetin dose required to maintain a given Hgb/Hct if the TSAT increases to ≥50% and/or the serum ferritin level increases to ≥800 ng/mL. (Evidence )

        Guideline 7: Monitoring iron status

        • 1.
          A. During the initiation of Epoetin therapy and while increasing the Epoetin dose in order to achieve an increase in Hgb/Hct, the TSAT and the serum ferritin should be checked every month in patients not receiving intravenous iron, and at least once every 3 months in patients receiving intravenous iron, until target Hgb/Hct is reached. (Opinion )
        • 2.
          B. Following attainment of the target Hgb/Hct, TSAT and serum ferritin should be determined at least once every 3 months. (Opinion )
        • 3.
          C. Intravenous iron therapy, if given in amounts of 100 to 125 mg or less per week, does not need to be interrupted in order to obtain accurate measurements of iron parameters. (Evidence )
        • 4.
          D. If individual doses of intravenous iron are 1,000 mg or larger, an interval of 2 weeks should occur before accurate assessment of serum iron parameters can be determined (Evidence ). Accurate assessment of iron parameters after intravenous infusion of 200 to 500 mg of iron may require an interval of 7 or more days (Opinion ).
        • 5.
          E. In CKD patients not treated with Epoetin and whose TSAT is ≥20% and serum ferritin is ≥100 ng/mL, the iron status should be monitored every 3 to 6 months. (Opinion )

        Guideline 8: Administration of supplemental iron

        • 1.
          A. Supplemental iron should be administered to prevent iron deficiency and to maintain adequate iron stores so that CKD patients can achieve and maintain an Hgb 11 to 12 g/dL (Hct 33% to 36%) in conjunction with Epoetin therapy. (Evidence )
        • 2.
          B. If oral iron is given, it should be administered at a daily dose of at least 200 mg of elemental iron for adults and 2 to 3 mg/kg for pediatric patients. (Evidence )
        • 3.
          C. The adult CKD, home hemodialysis, and peritoneal dialysis (PD) patient may not be able to maintain adequate iron status with oral iron. (Evidence ) Therefore, 500 to 1,000 mg of iron dextran may be administered IV in a single infusion, and repeated as needed, after an initial one-time test dose of 25 mg. As of January 2000, it is not recommended to give these large doses of iron gluconate as a single infusion. (Opinion )
        • 4.
          D. A trial of oral iron is acceptable in the hemodialysis patient (Opinion ), but is unlikely to maintain the TSAT >20%, serum ferritin >100 ng/mL, and Hgb/Hct at 33% to 36%/11 to 12 g/dL. (Evidence )
        • 5.
          E. To achieve and maintain an Hgb 11 to 12 g/dL (Hct of 33% to 36%), most hemodialysis patients will require intravenous iron on a regular basis. (Evidence )
        • 6.
          F. Intravenous iron can be given on a variety of dosage schedules. If the TSAT is <20% and/or the serum ferritin is <100 ng/mL, the Anemia Work Group recommends that, in adults, 100 to 125 mg of iron be administered IV at every hemodialysis for 10 to 8 doses, respectively. (Opinion ) If the TSAT remains <20% and/or the serum ferritin <100 ng/mL, another course of IV iron (100 to 125 mg per week for 10 to 8 weeks) is recommended. Once the patient’s TSAT is ≥20% and the serum ferritin is ≥100 ng/mL, the Anemia Work Group recommends that 25 to 125 mg of iron be given IV once per week (see Guideline 6: Target Iron Level). (Opinion ) Schedules for IV iron administration ranging from three times per week to once every 2 weeks are also reasonable in order to provide 250 to 1,000 mg of iron within 12 weeks. (Opinion )
        • 7.
          G. Most patients will achieve an Hgb 11 to 12g/dL (Hct of 33% to 36%) with TSAT and serum ferritin levels <50% and <800 ng/mL, respectively. (Evidence ) In patients in whom TSAT is ≥50% and/or serum ferritin is ≥800 ng/mL, IV iron should be withheld for up to 3 months, at which time the iron parameters should be re-measured before IV iron is resumed. (Opinion ) When the TSAT and serum ferritin have fallen to ≤50% and ≤800 ng/mL, IV iron can be resumed weekly at a dose reduced by one third to one half. (Opinion )
        • 8.
          H. It is anticipated that once optimal Hgb/Hct and iron stores are achieved, the required maintenance dose of IV iron may vary from 25 to 125 mg/week for hemodialysis patients. The goal is to provide a weekly dose of IV iron in hemodialysis patients that will allow the patient to maintain the target Hgb/Hct at a safe and stable iron level. The maintenance iron status should be monitored by measuring the TSAT and serum ferritin no less than every 3 months. (Opinion )
        • 9.
          I. Oral iron is not indicated for the CKD patient who requires maintenance doses of IV iron. (Opinion )

        Rationale for Guidelines 5-8

        Background
        Effective erythropoiesis requires both iron and erythropoietin. When CKD patients lack an adequate supply of either one or both, anemia results. Among United States ESRD patients receiving Epoetin, more than 50% are iron deficient, which probably accounts, at least in part, for why the mean Hct among ESRD patients in the United States in 1993 was 30.2%, with 43% having a Hct <30% (Endnote f).
        • US Renal Data System
        The USRDS Dialysis Morbidity and Mortality Study (Wave 1).
        To remedy this problem, clinicians will need to address three important issues regarding management of iron in CKD patients:
        • 1.
          Under what circumstances should a patient receive supplemental iron?
        • 2.
          How much iron should they receive?
        • 3.
          How (by what route and according to what dosing schedule) should they receive it?
        The Iron Support section of these guidelines (Guidelines 5-10) addresses how to ensure that patients have sufficient iron to achieve and maintain a target Hgb 11 to 12 g/dL (Hct of 33% to 36%). The Administration of Epoetin section (Guidelines 11-19) addresses how to ensure that patients receive sufficient Epoetin to achieve and maintain a target Hgb 11 to 12 g/dL (Hct of 33% to 36%).
        In formulating its recommendations regarding these issues, the Anemia Work Group focused on the following:
        • 1.
          The iron needs and the importance of maintaining adequate iron status in CKD patients
        • 2.
          Assessment of iron status: the sensitivity and specificity of the TSAT and serum ferritin in detecting absolute and functional iron deficiency, as well as iron overload
        • 3.
          An analysis of the effectiveness of oral versus IV iron
        • 4.
          Administration of IV iron, and its potential associated risks
        • 5.
          Iron overload
        Iron Needs in CKD Patients
        Iron deficiency is common in CKD, particularly in hemodialysis patients, for several reasons, including substantial losses of blood from frequent blood tests, blood remaining in the dialysis tubing and dialyzer, and gastrointestinal blood losses, that cannot be compensated for by sufficient absorption of iron from the gastrointestinal tract. Epoetin therapy increases the rate of erythropoiesis and therefore the demand for iron, which, when coupled with substantial blood losses, compounds the difficulty of maintaining adequate iron stores in hemodialysis patients.
        Normal body iron stores are 800 to 1,200 mg.
        • Council on Food and Nutrition
        • Committee on Iron Deficiency
        Iron deficiency in the United States.
        If the initial Hct is 25% and the target Hct is 35%, the magnitude of supplemental iron required by patients during the first 3 months of Epoetin therapy is approximately 1,000 mg. Of this, approximately 400 mg of iron are needed simply to replace iron losses during 3 months of hemodialysis (Endnote g). The other 600 mg of iron are needed to support production of sufficient numbers of red blood cells to achieve the target Hgb/Hct (Endnote h). Once the target Hgb/Hct is achieved, approximately 400 to 500 mg of supplemental iron will be needed every 3 months to replace iron losses and maintain adequate iron stores.
        In children, mean daily intestinal blood losses (pre-dialysis) are 6 mL/m2 BSA. For pediatric hemodialysis patients, mean daily GI blood losses increase to 11 mL/m2, and dialysis-associated blood losses are 8 mL/m2 per treatment. Cumulative annual iron losses therefore approximate 1.6 g/1.73 m2 in pediatric hemodialysis patients, and 0.9 gm/1.73 m2 in predialysis pediatric patients and probably in those on PD.
        • Muller-Wiefel DE
        • Sinn H
        • Gilli G
        • Scharer K
        Hemolysis and blood loss in children with chronic renal failure.
        Although there are no data on the calculated iron needs in pediatric patients on dialysis, the rationale for iron supplementation is similar to that described for adults.
        Assessment of Iron Status
        An ideal test of a CKD patient’s iron status would accurately indicate whether the patient has:
        • 1.
          Sufficient amount of iron available to support achievement and maintenance of an Hgb 11 to 12 g/dL (Hct of 33% to 36%); and
        • 2.
          An excessive amount of body iron.
        Unfortunately, no test exists which accomplishes either of these goals and which is practical to administer (Endnote i).
        Currently, the two best tests of iron status are the percent TSAT and the serum ferritin. The percent TSAT (serum iron multiplied by 100 and divided by total iron binding capacity [TIBC]) reflects iron that is readily available for erythropoiesis. The TIBC essentially measures circulating transferrin. The transferrin molecule contains two binding sites for transporting iron from iron storage sites to erythroid progenitor cells. A TSAT of 50% indicates that half of the binding sites are occupied by iron. Normally there is a diurnal variation in the level of serum iron and, thus, the TSAT. Since blood for these tests is generally obtained at the same time of day in relation to either clinic or dialysis visits, serial measurements of TSAT typically are not affected by this diurnal variation.
        The distinction between absolute and functional iron deficiency is crucial to understanding what constitutes adequate TSAT and serum ferritin levels in Epoetin-treated patients. In otherwise healthy subjects, iron deficiency is considered “absolute” when iron stores are depleted, as indicated by serum ferritin levels <12 ng/mL,
        • Jacobs A
        • Worwood M
        Ferritin in serum: Clinical and biochemical implications.
        and iron delivery to the erythroid marrow is impaired, as evidenced by TSAT levels below 16%.
        • Bainton DF
        • Finch CA
        The diagnosis of iron deficiency anemia.
        Absolute iron deficiency in CKD patients has been defined as serum ferritin levels <100 ng/mL and TSAT levels <20%. In contrast to absolute iron deficiency, functional iron deficiency results when there is a need for a greater amount of iron to support hemoglobin synthesis than can be released from iron stores (reticuloendothelial cells). This situation, which can be caused by pharmacological stimulation of erythropoiesis by Epoetin, can occur in the presence of adequate iron stores. As a result, the percent TSAT decreases to levels consistent with iron deficiency despite a normal or elevated serum ferritin.
        • Eschbach JW
        • Egrie JC
        • Downing MR
        • Browne JK
        • Adamson JW
        Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: Results of a combined phase I and II clinical trial.
        • Allegra V
        • Mengozzi G
        • Vasile A
        Iron deficiency in maintenance hemodialysis patients: Assessment of diagnosis criteria and of three different iron treatments.
        • Horl WH
        • Dreyling K
        • Steinhauer HB
        • Engelhardt R
        • Schollmeyer P
        Iron status of dialysis patients under rhuEPO therapy.
        • Fishbane S
        • Lynn RI
        The efficacy of iron dextran for the treatment of iron deficiency in hemodialysis patients.
        Patients with this condition do not meet traditional laboratory criteria for absolute iron deficiency, but may demonstrate an increase in Hgb/Hct when IV iron is administered.
        A common clinical problem is distinguishing between functional iron deficiency and an inflammatory iron block, since the TSAT may be <20% and serum ferritin may be 100 to 700 ng/mL in both situations (although the serum ferritin can be even higher in the presence of inflammation). In the former condition, serial levels of serum ferritin decrease during Epoetin therapy, yet remain elevated (>100 ng/mL); in contrast, in the latter condition, there is usually an abrupt increase in serum ferritin associated with a sudden drop in the TSAT. If it is not clear which of these conditions exists, it is recommended that weekly IV iron (50 to 125 mg) be given for up to 8 to 10 doses. If no erythropoietic response occurs, an inflammatory block is most likely, and no further IV iron should be given until the inflammatory condition has resolved.
        Transferrin Saturation Traditionally, a TSAT of <20% in hemodialysis patients has been considered to be indicative of iron deficiency. However, several studies
        • Silverberg DS
        • Iaina A
        • Peer G
        • Kaplan E
        • Levi BA
        • Frank N
        • Steinbruch S
        • Blum M
        Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.
        • Fishbane S
        • Kowalski EA
        • Imbriano LJ
        • Maesaka JK
        The evaluation of iron status in hemodialysis patients.
        • Tarng DC
        • Chen TW
        • Huang TP
        Iron metabolism indices for early prediction of the response and resistance to erythropoietin therapy in maintenance hemodialysis patients.
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        • Granolleras C
        • Oules R
        • Branger B
        • Fourcade J
        • Shaldon S
        Iron supplementation of hemodialysis patients receiving recombinant human erythropoietin therapy.
        • Rosenlof K
        • Kivivuori SM
        • Gronhagen-Riska C
        • Teppo AM
        • Slimes MA
        Iron availability is transiently improved by intravenous iron medication in patients on chronic hemodialysis.
        have demonstrated that a TSAT of <20% versus ≥20% is not an accurate discriminator between patients who are or are not iron deficient. Although the vast majority of patients who have a TSAT <20% are iron deficient, there are some patients who have a TSAT <20% who are able to achieve a Hct of 33% to 36% and/or do not respond to higher doses of iron (and TSAT levels) with either an increase in Hct or maintenance of Hct with a reduced dose of Epoetin. However, there also are many patients who have a TSAT >20% who are functionally iron deficient (ie, they respond to higher doses of iron, and a corresponding increase in their TSAT, with either an increase in their Hct or maintenance of their Hct at a reduced dose of Epoetin)
        • Silverberg DS
        • Iaina A
        • Peer G
        • Kaplan E
        • Levi BA
        • Frank N
        • Steinbruch S
        • Blum M
        Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.
        • Fishbane S
        • Kowalski EA
        • Imbriano LJ
        • Maesaka JK
        The evaluation of iron status in hemodialysis patients.
        • Tarng DC
        • Chen TW
        • Huang TP
        Iron metabolism indices for early prediction of the response and resistance to erythropoietin therapy in maintenance hemodialysis patients.
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        • Granolleras C
        • Oules R
        • Branger B
        • Fourcade J
        • Shaldon S
        Iron supplementation of hemodialysis patients receiving recombinant human erythropoietin therapy.
        • Rosenlof K
        • Kivivuori SM
        • Gronhagen-Riska C
        • Teppo AM
        • Slimes MA
        Iron availability is transiently improved by intravenous iron medication in patients on chronic hemodialysis.
        (Endnote j).
        Ferritin Whereas TSAT reflects iron that is readily available for erythropoiesis, serum ferritin reflects storage iron, ie, iron that is stored in liver, spleen, and bone marrow reticuloendothelial cells. As is the case with the TSAT, the serum ferritin level is most accurate as a predictor of iron deficiency or iron overload when it is extremely low or extremely high, respectively.
        Just as serum ferritin is not perfectly sensitive, it also is not perfectly specific. In part, this is due to the fact that, in addition to reflecting body iron stores, serum ferritin also is an acute phase reactant. As such, it can increase in the setting of either acute or chronic inflammation.
        While no single value of TSAT or serum ferritin accurately discriminates between CKD patients who are or are not functionally iron deficient, available data demonstrate that the lower the TSAT and the serum ferritin, the higher the likelihood that a patient is iron deficient, and the higher the TSAT and the serum ferritin, the lower the likelihood that a patient is iron deficient.
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        • Granolleras C
        • Oules R
        • Branger B
        • Fourcade J
        • Shaldon S
        Iron supplementation of hemodialysis patients receiving recombinant human erythropoietin therapy.
        • Rosenlof K
        • Kivivuori SM
        • Gronhagen-Riska C
        • Teppo AM
        • Slimes MA
        Iron availability is transiently improved by intravenous iron medication in patients on chronic hemodialysis.
        • Taylor JE
        • Peat N
        • Porter C
        • Morgan AG
        Regular, low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients.
        • Sunder-Plassmann G
        • Horl WH
        Importance of iron supply for erythropoietin therapy.
        • Sepandj F
        • Jindal K
        • West M
        • Hirsch D
        Economic appraisal of maintenance parenteral iron administration in treatment of the anaemia in chronic haemodialysis patients.
        Other tests of iron status, such as zinc protoporphyrin or RBC ferritin, are less widely available and appear to offer no increase in diagnostic sensitivity or specificity over serum ferritin and TSAT.
        • Fishbane S
        • Lynn RI
        The utility of zinc protoporphyrin for predicting the need for intravenous iron therapy in hemodialysis patients.
        The percent of hypochromic red blood cells does appear to be a sensitive and reliable indicator for iron deficiency and has been shown to be helpful in the diagnosis of functional iron deficiency.
        • Macdougall IC
        • Cavill I
        • Hulme B
        • Bain B
        • McGregor E
        • McKay P
        • Sanders E
        • Coles GA
        • Williams JD
        Detection of functional iron deficiency during erythropoietin treatment: A new approach.
        • Schaefer RM
        • Schaefer L
        The hypochromic red cell: A new parameter for monitoring of iron supplementation during rhEPO therapy.
        Normally, there are less than 2.5% of red blood cells with individual cell hemoglobin levels of less than 28 g/dL. Values exceeding 10% are compatible with iron deficiency in the Epoetin-treated patient. This measurement is presently performed as part of a routine full blood count sample that requires a Technicon H-1, H-2, or H-3 automated cell counter, which is specialized equipment (Bayer Diagnostics) available in parts of Europe, but is presently not available in most medical centers in the United States.
        Several recommendations of a European Erythropoietin Symposium regarding iron supplementation (whether oral or IV) during Epoetin therapy were as follows:
        • 1.
          Serum ferritin should be maintained at greater than 100 ng/mL. No upper limit was set.
        • 2.
          Transferrin saturation should be maintained at greater than 20%. Hypochromic red blood cells should be maintained at less than 10%. Iron status should be evaluated monthly initially, then every 2 to 3 months.
          • Horl WH
          How to get the best out of r-HuEPO.
        Use of Oral Versus Intravenous Iron
        Inadequacy of Oral Iron in Hemodialysis Patients A number of studies have documented the failure of oral iron supplements to maintain adequate iron stores in Epoetin-treated hemodialysis patients
        • Silverberg DS
        • Iaina A
        • Peer G
        • Kaplan E
        • Levi BA
        • Frank N
        • Steinbruch S
        • Blum M
        Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.
        • Allegra V
        • Mengozzi G
        • Vasile A
        Iron deficiency in maintenance hemodialysis patients: Assessment of diagnosis criteria and of three different iron treatments.
        • Horl WH
        • Dreyling K
        • Steinhauer HB
        • Engelhardt R
        • Schollmeyer P
        Iron status of dialysis patients under rhuEPO therapy.
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        • Bergmann M
        • Grutzmacher P
        • Heuser J
        • Kaltwasser JP
        Iron metabolism under rEPO therapy in patients on maintenance hemodialysis.
        • Wingard RL
        • Parker RA
        • Ismail N
        • Hakim RM
        Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin.
        • Kooistra MP
        • van Es A
        • Struyvenberg A
        • Marx JJM
        Iron metabolism in patients with the anaemia of end-stage renal disease during treatment with recombinant human erythropoietin.
        • Dunea G
        • Swagel MA
        • Bodiwala U
        • Arruda JAL
        Intradialytic oral iron therapy.
        • Anastassiades EG
        • Howarth D
        • Howarth J
        • Shanks D
        • Waters HM
        • Hyde K
        • Geary CG
        • Yin JAL
        • Gokal R
        Monitoring of iron requirements in renal patients on erythropoietin.
        (Table IV-2). Even though there may be temporary improvement in the Hct with oral iron therapy, blood (iron) losses exceed the absorption of iron from oral supplements in most Epoetin-treated hemodialysis patients and ultimately iron stores decrease (as indicated by decreasing serum ferritin levels; Table IV-2). Eventually, as negative iron balance continues, iron stores decrease and will become inadequate.
        Table IV2. Effects of Oral Iron Therapy in Hemodialysis Patients
        StudyNo. of PatientsElemental Iron/DayDuration (mo)Hgb/HctBaseline/Follow-UpEpoetin Dose
        %TSATFerritin
        Kooistra et al
        • Kooistra MP
        • van Es A
        • Struyvenberg A
        • Marx JJM
        Iron metabolism in patients with the anaemia of end-stage renal disease during treatment with recombinant human erythropoietin.
        191051022.8-32.825-24447-26575 U/Kg/wk
        Dunea et al
        • Dunea G
        • Swagel MA
        • Bodiwala U
        • Arruda JAL
        Intradialytic oral iron therapy.
        73260122-4,000 U/HD
        5027.0-33.7NA123-83
        2329.6-27.5NA99-126
        Bergmann et al
        • Bergmann M
        • Grutzmacher P
        • Heuser J
        • Kaltwasser JP
        Iron metabolism under rEPO therapy in patients on maintenance hemodialysis.
        7227522.0-29.0NA400-100360 U/kg/wk
        Macdougall et al
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        1312047.2-10.027-31309-10075 U/kg/wk
        Wingard et al
        • Wingard RL
        • Parker RA
        • Ismail N
        • Hakim RM
        Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin.
        46200626.3-29.720-21151-10610,660 U/HD
        Anastassiades et al
        • Anastassiades EG
        • Howarth D
        • Howarth J
        • Shanks D
        • Waters HM
        • Hyde K
        • Geary CG
        • Yin JAL
        • Gokal R
        Monitoring of iron requirements in renal patients on erythropoietin.
        3830036.9-10.429-27211-92110 U/kg/wk
        Fishbane et al
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        32195431.8-31.821-20179-1577563 U/HD
        Horl et al
        • Horl WH
        • Dreyling K
        • Steinhauer HB
        • Engelhardt R
        • Schollmeyer P
        Iron status of dialysis patients under rhuEPO therapy.
        1240-80322.5-33.0NA1,145-251150 U/Kg/wk
        Although there is no evidence to suggest that gastrointestinal iron absorption is impaired in patients with kidney failure,
        • Gokal R
        • Millard PR
        • Weatherall DJ
        • Callender STE
        • Ledingham JGG
        • Oliver DO
        Iron metabolism in haemodialysis patients: A study of the management of iron therapy and overload.
        • Eschbach JW
        • Cook JD
        • Scribner BH
        • Finch CA
        Iron balance in hemodialysis patients.
        • Milman N
        Iron absorption measured by whole body counting and the relation to marrow iron stores in chronic uremia.
        even in non-CKD individuals only a small fraction of oral iron is absorbed. Consequently, 200 mg of elemental iron ingested daily usually cannot meet the demands of Epoetin-induced increase in erythropoiesis and hemodialysis-associated blood losses. Moreover, since oral iron absorption is inversely correlated with body iron stores, it is unlikely that even a greater amount of oral iron would be absorbed when the serum ferritin level exceeds approximately 200 ng/mL
        • Eschbach JW
        • Cook JD
        • Scribner BH
        • Finch CA
        Iron balance in hemodialysis patients.
        • Donnelly SM
        • Posen GA
        • Ali MAM
        Oral iron absorption in hemodialysis patients treated with erythropoietin.
        or the transferrin saturation exceeds 20%
        • Eschbach JW
        • Cook JD
        • Finch CA
        Iron absorption in chronic renal disease.
        levels that are needed for optimal erythropoiesis. On the other hand, iron absorption also correlates with the degree of erythropoiesis, and can be increased during Epoetin therapy.
        • Hughes RT
        • Smith T
        • Hesp R
        • Hulme B
        • Dukes DC
        • Bending MB
        • Pearson J
        • Raja KB
        • Cotes PM
        • Pippard MJ
        Regulation of iron absorption in iron loaded subjects with end stage renal disease: Effects of treatment with recombinant human erythropoietin and reduction of iron stores.
        • Skikne BS
        • Cook JD
        Effect of enhanced erythropoiesis on iron absorption.
        However, in the latter study involving normal subjects,
        • Skikne BS
        • Cook JD
        Effect of enhanced erythropoiesis on iron absorption.
        enhanced erythropoiesis was achieved with amounts of Epoetin greater than those generally given to patients with CKD.
        Inadequate absorption of oral iron is exacerbated by the fact that patient compliance with oral iron regimens is often poor due to one or more of the following: the inconvenience of dosing (1 hour pre-prandial or 2 hours post-prandial administration for optimal absorption); side effects, including gastric irritation and constipation; and out-of-pocket cost.
        Although most Epoetin-treated hemodialysis patients will require intravenous iron to maintain iron stores, a small percentage of hemodialysis patients, as well as many peritoneal dialysis and CKD patients, are able to maintain adequate iron stores using only oral iron supplements, perhaps as a result of augmented intestinal iron absorption,
        • Skikne BS
        • Cook JD
        Effect of enhanced erythropoiesis on iron absorption.
        smaller blood losses, and/or lower Epoetin requirements.
        • Silverberg DS
        • Iaina A
        • Peer G
        • Kaplan E
        • Levi BA
        • Frank N
        • Steinbruch S
        • Blum M
        Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        IV Iron Intravenous iron has been shown to improve responsiveness to Epoetin in selected patients with CKD and PD patients
        • Silverberg DS
        • Iaina A
        • Peer G
        • Kaplan E
        • Levi BA
        • Frank N
        • Steinbruch S
        • Blum M
        Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        • Suh H
        • Wadhwa NK
        Iron dextran treatment in peritoneal dialysis patients on erythropoietin.
        and may reduce the amount of Epoetin needed (if used) to achieve and maintain a target Hgb/Hct. In addition, frequent administration of low doses of IV iron improves the Hgb/Hct and can reduce Epoetin requirements in hemodialysis patients (Table IV-3)
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        • Granolleras C
        • Oules R
        • Branger B
        • Fourcade J
        • Shaldon S
        Iron supplementation of hemodialysis patients receiving recombinant human erythropoietin therapy.
        • Taylor JE
        • Peat N
        • Porter C
        • Morgan AG
        Regular, low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients.
        • Sunder-Plassmann G
        • Horl WH
        Importance of iron supply for erythropoietin therapy.
        • Sepandj F
        • Jindal K
        • West M
        • Hirsch D
        Economic appraisal of maintenance parenteral iron administration in treatment of the anaemia in chronic haemodialysis patients.
        • Senger JM
        • Weiss RJ
        Hematologic and erythropoietin responses to iron dextran in the hemodialysis environment.
        (Endnote k). In addition, several studies have shown that even without the use of Epoetin, the Hgb/Hct can increase in a significant number of patients treated with frequent doses of IV iron, but not always to the target level
        • Silverberg DS
        • Iaina A
        • Peer G
        • Kaplan E
        • Levi BA
        • Frank N
        • Steinbruch S
        • Blum M
        Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.
        • Allegra V
        • Mengozzi G
        • Vasile A
        Iron deficiency in maintenance hemodialysis patients: Assessment of diagnosis criteria and of three different iron treatments.
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        (Table IV-3). Several studies have shown the superiority of IV iron therapy by comparing it to oral iron therapy and showing that IV iron therapy either increases the Hgb/Hct and/or reduces Epoetin requirements.
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        • Schaefer RM
        • Schaefer L
        Management of iron substitution during rHuEPO therapy in chronic renal failure patients.
        In the 8 studies, reported by 7 authors, in which iron stores were thought to be normal based upon a serum ferritin of >100 ng/mL (in 5 of these studies, the baseline TSAT values were 23% to 31%), the response to a prorated weekly dose of IV iron ranging from 30 to 200 mg resulted in an increase in Hgb/Hct of 19% ± 20% and a reduction in Epoetin requirements of 34% ± 27%.
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        • Granolleras C
        • Oules R
        • Branger B
        • Fourcade J
        • Shaldon S
        Iron supplementation of hemodialysis patients receiving recombinant human erythropoietin therapy.
        • Taylor JE
        • Peat N
        • Porter C
        • Morgan AG
        Regular, low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients.
        • Sepandj F
        • Jindal K
        • West M
        • Hirsch D
        Economic appraisal of maintenance parenteral iron administration in treatment of the anaemia in chronic haemodialysis patients.
        • Suh H
        • Wadhwa NK
        Iron dextran treatment in peritoneal dialysis patients on erythropoietin.
        • Senger JM
        • Weiss RJ
        Hematologic and erythropoietin responses to iron dextran in the hemodialysis environment.
        Other studies have shown the erythropoietic benefit of increasing the TSAT to >20% and serum ferritin to >100 ng/mL, respectively.
        • Tarng DC
        • Chen TW
        • Huang TP
        Iron metabolism indices for early prediction of the response and resistance to erythropoietin therapy in maintenance hemodialysis patients.
        • Rosenlof K
        • Kivivuori SM
        • Gronhagen-Riska C
        • Teppo AM
        • Slimes MA
        Iron availability is transiently improved by intravenous iron medication in patients on chronic hemodialysis.
        Table IV3. Effects of Intravenous Iron Therapy in Hemodialysis Patients
        StudyNo. of PatientsIV Iron (mg/wk)Duration (mo)Baseline/Follow-UpChanges
        Hgb/Hct%TSATFerritinHgb/HctEpoetin
        Effect in Iron Deficiency
         Sunder-Plassmann and Horl
        • Sunder-Plassmann G
        • Horl WH
        Importance of iron supply for erythropoietin therapy.
        5210069.4-11.113-2452-534+18%−17%
         Taylor et al
        • Taylor JE
        • Peat N
        • Porter C
        • Morgan AG
        Regular, low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients.
        1231610.1-11.0NA68-211+09−33%
         Sepandj et al
        • Sepandj F
        • Jindal K
        • West M
        • Hirsch D
        Economic appraisal of maintenance parenteral iron administration in treatment of the anaemia in chronic haemodialysis patients.
        505068.8-10.0NA36-217+14%−34%
        Effect with “Normal” Iron Stores
         Silverberg et al
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        4150628.7-33.727-3199-403+17%0
         Senger and Weiss
        • Senger JM
        • Weiss RJ
        Hematologic and erythropoietin responses to iron dextran in the hemodialysis environment.
        1325-501232.6-34.714-36111-609+06−75%
         Taylor et al
        • Taylor JE
        • Peat N
        • Porter C
        • Morgan AG
        Regular, low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients.
        343169.9-11.3NA176-305+14−33%
         Fishbane et al
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        20200432.5-34.423-75191-754+12−46%
         Granolleras et al
        • Granolleras C
        • Oules R
        • Branger B
        • Fourcade J
        • Shaldon S
        Iron supplementation of hemodialysis patients receiving recombinant human erythropoietin therapy.
        1830429.0-31.031-33321-654+07−30%
         Silverberg et al
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        4150633.7-33.631-29403-3830−61%
         Macdougall et al
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        1212547.3-11.926-23345-350+630
         Suh and Wadhwa
        • Suh H
        • Wadhwa NK
        Iron dextran treatment in peritoneal dialysis patients on erythropoietin.
        7*100729.0-38.018-35267-660+31−27%
        Effect without Epoetin
         Allegra et al
        • Allegra V
        • Mengozzi G
        • Vasile A
        Iron deficiency in maintenance hemodialysis patients: Assessment of diagnosis criteria and of three different iron treatments.
        119367.0-8.0NA60-5005/11 pts responded
        79367.0-7.0NA700-9000/7 pts responded
        Silverberg et al
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        5*50627.7-35.624-36145-460+17%
         Silverberg et al
        • Silverberg DS
        • Iaina A
        • Peer G
        • Kaplan E
        • Levi BA
        • Frank N
        • Steinbruch S
        • Blum M
        Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.
        33†50529.6-31.522-27106-29766%
        *CAPD patients.
        †CKD patients.
        IV Iron Protocol
        The protocol that the Anemia Work Group recommends for administering IV iron dextran or iron gluconate in adult hemodialysis patients with absolute iron deficiency is 100 mg of iron dextran or 125 mg of iron gluconate during each dialysis for 10 or 8 doses respectively. For maintenance iron therapy, and treatment and prevention of functional iron deficiency, the recommendation is 25 to 100 mg of IV iron dextran every week for 10 weeks, or 31.25 to 125 mg of iron gluconate every week for 8 weeks, with measurement of the TSAT and serum ferritin no sooner than 2 to 7 days after the last dose, depending on the magnitude of the above doses. Doses of 100 to 125 mg require 7 days to elapse for accurate monitoring.
        • Besarab A
        • Kaiser JW
        • Frinak S
        A study of parenteral iron regimens in hemodialysis patients.
        • Nissenson A
        • Lindsay R
        • Swan S
        • Seligman P
        • Strobos J
        Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American clinical trial.
        • Sunder-Plassmann G
        • Horl WH
        Safety of intravenous injection of iron saccharate in hemodialysis patients.
        • Zanen AL
        • Adriaansen HJ
        • van Bommel EFH
        • Posthuma R
        • de Jong GMT
        Oversaturation of transferin after intravenous ferric gluconate (Ferrlecit) in haemodialysis patients.
        • Roe DJ
        • Harford AM
        • Zager PG
        • Wiltbank TB
        • Kirlin L
        • Della Valle AM
        • Van Wyck DB
        Iron utilization after iron dextran administration for iron deficiency in patients with dialysis-associated anemia: A prospective analysis and comparison of two agents.
        Measurement of transferrin saturation and serum ferritin may be inaccurate if they are performed within 14 days of receiving a single dose of 1 gram or more of iron intravenously.
        • Rosenlof K
        • Kivivuori SM
        • Gronhagen-Riska C
        • Teppo AM
        • Slimes MA
        Iron availability is transiently improved by intravenous iron medication in patients on chronic hemodialysis.
        • Roe DJ
        • Harford AM
        • Zager PG
        • Wiltbank TB
        • Kirlin L
        • Della Valle AM
        • Van Wyck DB
        Iron utilization after iron dextran administration for iron deficiency in patients with dialysis-associated anemia: A prospective analysis and comparison of two agents.
        • Henderson PA
        • Hillman RS
        Characteristics of iron dextran utilization in man.
        The frequency of maintenance IV iron therapy can be thrice weekly (with every hemodialysis),
        • Granolleras C
        • Oules R
        • Branger B
        • Fourcade J
        • Shaldon S
        Iron supplementation of hemodialysis patients receiving recombinant human erythropoietin therapy.
        twice weekly,
        • Fishbane S
        • Frei GL
        • Maesaka J
        Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.
        • Taylor JE
        • Peat N
        • Porter C
        • Morgan AG
        Regular, low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients.
        weekly,
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        • Sunder-Plassmann G
        • Horl WH
        Importance of iron supply for erythropoietin therapy.
        • Suh H
        • Wadhwa NK
        Iron dextran treatment in peritoneal dialysis patients on erythropoietin.
        • Senger JM
        • Weiss RJ
        Hematologic and erythropoietin responses to iron dextran in the hemodialysis environment.
        or every other week,
        • Macdougall IC
        • Tucker B
        • Thompson J
        • Tomson CRV
        • Baker LRI
        • Raine AEG
        A randomized controlled study of iron supplementation in patients treated with erythropoietin.
        but should provide 250 to 1,000 mg of iron within 12 weeks. Iron status during the maintenance phase of Epoetin treatment should be monitored by measuring the TSAT and serum ferritin every 3 months.
        Table IV4. Iron Dextran Dosing Recommendations for Pediatric Hemodialysis Patients
        Patient Weight
        <10 kg10 to 20 kg>20 kg
        Each dose of a 10-dose course0.5 mL (25 mg)1.0 mL (50 mg)2.0 mL (100 mg)
        Table IV5. Iron Dextran Dosing Recommendations for Pediatric Predialysis and PD Patients
        Patient Weight
        <10 kg10 to 20 kg>20 kg
        Iron dose125 mg250 mg500 mg
        Volume of saline for infusion75 mL125 mL250 mL
        There have been no studies of the maintenance use of IV iron in pediatric patients. There is no rationale for prescribing oral iron supplements, given their inconvenience, cost, and side effects, when IV iron is required.
        Another recommendation of the European Erythropoetin Symposium regarding iron supplementation during Epoetin therapy was as follows: IV iron is preferable for hemodialysis patients and may also be appropriate for some patients on CAPD and for some CKD patients not on dialysis.
        • Horl WH
        How to get the best out of r-HuEPO.
        The rationale for recommending regular amounts of IV iron therapy to patients receiving Epoetin for treatment of anemia of CKD is that:
        • 1.
          Erythropoiesis requires both iron and erythropoietin.
        • 2.
          Oral iron fails to maintain adequate iron stores in most hemodialysis patients, resulting in persistence of moderate anemia, which increases morbidity and mortality.
        • 3.
          The use of IV iron will increase Hgb/Hct, and therefore improve morbidity and survival in CKD patients.
        • 4.
          The health benefits of IV iron are expected to exceed its adverse effects (see Guideline 9: Administration of a Test Dose of IV Iron Dextran), resulting in a net health benefit.
        The Use of Intravenous Iron Preparations
        There are two iron dextran preparations available for IV use in the United States, INFeD® and Dexferrum®, both of which are clinically effective. In 1999 the intravenous iron preparation, ferric sodium gluconate, Ferrlecit®, and in 2000 iron sucrose were approved for use by the Food and Drug Administration. Ferric sodium gluconate and iron sucrose have had extensive use in Europe and other countries and there is literature regarding their safety and efficacy.
        • Allegra V
        • Mengozzi G
        • Vasile A
        Iron deficiency in maintenance hemodialysis patients: Assessment of diagnosis criteria and of three different iron treatments.
        • Silverberg DS
        • Blum M
        • Peer G
        • Kaplan F
        • Iaina A
        Intravenous ferric saccharate as an iron supplement in dialysis patients.
        • Taylor JE
        • Peat N
        • Porter C
        • Morgan AG
        Regular, low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients.
        • Sunder-Plassmann G
        • Horl WH
        Importance of iron supply for erythropoietin therapy.
        • Sunder-Plassmann G
        • Horl WH
        Safety of intravenous injection of iron saccharate in hemodialysis patients.
        • Zanen AL
        • Adriaansen HJ
        • van Bommel EFH
        • Posthuma R
        • de Jong GMT
        Oversaturation of transferin after intravenous ferric gluconate (Ferrlecit) in haemodialysis patients.
        • Horl WH
        • Cavill I
        • Macdougall IC
        • Schaefer RM
        • Sunder-Plassmann G
        How to diagnose and correct iron deficiency during r-huEPO therapy—A concensus report.
        • Navarro JF
        • Teruel JL
        • Liano F
        • Marcen R
        • Ortuno J
        Effectiveness of intravenous administration of Fe-gluconate-Na complex to maintain adequate body iron stores in hemodialysis patients.
        • Rolla G
        • Bucca C
        • Brussino L
        Systemic reactions to intravenous iron therapy patients receiving angiotensin converting enzyme inhibitor.
        • Nyvad O
        • Danielsen H
        • Madsen S
        Intravenous iron-sucrose complex to reduce epoetin demand in dialysis patients.
        • Pascual J
        • Teruel JL
        • Liano F
        • Sureda A
        • Ortuno J
        Serious adverse reactions after intravenous ferric gluconate.
        Intravenous iron dextran may cause dose-related arthralgias and myalgias, as well as idiosyncratic reactions (anaphylactic-like, hypotension) that are not dose-related (see Guideline 9: Administration of a Test Dose of IV Iron Dextran). Dose-related adverse effects occur infrequently and are generally mild when doses of ≤100 mg are used.
        • Hamstra RD
        • Block MH
        • Schocket A
        Intravenous iron dextran in clinical medicine.
        • Stivelman JC
        Optimization of iron therapy in hemodialysis patients treated with rHuEPO.
        It is therefore recommended that in-center hemodialysis patients be given no more than 100 mg per dose of iron dextran IV to minimize the dose-related arthralgias/myalgias. The use of frequent, small doses of iron dextran, given as an IV “push” over 2 minutes, is also more economical than giving larger boluses administered as an intravenous infusion in dextrose in water or saline.
        • St. Peter WL
        • Lambrecht LJ
        • Macres M
        : Randomized cross-over study of adverse reactions and cost implications of intravenous push compared with infusion of iron dextran in hemodialysis patients.
        However, it is not realistic to expect a CKD, home hemodialysis, or PD patient to come to a clinic for 10 consecutive weeks to receive a cumulative iron dose of 1,000 mg in 100 mg increments. Therefore, for CKD, home hemodialysis, and PD patients who, despite oral iron supplementation, have developed evidence of iron deficiency, it is reasonable to administer IV iron dextran (in the clinic or dialysis center) in single doses of 500 to 1,000 mg diluted in 250 mL of normal saline and infused over 1 hour, and repeated as often as necessary to maintain adequate iron stores. Patients should be informed of the increased incidence of myalgias/arthralgias associated with such doses.
        Intravenous ferric sodium gluconate is now available in 62.5 mg/5.0 mL ampules. This form of IV iron has been claimed to cause “oversaturation” of transferrin, leading to hypotension, caused by free iron.
        • Zanen AL
        • Adriaansen HJ
        • van Bommel EFH
        • Posthuma R
        • de Jong GMT
        Oversaturation of transferin after intravenous ferric gluconate (Ferrlecit) in haemodialysis patients.
        However, it is now known that the term “oversaturation” may be an artifact, depending on how serum iron is measured in the clinical laboratory. One method used in the United States utilizes an acetate buffer with hydroxylamine hydrochloride, which mainly measures iron bound to transferrin (true bioavailable serum iron). However, a method that uses a buffer with ascorbic acid and guanidine, releases more iron from recently administered IV iron compounds, thus artifically raising the serum iron level, and contributing to possible “oversaturation” of transferrin, thus overestimating availability of “free iron.”
        • Seligman PA
        • Schleicher RB
        Comparison of methods used to measure serum iron in the presence of iron gluconate or iron dextran.
        If the ascorbic acid/guanidine buffer method is utilized, infusion of 62.5 mg over the course of 4 hours of dialysis will avoid this artifact, whereas the infusion of the same amount over 30 minutes and the infusion of 125 mg over 4 hours may result in transient “oversaturation” of transferrin.
        • Zanen AL
        • Adriaansen HJ
        • van Bommel EFH
        • Posthuma R
        • de Jong GMT
        Oversaturation of transferin after intravenous ferric gluconate (Ferrlecit) in haemodialysis patients.
        However, few adverse effects were reported when 62.5 mg and 125 mg doses of iron gluconate were mixed in 50 or 100 mL of saline, respectively, and infused over 30 or 60 minutes.
        • Nissenson A
        • Lindsay R
        • Swan S
        • Seligman P
        • Strobos J
        Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American clinical trial.
        Clinical trials are now in progress to determine whether bolus infusions of these amounts of iron gluconate over 5 to 10 minutes are safe. However, the infusion of more than 125 mg of iron gluconate as a bolus or infusion is not recommended at this time by the manufacturer. Therefore, the way in which intravenous iron is administered should depend upon the form of iron preparation that is used and the amount. Also, shortly after the IV administration of iron preparations, spuriously high transferrin saturation levels may occur due to the measurement of circulating drug iron.
        Possible Adverse Effects Related to Intravenous Iron Preparations The safety of IV iron dextran, iron gluconate, and iron sucrose must be considered before recommending their routine use in adult or pediatric patients as part of the overall approach to the management of anemia of CKD. There are very few large-scale studies that have examined the incidence of adverse effects associated with these preparations.
        • Faich G
        • Strobos J
        Sodium ferric gluconate complex in sucrose: Safer intravenous iron therapy than iron dextrans.
        The incidence of life-threatening/serious acute reactions to IV iron dextran has been reported to be 0.65% (3 of 471 general patients)
        • Hamstra RD
        • Block MH
        • Schocket A
        Intravenous iron dextran in clinical medicine.
        and 0.7% (4 of 573 dialysis patients).
        • Fishbane S
        • Ungureanu V
        • Maesaka JK
        • Kaupke CJ
        • Lim V
        • Wish J
        Safety of intravenous iron dextran in hemodialysis patients.
        Because patients may have a serious adverse reaction to IV iron dextran after having received IV iron dextran without incident in the past, and because patients who have a serious adverse reaction to IV iron dextran tend not to receive IV iron dextran again, the rate of serious or potentially life-threatening adverse reactions to IV iron dextran, as a proportion of injections, rather than patients, is even smaller—approximately 0.1%.
        • Hamstra RD
        • Block MH
        • Schocket A
        Intravenous iron dextran in clinical medicine.
        Although this incidence is low, it suggests that 1,200 life threatening/serious acute reactions could occur in the 200,000 hemodialysis patients in the United States if all received IV iron dextran. Some data are based on patients who received iron dextran formerly sold as Imferon®,
        • Hamstra RD
        • Block MH
        • Schocket A
        Intravenous iron dextran in clinical medicine.
        which is no longer produced in the United States, and InFeD®,
        • Fishbane S
        • Ungureanu V
        • Maesaka JK
        • Kaupke CJ
        • Lim V
        • Wish J
        Safety of intravenous iron dextran in hemodialysis patients.
        whose molecular weight is 96,000. Most of the reported adverse events were related to the use of Imferon. It is not clear whether the incidence of side effects from InFeD® is identical to that from Imferon®.
        • Lawrence R
        Development and comparison of iron dextran products.
        Another intravenous iron dextran preparation, DexFerrum® has a molecular weight of 265,000.
        • Roe DJ
        • Harford AM
        • Zager PG
        • Wiltbank TB
        • Kirlin L
        • Della Valle AM
        • Van Wyck DB
        Iron utilization after iron dextran administration for iron deficiency in patients with dialysis-associated anemia: A prospective analysis and comparison of two agents.
        • Faich G
        • Strobos J
        Sodium ferric gluconate complex in sucrose: Safer intravenous iron therapy than iron dextrans.
        There are no published data documenting the incidence of adverse events with the use of DexFerrum®. Prospective information needed to compare reaction rates between these two agents (InFeD® and DexFerrum®) is lacking. In the absence of information on mechanism of reaction, patients who have shown severe reactions to either agent should not be administered the other.
        Delayed reactions to IV iron dextran, characterized by arthralgias and myalgias, are dose-related and rarely occur with doses of 100 mg or less.
        • Hamstra RD
        • Block MH
        • Schocket A
        Intravenous iron dextran in clinical medicine.
        By contrast, as many as 59% of patients experience the arthralgia-myalgia syndrome after total dose infusion (TDI).
        • Kalantar-Zadeh K
        • Hoffken B
        • Wunsch H
        • Fink H
        • Kleiner M
        • Luft FC
        Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era.
        • Auerbach M
        • Chaudhry M
        • Goldman H
        • Ballard H
        Value of methylprednisolone in prevention of the arthralgia-myalgia syndrome associated with the total dose infusion of iron dextran: A double blind randomized trial.
        • Auerbach M
        • Winchester J
        • Wahab A
        • Richards K
        • McGinley M
        • Hall F
        • Anderson J
        • Briefel G
        A randomized trial of three iron dextran infusion methods for anemia in EPO-treated dialysis patients.
        • Ahsan N
        Intravenous infusion of total dose iron is superior to oral iron in treatment of anemia in peritoneal dialysis patients: A single center comparative study.
        Occurrence of an arthralgia-myalgia reaction should prompt a decrease in the dose of IV iron dextran administered. Low dose administration, however, may require more frequent dosing to maintain optimum iron status. Although arthralgias and myalgias have been reported with iron gluconate, these are acute, rather than delayed, and are likely attributable to the same mechanism as the arthralgias and myalgias associated with iron dextran. The relationship of arthralgias and myalgias to the rate of administered dose or total dose of iron gluconate has not been examined.
        Use of ferric sodium gluconate (Ferrlecit®) may rarely be associated with hypotension and flushing, loin pain and intense upper gastric pain, the latter without hypotension.
        • Pascual J
        • Teruel JL
        • Liano F
        • Sureda A
        • Ortuno J
        Serious adverse reactions after intravenous ferric gluconate.
        A subsequent report from the same institution regarding the same iron preparation claimed that there were no immediate or delayed adverse effects, when 62.5 mg was diluted in 50 mL of saline and given over 30 minutes.
        • Navarro JF
        • Teruel JL
        • Liano F
        • Marcen R
        • Ortuno J
        Effectiveness of intravenous administration of Fe-gluconate-Na complex to maintain adequate body iron stores in hemodialysis patients.
        Another report describes a study in which ferric gluconate was administered to three patients who were also receiving an ACE inhibitor. These patients all had iron deficiency and had normal renal function. One patient received 120 mg of ferric gluconate daily and, after the fourth infusion, developed abdominal cramps and hypotension.
        • Hamstra RD
        • Block MH
        • Schocket A
        Intravenous iron dextran in clinical medicine.
        Two other patients received 62.5 mg of ferric gluconate and developed abdominal cramps, diarrhea, and hypotension 1 hour after the end of a slow infusion of the compound. It is not clear whether the use of an ACE inhibitor was a factor in these reactions. Reactions to iron gluconate are somewhat less common than to iron dextran, and of lesser severity. There have been no reported deaths due to the IV use of iron gluconate.
        • Faich G
        • Strobos J
        Sodium ferric gluconate complex in sucrose: Safer intravenous iron therapy than iron dextrans.
        In the hemodialysis patients participating in one of the first US trials with sodium gluconate,there is no evidence that patients who react to iron dextran will react to iron gluconate.
        • Nissenson A
        • Lindsay R
        • Swan S
        • Seligman P
        • Strobos J
        Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American clinical trial.
        Iron sucrose (Venofer) has completed clinical trials in the United States, and is used extensively in Europe and Israel. The FDA approved this drug in November 2000. It is available in 100 mg (5 mL) vials. One report
        • Sunder-Plassmann G
        • Horl WH
        Safety of intravenous injection of iron saccharate in hemodialysis patients.
        noted that if transferrin levels were less than 180 mg/dL, free iron might occur if 100 mg of iron saccharate were administered. The administration of doses of 10, 20, or 40 mg of iron saccharate did not result in free iron.
        Since there are so little data published concerning the possible adverse effects of IV iron preparations, the Anemia Work Group recommends the establishment of a registry for monitoring the incidence of severe, acute, adverse reactions to IV iron in CKD patients. Such a registry should be designed by a committee of clinical, scientific, and methodological experts, maintained by parties, such as NKF-K/DOQI, without an economic interest in parenteral iron or Epoetin therapy, and used to provide periodic, published reports.
        Iron Overload
        There is little information in the literature which clearly establishes the upper limit of safety for serum ferritin in patients receiving IV iron therapy. For instance, iron overload has been defined as being present when the serum ferritin chronically remains above 1,000 ng/mL
        • Gokal R
        • Millard PR
        • Weatherall DJ
        • Callender STE
        • Ledingham JGG
        • Oliver DO
        Iron metabolism in haemodialysis patients: A study of the management of iron therapy and overload.
        or above 500 ng/mL
        • Anastassiades EG
        • Howarth D
        • Howarth J
        • Shanks D
        • Waters HM
        • Hyde K
        • Geary CG
        • Yin JAL
        • Gokal R
        Monitoring of iron requirements in renal patients on erythropoietin.