OPTA-therapy with iron and erythropoiesis-stimulating agents in chronic kidney disease

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1 Nephrol Dial Transplant (2007) 22 [Suppl 3]: iii2 iii6 doi: /ndt/gfm014 OPTA-therapy with iron and erythropoiesis-stimulating agents in chronic kidney disease W. H. Ho rl 1, I. C. Macdougall 2, J. Rossert 3 and R. M. Schaefer 4 1 Klinische Abteilung fu r Nephrologie und Dialyse, Medizinische Universita tsklinik III, Wa hringer Gu rtel 18 20, 1090 Wien, Austria, 2 King s College Hospital, London, UK, 3 Paris-Descartes University School of Medicine, AP-HP, Georges Pompidou European Hospital, Paris, France and 4 Universita tsklinikum Mu nster (UKM), Innere Medizin D, Albert-Schweitzer-Straße 33, Mu nster, Germany Introduction Anaemia is a severe problem for patients suffering from chronic kidney disease (CKD). Anaemia is occasionally observed among patients with glomerular filtration rate (GFR) of ml/min (stage III of CKD). Majority of the patients with GFR <30 ml/min exhibit renal anaemia. Diabetic patients may develop anaemia earlier than those with non-diabetic CKD (e.g. GFR of <45 ml/min). The European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure [1] recommend therapy with erythropoiesis stimulating agents (ESA) for patients in whom the haemoglobin concentration is <11 g/dl and additional causes for anaemia, such as iron deficiency, bleeding or malignancy are excluded. Early treatment of anaemia is recommended, since reduced haemoglobin values are associated with left ventricular hypertrophy, increases in morbidity and mortality, increases in the frequency and duration of hospitalization and reduction in quality of life. An adequate measurement of iron status at the beginning of treatment and regular monitoring of iron blood parameters are critical for cost-effective therapy with ESA. Monitoring of iron status Ferritin Serum ferritin levels, as a measure of iron storage in the body, should be quantitated every 3 months in CKD patients who are receiving iron supplementation. This is required to exclude iron deficiency or iron overload. Serum ferritin <15 mg/l in subjects with normal kidney function is an indication of absolute iron deficiency [2]. CKD patients are considered to have absolute iron deficiency if serum ferritin levels are <100 mg/l [3]. The recommended serum ferritin target level in ESA-treated CKD patients receiving iron supplementation is mg/l. In patients on maintenance dialysis therapy, ferritin target level is mg/l [4]. Intravenous administration of iron can result in transient increases in serum ferritin. Therefore, an interval of 1 week should be maintained between intravenous iron administration (i.e mg ferric gluconate or 100 mg iron sucrose) and measurement of serum ferritin. With lower doses of intravenous iron (i.e. 20 mg of ferric gluconate or iron sucrose following each haemodialysis treatment), serum ferritin can directly be measured. In certain conditions, serum ferritin increases due to causes unrelated to an increase in iron storage. Liver disease, malignancy, infection or inflammation can result in increased serum ferritin levels independent of iron status. Transferrin saturation Transferrin saturation (TSAT) is a parameter measuring the degree to which circulating transferrin is loaded with iron. The normal range is between 20 and 45%. Erythropoiesis usually becomes iron-deficient when TSAT falls <20%. Iron supplementation should be initiated around or below these TSAT levels. This is especially important when erythropoiesis is pharmacologically stimulated through ESA treatment. Iron supplementation is mandatory if TSAT levels are <15%. Treatment with higher ESA doses can result in a decrease in TSAT levels even under conditions of sufficient iron storage. This constellation is referred to as»functional iron deficiency«. A low TSAT (<20%) is a good indicator (approximately 90% sensitivity) of iron deficiency but specificity is low (approximately 40%). In the case of»functional iron deficiency«infection or inflammation should be ruled out by measurement of C-reactive protein (CRP). If the CRP is normal, supplementation of vitamin C (1 1.5 g orally per week or mg i.v. after haemodialysis ß The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 OPTA-therapy in CKD depending on the degree of vitamin C deficiency) may result in release of iron from storage reservoirs, increase in haemoglobin levels and decrease in ESA dose [5 7]. Serum iron concentrations follow a circadian rhythm with the highest values occurring in the morning and a nadir in the evening. As a result, the TSAT undergoes a similar circadian rhythm. It is recommended to draw blood for TSAT measurement if possible in the morning. It is difficult to compare TSAT values from blood samples collected at different times of the day. Evaluation of iron supply in the bone marrow percentage of hypochromic red blood cells The appearance of hypochromic red blood cells in the circulation is a sensitive parameter for iron-deficient erythropoiesis and insufficient iron supply in the bone marrow. Ferritin and TSAT are only indirect indicators of the amount of iron available for erythropoiesis. The percentage of hypochromic red blood cells, however, serves as a direct estimation of the iron available for red blood cell development. Circulating hypochromic erythrocytes normally correspond to <2.5% of red blood cells. Values >10% indicate with high sensitivity the occurrence of iron-deficient erythropoiesis. The percentage of hypochromic red blood cells can reach 50% in cases in which extended iron deficient erythropoiesis during ESA treatment occurs [8]. The quantitation of hypochromic red blood cells requires the employment of specific devices (Technikon H*3 or ADVIA-120 analysers) which measure haemoglobin content in single cells by flow cytometry. The parameter is stable over 24 h. Therefore, it is possible to draw a blood sample in an EDTA tube and ship it to a laboratory employing such devices. Haemoglobin content of reticulocytes (CHr) Modern blood cell analysers allow quantitation of reticulocytes as well as analysis of individual cells with respect to cell volume (MCVr) and haemoglobin content of reticulocytes (CHr) [6]. According to Fishbane et al. [9], a CHr <29 pg as measured by a Technikon H*3 blood analyser indicates the presence of iron-deficient erythropoiesis. In contrast to serum ferritin and TSAT, CHr is a direct indicator of iron availability in bone marrow [9]. Recently, Tsuchiya et al. [10] reported that iron-deficient erythropoiesis was already present in haemodialysis patients at CHr values below 32 pg. CHr was measured using an ADVIA-120 system. CHr was shown to be a stable and reliable parameter for estimation of iron availability in the bone marrow. The authors favoured quantitation of haemoglobin and CHr (obtained from a single blood sample) as laboratory parameters necessary for control of iron supplementation and response to epoetin administration [10]. Brugnara et al. [11] compared reticulocyte and red cell measurements iii3 of haemoglobin contents provided by the ADVIA 2120 and Sysmex XE 2100 analysers in 1500 adult and paediatric dialysis patients. The authors demonstrated that with a reticulocyte haemoglobin cut-off level of 27.2 pg, iron deficiency can be diagnosed with a sensitivity of 93.3% and a specificity of 83.2% [11]. In the presence of functional iron deficiency (normal or increased ferritin with simultaneous reduction in TSAT), the determination of the percentage of hypochromic red blood cells and CHr can be used to establish if iron supplementation should be initiated or continued [12]. Practical considerations Serum ferritin and TSAT should be determined before the start of ESA therapy. The response to ESA is optimal when serum ferritin is >200 mg/l and TSAT is >20%. Both parameters should be measured four times per year during maintenance epoetin therapy. The following causes should be excluded if the response to ESA is inadequate (Table 1). The determination of the percentage of hypochromic red blood cells or the haemoglobin content of reticulocytes is diagnostically helpful if functional iron deficiency is suspected. Intravenous iron supplementation is indicated even in the presence of elevated serum ferritin levels if the percentage of hypochromic erythrocytes is >10% and CHr is >29 pg [8]. However, iron supplementation should be used with extreme caution in patients with hepatitis B or C, and should be stopped at least temporarily in those with acute bacterial infections. The number of reticulocytes should be determined if haemoglobin values decrease approximately 0.1 g/dl per day or in cases in which the patient requires more than one unit of packed red cells per week. Reticulocyte values below /ml require testing for the presence of ESA-neutralizing antibodies and bone marrow examination. These analyses must be undertaken to rule out the occurrence of ESAinduced erythroblastopenia (normal bone marrow cellularity with <5% erythroblasts and disturbed differentiation of the erythroid lineage). The number Table 1. Causes of Reduced Response to ESA Absolute iron deficiency, serum ferritin <100 mg/l Functional iron deficiency, serum ferritin >100 mg/l with TSAT <20% and hypochromic erythrocytes >10% or CHr <29 pg Blood loss Infection, inflammation: elevated CRP Pharmacological therapy: high dose ACE-inhibitors and/or AT1-receptor antagonists, cyclophosphamide, azathioprine, mycophenolate-mofetil [13] Inadequate dialysis: Kt/V <1.2, urea reduction rate (URR) <60% Malignant disease Bone marrow diseases: plasmacytoma, myelodysplastic syndrome, leukaemia

3 iii4 of leucocytes and thrombocytes do not decrease in this disease state. Iron therapy Iron requirements Approximately 150 mg iron is required for each 1 g/dl increase in haemoglobin concentration. A typical correction of 3 4 g/dl requires mg of iron. During the maintenance phase of ESA treatment, the loss of blood resulting from the haemodialysis procedure increases the iron requirement to 1 3 g per year. Iron supplementation at such quantities is only possible through intravenous administration. The majority of patients cannot ingest such high doses of iron in oral form without intestinal adverse effects. The risk of iatrogenic iron overload with intravenous iron administration is low if regular measurements of serum ferritin are carried out [14]. Iron requirements for patients with chronic renal insufficiency (CKD stages 2 4), renal transplant patients and peritoneal dialysis patients are lower than those of patients undergoing haemodialysis. Pre-dialysis and renal transplant patients mostly suffer from less-pronounced anaemia, and iron loss does not occur in peritoneal dialysis patients as compared to haemodialysis patients. In those patients, oral iron supplementation ( mg iron per day) can be tried. If iron status does not improve at such a dosage, or if oral ingestion results in intestinal sideeffects, then iron can be administered intravenously. Iron preparations for intravenous administration There are different iron preparations for intravenous injection available in Europe, varying from country to country. In Germany, for example, there are three different products available:: Ferrlecit Õ, Venofer Õ and CosmoFer Õ. Ferrlecit Õ is an iron-(iii)-gluconate complex, Venofer Õ consists of iron-(iii)-hydroxide-sucrose and CosmoFer Õ is an iron-(iii)-hydroxide-dextrancomplex. The three compounds differ with regard to stability and incidence of anaphylactoid reactivity. Iron dextran is more stable than iron sucrose which in turn is more stable than ferric gluconate. The stability of the iron complexes is clinically relevant because stable complexes are less likely to lead to toxicity. This is reflected in the maximal single dosage recommendations: CosmoFer Õ 20 mg/kg body weight; Venofer Õ 500 mg; Ferrlecit Õ 62.5 mg [15 17]. Intravenously administered iron preparations can potentially induce anaphylactic reactions. According to the manufacturers, the frequency of anaphylactic reactions is <1/100 with CosmoFer Õ, <1/1000 with Ferrlecit Õ and <1/ with Venofer Õ. Some manufacturers suggest administration of a small test dose prior to the first intravenous iron administration. The injection should be carried out with the patient in a supine position. W. H. Ho rl et al. Dosage and frequency of administration The dosage of iron during the correction phase of anaemia therapy in haemodialysis patients should correspond to a total of 1000 mg iron (over a period of 6 12 weeks) to ensure that iron supply is sufficient to fill iron stores and to optimize ESA-stimulated erythropoiesis. Iron requirements during the maintenance phase of therapy vary considerably. Various therapeutic regimens can be used (Table 2). The dose spectrum varies from small amounts of iron (10 20 mg) at each dialysis session to 250 mg of iron sucrose as a single infusion once monthly [18]. Agarwal et al. [19] administered 100 mg of iron sucrose over 5 min, whereas Macdougall and Roche [20] administered 200 mg of iron sucrose as an intravenous bolus injection of 2 min in CKD patients. On the other hand, Leehey et al. [21] infused 125 mg of ferric gluconate over 1 h and 250 mg of ferric gluconate over 2 h in patients with CKD. These data indicate an enormous flexibility in the actual dose regimen. Intravenous iron has been linked to infection risk, systemic inflammation, tissue oxidation and atherosclerosis (for review [14]). A recent multicentre trial of Aronoff et al. [22] demonstrated that iron sucrose is safe when given as treatment for iron deficiency or for maintenance of iron stores. Iron requirements of pre-dialysis patients, peritoneal dialysis patients and renal transplant patients The iron requirements of pre-dialysis patients, peritoneal dialysis patients and renal transplant patients are usually lower than those of haemodialysis patients, since anaemia is usually less pronounced, and haemodialysis-associated blood loss does not occur. In long-term renal transplant recipients, the prevalence of iron deficiency, as indicated by a percentage of hypochromic red blood cells of 2.5%, was 20.1% [23]. Iron requirements are lower both during the correction phase and during the maintenance phase of ESA therapy. Iron can be administered in an oral form at the outset of treatment. In most of the studies, intravenous iron therapy was more effective than oral iron supplementation [24 29]. Table 2. Intravenous iron dosage and administration frequency in haemodialysis patients during maintenance of ESA-therapy Absolute iron deficiency mg Fe/dialysis session or mg Fe in 6 10 weeks Maintenance phase mg Fe sucrose/dialysis session or mg Fe gluconate/week or mg Fe gluconate/week or mg Fe sucrose/month or mg Fe dextran (low-molecular weight)/month > or mg Fe sucrose/month (depending on ferritin level) Hb correction phase 150 mg Fe/Hb increase of 1 g/dl

4 OPTA-therapy in CKD Guidelines for intravenous iron injection The available iron preparations allow safe and efficient intravenous administration of iron. Caution must be used to ensure strictly intravenous application. Intravenous iron must be injected slowly enough to mitigate any risk of side effect. Injection time should be even longer with high iron doses. Intravenous iron injection in haemodialysis patients is for the most part uncomplicated because patients usually have suitable intravenous access. Iron injection can proceed slowly during the dialysis session. iii5 growth of many microorganisms. Intravenous iron substitution should proceed conservatively in patients with permanent dialysis catheters (higher risk of infection) and/or in the presence of hepatitis B and/or hepatitis C infection (more unfavourable prognosis?). Patients with chronic inflammatory diseases (e.g. chronic arthritis, Crohn s disease) can receive intravenous iron therapy in a normal manner. Conflict of interest statement. None declared. Importance of intravenous iron therapy Intravenous iron supplementation is required to fill depleted iron stores in a short period of time and to provide the iron required for increased haemoglobin synthesis associated with ESA-stimulated erythropoiesis. It has been shown in a number of studies [30] that the most decisive factor for optimal utilization of epoetin is an adequate provision of iron. The studies by Sunder-Plassmann and Ho rl [31], Besarab et al. [32] as well as De Vita et al. [33] have shown impressively the large potential to reduce effective ESA doses when existing iron deficiency is corrected. Summary Serum ferritin concentration and TSAT are used as routine diagnostic parameters for the assessment of iron status during ESA therapy in CKD patients. The analyses of the percentage of hypochromic red blood cells or of reticulocyte haemoglobin content, although not available in many clinical centres, facilitate the decision to proceed with intravenous iron substitution in the presence of hyperferritinaemia and low TSAT. The risk of iron overloading is low if parenteral iron substitution therapy is adapted to haemodialysisassociated iron losses (1 3 g/year). The iron requirements of pre-dialysis patients, peritoneal dialysis patients and renal transplant patients are lower than those of haemodialysis patients. An initial course of oral iron substitution may be warranted in these patients. However, most of those patients must be switched eventually to intravenous iron administration, since oral administration becomes ineffective. Serum ferritin should be regularly measured (four times per year) during intravenous iron therapy. Ferritin concentrations above 500 mg/l (in the presence of normal CRP) should be avoided over an extended time period to prevent iatrogenic iron overloading. Iron therapy should be discontinued (while still continuing ESA therapy) in the vast majority of the patients if ferritin concentrations increase above 500 mg/l. Iron therapy should also be discontinued during acute bacterial infections since iron stimulates References 1. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004; 19 [Suppl 2]: ii1 ii Galloway MJ, Smellie WS. Investigating iron status in microcytic anaemia. Br Med J 2006; Ho rl WH, Cavill I, Macdougall IC, Schaefer RM, Sunder- Plassmann G. How to diagnose and correct iron deficiency during r-huepo therapy a consensus report. Nephrol Dial Transplant 1996; 11: K/DOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in adults. 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