meeting report www.kidney-international.org Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving OPEN Global Outcomes” (KDIGO) Controversies Conference Iain C. Macdougall1, Andreas J. Bircher2, Kai-Uwe Eckardt3, Gregorio T. Obrador4, Carol A. Pollock5,6, Peter Stenvinkel7, Dorine W. Swinkels8, Christoph Wanner9,Gu¨nter Weiss10, and Glenn M. Chertow11; for Conference Participants12 1Department of Renal Medicine, King’s College Hospital, London, UK; 2Allergy Unit, Dermatology Clinic, University Hospital Basel, Basel, Switzerland; 3Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 4Universidad Panamericana School of Medicine, Mexico City, Mexico; 5University of Sydney, Sydney, Australia; 6Royal North Shore Hospital, Sydney, Australia; 7Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Stockholm, Sweden; 8Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, the Netherlands; 9Renal Division, University Hospital of Würzburg, Würzburg, Germany; 10Department of Internal Medicine VI, Infectious Disease, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria; and 11Division of Nephrology, Stanford University School of Medicine, Palo Alto, California, USA Before the introduction of erythropoiesis-stimulating ron is a vital element for numerous bodily functions, most agents (ESAs) in 1989, repeated transfusions given to I notably as an ingredient of hemoglobin (Hb). Most healthy patients with end-stage renal disease caused iron overload, people can achieve a stable iron balance, managing to and the need for supplemental iron was rare. However, ingest the required amount of iron in the diet to compensate with the widespread introduction of ESAs, it was for the small amount of daily iron losses from the gut. recognized that supplemental iron was necessary to However, many patients with advanced chronic kidney dis- optimize hemoglobin response and allow reduction of ease (CKD) are in negative iron balance as a result of reduced the ESA dose for economic reasons and recent concerns dietary intake, impaired absorption from the gut, and about ESA safety. Iron supplementation was also found to increased iron losses. This is particularly true in hemodialysis be more efficacious via intravenous compared to oral (HD) patients, for whom supplemental iron is often essential administration, and the use of intravenous iron has to keep pace with blood loss and the requirements for escalated in recent years. The safety of various iron erythropoiesis. compounds has been of theoretical concern due to their Intravenous iron is a highly effective means of replacing potential to induce iron overload, oxidative stress, iron deficits and can enhance erythropoiesis, allowing lower hypersensitivity reactions, and a permissive environment requirements for ESA therapy. This is particularly important for infectious processes. Therefore, an expert group was since the realization that ESA therapy may result in a convened to assess the benefits and risks of parenteral iron, number of adverse clinical outcomes, most notably stroke, and to provide strategies for its optimal use while mitigating venous thromboembolic disease, and vascular access the risk for acute reactions and other adverse effects. thrombosis. However, aside from changes in laboratory Kidney International (2016) 89, 28–39; http://dx.doi.org/10.1016/ parameters, the evidence base evaluating outcomes related to j.kint.2015.10.002 the use of i.v. iron is sparse, and the effect of i.v. iron on hard KEYWORDS: chronic kidney disease; hypersensitivity; infections; iron; clinical outcomes including death and major health events overload; oxidative stress is uncertain. Moreover, there is evidence from laboratory, ª 2016 International Society of Nephrology. This is an open access article animal, and observational studies that i.v. iron may exacer- under the CC BY-NC-ND license (http://creativecommons.org/licenses/ bate oxidative stress, potentiate atherogenesis and cardio- by-nc-nd/4.0/). vascular (CV) toxicity, and increase the propensity for infections, as well as occasionally induce hypersensitivity Correspondence: Iain C. Macdougall, Department of Renal Medicine, King’s reactions. College Hospital, Denmark Hill, London SE5 9RS, UK. E-mail: This conference was convened to critically examine the [email protected] evidence base and to identify gaps in knowledge so as to 12See Appendix for list of other conference participants. inform future clinical research. The four main themes dis- Received 28 August 2015; revised 22 September 2015; accepted 29 cussed were: iron overload, oxidative stress, infections, and September 2015 hypersensitivity reactions. 28 Kidney International (2016) 89, 28–39 IC Macdougall et al.: Iron management in CKD: a KDIGO executive summary report meeting report ACHIEVING THE RIGHT BALANCE: IRON DEFICIENCY VERSUS deficiency is usually based on low serum ferritin concentra- IRON OVERLOAD tions (<20–30 mg/l) that reflect low body iron stores. In CKD Causes, definition, and diagnosis of iron deficiency patients, because of the presence of inflammation, threshold fi Patients with CKD are prone to iron de ciency, and its values indicating iron deficiency are generally considered to fi fi etiology is multifactorial. The de nition of iron de ciency can be higher than in those without kidney disease. Serum ferritin absolute be considered under 2 main categories: , when there is levels of 100 or 200 mg/l are frequently cited as a cutoff value fi functional 12 ade ciency of total body iron stores (Table 1); and , in non-dialysis CKD and dialysis patients, respectively. when there are ample or increased total body iron stores, but Although the evidence is rather limited, it is generally felt with sequestration of iron in the reticuloendothelial system that a transferrin saturation <20% is indicative of absolute (RES), with inadequate iron supply for erythropoiesis. iron deficiency, although transferrin saturations above this do fi 12 With respect to functional iron de ciency, sequestration not exclude this condition. fl of iron within the RES is primarily due to in ammation. Even when iron stores and circulating iron are sufficient, Since transferrin is a negative acute phase protein, serum iron supply for erythropoiesis can be inadequate, as in in- 1 transferrin tends to be reduced in CKD patients. As a stances during intense stimulation of erythropoiesis with result, total iron binding capacity is decreased. At a given ESAs, or under conditions of blocked iron release from transferrin saturation, the absolute amount of iron bound to macrophages by inflammation. transferrin in the circulation and available for erythropoiesis Percentage of hypochromic red cells and reticulocyte Hb is lower in CKD patients than in healthy people with content have been utilized as indicators of inadequate iron normal or near-normal kidney function. Stimulation of supply,11,13 but problems of analyzer availability and the need erythropoiesis with ESAs creates an increased demand for for the analysis to be performed soon after blood sampling iron and can unmask and/or aggravate decreased iron preclude their widespread adoption into routine clinical availability. practice. Iron loss is largely due to blood loss. The relation between Measuring serum hepcidin has been proposed as a means blood loss and iron loss depends on the Hb level (e.g., Hb of identifying patients who might benefit from increasing 12 g/dl: 0.40 mg iron per ml blood; Hb 10 g/dl: 0.36 mg iron either ESA or i.v. iron dosing,14 but to date, such an approach – per ml blood). In non-dialysis CKD patients, the average has not been shown to be clinically useful.13,15 17 Furthermore, – gastrointestinal blood loss can be elevated (estimated blood hepcidin assays are not harmonized or standardized.18 20 loss of 3.2 ml/d, approximately 1.2 L/yr, corresponding to about 0.4 g iron/yr) as compared to that of healthy people Doses of iron required to correct iron deficiency 2 (0.83 ml/d, corresponding to about 0.1 g iron/yr). In HD Since the true amount of iron loss in individual patients and patients, some evidence indicates an even larger increase of patient groups is uncertain, the precise doses required to 3 gastrointestinal blood loss (mean 5.0 ml/d). Procedure- and compensate for this loss inevitably remain uncertain. – laboratory test related blood loss of patients on HD is of the Applying doses of i.v. iron in excess of ongoing losses will – 4 order of 2 5 l/yr, but may vary considerably over time and result in positive iron balance, the consequences of which are fl among patients; blood loss is also in uenced, for example, by unknown. 5–7 anticoagulant and antiplatelet agent prescription. In In general, i.v. iron doses in excess of 3 g/yr are likely to be aggregate, iron losses in HD patients are considered to be of associated with an increased risk of exceeding the ongoing – the order of 1 2 g/yr, but may be highly variable, and in some iron loss and inducing positive iron balance. In patients who – patients may be as high as 4 5 g/yr. routinely receive i.v. iron, higher requirements for i.v. iron to Both ferritin and transferrin saturation have their short- maintain Hb within a target range, or within the patient’s comings in assessing iron status and guiding iron therapy in usual range, should prompt the