Management of Anaemia in Chronic Kidney Disease
Introduction
The development and progression of anaemia is an almost universal consequence of chronic kidney disease (CKD) and worsens with progressive loss of kidney function. Anaemia is considered both a risk marker and a risk amplifier in that it accelerates the risk of major events such as hospitalisations, stroke, myocardial infarction, and death in patients who have anaemia compared to those who do not. The mechanisms through which anaemia develops in CKD are diverse and complex. Studies over the past 20 years have elucidated mechanistic pathways and generated novel therapeutic interventions. Defective erythropoiesis, iron deficiency, and abnormal iron regulation coupled with a heightened inflammatory system have all conspired to drive the development of anaemia in CKD. The management of anaemia has been revolutionised with the wide availability of recombinant erythropoietin and increased utilisation of intravenous iron. More recently the discovery of a novel set of drugs, the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), has added to these treatment strategies. Optimisation of anaemia management is associated with improved quality of life, exercise tolerance, and lower risks of adverse clinical outcomes.
Evaluation of Anaemia in CKD
Anaemia is defined as a haemoglobin of <13g/dL in men and <12g/dL in non-pregnant women.1 The prevalence of anaemia increases with advancing age and with worsening kidney function.2 A recent study by Clancy et al found that the prevalence of anaemia among patients in the Irish health system increased from 8.2% in individuals with GFR > 90 ml/min/1.73m2 to 64% for those with advanced kidney disease eGFR < 30 ml/ min/1.73m2, compared with an overall prevalence of 12% in the general population.3 Once anaemia is diagnosed, a detailed evaluation should seek to identify underlying causes.
The majority of patients with CKD will have a multifactorial anaemia with contributions from iron deficiency and anaemia of chronic disease.4 A focused clinical evaluation should evaluate for blood loss, the presence of comorbidity, and prescribed medications especially the use of antiplatelet agents and anticoagulants. With more advanced CKD, erythropoietin deficiency becomes a more significant contributory factor. The routine full blood count may reveal a microcytic (MCV <80 fL) picture if iron deficiency is a predominant contributor. First-line investigations should include a full blood count (including white cell differential, platelets), absolute reticulocyte count, transferrin saturation (TSAT), ferritin, B12 and folate concentrations, as well as a faecal occult blood test.5
Importance of Iron Deficiency in CKD
Iron deficiency is common contributor to the anaemia of CKD with approximately 60% of patients affected at the start of dialysis. It can present either as functional iron deficiency – inadequate iron supply to meet demand despite normal iron stores – or absolute iron deficiency – a reduction in stored iron. In general, the detection of iron deficiency requires measurement of transferrin saturation ratio (TSAT), which is a measure of functional iron deficiency, and the plasma ferritin which measures iron storage. Absolute iron deficiency in CKD is generally defined as a TSAT <20% and serum ferritin <100ng/ mL (or <200ng/mL in patients on haemodialysis). This cut off is higher in CKD compared with the general population because plasma ferritin levels increase in states of inflammatory stress such as chronic kidney disease.6 In functional iron deficiency, the TSAT is generally <20% and plasma ferritin levels are elevated.
Management of Anaemia in CKD
The management of anaemia of CKD depends on many factors and requires a balanced approach to treatment. The approach will vary according to stage of CKD, the severity of anaemia, the co-presence of iron deficiency, and may differ according to practice patterns within countries. In general, guidelines recommend correction of iron deficiency in the first instance. Treatment with erythropoietin may be indicated where there is persistent anaemia in the setting of advanced CKD and a rise in haemoglobin level is desired. Oral iron supplementation should be considered in the initial treatment of absolute iron deficiency. Oral iron is cheap and easy to administer, but is associated with gastrointestinal upset, non-adherence, and poor absorption. Intravenous iron may be the preferred option in symptomatic or severe iron deficiency (TSAT <12%), and for those who do not tolerate or fail to respond to oral iron. Intravenous iron fully corrects iron deficiency, bypasses need for GI absorption and is incorporated more rapidly into RBCs than oral iron, and delays or avoids the need for erythropoietin therapy.6
The goal of treatment is to correct iron deficiency and increase the haemoglobin concentration. For patients who are receiving dialysis, the target haemoglobin levels are generally between 10-12 g/ dl. There are no evidence-based target haemoglobin concentrations for patients with CKD and not requiring dialysis, but in general levels should not exceed 13 g/ dl, due to an association between higher haemoglobin levels and adverse clinical outcomes.7
Erythropoietin stimulating agents (ESAs) are generally indicated for the correction of anaemia where patients have persistent anaemia, (Hb <10g/dl) despite adequate iron stores. These agents are administered subcutaneously for patients with non-dialysis dependent CKD or intravenously for those on dialysis. ESA are contraindicated in patients with active malignancy or prior stroke, where the risks may outweigh the benefits.8
A new class of agent, the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs) has emerged for the treatment of CKD-associated anaemia. Their novel mechanism of action mimics the natural response of the body to hypoxia and stimulates the transcription of the endogenous erythropoietin gene. Evidence from randomised clinical trials have shown them to increase haemoglobin levels, reduce blood transfusions, and improve iron homeostasis, though there are some concerns regarding the higher risk of thromboembolic events.9, 10
Conclusion
Anaemia in CKD is highly prevalent and confers a substantial burden on both patients and the healthcare system. The aetiology is multifactorial, and thus therapeutic strategies must be individualised. Targeted screening of high-risk groups should be performed on a routine basis. Simple measures should be implemented to correct deficiencies wherever possible. Novel therapies such as ESAs and HIF PHIs are emerging as treatments where first line measures are insufficient. Clinicians must remain vigilant and endeavour to continuously improve the identification and treatment of patients with anaemia and CKD.
References available on request
Written by Dr Niamh Corcoran1 Specialist Registrar in Nephrology and Professor Austin Stack1,2 Professor of Medicine, Consultant Nephrologist
1Department of Nephrology, University Hospital Limerick,
2School of Medicine, University of Limerick
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