2018/07/23 by Colin Geddes · 1 voice
Medicine · #Iron Metabolism and Disorders #Dialysis and Renal Disease Management #Hemoglobinopathies and Related Disorders
paper · doi:10.1093/ndt/gfy266
openalex publication_date 2018/07/23 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
Anaemia remains a prominent feature of chronic kidney disease (CKD). The prevalence is inversely correlated with kidney function, and the vast majority of patients with CKD Stage 5 develop anaemia [1]. Insight into the multiple factors involved in the pathogenesis of anaemia has improved recently and has led to important developments in treatment options. The dominant contributing factors are inadequate production of erythropoietin (Epo) and iron deficiency, but other factors are important for clinicians to consider (Figure 1). Schematic representation of factors involved in the pathophysiology of anaemia in patients with chronic kidney disease. The bold arrows represent the more dominant pathways. In health, the kidneys have a major role in the homeostasis of erythrocytosis to ensure optimal tissue oxygen delivery. The unique capillary architecture of the nephron means that peri-capillary interstitial fibroblasts in the cortex and outer medulla exist in a relatively oxygen-starved environment and hence are ideally suited to respond to subtle reductions in oxygen delivery. Reduced oxygen delivery activates hypoxia-inducible factors (HIFs) leading to increased transcription of genes, in turn leading to Epo synthesis [2]. Epo binds to the Epo receptor expressed on erythroid progenitor cells, inhibiting apoptosis and, therefore, enhancing the population of circulating red blood cells. As kidney function declines, most patients develop anaemia. This usually becomes clinically significant when the estimated glomerular filtration rate falls to <30 mL/min/1.73 m2, but there is wide inter-individual variability. Circulating Epo concentrations are usually normal in anaemia of CKD but inappropriately low for the level of anaemia. Patients with CKD are prone to both absolute iron deficiency and so-called functional iron deficiency. The hepatically derived hormone hepcidin plays a major role. Absolute iron deficiency occurs due to a combination of: Tendency to poor dietary iron intake when uraemia causes anorexia. Impaired iron absorption. This relates mainly to elevated hepcidin levels. Hepcidin was discovered at the beginning of this century. It is produced by the liver in response to a number of factors including body iron status and inflammatory cytokines, and binds to ferroportin on the basolateral surface of gut enterocytes, thereby inhibiting absorption of iron from the gut lumen [3]. Chronic inflammation is a feature of CKD. Hepcidin is also cleared by the kidneys. These two factors therefore contribute to increased hepcidin levels in CKD which in turn leads to reduced iron absorption [4]. Gastrointestinal bleeding is more common in patients with CKD due to a combination of gastrointestinal lesions such as mucosal angiodysplasia and uraemic platelet dysfunction [5]. Functional iron deficiency refers to the observation that patients with CKD tend to have an improvement in anaemia with exogenous iron administration when conventional measures of iron stores (serum ferritin, transferrin saturation and bone marrow iron staining) are normal. This is probably mainly mediated by elevated hepcidin levels removing non-transferrin-bound iron from the circulation by mediating trapping of iron in macrophages [4]. In health, the effect of trapping iron in macrophages denies pathogenic bacteria access to iron essential for proliferation. Inflammatory cytokines are known to impair responsiveness of the bone marrow to Epo, leading to anaemia of chronic disease. Elevated levels of inflammatory cytokines are common in patients with CKD [6]. Shortened circulating red blood cell survival has long been recognized as a feature of CKD but the mechanism remains elusive [7]. Secondary hyperparathyroidism is also a common feature of advancing CKD, and severe hyperparathyroidism is a recognized cause of resistance to erythropoiesis-stimulating agents (ESAs). The molecular mechanisms are poorly understood but seem to involve a combination of direct effects of parathyroid hormone (PTH), causing reduced Epo synthesis and inhibition of bone marrow erythroid progenitors, and a reduction of bone marrow tissue due to PTH-induced bone marrow fibrosis [8]. When clinicians are faced with a patient with CKD who is anaemic, it is important to consider other factors that may be contributing especially when there appears to be resistance to conventional doses of ESA and iron. These include vitamin B12 and folate deficiency due to poor dietary intake, numerous medicines that suppress bone marrow such as cyclophosphamide and mycophenolate mofetil, and medicines that suppress Epo production (angiotensin-converting inhibitors and angiotensin receptor blockers) [9]. The underlying cause of CKD may be a significant contributor, e.g. myeloma. Intra-dialytic haemolysis remains a rare but important consideration in patients on haemodialysis. Pure red cell aplasia caused by anti-Epo antibodies induced by ESA therapy has almost disappeared after withdrawal of the causative ESA preparations [10]. The dominant causes of anaemia in CKD are relative Epo and iron deficiencies, and in most patients anaemia can be successfully treated by ESA and by oral or intravenous iron supplementation. ESAs were a major progress in the management of advanced CKD 30 years ago, but subsequent clinical trials revealed unanticipated concerns about effectiveness and safety (beyond the scope of this review). The advances in our understanding of the pathophysiology of anaemia in CKD have led to emerging therapeutic interventions, such as HIF stabilizers, hepcidin antagonists, ferroportin stabilizers and novel oral iron therapies, which may prove to be better than the existing approaches. The lesson from the first 30 years of effective treatment for anaemia of CKD is that the pathophysiology is complex and the nephrology community should demand and embrace well-designed clinical trials to establish the safest and most effective way to use these newer agents. None declared. The results presented in this paper have not been published previously in whole or part.