Biomarkers for Assessing and Managing Iron Deficiency Anemia in Late-Stage Chronic Kidney Disease

Anemia is a common complication of chronic kidney disease (CKD). The management of anemia in CKD patients must strike an appropriate balance between stimulating generation of erythroblasts (erythropoiesis) and maintaining sufficient iron levels for optimum hemoglobin (Hb) production. As such, it is important to assess iron stores and the availability of iron for erythropoiesis, as adequate iron status is integral to both iron and anemia managements in CKD patients. Classical iron status tests, of which ferritin and transferrin saturation (TSAT) are the most widely used, exhibit large biological variability in the context of underlying inflammation of CKD. The accurate assessment of iron status is dependent on the validity and reliability of laboratory test results, and differences in test performance pose a dilemma regarding the most appropriate test to guide treatment decisions. Several novel biomarkers of iron status have been proposed as alternatives to the classical iron status tests. These include hemoglobin content of reticulocytes (CHr), reticulocyte hemoglobin equivalent (RetHe), percentage of hypochromic erythrocytes (%HYPO), erythrocyte zinc protoporphyrin (ZPP), soluble transferrin receptor (sTfR), and hepcidin. In addition, Superconducting Quantum Interference Devices (SQUIDs) are an alternative non-invasive means for detecting and quantifying liver iron content, via the paramagnetic properties of iron (magnetic resonance diminishes in the liver as iron concentration increases). The Tufts Evidence-based Practice Center (EPC) conducted a Comparative Effectiveness Review (CER) to systematically evaluate studies that examined the impact on patient-centered outcomes of using the newer laboratory biomarkers as a replacement for or as an add-on to classical laboratory biomarkers of iron status for assessing iron status and the management of iron deficiency in adult and pediatric CKD patients (nondialysis and dialysis). The Key Questions for the CER are presented below: Key Question 1 (Overarching Question) What is the impact on patient centered outcomes of using the newer laboratory biomarkers as a replacement for or an add-on to the older (classical) laboratory biomarkers of iron status for assessing iron status and management of iron deficiency in stages 3-5 CKD patients (nondialysis and dialysis), and in patients with a kidney transplant? Key Question 2 What is the test performance of newer markers of iron status as a replacement for or an addon to the older markers in stages 3-5 CKD patients nondialysis and dialysis, and in patients with a kidney transplant? a. What reference standards are used for the diagnosis of iron status in studies evaluating test performance? b. What are the adverse effects or harms associated with testing using newer and/or older markers of iron status? Key Question 3 In stages 3-5 nondialysis and dialysis CKD patients with iron deficiency, what is the impact of managing iron status based on newer laboratory biomarkers either alone or in addition to older laboratory biomarkers on intermediate outcomes (e.g., improvement in Hb levels, dose of erythropoiesis-stimulating agents, time in target Hb range), compared with managing iron status based on older laboratory biomarkers alone? a. What are the adverse effects or harms associated with the treatments guided by tests of iron status? Key Question 4 What factors affect the test performance and clinical utility of newer markers of iron status, either alone or in addition to older laboratory biomarkers, in stages 3-5 (nondialysis and dialysis) CKD patients with iron deficiency?