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Chung M, Moorthy D, Hadar N, et al. Biomarkers for Assessing and Managing Iron Deficiency Anemia in Late-Stage Chronic Kidney Disease [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Oct. (Comparative Effectiveness Reviews, No. 83.)

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

Biomarkers for Assessing and Managing Iron Deficiency Anemia in Late-Stage Chronic Kidney Disease [Internet].

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Introduction

Chronic kidney disease (CKD) is the gradual, progressive deterioration of kidney function leading to a toxic accumulation of wastes inside the body, which in turn gives rise to complications such as high blood pressure, decreased bone health, nerve damage, and anemia. The most common causes of CKD are diabetes and hypertension, though others include glomerulonephritis, inherited diseases such as polycystic kidney disease, congenital malformations of the kidney, autoimmune disorders such as lupus, and mechanical obstructions and chronic infections of the urinary tract.1 CKD patients are classified as having progressed to one of five stages, depending on the severity of their condition (CKD stage 1–5).2 When CKD progresses to its end stage (stage 5), dialysis or kidney transplantation become necessary.

CKD currently affects an estimated 26 million American adults, with a far higher number considered at risk.3 In addition to the significant detriment to the physical, mental, and social health of patients and their families that it poses, CKD comprises a tremendous individual and global financial burden.4

Background

Chronic Kidney Disease and Iron Management

Anemia is a common complication of CKD which develops early in the course of CKD and becomes increasingly severe as the disease progresses.5 Anemia remains common among patients presenting for renal transplantation, and persists in the post-transplant period.6,7 Anemia, with its associated fatigue, cognitive impairment, and diminished quality of life, is a significant problem for dialysis patients. According to the United States Renal Data System, 67 percent of patients initiating dialysis had hemoglobin (Hb) values below 11.0 g/dL.8 The most common cause of anemia in dialysis patients is inadequate erythropoietin production due to kidney damage. The second most common cause, iron deficiency, stems from inadequate diet and absorption, procedure-related iron losses from repeated laboratory testing, and blood retention in the dialyzer and tubing during dialysis.

Despite its prevalence, anemia is generally treatable, and antianemic therapy is associated with reductions in mortality, morbidity, hospitalization, and medical costs in dialysis patients.915 Before the development of erythropoietic stimulating agents (ESAs), blood transfusion was the primary treatment option for anemia associated with CKD. Now the management of anemia in CKD patients requires an appropriate balance between stimulating the generation of erythroblasts (erythropoiesis) and maintaining sufficient iron levels for optimum Hb production.16 ESAs are analogues of the natural hormone erythropoietin produced by the kidneys, the primary site of erythropoietin production in the adult. Erythropoietin enhances the growth and differentiation of erythroid progenitors. With increasing renal dysfunction, decreased levels of erythropoietin are observed, resulting in progressive anemia. With the advent of ESA therapy, the risk for transfusion-related complications (e.g., transfusion-transmitted infection, transfusion reactions, immunologic sensitization, and iron overload) has been substantially reduced.17 ESAs mobilize iron stores in promoting erythropoiesis; however, decreased iron stores or iron availability are the most common reasons for resistance to the effect of ESAs. Thus, most patients who receive ESA treatment will require supplemental (oral or intravenous) iron to ensure an adequate response with erythropietic agents. For this reason, iron management is an essential part of the treatment of anemia associated with CKD,16 as there are concerns regarding the adverse effects associated with elevated doses of ESAs18 and supplemental iron.19

Guidelines regarding the monitoring of iron deficiency and subsequent regimen of iron supplementation in patients on maintenance hemodialysis were first published by the National Kidney Foundation as part of their Kidney Disease Outcome Quality Initiative (KDOQI) in 1997, and then updated in 2000 and 2006.5,20 These guidelines describe the protocol to be followed in the management of anemia in CKD patients, including monitoring of iron status. As per the guidelines, Hb testing should be carried out annually in all patients with CKD, and such patients should be treated with ESAs when anemia is detected. Additionally, the guidelines stipulate that hemodialysis patients receiving erythropoietin should be monitored for iron deficiency using percent saturation of transferrin (TSAT, calculated as iron/total iron-binding capacity × 100), and serum ferritin (referred to as “ferritin”) concentrations every 3 months. However, the KDOQI guideline noted that there are no studies that have addressed the clinical benefit, cost-effectiveness, or risk benefit comparison of using different TSAT and ferritin levels for the diagnosis of iron deficiency. Older markers like serum iron and stainable iron in bone marrow are no longer used for monitoring in CKD patients. Serum iron is currently only assessed to aid in the calculation of TSAT. When treatment is required, the guidelines recommend the administration of sufficient iron to maintain a TSAT >20 percent and ferritin >100 ng/mL (>200 ng/mL for CKD patients on hemodialysis).5 Use of iron status markers is integral to assessment of deficiency, and to setting treatment goals in the successful management of anemia and iron deficiency in CKD patients. The National Kidney Foundation guidelines have been widely adopted in dialysis centers across the United States.

Laboratory Biomarkers of Iron Status

Assessing iron status is integral to both iron and anemia managements in CKD patients, as iron is essential for Hb formation (as is erythropoietin). Bone marrow iron stores are often regarded as the best indicator of iron status (although this is not universally accepted);16 however, taking a bone marrow sample is invasive and carries the risks of infection or bleeding at the biopsy site.21 Other classical iron status tests, of which ferritin and TSAT are the most widely used, reflect either the level of iron in tissue stores or the adequacy of iron for erythropoiesis. Serum ferritin reflects storage iron–iron that is stored in liver, spleen, and bone marrow reticuloendothelial cells. The percent TSAT (serum iron multiplied by 100 and divided by total iron binding capacity [TIBC]) reflects iron that is readily available for erythropoiesis. The TIBC essentially measures circulating transferrin. The transferrin molecule contains two binding sites for transporting iron from iron storage sites to erythroid progenitor cells. A TSAT of 50 percent indicates that half of the binding sites are occupied by iron. TSAT and ferritin level are individually most accurate as a predictors of iron deficiency or iron overload when it is either extremely low (TSAT) or extremely high (ferritin).20

Though widely used, current laboratory biomarkers of iron status are not without drawbacks when used in CKD patients: CKD is a pro-inflammatory state, and the biological variability of serum iron, transferrin saturation, and ferritin is known to be large in the context of underlying inflammation.2224 This is because transferrin and ferritin are both acute-phase reactants, and in the presence of an inflammatory condition, transferrin concentration decreases and ferritin concentration increases. There is also considerable variability in comparisons of different assays used to measure serum iron.25,26

Assessing the accuracy and reliability of laboratory biomarkers of iron status is likewise problematic, due to the lack of an established reference standard for these assays. This gap engenders an unavoidable component of measurement error in the reference standard used to assess diagnostic performance. Stainable iron from a bone marrow biopsy was previously used as a “gold standard,” but this is seldom performed, as bone marrow biopsy involves risks of infection or bleeding at the biopsy site.21 Further complicating the matter, patients with CKD may suffer from different manifestations of iron deficiency, including absolute iron deficiency (inadequate supply of iron in the body), functional iron deficiency (adequate supply but inefficient assimilation from body stores), and an extreme case of functional iron deficiency known as reticuloendothelial blockade (inadequate release of stored iron from macrophage cells of the body). These are typically identified by interpreting combinations of changes in the levels of ferritin and TSAT. The particular type of iron deficiency may affect the validity and reliability of laboratory test results for iron status and thus result in a dilemma regarding treatment decisions.24

In an attempt to find a more accurate and reliable test, several novel biomarkers of iron status have been proposed. These may address the disadvantages of using ferritin and TSAT in a pro-inflammatory state in CKD patients. Figure 1 provides an overview of iron metabolism in the body, and the role of classical as well as newer laboratory biomarkers in assessing the status of iron status. The figure indicates that these newer markers assess aspects of iron metabolism that are not assessed by those in current use, with the exception of the paramagnetic assessment of iron in the liver using Superconducting QUantum Interference Device (SQUID). These newer markers, highlighted in yellow, are thought to be less influenced by the underlying state of inflammation in CKD, and their measurement more accurately reflects the state of iron supply and demand, as compared with older markers.24

Figure 1 provides an overview of ironmetabolism in the body, and the role of classical as well as newer laboratory biomarkers in assessing iron status. The figure indicates that these newer markers, which include content of hemoglobin in reticulocytes, hepcidin, percentage of hypochromic red blood cells, reticulocyte hemoglobin equivalent, soluble transferrin receptor, and erythrocyte zinc protoporphyrin, evaluate aspects of ironmetabolism that are not assessed by those in current use, which include serum ferritin and transferrin saturation. A seventh newer marker is the paramagnetic assessment of iron in the liver using a superconducting quantum interference device. Newer markers are highlighted in yellow, while classical markers are highlighted in red.

Figure 1

Roles of current and newly proposed markers of iron status. %HYPO=percent hypochromic red blood cells; CHr=content of hemoglobin in reticulocytes; Hb=hemoglobin; SQUID= Superconducting QUantum Interference Device; sTfR=soluble transferrin receptor; ZPP=erythrocyte (more...)

As illustrated in Figure 1, three markers assess the impact of iron deficiency on formation and composition of red blood cells (RBC), usually in the context of increased demand brought on by ESA use (functional iron deficiency). The Hb content of reticulocytes (CHr) is a function of the amount of iron in the bone marrow that is available for incorporation into reticulocytes (immature RBCs)27—decreased levels of CHr indicate iron deficiency. Another is the percentage of hypochromic erythrocytes (%HYPO). This is a measurement of Hb in RBC, which factors in the absolute Hb content as well as the size of the RBC.28 This can be used to measure functional iron deficiency. (If iron supply is low in the face of ESA therapy, then there is lesser amount of Hb being incorporated into each RBC, and as a result, %HYPO levels are high.) However, this test cannot be used on stored blood, as storing blood samples causes an increase in RBC size, leading to invalid %HYPO results. The third, erythrocyte zinc protoporphyrin (ZPP) is a measure of iron incorporation in heme. When iron levels are low, zinc is used instead of iron in the formation of heme, a protein component of Hb. As a result, ZPP levels increase, indicating iron deficiency.29

A fourth marker, soluble transferrin receptor (sTfR), measures the availability of iron in the bone marrow. When the bone marrow is stimulated by ESAs, it results in increased expression of transferrin receptors on the surface of erythroblasts, the precursors of RBC. If iron supply is low, then levels of transferrin containing iron are low, and there is a mismatch between the numbers of transferrin receptors and the transferrin-iron complexes to bind with them. Some of the transferrin receptors which are not bound by iron-containing transferrin then get detached and can be detected in the blood. Increased concentration of sTfRs in the blood is an indicator of iron deficiency.

Another lesser known marker, hepcidin, a peptide produced by the liver that regulates both iron absorption in the intestine as well as release of iron from macrophages, has also been suggested as a marker of iron deficiency in CKD patients. Increased levels of hepcidin have indeed been associated with a decrease in available iron.30

It has also been hypothesized that paramagnetic assessment of iron in the liver could indicate deficiency in iron stores, but this test has only been used in the context of iron overload.31

Although a number of international guidelines have examined the use of both classical and new serum iron biomarkers, their recommendations differ. Across guidelines, it is agreed that the optimal management of anemia in hemodialysis patients depends on accurate assessment of iron status. However, a number of questions remain, including: Which combination of iron biomarkers is required? Should the newer biomarkers be used as a replacement for or in addition to classical markers?

Accurate assessment and careful management of iron status is expected to garner increased attention following the Centers for Medicare and Medicaid Services’ recent adoption of a bundled reimbursement system for dialysis, where payments are made for groups of services rather than for individual treatments.32 In view of this development and considerable clinical uncertainty, the high biological variability associated with laboratory biomarkers, and the need for frequent assessment to guide treatment for anemia, a systematic review of the relevant literature is of priority. The focus of the current review is to evaluate the strength of evidence for using these newly suggested markers, either as replacements for or additions to currently used markers, in managing iron-replacement therapy in patients with CKD.

Scope and Key Questions

Scope of the Review

The purpose of this review is to evaluate the impact on patient-centered outcomes of the use of newer versus classical laboratory biomarkers of iron status as part of the management strategies for anemia in patients with stages 3–5 CKD patients, that is, nondialysis or dialysis, or kidney-transplant patients. The newer laboratory biomarkers of interest include CHr, %HYPO, ZPP, sTfR, hepcidin, and SQUID. The classical laboratory biomarkers of interest include bone marrow iron stores, serum iron, TSAT, iron-binding capacity, and ferritin. These parameters were defined a priori with input from a panel of Key Informants and clinical experts (see Topic Refinement and Review Protocol for more details on the process).

As test results have little direct impact on patient-relevant outcomes, the utility of a medical test is usually determined by its indirect effect on outcomes, that is, through its influence on therapeutic decisionmaking and subsequently on patient outcomes. Although studies that assess the overall impact of tests on the clinical management process would provide the most direct evidence for this CER, they are often challenging or infeasible to conduct. Because we expected to find little of such evidence, the question of overall impact (Key Question 1, see below for full descriptions of all Key Questions) was broken out into three component Key Questions (Key Questions 2 to 4). Combining evidence gather to address these three component Key Questions can thus inform the conclusions for this reviews primary, overarching question.

Key Questions and Analytic Framework

Figure 2 depicts the analytic framework used in structuring this report. Broadly, it shows how the individual Key Questions are addressed within the context of the Populations, Interventions, Comparators, and Outcomes of interest.

Figure 2 depicts the logical interconnection of Key Questions within the context of PICO (patient populations, interventions, comparators, and outcomes of interest). In general, the figure illustrates how alternative diagnostic tests and test-directed treatments may result in intermediate outcomes, such as changes in iron status, hemoglobin, and ESA dosing, and other clinical and patient centered outcomes, such as mortality, morbidity, and quality of life. Adverse events may occur at any point, related to testing or to test-directed treatment. Influencing factors may affect both test performance as well as have an impact on intermediate and patient-centered outcomes.

Figure 2

Analytic framework. CKD=chronic kidney disease; ESA=erythropoiesis-stimulating agents; Hb=hemoglobin level

Key Question 1 subsumes Key Questions 2, 3 and 4, which collectively address the impact on patient centered outcomes of using the newer laboratory biomarkers as a replacement for or in addition to classical laboratory biomarkers of iron status for assessing and management of iron deficiency. Specifically, Key Question 2 addresses the performance of newer markers of iron status as a replacement for or in addition to classical markers, and Key Question 3 focuses on comparative studies of management strategies where treatment decisions are guided by test results. Since these tests are also used for monitoring purposes (e.g., predict a response to intravenous iron treatment or setting treatment targets), treatment decisions may be altered by results of the subsequent tests at every time point of their measurement. In this way, the impact of testing on outcomes is mediated through a series of treatment decisions. We aim to capture “test effectiveness” by incorporating management strategies. Additionally, we aim to evaluate whether newer laboratory markers represent iron status, and better define (with respect to older markers) targets for iron therapy.

Tests of iron status as well as the treatments guided by these tests may be associated with adverse effects or harms. These can be related to testing directly, such as test-related anxiety, adverse events secondary to venipuncture, or indirectly, through downstream treatment decisions that were influenced by testing, such as iron overload with iron treatments. Sub-Key Question 2b and 3a address these potential harms.

Key Question 4 addresses the factors that may affect test performance and clinical utility of newer markers of iron status, such as biological variation in diagnostic indices, use of different diagnostic reference standards, and patient subgroups.

The full text of the Key Questions addressed in this report appears below.

Key Question 1 (Overarching Question)

What is the impact on patient centered outcomes of using newer laboratory biomarkersa as a replacement for or an add-on to the older laboratory biomarkers of iron statusb for the 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 statusa as a replacement for or an add-on to the older markersb in stages 3–5 CKD patients nondialysis and dialysis, and in patients with a kidney transplant?

  1. What reference standards are used for the diagnosis of iron deficiency in studies evaluating test performance?
  2. 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 CKD patients, nondialysis and dialysis, 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 ESA, time in target Hb range), compared with managing iron status based on older laboratory biomarkers alone?

  1. 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 CKD patients (nondialysis and dialysis) with iron deficiency? For example:

  • Biological variation in diagnostic indices
  • Use of different diagnostic reference standards
  • Type of dialysis (i.e., peritoneal or hemodialysis)
  • Patient subgroups (i.e., age, sex, comorbid conditions, erythropoiesis-stimulating agent resistance, protein energy malnutrition secondary to an inflammatory state, hemoglobinopathies [e.g., thalessemia and sickle cell anemia])
  • Route of iron administration (i.e., oral or intravenous)
  • Treatment regimen (i.e., repletion or continuous treatment)
  • Interactions between treatments (i.e., patients treated with versus without ESA, patients treated with versus without iron-replacement therapy)
  • Other factors (based on additional information in the reviewed papers)

Organization of This Report

The results chapter of this report is organized in the order of the Key Questions. The majority of the included studies were related to test performance (Key Question 2), and they addressed many different laboratory markers and reference standard pairs. Thus, we organized studies included in Key Question 2 alphabetically by newer laboratory markers of iron status.

A list of abbreviations and acronyms can be found at the end of the report, following the references.

Content of hemoglobin [Hb] in reticulocytes, percentage of hypochromic red blood cells, erythrocyte zinc protoporphyrin, soluble transferrin receptor, hepcidin, and superconducting quantum interference devices.

Bone marrow iron stores, serum iron, transferrin saturation, iron-binding capacity, and ferritin.

Footnotes

a

Content of hemoglobin [Hb] in reticulocytes, percentage of hypochromic red blood cells, erythrocyte zinc protoporphyrin, soluble transferrin receptor, hepcidin, and superconducting quantum interference devices.

b

Bone marrow iron stores, serum iron, transferrin saturation, iron-binding capacity, and ferritin.

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