Management of chronic kidney disease and iron deficiency | Lesson

Anaemia is a common finding in chronic kidney disease (CKD) patients, underlying many of the symptoms of CKD as well as being associated with increased morbidity and mortality. Iron deficiency is the most common reversible cause of anaemia in CKD patients.

What causes iron deficiency in CKD?

Patients with advanced CKD are in negative iron balance as a result of repeated phlebotomy, gastrointestinal losses, reduced intestinal iron absorption (due to increased hepcidin levels, and medications (e.g., proton pump inhibitors and calcium-containing phosphate binders) and reduced intake due to poor appetite, malnutrition, and dietary restrictions.

How should I screen for iron deficiency in a CKD patient?

All patients with CKD 3A and above (GFR <60 mL/min) should be screened for anaemia on initial evaluation by measurement of hemoglobin (Hb) concentration. The initial work-up for anaemic patients with CKD is generally the same for CKD patients as in the general population. The work-up should include full blood count, red blood cell (RBC) indices, reticulocyte count, serum iron, total iron-binding capacity (TIBC), percent transferrin saturation (TSAT), serum ferritin, serum folate and vitamin B12 levels, and testing for occult blood in stool.

After the initial screen and evaluation, one should routinely monitor all CKD patients for the development of anaemia and iron deficiency, including FBC, TSAT (plasma iron divided by TIBC x 100), and the serum ferritin concentration.

What is the difference between ‘absolute’ and ‘functional’ iron deficiency in CKD?

It’s important to understand the difference between ‘absolute’ and ‘functional’ iron deficiency, as they are treated differently. In absolute iron deficiency there is severely reduced or absent iron stores in bone marrow, liver, and spleen. Functional iron deficiency affects iron mobilization, such that total body iron stores are adequate but there is insufficient iron available for incorporation into red blood cells.

What are the causes of functional iron deficiency in CKD?

Functional iron deficiency is frequently seen in CKD patients taking erythropoiesis-stimulating agents (ESAs), where iron release from stores into the circulation is not fast enough to keep pace with the rate of red cell production stimulated by the ESA.

Functional iron deficiency in CKD patients is also frequently due to anaemia of chronic disease due to an underlying inflammatory state, which leads to upregulation of hepcidin by inflammatory cytokines. Hepcidin is a hormone that is produced and secreted by the liver and inhibits release of iron from reticuloendothelial macrophages and hepatocytes into plasma. Hepcidin levels are increased in CKD patients. Patients with this form of functional iron deficiency frequently have elevated circulating ferritin levels.

How can one differentiate functional iron deficiency due to ESAs from the anaemia of chronic disease?

Functional iron deficiency related to ESA administration should improve with intravenous iron, while anaemia of chronic disease will not respond. As such, the distinction is usually made retrospectively by observing the response in erythropoeisis to intravenous iron while maintaining a stable ESA dose.

What tests are commonly used to diagnose iron deficiency in CKD?

Ideally diagnostic tests for anaemia should detect iron deficiency, differentiate between absolute and functional iron deficiency and predict responsiveness to iron replacement. However, no such single test exists. The gold standard for the diagnosis of iron deficiency is measurement of iron stores in bone marrow, but bone marrow biopsy is rarely performed in this setting. Instead, iron stores are usually estimated by interpreting a combination of measurements of serum iron, total iron-binding capacity (TIBC), ferritin and calculation of the TSAT.

How do the laboratory criteria used to define iron deficiency differ in CKD patients compared with patients with normal kidney function?

CKD patients tend to have higher ferritin levels than the general population, which has important implications for the diagnosis of iron deficiency. Among CKD patients not on dialysis, absolute iron deficiency is likely to be present when the TSAT is ≤20% and the serum ferritin concentration is ≤100 ng/mL. By comparison, patients with normal renal function and severe iron deficiency anaemia usually have serum ferritin concentrations under 30 ng/mL.

As kidney disease approaches end-stage, neither the TSAT nor serum ferritin predicts iron status accurately. For example, many dialysis patients with TSAT up to 30% and serum ferritin up to 500 ng/mL will respond to supplemental intravenous iron. As a result, patients with advanced CKD are usually treated with iron prior to starting an ESA.

In patients with advanced CKD, how does the response to intravenous iron differ in patients with ESA-induced functional deficiency vs. the anaemia of chronic disease?

Both of these conditions are characterised by low TSAT (usually ≤20%) and high ferritin levels (often >800 ng/mL). Patients with ESA-induced functional iron deficiency will have an erythropoietic response in conjunction with a decreasing ferritin level. By contrast, patients with anaemia of chronic disease fail to achieve increased erythropoiesis after intravenous iron. Furthermore, a course of iron therapy typically causes a progressive increase in ferritin concentration.

What are the indications for treatment with iron therapy?

Even in the absence of anaemia, most CKD patients with a TSAT under 20 percent and a serum ferritin less than 100 ng/mL have absolute iron deficiency and should be treated, initially with oral iron.

In CKD patients with anaemia, the thresholds for giving iron is lower. While most CKD patients with TSAT between 20 to 30% and ferritin up to 500 ng/mL have normal iron stores on bone marrow biopsy, many will nonetheless respond to iron. As such, iron therapy is indicated in anaemic CKD patients with TSAT under 30% and ferritin ≤500 ng/mL. CKD patients with TSAT and ferritin levels above this are unlikely to respond to iron, although each patient should be individually assessed.

How should I decide between oral versus intravenous iron?

Intravenous iron is more effective than oral iron in raising Hb levels in CKD, a finding that was confirmed in a meta-analysis of 5 trials comprising 1404 non-dialysis CKD patients.¹  However, because oral iron is cheap and does not require intravenous access, it is the initial choice in most patients with CKD not on dialysis.

Oral iron absorption tends to deteriorate as CKD advances, such that intravenous iron is often required over time, and is always required in patients on ESAs or on dialysis. Furthermore, intravenous iron may be given as first line therapy in patients that require rapid repletion of iron (e.g. symptomatic or severe anaemia, severe iron deficiency, ongoing blood loss) or are unlikely to respond to oral iron based on prior use or side effects.

A number of guidelines support this approach. The NICE guidelines suggest oral iron only for CKD patients not taking ESAs, and switching to intravenous iron if they do not respond within 3 months.²  The European Best Practice Guidelines acknowledge that intravenous iron is the optimal route of administration, but, for practical reasons, oral iron may be used first line among non-dialysis CKD patients.³ 

Importantly, intravenous iron should not be administered concomitantly with oral iron, since the absorption of oral iron will be decreased via negative feedback.

Is intravenous iron as safe as oral iron?

It is important to appreciate that in the days before the introduction of ESAs, renal anaemia was an intractable problem that could only be managed by repeated blood transfusions. ESAs have recently been linked to a number of serious adverse clinical outcomes, most notably stroke and venous thromboembolic disease. Thus, when assessing the risks of intravenous iron, one must consider that the use of iv iron results in lower requirements for ESA therapy and blood transfusions.

Historically, first generation intravenous iron preparations such as iron dextran were associated with high rates of hypersensitivity reactions, although this is less of a problem with newer formulations. There is also a body of evidence that intravenous iron may exacerbate oxidative stress, potentiate atherogenesis and cardiovascular toxicity, and increase the propensity for infections.⁴

Data on the relative safety of intravenous vs. oral iron tend be conflicting, with some showing an increased risk of adverse effects in non-dialysis CKD patients. However, observational studies of iron therapy in CKD tend to be strongly confounded by indication, as patients receiving intravenous iron tend to be generally sicker and have a higher rate of co-morbidity. In a meta-analysis of 16 randomised trials and 2612 patients, the majority of whom were non-dialysis CKD patients, there was no difference between the routes of administration in terms of all-cause mortality and adverse effects. Based on this, the general consensus is that the benefit outweighs the risk of intravenous iron in appropriately selected CKD patients.¹

What are some practical tips for the administration of intravenous iron?

All intravenous iron preparations can rarely cause hypersensitivity reactions, though the total number of life-threatening reports is low. Consequently, the first dose (either in a CKD or dialysis setting) should be administered in a clinical facility. There is no physiological basis to recommend that patients should be observed for 30 minutes after an infusion of iron is completed, since intravenous iron delivery should not be associated with a severe delayed reaction.

There is no evidence that pre-treatment with corticosteroids or antihistamines (H1 channel blockers) reduces the risk of severe reactions to intravenous iron. Paradoxically, intravenous antihistamines may be associated with unwanted side effects, particularly drowsiness or flushing upon rapid infusion. Hence no pre-treatment with corticosteroids or antihistamines is recommended in patients identified as being at potential risk of a hypersensitivity reaction.

Desensitization protocols to limit hypersensitivity reactions are not established and, therefore, not recommended. Intravenous iron should not be administered in the first trimester of pregnancy. A test dose is not useful in any circumstance to predict the risk of hypersensitivity to intravenous iron.⁴

 Are there differences between individual agents?

For oral therapy, ferrous fumarate is most commonly used in Ireland. It should be given between meals, if tolerated. Intestinal iron absorption may be normal or impaired in patients with renal failure and may be reduced by food and antacids. Giving one of the doses at bedtime may be a simple and effective approach. Other oral agents are available but none have been shown to have greater efficacy or consistently fewer side effects.

The intravenous iron compounds are all assumed to be of equal efficacy, milligram for milligram, and vary only by how much iron you can give in each single dose. There are a number of intravenous iron preparations available in Ireland, including iron dextran (Cosmofer), ferric carboxymaltose (Ferinject), iron isomaltoside (Monover; Diafer) and iron sucrose (Venofer).

The use of iron dextran has generally declined, as it is associated with a higher incidence of adverse effects, particularly anaphylaxis. Other intravenous iron preparations appear equally effective in treating iron deficiency and have similar side effect profiles, such that choosing between them comes down to cost, local formulary arrangements, and number of visits/time required to administer the full dose. Dosing regimens for individual agents are as follows:

• Iron sucrose (Venofer) – The preferred dose is 200 mg x five doses administered over two weeks, which is generally well tolerated. This dosing regimen is best suited to patients attending hospital for regular haemodialysis, with other preparations preferred in non-dialysis CKD for convenience.
• Ferric carboxymaltose (Ferinject) is effective and relatively safe. The maximum recommended cumulative dose of Ferinject is 1,000 mg of iron (20 mL Ferinject) per week.
• Iron isomaltoside (Monover) is a high-dose intravenous preparation that appears safe and effective in increasing Hb. Unlike most other intravenous iron preparations, iron isomaltoside may be given in single doses exceeding 1000 mg, up to 20 mg iron/kg body weight as an infusion.