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Treatment of iron deficiency in patients on dialysis

Treatment of iron deficiency in patients on dialysis
Literature review current through: Jan 2024.
This topic last updated: Jun 13, 2023.

INTRODUCTION — Patients on dialysis are often iron deficient due to gastrointestinal bleeding, blood drawing, operations, and the dialysis treatment itself. Patients on hemodialysis lose an average of 1 to 2 g of iron per year [1].

Adequate iron stores are essential for achieving optimal hemoglobin (Hb) levels and maximum benefit from erythropoiesis-stimulating agents (ESAs) or hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs). Decreased iron stores or decreased availability of iron are the most common reasons for resistance to the effect of these agents.

This topic reviews surveillance for iron deficiency, the indications for iron therapy, and options for treatment of iron deficiency among patients on dialysis. The evaluation and management of anemia among patients with dialysis and nondialysis chronic kidney disease is discussed elsewhere:

(See "Treatment of anemia in patients on dialysis".)

(See "Treatment of anemia in nondialysis chronic kidney disease".)

(See "Treatment of iron deficiency in patients with nondialysis chronic kidney disease (CKD)".)

(See "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)

DIAGNOSIS OF IRON DEFICIENCY — Among all individuals, the gold standard for the diagnosis of iron deficiency is a bone marrow biopsy that shows a lack of stainable iron in erythroid precursors and marrow macrophages (see "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'). However, bone marrow biopsies to assess iron stores are rarely done in patients on dialysis. Instead, iron stores are estimated in such patients. Estimation methods include measurement of the serum iron, total iron-binding capacity (TIBC), and ferritin and calculation of the percent transferrin saturation (TSAT); determination of the percentage of hypochromic red blood cells (RBCs); and determination of the reticulocyte hemoglobin (Hb) content. (See "Diagnosis of iron deficiency in chronic kidney disease".)

We use the serum iron, TIBC, and ferritin and calculation of the percent TSAT to estimate iron stores. Other methods may be more extensively used in Europe but are not widely available in the United States. (See "Diagnosis of iron deficiency in chronic kidney disease", section on 'Percent hypochromic HRCs and reticulocyte hemoglobin content'.)

The laboratory criteria that are used to define iron deficiency and provide indication for treatment are markedly different among chronic kidney disease (CKD) patients compared with patients with relatively normal kidney function. Laboratory criteria for the diagnosis of absolute and functional iron deficiency in dialysis and nondialysis CKD patients are discussed elsewhere. (See "Diagnosis of iron deficiency in chronic kidney disease".)

SURVEILLANCE — All patients should be surveilled for anemia when they start dialysis, particularly if they have not been closely followed prior to initiation of dialysis. Patients who are anemic should be surveilled for iron deficiency. (See "Treatment of anemia in patients on dialysis", section on 'Surveillance'.)

After the initial evaluation, we continue to routinely monitor all patients on dialysis for anemia and iron deficiency. Both are common among patients on dialysis; iron deficiency is a particular concern among patients on hemodialysis because of blood loss associated with the dialysis treatment and associated lab tests. Surveillance tests for iron deficiency include the percent transferrin saturation (TSAT), which is the plasma iron divided by total iron-binding capacity (TIBC) x 100, and the serum ferritin concentration. The frequency of surveillance is discussed elsewhere. (See "Treatment of anemia in patients on dialysis", section on 'Continued monitoring'.)

TREATMENT

Indications — The indications for treatment with iron vary depending upon the hemoglobin (Hb) level, whether the patient is also on erythropoiesis-stimulating agents (ESAs), and the likelihood of benefit from attaining and maintaining a higher Hb level. A detailed discussion of specific indications is presented at length elsewhere. (See "Treatment of anemia in patients on dialysis", section on 'Indications for treatment'.)

Dosing and administration

Loading dose iron — We give a loading dose of iron among patients who meet indications for treatment of iron deficiency anemia as discussed elsewhere. (See "Treatment of anemia in patients on dialysis", section on 'Indications for treatment'.)

Patients with symptoms of an underlying infection should undergo appropriate evaluation and treatment prior to treatment with iron.

We do not prescribe oral iron for treatment of iron deficiency in patients on dialysis. Our preferred regimens include:

125 mg of sodium ferric gluconate complex in sucrose given at each consecutive hemodialysis treatment for a total of eight doses (1000 mg in total) [2-7]. In patients on peritoneal dialysis, three to four doses are given weekly or less frequently (eg, monthly at dialysis clinic visits) for patient convenience.

OR

100 mg iron sucrose given at each consecutive hemodialysis treatment for a total of 10 doses (1000 mg in total) [8-14]. In patients on peritoneal dialysis, five doses are typically given (often monthly for patient convenience).

OR

Ferumoxytol 510 mg given at the end of two hemodialysis sessions one to four weeks apart [15-19]. Dosing is similar in patients receiving peritoneal dialysis.

In the United States, approximately 90 percent of patients receive iron sucrose, and most of the remaining patients receive sodium ferric gluconate [20].

Our goal with any loading regimen is to increase Hb levels and raise the transferrin saturation (TSAT). However, if the patient continues to meet criteria for iron deficiency anemia based on repeat testing of TSAT and serum ferritin at least two to three weeks after the last intravenous (IV) dose, then we give another 500 to 1000 mg of iron. (See "Treatment of anemia in patients on dialysis", section on 'Indications for treatment'.)

All IV iron preparations have the potential to be associated with acute reactions, including abdominal pain, nausea, chest pain, shortness of breath, flushing, pruritus, rash, hypotension, and anaphylactic-like reactions. The prevention and management of such reactions is discussed at length elsewhere. (See "Treatment of iron deficiency anemia in adults", section on 'Allergic and infusion reactions'.)

The approach of administering loading iron in the IV form (rather than oral) is consistent with the 2012 KDIGO guidelines and National Institute for Health and Care Excellence (NICE) guidelines [21,22]. Among patients on maintenance dialysis, compared with oral iron, IV iron is more effective for increasing Hb concentrations and iron stores [23-27]. The best data are from a meta-analysis of three trials including 300 patients on dialysis, which showed more patients achieved an Hb increase >1 g/dL with IV compared with oral iron (risk ratio [RR] 2.14, 95% CI 1.68-2.72) [27]. If patients are also being treated with an ESA, then 1 g of IV iron is expected to raise the Hb from approximately 8 g/dL to 11 to 12 g/dL [28].

Other less commonly used IV iron preparations include ferric carboxymaltose [29-32], ferric derisomaltose (formerly known as iron isomaltoside) [33], ferric pyrophosphate citrate [34], and low-molecular-weight iron dextran. In the United States, ferric carboxymaltose and ferric derisomaltose are not approved for use in patients on dialysis. However, in other countries, ferric derisomaltose is approved for use among patients receiving dialysis.

We do not use low-molecular-weight iron dextran unless it is the only IV iron preparation available because of the associated risk of adverse events (primarily anaphylaxis) [35]. The risk of anaphylaxis with the low-molecular-weight formulation, which is the only available preparation, is not likely appreciably different from other IV iron formulations. Nonetheless, because of this risk, iron dextran should be administered after an initial test dose of 25 mg. It is not necessary to premedicate patients prior to the test dose, but emergency medications (eg, epinephrine, diphenhydramine, and corticosteroids) must be readily available. Anaphylaxis may still occur when the full dose is given, despite minimal or no reactions to the test dose [35,36].

Maintenance dose iron — To ensure an adequate response with ESAs, most patients on dialysis require supplemental iron on a continuing basis for effective erythropoiesis. We give a maintenance dose of iron among patients who are deemed likely to benefit from supplemental iron while on an ESA. The indications for iron and ESAs in patients on dialysis is presented separately. (See "Treatment of anemia in patients on dialysis", section on 'Indications for treatment'.)

We prefer the following IV iron regimens for maintenance:

Sodium ferric gluconate complex in sucrose at a dose of 125 mg administered once weekly or every other week

OR

Iron sucrose at a dose of 100 mg administered once weekly or every other week  

As noted above, IV iron has been shown to be more effective than oral iron [23-27]. Thus, among patients on hemodialysis, as with the loading dose of iron, we administer maintenance iron therapy parenterally rather than orally.

Similarly, among patients on peritoneal dialysis, we give IV rather than oral iron. An exception may be among patients who have limited IV access and who require preservation of sites for hemodialysis access; among such patients, we try oral iron first. Oral iron in patients with CKD is discussed elsewhere. (See "Treatment of iron deficiency in patients with nondialysis chronic kidney disease (CKD)", section on 'Oral iron' and "Treatment of iron deficiency anemia in adults", section on 'Oral iron'.)

In addition, we identify and treat any underlying infections, if indicated, prior to treatment with iron. (See 'Loading dose iron' above.)

Once the desired Hb level is achieved, approximately 250 to 500 mg of iron may be required every three months to maintain adequate iron stores for support of erythropoiesis with ESA therapy.

Several well-designed trials have demonstrated that patients require a lower ESA dose and maintain a higher Hb when maintenance iron therapy is given [37-40]. The efficacy and safety of maintenance iron was evaluated in a noninferiority trial of 2141 patients on hemodialysis [37]. At the beginning of the trial, all patients were receiving ESA therapy and had a serum ferritin of <400 ng/mL and TSAT <30 percent. Patients were randomly assigned to receive high-dose IV iron sucrose administered proactively (400 mg monthly, unless the serum ferritin level was >700 ng/mL or TSAT was ≥40 percent) or low-dose iron sucrose administered reactively (0 to 400 mg monthly, given if serum ferritin was <200 ng/mL or TSAT was <20 percent). The median monthly dose of IV iron was 264 mg in the high-dose, proactive group and 145 mg in the low-dose, reactive group. At a median follow-up of 2.1 years, there was no difference between the groups in the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death. However, patients in the high-dose, proactive treatment group required lower ESA doses (median monthly dose 29,757 versus 38,805 units) and were less likely to receive blood transfusions than those in the low-dose, reactive group. Rates of adverse events, including infection, were comparable between the two groups [37,41].

Adverse effects — Adverse effects that have been reported with IV iron include allergic reactions (including anaphylaxis) and nonallergic infusion reactions such as self-limiting urticaria, palpitations, dizziness, and neck and back spasm and an increased risk of bacterial infection and cardiovascular events. (See "Treatment of iron deficiency anemia in adults", section on 'Allergic and infusion reactions'.)

The risk of anaphylaxis varies with individual agents. The risk is highest with iron dextran and generally lower with newer agents such as sodium ferric gluconate complex in sucrose, iron sucrose, and ferumoxytol but is very low with all available preparations.

Some studies have reported increased mortality and infection risk related to high doses of IV iron [42-44]. However, in a 2018 meta-analysis of trials and observational studies of over 241,000 patients on dialysis, compared with low-dose iron (either oral or IV), there was no increased risk of adverse events with high-dose IV iron (defined as >400 mg per month) [45]. Specifically, there was no increased risk of mortality in the analysis of the trial data (403 patients, RR 0.93, 95% CI 0.47-1.84) or observational studies (241,408 patients, RR 1.09, 95% CI 0.98-1.21). Additionally, there was no increased risk of infections, cardiovascular events, or hospitalizations with high-dose IV iron. However, the relatively small number of events and participants in the included trials and the presence of significant heterogeneity in the included observational studies were limitations that reduce the certainty around these findings. In addition, the included trials used several different iron formulations and were performed over a period of time when guidelines regarding the target Hb concentration and iron dosing practices were evolving, likely contributing to some of the heterogeneity [46].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in chronic kidney disease".)

SUMMARY AND RECOMMENDATIONS

Overview – Adequate iron stores are essential for achieving maximum benefit from erythropoiesis-stimulating agents (ESAs) or hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs). Decreased iron stores or decreased availability of iron are the most common reasons for resistance to the effect of these agents. (See 'Introduction' above.)

Diagnosis of iron deficiency – We use the serum iron, total iron-binding capacity (TIBC), and ferritin and calculation of the percent transferrin saturation (TSAT) to identify iron deficiency. (See 'Diagnosis of iron deficiency' above.)

Indications for treatment – The indications for iron treatment are discussed at length separately. (See 'Indications' above and "Treatment of anemia in patients on dialysis", section on 'Indications for treatment'.)

Dosing and administration of iron therapy – Among patients on dialysis selected for iron therapy, we recommend parenteral rather than oral iron therapy (Grade 1B). In this population, intravenous (IV) iron is more effective compared with oral iron for increasing hemoglobin (Hb) concentrations and iron stores. (See 'Dosing and administration' above.)

Loading dose – Among patients who need a loading dose of iron, we prefer one of the following regimens (see 'Loading dose iron' above):

-Sodium ferric gluconate complex in sucrose at a dose of 125 mg given at each consecutive hemodialysis session for a total of eight doses; in patients on peritoneal dialysis, three to four doses are given weekly or less frequently (eg, monthly) for patient convenience.

-Iron sucrose at a dose of 100 mg given at each consecutive hemodialysis session for a total of 10 doses; in patients on peritoneal dialysis, five doses are given (often monthly for patient convenience).

-Ferumoxytol at a dose of 510 mg given at the end of two hemodialysis sessions one to four weeks apart; dosing is similar in patients receiving peritoneal dialysis.

Maintenance dose – Among patients who need maintenance dose of iron (eg, patients on an ESA), we prefer one of the following regimens (see 'Maintenance dose iron' above):

-Sodium ferric gluconate complex in sucrose at a dose of 125 mg administered once weekly or every other week.

-Iron sucrose at a dose of 100 mg administered once weekly or every other week.

Oral iron is sometimes used in patients receiving peritoneal dialysis who have limited IV access and who require preservation of sites for hemodialysis access.

Adverse effects – Adverse effects that have been reported with IV iron include allergic reactions (including anaphylaxis) and nonallergic infusion reactions such as self-limiting urticaria, palpitations, dizziness, and neck and back spasm and an increased risk of bacterial infection and cardiovascular events. (See 'Adverse effects' above and "Treatment of iron deficiency anemia in adults", section on 'Allergic and infusion reactions'.)

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