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

INTRODUCTION — Anemia is common among patients with chronic kidney disease (CKD). Anemia underlies many of the symptoms associated with reduced kidney function and is associated with increased mortality and hospitalizations [1-4].

Among patients with CKD, iron deficiency is a common, reversible cause of anemia and resistance to erythropoiesis-stimulating agents (ESAs). The administration of iron is necessary for treatment of iron deficiency and, in selected patients, may allow a higher hemoglobin (Hb) in the absence of ESAs.

This topic reviews screening for iron deficiency, the indications for iron therapy, and options for treatment of iron deficiency among patients with nondialysis CKD. The treatment of iron deficiency in patients on dialysis is discussed elsewhere.

●(See "Treatment of iron deficiency in patients on dialysis".)

Indications for treatment with ESAs are discussed separately.

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

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

DIAGNOSIS OF IRON DEFICIENCY — We use the serum iron, total iron-binding capacity (TIBC), serum ferritin, and calculation of the percent transferrin saturation (TSAT) to estimate iron stores. Other methods including the percentage of hypochromic red blood cells (RBCs) or reticulocyte hemoglobin (Hb) content are not widely available in the United States but may be more widely used in Europe [5]. Bone marrow biopsies are considered the gold standard for diagnosis but are not commonly used among patients with CKD.

The laboratory criteria for TSAT and serum ferritin that are used to diagnose iron deficiency in patients with CKD are markedly different from those in patients with relatively normal kidney function. Laboratory criteria for the diagnosis of absolute and functional iron deficiency in patients with nondialysis CKD and in patients on dialysis are discussed elsewhere. (See "Diagnosis of iron deficiency in chronic kidney disease".)

SCREENING FOR ANEMIA AND IRON DEFICIENCY

Initial screen — All patients with CKD, particularly those with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², should be screened for anemia on initial evaluation for CKD. We screen for anemia using measurement of hemoglobin (Hb) concentration.

Patients who are found to be anemic should be evaluated for cause. The initial evaluation of anemia is generally the same for patients with CKD as in the general population. The evaluation should include complete 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. (See "Diagnostic approach to anemia in adults".)

In a recent study of over 5 million individuals, low iron indices (defined as TSAT ≤20 percent and/or ferritin ≤100 ng/mL) were noted in approximately half of males and over half of females who had anemia and eGFR < 60 mL/min/1.73 m² [6].

Continued monitoring — After the initial screen and evaluation, we continue to routinely monitor all patients with CKD for anemia and iron deficiency. Screening tests for iron deficiency include the percent TSAT, which is the serum iron divided by TIBC x 100, and the serum ferritin concentration. (See "Diagnostic approach to anemia in adults".)

The optimal frequency of repeat testing is discussed elsewhere. (See "Treatment of anemia in nondialysis chronic kidney disease" and "Treatment of anemia in nondialysis chronic kidney disease", section on 'Continued monitoring'.)

INDICATIONS FOR TREATMENT — The indications for iron administration are based upon the transferrin saturation (TSAT), ferritin, and, in some patients, the hemoglobin (Hb).

●We give iron to most anemic patients with CKD who have a TSAT ≤20 percent and/or a serum ferritin concentration ≤100 ng/mL. Such patients are likely to have decreased iron stores (ie, absolute iron deficiency) and will have an increase in Hb concentration with iron supplementation. (See "Diagnosis of iron deficiency in chronic kidney disease", section on 'Definitions'.)

While anemia is commonly defined as an Hb concentration <13.0 g/dL for adult males and postmenopausal women and an Hb <12.0 g/dL for premenopausal women, we would not treat all such patients, but rather only those for whom an increase in Hb concentration is desired [7]. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Definition'.)

●We give iron to some anemic patients with CKD who have a TSAT between 20 and 30 percent and ferritin between 100 and 500 ng/mL. Although such patients are likely to have adequate iron stores, they may have insufficient iron availability for erythropoiesis (ie, functional iron deficiency) and many will respond to iron with an increase in Hb concentration or decrease in erythropoiesis-stimulating agent (ESA) dose [8-14]. Thus, we give iron if an increase in Hb and/or avoidance of ESAs is desired. (See "Diagnosis of iron deficiency in chronic kidney disease", section on 'Definitions' and "Treatment of anemia in nondialysis chronic kidney disease", section on 'Definition'.)

●We do not give iron to patients with CKD who have a TSAT >30 percent, since such patients are unlikely to respond to iron. We do not routinely administer iron to patients with ferritin levels >500 ng/mL, although each patient should be individually assessed. As an example, some patients at high risk for iron deficiency (such as those with chronic gastrointestinal bleeding) will have a TSAT ≤20 percent and may have a ferritin >500 ng/mL and may benefit from iron. Among such patients, trends in ferritin concentration and TSAT in response to iron should be followed.

Among patients with CKD, absolute iron deficiency was associated with a higher risk of hospitalization for cardiovascular disease, but not with mortality or need for dialysis [15]. Whether treatment of iron deficiency modifies this risk is not known.

TREATMENT

Route of administration — Iron may be given orally or intravenously [5]. The route of administration is selected based upon the severity of anemia and iron deficiency, the patient's ability to tolerate oral iron, the response to prior oral iron therapy, history of adverse reactions to intravenous iron, and the availability of venous access.

We give oral iron to most patients with nondialysis CKD who are selected for iron therapy. Oral iron is inexpensive, readily available, and does not require intravenous access.

We give intravenous iron to selected patients who require more rapid repletion of iron, who cannot tolerate oral iron, who have not responded to it, or who are unlikely to be effectively treated with oral iron, including most patients with symptomatic anemia, provided that blood transfusion can be safely deferred. As examples, we give intravenous iron to patients with:

●Severe iron deficiency (ie, transferrin saturation [TSAT] <12 percent)

●Severe anemia (hemoglobin [Hb] <7 g/dL) in asymptomatic patients

●Risk of ongoing blood loss (such as a patient with chronic gastrointestinal blood loss)

●History of side effects to oral iron that limit adherence

●History of not responding adequately to oral iron

Randomized studies have reported inconsistent findings concerning the relative efficacy of oral iron and intravenous iron therapy among patients with nondialysis CKD [14,16-20]. In a meta-analysis including over 3000 adults and children with all stages of CKD, intravenous iron was superior to oral iron for achieving target Hb, increasing Hb and iron test parameters, and avoiding ESAs [21]. Compared with patients who received oral iron, more patients who received intravenous iron experienced allergic reactions and hypotension, but fewer had gastrointestinal adverse effects. There was insufficient evidence to determine whether the route of administration (oral or intravenous) affected mortality, infection risk, or quality of life.

We and others believe that the benefit outweighs the risk of intravenous iron in most patients with CKD who meet the criteria listed above [22,23].

The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines have recommended that either oral iron therapy or intravenous iron therapy can be given in patients not on dialysis [24]. The National Institute for Health and Care Excellence (NICE) guidelines suggest using oral iron for individuals who are not on ESAs and offering intravenous iron to those who do not tolerate oral therapy or do not reach targets within three months [25]. The NICE guidelines suggest intravenous iron for those who are being treated with ESAs [25]. The European Best Practice Guidelines suggest that intravenous iron is the optimal route of administration, but, for practical reasons, oral iron may be considered among patients with CKD who are not on dialysis [26].

Goals of therapy — The goal of iron therapy is to correct absolute iron deficiency and/or to increase Hb level to that desired for the particular patient. We generally provide sufficient iron to accomplish this while attempting to maintain the TSAT ≤30 percent and the ferritin level ≤500 mg/mL. Although the dose varies among individual agents, a course of intravenous iron usually provides 1000 mg elemental iron. (See 'Intravenous iron' below.)

Some patients will not increase Hb to desired values despite achieving a TSAT of approximately 30 percent. Such patients may be candidates for treatment with ESAs. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Erythropoiesis-stimulating agents'.)

There are no randomized, controlled trials that have compared different iron target levels among nondialysis patients. Support for the specific iron target levels are derived almost entirely from data among in-center hemodialysis patients. However, evidence from in-center hemodialysis patients may not directly apply to nondialysis and peritoneal dialysis patients, since dialysis-related blood loss does not occur. The studies that have examined these issues are discussed in detail separately.

Iron indices should be re-evaluated after therapy, typically one month following a dose of intravenous iron or the last dose of a planned series of infusions, and every three months among patients receiving oral iron. For patients treated with oral iron, we usually switch to intravenous treatment if iron status tests and Hb are not improving and remain below goal.

Iron indices generally respond to intravenous iron therapy. Patients who do not achieve target TSAT and ferritin values, or at least show significant improvement in iron stores, despite intravenous iron should be evaluated for sources of blood loss, particularly gastrointestinal bleeding.

Individual agents

Oral iron — Oral iron can be given among patients with nondialysis CKD using either one of the following dosing regimens:

●Daily dosing – Daily administration with goal elemental iron intake of approximately 200 mg per day in up to three divided doses.

●Alternate-day dosing – Alternate-day administration with goal elemental iron intake of approximately 65 mg per day in a single dose.

We typically use ferrous sulfate 325 mg (65 mg elemental iron) to achieve this goal elemental iron dose. Other alternative iron preparations include ferrous fumarate and ferrous gluconate; these are available in various doses with variable elemental iron content (table 1).

Oral iron should be administered between meals, if tolerated. Intestinal iron absorption can be impaired in patients with CKD and may be further reduced by food and antacids. Among patients who are on daily dosing, giving one of the doses at bedtime may be a simple and effective expedient. Among patients who are on alternate-day dosing, administering iron on a set schedule (eg, Monday, Wednesday, and Friday) may improve adherence.

The daily dosing regimen is consistent with the KDIGO guidelines and our long-standing practice among patients with nondialysis CKD. The alternate-day dosing regimen is adopted from a shift in practice among the general population based upon small trials, which show that alternate-day dosing results in equivalent or better iron absorption and fewer side effects (see "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'). However, the alternate-day dosing regimen has not been tested in patients with CKD and, therefore, the efficacy of this regimen in this population is not known. Despite the lack of data, it is reasonable to choose the alternate-day regimen due to potential benefits with regards to iron absorption and side effects.

Among patients who do not achieve goals of iron supplementation (see 'Goals of therapy' above) after one to three months of adequately dosed oral iron therapy, we switch to intravenous iron. (See 'Intravenous iron' below.)

Other available iron preparations include ferric maltol [27,28], ferric citrate [29], and sucroferric oxyhydroxide [30]. Ferric citrate and sucroferric oxyhydroxide are oral phosphate binders that may be useful for oral iron supplementation in patients who also have hyperphosphatemia and in whom there is a desire to lower the serum phosphorous concentration [31]. However, we do not use them because they more expensive and do not offer greater efficacy or fewer side effects. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Phosphate binders'.)

Intravenous iron — There are a number of options available for treatment with an intravenous iron preparation including ferumoxytol, iron sucrose, ferric gluconate in sucrose complex, ferric carboxymaltose, and low-molecular-weight iron dextran [31]. When available, we prefer ferumoxytol because of fewer doses needed to replete iron stores. When ferumoxytol is not available, we give iron sucrose, although ferric gluconate is a reasonable alternative. We generally do not give iron dextran unless the other agents are unavailable. (See "Treatment of iron deficiency in patients on dialysis".)

All of these products are equally effective in treating iron deficiency [32]. Major differences include cost, formulary/purchasing agreements, insurance coverage, and number of visits/time required to administer the full dose. The frequency of serious adverse events is comparable among products. One exception is high-molecular-weight iron dextran, which has a greater frequency of allergic reactions [33,34] and is no longer available in most of the world. A low-molecular-weight iron dextran preparation remains available but is used infrequently in patients with nondialysis CKD unless other preparations are not available. (See "Treatment of iron deficiency anemia in adults", section on 'Allergic and infusion reactions'.)

Dosing regimens for individual agents are as follows:

●Ferumoxytol – The preferred regimen consists of two doses that are 510 mg administered at least a week apart. This regimen of two doses is usually sufficient to replete iron to therapeutic targets, although additional doses may be necessary for severe iron deficiency [35-38]. (See 'Goals of therapy' above.)

●Iron sucrose – The preferred regimen consists of five doses of 200 mg administered over a two-week period. The 200 mg dose is generally well tolerated [39]. The regimen may be altered by administering higher doses less frequently, if necessary. As an example, 300 mg of iron sucrose can be administered once weekly, or less often, for a total dose of 600 to 900 mg [40].

●Ferric gluconate in sucrose complex – The preferred regimen consists of three or four 250 mg doses, as needed, administered once weekly.

●Ferric carboxymaltose – The preferred regimen consists of two doses of 750 mg, which may be administered in the same week [41-43].

●Ferric derisomaltose (formerly known as iron isomaltoside) – The preferred dose is 20 mg/kg for a maximum dose of 1000 mg administered in a single intravenous infusion [44-46].

Though it is not a preferred agent, low-molecular-weight iron dextran may be used if other agents are not available. A 25 mg test dose is generally administered first. If the test dose is tolerated, 500 to 1000 mg of iron dextran may be given in a single infusion; this dose can be repeated as required [40,47-54].

Caution must be exercised when administering intravenous iron. All intravenous iron preparations have been associated with anaphylaxis, although the incidence is not high (ie, less than 0.5 percent for non-dextran preparations) [39]. The most common side effects of intravenous iron are hypotension, nausea, vomiting, and abdominal discomfort; these effects are generally self limited. The management of such infusion reactions is discussed at length elsewhere. (See "Treatment of iron deficiency anemia in adults", section on 'Allergic and infusion reactions'.)

More than other intravenous iron preparations, ferric carboxymaltose has been associated with a syndrome of high fibroblast growth factor 23 (FGF23), hypophosphatemia, phosphaturia, hypocalcemia, low vitamin D levels, and secondary hyperparathyroidism [31,55-57].

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Dialysis or kidney transplantation — which is right for me? (Beyond the Basics)" and "Patient education: Hemodialysis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Monitoring iron stores – Iron deficiency is common among patients with chronic kidney disease (CKD). We monitor all patients with CKD for anemia and iron deficiency. Screening 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. (See 'Introduction' above and 'Continued monitoring' above.)

●Indications for treatment – Indications for iron administration are based on the TSAT, ferritin, and, in some patients, the hemoglobin (Hb).

•We give iron to most anemic patients with CKD who have a TSAT ≤20 percent and/or a serum ferritin concentration ≤100 ng/mL. Such patients are likely to have decreased iron stores (ie, have absolute iron deficiency). (See 'Indications for treatment' above.)

•We give iron to some anemic patients with CKD who have a TSAT between 20 and 30 percent and ferritin between 100 and 500 ng/mL. Such patients may respond to supplemental iron administration with an increase in Hb level (or, among patients who are on an erythropoiesis-stimulating agent [ESA], with a reduction in ESA dose). (See 'Indications for treatment' above.)

•We do not treat with iron patients who have a TSAT >30 percent, since such patients are unlikely to respond to iron. We do not routinely administer iron to patients with ferritin levels >500 ng/mL and anemia, although each patient should be individually assessed. (See 'Indications for treatment' above.)

●Oral iron – Among most patients with nondialysis CKD who are selected for iron therapy, we give oral iron. We usually give ferrous sulfate 325 mg three times daily, which provides approximately 200 mg elemental iron. Although multiple other agents are available, they tend to be more expensive, without greater efficacy or consistently fewer side effects. (See 'Route of administration' above and 'Oral iron' above.)

●Intravenous iron – We give intravenous iron to selected patients who are defined above. Multiple intravenous iron agents are available. Although regimens vary among individual agents, a course of intravenous iron usually provides 1000 mg elemental iron. (See 'Route of administration' above and 'Intravenous iron' above.)