Iron replacement and supplementation in patients with chronic kidney disease.
Subject: Chronic kidney failure (Complications and side effects)
Chronic kidney failure (Care and treatment)
Iron in the body (Health aspects)
Iron deficiency anemia (Risk factors)
Iron deficiency anemia (Care and treatment)
Practice guidelines (Medicine)
Authors: Wazny, Lori D.
Raymond, Colette B.
Pub Date: 10/01/2011
Publication: Name: CANNT Journal Publisher: Canadian Association of Nephrology Nurses & Technologists Audience: Trade Format: Magazine/Journal Subject: Health care industry Copyright: COPYRIGHT 2011 Canadian Association of Nephrology Nurses & Technologists ISSN: 1498-5136
Issue: Date: Oct-Dec, 2011 Source Volume: 21 Source Issue: 4
Product: Product Code: 2834740 Iron & Other Tonics NAICS Code: 325412 Pharmaceutical Preparation Manufacturing SIC Code: 2834 Pharmaceutical preparations
Geographic: Geographic Scope: Canada Geographic Code: 1CANA Canada
Accession Number: 276137583
Full Text: Introduction

There has been renewed interest in iron therapy for the treatment of anemia of chronic kidney disease (CKD), in part due to concerns that high doses of erythropoiesis stimulating agents (ESAs) might contribute to the high cardiovascular morbidity and mortality observed in patients with chronic kidney disease (Szczech et al., 2010; Zhang, Thamer, Kaufman, Cotter, & Hernan, advance online publication June 22, 2011) In addition, judicious use of iron can result in significantly lower doses of ESAs required to increase hemoglobin with much lower cost.

Current iron guidelines

Table 1 provides the current iron targets from several international guidelines. Target for transferrin saturation (TSAT) are similar, but there is controversy around the maximum serum ferritin with recommendations differing between guidelines. Serum ferritin is not an ideal laboratory measure of iron status, as it has been shown to be a poor predictor of response to iron due to the fact that it is an acute phase reactant and, therefore, increases in response to infection or inflammation (Spiegel & Chertow, 2009).

Iron deficiency

There are two types of iron deficiency in patients with CKD. Absolute iron deficiency is defined as both a TSAT and ferritin below the recommended guidelines. Functional iron deficiency occurs when the ferritin is either within target or high, but the patient still responds to iron administration with an increase in hemoglobin. This type of iron deficiency is related to an imbalance between the iron demands of the erythroid marrow and iron delivery by transferrin, the iron carrier protein in the blood. It can be caused by accelerated red blood cell production induced by ESA therapy, low transferrin levels secondary to malnutrition, and/or iron mobilization impairment from stores in the reticuloendothelial system in the setting of inflammation or infection (With, 2011).

Iron administration in patients with elevated serum ferritin

The only randomized controlled trial to address treatment with intravenous (IV) iron in patients with elevated ferritin enrolled patients on hemodialysis receiving high-dose epoetin alfa (> 225 IU/kg/week or > 22,500 IU/week) who had hemoglobin values below target, serum ferritin concentrations of 500 to 1,200 ng/mL, and lower TSATs of less than 25 per cent (Coyne et al., 2007; Kapoian et al., 2008). Patients were stratifide by baseline ferritin levels above or below 800 ng/mL and randomized to either no iron or to intravenous ferric gluconate 125 mg given over eight consecutive hemodialysis sessions. The epoetin alfa dose was increased by 25% in both groups. Hemoglobin increased faster and significantly more in the intravenous iron group than in the control group (16 [+ or -] 13 versus 11 [+ or -] 14 g/L; P = 0.028). The baseline serum ferritin value was not predictive of iron responsiveness. However, this study was not powered to look at safety and was of very short duration (6 to 12 weeks). The 2008 Canadian Society of Nephrology iron management guidelines state that if ferritin is > 800 ng/mL to consider iron administration if the patient is receiving high ESA doses defined as > 20,000 units/week epoetin alfa or > 100 ug/week darbepoetin and still has a hemoglobin below target and the TSAT is less than 25 per cent (Madore et al., 2008). However, this recommendation was only rated as Grade C evidence and clinicians must also weigh the risks of ongoing iron administration in these patients.

Monitoring of iron

Patients receiving iron or ESA therapy should have their serum ferritin and TSAT checked every one to three months. (KDOQI & National Kidney Foundation, 2006; Madore et al., 2008). The optimal timing between IV iron administration and measurement of iron studies is provided in Table 2. Ferritin and TSAT may be checked at any time during treatment with oral iron.

Oral or intravenous iron

The use or IV or oral iron in patients with CKD depends on the patient population (hemodialysis, peritoneal dialysis, or nondialysis CKD). The Canadian and international guidelines recommend that IV iron should be used for patients receiving hemodialysis. These patients tend to be iron deficient for several reasons including increased blood losses from the 00hemodialysis procedure itself and increased blood laboratory testing. IV iron is also easy to administer to these patients, as it may be given any time during the hemodialysis procedure since no IV iron is removed by hemodialysis. A recent meta-analysis found a better hemoglobin response and that lower doses of erythropoietic stimulating agents (ESAs) were required when these patients received IV iron instead of oral iron (Rozen-Zvi et al., 2008). Other studies have also found that IV iron treatment in hemodialysis patients results in lower ESA doses (Fishbane, Frei, & Maesaka, 1995; Kapoian, 2008). This is desirable because a reduction in ESA doses leads to a substantial reduction in drug costs, as IV iron is significantly less expensive than ESAs. More recently there have been concerns raised that high-dose ESAs may exacerbate cardiovascular morbidity and mortality as a result of negative effects on endothelial function and thrombocytosis due to iron deficiency (Dahl, Henry, & Coyne, 2008; Vaziri & Zhou, 2009).

Peritoneal dialysis and non-dialysis patients with CKD typically receive oral iron first-line and IV iron is reserved for patients not meeting the TSAT and ferritin targets or who cannot tolerate oral iron due to adverse effects such as constipation or diarrhea. There are no randomized controlled trials that have examined the use of oral versus IV iron in peritoneal patients and the previous meta-analysis only included 12 patients receiving peritoneal dialysis (Rozen-Zvi et al., 2008). It is more difficult to administer IV iron to peritoneal dialysis and non-dialysis patients with CKD, as these patients are seen in the outpatient renal clinic setting and do not readily have IV access available. In non-dialysis patients with CKD, IV iron had a small but significant difference in increasing hemoglobin level versus oral iron (mean difference 3.1 g/L; 95% confidence interval 0.9-5.3 g/L) (Rozen-Zvi et al., 2008). The target dose of oral iron is 200 mg elemental iron per day (KDOQI & National Kidney Foundation, 2006). The percentage of elemental iron contained in the most common oral iron salts is provided in Table 3.

Intravenous iron products

There are three IV iron products available in Canada: iron dextran (DexIron[R], Infufer[R]), sodium ferric gluconate (Ferrlecit[R]), and iron sucrose (Venofer[R]). Iron dextran requires administration of a 25 mg test dose the first time it is administered. The approved dose for patients receiving hemodialysis is 100 mg during the last hour of dialysis. However, iron dextran can also be administered by IV push over two minutes and also in larger doses of 1 g over one to three hours for non-dialysis CKD and peritoneal dialysis patients (Sandoz, 2011). Adverse reactions are primarily due to antibodies to the dextran component and include arthralgias and myalgias (typically chest and back tightness) in less than one in 200 patients (Auerbach & Al Talib, 2008). These reactions occur near the start of the infusion, abate within minutes, and do not occur upon rechallenge. Methylprednisolone 125 mg IV pre-infusion has been used successfully to treat these reactions (Auerbach & Al Talib, 2008). However, life-threatening and fatal anaphylaxis has occurred and appears to be higher than the nondextran IV irons in spontaneous adverse event reporting to the U.S. Food and Drug Administration (FDA) (see Table 4).

Sodium ferric gluconate and iron sucrose are covalently bound irons and have adverse reactions primarily due to the release of free iron. Typical adverse effects include hypotension, nausea and vomiting, and diarrhea. These reactions are most often seen near the end of the infusion when the concentration of free iron is highest. The approved doses are 125 mg over five to 10 minutes for sodium ferric gluconate and 200 mg over two to five minutes for iron sucrose. Maximum doses are 250 mg for sodium ferric gluconate and 300 mg to 500 mg for iron sucrose (Blaustein et al., 2003; Folkert et al., 2003; Schroder et al., 2004). Post-marketing spontaneous reporting does include the risk of life-threatening reactions such as anaphylactoid and anaphylactic shock, but at lower rates than iron dextran (see Table 4). Based on currently published studies, iron sucrose appears to have the most favourable safety profile (Coppol, Shelly, Cheng, Kaakeh, & Shepler, 2011). However, direct head-to-head comparisons designed to examine the safety of IV iron products in patients receiving hemodialysis are scarce and have serious limitations including small sample sizes, inclusion and exclusion criteria that limit external validity, and the use of retrospective historical control groups that contained patients who received both high (older product associated with more adverse reactions) and low molecular weight iron dextran (Coppol et al., 2011). As a result, others have argued these limitations do not support the viewpoint that nondextran irons are safer and that low molecular weight iron dextran can be used (Auerbach & Al Talib, 2008).

A new IV iron, ferumoxytol (Feraheme[R]), was approved for use in the United States in June 2009 and is not yet available in Canada. Ferumoxytol is an encapsulated iron and adverse reactions are primarily due to its polysaccharide coating (Wish, 2011). It is administered by a large dose rapid injection (510 mg over 17 seconds) that can be repeated three to eight days later. As a result, ferumoxytol may be useful in the management of patients with non-dialysis CKD or those receiving peritoneal dialysis who require IV iron in the outpatient setting. However, in the hemodialysis population, the use of regular smaller maintenance dosing of IV iron (e.g., 100 mg or 125 mg weekly or every two weeks) has been shown to lower ESA doses versus intermittent large-dose IV iron dosing, so the role of ferumoxytol in this patient population is not as certain (Coppol et al., 2011; Van Wyck, Bailie, & Aronoff, 2002). Interestingly, ferumoxytol is an ultrasmall superparamagnetic iron oxide and can also be used as a contrast agent for magnetic resonance imaging (MRI) in doses of 1 mg/kg to 4 mg/kg (Neuwelt et al., 2009). Administration of ferumoxytol may affect MRI imaging for up to three months (Lu, Cohen, Rieves, & Pazdur, 2010; AMAG Pharmaceuticals Inc., 2011). Ferumoxytol may be an alternative to gadolinium-based contrast agents, which have been associated with nephrogenic systemic fibrosis (NSF) in patients with Stage 4-5 CKD and acute kidney injury (Elmholdt et al., 2011). Head-to-head studies and long-term safety data are not yet available for ferumoxytol (Coppol et al., 2011). The most commonly reported adverse events in the randomized clinical trials included nausea, dizziness, hypotension, and peripheral edema (AMAG Pharmaceuticals Inc., 2011). In post-marketing spontaneous reports life-threatening anaphylactic-type reactions, cardiac/cardiorespiratory arrest, syncope, tachycardia/rhythm abnormalities, angioedema, ischemic myocardial events, congestive heart failure, absent pulse, and cyanosis (AMAG Pharmaceuticals Inc., 2011). Patients must be observed for at least 30 minutes after an infusion of ferumoxytol

Safety concerns with iron therapy

There are safety concerns with repeated administration of iron. Iron overload can lead to organ damage due to hemochromatosis. However, these patients tend to have dramatically higher ferritin levels than observed in the dialysis population (Madore et al., 2008). Several observational studies in hemodialysis patients have shown associations between ferritin levels > 500 ng / mL and infections (Boelaert et al., 1990; Hoen, Kessler, Hestin, & Mayeux, 1995; Jurado, 1997; Madore et al., 2008). Experimental studies in animals have suggested that IV iron is harmful in the presence of severe infections and, hence, it should be used with caution or discontinued in patients with an active infection (Madore et al., 2008). Free iron is also linked to oxidative stress and there is some evidence that oxidative stress may be linked to the development of atherosclerosis and cardiovascular disease in patients with CKD (Agarwal Vasavada, Sachs, & Chase, 2004). The currently available IV iron products differ in their release of free iron with ferumoxytol < iron dextran < iron sucrose < sodium ferric gluconate (Schwenk, 2010).

Despite the widespread use of iron therapy in patients with CKD, no randomized controlled trials have examined the longterm effects of iron therapy with the published trials only lasting two to three months in duration.

Future agents

Ferric carboxymaltose is another encapsulated IV iron that can be administered as a large-dose rapid injection. This agent is approved in Europe and is undergoing phase 3 trials in the United States: Evaluation of efficacy and safety of ferric carboxymaltose (FCM) in patients with iron deficiency anemia and impaired renal function (REPAIR-IDA). NCT00981045 (ClinicalTrials.gov, 2009). Iron pyrophosphate is an iron additive to the hemodialysis dialysate and is also in phase 3 clinical trials: Dose ranging study of dialysate containing soluble iron to treat subjects with end stage renal disease (ESRD) receiving chronic hemodialysis. NCT00548249 (ClinicalTrials.gov, 2007). Iron pyrophosphate is effective in iron replete patients in order to maintain iron targets, but it does not provide enough iron to correct an iron deficit (Gupta et al., 1999).

Interprofessional IV iron management

Interprofessional care of CKD patients has been advocated (Barrett, 2003; Valderrabano, Golper, Muirhead, Ritz, & Levin, 2001). With regards to anemia and iron management, nephrology nurses and clinical pharmacists have demonstrated benefits in cooperative anemia care with nephrologists, including better achievement of iron targets and lower ESA doses through either algorithms or management protocols in patients receiving dialysis and those with non-dialysis CKD (Bacchus, O'Mara, Manley, & Fishbane, 2009; Bayliss, Bhardwaja, Ross, Beck, & Lanese, 2011; Bennett, 1998; Calissi, Pylypchuk, & Stryker, 2004; Curtis et al., 2005; Dixon, Borden, Kaneko, & Schoolwerth, 2011; Goldstein, Yassa, Dacouris, & McFarlane, 2004; Joy et al., 2005; Patterson & Allon, 1998).

Summary

Interest in optimizing iron management in the treatment of anemia of CKD is growing due to concerns that high doses of ESAs may have deleterious effects and the high cost of ESAs in comparison to iron therapy. International guidelines have defined iron targets for this patient population, but there are some unanswered questions with respect to long-term use of iron, such as the maximum TSAT or ferritin concentration and concerns with oxidative stress. Large head-to-head safety studies of the different IV iron preparations have not been performed to date and current safety data rely on small studies and spontaneous adverse event reporting. Interprofessional management of anemia, including iron therapy, has shown beneficial effects and should be encouraged.

Copyright [c] 2011 Canadian Association of Nephrology Nurses and Technologists

References

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1. The Canadian guidelines for iron deficiency recommend which target ferritin in patients receiving dialysis?

(a) > 100 ng/mL

(b) > 200 ng/mL

(c) > 500 ng/mL

(d) > 800 ng/mL

2. Serum ferritin will increase if a patient has an infection or inflammation present.

(a) true

(b) false

3. A patient receives iron sucrose (Venofer [R]) 100 mg IV on their Wednesday hemodialysis session. On which following day can their transferrin saturation (TSAT) and ferritin be accurately measured?

(a) Monday

(b) Friday

(c) one week later

(d) two weeks later

4. Which of the following oral iron preparations contains the highest percentage of elemental iron?

(a) ferrous gluconate

(b) ferrous sulfate

(c) ferrous fumarate

(d) Apo-ferrous gluconate[R]

5. What is the maximum dose of IV sodium ferric gluconate (Ferrlecit[R]) that can be administered at one time?

(a) 125 mg

(b) 250 mg

(c) 375 mg

(d) 500 mg

6. Which of the following iron preparations requires a test dose before administration?

(a) sodium ferric gluconate (Ferrlecit[R])

(b) iron sucrose (Venofer[R])

(c) iron dextran (DexIron[R])

(d) ferumoxytol (Feraheme[R])

7. Safety concerns with iron therapy include which of the following?

(a) infections

(b) oxidative stress

(c) atherosclerosis

(d) all of the above

8. How quickly can 510 mg of ferumoxytol (Feraheme[R]), an encapsulated IV iron, be administered?

(a) 17 seconds

(b) 1 minute

(c) 15 minutes

(d) 1 hour

9. Collaborative management of anemia between nephrology nurses or pharmacists and nephrologists have resulted in better achievement of iron targets and lower erythropoiesis stimulating agent (ESA) doses.

(a) true

(b) false

10. Unanswered questions about iron management in patients with chronic kidney disease include which of the following?

(a) maximum ferritin concentration

(b) role of oxidative stress and repeated IV iron therapy

(c) safety of repeated IV iron administration beyond two to three months of treatment

(d) all of the above

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By Lori D. Wazny, PharmD, and Colette B. Raymond, PharmD, MSc

Lori D. Wazny, PharmD, Clinical Pharmacist, Winnipeg Regional Health Authority, Manitoba Renal Program, Winnipeg, MB

Colette B. Raymond, PharmD, MSc, Clinical Pharmacist, Winnipeg Regional Health Authority, Manitoba Renal Program, Winnipeg, MB

Address correspondence to: Lori Wazny, PharmD, Dept. of Pharmaceutical Services, Health Sciences Centre, 820 Sherbrook St., Winnipeg, MB R3A 1R9

Email: Lwazny@hsc.mb.ca
Table 1. International iron targets for patients with CKD

Lab value    Canada (Madore  U.S. (KDOQI    Europe       U.K.
             et al., 2008)   & National   (Locatelli  (National
                               Kidney       et al.,     Institute
                             Foundation,    2009)         for
                                2006)                  Clinical
                                                        Excellence
                                                          [NICE],
                                                          2011)

Ferritin     Nondialysis     Same as      Same as        200-500
             > 1OOng/mL      Canada       Canada           ng/mL
             Dialysis >
             200 ng/mL

Maximum      > 800           > 500        > 800            > 800
ferritin     ng/mL but       ng/mL hold   ng/mL            ng/mL
             consider iron   iron
             if TSAT< 25%,
             high ESA dose
             (> 20,000
             units/ week
             epoetin alfa
             or > 100
             ug/week
             darbepoetin),
             & Hgb below
             target

Transferrin  > 20%           Same as      Same as         > 20%
saturation                   Canada       Canada          unless
(TSAT)                                                    ferritin
                                                          > 800
                                                          ng/mL

Lab value      Australia
               (Roger &
               Caring for
             Australasians
               with Renal
               Impairment
             [CARI],2006)

Ferritin     Not on ESA
             > 100
             ng/mL During
             ESA therapy:
             200-500 ng/mL

Maximum      > 800
ferritin     ng/mL

Transferrin  Not on ESA
saturation   > 20%
(TSAT)       During ESA
             therapy:
             30-40% TSAT
             >  40%
             hold iron

ESA: erythropoiesis stimulating agent


Table 2. Timing between IV iron and iron studies
(KDOQI & National Kidney Foundation, 2006; Schwenk,
2010; Shalansky, Hanko, Pudek, Li, & Jastrzebski, 2011)

IV iron                  Timing of ferritin and TSAT

Iron dextran             100 mg dose -- wait 1 week
                         [greater than or equal to] 500 mg dose --
                         wait 2 weeks

Iron sucrose             24 -- 48 hours post dose

Sodium ferric            24 -- 48 hours post dose, but recent
gluconate                 study from Vancouver suggests waiting 1
                          week

Ferumoxytol              1 -- 2 weeks


Table 3. Elemental iron content in oral iron salts

Iron salt                      Percent elemental iron

Ferrous fumarate     33% (300 mg tablet = 99 mg elemental iron)

Ferrous sulfate      20% (300 mg tablet = 60 mg elemental iron)

Ferrous gluconate    12% (300 mg tablet = 36 mg elemental iron)

Iron polysaccharide  100% (150 mg elemental iron/capsule)

Note: IV iron concentrations are provided as elemental iron,
therefore no conversion is necessary.


Table 4. IV iron adverse reactions reported to the FDA
(Chertow, Mason, Vaage-Nilsen, &Ahlmen, 2006; Schwenk, 2010)

IV iron          Major adverse          Life-threatening adverse
                   reactions            reactions

Dexferrum (iron     12/100,000              11.3/million
dextran*)

INFeD
(iron                4/100,000               3.3/million
dextran*)

Iron sucrose         2/100,000               0.9/million

Sodium ferric        2/100,000               0.6/million
gluconate

* This brand of iron dextran not available in Canada
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