IV iron: to give or to hold in the presence of infection in adults undergoing hemodialysis.
To discuss contemporary evidence that addresses the clinical question of whether to give or to hold intravenous (IV) iron in the presence of infection in adults undergoing hemodialysis.
1. Discuss the use of IV iron to treat anemia in adults undergoing hemodialysis.
2. Describe the risks of administering IV iron in the presence of infection in adults undergoing hemodialysis.
3. Explain the implications for nephrology nursing practice when considering the administration of IV iron in the presence of infection in adults undergoing hemodialysis.
Over the past several decades, nephrology nurses have administered intravenous (IV) iron to treat iron deficiency anemia in adults with end stage renal disease (ESRD). In this population, iron deficiency can be a major contributor to suboptimal erythropoiesis-stimulating agent (ESA) response (Fishbane & Shah, 2015). Most often, the cause of iron deficiency is related to treatment with ESA when the iron demand for erythropoiesis outweighs the availability of iron (functional iron deficiency). However, it can also be due to absolute iron deficiency related to either chronic or acute blood loss (see Table 1). In adults undergoing hemodialysis, iron therapy should be considered when serum ferritin is less than 200 ng/mL or transferrin saturation (TSAT) is less than 20% (Fishbane & Shah, 2015).
The decision regarding iron replacement therapy is based on the need to correct anemia in the presence or absence of ESA treatment and to decrease ESA doses in patients receiving an ESA (Kidney Disease Improving Global Outcomes [KDIGO] Anemia Work Group, 2012). The route for iron therapy often depends on which renal replacement therapy (RRT) a person is receiving, with IV iron being the most common route in those undergoing hemodialysis (Hodson & Craig, 2014). Ordinarily, patients tolerate IV iron, but there is an added level of concern if the patient has an infection. To help address the clinical question to give or to hold IV iron in the presence of infection, this article presents a review of the literature and provides implications for nephrology nursing practice in caring for adults undergoing hemodialysis who have iron deficiency anemia.
A systematic review of the literature was conducted using advanced search features of CINAHL, PubMed, and Medline electronic databases. The search was limited to publications in the English language using the search terms iron deficiency, anemia, TV iron, iron replacement, inflammation, infection, ESRD, adults, and nursing. In some instances, articles were located using an ancestry search of an original article. In addition, nephrology-specific books were used to answer the clinical question.
Currently, four IV iron preparations are being used in the U.S.: iron dextran, ferric gluconate, ferumoxytol, and iron sucrose. In people undergoing hemodialysis, IV iron has better bioavailability and efficacy despite the higher cost and safety risks when compared to oral iron preparations (Fishbane & Shah, 2015).
All iron replacement products have potential life-threatening anaphylactoid reactions (e.g., hypotension, dyspnea, flushing, and back pain), with iron dextran having the highest risk as compared to the other iron preparations (Fishbane & Shah, 2015; KDIGO Anemia Work Group. 2012). More recently, due to serious reactions, including deaths, ferumoxytol has a U.S. Food and Drug Administration (FDA) Box Warning, which is the strongest type of warning (FDA, 2015). It is important to be prepared for emergency intervention when administering IV iron. Most severe reactions that occur, with the administration of iron dextran, have been reported to happen when the test dose is administered but can occur anytime during the course of therapy (Walters & Van Wyck, 2005). Other reactions may be related to milder immediate hypersensitivity reaction (e.g., itching and urticarial reaction) or delayed reaction of myalgia, fever, and headache.
Another concern when administering IV iron is the risk of infection. Evidence supports that iron is an important growth factor for some microorganisms, and the use of IV iron can provide more iron that pathogens can use (Fishbane & Shah, 2015). This should be considered when making the decision to give or to hold IV iron (i.e., a patient experiencing an infection). The first step in making this decision is to recognize the associated risks of giving IV iron in the presence of infection.
Associated Risks of IV Iron in the Presence of Infection
The clinical dilemma of whether to give IV iron in the presence of infection can't be addressed without first understanding the basic principles about the metabolism of iron in the body. Iron is stored in the organism as heme (largest pool), non-heme ferritin (storage), and transferrin (transporting and delivering iron in the circulation to tissues) (Johnson & Wessling-Resnick, 2012). As heme, iron has a role in oxygen transport (hemoglobin), oxygen storage, and cytochrome function (electron transport). Ferritin is known to be an acute phase reactant, and together with transferrin, helps in cellular defense against oxidative stress and inflammation (Torti & Torti, 2002).
Hepcidin, a peptide hormone secreted mainly from hepatocytes, is a key regulator of iron absorption and plasma iron levels (Ganz, 2011; Goodnough, 2012). Increased iron stores stimulate hepcidin production, leading to inhibition of dietary iron absorption, and when iron deficiency and increased erythropoietic activity are present, hepcidin is suppressed, leading to enhanced absorption of dietary iron and release of iron from storage (Goodnough, 2012). A rapid increase in hepcidin occurs following administration of oral and IV iron (Coyne, 2011). Interestingly, even though an injection of an ESA decreases hepcidin within 24 hours of administration, ESAs do not play a regulatory role in hepcidin (Ashby et al., 2010). Hepcidin also has a strong connection with the immune system in response to infection and inflammation. It is an acute phase reactant, and it is up-regulated by an increase in iron levels, inflammation, endotoxin, and infection; decreasing circulating iron; IF6 (an inflammatory cytokine); and activation of hepcidin transcription (Drakesmith & Prentice, 2012; Weizer-Stem et al., 2007). Inflammation and infection leads to increased hepcidin synthesis and release, which in turn, results in reticuloendothelial cell iron blockade preventing iron release into the plasma (Auerback, Goodnaugh, & Shander, 2013; Babitt & Fin, 2012). This leads to hypoferremia, restriction of iron for erythropoiesis, and anemia of inflammation (Ganz & Nemeth, 2011). It is thought that this is a way to sequester iron and keep invading bacteria from using unbound iron to enhance bacterial growth (Babitt & Lin, 2012).
Other factors are also important in iron metabolism in the body. Iron is taken up by intestinal epithelial tissues, is transported by ferroportin (major membrane exporter of iron) and lactoferrin (found in surface secretions like saliva, tears, and bile), which chelates ferric iron and is released during infection (Bullen, Rogers, Spalding, & Ward, 2002). It is thought that IV iron will increase the saturation of iron-binding proteins, and with that, increase free iron and promote bacterial growth (Parkkinen, von Bonsdorff, Peltonen, Gronhagen-Riska, & Rosenlof, 2000). Many bacteria depend on iron for their growth (Escherichia coli, Klebsiella, Salmonella, Yersinia, Listeria, and Staphylococcus species), and in vitro studies have linked increased bacterial growth with increased levels of transferrin saturation in the plasma (Maynor & Brophy, 2007). The aforementioned are some of the various complex interactions of iron metabolism that may be affected during inflammation and infection. The next sections of this article provide further evidence of the relationship between IV iron and infections by discussing contemporary research studies and clinical practice guidelines
Over the past decade, several studies have shown an association between iron and infection, with more contemporary evidence supporting avoidance of IV iron when an individual has an active infection (Ishida & Johansen, 2014). As nephrology clinicians continue to use iron to help improve anemia and reduce ESA dose, it is important to consider risks associated with IV iron. In an attempt to shed more light on the connection between iron and infection in those undergoing hemodialysis, Ishida and Johansen (2014) conducted a literature review. Out of 13 studies (samples ranging from 61 to 2,662) exploring the link between ferritin and infection, nine studies showed higher incidence of bacterial infection or infection-related mortality with higher serum ferritin (typically defined in studies as greater than 500 ng/mL or greater than 1,000 ng/mL). Conversely, four studies showed a negative association. In one study, researchers found that serum ferritin was not a significant risk factor for bacteremia (Hoen, Paul-Dauphin, Hestin, & Kessler, 1998), which is the opposite of what was found in an earlier study (Hoen, Kessler, Hestin, & Mayeax, 1995). Interestingly, the authors suspected that this difference may be related to a lower prevalence of iron overload (ferritin over 1,000 ng/mL). This hypothesis is further supported in a prospective study (Hoen, Paul-Dauphin, & Kessler, 2002) that explored the link between iron administration and bacteremia. The researchers found that the association was related to more frequent administration and higher doses of IV iron. Iron overload can adversely impact cellular immunity by decreasing polymorphonuclear lymphocytes, which are needed to eradicate bacteria (Cieri, 1999; Ichii et al., 2012). This is believed to occur when the transferrin saturation exceeds a critical threshold and free iron is available for bacteria to use (Maynor & Brophy, 2007).
Brookhart and colleagues (2013) conducted a retrospective cohort study of adults undergoing hemodialysis (n = 117,050 from a large dialysis organization) to compare the effect of iron bolusing (large amounts over consecutive dialysis sessions on an as needed basis) versus maintenance dosing (small scheduled doses) on the risk of mortality and infection-related hospitalizations. When studying iron usage and infection, it was noted that most studies were observational. Bolus and high dose IV iron were independently associated with high hazard of infection-related hospitalization or infection-related mortality (Brookhart et al., 2013). They also showed that in comparison with maintenance doses, bolus doses may cause an additional 25 infection-related hospitalizations per year per 1,000 patients treated. Despite this emerging evidence, there continues to be a need for more rigorous clinical trials exploring the risk of IV iron in the face of infection. It appears that IV iron bolusing may present a higher risk for hospital-related infections, especially in those already at risk for infection (e.g., patients with dialysis catheter or history of recent infection) (Brookhart et al., 2013). Until there is more evidence, the controversy of whether clinicians should administer IV iron in the presence of infection will continue (Daoud, Nakhla, & Sharma, 2011). Considering the relationship between IV iron and infection, one could ask why oral iron is not used in this population.
Is Oral Iron a Good Alternative to TV Iron in Adults Undergoing Hemodialysis?
A literature review comparing oral iron with no iron or placebo showed little benefit of increasing hemoglobin and iron stores among people receiving hemodialysis (Hodson & Craig, 2014). It is important to note that the majority of participants across various studies were unable to tolerate oral iron due to adverse events (most often gastrointestinal related), which led to dose reductions to nontherapeutic levels or patient self-discontinuation. However, observational data indicated that some patients were able to tolerate oral iron and achieve target iron stores (TSAT 20% or greater) (Lenga et al., 2007). Due to the paucity of robust evidence, Hodson and Craig (2014) concluded that oral iron may not be beneficial for those undergoing hemodialysis and called for more rigorous research to determine the benefit of oral iron in people undergoing dialysis. At this time, considering patient tolerability and medication efficacy, IV iron seems to be the better choice in adults undergoing hemodialysis, and oral iron should not be given for the majority of adults undergoing hemodialysis (Fishbane & Shah, 2015).
The next section of this article discusses clinical practice guidelines that can be used to guide nephrology nurses' clinical decision making about giving IV iron in the presence of infection.
Clinical Practice Guidelines
The 2000 KDIGO anemia guidelines stated that maintaining a ferritin in the recommended range was unlikely to cause a risk of bacterial infection on people with chronic kidney disease (CKD) (National Kidney Foundation [NKF], 2000). Since its publication, KDIGO guidelines recommend IV iron therapy for people undergoing hemodialysis with a TSAT of 30% or less and ferritin of 500 ng/mL or less as an intervention to raise the hemoglobin (see Table 2) (KDIGO Anemia Work Group, 2012). The guidelines also recommend that due to limited and conflicting evidence regarding IV iron and increased risk of infection or the chance of poorer health outcomes when given during an infection, it may be best to avoid IV iron in patients with an active systemic infection. It is important to note that this is more of a precautionary measure, so clinical judgment should be based on individual patient factors (e.g.. active infection and the severity of the infection) and the immediate need for IV iron. In some cases, patients may have an elevated ferritin because of chronic inflammation (high ferritin and low TSAT) and may experience hyporesponsiveness to ESA (KDIGO Anemia Work Group, 2012). In these situations, obtaining a reticulocyte hemoglobin content (CHr), a direct measure of iron availability at the level of the red blood cell production, may assist with diagnostic accuracy of iron deficiency (CHr value less than 29 to 32 pg/cell) and determine the benefit of IV iron (KDIGO Anemia Work Group, 2012).
Implications for Nephrology Nursing Practice
Thus far, evidence supports an association between IV iron and infection, but it still remains unclear whether the clinician should give or hold IV iron in the presence of infection in adults receiving hemodialysis. More research is needed to explore the use of IV iron in acute infectious episodes and if there are better predictors of iron stores indicating the need for iron replacement in adults with anemia who are undergoing hemodialysis. Emerging evidence has shown the important role hepcidin has as regulator of iron stores, but the question remains: Can hepcidin levels provide additional diagnostic information?
Hepcidin correlates with iron status and demands, but so does ferritin (Coyne, 2011). Hepcidin and ferritin both have intra-patient variability and are influenced by inflammation. So at this time, serum hepcidin levels may not provide additional information beyond what ferritin levels do (Ford, Eby, Scot, & Coyne, 2010). Intravenous iron has been shown to improve hepcidin-mediated iron blockade; however, caution must be taken because iron overload allows free iron to be available for proliferation of pathogens (Van Buren, Velez, Varirir, & Zhan, 2012). Obtaining a baseline ferritin with regularly scheduled repeated measures may help identify iron deficiency and higher values may indicate iron overload. However, it is important to note that values as high as 1,200 mcg/L may not signify iron overload, but rather, inflammation or infection. Transferrin saturation will fall during an acute illness as well as when there is iron deficiency (Thomas et al., 2013). Presently, the standard of care is to obtain baseline and ongoing ferritin and transferrin saturation levels to determine the need for iron replacement (see Table 2).
Until more evidence becomes available, nephrology nurses should consider contemporary evidence, such as clinical practice guidelines and research studies, as they engage in clinical decision-making aimed at achieving optimal patient outcomes. Most importantly, nephrology nurses can start with a comprehensive assessment of the patient to help determine the "potential benefits (avoiding or minimizing blood transfusing, ESA therapy, and anemia-related symptoms) versus the risks of harm (e.g. anaphylactoid and other acute reactions, unknown long-term risks) in individual patients" (KDIGO Anemia Work Group, 2012, p. 292).
There is no clear answer to the clinical question to give or to hold IV iron in the presence of infection. It appears that IV iron administration itself may not cause bacterial growth, but rather, it occurs when there is iron overload and free iron becomes available for bacteria to use (Maynor & Brophy, 2007). As more attention is given to this clinical dilemma, it is likely that over the next decade, the answer will become clearer, thus providing evidence to guide best practice.
Exploring the Evidence is a department in the Nephrology Nursing Journal designed to provide a summary of evidence-based research reports related to contemporary nephrology nursing practice issues. Content for this department is provided by members of the ANNA Research Committee. Committee members review the current literature related to a clinical practice topic and provide a summary of the evidence and implications for best practice. Readers are invited to submit questions or topic areas that pertain to evidence-based nephrology practice issues. Address correspondence to: Tamara Kear, Exploring the Evidence Department Editor, ANNA National Office, East Holly Avenue/Box 56, Pitman, NJ 08071-0056; (856) 256-2320; or via e-mail at NNJEvidence@ajj.com. The opinions and assertions contained herein are the private views of the contributors and do not necessarily reflect the views of the American Nephrology Nurses' Association.
Debra Hain, PhD, ARNP, ANP-BC, GNP-BC, FAANP, is an Associate Professor/Lead AGNP and Faculty, Florida Atlantic University, Christine E. Lynn College of Nursing, Boca Raton, FL; Nurse Practitioner, Cleveland Clinic Florida, Department of Nephrology, South Florida, Weston, FL; and President of ANNA's Flamingo Chapter. She may be contacted directly via email at email@example.com
Mauro Braun, MD, FASN, is a Nephrologist, Cleveland Clinic Florida, Department of Nephrology, Weston, FL.
Statement of Disclosure: The authors reported no actual or potential conflict of interest in relation to this continuing nursing education activity.
Note: Additional statements of disclosure and instructions for CNE evaluation can be found on page 284.
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Table 1 Possible Causes of Absolute Iron Deficiency Absolute Iron Deficiency Excessive iron loss (bleeding) * Frequent blood sampling for laboratory tests * Retention of blood in dialyzer and blood lines * Inflammatory bowel disease * Gastrointestinal neoplasms * Peptic ulcer disease * Surgical procedures (such as creation of vascular access) Women's health * Menstruation Nutritional * Inadequate diet Impaired iron absorption * Celiac disease * Helicobacter pylori infection * Medications (gastric acid inhibitors and phosphate binders) * Uremia Sources: Goodnough, Nemeth, & Ganz, 2010; KDIGO Anemia Work Group, 2012. Table 2 Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines * When making the decision to start IV iron, it is important to determine benefits of improving the patient's overall well-being and anemia-related symptoms, as well as avoiding or minimizing blood transfusion against harm, such as anaphylactoid reaction. * If the patient has anemia and is not receiving iron or ESA therapy, consider a trial of IV iron if 1) an increase in Hgb concentration without starting ESA treatment is desired; and 2) TSAT is 30% or less, and ferritin is 500 ng/mL or less. It is recommended that active infection is ruled out first. * Additional IV iron is based on Hgb response; evaluate for ongoing blood losses, iron status with laboratory studies (TSAT and ferritin), and response to ESA in those receiving this medication and the patient's clinical status. * Evaluate iron status (TSAT and ferritin) at least every three months during ESA therapy and test more frequently when initiating or increasing ESA dose, when there is blood loss, and when monitoring response after a course of IV iron. * When administering initial dose of IV iron, monitor the patient for 60 minutes after infusion, and have resuscitative equipment and trained personnel available to evaluate and treat serious adverse reactions if they occur. Source: KDIGO Anemia Work Group, 2012.
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|Title Annotation:||Exploring the Evidence|
|Author:||Hain, Debra; Braun, Mauro|
|Publication:||Nephrology Nursing Journal|
|Date:||May 1, 2015|
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