Is IV Iron beneficial or harmful in ESRD



Pumping Iron:

Revisiting Risks, Benefits and Strategies in Treatment of Iron Deficiency in End Stage Renal Disease

Neeraj Singh MD

Neeraj.singh@osumc.edu

Anil K. Agarwal MD

Anil.agarwal@osumc.edu

Corresponding Author:

Anil K. Agarwal MD

Professor of Medicine

Division of Nephrology

The Ohio State University

395 W 12th Avenue, Ground Floor

Columbus, Ohio 43210

Email: anil.agarwal@osumc.edu

Tel: 614 293 4997

Fax: 614 293 3073

Words: 4236 (including abstract and references

Key Words: Iron deficiency, anemia of CKD, End stage renal disease, intravenous iron

Conflict of interest: Dr. Singh- None. Dr. Agarwal- ad hoc advisor to Amgen, Amag, Hospira.

Abstract

Iron deficiency is a common cause of anemia in patients with end stage renal disease (ESRD). Intravenous iron administration, especially in those requiring treatment with erythropoiesis stimulating agents (ESA) is an essential component of the management of anemia in ESRD patients. Iron improves hemoglobin, reduces ESA dose requirement and also has non-erythropoietic effects including improvement in physical performance, cognition and amelioration of restless leg syndrome. However, iron can promote oxidative stress, cause endothelial dysfunction, inflammation and tissue injury, and has a potential to cause progression of both CKD and cardiovascular disease. In this review, we discuss the benefits and risks associated with IV iron and the practical aspects of iron administration that can minimize the complications related to iron therapy in ESRD.

Anemia of chronic kidney disease (CKD) affects a majority of patients with End Stage Renal Disease (ESRD) and results from a multitude of factors, primarily a combination of decreased production of erythropoietin and low levels of iron or its poor utilization. Although administration of erythropoiesis stimulating agents (ESA) is remarkably effective in improving hemoglobin levels, iron deficiency produces a state of hyporesponse to this therapy, which is frequently associated with adverse outcomes.

Iron is a trace element that plays an essential role in a number of physiologic processes among which the most evident is its role in oxygen transport as a component of hemoglobin. Apart from this, iron also contributes to energy production, immune function, cell growth and inflammation. Iron is stored in the body as ferritin and is transported in the blood by transferrin to make it available to bone marrow. A small concentration of non-transferrin bound iron is present in blood normally, but can increase in presence of iron overload and cause production of reactive oxygen species and tissue damage. Control of iron absorption, primarily through hepcidin, is the most important mechanism of regulating iron stores in the body.

Iron deficiency in ESRD

Iron deficiency is common in patients with ESRD and is multifactorial, resulting from loss of blood left in the dialyzer circuit, frequent blood sampling, low-grade gastrointestinal bleeding, multiple vascular access surgeries and decreased oral iron absorption because of dietary restrictions and loss of taste for iron-rich foods. Absolute iron deficiency is generally defined by transferrin saturation (Tsat) < 20 % and ferritin < 100 ng/ml)1. However, assessment of adequacy of iron remains an imperfect and controversial science and is a frequent topic of debate. Common evaluation of iron stores utilizes measurement of such biomarkers as serum iron, ferritin, transferrin saturation, and percentage of hypochromic red cells. All these biomarkers have independent variability and are not always reliable (Table 1)2. Soluble transferrin receptor levels may sometimes help, but their use has not been widespread. Although bone marrow iron content is considered the gold standard for evaluation of iron stores, it is not practical or routine to perform. Further, while iron deficiency can be defined based on these measurements, it is even more difficult to predict a safe and optimal level of iron to maintain hemoglobin, making subclinical deficiency of iron an even more difficult clinical issue.

To make the issues even more confusing, while absolute or subclinical iron deficiency is prevalent in patients with ESRD, it is all too common to find anemic patients with ‘adequate’ iron stores indicating poor utilization of iron. This functional iron deficiency (TSat < 20%; ferritin > 200-500 ng/ml) happens because iron stored in reticuloendothelial system (RES) gets “locked up” and is not released to transferrin. As a result, transferrin-bound iron that represents functionally available pool of iron for erythropoiesis (reflected by Tsat) remains low despite a normal or elevated ferritin. This RES blockade is mediated by hepcidin, a key iron regulatory hormone produced by liver in response to inflammatory cytokines. Hepcidin reduces release of iron from macrophages and hepatocytes and blocks ferroportin to decrease uptake of iron in enterocytes. Additionally, inflammatory cytokines such as TNF-alpha, interferon gamma and IL-6 increase iron uptake and upregulate ferroportin to cause retention of iron.

Benefits of iron replacement

Iron is essential to support erythropoiesis. Iron deficiency is the most common cause of a suboptimal response to ESA therapy in ESRD patients. Not only optimal levels of iron in patients with ESRD are difficult to define, iron therapy can enhance the response to ESA, even in ‘iron-replete’ patients resulting in better hemoglobin levels, decrease in ESA dosages and significant cost savings3-4.

Higher doses of ESA administered to increase hemoglobin to higher targets have recently been implicated in worse clinical outcomes5-6. Use of ESA eventually depletes iron stores leading to iron deficient erythropoiesis. Such clinical situation is commonly associated with an increased platelet count (thrombocytosis), which in turn is believed to contribute to the increased mortality seen with high hemoglobin targets. Hence, optimal ESA therapy requires concurrent iron administration to prevent this phenomenon from occurring. Intravenous (IV) iron administration has been shown to not only decrease hemoglobin variability and ESA hyporesponsiveness, it may also reduce the risk of ESA-driven cardiovascular events7. Additionally, IV iron has been shown to improve New York Heart Association functional class, cardiac and renal function, quality of life and exercise capacity in CKD patients with heart failure8.

Iron also has benefits that are independent of the correction of anemia. Both iron and ESA cause a significant fall in hemoglobin A1C values without a change in glycemic control in patients with diabetes and CKD9. Iron deficiency is commonly associated with effort intolerance, fatigability, cold intolerance and failure to concentrate. The benefits of iron supplementation, independent of increasing hemoglobin, also include better immune function, physical performance, thermoregulation, cognition, and improvement in restless leg syndrome 10.

Safety concerns related to iron therapy

There are a number of concerns related to use of iron in patients with ESRD, who require intravenous (IV) iron supplementation, frequently on a regular basis. These include hypersensitivity reactions, infections, immune dysregulatoin, oxidative injury, inflammation and iron overload.

Hypersensitivity reactions

Intravenous (IV) iron preparations have been associated with hypersensitivity reactions (e.g., pruritus, rash, urticaria, or wheezing) and/or hypotension. These reactions were more common with older iron preparations. Hence most IV iron preparations require a test dose except for the newer IV iron preparations ferumoxytol (Feraheme) and ferric carboxymaltose (Ferniject). The risk of adverse events and anaphylactoid reactions seem to be highest with high molecular weight iron dextran and least with iron sucrose11-13. Low molecular weight iron dextran and ferric gluconate fall in between these two for risk of adverse drug events11 .

Infections

Most common infectious agents in ESRD patients require iron for their growth and virulence. Staphylococcus epidermidis requires free iron, staphylococcus aureus requires transferrin bound iron and E coli and klebsiella secrete siderophores to bind iron. Transferrin bound iron is unavailable to most bacteria. Free iron suppresses polymorphonuclear leukocyte function, impairs T cell development and facilitates growth of bacteria by adversely affecting cell-mediated immune effector mechanisms against invading microorganisms14. Free iron also inhibits phagocytosis and cell lysis. Therefore in patients with sepsis, treatment with IV iron should be avoided. Iron Overload with ferritin >1000 microgram/l in haemodialysis patients has also been shown to increases the risk of bacteremia15 although another surveillance study of 998 patients in France did not show worsening effect of IV iron on infection16.

Oxidative injury

Chronic kidney disease (CKD) is a pro-oxidant state, and the concern exists that iron excess may exacerbate oxidative stress17-18. In one study, IV iron sucrose was shown to increase the level of inflammatory chemokine monocyte chemoattractant protein which can potentially lead to progression of CKD19. Additionally, increased ferritin level has been linked to acute renal failure20. Some evidence suggests that IV iron sucrose could be associated with proteinuria and tubular damage21-22. This is supported by the fact that renal hemosiderosis secondary to both chronic repetitive hemolytic episodes and transfusion-related iron overload in patients with paroxysmal nocturnal hemoglobinuria can lead to Fanconi syndrome and chronic kidney disease23. Despite the above evidence suggesting harmful effects of iron overload on kidneys, no study has shown evidence of direct acute kidney injury with IV iron.

Iron Overload

Iron overload may induce insulin resistance and metabolic alterations which may promote cardiovascular adverse outcomes24. One study found correlation between increased serum ferritin levels and severity of stroke25. Cases of hemochromatosis have been reported with serum ferritin levels >2000 ng/ml2. Parenteral iron has also been reported to suppress renal tubular phosphate reabsorption and 1-alpha-hydroxylation of vitamin D resulting in hypophosphatemic osteomalacia, an action mediated by an increase in fibroblast growth factor 23 (FGF23)26-28.

How to replace iron in ESRD?

Iron deficiency in ESRD patients is easily corrected by intravenous iron. Indeed, intravenous iron can raise levels of hemoglobin even without the use of ESAs and enhance the efficacy of ESAs. A meta-analysis of studies in CKD and ESRD showed that patients on hemodialysis therapy have better Hb level response when treated with IV iron as compared to oral iron 29-30. It is estimated that patients requiring maintenance hemodialysis treatments may lose up to 3 g of iron each year and hence intravenous iron is routinely used either weekly to monthly in dialysis patients. Regular iron infusion of 50 to 100 mg per week is able to cover the basic needs of most hemodialysis patients. The 2006 K/DOQI guidelines however suggest that oral iron be administered in peritoneal dialysis as well as for initial iron therapy in hemodialysis patients1.

Available IV Iron Formulations

The most desirable iron supplement should have ease of administration, freedom from side effects, no toxicity, efficacy and economy. No such iron preparation is currently available. Iron is inherently toxic and all preparations of iron- oral or IV- are ionic and have side effects. IV iron preparations are colloidal nanoparticles consisting of a core of iron and outer carbohydrate shell to protect from toxicity of free iron. The size and shape of core and shell determine biologic characteristics of iron preparation- such as iron release, uptake, clearance, bioactivity, tolerance and rate of infusion. Acute reactions to iron seem to be related to free iron toxicity and amount of labile iron released is inversely proportional to the size of the molecule. The amount of labile iron released also increases with the increase in the dose and limits the maximum tolerated dose and rate of infusion. The currently available preparations have limitations due to side effects or dose limitations.

The carbohydrate shell of currently available IV iron preparations is composed of dextran, sucrose, dextrin or gluconate molecule31(Table 2). Iron dextrans (INFeD- molecular weight 96-165Kd, Dexferrum molecular weight 265Kd) - deliver iron to RES receptors from where it is transferred to transferrin, precluding generation of free iron. These have a half-life of 40-60 hours and a volume of distribution of 6 liters. There is no renal elimination32. Major advantage of iron dextran is the ability to administer a full gram of iron over one session. However, dextrans are the only IV iron preparations with reported deaths due to allergic reactions (much more with Dexferrum than with InFeD). In one study of 573 dialysis patients, 1.7% incidence of anaphylactoid reaction was noted with IV iron33.

Low-molecular-weight iron dextran, which is approved for total dose infusion in the United Kingdom, has been shown to be safe and efficacious compared to iron sucrose34.

Ferric gluconate in sucrose (Ferrlecit) has a lower molecular weight (29-44Kd), half-life of 1 hour and is devoid of direct transfer of iron to transferrin. It has a volume of distribution of 6 L and does not have renal elimination. However, it has low dissociation constant releasing iron quickly35.

IV iron saccharate used to replenish and maintain iron stores in stable EPO treated HD patients is safe and effective. It results in achieving target hemoglobin with significantly lower doses of EPO36. Iron sucrose has a molecular weight of 34-60 Kd and is also taken up by RES with some direct transfer to transferrin. It has a half-life of 6 hours and has 20 percent and serum ferritin concentration >200 ng/mL as the goals of iron therapy in patients undergoing hemodialysis1. However, the desirable upper targets of ‘iron indices’ that should be used as goals to guide iron therapy remain undefined. Serum ferritin and transferrin saturation are often confounded by non-iron-related conditions. For instance, serum ferritin is also elevated in the setting of inflammation, latent infections, malignancies, or liver disease7. Hence moderate-range hyperferritinemia (500 to 2000 ng/ml) has been shown to be a misleading marker of iron stores in dialysis patients2. In fact, serum ferritin is increased above 500 ng/ml in almost half of all hemodialysis patients and in the range of 500-1,200 ng/ml it does not increase risk of death42. Additional IV iron given to dialysis patients in this ferritin range increases Hgb4 and may even increase survival2.

KDOQI recommends that when serum ferritin level is > 500 ng/ml, decision on IV iron administration should weigh several factors including erythropoietin responsiveness, hemoglobin and transferrin saturation level, and the patient's clinical status. However no upper limit of serum ferritin at which to withhold IV iron is defined.

An increased erythropoietic response to iron supplementation is also widely accepted as a good reference standard of iron-deficient erythropoiesis43. However, a recent study showed that both peripheral-iron indices and erythropoietic response had equivalent, but limited, utility in identifying depletion of bone marrow iron stores44.

In absence of clear strategies to assess iron status and arbitrary goals guiding I.V iron therapy, concern exists that excessive IV iron may lead to iron overload and toxicity in the long term. Iron overload itself stimulates hepcidin45 , which by blocking release of iron from the RES, may cause further buildup of iron in tissue stores.

Long-term outcomes with IV iron

While it is clear that IV iron could be a 'two-edged sword' with both benefits and potential concerns in short-term, less remains known about the overall clinical safety and risk to benefit ratio of iron supplementation in the long-term. Further prospective research should address the optimal amount of iron supplementation, ideal therapeutic approach and long-term safety of IV iron, especially of the newer IV iron preparations.

Minimizing iron overload/toxicity

Iron acts as a catalyst in the generation of oxygen-free radicals and thereby increases oxidative stress. As catalytically active iron is potentially toxic, some authors have recommended using dosage regimens that would not release iron into plasma in amounts exceeding the iron binding capacity of transferrin46. Use of certain IV iron preparations like ferumoxytol that release less free iron could potentially be less nephrotoxic47. Iron chelators with their role in binding labile iron may provide a new modality of prevention and treatment of kidney disease48. However oxidative stress can develop even when transferrin is not completely saturated suggesting that free iron independent mechanisms could also be important22. In addition, nephrotoxicity of iron may depend upon type of IV iron. A study examined the differences in proteinuria between two IV iron preparations and reported that in contrast to ferric gluconate, which produced only mild transient proteinuria, iron sucrose produced a consistent and persistent proteinuric response that was on average 78% greater49. As both serum ferritin and TSat can be altered by a number of non-iron-related factors, it is important to draw upon additional data when necessary such as patient’s clinical condition, percentage of hypochromic red blood cells, and/or the reticulocyte hemoglobin concentration. This may be helpful in correctly assessing patient's iron status and avoiding iron overdose.

Conclusion

Iron is necessary to optimize ESA therapy in patients on dialysis. It is essential to correctly ascertain precise cause of anemia and prudently consider iron status to optimally supplement iron and minimize iron overload. Quest for an accurate marker of iron stores and a safe and effective iron preparation will need to continue. Clinicians should carefully consider the benefits and hazards of iron therapy before using intravenous iron in the management of renal anemia until better data is available regarding the long-term safety of iron use in dialysis patients.

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