Iron Therapy in CKD Patients -- Harm or Benefit?

Iron Therapy in CKD Patients -- Harm or Benefit?

Rajiv Agarwal, MD

Medscape Nephrology. 2008; ©2008 Medscape
Posted 09/09/2008

Introduction

The use of parenteral iron therapy has increased rapidly among patients with chronic kidney disease (CKD). This may be so for several potential reasons: First, it is now well established that in patients on hemodialysis requiring recombinant human erythropoietin (rHuEpo), intravenous (IV) iron is superior to oral iron in correcting anemia with less rHuEpo.[1] Second, because of concerns that have surrounded the use of high doses of rHuEpo, which is associated with all-cause mortality,[2] sparing the high doses of rHuEpo through the use of IV iron may improve outcomes. Third, there is growing recognition that iron may have benefits beyond repair of anemia. However, the benefits of iron come at the expense of increased risks. For example, anaphylactic reactions, oxidative stress, infection, potentiating inflammatory responses, endothelial dysfunction, and accelerated progression of cardiovascular and kidney disease are all potential dangers of IV irons. In this review, I discuss the risks and benefits of parenteral iron therapy and conclude with a personal view of how parenteral iron therapy may be used given this risk-benefit profile.

Risks for IV Iron
Anaphylactic Reactions

Iron dextrans are associated with a rate of anaphylaxis that exceeds the rate seen with nondextran irons.[3] Anaphylactic reactions are more common in patients with multiple drug allergies.[4] There are 2 types of iron dextrans available in the US market -- the low-molecular-weight form (INFeD) and the high-molecular-weight form (Dexferrum). The latter is more likely to produce anaphylactic reactions.[5]
Oxidative Stress and Injury

A large body of literature exists demonstrating that all IV irons cause oxidative stress, but their ability to produce cytotoxicity is dependent on the type of drug used.[6] In general, iron sucrose has the greatest potential to cause cytotoxicity, followed by iron gluconate, followed by iron dextran.[6]

Iron can generate oxidative stress in patients with CKD. Free iron released after the injection of iron sucrose is highly reactive and contributes to oxidative stress. Elevated total peroxide levels and malondialdehyde (markers of oxidative stress), and bleomycin-detectable nontransferrin iron (marker of free iron), were detected in 22 hemodialysis patients who were given 100 mg of IV iron sucrose.[7] Pretreatment of these patients with oral vitamin E appeared to block these effects, consistent with its antioxidant effect. Carbonylated fibrinogen (marker of oxidative protein damage) can be detected after IV infusion of 125 mg iron gluconate.[8]

In patients with CKD, IV iron sucrose given in recommended doses led to increased generation of oxidative stress and renal injury, as measured by markers of tubular damage and proteinuria.[9] Iron gluconate, on the other hand, while generating oxidative stress did not result in greater albuminuria,[10] a result that was confirmed in a head-to-head crossover trial of comparative renal toxicities.[11] Whether persistent exposure to IV iron accelerates the loss of renal function or whether the improvement in anemia, reduction in rHuEpo dose, and correction of iron deficiency improve renal outcomes will need further research. Of note, case reports from Japan have described proximal tubule toxicity with the development of a renal phosphate leak, calcitriol deficiency, and overt osteomalacia after several years of daily exposure to iron sucrose.[12]
Infections

Iron is a growth factor for many bacteria.[13] IV iron sucrose has been shown to cause neutrophil dysfunction.[14] However, epidemiologic studies do not point to increased risk for infections when iron is used in hemodialysis patients.[15]
Inflammation

Whereas iron by itself does not cause inflammation, when given in the setting of inflammation, it can compound the inflammatory response.[16] Given that in mice injected with intraperitoneal heat-killed Escherichia coli IV iron caused increased inflammation and mortality, iron should be avoided in septic patients.[17]
Endothelial Dysfunction

In healthy volunteers given the usual dose of IV iron sucrose, transient and reversible endothelial dysfunction has been observed.[18] There was a concomitant increase in non-transferrin-bound iron and increase in superoxide radical production, suggesting that oxidative stress may have caused the endothelial dysfunction. The long-term effects of this transient dysfunction are unknown.
Accelerated Progression of Cardiorenal Disease

A low-iron diet protects against glomerulosclerosis in rats that develop spontaneous renal disease independent of renal hemodynamic changes.[19] Renal biopsies from patients with nephrotic syndrome and/or CKD revealed higher iron accumulation in the proximal tubular lysosomes of patients with nephrotic syndrome than patients without the syndrome. The extent of tubular damage correlates with the amount of iron in lysosomes and suggests the association of iron and morphologic injury to the kidney.[20] Long-term exposure to iron in animals can cause tubulointerstitial fibrosis.[21]

Although epidemiologic data in patients with CKD on hemodialysis have suggested an association of increased iron exposure and atherosclerosis as assessed by carotid intima thickness,[22] at least 1 animal study has suggested otherwise. Apolipoprotein E (apoE)-deficient mice, a model of atherosclerosis, fed a high-iron diet had twice as much iron in their plasma, a 9-fold increase in bleomycin-detectable free iron in their plasma and 10 times as much iron in their livers as control mice at 24 weeks.[23] Nonetheless, this regimen did not exacerbate, but rather reduced the severity of atherosclerosis by 50%, and it failed to elevate hepatic levels of heme oxygenase mRNA, which is induced by many different oxidative insults in vitro. Moreover, hepatic levels of oxidative damage failed to rise in iron-overloaded animals. These data, therefore, call into question the hypothesis that elevated levels of tissue iron can promote atherosclerosis in vivo.

Thus, it remains to be demonstrated that IV iron in patients with CKD can accelerate cardiorenal disease.

Benefits of IV Iron
Sparing of rHuEpo Dose and Hemoglobin Response

A large amount of data, especially in patients on hemodialysis receiving rHuEpo, has suggested that IV iron is rHuEpo-sparing and elicits a more complete correction of anemia. In patients who are not on hemodialysis, oral or IV iron therapies produce similar responses.[24]
Nonhematologic Benefits

The nonhematologic benefits of iron have been documented largely in patients without CKD.[25] These include improvements in immune function, physical performance, thermoregulation, cognition, and restless legs syndrome and aluminum absorption. If iron indeed has benefits beyond correction of anemia, then correction of iron deficiency may become a simple and attractive option to enhance the well-being of patients with CKD.

Conclusion

Until the long-term risk-benefit ratio is clarified with randomized controlled trials, it is prudent to use oral iron as first-line therapy in iron-deficient, anemic CKD patients who are not on hemodialysis. If therapy fails, IV iron can be used. Because nondextran irons have reduced risk for anaphylaxis that can be fatal, I have preferred to use nondextran irons. In hemodialysis patients, the key is to limit the dose of iron, and slow continuous therapy appears to be a more logical iron replacement method compared with single, high-dose repletion. Iron should be avoided in patients who are septic or otherwise have uncontrolled inflammation.
References

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Rajiv Agarwal, MD, Professor of Medicine, Indiana University, Indianapolis, Indiana

Disclosure: Rajiv Agarwal, MD, has disclosed that he has served on the scientific advisory boards of Watson and Rockwell.

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