Clinicians administering intravenous (IV) iron therapy to anemic patients with end-stage renal disease (ESRD) have voiced concerns about iron overload and infectious and cardiovascular complications. In a recent issue of Advances in Chronic Kidney Disease, Abhijit V. Kshirsagar, MD, MPH, of the University of North Carolina at Chapel Hill, and Xiaojuan Li, PhD, of Harvard Medical School in Boston, discussed trends in IV iron use and potential toxicity and complications, and underscored the importance of the findings from the PIVOTAL trial.

Despite the prospect of novel oral iron drugs, IV iron “will continue to be a necessary part of anemia management in the near future,” according to the reviewers.

Guidelines recommend initiation of IV iron therapy for iron deficiency, but there remains no consensus on the upper target limits of transferrin saturation (TSAT) and serum ferritin. Common practice is to halt IV iron when TSAT exceeds 50% or serum ferritin exceeds 800 ng/mL, although some use an upper limit of 1200 ng/mL. Repeated doses of large quantities of IV iron are typically given in routine practice.

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Nephrologists have been concerned about the safety of IV iron and iron overload. In theory, labile iron in the human body may spur atherosclerosis and bacterial growth. The current literature has yielded conflicting results with respect to both cardiovascular and infectious complications, the reviewers stated.

The recently published PIVOTAL (Proactive IV iron therapy in hemodialysis patients) randomized clinical trial, however, demonstrated that a proactive high IV iron dosing regimen (400 mg monthly up to a TSAT of 40% or a serum ferritin concentration of 700 ng/mL or less was superior to a reactive dosing regimen (0-400 mg monthly to maintain TSAT of 20% and a serum ferritin of 200 ng/mL) for major adverse cardiovascular events. Investigators also found no difference in infection risks between the 2 groups.

The PIVOTAL trial, which was the first of its kind to evaluate 2 dynamic IV iron dosing regimens, was an open-label trial involving 2141 adult patients undergoing maintenance HD for fewer than 12 months, Drs Kshirsagar and Li noted. It was conducted at 50 centers in the United Kingdom.

“The recently published PIVOTAL trial adds important new information that should help nephrologists allay their concerns of IV iron supplementation,” Drs Kshirsagar and Li concluded. The reviewers also highlighted important caveats. IV iron doses in PIVOTAL would be considered moderate by US standards and hold parameters of serum ferritin up to 700 ng/mL conservative. Patients in the proactive group received a median monthly dose of 264 mg iron (and a maximum of 400 mg), which is significantly lower than current practice. In addition, all PIVOTAL patients recently initiated hemodialysis or had a short dialysis vintage.

“Although it is tempting to apply this approach to all patients receiving dialysis, we still do not know whether a moderate approach is more effective than high dose (bolus and half-bolus) with respect to hemoglobin, ESA dosing, cardiovascular end points, and infections,” the authors wrote. “Nonetheless, we are now closer to understanding optimal IV iron dosing thanks to the study.”

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Kshirsagar AV, Li X. Long-term risks of intravenous iron in end-stage renal disease patients. Adv Chronic Kidney Dis. 2019;26:292-297. doi: 10.1053/j.ackd.2019.05.001