Proactive High-Dose IV Iron Is Preferred Therapy in ESKD Patients: COMMENTARY

• dialysis
• anemia
• chronic kidney disease
• debate
• iron

Anemia is one of the most common complications of CKD and ESKD, with >75% of patients with ESKD requiring pharmacologic therapy to reach anemia management goals (1). Erythropoietin-stimulating agents (ESAs) have revolutionized the treatment of anemia for these patients; before their availability, patients with ESKD were often extremely anemic and many required periodic blood transfusions. Given its central role in red blood cell production, adequate patient iron availability is paramount to maximizing the efficacy of ESA therapy. Estimating blood iron content at about 0.4 mg of iron per milliliter of blood, patients may lose, on average, up to 2–3 g of iron per year as a result of an average blood loss of 4–5 L per patient per year (2). Oral iron therapy has historically been ineffective (3) and, as such, intravenous iron is nearly universally used by dialysis facilities to augment red blood cell production and bone marrow responsiveness to ESAs (1).

Adding to the clinical importance of optimal anemia management is the financial reality of treating anemia. Pharmaceutical costs associated with anemia management in ESKD are responsible for approximately 25% of the Medicare bundled payment, with approximately 90% of these costs attributable to ESAs and the rest to iron agents (4). The confluence of the high costs of ESAs and evidence that high ESA doses are associated with adverse cardiovascular and oncologic outcomes has resulted in intense study of optimal iron usage. However, despite the central role of iron therapy in anemia management in ESKD, no clear consensus exists on the optimal dosing of iron, with varying guidelines from expert panels (5). Underlying this lack of consensus is the unfortunate fact that estimating the degree to which a patient has enough available iron for erythropoiesis remains a black box—commonly used measures, such as ferritin and transferrin saturation (TSAT), do not always reliably predict response to iron therapy in patients with ESKD (6).

In this issue of Kidney360, Dr. Coyne and Dr. Kshirsagar present their views on whether proactive, high-dose intravenous iron therapy is advisable, with the Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL) as the linchpin. In the PIVOTAL trial (7), patients on in-center hemodialysis for <1 year were randomized to either a more aggressive iron regimen (200 mg iron sucrose on the two subsequent treatments after monthly laboratory test results if TSAT was <40% and/or ferritin was <700 μg/L) or a conservative regimen (0–400 mg iron sucrose on the basis of ferritin being <200 μg/L or TSAT <20%). Patients were followed for a median of 2.1 years. The bottom-line outcome of the trial found that the more proactive higher-dose iron regimen required 23% less ESAs than the lower-dose group, was at least noninferior (if not superior) in terms of the composite primary outcome (nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death), with no statistically significant signal in terms of increased infection risk. On the basis of the results of this trial and in combination with numerous other trials and meta-analyses suggesting improvement in cardiovascular outcomes, lower ESA requirements, and no overtly increased risk for infection or iron-related organ dysfunction, Dr. Coyne endorses using higher-dose iron proactively. In fact, he is more liberal in his own practice than even the PIVOTAL trial high-dose arm; he continues IV iron therapy until the ferritin is >1200 μg/L.

Dr. Kshirsager, on the other hand, does not dispute the findings of the PIVOTAL trial in his “con” argument, but rather points out several issues with the argument that “high-dose” iron therapy is definitely the proper approach. First, he argues that, mechanistically, the doses of iron given are likely to overwhelm endogenous iron homeostatic pathways, increasing potential risk of labile iron formation and lipid peroxidation via the Fenton reaction. Second, he asserts high-dose iron is not well defined, in that the dosing amount and schedule of iron therapy is quite variable in practice. Furthermore, PIVOTAL and other trials still do not provide enough specificity to treat patients in the United States, where the majority of patients have iron parameters above the “stop-iron” cutoff of PIVOTAL (8), and where many patients do not fall into the study population of these trials. Third, he questions whether proactive high-dose iron is actually what benefits the patient, or whether the conservative group was just allowed to become iron deficient. And lastly, although clinical trials and meta-analyses have not yet borne out the potential risks of increases in labile iron or organ iron overload, the patients at highest risk are often excluded from these trials. As such, when expanded outside the strict settings of a trial, high-dose iron may ultimately be found to be harmful.

From our perspective, the evidence suggests strongly that iron should be used proactively. Patients should not be allowed to become iron deficient—the benefits of iron repletion in terms of hard clinical end points and lower ESA use are relatively clear. In contrast, despite plausible biologic mechanisms by which high-dose iron may be harmful to patients, it has not been convincingly shown in patients on dialysis that these are real-world, clinically significant, adverse outcomes.

However, Dr. Kshirsagar’s points remain important and relevant. What is the correct clinical target, and which measures are most important? For instance, whereas PIVOTAL withheld IV iron in patients with ferritin >700 μg/L, the average ferritin level for American patients on dialysis is >800 μg/L (8, 9). This begs the question: what to do with the majority of patients on dialysis in the United States? Is there a maximum ferritin above which intravenous iron becomes either dangerous or ineffective? Given the lack of data demonstrating iron-based end-organ damage, is the ferritin level even important unless coupled with other signs of ongoing infection or inflammation? As Dr. Kshirsagar notes, it may actually be iron deficiency that is harmful, and so the “conservative” group in PIVOTAL may have been set up to fail. Indeed, TSAT <25% and ferritin <600 μg/L have been shown to be associated with worse outcomes (10).

In our own practice, we give smaller weekly doses of intravenous iron (50 mg iron sucrose) as maintenance to offset ongoing losses, and do not stop iron unless TSAT >45%. If the TSAT is <25%, we load with 1 g of iron (over ten doses) regardless of the ferritin concentration. However, clinical context still matters—if a patient has a known or suspected active infection, has just been discharged from the hospital, or has elevated nonferritin inflammatory markers (i.e., C-reactive protein), we may hold the iron or give more judiciously until the clinical situation is clarified.

Outstanding questions include what should be done with relatively new players to the market? For example, oral ferric citrate has been shown to decrease need for intravenous iron and ESA requirement while also doubling as a phosphate binder and, presumably, would not carry the same risk of labile iron formation as intravenous preparations (11). In addition, ferric pyrophosphate citrate, distributed via dialysate, has been studied as a way to deliver smaller doses of iron over the entirety of the dialysis treatment (12). There are currently insufficient data to compare these newer agents with the incumbent intravenous iron therapies, and their use is relatively limited due to cost constraints.

Furthermore, PIVOTAL and related trials studied in-center patients on hemodialysis, and did not include patients on either peritoneal or home hemodialysis, who now comprise >12% of the total dialysis population (1). Iron therapy, in particular, presents significant operational difficulties due to the fact that patients are not in center for its administration and, in the case of patients on peritoneal dialysis, do not even have intravenous access. In the era of the Advancing American Kidney Health Initiative and its associated payment models, optimizing anemia management for home patients will continue to grow in importance.

• Received July 26, 2021.
• Accepted August 6, 2021.

• Copyright © 2022 by the American Society of Nephrology