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

Introduction

We would like to start the debate by affirming that there are likely several points of agreement with the “pro” high-dose intravenous iron therapy. First, hemoglobin synthesis requires iron, which sits at the center of the heme porphyrin ring and allows red blood cells to transport oxygen to tissues throughout the body. Next, patients with ESKD are highly susceptible to iron deficiency from two concurrent processes—impaired iron metabolism and ongoing blood loss. Patients with ESKD have impaired iron metabolism because of underlying inflammation, which promotes production of the liver protein hepcidin, a key regulatory protein that inhibits the transfer of iron in enterocytes, macrophages, and hepatocytes through it effect on another regulatory protein, ferroportin. The net result is reduced availability of iron for erythropoiesis. Individuals with advanced CKD, especially persons on hemodialysis, have ongoing blood loss from repeat cannulation of the access, residual blood in the dialysis circuit tubing, and frequent blood draws—leading to profound iron deficiency. Up to 7 mg of iron may be lost per hemodialysis session, totaling up to 1600 mg/yr (¹). Patients with advanced CKD have angiodysplasia of the gastrointestinal tract, leading to additional blood loss. Thus, we concede that intravenous iron is likely the preferred mode of administration because oral iron is unlikely to replenish the losses. Current practice patterns confirm that most patients with ESKD regularly receive intravenous iron (²). Yet, dose matters, and we would argue against the use of high-dose intravenous iron in ESKD for the following four reasons.

Reason 1: High-Dose Intravenous Iron May Contribute to Labile Iron Formation

All current formulations of intravenous iron also have a carbohydrate shell surrounding a core of iron that shifts between the ferrous and ferric states. After administration, intravenous iron bypasses enteric absorption and goes directly to the cells of the reticuloendothelial system within the liver and spleen; a large majority of the iron goes to the liver because of its high blood flow relative to the spleen (³). The iron is transferred slowly into the marrow by an intermediate step of binding to transferrin, which then delivers the iron to the marrow. The time course of transfer after administration is important—the uptake of iron sucrose into the liver and the spleen is nearly complete within 1–2 hours and then transferred to the marrow. Yet, specialized magnetic resonance imaging of individuals with CKD and ESKD reveals that the liver sequesters the iron for long periods, sometimes well over 3 months (⁴).

Homeostatic pathways in the body handle 20–25 mg of iron daily. Currently, typical doses of intravenous iron include the following: iron sucrose, 25–100 mg per dose; ferric gluconate, 62.5–125 mg per dose; ferumoxytol, 510 mg per dose; and ferric carboxymaltose, 750 mg per dose. Even at relatively low doses, the absolute quantity of administered intravenous iron largely surpasses the quantity that is routinely handled by the hemostatic pathways.

The potentially large amount of excess iron may serve as a pool for the development of labile iron when it exceeds to carrying capacity of transferrin. Labile iron can participate in the generation, via the Fenton reaction (⁵), of harmful radicals that oxidize lipids and DNA. In this way, excess iron may contribute to accelerated atherosclerosis and eventually, clinical cardiovascular disease.

Reason 2: What Constitutes High-Dose Intravenous Iron Is Not Well Defined

In this debate regarding the use of high-dose intravenous iron, it is important to clearly define what constitutes high dose due to the great variation that exists in practice across clinics worldwide. In many countries, but especially the United States, high dose has been generally synonymous with dosing practices often called “bolus” that administer up to 1000 mg/mo, often over consecutive hemodialysis sessions; low dose has been considered as dosing practices often called “maintenance” that administer <200 mg/mo, typically divided equally into weekly allotments. Since the publication of the recent Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial (⁶), a proactive repletion strategy is becoming synonymous with high-dose intravenous iron. In PIVOTAL, patients assigned to the proactive regimen received a median monthly dose of 264 mg (maximum of 400 mg). However, this dosing regimen differs from the common practice in the United States. Currently in the United States, at least 40% of dialysis clinics administer ≥250 mg/mo (20% averaging ≥500 mg) with marked variation by facility size and profit status (²).

A more precise definition of high-dose intravenous iron should also incorporate frequency of dosing and dynamic laboratory parameters. For example, administration of 100 mg of intravenous iron consecutively for ten hemodialysis sessions and administration of 250 mg once weekly for 4 weeks would both total 1000 mg in a month; however, duration of time between doses and the absolute amount give per dose may result in differential metabolism. Furthermore, clinicians use laboratory parameters, such as transferrin saturation, ferritin, and hemoglobin levels, to make decisions on iron administration. Administration of proactive iron dosing in the PIVOTAL trial was terminated at a serum ferritin value of >700 μg/L or transferrin saturation of ≥40% (⁶), and these are lower than thresholds commonly used in United States clinical practice. Yet currently, there is lack of consensus for initiation and termination recommendations for intravenous iron therapy with different cutoffs recommended by different organizations, including Kidney Disease Global Outcomes, European Renal Best Practices, Kidney Disease Outcome Quality Initiative, the Canadian Society of Nephrology, Kidney Health Australia, and the National Institute for Health and Care Excellence (⁷).

In our opinion, the net effect of the varying definitions of high-dose intravenous iron is that it limits our ability to make valid conclusions on its safety and efficacy relative to other dosing approaches because we do not know what constitutes high dose. The proactive dose is not synonymous with high dose. Extrapolating the safety and efficacy profile of the proactive dosing approach to all high-dose intravenous iron is not appropriate.

Reason 3: The Benefits of High-Dose Intravenous Iron May Be Overemphasized

Typically, the benefits of high-dose iron include a rapid versus delayed rise in hemoglobin, reduced dosing of erythropoietin-stimulating agents (ESAs), and improved quality of life. The results of the PIVOTAL trial seemingly support this hypothesis by showing that the proactive regimen resulted in lower administered doses of ESA compared with the reactive regimen. However, there may be two sides to PIVOTAL. A closer inspection of the reactive regimen demonstrates that patients in this group may have become iron deficient. Thus, a nuanced (skeptical) interpretation of the PIVOTAL results would be that iron deficiency is harmful relative to iron repletion.

Furthermore, in a retrospective cohort study of patients with ESKD comparing the difference in hemoglobin between high-dose versus low-dose intravenous iron hemoglobin during 6 weeks of follow-up, the average absolute difference was only 0.15 g/dl between the two approaches (⁸). In the same study, the difference in erythropoietin dosing between the two iron dosing groups varied by time. At week 2 of follow-up, there was no difference in erythropoietin dose. At week 3, there was a modest difference; and by week 6, there was an approximately 1000-unit/wk difference in average erythropoietin dose for the high-dose compared to the low-dose intravenous iron group. It is not clear whether either the absolute hemoglobin difference or ESA dose between groups receiving high-dose and low-dose intravenous iron is clinically meaningful.

Data for quality of life outcomes are even less clear than for hemoglobin or erythropoietin. In a retrospective cohort study of high-dose versus low-dose intravenous iron among patients with ESKD, there was no improvement in overall quality of life measures as assessed by the Kidney Disease Quality of Life survey for the group. However, among a subset of patients with low hemoglobin, <11 g/dl at baseline, high-dose intravenous iron was associated with improved mental health scores compared with low-dose intravenous iron, whereas there was no difference in reported physical scores or symptom scores (⁹).

Reason 4: The Risks of Intravenous Iron Are Not Fully Quantified

PIVOTAL has shed light on the potential risks of intravenous iron (⁶). The trial found no infectious risk associated with proactive dosing compared with reactive dosing. Proactive dosing demonstrated a cardiovascular benefit with respect to heart failure—consistent with studies from a non-ESKD population of individuals with chronic heart failure. However, there remains uncertainty because of current practice patterns, especially in the United States.

As previously stated, proactive dosing does not approximate high-dose intravenous iron used in the United States. Therefore, there are no trial data for the risk of high-dose intravenous iron used for many patients with ESKD. Acknowledging that randomized controlled trials are not equivalent to cohort studies, there is remarkable consistency of the estimated risk of infections and cardiovascular events associated with high-dose intravenous iron among multiple epidemiologic studies included in a recent meta-analysis (¹⁰). In fact, the marked heterogeneity of the studies makes the reported aggregate estimate potentially problematic. Furthermore, the studies with risk estimates whose 95% confidence intervals cross the null may have been underpowered.

Also, the risks of high-dose intravenous iron remain undefined among certain subgroups of the ESKD population. These groups include individuals with active infections, hemodialysis catheters, and concomitant liver disease, such as hepatitis B or C virus coinfection, nonalcoholic fatty disease, or cirrhosis. Should these individuals receive high-dose intravenous iron? Out of an abundance of caution, low-dose intravenous iron therapy may be the safe choice for them. Finally, we are only beginning to learn about the interaction of intravenous iron with an important marker bone and mineral disease, fibroblast growth factor 23 (FGF-23). Currently, the known intravenous iron preparations vary with respect to their ability to cleave and transcribe FGF-23. In current practice, we lack the ability to identify patients who may be harmed from rising FGF-23 values after intravenous iron administration.

Disclosures

A.V. Kshirsagar reports consultancy agreements with Rockwell Medical; honoraria as a contributor to UpToDate since 2006; and scientific advisor or membership with American Journal of Kidney Disease and Kidney Medicine. The remaining author has nothing to disclose.

Funding

None.