Editor’s note: This article is the opening editorial by Dr. Wish for a special supplement published by Nephrology News & Issues in the February 2014 issue entitled, “Iron therapy and a quarter century of ESAs: What have we learned?”

The typical adult human body contains about 3,000 to 4,000 mg of iron, which must be tightly regulated to avoid iron deficiency and overload. The inflammatory state of chronic kidney disease and end-stage renal disease complicates the task of defining iron deficiency and overload, which result in impaired iron mobilization within the body.

Iron deficiency in red blood cells (RBC; normal iron content around 2,500 mg) can coexist with iron overload in other tissues (normal iron content around 1,000 mg) in the same patient at the same time. This paradox makes iron management in patients with CKD challenging, to say the least, and helps to explain why the controversy regarding iron supplementation persists despite three iterations of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) and one iteration of the Kidney Disease Improving Global Outcomes (KDIGO) anemia practice guidelines over the past 17 years.

This supplement to Nephrology News & Issues provides a number of perspectives regarding iron management in patients with CKD, some more conservative and some more liberal, some based on evidence and some based on experience. The big problem in nephrology is that the evidence is relatively scant because the appropriate large-scale randomized clinical trials to establish best practice have not been done. So what we have is extrapolation from basic science, observational studies, mathematical models, and consensus building.

Risks of IV iron

In his article, Dr. Vaziri enumerates the potential consequences of the “indiscriminate” use of intravenous (IV) iron, including cardiovascular injury, impaired host defenses, increased risk of infections, liver disease, and progression of diabetes and its complications. Dr. Vaziri doesn’t mention the acute reactions to IV iron, including anaphylaxis, hypotension and gastrointestinal symptoms. As Dr. Vaziri points out, the use of IV iron bypasses the normal regulatory channels that are designed to keep excess iron out of the body, and the large doses of IV iron overwhelm the capacity of iron-binding proteins in the plasma and increase the risk that catalytically active iron will cause injury.

Furthermore, the large boluses of IV iron that are typically administered to dialysis patients are far in excess of what even an iron-deficient erythron can assimilate on a daily basis. In the setting of normal rates of RBC production, around 25 mg of iron are recycled from stores into new RBC. Even if RBC production is accelerated by the use of erythropoiesis-stimulating agents (ESAs), iron incorporation will be far less than that contained in typical IV iron administration protocols. Therefore, the extra iron must be “parked” somewhere, typically in the reticuloendothelial (RE) system, where its release is impaired by hepcidin from the chronic inflammatory state of CKD. This explains the disproportionate rise in serum ferritin over transferrin saturation (TSAT) after IV iron is administered.

Is that additional storage iron dangerous? One could argue that it is “safe” in storage and that the hepcidin is actually protective because it doesn’t allow too much iron to be released into the circulation at any one time. Nonetheless, there remains concern that too much storage iron can spill over into cells where it doesn’t belong, as in hemochromatosis. However, the threshold for that spillage remains to be determined, and may vary from patient to patient. It depends on the underlying vulnerability of the cells, particularly the hepatocytes.

The when and how of IV iron

When is the administration of IV iron “indiscriminate” vs. appropriate?  If there were an easy answer, then we could give patients just the right amount of IV iron and avoid iron toxicity. Unfortunately, as Drs. Kelepouris and Kalantar-Zadeh point out in their article, the most commonly used laboratory tests of iron status have significant limitations. The controversy continues to exist regarding the “sweet spot” for TSAT and serum ferritin that maximizes ESA responsiveness while minimizing iron toxicity. A number of studies, mostly observational but some interventional, have suggested maintaining TSAT > 30% to maximize ESA responsiveness. However, given the inflammation present in many of these patients, pushing the TSAT to > 30% with IV iron will often result in a serum ferritin > 800 ng/dL. This is not necessarily a contraindication to additional IV iron administration, but should prompt an evaluation to determine the source of the inflammation and interventions, if possible, to treat it.

Some nephrologists remain unconvinced that the benefits of IV iron administration outweigh the risks in patients with ferritin 500 to 1200 ng/mL. It must be recalled that the storage iron in these cases is not catalytically active, that the elevated serum ferritin may be as much an acute phase reactant as a marker for storage iron, and that tissue studies in patients with this level of serum ferritin have demonstrated that all the iron is in RE cells and virtually none in cells where it doesn’t belong.

As Dr. Winkelmeyer notes in his article, the administration of IV iron in hemodialysis (HD) patients is seldom a question of whether, but more often how much, how often, and which agent. A typical HD patient loses around 2500 mg of iron per year via blood left in the extracorporeal circuit, oozing from needle sites, phlebotomy for blood testing, and vascular access procedures, so the need for IV iron is virtually inevitable. Based on observational studies, bolus (as opposed to maintenance) IV iron therapy appears to be associated with increased efficacy (as measured by hemoglobin response) as well as increased risk of infection. Iron sucrose (as opposed to ferrous gluconate) therapy, perhaps because of its longer plasma half-life, appears to be associated with increased efficacy as well as increased risk of infection. These results are hypothesis generating and will require randomized controlled trials for confirmation, but such head-to-head studies are unlikely to occur.

Alternatives to IV iron

As safety concerns regarding the use of IV iron agents accumulate, attention has turned to the potential for non-IV routes of iron delivery in HD patients. In his article, Dr. Besarab reviews the barriers to oral iron absorption in patients with CKD, noting that ferric citrate, a phosphate binder currently in development, is associated with significant iron absorption and a decrease in IV iron requirements. Whether the rise in serum ferritin that occurs with the ferric citrate is “safer” than a comparable rise in serum ferritin from an IV iron agent is yet to be determined. Soluble iron pyrophosphate (SFP) is delivered to HD patients via the dialysate and has been associated with a 48% reduction in IV iron requirements and a 35% reduction in ESA requirements. This occurred without the increase in serum ferritin levels associated with comparable ESA sparing doses of IV iron, either because the SFP is associated with less inflammation than IV iron or because the iron in the SFP is delivered to the erythron more efficiently, requiring less of the iron to be “parked” in RE stores. Since IV iron is associated with acute toxicity independent of the potential long-term safety issues associated with the accumulation of iron from all routes of delivery, effective non-IV iron agents could prove to be a welcome alternative.

Standardizing IV iron administration

As anemia management in HD patients shifted from multiple transfusions and iron overload (typical serum ferritins in the 1500 ng/dL range) to ESAs and iron deficiency in the early 1990s, many nephrologists were reluctant to use adequate amounts of IV iron to overcome the functional iron deficiency caused by superphysiologic rates of RBC production and iron mobilization impairment related to inflammation (now known to be mediated by hepcidin).

Now many would say that the pendulum has swung too far in the direction of overuse of IV iron as ESA-sparing and cost reduction became priorities in the post-bundling era and average serum ferritin levels are approaching 800 ng/dL. Drs. Aronoff and Gaweda recount some of these economic drivers to anemia management over the last 25 years, noting that the physiology of the interaction between ESAs and iron, both of which are required for RBC production, has been largely forgotten amid the preoccupation with cost centers and profit centers. They propose a mathematical model that focuses on RBC indices: mean corpuscular Hb (MCH), mean corpuscular volume (MCV) and RBC distribution width (RDW, the intrapatient variability of MCV) as the outcomes of interest for iron sufficiency. By using such a model, they have been able to significantly decrease ESA and iron use while consistently achieving individualized Hb targets and minimizing intrapatient Hb variability. This has been the “holy grail” of anemia management, namely “best” and consistent outcomes with minimal risk of therapy. Such a model becomes increasingly relevant as the potential toxicities of both ESA and iron therapies have become recognized.

In the final article of this supplement, Dr. Schiller addresses another barrier in achieving optimal iron management: the dissemination of best practice to individual providers. Evidence and practice guidelines are ineffective in improving patient care if they are not incorporated into algorithms, care paths, and protocols to achieve consistency of process and outcomes. Given all the controversies regarding iron management in dialysis patients, Satellite Healthcare has taken a democratic and iterative approach in establishing its iron administration protocols, which has led to near universal buy-in by the referring nephrologists. The recognition that ESAs and iron are inextricably linked in the production of RBCs as also noted by Drs. Aronoff and Gaweda has led Satellite to require that nephrologists opt into both their ESA and iron protocols together; there is no choice to opt out of only one of them. Nephrologists are allowed to order additional IV iron above what the protocol may provide, and the protocol addresses concerns regarding the administration of IV iron in the presence of acute infection and inflammatory states. The current target serum ferritin is 500 to 800 ng/dL, which represents the consensus of the nephrologists despite strong sentiments by some and amid a lack of clarity from KDIGO regarding this issue.

Individualizing IV iron administration

Iron management in CKD patients has been a moving target over the past 25 years since the introduction of ESAs, and there remains considerable controversy, particularly related to the safety of IV iron, in patients with higher serum ferritin levels. If “higher” serum ferritin levels means > 800 ng/dL, then that involves almost half the hemodialysis (HD) population in the United States because the mean serum ferritin was almost 800 ng/dL in early 2013, according to data from the Dialysis Outcomes and Practice Patterns Study (DOPPS). The DOPPS data also demonstrate that since 2010, the mean hemoglobin in HD patients has decreased from 11.5 to 10.8 g/dL, but the average IV iron dose has remained unchanged at around 200 mg/month. If the RBC mass has decreased by 6%, where is the rest of the IV iron going?  Not surprisingly, it is going into stores; the mean serum ferritin has increased from close to 600 to close to 800 ng/dL. The business-as-usual approach (not the increase in IV iron as an ESA-sparing strategy under bundling that some predicted) has failed to account for the lower Hb targets that have resulted from changes in FDA labeling for ESAs and the Quality Incentive Program. It is convenient to administer IV iron in multiples of the vial size, but attention to the recent changes in RBC mass required to support the IV iron dose demands otherwise.

Rather than adopting a “one size fits all” serum ferritin ceiling for iron therapy in all dialysis patients, efforts should be made to evaluate each patient with high serum ferritin to determine the cause and to consider whether the risks of iron therapy outweigh the benefits. If the patient has lab parameters to suggest functional iron deficiency (e.g., low TSAT, low reticulcyte hemoglobin content [CHr], low MCV, high RDW), severe anemia, and no active infection to contraindicate iron therapy, then perhaps a trial of supplemental iron may be effective. This trial of supplemental iron may deliver at least some iron to the erythron while the rest of the iron will be sequestered safely in RE stores by hepcidin, where it will become available when the inflammation subsides. On the other hand, a transient mild decrease in Hb may be acceptable (or even adaptive) in the setting of inflammation, and administration of supplemental iron may be associated with risk without benefit.

Individualization of anemia management has become the new paradigm for ESA therapy. It should apply to iron therapy as well in the non-routine patients for whom the use of standardized protocols are confounded by significant comorbidities, poor Hb response, high serum ferritin, and/or adverse reactions to the iron agent.

Read more from the iron management series