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CKD and anemia go together like Donald Trump and hairspray. And as with every lab abnormality, nephrologists want to fix the anemia despite a thin trail of evidence supporting improved outcomes with improved hemoglobin. This is reflected in the most recent FDA labeling for erythropoiesis stimulating agents (ESAs), which indicates they are indicated only to decrease the need for transfusions in dialysis patients.

The same FDA label also states that transferrin should be greater than 20% and ferritin > 100 ng/mL prior to starting an ESA, which brings us to the topic of a recent AJKD Perspective article. This is a review of iron prescribing strategies and currently available options.  This review is written by Drs. Vaziri, Kalantar-Zadeh, and Wish, all of whom have received financial support from Keryx, which manufactures ferric citrate.

Oral iron is generally safe, but poorly absorbed in dialysis patients. Intravenous (IV) iron, on the other hand, is effective at improving iron studies and hemoglobin, and decreasing ESA requirements, but have safety concerns that include anaphylaxis, cardiovascular disease, and risk of infection. Despite these safety concerns, IV iron is used in 81.9% of dialysis patients in the U.S. according to DOPPS.

The authors provide a table demonstrating the progressive rise in mean ferritin levels since the approval of erythropoietin in 1989 from 302 ng/mL to 825 ng/mL in 2014. The rising ferritin occurred despite KDOQI recommendations for a target ferritin of 200-500 in 2006, and a KDIGO recommendation against IV iron if the ferritin is greater than 500 in 2012.

The article then reviews the data on IV versus oral iron supplementation. They highlight Dr. Agarwal’s KI study showing increased cardiovascular and infectious complication with IV compared to oral iron (as discussed in NephJC). The article repeatedly highlights a critical weakness in the canon of anemia research, the dominance of short studies with laboratory-based rather than patient-oriented outcomes. They argue this research is less likely to detect infrequent, but important, potential adverse events. They caution that the apparent safety of IV iron maybe overstated due to the nature of the investigations on these drugs.

The authors spend some time exploring various pharmacokinetic dosing strategies and provide compelling data that lower, more frequent dosing is more effective than higher, less frequent doses. This efficacy almost certainly translates to improved safety since less of the drug (and less ESA) is ultimately used.

The last half of the article focuses on two new iron agents, one oral and the other delivered in the dialysate.

The oral agent is ferric citrate, a drug recently approved as a phosphate binder but also delivers significant iron to the patient. This differentiates it from the other iron containing phosphorus binder, sucroferric oxyhydroxide (Velphoro), which doesn’t show significant iron absorption or change in ferritin. In a recent clinical trial, iron citrate raised the ferritin by 114 and TSAT by 8.6%, while reducing the need for IV iron by roughly half and ESA dosing by roughly 20%.

The reasons that ferric citrate has better bioavailability than conventional iron preparations is discussed. They propose three theories, but the simplest one is most appealing; ferric citrate, in conventional doses, contains 1,200-2,400 mg of elemental iron per day, 6 to 12 times the amount recommended in KDIGO.

The authors conclude with a discussion of dialysate-delivered iron. This was first explored in 1999, and approved by the FDA in 2015 as ferric pyrophosphate citrate. This compound is added to the bicarbonate concentrate of the dialysis machine and provides 5-7 mg of elemental iron with each dialysis session. This 5-7 mg is the reported amount of iron lost during dialysis, so this drug negates the normal iron deficiency of dialysis. The article summarizes the two randomized trials that show this drug to be effective, and then discusses some of the limitations of using dialysate to deliver drugs.

Overall, this review summarizes the evidence for the use of IV iron and introduces us to novel oral iron agents and newer ways to deliver iron to our patients.

Joel Topf, MD
AJKD Blog Advisory Board member

To view the article abstract or full-text (subscription required), please visit AJKD.org.