This article is part of 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?"

Introduction

Management of anemia in patients with chronic kidney disease requires recognizing that decreased erythropoietin production is not the sole reason for anemia; decreased iron availability also contributes. In fact, iron deficiency is the major impediment to the cost-effective use of erythropoiesis-stimulating agents (ESAs). Use of oral or intravenous (IV) iron without ESA treatment can be successful in non-dialysis CKD patients and delay or reduce the need for ESAs. As harm from ESAs may be due to use of higher doses rather than achievement of higher hemoglobin (Hb) levels, proper use of iron to reduce ESA cardiovascular risks in patients is appropriate. Oral iron has been used for centuries whereas parenteral iron has been in use for about 40 years. A number of concerns about the risks of using parenteral iron have been raised, 1 particularly as the use of this form of iron has increased. Importantly, the long-term safety of IV iron administration has not been thoroughly tested in CKD patients despite the results of the DRIVE study.2

This review will discuss the benefit and risks of parenteral iron and opportunities to alter these risks through new options for non-intravenous delivery of iron to patients with CKD.

 

Iron delivery to the erythron

Patients with CKD differ from healthy, non-CKD individuals in two important ways with respect to iron transport and distribution. First, they have a lower transport capacity (low total iron binding capacity), which impairs the metabolic cycling of iron. CKD is a pro-inflammatory state, and the biological variability of serum iron, transferrin saturation (TSAT), and ferritin is known to be large in the context of underlying inflammation. The second abnormality is the inability to effectively mobilize stored iron from body depots, called macrophages, resulting from increases in the key iron regulatory hormone hepcidin. A meta-analysis evaluating newer versus classical laboratory parameters in CKD patient stages 3–5 by the Agency for Healthcare Research & Quality (AHRQ) suggested that reticulocyte hemoglobin content and percent hypochromic cells have better predictive power of a Hb response to 1 g of iron than the classic markers of TSAT < 20% and ferritin < 100 ng/mL.3

(Related: Balancing ESA and iron therapy in a prospective payment environment)

Iron delivery to the erythron requires absorption of iron from the gastrointestinal tract and movement of recycled or stored iron from macrophages into the usable iron pools. The normal diet provides 15-20 mg/day of iron as heme and non-heme (elemental) moieties, of which 1-2 mg is absorbed and is sufficient to maintain erythropoiesis. Dietary iron absorbed can increase to several mg/day if ferritin levels are < 15–20 ng/mL, indicating iron depletion. However the needs of patients on hemodialysis (HD) are much greater, estimated to be 6–8 mg/day, 4 and iron contained in food is usually not sufficient to meet the requirements for active erythropoiesis.

Iron absorption from food in CKD appears unimpaired as long as the serum ferritin level is < 100 ng/mL.5  The great majority of CKD patients, other than those having GI bleeding, have ferritin levels much higher due to a variety of factors. Typically, serum ferritin is > 200 ng/mL, a value where little duodenal iron absorption can occur.

Several other processes further impair the effectiveness of iron derived from food or supplemental oral iron in CKD patients. First, interference with oral iron absorption may be due to concomitant food and drug ingestion by CKD patients. Iron salts should be taken on an empty stomach; however, an increase in gastric symptoms often hinders compliance. Proton pump inhibitors that alter duodenal pH and the conversion of iron from Fe2+ (ferrous) to Fe3+ (ferric), interfere with iron absorption. Other commonly prescribed medications such as calcium acetate, lanthanum carbonate, and aluminum-containing antacids also influence iron absorption negatively.

Serum ferritin levels correlate with hepcidin levels over a wide range and on average increase with the severity of CKD stages 2–5.6 Hepcidin is a 25-amino acid peptide synthesized in the hepatocytes. Hepcidin inhibits the absorption of iron in the gut by binding to ferroportin channels located on the basolateral membrane of enterocytes. Hepcidin also impairs the efflux of stored recycled iron from splenic and hepatic macrophages through ferroportin channels. Hepcidin synthesis is stimulated by excessive plasma iron and liver iron stores and in response to inflammation; its synthesis is inhibited by increased erythropoietic activity. However, variation in hepcidin levels among or within the same individual may reflect not only changes in iron state but also changes occurring directly from inflammation.7

Possible solutions to augment iron delivery without overloading the storage capacity

Most studies with oral iron in CKD have used the ferrous form of the element. Yet the absorption in the gut requires that it be in the trivalent ferric form. In view of the barriers to iron absorption discussed previously, it is not surprising that most studies in hemodialysis patients have shown futility 8 and resulted in the movement to parenteral iron supplementation as standard practice. The use of phosphate binders containing iron in the trivalent state has produced unexpected increases in TSAT.9 A recent Phase 3 study reported HD patients (n=192) treated with ferric citrate had significant increases in both serum ferritin and TSAT compared to control patients treated with either calcium acetate and/or sevelamer carbonate. Patients treated with ferric citrate required significantly less EPO and IV iron; during the last 6-months of the 52-week safety assessment period, 58% of ferric citrate treated patients did not require IV iron.10,11 Similar results have been reported in Phase 2 and open-label extension studies of ferric citrate.9,12,13 Whether this increase results from direct absorption of Fe3+ via intact transepithelial transport or via disrupted tight junctions14is unknown. Although direct absorption of the entire molecule could lead to non-transferrin-bound Fe3+ citrate iron in plasma, the Fe3+ citrate complex is likely to directly donate its iron to apoferritin when phosphate levels are lowered.15 Ferric citrate, as a phosphate binder, not only addresses the hyperphosphatemia in HD patients but is also likely to reduce dependence on parenteral iron and EPO.

The use of ferric compounds in dialysate may also reduce our dependence on parenteral iron, but the data are more limited. The recent report that soluble iron pyrophosphate (SFP) can deliver sufficient iron via dialysate in the maintenance phase of anemia management offers an alternative delivery system. In the PRIME Phase 3 study, 52 HD patients were randomized to receive SFP in their dialysate. Although 11 subjects discontinued prematurely and 12 subjects required IV iron in the SFP arm, less EPO and less IV iron dose were observed in this trial.16 Similarly, the Phase 3 CRUISE-1 and CRUISE-2 efficacy studies reported dialysate with SFP was able to effectively deliver iron to increase Hb levels without increasing ferritin levels.17  These approaches do not address the other abnormality: iron locked up in macrophages due to hepcidin blockage leading to persistent elevation of serum ferritin levels.

Table1

There are good reasons to believe that anemia treatment can be enhanced by the development of hepcidin antagonists or pharmacologic means of suppressing hepcidin levels in patients.18  A novel class of agents has been developed that selectively inhibit one of the 4 prolyl hydroxylases (PHD), stabilizing hypoxia inducible factor (HIF). HIF is a key regulatory protein which stimulates endogenous erythropoietin production, increases transferrin production, and down-regulates hepcidin.19  To test the PHD inhibitor FG4592, a Hb correction study was conducted in which 60 incident patients with marginal iron stores (mean ferritin < 200 ng/mL) and TSAT levels (mean < 20%) were randomized to one of three groups: no oral or IV iron, oral iron only, or parenteral iron at 60 mg/wk. All three groups received FG4592. Oral iron was as efficacious as parenteral iron for smooth Hb correction from a mean of 8 to 11+ g/dL over 12 weeks.20 Remarkably, correction in both iron groups was achieved despite decreases in both TSAT and ferritin from the initial suboptimal states (average ferritin < 200 ng/mL and TSAT < 20%). The no iron group initially responded to FG4592 but then Hb trailed off, presumably from lacking iron. In a separate study in China, use of the same PHD inhibitor was associated with an increase in TIBC (unpublished data). PHD inhibitors increase Hb while decreasing hepcidin levels in a dose-dependent manner.21

Conclusions

The use of oral iron preparations or the transfer of iron via safe dialyzable moieties that can potentially donate iron directly to transferrin should significantly reduce our dependency on parenteral iron for erythropoiesis. Inhibitors of PHD may remove the dependency completely by mediating more coordinated processes that result in moderate erythropoietin production, suppression of hepcidin permitting oral iron absorption and unlocking of macrophage iron stores, and increasing the transport capacity via increased TSAT. In fact, such therapy may allow our patients to have “normal iron indices.”  This should improve the risk/benefit ratio of iron therapy but all of these approaches need long-term studies to determine the full change in risk/benefit.

References

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16. Lin VH, Gupta A, Farmer TM, Guss CD, Pratt RD. Soluble ferric pyrophosphate (SFP) administered via dialysate reduces ESA and IV iron requirements while maintaining hemoglobin in CKD HD patients. Journal of the American Society of Nephrology. 2013;24:215A.

17. Rockwell Medical Latest News. http://www.rockwellmed.com/. Accessed October 17, 2013.

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19. Muchnik E, Kaplan J. HIF prolyl hydroxylase inhibitors for anemia. Expert opinion on investigational drugs. May 2011;20(5):645-656.

20. Besarab A, Chernyavskaya EN, Motylev I. et al. FG-4592, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, Corrects anemia without Iron supplementation in incident dialysis patients. Journal of the American Society of Nephrology. 2012;23:21A.

21. Holdstock L, Meadowcroft AM, Maier R. et al. Four-week safety, efficacy and pharmacodynamic study of prolyl hydroxylase inhibitor GSK1278863 in anemic non-dialysis subjects not receiving recombinant human erythropoietin. Journal of the American Society of Nephrology. 2013;24:138A.