Novel iron-containing phosphate binders and anemia treatment in CKD: oral iron intake revisited

Abstract

Recent reports have shown that novel phosphate binders containing iron are not only efficacious for the treatment of hyperphosphatemia but also may reduce the need for erythropoiesis-stimulating agents and intravenous (IV) iron for anemia management in patients on maintenance hemodialysis (MHD). Possible healthcare cost savings, which have not been demonstrated in a long-term study, may be an additional advantage of using such multi-pronged treatment strategies for the control of both hyperphosphatemia and iron needs. It is currently assumed that oral iron supplementation is less efficient than the IV route in patients with chronic kidney disease (CKD). The unexpected efficacy of novel iron-containing phosphate binders, such as ferric citrate, in repleting insufficient iron stores and improving the anemia of CKD could change this view. Previous assumptions of self-controlled iron uptake by ‘mucosal block’ or hepcidin, or else by impaired intestinal iron absorption due to CKD-associated inflammation cannot be reconciled with recent observations of the effects of ferric citrate administration. Citrate in the intestinal lumen may partly contribute to the acceleration of iron absorption. Animal experiments and clinical studies have also shown that oral iron overload can cause excessive iron accumulation despite high hepcidin levels, which are not able to block iron absorption completely. However, like with IV iron agents, no long-term safety data exist with respect to the effects of iron-containing phosphate binders on ‘hard’ patient outcomes. Future randomized prospective studies in patients with CKD are necessary to establish the safety of oral iron-containing phosphate binders for the control of both hyperphosphatemia and renal anemia.

INTRODUCTION

Patients with advanced stages of chronic kidney disease (CKD) generally suffer from anemia and often require treatment with erythropoiesis-stimulating agents (ESA) and iron supplementation. With regard to iron administration, the most recent international guideline based on the results of previous studies has been set up by Kidney Disease: Improving Global Outcomes (KDIGO). This guideline provides evidence for its recommendation, especially in CKD stage 5D patients, to prefer intravenous (IV) when compared with oral iron administration in order to supply sufficient amounts of iron needed for erythropoiesis [1]. The correction of iron deficiency with oral iron has been shown to be limited by impaired gastrointestinal (GI) absorption, being particularly ineffective in patients on maintenance hemodialysis (MHD) [2]. These observations have been primarily explained by inflammation, especially due to the upregulation of hepcidin [3], which leads to reduced gut iron absorption. Oral iron therapy is associated with the greater frequency of gastrointestinal intolerance, which results in poor compliance [4, 5]. Recently, however, several iron-containing phosphate binders have been made available for the treatment of hyperphosphatemia [6–8]. These compounds have been shown to be efficacious in raising iron stores, as evidenced by significantly increased serum ferritin levels as well as decreased IV iron and ESA needs [8]. As a result, oral iron supplementation is being given renewed consideration for anemia management. In this review, we discuss the regulatory mechanisms of intestinal iron absorption, including hepcidin-dependent and -independent pathways, and possible means to overcome impaired iron uptake from the gut in patients with CKD.

Importance of iron regulation

The correction of anemia is essential for the well-being and perhaps the survival of patients on MHD. ESA therapy can correct anemia, depending in part on adequate iron availability for erythropoiesis [3, 9]. Iron supplementation is often required in these patients because they are subject to enhanced blood loss via the gut and the dialysis route, frequent blood sampling and functional or effective iron deficiency [3, 10].

Although iron is essential for all cells in the body, sufficient iron availability is particularly important for erythropoiesis. Excessive intracellular and extracellular free iron Fe2⁺ can catalyze the formation of strong reactive oxygen species (e.g. hydroxyl radicals), causing oxidative stress, damage to cellular macromolecules and loss of cell viability [11, 12]. Because of its high reactivity, tight regulation of Fe2⁺ entry and storage is of utmost importance. Under physiological conditions, iron enters the human body only across the highly protective wall of the small intestine. Intestinal iron absorption is tightly regulated to guarantee optimal iron balance, avoiding both iron excess and iron deficiency. Over the past half-century, we have learned a great deal about the regulatory mechanisms controlling iron absorption from the gut, including the ‘mucosal block’ and the major role of hepcidin [13–16].

‘Mucosal block’ is referred to as the dietary regulator of iron absorption. It reduces iron uptake following the ingestion of high amounts of iron, presumably by diminishing the expression of iron transporters in the intestinal mucosa [14]. Previously, these mechanisms were thought to effectively shield the body from iron overload [17]. However, more recently, the immediate defence against excessive iron absorption has been explained by a ferritin-mediated, extremely rapid change in the expression of enterocyte iron regulatory proteins (IRP) in response to an oral iron load, an effect apparently independent of intestinal sensing of body iron stores and erythropoietic iron need [18]. Briefly, IRP in the enterocytes could switch to the form which fails to bind to iron-responsive element of 5' region of ferritin mRNA and increase the translation of enterocytic ferritin proteins, thereby limiting dietary iron intake.

Iron absorption occurs primarily via the mucosa of the duodenum and jejunum, whose absorptive epithelial cells remain attuned to the body's current requirements for iron [19–21]. The discovery of hepcidin was a major breakthrough in our understanding of the endocrine control of intestinal iron uptake. Hepcidin binds to the transmembrane iron exporter ferroportin [22, 23], which is present on the basolateral surface of enterocytes and also of macrophages. In-vitro studies subsequently showed that hepcidin induces the internalization and degradation of ferroportin [24]. Hepcidin levels are up-regulated in response to iron overload and inflammation but down-regulated in response to increased erythropoiesis. Rapid iron uptake by the proximal duodenum leads to influx of iron into portal blood and uptake by hepatocytes, in turn leading to rapid increases in hepcidin production and subsequent inhibition of iron absorption [12]. It was previously thought that these mechanisms could prevent excessive iron absorption following the persistent administration of oral iron without discontinuation of medication. But novel iron-containing phosphate binders may break the preconception.

Intestinal iron absorption in patients with CKD

In patients with CKD, the correction of iron deficiency by oral iron is generally thought to be limited due to impaired GI absorption, and iron supplementation is particularly ineffective for erythropoiesis. The KDIGO guideline states that, especially in CKD stage 5D patients, literature-based evidence is in support of IV, rather than oral, iron administration to supply sufficient amounts of iron needed for erythropoiesis. These conclusions were based on randomized controlled trials and observational studies comparing IV administered iron with oral iron and placebo, respectively, in the presence or absence of concomitant ESA treatment [1, 3, 25–27]. In most of these studies, IV iron administration led to a greater increase in hemoglobin (Hb) concentration, lower need of ESA doses or both. These observations have been primarily explained by the concomitant presence of inflammation, hampering efficacious iron absorption from the gut. In addition, the role of hepcidin has become increasingly recognized, and it is generally believed that impaired iron absorption is primarily due to high serum hepcidin levels, which have been repeatedly found to be associated with inflammation in patients on CKD [3, 26, 28, 29].

Iron-containing phosphate binders promote iron absorption

Recently, several iron-containing phosphate binders, including an iron(III)-oxyhydroxide-based phosphate-binder and ferric citrate, have been made available for the treatment of hyperphosphatemia. These two drugs were consistently efficacious at achieving a rapid reduction in serum phosphorus, and were well tolerated in the majority of cases. In the randomized, open-label trials of both drugs, incidences of severe and serious adverse events and deaths were similar compared with control groups [8, 30].

As for the iron parameters of the study of an iron(III)-oxyhydroxide (PA21), the efficacy and safety of PA21 was compared with that of sevelamer carbonate. There were no significant changes in hemoglobin and iron parameters between both treatment groups, despite the larger increases in ferritin and transferrin saturation. Then authors indicated no or minor accumulation of iron in the use of PA21 [30].

On the other hand, the treatment with ferric citrate, when compared with sevelamer, resulted in a significant increase of both Hb and ferritin levels at the end of a 12-week exposure time period in a randomized, open-label, parallel-group study [7]. In addition, longer-term trials have shown that ferric citrate reduces the need for IV iron to support erythropoiesis and reduces the ESA doses required for maintaining Hb levels constant [31]. Similar observations were made in other studies for efficacious phosphate binders and iron supplements in the treatment of patients on MHD [32, 33]. To date, however, there are only few randomized controlled trials (Table 1) evaluating the efficacy of ferric citrate in CKD patients. Intriguingly, Lewis et al. [8] concluded that these changes were likely due to enhanced GI absorption of iron from ferric citrate in the Collaborative Study. The concomitantly observed increases in serum ferritin were unlikely to be caused by inflammation, given that transferrin saturation (TSAT) was also increased and patients receiving ferric citrate showed less evidence of inflammation [34]. These findings are in favor of a pivotal role of enhanced intestinal iron absorption. They appear to be inconsistent with the widely held view that oral iron administration is ineffective for erythropoiesis in patients with CKD. However, we should take into consideration that this study was carried out in relatively low comorbid patients with lower weekly dosage of ESA and IV iron. Therefore, further study would be needed for the generalization of the present study to more inflamed/malnourished patients.

Although the main drawbacks with oral iron were gastrointestinal complaints associated with poor compliance in a dose-related manner, ferric citrate appeared well tolerated as the percentages of subjects’ gastrointestinal serious adverse events were only 6.9% in the ferric citrate group compared with 12.8% in the active control group in the Collaborative Study [8]. Thus an apparent advantage of ferric citrate is related to the lower gastrointestinal adverse effect when compared with other oral iron formulations ranging from 13 to 46% [4, 5, 35]. Accordingly, a huge amount of elemental iron could be administered for the control of serum phosphorus concentrations. As the median daily dose of ferric citrate was 8.0 tablets/day and each 1-g tablet contains 210 mg ferric iron, total dose of iron should be over 600 g during the 52 weeks of the study, which were far more than the usually prescribed ferrous sulfate. It may not be strange that such massive amount of iron in intestine can be absorbed and utilized for erythropoiesis.

On the other hand, from the perspective of medical economics, the use of such multiple-pronged medicines may be advantageous [36]. Because healthcare costs for anemia management in patients with CKD have been steadily increasing in the last decades, reduction of such costs using ferric citrate as a phosphate binder looks attractive to both nephrologists and insurance providers. However, the reduction of the economic burden of treating patients with this drug has not been demonstrated in a long-term study, as in the Collaborative Study mentioned earlier, the reduction in IV iron is only on average 12.5 mg/week and may lead to a tiny savings [8]. In addition, the functions of ferric citrate as a phosphate binder and iron source should be separately evaluated for the proper control of serum phosphate and iron parameters. Further studies, including long-term analyses, will be needed to demonstrate that the potential reduced cost of anemia management with ferric citrate provides benefits to patients.

Given that these agents are being promoted for CKD-MBD and renal anemia treatment, safety considerations require that their mechanisms of action, the degree of iron absorption and potential side effects be submitted to close scrutiny.

Iron overload caused by oral iron administration in man

It is well known that large, continuously ingested amounts of iron may produce iron overload, as previously reported for the excessive intake of dietary iron in the Bantu tribe (although these were case reports) [37, 38]. In an elderly cohort using Cycle 20 data from the Framingham Heart Study, an association between iron supplement use (≥30 mg Fe/day) and the risk of high iron stores was demonstrated, indicating that the capacity of the regulatory mechanisms of iron absorption, including ‘mucosal block’ and hepcidin to prevent iron overload, could be overcome at high oral iron intakes [39].

Oral iron loading in animal studies

In several animal studies, oral iron administration did not show self-control in iron uptake, and the upper limits of iron intake were undetermined. However, several reports of hepatic iron overload in animals fed with an Fe-rich diet have provided consistent findings [40–42]. In particular, even in iron-deficient rats, oral iron supplementation led to hepatic iron overload within 4 weeks in a dose-dependent manner, despite high liver hepcidin expression [42]. Although the relative iron absorption rate, estimated from the feces and divided by iron intake, decreased in parallel with the amount of iron in the daily feed, the total amount of iron absorbed was increased [42].

These observations call into question the belief that endogenous hepcidin, which increases in parallel with iron accumulation in the liver, is able to defend the organism even against heavy iron overload via the oral route. There have also been reports questioning whether exogenous hepcidin can effectively block iron absorption in response to high iron intake [40]. Thus in a mouse model, injected hepcidin significantly decreased the levels of available circulating iron, as measured by transferrin saturation. However, when the mice were fed an iron-rich diet, the continuous administration of hepcidin at 12-h intervals for 14 days did not prevent or decrease hepatic iron loading. In addition, continued hepcidin injection did not decrease basal hepatic iron levels in animals fed a normal diet [40, 43].

In an analysis of mice whose intestinal iron transport was separated into mucosal retention and mucosal transfer, hepcidin injection did not affect the proportion of mucosal iron transfer, whereas dietary iron deficiency was found to significantly increase intestinal iron absorption [43]. The authors presumed that a factor other than hepcidin may be involved in the regulation of mucosal transfer of iron in response to iron deficient diets [43].

From these observations, it could be concluded that hepcidin does not necessarily block iron transport systems as effectively as generally assumed. Clearly, intestinal iron absorption is not completely inhibited in conditions of iron overload and elevated hepcidin levels, although a decline in hepcidin could play a significant role in promoting intestinal iron absorption under iron-deficient conditions. Therefore, it may be useful to focus on iron absorption from the gut that may occur independently of the effects of hepcidin.

In addition, as to the use of ferric citrate, we should take into consideration that the material with which iron is complexed in the intestinal lumen may determine the extent of its absorption, similarly to what has been observed with aluminium many years ago [44]. Thus several previous reports showed that citrate was able to accelerate the absorption of iron from the gut [45–47]. Enhancing effect of citrate on the gastrointestinal absorption of alminium has been explained by two mechanisms; citrate enhances proximal gastrointestinal metal absorption by increasing its solubility and by chelating calcium, which disrupts tight junctions and allows for the markedly increased paracellular flux of the metal [48]. Therefore, we suspect that these effects may accelerate intestinal iron absorption in the presence of citrate.

Suspected mechanism of iron overload from previous animal studies

Most of our knowledge on iron homoeostasis comes from studies carried out in animals, including dogs, rats and mice [49–51]. In the past, iron absorption has been measured primarily by tying off the intestinal tract in combination with the use of radioisotopes [21, 50].

Based on such animal studies, iron absorption has been shown to primarily occur within the small intestine, the duodenum and proximal jejunum (Figure 1). A sharp decline in iron transfer from the gut to the body interior has been observed with progression from the duodenum to the jejunum and the ileum [21, 50]. The distal ileum and colon contribute very little to total iron absorption [21]. In iron-deficient animals, iron transfer increased approximately 3–4 times in duodenal segments compared with iron-replete controls, while no such adaptive changes were found in the distal jejunum [50]. We suspect that the increase of iron transport in the duodenum can be attributed to a decline in hepcidin concentration.

In an old study in normal rats, a single dose of varying amounts of radiolabeled iron showed a statistically significant, linear relationship between the dose of iron administered and both mucosal uptake from the lumen and transmucosal transfer to the serosal side of the intestinal wall. These results were suggestive of passive diffusion of iron across the intestinal mucosa. The normal regulation of limited mucosal transport and storage capacity for iron, which could be regarded as ‘mucosal block’, was exceeded to such an extent that passive diffusion of iron across the intestinal mucosa began to occur [21].

Iron metabolism in the colon has rarely been examined, although recent findings suggested that iron might play a role in colonic carcinogenesis. Further study into this area is needed. One surprising finding was that the two iron transport proteins, ferroportin and divalent metal transporter 1 (DMT1), are expressed at significant levels in the mouse colon [51, 52]. In parallel with this finding, it has been demonstrated that the rat colon might be capable of transporting iron, even if only to a very limited degree, with the transport capacity (measured as the appearance of iron in the blood over a 30-min period) of the colon being negligible when compared with that of the duodenum (1: ∼75) (Figure 1) [52, 53].

We would like to emphasize that in conditions of oral iron overload, where hepcidin has been shown to block intestinal iron transport at sites of high-absorption capacity, such as the duodenum, larger amounts of iron than usual may progress towards more distal sites of the gut, that is colorectum. Although these sites have much lower active absorption efficiency, a substantial amount of iron may be absorbed via passive diffusion.

Considering the risks of iron administration via the oral route

The benefit of oral iron administration has to be weighed against possible harm. High intraluminal iron concentrations may directly damage the intestinal wall, alter vascular endothelium, and exert toxic effects on intracellular compartments [16, 54]. Several studies assessing the effects of various oral iron preparations provided evidence of oxidative stress in the GI tract as in other visceral organs such as the liver, kidneys and heart [54, 55]. Koskenkorva-Frank et al. [54] summarized clinical and non-clinical studies that identified oxidative and/or nitrosative stress in association with oral iron therapy. They shared the hypothesis previously made by others that a rapid increase of serum iron after an oral iron overload leads to full saturation of transferrin with iron, subsequent formation of non-transferrin bound iron and an increase in the labile iron pool, which in turn induces oxidative damage [11, 54, 56].

In addition, a massive amount of iron-containing phosphate binders reached more distal sites of the intestinal tract as mentioned earlier. There have been several reports regarding the association between iron in the diet and colorectal cancer [57]. Therefore, we should be more cautious about the colorectal carcinogenesis, especially in the elderly CKD patients.

CONCLUSION

Novel iron-containing phosphate binders are efficacious both in terms of hyperphosphatemia control and reduced ESAs and IV iron needs for anemia management among patients with CKD. As healthcare cost savings can be expected with such treatments [36], iron-containing phosphate binders are at present regarded as useful, multi-pronged medicines. It is widely assumed that the oral iron supplementation is less efficient than IV administration. However, the unexpected finding that the novel iron-containing phosphate binder ferric citrate reduces the amount of IV iron and ESA needed to maintain Hb levels constant, which has not been demonstrated in a long-term study, may suggest a potential advantage of this compound over iron-free phosphate binders and IV iron. It is noteworthy that self-regulated iron uptake mechanisms, including ‘mucosal block’, hepcidin or impaired iron absorption from the gut due to inflammation (often present in patients with CKD) are not able to limit iron uptake from ferric citrate. It is possible that this type of iron formulation allows an easier uptake of iron than with conventional iron formulations. Of interest, previous animal experiments and clinical studies have shown that high-dose iron administration via the oral route can cause iron overload, even in the presence of high hepcidin levels, unable to block iron absorption as efficiently as generally thought.

Finally, we need to know more about possible safety hazards with iron-containing phosphate binders. In particular, we need to have information on whether ferric citrate induces oxidative stress to the same extent or not as high-dose IV iron. No long-term safety data on hard outcomes in patients with CKD are so far available with ferric citrate. Note, however, that this is also true for IV iron administration in general to such patients. Future randomized prospective cohort studies are necessary to address these important issues.

CONFLICT OF INTEREST STATEMENT

T.N. was awarded grant from Chugai Pharmaceutical Company, Takeda Pharmaceutical Company, and Kyowa Kirin Pharmaceutical Company, as well as received a speaker fee from Chugai Pharmaceutical Company, Kyowa Kirin Pharmaceutical Company and Bayer Yakuhin. T.K. received a speaker fee from Chugai Pharmaceutical Company.

ACKNOWLEDGEMENT

We gratefully acknowledge the advice and editorial assistance of Tilman B. Drueke, M.D., Amiens, France.

REFERENCES