Iron and anemia in chronic kidney disease: New treatments changing old paradigms

In this special supplement issue to Hemodialysis International the ISHD is very pleased to present a compendium of articles dealing with one of the major clinical challenges faced by caregivers when treating patients with chronic kidney disease (CKD)—how to manage iron stores in such patients while optimizing hemoglobin levels to safely prevent the anemia of CKD that can adversely impact quality of life, cognitive performance, and cardiovascular function, as well as increase the need for, and risks associated with, blood transfusions. Thirteen noted groups of experts in the field have put together outstanding review articles, each focusing on a problem of practical importance or describing new treatments that may change how we approach iron repletion in CKD. Dev and Babbitt lead off the issue with a wonderful review of iron metabolism in health and disease. They discuss how humans normally efficiently conserve and recycle iron, such that typically only 1 to 2 mg/day is lost, a loss compensated for by dietary absorption of a similar amount in the duodenum and upper jejunum. They go on to describe how ionized forms of iron, as well as dietary heme and ferritin, are absorbed into enterocytes and then transported out to the bloodstream by ferroportin, an iron exporter that also is utilized to mobilize iron from various body storage sites. They go on to describe the role of iron regulatory proteins and their interactions with the hypoxia-inducible factor (HIF) system of signaling. The iron hormone hepcidin is a major player in iron regulation; it binds to ferroportin, inducing its degradation in cell lysosomes. Increased serum levels of hepcidin, a hormone responsive to inflammation, reduces overall iron transport by reducing ferroportin-mediated uptake of iron by enterocytes and ferroportin-enabled transport of iron out of cell storage sites. The inflammation-mediated down-regulation of hepcidin is thought to have a potentially beneficial effect of limit the access of invading bacteria to bloodstream iron but complicates iron repletion in conditions where chronic inflammation is present such as CKD. Hepcidin is also regulated by the state of iron repletion and by the severity of anemia and also by erythropoietin. The presence of inflammation associated with a number of chronic illnesses can cause so-called “anemia of chronic inflammation,” partially mediated by the increased levels of hepcidin. Dev and Babitt also discuss the potential adverse effects of excess iron storage on liver disease, diabetes mellitus, cardiovascular disease, neurodegenerative diseases, cancer, bone and mineral disorder, immunity and infection, and finally, kidney disease; testimony to how important optimal management of iron supplementation can be in the course of anemia treatment. Gaweda summarizes the methods commonly used to assess iron stores in CKD patients, including serum ferritin, transferrin saturation, reticulocyte hemoglobin content, and the percentage of hypochromic red blood cells. He also discusses the potential utility of measuring blood levels of soluble transferrin receptor and hepcidin, two assays not yet in general clinical use. At present, there is much discussion about the potential role of the gut microbiome in health and disease, and the realization that some uremic toxins such as p-cresyl sulfate and indoxyl sulfate as well as the cardiovascular toxin precursor trimethyl amine may be generated primarily by gut bacteria. For this reason, it is of importance to determine what, if any, effects oral iron supplementation might have on bacteria populations in the intestine. Kortman, Reijnders, and Swinkels, who have done pioneering work, review this important topic. Oral iron supplementation might affect gut-bacteria generated toxins in two ways. Oral iron often causes constipation, which increases gut transit time and allows more time for such toxin generation by gut bacteria to occur. Additionally, oral iron administration may select for subpopulations of bacteria which may incidentally be generating higher or lower amounts of absorbable toxic wastes. Kortman et al. point out that in several third world countries, treatment of severely malnourished infants with oral iron was found to be accompanied by changes in gut microbiome composition, and specifically, by reduction of beneficial bacteria such as Lactobacillus and Bifidobacterium, and an increase in the abundance of potentially pathogenic Escherichia coli strains. Studies by the authors in the laboratory using an in vitro model of the microbiome have shown that adding iron to the intraluminal compartment can increase bacterial protein fermentation and generation of branched-chain fatty acids, ammonia, phenols, and indoles. Studies in patients are just beginning, and one early result (done in non-CKD patients with either Crohn's disease or iron-deficiency anemia) was able to identify a change in bacterial composition of the gut in patients receiving oral vs. intravenous iron. Langer and Ginzburg relook at the concept of “anemia of chronic inflammation” through the prism of the effects of inflammation on ferroportin and its inhibitor, hepcidin. Inflammation-induced increases in certain interleukins (e.g., IL-6) cause induction of hepcidin, resulting in iron sequestration. Under conditions of hypoxia, HIF increases, activating erythropoiesis. Hypoxia-inducible factor induction can also lead to suppression of hepcidin, which is a potential clinical advantage of drugs being developed to treat anemia that act by inhibiting HIF degradation. The authors also discuss several additional pharmacological approaches that are currently being explored to reduce the elevated hepcidin levels commonly found in patients with anemia of chronic inflammation. What about genetic control of iron metabolism? Should the presence of a mutation in genes affecting iron, for example, hemochromatosis, alter our approach to treating anemia in CKD patients? Do we need to test our anemic dialysis patients for hemochromatosis genes? Valenti and Pelusi review the current knowledge. The most common mutation causing hemochromatosis involves the so-called HFE gene, which encodes a protein of the same name. The HFE protein affects the interaction of transferrin receptor with transferrin and affects the transcription and secretion of hepcidin. The end result is, that patients with HFE mutations do not increase hepcidin levels as iron stores become satiated, resulting in continued, undesirable, iron absorption from food. When studies in hemodialysis patients are reviewed, paradoxically, presence of some HFE mutations was found to be a “good” thing, in that erythropoietin and iron requirements were reduced. However, it is all not happy news, because serum ferritin levels, as well as iron-associated cardiovascular risk, may be increased in patients with certain HFE mutations. The overall risk vs. benefit of mutations in iron storage in hemodialysis patients remains controversial, and the presence or absence of additional mutations apart from the HFE gene may play a modulating role. The potential problem of iron overload is reviewed by Ramanathan, Olynyk, and Ferrari. Although some have taken a rather blasé attitude regarding the high prevalence of serum ferritin levels far above normal in CKD patients treated with hemodialysis, there are recent data based on magnetic resonance imaging of the liver suggesting that liver iron content is often quite high. The clinical relevance of elevated liver iron content with regard to mortality or morbidity is unclear. Another potential risk of loading the liver with iron has to do with the course of chronic hepatitis. Both iron loading and chronic viral infection increase the risk of liver fibrosis. Rostoker and Vaziri take on this important topic. They point out that in patients with hepatitis C (HCV) infection, serum ferritin values are increased, and among those with HCV, higher ferritin levels associated with serum markers of liver cell injury and with a poor response to antiviral treatment. High serum ferritins were also predictors of liver fibrosis and steatosis. Further emphasizing the role of liver iron, phlebotomy has been shown to improve the virologic response of patients with HCV to interferon. Rostoker and Vaziri review the cellular mechanisms of iron injury to the liver, and also point out literature regarding an increased risk of liver cancer in patients with iron overload. After this initial group of 7 articles, part two of the supplement focuses on clinical implications. Agarwal describes the experience of treating patients with nondialysis CKD with oral vs. intravenous iron. He argues that in nondialysis patients with CKD, the evidence for the superiority of IV iron is weak if not absent, as in one trial the dose of oral iron used was suboptimal, and in another trial where there were similar responses to oral vs. intravenous iron, the frequency of cardiovascular events and hospitalizations was higher with IV iron. Even in dialysis patients, Agarwal suggests that a trial of oral iron therapy be given before using intravenous iron, citing concerns about potential adverse cardiovascular effects associated with intravenous iron administration. Auerbach and Macdougall review the safety and efficacy of various intravenous iron preparations. Providing a valuable historical timeline, they discuss how these iron preparations improved over time. In particular, they point out that the markedly increased risk of anaphylaxis seen with initial versions of iron-dextran contained mostly high-molecular-weight dextran, and the risk was markedly reduced with the newer, low-molecular weight products available today. They review commonly used intravenous iron preparations one by one, pointing out the relative advantages and disadvantages of each, as well as differences in pharmacokinetic properties. They emphasize that only a subset of these products allows administration of larger doses of iron during a single infusion, and emphasize the potential advantages of treating patients with larger doses episodically, especially patients who are not interacting with the health care system on a regular, frequent time schedule. Li, Kshirsagar and Brookhart emphasize that the potential risks associated with intravenous iron preparations with regard to cardiovascular events and infections are still not completely quantified. They summarize what we know regarding risk of iron reactions, including anaphylactoid reactions, with the various preparations, and point out that the risk of such reactions is still higher with dextran containing products compared to some non-dextran formulations, even when low-molecular weight dextran is used. They also review several large observational studies and meta-analyses regarding infection and cardiovascular risk with intravenous iron products, and discuss the potential for lower risk when using a maintenance vs. episodic bolus dosing strategy. However, they conclude that much remains unknown regarding the long-term safety of iron given intravenously. Fishbane and Shah describe a novel approach to replace iron in hemodialysis patients—by addition of ferric pyrophosphate citrate (FPC) to the dialysis solution, relying on diffusion of this compound through the dialyzer membrane to replace the small amount of iron normally lost in the course of dialysis. They discuss trials demonstrating efficacy of iron replacement with this approach. They describe a protocol for treating patients in dialysis units that use centrally delivered dialysis solution. Ferric pyrophosphate citrate is added to the bicarbonate component of the dialysis solution. However, the authors emphasize that use of FPC-supplemented dialysis solution should be stopped in those patients in whom serum ferritin levels exceed markedly elevated values. Haase describes the basic science, as well as recent clinical experience, in treating anemia of CKD with drugs that inhibit HIF breakdown. This review is divided into two segments, the first providing a detailed overview of the cell biology of the HIF signaling system, and the second describing the growing number of candidate drugs from this category currently in trials to treat anemia in dialysis patients. One advantage of treating anemia with this group of drugs is a marked reduction in the need for ESAs (erythropoiesis stimulating agents) and IV iron, and treatment often is accompanied by decreases, rather than the usual increases, in plasma hepcidin levels. In some studies serum ferritin, and transferrin saturation levels are also reduced. Haase points out that this therapy may have some theoretical disadvantages, as the HIF system also has metabolic and cardiovascular effects, and augmenting and extending its operation might have as yet unknown consequences. The final article in the supplement, by Del Vecchio and Locatelli, reviews guidelines and position papers that have been prepared by nephrology caregiver professional organizations with respect to treating anemia of CKD. Various organizations around the world have slightly different perspectives, and it is useful to have in one place a summary of recommendations relating to iron therapy. In the name of the ISHD, I would like to thank all of the authors for setting aside time from their busy schedules to prepare these excellent reviews and agreeing to share their personal experiences and knowledge. I would also like to thank the three companies that financially supported publication costs of this supplement: FibroGen and AstraZeneca; Fresenius Medical Care; and Rockwell Medical, Inc.

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