Iron therapy for renal anemia: how much needed, how much harmful?

Abstract

Iron deficiency is the most common cause of hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in end-stage renal disease (ESRD) patients. Iron deficiency can easily be corrected by intravenous iron administration, which is more effective than oral iron supplementation, at least in adult patients with chronic kidney disease (CKD). Iron status can be monitored by different parameters such as ferritin, transferrin saturation, percentage of hypochromic red blood cells, and/or the reticulocyte hemoglobin content, but an increased erythropoietic response to iron supplementation is the most widely accepted reference standard of iron-deficient erythropoiesis. Parenteral iron therapy is not without acute and chronic adverse events. While provocative animal and in vitro studies suggest induction of inflammation, oxidative stress, and kidney damage by available parenteral iron preparations, several recent clinical studies showed the opposite effects as long as intravenous iron was adequately dosed. Thus, within the recommended international guidelines, parenteral iron administration is safe. Intravenous iron therapy should be withheld during acute infection but not during inflammation. The integration of ESA and intravenous iron therapy into anemia management allowed attainment of target hemoglobin values in the majority of pediatric and adult CKD and ESRD patients.

Characterization of a Rat Model of Moderate Chronic Renal Failure—Focus on Hematological, Biochemical, and Cardio-Renal Profiles

“…Several causes were proposed to underlie this situation, such as a functional iron deficiency, inadequate dietary iron intake, blood loss during the hemodialysis processes or from gastrointestinal tract (bleeding), inadequate intestinal iron absorption, and inhibition of iron mobilization from macrophages. [12][13][14][15][16]18] In our study, CRF rats presented serum iron values similar to those of the control, and no significant changes were observed along the experiments; however, a trend toward higher values of ferritin were observed along the experiments and reached a significantly higher value at the end (15 weeks). These changes in ferritin were accompanied by a significant reduction in transferrin (observed at 3 weeks and afterward), suggesting an inhibition in iron traffic, from macrophages to erythroid cells, leading to the progressive increase in iron storage, as shown by the progressive increase in ferritin observed throughout the experiments.…”

“…Indeed, a functional iron deficiency has been reported in CKD patient under hemodialysis, namely, in moderate stages. [18,19] Concerning the other biochemical parameters, our model demonstrated important changes in liver function markers, with AST and ALT being significantly higher at 9 weeks and at the end of experiments in CRF rats, accompanied by a trend to increased liver weight. We might hypothesize that renal dysfunction leads to a progressive deterioration of liver function, but the exact interacting mechanism(s) between the kidney and the liver deserve further clarification.…”

Manipulation of the hepcidin pathway for therapeutic purposes

“…Treatment options for these diseases include erythropoiesis-stimulating agents (ESAs) with or without highdose intravenous iron, but erythropoietin resistance is commonly observed as a consequence of inflammation. 64,65 The long-term effects of high doses of ESAs and IV iron are not known but concerns have arisen about the potential side effects of ESAs 66,67 most of which appear to be dose-related. More specific interventions are needed, and hepcidin antagonists may offer an alternative and/or allow safer dosing of erythropoietic drugs.…”

Proteinuria Induced by Parenteral Iron in Chronic Kidney Disease—A Comparative Randomized Controlled Trial

“…Current guidelines recommend that iron-deficiency anemia among patients with CKD not on hemodialysis may be treated with oral or intravenous (IV) iron (2,3); however, the IV route is being frequently utilized. Although the IV route offers some advantages such as improved adherence to treatment (4,5), concerns have been raised regarding the long-term risk of IV iron (6,7). Because of their more favorable short-term side effect profile (8,9), especially the risk for anaphylaxis, ferric gluconate and iron sucrose have largely replaced iron dextrans for use in practice in the United States.…”