The Labile Side of Iron Supplementation in CKD - PubMed
Review
The Labile Side of Iron Supplementation in CKD
Itzchak Slotki et al. J Am Soc Nephrol. 2015 Nov.
Abstract
The practice of intravenous iron supplementation has grown as nephrologists have gradually moved away from the liberal use of erythropoiesis-stimulating agents as the main treatment for the anemia of CKD. This approach, together with the introduction of large-dose iron preparations, raises the future specter of inadvertent iatrogenic iron toxicity. Concerns have been raised in original studies and reviews about cardiac complications and severe infections that result from long-term intravenous iron supplementation. Regarding the iron preparations specifically, even though all the currently available preparations appear to be relatively safe in the short term, little is known regarding their long-term safety. In this review we summarize current knowledge of iron metabolism with an emphasis on the sources and potentially harmful effects of labile iron, highlight the approaches to identifying labile iron in pharmaceutical preparations and body fluids and its potential toxic role as a pathogenic factor in the complications of CKD, and propose methods for its early detection in at-risk patients.
Keywords: anemia; chronic renal disease; inflammation; labile iron; mortality risk.
Copyright © 2015 by the American Society of Nephrology.
Figures

Where and how does labile iron cause cell damage? Schematic representation of iron distribution among cell compartments (see number 1 in circle). Transferrin (Tf) bound iron (TBI) is the physiologic source of circulating Fe that is captured by cells via RME (see number 2 in circle), whereby the TBI is delivered into cells and the metal is released into the cytosol as LCI (see number 3 in circle) that is comprised of Fe (II and III). LCI can permeate into mitochondria (see number 4 in circle) where it serves as a metal source for heme and iron-sulfur cluster proteins. Labile iron in mitochondria (LMI) (see number 5 in circle) or in cytosol (not shown) can catalyze formation of ROS (e.g., OH•) from ROI (see number 6 in circle) (e.g., O2•− and H2O2, approximately 33 g/day from respiration) that are normally eliminated by cell enzymes such as superoxide dismutase (sod) and glutathione peroxidases (gpx) or catalase (see number 7 in circle). ROS can chemically damage membrane components such as lipids by peroxidation, proteins by oxidation of amino acids (AA) such as tyrosine (tyr), methionine (met), lysine (lys) and cysteine (cys), or via CO formation and nucleic acids by base modification and DNA breaks. Excess LCI is generally absorbed into ferritin iron shells (see number 8 in circle) that then can be dissolved by proteolytic cleavage of the protein in lysosomes (see number 9 in circle) whereby iron can be recycled into the LCI pool. In systemic iron overload, LPI forms (which are non-TBI, NTBI) (see number 10 in circle) can infiltrate cells, raise LCI and LMI and cause cell iron overload.

Macrophage processing of red blood cells (RBCs) (left) and of PIPs (right). Left. Macrophages phagocytose aged RBCs (see number 1 enclosed in a circle). into a phagosome that after acquisition of hydrolytic enzymes from fusion processes (see number 2 enclosed in a circle) disrupt the cell and proteolyse Hb leading to release of the heme moiety (H) and its transfer across the cytosol via hrg1 (see number 3 enclosed in a circle) to the endoplasmic reticulum, where heme oxygenase 1 (hox1) (see number 4 enclosed in a circle) cleaves heme and releases biliverdin (BLVD), Fe(II) and CO. The Fe(II) can be exported from the cells into the plasma via ferroportin1 (FPN1) (see number 5 enclosed in a circle) where it can be incorporated into transferrin or stored as ferritin (see number 1 enclosed in a circle) that eventually can enter the lysosomal pathway of degradation (see number 7 enclosed in a circle) and release Fe(II) into the LCI pool. Right. Same as for RBCs, except that the hydrolytically processed PIP Fe(II) is released into the cytosol. Hb, hemoglobin.
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