Parenteral iron formulations are widely used in patients with end stage renal disease (ESRD) in order to correct, or prevent, iron deficiency, and to enhance red blood cell production in conjunction with exogenous erythropoietin (Epo) therapy. The use of IV iron is likely to expand, given a burgeoning ESRD patient population, and a growing trend towards correcting anemia is pre-ESRD patients. Despite increasing use, little is known about parenteral Fe mediated cytotoxicity, and its potential long-term implications. Indeed, recent data from this laboratory indicate that these compounds exert striking pro-oxidant effects. In vitro and in vivo correlates of this toxicity include the following: i) lipid peroxidation (in plasma, heart, kidney; isolated proximal tubules, myeloid, and endothelial cells); ii) mitochondrial toxicity (ATP depletion; cytochrome c release); iii) anti-proliferation; iv) systemic inflammation (increased ESR; decreased serum albumin); and v) deranged cellular cholesterol homeostasis. The latter culminates in increased endothelial cell, and plasma, cholesterol concentrations, and arises in part from an Fe-induced upregulation of HMG CoA reductase levels and activity. Given these considerations, this application proposes four Specifics Aims: 1) Because 'catalytic' (pro-oxidant) iron is a well recognized mediator of progressive renal injury, and because IV Fe is being administered to pre-ESRD patients, the impact of such therapy on nephron loss in the setting of experimental nephropathy will be addressed. 2) Because atherosclerosis is the leading cause of morbidity and mortality in ESRD patients, and because of iron's potential pro-atherogenic effects, as noted above, the hypothesis that parenteral Fe can accelerate in vivo atherogenesis will be tested. This will be done by administering parenteral irons to pro-atherogenic (ApoE knockout) mice with and without superimposed renal insufficiency. 3) ESRD, and its attendant dialytic therapy, represents a pro-inflammatory state which correlates with poor patient outcomes. Fe can trigger inflammation, in part via the NF Kappa B pathway. Thus, the potential for parenteral Fe to induce, or enhance, systemic inflammatory responses will be sought; and 4) Previous data from this laboratory indicate that substantial differences in toxicity exist amongst currently available parenteral Fe formulations. Potential reasons for these differences will be assessed, with the ultimate goal of defining the safest way of administering parenteral irons to renal disease patients.
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