Iron Therapy in Renal Disease: Potential Toxicities

肾脏疾病的铁疗法：潜在毒性

• 批准号: 6802635
• 负责人: Richard A. Zager
• 金额: $ 38.06万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-02 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802635
• 关键词: anemia; atherosclerosis; cholesterol; chronic renal failure; cytotoxicity; drug adverse effect; genetically modified animals; histology; inflammation; intravenous administration; iron; kidney disorder chemotherapy; laboratory mouse; laboratory rabbit; laboratory rat; male; oxidative stress; pathologic process; pharmacokinetics; proteinuria; renal toxin; renal tubule; toxicology

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：肠外铁制剂广泛用于终末期肾病（ESRD）患者，以纠正或预防铁缺乏症，并与外源性促红细胞生成素（Epo）治疗联合增强红细胞生成。考虑到ESRD患者人群的不断增加，静脉铁剂的使用可能会扩大，并且纠正ESRD前患者贫血的趋势日益增长。尽管使用越来越多，但对胃肠外Fe介导的细胞毒性及其潜在的长期影响知之甚少。事实上，该实验室的最新数据表明，这些化合物具有显著的促氧化作用。这种毒性的体外和体内相关性包括以下内容：i）脂质过氧化（在血浆、心脏、肾脏;分离的近端小管、骨髓和内皮细胞中）; ii）线粒体毒性（ATP耗竭;细胞色素c释放）; iii）抗增殖; iv）全身性炎症（ESR增加;血清白蛋白降低）;和v）细胞胆固醇稳态紊乱。后者最终导致内皮细胞和血浆胆固醇浓度增加，部分原因是铁诱导的HMG CoA还原酶水平和活性上调。鉴于这些考虑，本申请提出了四个具体目的：1）因为“催化”（促氧化剂）铁是公认的进行性肾损伤的介质，并且因为IV Fe被施用给ESRD前患者，所以将解决这种疗法对实验性肾病背景下肾单位损失的影响。2)由于动脉粥样硬化是ESRD患者发病和死亡的主要原因，并且如上所述，由于铁具有潜在的促动脉粥样硬化作用，因此将测试胃肠外铁可以加速体内动脉粥样硬化形成的假设。这将通过对伴有和不伴有叠加肾功能不全的促动脉粥样硬化（ApoE敲除）小鼠进行肠外铁给药来完成。3)ESRD及其伴随的透析治疗代表了与不良患者结局相关的促炎状态。铁可以引发炎症，部分通过NF κ B途径。因此，将寻求胃肠外Fe诱导或增强全身炎症反应的潜力;和4）来自该实验室的先前数据表明，目前可用的胃肠外Fe制剂之间存在毒性的实质性差异。将评估这些差异的潜在原因，最终目标是确定肾脏疾病患者胃肠外铁剂给药的最安全方式。