Iron Therapy in Renal Disease: Potential Toxicities

肾脏疾病的铁疗法：潜在毒性

• 批准号: 6917161
• 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/6917161
• 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）：肠胃铁剂制剂被广泛用于终阶段肾脏疾病（ESRD）的患者，以纠正或预防，铁缺乏症，并与外源性红细胞生成素（EPO）疗法一起增强红细胞的产生。鉴于ESRD患者的群体迅速发展，静脉铁的使用可能会扩大，而纠正贫血的趋势的增长是ESRD前患者。尽管使用越来越多，但对肠胃外介导的细胞毒性及其潜在的长期影响知之甚少。实际上，该实验室的最新数据表明，这些化合物具有引人注目的促氧化作用。这种毒性的体外和体内相关性包括：i）脂质过氧化（在血浆，心脏，肾脏中；分离的近端小管，髓样和内皮细胞）； ii）线粒体毒性（ATP耗竭；细胞色素C释放）； iii）抗增殖； iv）系统性炎症（ESR增加；血清白蛋白降低）；和v）精神错乱的细胞胆固醇稳态。后者最终导致内皮细胞增加，血浆，胆固醇浓度，部分原因是Fe诱导的HMG COA还原酶水平和活性的上调。考虑到这些考虑因素，该应用提出了四个具体目的：1）因为“催化”（促氧化剂）铁是良好的进行性肾脏损伤的介体，并且由于对ESRD患者进行了IV FE，因此该治疗对实验性肾病的环境中这种疗法对肾脏损失的影响。 2）由于动脉粥样硬化是ESRD患者发病率和死亡率的主要原因，并且由于铁的潜在促动脉粥样硬化作用，如上所述，将测试肠胃外铁可以加速体内动脉粥样硬化的假说。这将通过对肾脏不足和没有叠加的肾脏不足的肌源性（APOE敲除）小鼠进行肠胃屈肌来完成。 3）ESRD及其随之而来的透析疗法代表了一种促炎性状态，与患者的预后不良相关。 FE可以部分通过NF Kappa B途径触发炎症。因此，将寻求肠胃外铁诱导或增强全身性炎症反应的潜力； 4）该实验室的先前数据表明，目前可用的肠胃外fe制剂中存在毒性的实质性差异。将评估这些差异的潜在原因，其最终目的是定义为肾脏疾病患者使用肠胃铁的最安全方法。