Etiology of Balkan endemic nephropathy

描述（由申请人提供）：地方性（巴尔干半岛的）肾病（EN）是一种破坏性疾病，影响生活在多瑙河流域农村地区的男性和女性，包括克罗地亚、保加利亚、罗马尼亚、塞尔维亚和波斯尼亚。EN的临床过程的特点是起病隐匿，不变地进展为慢性肾功能衰竭，并与尿路上皮癌密切相关。EN的重要流行病学特征包括其发生在某些村庄;在这些村庄中，只有某些家庭的成员受到影响。一般认为，EN是一种与流行地区的农业生活方式有关的环境性疾病。多年来，人们提出了各种假说来解释EN的病因;我们正在追求一个早期的、在很大程度上被忽视的和未经检验的假说，即马兜铃的种子污染了用于烘烤面包的谷物，这是流行地区的一种主食。EN的病理生理学和最近认识到的马兜铃酸肾病综合征之间惊人的相似性支持了这一假设。萨格勒布大学医学院和Rudjer Boskovic研究所（萨格勒布）的科学家与负责EN（Slavonski Brod）患者临床护理的医生一起，建议通过对三个流行病村庄的750名成年居民进行分子流行病学病例对照研究来验证马兜铃酸病因学假设。居民（150）附近的非流行村作为对照。克罗地亚科学家将进行分析研究，旨在量化指导假设预测的标志性生物标志物;即EN患者肾组织中的DNA-马兜铃内酰胺加合物和尿液中的脱叶酸尿路上皮细胞。此外，将建立从流行地区的长期居民获得的尿路上皮肿瘤组织中P53突变的谱。如果我们的假设被证明是正确的，公共卫生措施可能会导致在克罗地亚和整个巴尔干半岛的地区，其中100，000人目前处于危险之中根除EN。为了推进这一目标，我们建议在波斯尼亚和保加利亚的流行病地区同时开展试点流行病学研究，通过测量面粉中马兜铃酸的含量来监测目前的接触情况。FIRCA将几乎完全在克罗地亚进行，与首席外国研究员Bojan Jelakovic博士（萨格勒布大学医学院）合作，P01 ES 04068作为母基金。

DESCRIPTION (provided by applicant): Endemic (Balkan) nephropathy (EN) is a devastating disease affecting men and women living in rural areas within the Danube river basin, encompassing regions of Croatia, Bulgaria, Romania, Serbia and Bosnia. The clinical course of EN is characterized by an insidious onset, invariable progression to chronic renal failure and a strong association with urothelial cancer. Significant epidemiologic features of EN include its occurrence within certain villages; among these villages, only members of certain households are affected. It is generally believed that EN is an environmental disease related to the farm life style in endemic regions. Hypotheses have been advanced over many years to explain the etiology of EN; we are pursuing an earlier, largely ignored and untested hypothesis that seeds of Aristolochia clemantitis contaminate grain used in baking bread, a dietary staple in the endemic region. This hypothesis is supported by striking similarities between the pathophysiology of EN and the recently recognized syndrome of aristolochic acid nephropathy. Scientists based at the Univ. of Zagreb School of Medicine and Rudjer Boskovic Inst. (Zagreb), together with physicians responsible for the clinical care of patients with EN (Slavonski Brod), propose to test the aristolochic acid etiology hypothesis by conducting a molecular epidemiologic, case-control study involving 750 adult residents of three endemic villages. Residents (150) of a nearby nonendemic village serve as controls. Croatian scientists will conduct analytical studies designed to quantify the hallmark biomarker predicted by the guiding hypothesis; namely, DNA-aristolactam adducts in renal tissues and exfololiated urothelial cells in urine of patients with EN. In addition, the spectra of P53 mutations in urothelial tumor tissues obtained from long-term residents of the endemic region will be established. If our hypothesis proves to be correct, public health measures could be instituted that would lead to the eradication of EN in Croatia and throughout the Balkan region, where 100,000 persons are currently at risk. To advance that goal, we propose to initiate, in parallel, pilot epidemiologic studies in the endemic regions of Bosnia and Bulgaria where current exposure will be monitored by measuring the aristolochic acid content of flour. This FIRCA will be conducted almost entirely in Croatia, in collaboration with Dr. Bojan Jelakovic, lead foreign investigator (University of Zagreb School of Medicine) with P01 ES04068 serving as the parent grant.