Etiology of Balkan endemic nephropathy

描述(申请人提供)：地方性(巴尔干)肾病(EN)是一种破坏性疾病，影响居住在多瑙河流域农村地区的男子和妇女，包括克罗地亚、保加利亚、罗马尼亚、塞尔维亚和波斯尼亚地区。EN的临床病程特点是起病隐匿，无休止地进展为慢性肾功能衰竭，并与尿路上皮癌密切相关。EN的显著流行病学特征包括发生在某些村庄；在这些村庄中，只有某些家庭的成员受到影响。一般认为，EN是一种与疫区农民生活方式有关的环境疾病。多年来，人们一直在提出假说来解释EN的病因；我们正在探索一个更早的、基本上被忽视的、未经检验的假说，即马兜铃的种子污染了用于烘焙面包的谷物，面包是流行地区的主食。EN的病理生理学与最近发现的马兜铃酸肾病综合征之间的惊人相似性支持了这一假说。以大学为基地的科学家。萨格勒布医学院和Rudjer Boskovic Inst。萨格勒布)与负责马兜铃酸病因学假说的医生一起，对三个流行村庄的750名成年居民进行了一项分子流行病学病例对照研究，以检验马兜铃酸病因学假说。附近一个非流行村庄的居民(150人)作为对照。克罗地亚科学家将进行分析研究，以量化指导性假说预测的标志性生物标记物，即肾组织中的DNA-马兜铃内酰胺加合物和EN患者尿液中的尿脱落细胞。此外，还将建立从流行区长期居民那里获得的尿路上皮肿瘤组织中的p53突变谱。如果我们的假设被证明是正确的，就可以采取公共卫生措施，从而在克罗地亚和整个巴尔干地区根除EN，那里目前有10万人处于危险之中。为了推进这一目标，我们提议在波斯尼亚和保加利亚的流行地区同时启动试点流行病学研究，在这些地区，将通过测量面粉中马兜铃酸的含量来监测目前的接触情况。这项FIRCA将几乎全部在克罗地亚进行，与首席外国研究员Bojan Jelakovic博士(萨格勒布大学医学院)合作，P01 ES04068作为父母赠款。

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.