Abstract PL02-02: Aristolochic acid-induced nephropathy and urothelial carcinoma: A preventable global disease

Abstract

Abstract Balkan endemic nephropathy (BEN) is a chronic renal disease affecting residents of rural farming villages located near tributaries of the Danube river. Otherwise rare urothelial carcinomas of the upper urinary tract (UTUC) develop in ~ 50% of patients with BEN. Our studies of the etiology of this disease were informed by reports of a similar syndrome affecting ~ 100 Belgian women who ingested Aristolochia fangchi as part of a weight loss routine (1). In this case, the responsible toxin proved to be aristolochic acid (AA), a component of all Aristolochia plants. In the Balkans, a pilot epidemiologic study confirmed earlier reports that Aristolochia clematitis (birthwort) often is found as a weed growing in cultivated fields. Traditional methods used for harvesting and milling of wheat allowed seeds of this plant to contaminate grain used to prepare bread, a dietary staple among residents of the endemic region. Aristolactam (Al)-DNA adducts were detected in the renal cortex and urothelial tumor tissue of patients with BEN (2). Moreover, a pattern of A:T to T:A mutations unique to AA was demonstrated first in TP53 (3, 4) and, subsequently throughout the genome (5). Based on these observations, it was proposed that the name, BEN, be changed to aristolochic acid nephropathy (AAN). With respect to prevention of BEN, scientific designation of this environmental toxin is important to public health authorities as it legitimizes efforts to change traditional agricultural practices. The experimental methods developed in our studies proved indispensable in our subsequent efforts to demonstrate that AAN and UTUC are prevalent in Asian countries, where Aristolochia herbs have been used for medicinal purposes for centuries. For example, in Taiwan, where the incidence of UTUC and of chronic kidney disease are the highest in the world, at least one-third of the population has been prescribed herbs containing AA (6). Remarkably, the unique TP53 mutational signature for AA established in our studies of BEN was recapitulated in cases of UTUC from Taiwan (7). Moreover, aristolactam-DNA adducts, which persist for decades in the renal cortex, were detected in patients with the signature mutation spectrum in TP53, thereby documenting the relationship between exposure to AA and its mutagenic effects. Millions of people in China are estimated to have ingested Aristolochia herbal remedies, highlighting the potential morbiditity and mortality associated with the medicinal use of this family of herbs (8). Studies designed to document AA exposure in countries where Aristolochia herbs are used in the practice of traditional Chinese medicine are currently underway. Importantly, the nephrotoxic effects of AA are irreversible and its carcinogenic effects may not become manifest until 30 or more years after exposure. Thus, the development of non-invasive, biomarker-based tests that can be used to detect AA-induced UTUC are highly desirable, as this cancer is often curable by surgery if detected early in the course of the disease. (Research supported by grants from the NIEHS (ES04068) Fogarty International Center, Croatian Ministry of Science, Taiwan Dept of Health, Zickler Family Foundation and Henry and Marsha Laufer).