Variation in Presentation and Presence of DNA Adducts and p53 Mutations in Patients with Endemic Nephropathy - an Environmental Form of the Aristolochic Acid Nephropathy

Abstract

Background: Endemic nephropathy (EN) and associated urothelial cell cancers (UUC) are an environmental form of aristolochic acid nephropathy where the most probable rout of ingestion of aristolochic acid (AA) was made by bread contaminated with AA, leading to chronic dietary intoxication. Clinical courses of three members of the same family, similarly exposed to toxin, who exhibited different clinical courses of the disease are presented. Methods: Questionnaires on AA exposure were taken. Tissue samples were obtained during therapeutic nephrouretectomies. Histopathology, immunohistochemical detection of p53, p53 mutation screening in tumor DNA and analysis on the presence of aristolactam (AL)-DNA adducts were performed. Results: Case 1 had UUC with typical EN histopathological signs, whereas Case 2 had bilateral UUCs with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T→ T:A transversion) were found in tissues of cases 1 and 2. Conclusion: Diverse clinical courses seem to be related not to differences in exposure but to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms.

Yiqihuoxue Formula Activates Autophagy and Offers Renoprotection in a Rat Model of Adenine-Induced Kidney Disease

“…However, the histological staining of the kidney was only conducted on the left kidneys. While several reports mentioned that the two kidneys responded differently towards the injury [17]. us, the histological changes of the right kidneys need further studies to confirm.…”

Bioinformatics facilitating the use of microarrays to delineate potential miRNA biomarkers in aristolochic acid nephropathy

“…miR-584 has anti-inflammatory effects that modulate AA functions [61]. Subsequently, miR-584 regulated pathways such as MAPK signalling pathways, pathways in cancer, Wnt signalling pathways, p53 signalling pathways, and TGF-beta signalling pathways are associated with AAN [9, 53, 62–66]. Thus, has-miR-33a and has-miR-584 may be biomarkers for the diagnosis and prognosis of AAN, which must be confirmed in further experiments.…”

“…Previous studies also showed that AA stimulated the p53 pathway, mediating TEC apoptosis in acute AAN [7, 8]. Moreover, AA-DNA adducts are an AA exposure marker and risk factors of AA nephropathy-associated cancer [9]. AA commonly induces tumours in the renal cortex, renal pelvis and urinary bladder.…”

Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid

“…Ochratoxin A (OTA) was mostly investigated but in 2006 the EU Committee on Food Safety reported that there was no convincing evidence from human epidemiology to confirm the association between OTA exposure and the prevalence of BEN or UTUC. 27 This conclusion was based on several important facts: (1) OTA is present in food worldwide; (2) significant overlap was found in the average OTA contamination levels of relevant food categories between BEN and non-BEN areas; (3) higher average blood OTA concentrations 48 ; small kidney: length 7 cm, weight 26 gram, smooth surface) (first row, left). Photomicrograph of gradual decrease in fibrosis severity and tubular atrophy from outer-to-inner cortex (hematoxylin-eosin, £40) (first row, right).…”