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Joëlle Nortier - One of the best experts on this subject based on the ideXlab platform.
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the epidemiology diagnosis and management of Aristolochic Acid nephropathy a narrative review
Annals of Internal Medicine, 2013Co-Authors: Refik M Gokmen, Monique S. J. Simmonds, Volker M. Arlt, Marie Stiborová, Heinz H. Schmeiser, Jeanlouis Vanherweghem, Jeanpierre Cosyns, David H Phillips, Terence H Cook, Joëlle NortierAbstract:It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing Aristolochic Acid (AA) and is now termed Aristolochic Acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic Acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.
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Probenecid prevents acute tubular necrosis in a mouse model of Aristolochic Acid nephropathy
Kidney international, 2012Co-Authors: Thomas Baudoux, Agnieszka Pozdzik, Volker M. Arlt, Eric De Prez, Marie-hélène Antoine, Nathalie Quellard, Jean-michel Goujon, Joëlle NortierAbstract:Experimental Aristolochic Acid nephropathy is characterized by early tubulointerstitial injury followed by fibrosis, reproducing chronic lesions seen in humans. In vitro , probenecid inhibits Aristolochic Acid entry through organic anion transporters, reduces specific Aristolochic Acid-DNA adduct formation, and preserves cellular viability. To test this in vivo , we used a mouse model of Aristolochic Acid nephropathy displaying severe tubulointerstitial injuries consisting of proximal tubular epithelial cell necrosis associated to transient acute kidney injury followed by mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis. Treatment with probenecid prevented increased plasma creatinine and tubulointerstitial injuries, and reduced both the extent and the severity of ultrastructural lesions induced by Aristolochic Acid, such as the loss of brush border, mitochondrial edema, and the disappearance of mitochondrial crests. Further, the number of proliferating cell nuclear antigen–positive cells and total Aristolochic Acid-DNA adducts were significantly reduced in mice receiving Aristolochic Acid plus probenecid compared with mice treated with Aristolochic Acid alone. Thus, we establish the nephroprotective effect of probenecid, an inhibitor of organic Acid transporters, in vivo toward acute proximal tubular epithelial cell toxicity in a mouse model of Aristolochic Acid nephropathy.
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Aristolochic Acid nephropathy a worldwide problem
Kidney International, 2008Co-Authors: Frederic Debelle, Jeanlouis Vanherweghem, Joëlle NortierAbstract:Aristolochic Acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies, was initially reported in a Belgian cohort of more than 100 patients after the intake of slimming pills containing a Chinese herb, Aristolochia fangchi. Although botanicals known or suspected to contain Aristolochic Acid (AA) were no longer permitted in many countries, several AAN cases were regularly observed all around the world. The incidence of AAN is probably much higher than initially thought, especially in Asia and the Balkans. In Asian countries, where traditional medicines are very popular, the complexity of the pharmacopoeia represents a high risk for AAN because of the frequent substitution of the botanical products by AA-containing herbs. In the Balkan regions, the exposure to AA found in flour obtained from wheat contaminated with seeds of Aristolochia clematitis could be responsible for the so-called Balkan-endemic nephropathy. Finally, despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing AA, these herbs are still sold via the Internet.
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Aristolochic Acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation
Kidney International, 2008Co-Authors: Agnieszka Pozdzik, Frederic Debelle, Jeanlouis Vanherweghem, Isabelle Salmon, Christine Decaestecker, C Van Den Branden, D Verbeelen, Monique Deschodtlanckman, Joëlle NortierAbstract:Aristolochic Acid contamination in herbal remedies leads to interstitial fibrosis, tubular atrophy, and renal failure in humans. To study the cellular mechanisms contributing to the pathophysiology of this renal disease, we studied Wistar rats treated with Aristolochic Acid and measured tubular and interstitial cell proliferation, epithelial/mesenchymal cell marker expression, tubular membrane integrity, myofibroblast accumulation, oxidative stress, mitochondrial damage, tubular apoptosis, and fibrosis. Oxidative stress, a loss of cadherin concomitant with vimentin expression, basement membrane denudation with active caspase-3 expression, and mitochondrial injury within tubular cells were evident within 5 days of administration of the toxin. During the chronic phase, interstitial mesenchymal cells accumulated in areas of collagen deposits. Impaired regeneration and apoptosis of proximal tubular cells resulted in tubule atrophy with a near absence of dedifferentiated cell transmembrane migration. We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during Aristolochic Acid toxicity.
Volker M. Arlt - One of the best experts on this subject based on the ideXlab platform.
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In Vivo Metabolism of Aristolochic Acid I and II in Rats Is Influenced by Their Coexposure.
Chemical research in toxicology, 2020Co-Authors: Alena Dedı́ková, Volker M. Arlt, Marie Stiborová, Václav Martínek, František Bárta, Kevin Kotalík, Šárka Dušková, Jaroslav Mráz, Petr HodekAbstract:The plant extract Aristolochic Acid (AA), containing Aristolochic Acid I (AAI) and II (AAII) as major components, causes Aristolochic Acid nephropathy and Balkan endemic nephropathy, unique renal d...
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Enzymes metabolizing Aristolochic Acid and their contribution to the development of Aristolochic Acid nephropathy and urothelial cancer.
Current drug metabolism, 2013Co-Authors: Marie Stiborová, Volker M. Arlt, Václav Martínek, Eva Frei, Heinz H. SchmeiserAbstract:Aristolochic Acid (AA), a plant nephrotoxin and carcinogen, causes Aristolochic Acid nephropathy (AAN) and its associated urothelial malignancy, and is hypothesized to be responsible for Balkan endemic nephropathy (BEN). The major component of AA, Aristolochic Acid I (AAI), is the predominant compound responsible for these diseases. The reductive activation of AAI leads to the formation of covalent DNA adducts. The most abundant DNA adduct, 7-(deoxyadenosin-N6-yl)aristolactam I, causes characteristic AT→TA transversions found in the TP53 tumor suppressor gene in tumors from AAN and BEN patients. Understanding which human enzymes are involved in AAI activation to species forming DNA adducts and/or detoxication to the AAI O-demethylated metabolite, Aristolochic Acid Ia (AAIa), is important in the assessment of the susceptibility to this carcinogen. This review summarizes the latest data on identifying human and rodent enzymes participating in AAI metabolism. NAD(P)H:quinone oxidoreductase (NQO1) is the most efficient cytosolic nitroreductase activating AAI in vitro and in vivo. In human hepatic microsomes, AAI is activated by cytochrome P450 1A2 (CYP1A2) and, to a lesser extent, by CYP1A1; NADPH:CYP oxidoreductase also plays a minor role. Human and rodent CYP1A1 and 1A2 are also the principal enzymes involved in oxidative detoxication of AAI to AAIa in vitro and in vivo. The orientation of AAI in the active sites of human CYP1A1/2 and NQO1 was predicted from molecular modeling and is consistent with the efficient reduction of AAI by them observed experimentally. Molecular modeling also shows why CYP1A2 plays an important role in the oxidation of AAI to AAIa.
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the epidemiology diagnosis and management of Aristolochic Acid nephropathy a narrative review
Annals of Internal Medicine, 2013Co-Authors: Refik M Gokmen, Monique S. J. Simmonds, Volker M. Arlt, Marie Stiborová, Heinz H. Schmeiser, Jeanlouis Vanherweghem, Jeanpierre Cosyns, David H Phillips, Terence H Cook, Joëlle NortierAbstract:It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing Aristolochic Acid (AA) and is now termed Aristolochic Acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic Acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.
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Probenecid prevents acute tubular necrosis in a mouse model of Aristolochic Acid nephropathy
Kidney international, 2012Co-Authors: Thomas Baudoux, Agnieszka Pozdzik, Volker M. Arlt, Eric De Prez, Marie-hélène Antoine, Nathalie Quellard, Jean-michel Goujon, Joëlle NortierAbstract:Experimental Aristolochic Acid nephropathy is characterized by early tubulointerstitial injury followed by fibrosis, reproducing chronic lesions seen in humans. In vitro , probenecid inhibits Aristolochic Acid entry through organic anion transporters, reduces specific Aristolochic Acid-DNA adduct formation, and preserves cellular viability. To test this in vivo , we used a mouse model of Aristolochic Acid nephropathy displaying severe tubulointerstitial injuries consisting of proximal tubular epithelial cell necrosis associated to transient acute kidney injury followed by mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis. Treatment with probenecid prevented increased plasma creatinine and tubulointerstitial injuries, and reduced both the extent and the severity of ultrastructural lesions induced by Aristolochic Acid, such as the loss of brush border, mitochondrial edema, and the disappearance of mitochondrial crests. Further, the number of proliferating cell nuclear antigen–positive cells and total Aristolochic Acid-DNA adducts were significantly reduced in mice receiving Aristolochic Acid plus probenecid compared with mice treated with Aristolochic Acid alone. Thus, we establish the nephroprotective effect of probenecid, an inhibitor of organic Acid transporters, in vivo toward acute proximal tubular epithelial cell toxicity in a mouse model of Aristolochic Acid nephropathy.
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dna adducts and p53 mutations in a patient with Aristolochic Acid associated nephropathy
American Journal of Kidney Diseases, 2004Co-Authors: Graham M. Lord, Volker M. Arlt, Monica Hollstein, Candice Roufosse, Charles D Pusey, T Cook, Heinz H. SchmeiserAbstract:Abstract Background: Aristolochic Acid-associated nephropathy (AAN) is a specific type of renal disease that predisposes patients to a high risk of urothelial carcinoma. The authors have analyzed DNA from a patient who had urothelial malignancy 6 years after presenting with AAN and later had a breast carcinoma that metastasized to the liver. Methods and Results: DNA was isolated from the primary breast tumor, the liver tumor, and the original urothelial malignancy and assayed for Aristolochic Acid (AA)-DNA adducts and mutations in the p53 gene. The adduct detected was the adenosine adduct of Aristolochic Acid I 7-(deoxyadenosin- N 6 -yl)aristolactam I (dA-AAI). In DNA from the breast and liver tumors the authors showed the same missense mutation in codon 245 (GGC→GAC; Gly→Asp) of exon 7 of p53 . In contrast, DNA extracted from the urothelial tumor showed an AAG to TAG mutation in codon 139 (Lys→Stop) of exon 5. Conclusion: A to T transversions, as observed here, are the typical mutations observed in the H- ras gene of tumors induced when rodents are treated with AA and correspond with DNA adduct formation at adenosine residues. These data indicate the probable molecular mechanism whereby AA causes urothelial malignancy.
Arthur P. Grollman - One of the best experts on this subject based on the ideXlab platform.
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Aristolochic Acid and its effect on different cancers in uro-oncology
Current opinion in urology, 2020Co-Authors: Katharina Rebhan, Arthur P. Grollman, Iris E. Ertl, Shahrokh F. Shariat, Thomas A. RosenquistAbstract:Purpose of review To acquaint urologists with Aristolochic Acid nephropathy, an iatrogenic disease that poses a distinct threat to global public health. In China alone, 100 million people may currently be at risk. We illustrate the power of molecular epidemiology in establishing the cause of this disease. Recent findings Molecular epidemiologic approaches and novel mechanistic information established a causative linkage between exposure to Aristolochic Acid and urothelial carcinomas of the bladder and upper urinary tract. Noninvasive tests are available that detect urothelial cancers through the genetic analysis of urinary DNA. Combined with cytology, some of these tests can detect 95% of patients at risk of developing bladder and/or upper urothelial tract cancer. Robust biomarkers, including DNA-adduct and mutational signature analysis, unequivocally identify Aristolochic Acid-induced tumours. The high mutational load associated with Aristolochic Acid-induced tumours renders them candidates for immune-checkpoint therapy. Summary Guided by recent developments that facilitate early detection of urothelial cancers, the morbidity and mortality associated with Aristolochic Acid-induced bladder and upper tract urothelial carcinomas may be substantially reduced. The molecular epidemiology tools that define Aristolochic Acid-induced tumours may be applicable to other studies assessing potential environmental carcinogens.
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Aristolochic Acid nephropathy: Harbinger of a global iatrogenic disease.
Environmental and molecular mutagenesis, 2012Co-Authors: Arthur P. GrollmanAbstract:This review constitutes an overview of our investigations of Aristolochic Acid nephropathy, a chronic kidney disease associated with carcinomas of the upper urinary tract. Our studies began by confirming the hypothesis that chronic dietary poisoning by Aristolochic Acid was responsible for endemic (Balkan) nephropathy. A unique TP53 mutational signature in urothelial tumors and the presence of aristolactam-DNA adducts in the renal cortex, defined in the course of this research, proved to be robust biomarkers of exposure to this potent nephrotoxin and human carcinogen. Armed with this information, we used molecular epidemiologic approaches and novel mechanistic information to establish the causative role of Aristolochic Acid in upper urinary tract carcinoma in Taiwan, where one-third of the population had been prescribed herbal remedies containing Aristolochia, and the recorded incidence of upper urinary tract cancers is the highest in the world. As traditional Chinese medicine is practiced similarly in Taiwan and China, it is likely that upper urinary tract carcinomas and their attendant Aristolochic Acid nephropathy are prevalent in China and other Asian countries where Aristolochia herbs have been used for centuries in the treatment and prevention of disease, creating a potential public health problem of considerable magnitude.
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Aristolochic Acid associated urothelial cancer in taiwan
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Chung-hsin Chen, Robert J. Turesky, Karen L Edwards, Kathleen G. Dickman, Masaaki Moriya, Jiri Zavadil, Viktoriya S Sidorenko, Dmitri V Gnatenko, Arthur P. GrollmanAbstract:Aristolochic Acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, Aristolochic Acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of 5′AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to Aristolochic Acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.
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Aristolochic Acid nephropathy in Taiwan: Harbinger of a global iatrogenic disease.
Journal of Clinical Oncology, 2011Co-Authors: Arthur P. Grollman, Kathleen G. Dickman, Chung-hsin Chen, M. Moriya, G. Mihalyne, K. L. Edwards, K. SnappinAbstract:1592 Background: Aristolochic Acid (AA), a powerful nephrotoxin and human carcinogen, was shown recently to be the causative agent of endemic (Balkan) nephropathy, a chronic renal disease associate...
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chapter 7 Aristolochic Acid nephropathy an environmental and iatrogenic disease
Advances in Molecular Toxicology, 2009Co-Authors: Arthur P. Grollman, John Scarborough, Bojan JelakovicAbstract:Publisher Summary This chapter reviews the molecular and clinical toxicology of Aristolochic Acid (AA), nephrotoxic chemical carcinogen. Recently, AA, a principal component of all Aristolochia sp., is shown to be the toxin responsible for the clinical syndromes known as Chinese herb nephropathy (CHN) and endemic (Balkan) nephropathy (EN). The epidemiology and pathophysiology of CHN and EN are reviewed extensively and the association of these diseases with human cancer is the subject of several comprehensive reports. Both disorders are associated with a high incidence of urothelial (transitional cell) cancer and appear to constitute a single disease entity, designated Aristolochic Acid nephropathy (AAN). The dramatic revelation that AA is a powerful nephrotoxin and carcinogen for humans drew attention to the worldwide distribution and extensive use of Aristolochia sp. as herbal remedies. The subsequent reports described almost 200 patients outside of Belgium in whom chronic renal failure followed ingestion of Aristolochia herbs. In addition based on the traditional use of Aristolochia in herbal remedies, the chapter posits that AAN represents a long-overlooked iatrogenic disease and an international public health problem of considerable magnitude.
Jeanlouis Vanherweghem - One of the best experts on this subject based on the ideXlab platform.
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the epidemiology diagnosis and management of Aristolochic Acid nephropathy a narrative review
Annals of Internal Medicine, 2013Co-Authors: Refik M Gokmen, Monique S. J. Simmonds, Volker M. Arlt, Marie Stiborová, Heinz H. Schmeiser, Jeanlouis Vanherweghem, Jeanpierre Cosyns, David H Phillips, Terence H Cook, Joëlle NortierAbstract:It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing Aristolochic Acid (AA) and is now termed Aristolochic Acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic Acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.
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Aristolochic Acid nephropathy a worldwide problem
Kidney International, 2008Co-Authors: Frederic Debelle, Jeanlouis Vanherweghem, Joëlle NortierAbstract:Aristolochic Acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies, was initially reported in a Belgian cohort of more than 100 patients after the intake of slimming pills containing a Chinese herb, Aristolochia fangchi. Although botanicals known or suspected to contain Aristolochic Acid (AA) were no longer permitted in many countries, several AAN cases were regularly observed all around the world. The incidence of AAN is probably much higher than initially thought, especially in Asia and the Balkans. In Asian countries, where traditional medicines are very popular, the complexity of the pharmacopoeia represents a high risk for AAN because of the frequent substitution of the botanical products by AA-containing herbs. In the Balkan regions, the exposure to AA found in flour obtained from wheat contaminated with seeds of Aristolochia clematitis could be responsible for the so-called Balkan-endemic nephropathy. Finally, despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing AA, these herbs are still sold via the Internet.
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Aristolochic Acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation
Kidney International, 2008Co-Authors: Agnieszka Pozdzik, Frederic Debelle, Jeanlouis Vanherweghem, Isabelle Salmon, Christine Decaestecker, C Van Den Branden, D Verbeelen, Monique Deschodtlanckman, Joëlle NortierAbstract:Aristolochic Acid contamination in herbal remedies leads to interstitial fibrosis, tubular atrophy, and renal failure in humans. To study the cellular mechanisms contributing to the pathophysiology of this renal disease, we studied Wistar rats treated with Aristolochic Acid and measured tubular and interstitial cell proliferation, epithelial/mesenchymal cell marker expression, tubular membrane integrity, myofibroblast accumulation, oxidative stress, mitochondrial damage, tubular apoptosis, and fibrosis. Oxidative stress, a loss of cadherin concomitant with vimentin expression, basement membrane denudation with active caspase-3 expression, and mitochondrial injury within tubular cells were evident within 5 days of administration of the toxin. During the chronic phase, interstitial mesenchymal cells accumulated in areas of collagen deposits. Impaired regeneration and apoptosis of proximal tubular cells resulted in tubule atrophy with a near absence of dedifferentiated cell transmembrane migration. We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during Aristolochic Acid toxicity.
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late onset of bladder urothelial carcinoma after kidney transplantation for end stage Aristolochic Acid nephropathy a case series with 15 year follow up
American Journal of Kidney Diseases, 2008Co-Authors: Anne Lemy, Isabelle Salmon, Christine Decaestecker, Karl Martin Wissing, Sandrine Rorive, Alexandre R Zlotta, Thierry Roumeguere, Marie Carmen Muniz Martinez, Daniel Abramowicz, Jeanlouis VanherweghemAbstract:Background Aristolochic Acids are nephrotoxins and predispose to upper-tract urothelial carcinoma. The risk of bladder urothelial carcinoma after kidney transplantation and its relationship to upper-tract urothelial carcinoma is not well defined. Study Design Case series. Setting & Participants Single-center cohort of 38 women given kidney transplants for end-stage Aristolochic Acid nephropathy. Outcomes & Measurements The prevalence of upper urinary tract urothelial carcinoma was determined by collecting pathological results of specimens obtained by means of bilateral ureteronephrectomy. We also established the cumulative incidence of bladder urothelial carcinoma in biopsies performed during prospective screening cystoscopies during a 15-year follow-up. Results Upper-tract urothelial carcinoma was found in 17 patients with Aristolochic Acid nephropathy (44.7%). During follow-up, bladder urothelial carcinoma was diagnosed in 15 patients 68 to 169 months after cessation of Aristolochic Acid exposure (39.5%): 8 urothelial carcinoma in situ, 4 noninvasive low-grade papillary urothelial carcinoma, and 3 infiltrating urothelial carcinoma. 12 of 17 patients (71%) with a history of upper-tract urothelial carcinoma developed bladder urothelial carcinoma during follow-up, whereas this occurred in only 3 of 21 patients (14%) without upper-tract urothelial carcinoma ( P Limitations Small sample size of this case series. Conclusions Upper-tract and bladder urothelial carcinoma are dramatic complications in kidney transplant recipients with Aristolochic Acid nephropathy, confirming the carcinogenic properties of Aristolochic Acids. We identified upper-tract urothelial carcinoma as a potent risk factor for the subsequent development of bladder urothelial carcinoma after kidney transplantation for Aristolochic Acid nephropathy. Because this complication may occur years after Aristolochic Acid discontinuation, we suggest regular cystoscopies in addition to the bilateral ureteronephrectomy in kidney transplant recipients with Aristolochic Acid nephropathy.
Heinz H. Schmeiser - One of the best experts on this subject based on the ideXlab platform.
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Enzymes metabolizing Aristolochic Acid and their contribution to the development of Aristolochic Acid nephropathy and urothelial cancer.
Current drug metabolism, 2013Co-Authors: Marie Stiborová, Volker M. Arlt, Václav Martínek, Eva Frei, Heinz H. SchmeiserAbstract:Aristolochic Acid (AA), a plant nephrotoxin and carcinogen, causes Aristolochic Acid nephropathy (AAN) and its associated urothelial malignancy, and is hypothesized to be responsible for Balkan endemic nephropathy (BEN). The major component of AA, Aristolochic Acid I (AAI), is the predominant compound responsible for these diseases. The reductive activation of AAI leads to the formation of covalent DNA adducts. The most abundant DNA adduct, 7-(deoxyadenosin-N6-yl)aristolactam I, causes characteristic AT→TA transversions found in the TP53 tumor suppressor gene in tumors from AAN and BEN patients. Understanding which human enzymes are involved in AAI activation to species forming DNA adducts and/or detoxication to the AAI O-demethylated metabolite, Aristolochic Acid Ia (AAIa), is important in the assessment of the susceptibility to this carcinogen. This review summarizes the latest data on identifying human and rodent enzymes participating in AAI metabolism. NAD(P)H:quinone oxidoreductase (NQO1) is the most efficient cytosolic nitroreductase activating AAI in vitro and in vivo. In human hepatic microsomes, AAI is activated by cytochrome P450 1A2 (CYP1A2) and, to a lesser extent, by CYP1A1; NADPH:CYP oxidoreductase also plays a minor role. Human and rodent CYP1A1 and 1A2 are also the principal enzymes involved in oxidative detoxication of AAI to AAIa in vitro and in vivo. The orientation of AAI in the active sites of human CYP1A1/2 and NQO1 was predicted from molecular modeling and is consistent with the efficient reduction of AAI by them observed experimentally. Molecular modeling also shows why CYP1A2 plays an important role in the oxidation of AAI to AAIa.
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the epidemiology diagnosis and management of Aristolochic Acid nephropathy a narrative review
Annals of Internal Medicine, 2013Co-Authors: Refik M Gokmen, Monique S. J. Simmonds, Volker M. Arlt, Marie Stiborová, Heinz H. Schmeiser, Jeanlouis Vanherweghem, Jeanpierre Cosyns, David H Phillips, Terence H Cook, Joëlle NortierAbstract:It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing Aristolochic Acid (AA) and is now termed Aristolochic Acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic Acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.
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dna adducts and p53 mutations in a patient with Aristolochic Acid associated nephropathy
American Journal of Kidney Diseases, 2004Co-Authors: Graham M. Lord, Volker M. Arlt, Monica Hollstein, Candice Roufosse, Charles D Pusey, T Cook, Heinz H. SchmeiserAbstract:Abstract Background: Aristolochic Acid-associated nephropathy (AAN) is a specific type of renal disease that predisposes patients to a high risk of urothelial carcinoma. The authors have analyzed DNA from a patient who had urothelial malignancy 6 years after presenting with AAN and later had a breast carcinoma that metastasized to the liver. Methods and Results: DNA was isolated from the primary breast tumor, the liver tumor, and the original urothelial malignancy and assayed for Aristolochic Acid (AA)-DNA adducts and mutations in the p53 gene. The adduct detected was the adenosine adduct of Aristolochic Acid I 7-(deoxyadenosin- N 6 -yl)aristolactam I (dA-AAI). In DNA from the breast and liver tumors the authors showed the same missense mutation in codon 245 (GGC→GAC; Gly→Asp) of exon 7 of p53 . In contrast, DNA extracted from the urothelial tumor showed an AAG to TAG mutation in codon 139 (Lys→Stop) of exon 5. Conclusion: A to T transversions, as observed here, are the typical mutations observed in the H- ras gene of tumors induced when rodents are treated with AA and correspond with DNA adduct formation at adenosine residues. These data indicate the probable molecular mechanism whereby AA causes urothelial malignancy.
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Aristolochic Acid as a probable human cancer hazard in herbal remedies a review
Mutagenesis, 2002Co-Authors: Volker M. Arlt, Marie Stiborová, Heinz H. SchmeiserAbstract:Aristolochic Acid as a probable human cancer hazard in herbal remedies a review. The old herbal drug Aristolochic Acid (AA), derived from Aristolochia spp., has been associated with the development of a novel nephropathy, designated Aristolochic Acid nephropathy (AAN), and urothelial cancer in AAN patients. There is clear evidence that the major components of the plant extract AA, Aristolochic Acid I (AAI) and Aristolochic Acid II (AAII), both nitrophenanthrene carboxylic Acids, are genotoxic mutagens forming DNA adducts after metabolic activation through simple reduction of the nitro group. Several mammalian enzymes have been shown to be capable of activating both AAI and AAII in vitro and in cells. The activating metabolism has been elucidated and is consistent with the formation of a cyclic nitrenium ion with delocalized charge leading to the preferential formation of purine adducts bound to the exocyclic amino groups of deoxyadenosine and deoxyguanosine. The predominant DNA adduct in vivo, 7-(deoxyadenosin-N-6- yl)aristolactam I (dA-AAI), which is the most persistent of the adducts in target tissue, is a mutagenic lesion leading to AT-- >TA transversions in vitro. This transversion mutation is found at high frequency in codon 61 of the H-ras oncogene in tumours of rodents induced by AAI, suggesting that dA-AAI might be the critical lesion in the carcinogenic process in rodents. DNA- binding studies confirmed that both AAs bind to the adenines of codon 61 in the H-ras mouse gene and preferentially to purines in the human p53 gene. In contrast, the molecular mechanism of renal interstitial fibrosis in humans after chronic administration of AA remains to be explored. However, preliminary findings suggest that DNA damage by AA is not only responsible for the tumour development but also for the destructive fibrotic process in the kidney. It is concluded that there is significant evidence that AA is a powerful nephrotoxic and carcinogenic substance with an extremely short latency period, not only in animals but also in humans. In particular, the highly similar metabolic pathway of activation and resultant DNA adducts of AA allows the extrapolation of carcinogenesis data from laboratory animals to the human situation. Therefore, all products containing botanicals known to or suspected of containing AA should be banned from the market world wide.