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The Epidemiology, Diagnosis, and Management of Aristolochic Acid Nephropathy: A Narrative Review

M. Refik Gökmen, PhD, MA, MBBS; Jean-Pierre Cosyns, MD, PhD; Volker M. Arlt, PhD; Marie Stiborová, PhD; David H. Phillips, PhD, DSc; Heinz H. Schmeiser, PhD; Monique S.J. Simmonds, PhD; H. Terence Cook, MBBS; Jean-Louis Vanherweghem, MD, PhD; Joëlle L. Nortier, MD, PhD; and Graham M. Lord, MD, PhD, MA
[+] Article and Author Information

From King's College London and Imperial College London, London, United Kingdom; Cliniques Universitaires St-Luc, Université Catholique de Louvain and Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium; Charles University, Prague, Czech Republic; German Cancer Research Center, Heidelberg, Germany; and Royal Botanic Gardens, Kew, Surrey, United Kingdom.

Disclaimer: The views expressed are those of the authors and are not necessarily those of the U.K. National Health Service (NHS), the National Institute for Health Research (NIHR), or the Department of Health.

Acknowledgment: The authors thank Professor Dusan Ferluga and Dr. Alenka Vizjak for the histologic image of BEN.

Financial Support: The preparation of this review was supported in part by a project grant from the Association for International Cancer Research. Dr. Gökmen is supported by an NIHR Clinical Lectureship and was previously supported by Kidney Research UK. Drs. Gökmen and Lord are supported by the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Drs. Arlt and Phillips are supported by Cancer Research UK.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1902.

Requests for Single Reprints: Graham M. Lord, MD, PhD, MA, Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom; e-mail, graham.lord@kcl.ac.uk.

Current Author Addresses: Drs. Gökmen and Lord: Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom.

Dr. Cosyns: Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Department of Pathology (Tour Franklin-1), 10 Avenue Hippocrate, 200 Brussels, Belgium.

Drs. Arlt and Phillips: Analytical and Environmental Sciences Division, MRC-HPA Centre for Environment & Health, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.

Dr. Stiborová: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic.

Dr. Schmeiser: Research Group Genetic Alterations in Carcinogenesis, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

Dr. Simmonds: Director Kew Innovation Unit, Royal Botanic Gardens, Kew, Surrey TW9 3AB, United Kingdom.

Dr. Cook: Professor of Renal Pathology, Department of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom.

Drs. Vanherweghem and Nortier: Department of Nephrology, Hôpital Erasme, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium.

Author Contributions: Conception and design: M.R. Gökmen, V.M. Arlt, M. Stiborová, H.H. Schmeiser, M.S.J. Simmonds, G.M. Lord.

Analysis and interpretation of the data: M.R. Gökmen, J.P. Cosyns, D.H. Phillips, H.H. Schmeiser, M.S.J. Simmonds, J.L. Vanherweghem, J.L. Nortier, G.M. Lord.

Drafting of the article: M.R. Gökmen, J.P. Cosyns, V.M. Arlt, D.H. Phillips, H.T. Cook, J.L. Vanherweghem, G.M. Lord.

Critical revision of the article for important intellectual content: J.P. Cosyns, V.M. Arlt, H.H. Schmeiser, M.S.J. Simmonds, H.T. Cook, J.L. Vanherweghem, J.L. Nortier, G.M. Lord.

Final approval of the article: M.R. Gökmen, J.P. Cosyns, V.M. Arlt, M. Stiborová, D.H. Phillips, H.H. Schmeiser, M.S.J. Simmonds, H.T. Cook, J.L. Vanherweghem, J.L. Nortier, G.M. Lord.

Administrative, technical, or logistic support: M.R. Gökmen.

Collection and assembly of data: M.R. Gökmen, J.P. Cosyns, M.S.J. Simmonds, J.L. Vanherweghem, G.M. Lord.


Ann Intern Med. 2013;158(6):469-477. doi:10.7326/0003-4819-158-6-201303190-00006
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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.

Figures

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Figure 1.

World map showing the epidemiology of AAN or BEN.

Countries in which cases of AAN or BEN have been reported in the literature are highlighted. It is likely that the true worldwide distribution of the diseases extends beyond the countries highlighted, especially in the Far East and South Asia. AAN = aristolochic acid nephropathy; BEN = Balkan endemic nephropathy.

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Grahic Jump Location
Figure 2.

AA metabolism and proposed mechanism of AA-induced urothelial carcinogenesis in humans and metabolic activation and DNA adduct formation of AAI and AAII.

After reductive metabolic activation mediated by cytosolic and/or microsomal nitroreductases or COX, 7-(deoxyadenosine-N 6-yl) aristolactam I or II (dA–AAI or dA–AAII) and 7-(deoxyguanosine-N 6-yl), aristolactam I or II (dG–AAI or dG–AAII) is formed. The presence of these adducts has been associated with characteristic A:T→T:A transversion mutations in codon 139 of the TP53 gene. The relationship between the molecular mechanisms of carcinogenesis and those of AA-induced nephrotoxicity is still poorly characterized. AAI = aristolochic acid I; AAII = aristolochic acid II; AAN = aristolochic acid nephropathy; COX = cyclooxygenase; CYP = cytochrome P450; NQO1 = NAD(P)H:quinone oxidoreductase 1; POR = P450 oxidoreductase.

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Grahic Jump Location
Figure 3.

Extensive hypocellular interstitial fibrosis associated with tubular atrophy decreasing from the outer to the inner cortical labyrinth of a patient with AAN associated with herbal medicine use (A) and BEN (C).

AAN = aristolochic acid nephropathy; BEN = Balkan endemic nephropathy. A to C. Moderately cellular tubulointerstitial fibrosis and atrophy without corticomedullary gradients are visible in medullary rays and attending outer medulla. All images are stained with hematoxylin–eosin; obj. 4× for panels A and C and obj. 10× for panel B (insert of A at higher magnification). Image shown in panel C is courtesy of Professor Dusan Ferluga and Dr. Alenka Vizjak. D. Flat partially denuded grade II transitional cell carcinoma (arrowheads) from the right upper ureter in a patient with AAN (26) infiltrating the lamina propria as cords (thick arrows) and individual malignant cells (thin arrows). Hematoxylin–eosin stain, ×200; insert, ×500.

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Figure 4.

Proposed diagnostic criteria and management.

AA = aristolochic acid; AAN = aristolochic acid nephropathy; CKD = chronic kidney disease; CT = computed tomography; eGFR = estimated glomerular filtration rate; RRT = renal replacement therapy.

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