Aristolochic Acid Nephropathy: Molecular Mechanisms, Clinical Impact and Therapeutic Challenges in a Progressive Renal Disease
Nefropatía por ácido aristolóquico: mecanismos moleculares, impacto clínico y desafíos terapéuticos en una enfermedad renal progresiva
Juan José Reinoso-Calle, Christian Anthony Laso-Barrera, Jhomayra Michelle Segovia-Valdiviezo
Abstract
Aristolochic acid nephropathy (AAN) is a rapidly progressive form of interstitial nephritis associated with the use of medicinal plants from the Aristolochiaceae family, which contain aristolochic acid (AA) and environmental pollutants. It was first discovered in Belgium in the 1990s and is associated with progressive renal fibrosis and a high risk of urothelial carcinoma. Development and discussion: AAN is a toxic kidney disease associated with the consumption of medicinal plants with AA or contaminated food. It is characterized by progressive interstitial nephritis, renal fibrosis and an increased risk of urothelial carcinoma. Its pathogenesis includes mitochondrial DNA damage, TP53 mutations, inflammation and fibrosis. Clinically, the disease presents as progressive renal disease in chronic forms, acute renal damage after massive ingestion or mild tubular dysfunction. Diagnosis is based on the history of exposure, clinical findings, renal biopsy and urinary biomarkers. Complications include urothelial carcinoma, severe fibrosis and end-stage renal disease. Treatment requires elimination of AA exposure, oncologic surveillance, and advanced renal support. This emphasizes the need for targeted therapies to slow disease progression and improve prognosis. AAN is a multifactorial disease with severe renal impact and high oncologic morbidity. Prevention, early diagnosis and multidisciplinary management are crucial to improve the prognosis and quality of life of patients.
Keywords
Resumen
La nefropatía por ácido aristolóquico (NAA) es una forma rápidamente progresiva de nefritis intersticial asociada al uso de plantas medicinales de la familia Aristolochiaceae, que contienen ácido aristolóquico (AA) y con la presencia de contaminantes ambientales. Esta patología se descubrió por primera vez en Bélgica en la década de 1990 y se asocia a una fibrosis renal progresiva y a un alto riesgo de carcinoma urotelial. El desarrollo y la discusión de este tema se centran en la comprensión de la NAA como una enfermedad renal tóxica asociada al consumo de plantas medicinales que contienen AA o alimentos contaminados. Esta condición se caracteriza por una progresión de la nefritis intersticial, seguida de fibrosis renal y un riesgo aumentado de carcinoma urotelial. La investigación en torno a la patogénesis de la NAA revela daños en el ADN mitocondrial, mutaciones en el gen TP53, inflamación y fibrosis. En términos clínicos, la enfermedad se manifiesta como una enfermedad renal progresiva en las formas crónicas, daño renal agudo tras una ingesta masiva o disfunción tubular leve. El diagnóstico se fundamenta en los antecedentes de exposición, los hallazgos clínicos, la biopsia renal y los biomarcadores urinarios. Las complicaciones asociadas incluyen carcinoma urotelial, fibrosis grave y enfermedad renal terminal. El tratamiento requiere la eliminación de la exposición a la NAA, vigilancia oncológica y soporte renal avanzado, lo que subraya la importancia de las terapias dirigidas para ralentizar la progresión de la enfermedad y mejorar el pronóstico. La NAA es una enfermedad multifactorial con graves repercusiones renales y una elevada morbilidad oncológica. Por lo tanto, se hace evidente que la implementación de medidas preventivas, el diagnóstico temprano y un abordaje multidisciplinario son de suma importancia para mejorar el pronóstico y la calidad de vida de los pacientes afectados.
Palabras clave
References
1.Ji H, Hu J, Zhang G, Song J, Zhou X, Guo D. Aristolochic acid nephropathy: A scientometric analysis of literature published from 1971 to 2019. Medicine (Baltimore). 2021;100(27):e26510. doi: 10.1097/MD.0000000000026510.
2.Jadot I, Declèves AE, Nortier J, Caron N. An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature. Int J Mol Sci. 2017;18(2):297. doi: 10.3390/ijms18020297.
3.Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Dratwa M, Jadoul M, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet. 1993;341(8842):387-91. doi: 10.1016/0140-6736(93)92984-2.
4.IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monogr Eval Carcinog Risks Hum. 2002;82:1-556.
5.Nortier JL, Martinez MC, Schmeiser HH, Arlt VM, Bieler CA, Petein M, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med. 2000;342(23):1686-92. doi: 10.1056/NEJM200006083422301.
6.Lai MN, Lai JN, Chen PC, Tseng WL, Chen YY, Hwang JS, et al. Increased risks of chronic kidney disease associated with prescribed Chinese herbal products suspected to contain aristolochic acid. Nephrology (Carlton). 2009;14(2):227-34. doi: 10.1111/j.1440-1797.2008.01061.x.
7.Nortier J, Pozdzik A, Roumeguere T, Vanherweghem JL. [Aristolochic acid nephropathy ("Chinese herb nephropathy")]. Nephrol Ther. 2015;11(7):574-88. doi: 10.1016/j.nephro.2015.10.001.
8.Baudoux T, Jadot I, Declèves AE, Antoine MH, Colet JM, Botton O, et al. Experimental Aristolochic Acid Nephropathy: A Relevant Model to Study AKI-to-CKD Transition. Front Med (Lausanne). 2022;9:822870. doi: 10.3389/fmed.2022.822870.
9.Gökmen MR, Cosyns JP, Arlt VM, Stiborová M, Phillips DH, Schmeiser HH, et al. The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review. Ann Intern Med. 2013;158(6):469-77. doi: 10.7326/0003-4819-158-6-201303190-00006.
10.Zhang L, Zhang P, Wang F, Zuo L, Zhou Y, Shi Y, et al. Prevalence and factors associated with CKD: a population study from Beijing. Am J Kidney Dis. 2008;51(3):373-84. doi: 10.1053/j.ajkd.2007.11.009.
11.Su T, Zhang L, Li X, Zuo L, Zhang P, Wang H. Regular use of nephrotoxic medications is an independent risk factor for chronic kidney disease--results from a Chinese population study. Nephrol Dial Transplant. 2011;26(6):1916-23. doi: 10.1093/ndt/gfq679.
12.Zhou Q, Jiang L, Su T, Liu G, Yang L. Overview of aristolochic acid nephropathy: an update. Kidney Res Clin Pract. 2023;42(5):579-90. doi: 10.23876/j.krcp.22.211.
13.Jelaković B, Dika Ž, Arlt VM, Stiborova M, Pavlović NM, Nikolić J, et al. Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid. Semin Nephrol. 2019;39(3):284-96. doi: 10.1016/j.semnephrol.2019.02.007.
14.Ban TH, Min JW, Seo C, Kim DR, Lee YH, Chung BH, et al. Update of aristolochic acid nephropathy in Korea. Korean J Intern Med. 2018;33(5):961-69. doi: 10.3904/kjim.2016.288.
15.Luciano RL, Perazella MA. Aristolochic acid nephropathy: epidemiology, clinical presentation, and treatment. Drug Saf. 2015;38(1):55-64. doi: 10.1007/s40264-014-0244-x.
16.Han J, Xian Z, Zhang Y, Liu J, Liang A. Systematic Overview of Aristolochic Acids: Nephrotoxicity, Carcinogenicity, and Underlying Mechanisms. Front Pharmacol. 2019;10:648. doi: 10.3389/fphar.2019.00648.
17.Chan W, Ham YH. Probing the Hidden Role of Mitochondrial DNA Damage and Dysfunction in the Etiology of Aristolochic Acid Nephropathy. Chem Res Toxicol. 2021;34(8):1903-9. doi: 10.1021/acs.chemrestox.1c00175.
18.Zhang Q, Luo P, Chen J, Yang C, Xia F, Zhang J, et al. Dissection of Targeting Molecular Mechanisms of Aristolochic Acid-induced Nephrotoxicity via a Combined Deconvolution Strategy of Chemoproteomics and Metabolomics. Int J Biol Sci. 2022;18(5):2003-17. doi: 10.7150/ijbs.69618.
19.Chen L, Cheng S, Ying J, Zhang Q, Wang C, Wu H, et al. Aristolochic acid I promotes renal tubulointerstitial fibrosis by up-regulating expression of indoleamine 2,3-dioxygenase-1 (IDO1). Toxicol Lett. 2024;402:44-55. doi: 10.1016/j.toxlet.2024.11.003.
20.Wang S, Fan J, Mei X, Luan J, Li Y, Zhang X, et al. Interleukin-22 Attenuated Renal Tubular Injury in Aristolochic Acid Nephropathy via Suppressing Activation of NLRP3 Inflammasome. Front Immunol. 2019;10:2277. doi: 10.3389/fimmu.2019.02277.
21.Upadhyay R, Batuman V. Aristolochic acid I induces proximal tubule injury through ROS/HMGB1/mt DNA mediated activation of TLRs. J Cell Mol Med. 2022;26(15):4277-91. doi: 10.1111/jcmm.17451.
22.Pozdzik AA, Salmon IJ, Debelle FD, Decaestecker C, Van den Branden C, Verbeelen D, et al. Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation. Kidney Int. 2008;73(5):595-607. doi: 10.1038/sj.ki.5002714.
23.Grollman AP. Aristolochic acid nephropathy: Harbinger of a global iatrogenic disease. Environ Mol Mutagen. 2013;54(1):1-7. doi: 10.1002/em.21756.
24.De Broe ME. Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy. Kidney Int. 2012;81(6):513-5. doi: 10.1038/ki.2011.428.
25.Yang L, Su T, Li XM, Wang X, Cai SQ, Meng LQ, et al. Aristolochic acid nephropathy: variation in presentation and prognosis. Nephrol Dial Transplant. 2012;27(1):292-8. doi: 10.1093/ndt/gfr291.
26.Witkowicz J. [Aristolochic acid nephropathy]. Przegl Lek. 2009;66(5):253-56.
27.Chen CH, Dickman KG, Huang CY, Moriya M, Shun CT, Tai HC, et al. Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes. Int J Cancer. 2013;133(1):14-20. doi: 10.1002/ijc.28013.
28.Rebhan K, Ertl IE, Shariat SF, Grollman AP, Rosenquist T. Aristolochic acid and its effect on different cancers in uro-oncology. Curr Opin Urol. 2020;30(5):689-95. doi: 10.1097/MOU.0000000000000806.
29.Kim MJ, Tam FW. Urinary monocyte chemoattractant protein-1 in renal disease. Clin Chim Acta. 2011;412(23-24):2022-30. doi: 10.1016/j.cca.2011.07.023.
30.Wu Y, Yang L, Su T, Wang C, Liu G, Li XM. Pathological significance of a panel of urinary biomarkers in patients with drug-induced tubulointerstitial nephritis. Clin J Am Soc Nephrol. 2010;5(11):1954-9. doi: 10.2215/CJN.02370310.
31.Xu C, Wang Q, Du C, Chen L, Zhou Z, Zhang Z, et al. Histone deacetylase-mediated silencing of PSTPIP2 expression contributes to aristolochic acid nephropathy-induced PANoptosis. Br J Pharmacol. 2024;181(9):1452-73. doi: 10.1111/bph.16299.
32.Baudoux TE, Pozdzik AA, Arlt VM, De Prez EG, Antoine MH, Quellard N, et al. Probenecid prevents acute tubular necrosis in a mouse model of aristolochic acid nephropathy. Kidney Int. 2012;82(10):1105-13. doi: 10.1038/ki.2012.264.
33.Zhou Y, Bian X, Fang L, He W, Dai C, Yang J. Aristolochic acid causes albuminuria by promoting mitochondrial DNA damage and dysfunction in podocyte. PLoS One. 2013;8(12):e83408. doi: 10.1371/journal.pone.0083408.
34.Chen J, Luo P, Wang C, Yang C, Bai Y, He X, et al. Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy. JCI Insight. 2022;7(16):e157360. doi: 10.1172/jci.insight.157360.
35.Shan H, Tian W, Hong Y, Xu B, Wang C, Yu B, et al. Clinicopathologic characteristics and prognosis of upper tract urothelial carcinoma complicated with aristolochic acid nephropathy after radical nephroureterectomy. BMC Complement Med Ther. 2020;20(1):166. doi: 10.1186/s12906-020-2861-5.
Submitted date:
02/13/2025
Reviewed date:
04/07/2025
Accepted date:
04/14/2025
Publication date:
04/15/2025
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email