Nephropathy induced by aristolochic acid (AA) containing herbs
- Marc E De Broe, MD, PhD
Marc E De Broe, MD, PhD
- Emeritus Professor of Medicine
- University of Antwerp, Belgium
In 1991, physicians in Belgium noted an increasing number of women who presented with acute, often near end-stage renal disease (ESRD) following exposure to aristolochic acid (AA) at a weight reduction clinic [1,2]. An initial survey of seven nephrology centers in Brussels identified 14 women under the age of 50 years who had presented with advanced renal failure due to biopsy-proven chronic tubulointerstitial nephritis over a three-year period; nine of these patients had been exposed to the same slimming regimen . A total of more than 300 cases have been identified, a third of whom have already undergone renal transplantation.
The epidemiology is unknown, as is the risk for development of severe renal damage. However, the publication of case reports from several countries in Europe and Asia, particularly in China, indicate that the incidence of herbal medicine-induced nephrotoxicity is more common than previously thought [3-6].
The major lesion, which is located principally in the cortex, is extensive interstitial fibrosis with atrophy and loss of the tubules. Cellular infiltration of the interstitium is scarce. Thickening of the walls of the interlobular and afferent arterioles result from endothelial cell swelling. The glomeruli are relatively spared, and immune deposits are not observed. These findings suggest that the primary lesions may be centered in the vessel walls, thereby leading to ischemia and interstitial fibrosis.
An extremely high incidence of cellular atypia and urothelial (transitional cell) carcinoma of the renal pelvis, ureter, and bladder has been associated with AA nephropathy [7-9].
In 1969. it was first suggested that ingestion of flour contaminated with seeds from Aristolochia clematitis may be the cause of Balkan endemic nephropathy (BEN) when it was noted that seeds from these plants, which grew abundantly in local wheat fields, commingled with wheat grain during the harvesting process . Support for AA as the major nephrotoxin is provided by more recent findings in animal models (rabbit, rat, and mice) of disease [11-15]. In one study, for example, rabbits were given intraperitoneal injections of AA (0.1 mg AA/kg five days a week for 17 to 21 months) . Histologic examination of the kidneys and genitourinary tract revealed renal hypocellular interstitial fibrosis and atypical and malignant uroepithelial cells.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Vanherweghem JL, Depierreux M, Tielemans C, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341:387.
- Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL. Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 1994; 24:172.
- Yang CS, Lin CH, Chang SH, Hsu HC. Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs. Am J Kidney Dis 2000; 35:313.
- Wu Y, Liu Z, Hu W, Li L. Mast cell infiltration associated with tubulointerstitial fibrosis in chronic Aristolochic Acid Nephropathy. Hum Exp Toxicol 2005; 24:41.
- Guh JY, Chen HC, Tsai JF, Chuang LY. Herbal therapy is associated with the risk of CKD in adults not using analgesics in Taiwan. Am J Kidney Dis 2007; 49:626.
- Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy: a worldwide problem. Kidney Int 2008; 74:158.
- Cosyns JP, Jadoul M, Squifflet JP, et al. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999; 33:1011.
- Nortier JL, Martinez MC, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000; 342:1686.
- Isnard Bagnis C, Deray G, Baumelou A, et al. Herbs and the kidney. Am J Kidney Dis 2004; 44:1.
- Ivić M. [Etiology of endemic nephropathy]. Lijec Vjesn 1969; 91:1273.
- Cosyns JP, Dehoux JP, Guiot Y, et al. Chronic aristolochic acid toxicity in rabbits: a model of Chinese herbs nephropathy? Kidney Int 2001; 59:2164.
- Debelle FD, Nortier JL, De Prez EG, et al. Aristolochic acids induce chronic renal failure with interstitial fibrosis in salt-depleted rats. J Am Soc Nephrol 2002; 13:431.
- Van Vleet TR, Schnellmann RG. Toxic nephropathy: environmental chemicals. Semin Nephrol 2003; 23:500.
- Nortier JL, Vanherweghem JL. For patients taking herbal therapy--lessons from aristolochic acid nephropathy. Nephrol Dial Transplant 2007; 22:1512.
- Zhou L, Fu P, Huang XR, et al. Mechanism of chronic aristolochic acid nephropathy: role of Smad3. Am J Physiol Renal Physiol 2010; 298:F1006.
- De Broe ME. On a nephrotoxic and carcinogenic slimming regimen. Am J Kidney Dis 1999; 33:1171.
- Debelle FD, Nortier JL, Husson CP, et al. The renin-angiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids. Kidney Int 2004; 66:1815.
- Pozdzik AA, Salmon IJ, Debelle FD, et al. Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation. Kidney Int 2008; 73:595.
- Zhou L, Fu P, Huang XR, et al. Activation of p53 promotes renal injury in acute aristolochic acid nephropathy. J Am Soc Nephrol 2010; 21:31.
- Diamond JR, Pallone TL. Acute interstitial nephritis following use of tung shueh pills. Am J Kidney Dis 1994; 24:219.
- Lord GM, Cook T, Arlt VM, et al. Urothelial malignant disease and Chinese herbal nephropathy. Lancet 2001; 358:1515.
- Grollman AP, Shibutani S, Moriya M, et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A 2007; 104:12129.
- Schmeiser HH, Janssen JW, Lyons J, et al. Aristolochic acid activates ras genes in rat tumors at deoxyadenosine residues. Cancer Res 1990; 50:5464.
- Jelaković B, Karanović S, Vuković-Lela I, et al. Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid. Kidney Int 2012; 81:559.
- Lebeau C, Arlt VM, Schmeiser HH, et al. Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cells. Kidney Int 2001; 60:1332.
- De Broe ME. Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy. Kidney Int 2012; 81:513.
- Kabanda A, Jadoul M, Lauwerys R, et al. Low molecular weight proteinuria in Chinese herbs nephropathy. Kidney Int 1995; 48:1571.
- Gökmen MR, Cosyns JP, Arlt VM, et al. The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review. Ann Intern Med 2013; 158:469.
- Reginster F, Jadoul M, van Ypersele de Strihou C. Chinese herbs nephropathy presentation, natural history and fate after transplantation. Nephrol Dial Transplant 1997; 12:81.
- Vanherweghem JL. Nephropathy and herbal medicine. Am J Kidney Dis 2000; 35:330.
- Vanherweghem JL, Abramowicz D, Tielemans C, Depierreux M. Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis: a pilot study in Chinese herbs nephropathy. Am J Kidney Dis 1996; 27:209.