Aristolochic Acid, Balkan Nephropathy, Chinese Herbal Nephropathy: A Saga of Upper Tract Urothelial Cancer

Urothelial cancer refers to cancer of the lining of the urinary tract.  Urothelial cancers can occur in the bladder or the upper tract of the urinary system which includes the lining of the kidney (otherwise known as the renal pelvis) and the ureter.

There are a number of risk factors for the development of upper tract urothelial cancer (UTUC).  Most of these risk factors are related to chronic exposure to carcinogens.  This blog will focus on one of the more rare, but interesting dietary risk factors for UTUC, Aristolochic Acid.  The other known risk factors for UTUC are:

• smoking - the most important modifiable risk factor
• coffee - higher risk of UTUC if >7 cups of coffee per day [1]
• not as big an impact if cigarette smoking is considered
• analgesics - phenacetin, caffeine, codeine, acetaminophen, and aspirin or other salicylates have all been implicated
• arsenic - discovered in Taiwan, where drinking wells are contaminated by arsenic; natives have a higher risk of Blackfoot Disease and UTUC, both believed to be caused by arsenic [2] 
• occupation - chronic exposure to chemicals, dyes, asphalt, tar, petroleum and plastics

Aristocholic Acid - For many years, it was observed that rates of UTUC were higher in the Balkans of Southeastern Europe (Bosnia, Bulgaria, Croatia, Romania, and Serbia) and many Asian countries including China and Taiwan.  The incidence of UTUC in the US is approximately 0.7-1.0 per 100,000 person-years.[3]  In these affected Asian countries and Balkan families, the risk of UTUC rises dramatically, reaching as high as 100-200x the risk of the general population.[4,5]  

The The Balkan Peninsula, popularly referred to as the Balkans,
is a geographical region of Southeast Europe. The region takes
its name from the Balkan Mountains that stretch from
the east of Bulgaria to the very east of Serbia.

China and Taiwan.

Both regions share a common plant genus, Aristolochia (which includes over 500 plant species), that is commonly incorporated into the diet.  In the Balkans, Aristolochia plants grow as weeds alongside wheat and are incorporated into locally produced breads and bread-products.  In Asia, Aristolochia plants are incorporated into many herbal and natural remedies.  While the higher rate of UTUC runs in families, studies demonstrate that the increased risk of UTUC is related to diet and not genetics.   These studies include examination of both molecular markers that implicate diet, and epidemiologic studies that demonstrate that family members who leave home early in life are less likely to develop UTUC.[6,7]

Aristolochia Plant Species, of which over 500 individual species exist.
These plants are known for their strong scent and are often nicknamed
"Birtwort," referring to the birth canal-like shape of the plants.   

A number of studies validate Aristolochic Acid (AA) as a strong carcinogen, demonstrating higher rates of somatic DNA mutations in patients exposed to long-term AA.[8,9]  AA creates DNA mutations by entering the cell nucleus, binds to DNA where it can cause replication errors.[10]  

Patients with AA-related UTUC often present with multiple and/or bilateral, low-grade tumors.[7]  Women, patients with large tumors (>3cm) and invasive tumors (T3 or T4) have worse outcomes.[11]

SUMMARY

• Aristolochic Acid is a risk factor for the development of UTUC through chronic dietary exposure.
• Laboratory studies demonstrate mechanisms by which AA exposure can cause cancer.
• Epidemiologic studies demonstrate increased risk of UTUC related to dietary exposure and not familial genetics.
• Countries of the Balkans and Eastern Asia are two areas in the world where AA ingestion can be considered an endemic cause of UTUC.

[1] Ross RK, Paganini-Hill A, Landolph J,et al: Analgesics, cigarette smoking, and other risk factors for cancer of the renal pelvis and ureter. Cancer Res 1989; 49: 1045.

[2] Tan LB, Chen KT, Guo HR,et al: Clinical and epidemiological features of patients with genitourinary tract tumour in a blackfoot disease endemic area of Taiwan. BJU Int 2008; 102: 48-54.

[3] Munoz JJ, Ellison LM: Upper tract urothelial neoplasms: incidence and survival the last 2 decades. J Urol 2000; 164: 1523-1525.

[4] Petkovic SD: Epidemiology and treatment of renal pelvic and ureteral tumors. J Urol 1975; 114: 858-865.

[5] Yang MH, Chen KK, Yen CC, et al. Unusually high incidence of upper tract urothelial carcinoma in Taiwan. Urology, 2002.  59: 681.

[6] Grollman AP, Shibutani S, Monya M,et al: Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A 2007; 104: 12129-12134.

[7] Radovanovic Z, Krajinovic S, Jankovic S,et al: Family history of cancer among cases of upper urothelial tumours in the Balkan nephropathy area. J Cancer Res Clin Oncol 1985; 110: 181.

[8] SL Poon, ST Pang, JR McPherson, et al. Genome-Wide Mutational Signatures of Aristolochic Acid and Its Application as a Screening Tool.Sci. Transl. Med. 5, 197ra101 (2013)

[9] M. L. Hoang, C.-H. Chen, V. S. Sidorenko, et al.  Mutational Signature of Aristolochic Acid Exposure as Revealed by Whole-Exome Sequencing. Sci. Transl. Med. 5, 197ra102 (2013)

[10]  Chen, C., et al. (2012) Aristolochic acid-associated urothelial cancer in Taiwan. Proceedings of the National Academy of Sciences 109(21) 8241-46.

[11] Dragicevic D, Djokic M, Pekmezovic T,et al: Survival of patients with transitional cell carcinoma of the ureter and renal pelvis in Balkan endemic nephropathy and non-endemic areas of Serbia. BJU Int 2007; 99: 1357-1362.