In 1956, Bulgarian doctors reported that they found a strange chronic kidney disease in some small villages in the Danube valley of Bulgaria, which was very different from the common chronic kidney disease. Later, this chronic kidney disease was also found in some villages in the Danube Valley in Croatia, Serbia, Bosnia and Herzegovina, and Romania, so it became known as Balkan endemic kidney disease. People with the disease usually develop severe anemia and uremia at the age of 40 to 60, characterized by fibrosis and atrophy of the kidneys, with the kidneys eventually shrinking to only one-third of a normal kidney. There is no cure except for kidney transplantation. In the 1960s, the average life expectancy was only 45 years, and in the 1970s, hemodialysis clinics became available in these areas, allowing patients to avoid uremia by having regular hemodialysis and extending their life expectancy to an average of 69 years. But with this increase in life expectancy came a new problem: about half of the patients developed malignant tumors in the renal pelvis and urethra. What causes this endemic disease in Li Hongzhao, Department of Urology, Beijing 301 Hospital? Because the onset areas were all in the Danube River basin, the first thing that came to the doctors’ minds was, could it be that the drinking water contained some special toxin? This idea was later ruled out. Then new hypotheses were put forward, such as the idea that the grain eaten by the locals was contaminated with some kind of mold when it was stored, and that the mold could secrete toxins that could damage the kidneys. However, none of these hypotheses has been conclusively proven. In 1991, a strange kidney disease was also discovered in Belgium. Van Heuwegen, a doctor at a hospital in Brussels, was treating two young female patients suffering from acute kidney failure when he learned that they were both taking diet pills provided by a weight loss clinic. He suspected that the diet pills were the cause of the disease and immediately launched an investigation, finding that a total of 70 patients with acute kidney failure had taken the same diet pills provided by the same diet clinic. These patients all had similar symptoms, with fibrosis and atrophy of the kidneys and uremia, necessitating kidney replacement or lifelong hemodialysis. Because of the fear of cancer in the kidney, doctors recommended that these patients have both the kidney and urethra removed. Thirty-nine people agreed to have the removal surgery, 18 of whom had grown uroepithelial cancer, and 19 others had precursor cancer in their urinary tract. The clinic had been in business for 15 years without problems, and it was only in 1990, when the clinic changed the formula of its diet pills to use two herbs, that there were suddenly kidney failure patients among its consumers. One of the herbs was Aristolochia, a plant of the genus Aristolochia. The Belgian researchers suspected that the antibiotic was the culprit. Experiments proved their suspicions that the aristolochic acid in the herb could cause irreversible kidney damage. When the news spread, it caused a great shock in the world medical community. France, Japan, Taiwan and other places also reported finding cases of kidney failure caused by taking Aristolochiaceae Chinese medicine, and this kidney disease was thus called herbal nephropathy. Countries have banned or warned against taking herbal medicines containing aristolochic acid. Mainland China’s drug regulatory authorities, medical institutions, and pharmaceutical companies ignored this, insisting that Chinese medicine has its own standards for use, and blaming the problems found abroad on their inability to use Chinese medicine properly. It was only in February 2003 that the Xinhua News Agency revealed for the first time in a series of reports to the public that the main ingredient of Beijing Tongrentang Pharmaceutical Group’s “good medicine for clearing fire”, Guanmutong, contained aristolochic acid, which caused many people to develop uremia. After the Belgian doctor’s report came out, some nephrologists soon thought that the symptoms of herbal nephropathy and Balkan endemic nephropathy are very similar, could they both be caused by aristolochic acid? Grohmann, a professor of pharmacology at the State University of New York at Stony Brook, traveled to Croatia to visit patients with Balkan endemic nephropathy, taking pictures of aristolochia and asking them if they had taken the herb. To his dismay, the patients had not taken it, but they told him that the herb was common in the region. So Groman went on a field trip to the countryside and found that there were many aristolochia growing in the fields of the local wheat fields, and when the wheat was harvested, the aristolochia would be mixed in with the wheat and harvested together. Could it be that the flour consumed locally was contaminated with aristolochia seeds? Back in the United States, Grohmann and colleagues studied kidney specimens from patients with herbal kidney disease and found that aristolochic acid reacted with DNA in kidney cells to form adducts that were not present in patients with common kidney disease. Subsequently, aristolochic acid-DNA adducts were also found in kidney specimens from patients with Balkan endemic nephropathy in Croatia, providing strong evidence that aristolochic acid is the cause of Balkan endemic nephropathy, and that Balkan endemic nephropathy and herbal nephropathy are the same disease and should be called aristolochic acid nephropathy. Grohmann and colleagues further found a specific gene mutation in a gene associated with carcinogenesis in the tumor cells of patients with aristolochic acid nephropathy, which could explain why about half of the patients with aristolochic acid nephropathy grow malignant tumors. If an aristolochic acid-DNA adduct or a specific gene mutation is found in a patient, it can be concluded that he has taken herbs containing aristolochic acid. There are hundreds of species of plants in the Aristolochiaceae family that commonly contain aristolochic acid, and dozens of them are used as herbal medicines. The largest population of people taking aristolochic acid-containing herbs is, of course, in China and Taiwan, where a medical insurance system was established in 1995, allowing almost all Taiwanese to be reimbursed for their medical expenses, including the cost of herbal medicines. By analyzing the Taiwan health insurance reimbursement database, it is possible to know how many Taiwanese have ever taken herbal medicines containing aristolochic acid. The results were striking: between 1997 and 2003, more than one-third of Taiwanese had taken Chinese medicine containing aristolochic acid. As long as one has ever taken Chinese medicine containing aristolochic acid, even just once, there will be irreversible and permanent damage to the kidneys, and the probability of developing kidney disease and upper urinary tract epithelial cancer is higher than the average person. The more times you take it, the more damage it will do to your kidneys, eventually leading to uremia and cancer. In Taiwan, 12% of the population suffers from chronic kidney disease, the highest incidence in the world, and the Taiwanese medical profession believes that the main factor is the use of herbal medicines containing aristolochic acid. The situation in mainland China is not necessarily much better than in Taiwan. According to Groman, his counterparts in China told him that they suspect that most kidney failure cases in mainland China are caused by taking herbal medicines containing aristolochic acid. Currently, the State Drug Administration has only removed the medication standards for three herbs of the Aristolochia genus, Guanmutong, Guangfangji and Qingmuxiang, but there are actually more than a dozen commonly used Chinese herbs known to contain aristolochic acid, including Aristolochia, Hosin, Tianxianvine, Bone Seeking Wind, Hanzhongfangji, Huai Tong, Zhu Sha Lian, and Sanchun Guan, involving hundreds of Chinese herbal prescriptions (proprietary Chinese medicines), such as more than 100 state-approved Chinese herbal prescriptions that contain Hosin. This also includes many pediatric herbs. Whenever a child has a cold or cough, doctors in China like to prescribe the Chinese patent medicine Monkey Date San, which is claimed to be a famous phlegm-removing medicine. One of the ingredients of Monkey Jujube San is the pine of Aristolochiaceae, which is known to contain aristolochic acid. Not to mention the unproven efficacy of Monkey Jujube San, even if it really is effective for coughing or something, there is no need to risk chronic poisoning of children to use it for this minor problem. Aristolochic acid is very stable, and there is nothing to counteract its toxicity, so don’t believe that the toxicity of aristolochic acid can be removed by “compounding” the herb concoction. Don’t think that if you take it now, you’ll be fine, because there is a 20-40 year latency period for small doses of aristolochic acid.