Guan Mu Tong

Three unrelated stems have been sold under names containing Mu Tong: Akebia quinata, Clematis armandii or C. montana, and Aristolochia manshuriensis. Only Aristolochia manshuriensis contains aristolochic acid. The name traditionally attached to Mu Tong is Akebia quinata, and the Japanese Pharmacopoeia lists only Akebia because it follows the traditional literature. Market survey work records that when Akebia quinata ran short, Aristolochia manshuriensis was substituted in the widely used patent formula Long Dan Xie Gan Wan, with renal failure in some patients as the result. A 2004 case is documented of a 60-year-old man diagnosed with kidney failure and urinary tract cancer traced to confusion over a name in a herbal prescription. Because the toxin acts by covalent DNA adduct formation rather than by a reversible receptor effect, an unintended substitution that lasts weeks can commit the patient to lifelong risk.

A number of Chinese patent medicines have been assayed for aristolochic acid content and some were associated with aristolochic acid nephropathy in reported cases. Long Dan Xie Gan Wan is the formula most closely tied to the Chinese outbreak, because Aristolochia manshuriensis was used as the Mu Tong ingredient during a shortage of Akebia quinata. Finished products are the hardest exposure to detect, since the label names the formula rather than the species and the patient has no way to know which stem was used. Aristolochia-containing remedies remain accessible despite bans in many countries, and sporadic cases continue to be reported.

The regulatory chronology is what lets a practitioner date a patient's possible exposure. In China, Guan Mu Tong (Aristolochia manshuriensis) lost its national drug standard and was removed from the Chinese Pharmacopoeia in 2003; the standards for Qing Mu Xiang (Aristolochiae Radix) and Guang Fang Ji (Aristolochia fangchi Radix) were cancelled the following year, in 2004, and Ma Dou Ling (Aristolochiae Fructus) and Tian Xian Teng (Aristolochiae Herba) were dropped from the 2020 Pharmacopoeia. Outside China, the United Kingdom prohibited Aristolochia by emergency order in 1999 (SI 1999/2109, followed by SI 1999/2889), extended the prohibition to Mu Tong and Fangji material in 2000 (SI 2000/1368), and made it permanent from 1 July 2001 by the Medicines (Aristolochia and Mu Tong etc.) (Prohibition) Order 2001 (SI 2001/1841). That order is unusually broad and worth knowing: it bans not only every species of the genus Aristolochia but also Akebia quinata, Akebia trifoliata, Clematis armandii, Clematis montana, Cocculus and Stephania tetrandra, and separately bans any product whose label or accompanying document indicates in any language that it contains Mu Tong or Fangji. In other words the UK regulator judged the substitution hazard unmanageable and banned the intended substitutes too. The US FDA issued warnings and an import alert covering aristolochic acid-containing botanical dietary ingredients in 2001, together with a request to manufacturers and distributors for voluntary recall. Taiwan embargoed these herbs in 2003 and Hong Kong in 2004, Korea prohibited aristolochic acid-containing ingredients from 2005, and the European ban took effect with enforcement of the Traditional Herbal Medicinal Products Directive in 2011. IARC classified aristolochic acid and plants containing it as Group 1 human carcinogens in 2012.

Aristolochic acid nephropathy is a rapidly progressive tubulointerstitial fibrosis with a worse prognosis than tubulointerstitial disease of other causes; two-year kidney survival in one series was 17%, and renal dysfunction is irreversible in most cases. Cumulative aristolochic acid dose determines progression, and a Chinese survey found that regular use of nephrotoxic medications, whether analgesics or aristolochic acid-containing pills, raised the odds of renal impairment (OR 2.19). Any further nephrotoxic insult is being applied to a kidney with reduced reserve and ongoing fibrosis.