Herbal 'remedy' may trigger widespread kidney failure

— -- Kidney stones. Snakebites. Head wounds. To the ancients, a weed called birthwort was a wonder drug that treated them all, and more.

Medical detectives, however, are finding that the ancient remedy likely has caused centuries of kidney failure and cancer, as well as being the culprit in a widespread syndrome of kidney disease in some parts of the world.

"The big clue was the plant itself," says pharmacologist Arthur Grollman of Stony Brook (N.Y.) University. "Once it was appreciated that it contained a potent kidney toxin and human carcinogen, we could get to the bottom of things."

Grollman and colleagues have unraveled a genetic signature left behind by birthwort in cases of cancers and kidney failure, as reported in the March journal ofKidney International. And in upcoming work, they report signs that use of the drug in Chinese medicines may be responsible for Taiwan's sky-high rate of kidney disease.

Over a century ago, toxicologists first recognized harmful properties of aristolochic acid, found in the Aristolochia (Ah-wrist-oh-LOW-key-ah) plant family that includes hundreds of species of birthworts (sometimes called "Dutchman's pipes" for the long curved shape of their flowers). The knowledge caused little medical concern about the herb, which produces dirty yellow to red flowers and had been catalogued since at least 300 B.C., by one of Aristotle's students as an herbal remedy.

In 1969, however, a Croatian researcher first noted that Aristolochia poisoning may play a role in unusual kidney failure and urinary tract cancer cases afflicting farming villages along the Danube River valley in Croatia, Bulgaria, Romania and elsewhere in the region. Only about 700 villages suffered from "Balkan endemic nephropathy" and families suffered the syndrome in a patchy way, suggesting an environmental explanation. Based on observations that birthwort grew thickly in and around the wheat that farmers grew, researchers began to suspect that they were baking birthwort seeds in their bread, which concentrate aristolochic acid. However, there were many other explanations for the syndrome as well to check, ranging from pollution to fungal contamination of grain, so the idea lay fallow.

Modern medicine became alarmed by birthwort in 1991, when dozens of young women from a "slimming" clinic in Brussels, Belgium, appeared in doctor's offices with kidney failure. The case triggered warnings and a 2000 New England Journal of Medicine report noting that about 5% of 1,800 women given the Chinese herb, Aristolochia fangchi (another birthwort species), in a weight-loss treatment at the clinic had developed kidney failure. That triggered a Food and Drug Administration warning about the herb that mentioned 16 weight-loss products then on store shelves, and also offered a clue that only some people suffered from a genetic susceptibility to the herb causing kidney failure, Grollman says.

But it wasn't until a 2007 Proceedings of the National Academy of Sciences paper that Grollman and his colleagues showed the Balkan and Belgian cases were caused by the same toxin, finding mutations in the genes of Croatian patients that exactly matched those of mice poisoned with aristolochic acid. The mutations were pinpoint changes in a well-known tumor-suppressing gene called p53. The finding "was a breakthrough," says kidney expert Marc De Broe of Belgium's University of Antwerp, in a commentary in Kidney International. DeBroe added, "this magic plant turned out to contain a powerful nephrotoxic (kidney-poisoning) substance with an ability to induce urothelial (urinary tract) cancer."

But the damage from birthwort poisoning may well go beyond clusters of unexplained kidney failure, Grollman suggests. In an upcoming study, he and his colleagues looked at Taiwan, the " Land of Dialysis" in some news reports, where the herb is widely used in traditional medicine. A 2006 survey in The Lancet suggested that nearly 12% of Taiwan's population suffers chronic kidney disease. Health service statistics there also show that about 1 in 3 patients are prescribed Aristolochia as part of traditional medical treatments delivered at doctor's offices. And Taiwanese kidney failure patients in the upcoming study widely show the same pinpoint changes in the p53 gene seen in patients in the Balkans and Belgium, Grollman says.

Such a genetic signature of a disease is a rarity in medicine. Two decades ago, work linked signature mutations in the p53 gene to cancer triggered by exposure to UV light. But aristolochic acid is only the third toxin shown to leave such a telltale trace in the genes of its victims, so far.

And researchers should start looking for that signature anywhere traditional Chinese medicine is practiced, Grollman adds. A 2004 report in the journal Toxicology reported that Chinese farmers harvest enough of the plant to dose 100 million people with the toxin yearly. As a result, Aristolochia poisoning likely "represents a long-overlooked disease and an international public health problem of considerable magnitude," Grollman and his colleagues concluded in the recent Kidney International study.

Under 1994 "dietary supplement" laws, U.S. manufacturers bear the responsibility for keeping Aristolochia out of herbal products, following FDA warnings. The agency detains any imported remedies that list the herb as an ingredient, and last year updated its list of traditional medicines thought to contain birthwort or its cousins.

"Banning the herb doesn't make everything safe, because the cancer it may have initiated takes decades to develop," Grollman says. However, since early treatment would benefit patients, he says, "getting out the word about Aristolochia's toxicity would certainly help." In response to the earlier birthwort findings, the U.S. Public Health Service added aristolochic acid to its list of human carcinogens in 2009. But that doesn't mean there aren't other traditional remedies posing just as much concern as birthwort out there on health food store shelves, because under U.S. law, such dietary supplements aren't subject to the same safety testing that drugs and other medical treatments must undergo.

"An important message for Americans is that Congress is inviting similar problems in our country by not holding dietary supplements — which includes herbs —to reasonable standards of safety and efficacy," Grollman says. "We simply don't know whether other herbal supplements like Aristolochia are being marketed right now."