Article,
Aristolochic Acid and `Chinese Herbs Nephropathy': A Review of the Evidence to Date
Drug Saf., 26 (1): 33--48 (2003)
Abstract
Chinese herbs nephropathy (CHN) is a rapidly progressive interstitial
nephropathy reported after the introduction of Chinese herbs in
a slimming regimen followed by young Belgian women. It is characterised
by early, severe anaemia, mild tubular proteinuria and initially
normal arterial blood pressure in half of the patients. Renal histology
shows unusual extensive, virtually hypocellular cortical interstitial
fibrosis associated with tubular atrophy and global sclerosis of
glomeruli decreasing from the outer to the inner cortex. Urothelial
malignancy of the upper urinary tract develops subsequently in almost
half of the patients.Suspicion that the disease was due to the recent
introduction of Chinese herbs in the slimming regimen was reinforced
by identification in the slimming pills of the nephrotoxic and carcinogenic
aristolochic acid (AA) extracted from species of Aristolochia. This
hypothesis was substantiated by the identification of premutagenic
AA-DNA adducts in the kidney and ureteric tissues of CHN patients.
Finally, induction of the clinical features (interstitial fibrosis
and upper urothelial malignancy) typical of CHN in rodents given
AA alone removed any doubt on the causal role of this phytotoxin
in CHN, now better called aristolochic acid nephropathy (AAN).AAN
is not restricted to the Belgian cases. Similar cases have been
observed throughout the world, but AA is sometimes incriminated
on the basis of the known content of AA in the herbs. The possibility
remains that in some individuals in whom AA has not been demonstrated,
other phytotoxins might be implicated.Biological and morphological
features of AAN are strikingly similar to those reported in another
fibrosing interstitial nephropathy of still unknown aetiology, Balkan
endemic nephropathy (BEN). Interestingly, AA was incriminated as
the cause of BEN many years ago, a hypothesis yet to be fully explored.
The intake of AA and the presence of tissular AA-DNA adducts in
patients with an unequivocal diagnosis of BEN remains to be demonstrated.The
tragic phenomenon of CHN, recognised only 10 years ago, has been
at the root of significant research and progress both in nephrology
and oncology. It has provided a fascinating opportunity to understand
the link between a fibrosing interstitial nephropathy and urothelial
carcinoma. It allows the categorisation of interstitial nephritis
on the basis of histological findings, of initiating toxic substances
and of associated clinical features. Finally, it has led to the
withdrawal in several countries of a previously unsuspected carcinogenic
and nephrotoxic substance.
