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Valvular heart disease and Chlnese-herb nephropathy Snt-Jean-Louis Vanhenveghem (Dec 20127, p 1858)‘ wonders whether Chinese-herb nephropathy might not be caused by the intake of fenfluramine. We do not believe that this hypothesis is supported by available evidence. We previously reported aortic insdliciency in five of 12 patients, one of whom required valvular surgery: a finding now corroborated by Vanhenveghem, and speculated that aortic insufficiency could be another extrarenal manifestation of Chineseherb intoxication. The observation that appetite suppressants lead to valvular disease raises the more likely hypothesis that the aortic insufficiency in our patients was due to the concomitant intake of fenfluramine and diethylpropion.’ It is, however, unlikely that appetite suppressants are implicated in Chineseherb nephropathy. Indeed, since 1975 fenfluramine and diethylpropion have been included in the Brussels slimming regimen. The rapidly progressive interstitial disease has been observed only after 199&ie, when the Chinese herbs Srephaniu retrundra and Mugnoliu oficinalis replaced pancreas powder, laminaria powder, and fucus extract? The discovery that Srephaniu tetrandru had been inadvertently replaced by the aristolochic-acidrich Aristolochiufung chi led to the suggestion that aristolochic acid, a known carcinogenic agent, was the cause of Chinese-herb nephropathy. Our subsequent finding of aristolochic acid DNA adducts in the renal tissue of six patients with Chinese-herb nephropathy: together with urothelial cellular atypias and in-situ carcinomas,2 strongly supported a causal effect of aristolochic acid. The uneven distribution of Chineseherb nephropathy among patients given the same herbal mixture means that the toxic effect of aristolochic acid might have been potentiated by another agent, perhaps the simultaneously ingested appetite suppressants. Charles Van Ypersele de StrihOU University of Louvain Medical School, Nephrology Department, Cliniques Universitaires St-Luc, 1200 Brussels, Belgium 1 VanherweghemJ-L. Association of valvular heart disease with Chinese-herb nephropathy. Lancer 1997; 350: 1858. 2 Reginster F, Jadoul M, van Ypersele de Sttihou C. Chinese herbs nephropathy presentation, ~ m ahistory l and fate after transplantation. Nephrol Dial Transplant 1997; 12: 81-86. 3 Kuaz X, Van Ermen A. Valvular heart disease associated with fenfluramine-phentennine.N EnglJMed 1997; 331: 1772-73. 4 VanherweghemJ-L, Depierreux M,
THE LANCET * Vol351 * March 28,1998
Tielemans C, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancer 1993; 341: 387-91. 5 Bieler CA, Stiborova M, Wiessler M, et al. 32P post-labelling analysis of DNA adducts formed by aristolochic acid in tissues from patients with Chinese herbs nephropathy. CarcimgmestS 1997; 18: 1063-67.
Sir-After
the series of reports by Jean-
Louis Vanhenveghem and coUeagues’J between 1993 and 1997, Chinese-herb nephropathy has become known as a new renal disease caused by nephrotoxins contained in medicinal plants. This disease was first described in Belgium, and aristolochic acid was identified in the herbal formulation. Pathological findings of the nephrotoxicity of aristolochic acid were confirmed by experiments in rats’ and were similar to those of Chinese-herb nephropathy. In Japan Kuwahara and colleag~es~,~ have reported two cases of Chinese-herb nephropathy. Although the formulae differed, aristolochic acid was detected in the herbs taken by both patients, and no appetite suppressants were given concomitantly. In these patients, no particular symptoms of valvular heart disease were recorded. The valvular heart disease in Chineseherb nephropathy seen in Belgium seems most likely to be due to the combined use of (dex)fenfluramine and Chinese herbs, as Vanhenveghem mentions. It is also obvious that the nephropathy recorded both in Belgium and in Japan is not caused by (dex)fenfluramine, and that tubulointerstitial disorders are induced by the prolonged use of Chinese herbs that contain aristolochic acid. It seems appropriate that the nomenclature of this Chinese-herb nephropathy, which is ambiguous, should be changed to aristolochic-acidnephropathy. Vakahiko Ono, Muso Eri, Gisho Honda, Takashi Kuwahara *Department of Cardiovascular Medicine, Graduate School of Medicine, and Department of Pharmacognosy,Graduate School of Pharmaceutical Sciences, Kyoto University, SakycFku, Kyoto 606 Japan; and Department of Nephrology, Saiseikai Nakatsu Hospital, Osaka
1 Vanhenveghem J-L, Depierreux M, Tielemans C, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341: 387-91. 2 VanherweghemJ-L.Association of valvular heart disease with Chinese-herb nephropathy. Lancer 1997; 350 1858. 3 Mengus U, Stotzem CD. Renal toxicity of aristolochic acid in rats as an example of nephrotoxicity testing in routine toxicology. Arch Toxic01 1993; 67: 307-11. 4 Tanaka A, Shmkai S, Kasuno K, et al. Chinese herbs nephropathy in the Kansai area: a warning report.a n 3 Nephroll997; 39: 438110. 5 Tanaka A, Nishida FC, Sawai K, et al. Traditional remedy-induced Chinese herbs
nephropathy showing rapid deterioration of renal function. 3p3 Nephmll997; 39: 794-97.
A uthors’ reply Sir-Judging by the comments of Charles Van Ypersele de Strihou some confusion has arisen about Vanherweghem’s report. The conclusion was intended to indicate the existence of two distinct diseasesnephropathy secondary to the misuse of Chinese herbs and a fenfluraminerelated aortic insufficiency. We report a woman with Chinese-herb nephropathy who had not been treated by the incriminated medical office,’ and was not following a slimming regimen, and was not taking appetite suppressants. A 49-year-old woman was admitted in October, 1996, because of terminal renal failure. Such as is seen in Chineseherb nephr~pathy,~,’renal biopsy showed severe interstitial fibrosis, tubular atrophy, fibrous intima thickening of arterioles, glomerular sclerosis, and cellular atypia of urothelium. Previous laboratory data indicated that renal function had been normal in 1992 (serum creatinine 86 pmoVL). The medical history disclosed the use of Chinese herbal powders from 1991 until 1993 for non-specific arthralgias. The Chinese herbs were provided by the patient’s physiotherapist. A batch of powders from 1992 was still available for analysis, and was labelled as Stephaniu. However, chemical analyses of this batch, conducted by M Vanhaelen (Pharmacy Institute, Universite Libre de Bruxelles), did not show the presence of tetradinine (the alkaloid characteristic of Srephania tetrandra), or the presence of ochratoxin. On the other hand, aristolochic acids I and I1 (at a concentration of 52 mg per g of powder) were present. One of us aLv> has summarised elsewhere‘ arguments in favour of the arismbchia hypothesis, which is once again supported by Takahiko Ono and colleagues and our reports of nephropathies in patients taking only herb mixtures containing Arisrobchiu spp outside the framework of a slimming regimen. As suggested by Ono and coworkers the term aristolochia nephropathy has already been used.’ *J L Vanherweghem, J J Cuykens, Ph Vandenbergh, K P Bouman, Y Hagers Algemeen Ziekenhuis Middelheim, Antwerpen, Belgium; and *UniversitB Libre de Bruxelles, Hdpital Erasme, 8-1070 Brussels, Belgium 1 Vanhenveghem Tr, Depierrew M, Tielemans C, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancer 1993; 341: 387-91. 2 Depierreux M, Van Damme B, Van Den Houte K, VanherweghemIT-. Pathologic aspects of a newly described
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CORRESPONDENCE nephropathy related to prolonged use of Chinese herbs. A m 3 Kidnej Dis 1994; 24: 172-80. 3 Cosijns JP. Jadoul M, Squifnet JP,et al. Chinese herbs nephropathy: a clue to balkan endemic nephropathy?Kidmy Int 1994; 45: 1680-88. 4 VanherweghemJL. Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium (Chinese herbs nephropathy).JAltern Compl Med (in press). 5 Vanhenveghem JL.Arisrolochia nephropathy in humans: an outbreak in Belgium. 3 A m Soc Nephrol 1993; 4: 327.
Maternal mortality Sir-Carine Ronsmans and colleagues (Dec 20/27, p 1810)’ state that simple “before and after” studies can be useful in the evaluation of safe motherhood programmes. This suggestion is dangerous irrespective of its simplicity and affordability. Without a contemporaneous control group, it is not possible to ascribe cause. If an epidemic or other crisis occurs between the beginning and end of a project and maternal mortality rises, we cannot know without a control group whether this negative outcome is due to the intervention. We cannot know from a simple before and after comparison whether a reduction in maternal mortality is the result of our intervention or other unknown factors, for example, an improvement in the economy or a successful nutrition programme. Very good control groups can be attained, as shown in the recent randomised controlled trial of vitamin A supplementation and maternal mortality in Nepal. Conducting a randomised controlled trial requires resolve, substantial funding, good, and usually large, samples, knowledge of sampling and study design, and good field management. Further evaluation with the best research design possible-ie, one that randomises sampling units at the lowest level possible-is needed to make evidence-based decisions to reduce maternal mortality. When adequate funding or the necessary commitment does not exist, further assessment of the intervention may be best implemented by simpler controlled “before and after” evaluative approaches. The progress of safe motherhood can only be hindered by avoiding the difficult but necessary controlled evaluations of safe motherhood interventions. Nancy L Sloan Population Council. New York, New York 10017. USA ernail:
[email protected] 1
Ronsmans C, Vanneste AM,Chakraborty J, van Ginneken J. Decline in maternal mortality in Matlab, Bangladesh a cautionav tale. Lancet 1997; 350: 1810-14.
992
Lice burled under the ashes of Herculaneum Sir-On Aug, 24, 79 AD, during the festival of the Divine Augustus, a dramatic eruption of Mount Vesuvius overwhelmed Pompeii, Herculaneum, and several other nearby small towns and villages, burying unique archeological treasures and many inhabitants under a hail of ashes and pumice or steaming mud lava.’ The eruption is vividly described by Pliny the Younger, in a letter to Tacitus. Recent paleopathological investigations of the skeletons of the so-called fugitives discovered in the boat sheds on the ancient beach of Herculaneum provide insight into common diseases of classical antiquity. In particular, the skull of individual E52 presents a thick brownish encrustation around the vertex. The individual was a woman, about 25 years old, who was 8 months pregnant when she died; the tiny bones of her fetus are perfectly preserved. The encrustation on her skull is strongly radio-opaque, and consists mainly of iron dioxide and carbon, which is what remains of an iron hairpin. The acidity of the hot vulcanic mud that buried the woman rapidly rusted the pin; the iron salts that were released impregnated the immediate area, including her hair, which is remarkably well preserved, showing the elaborate hairstyle typical of wealthy, high ranking young Roman women. Chemical analysis showed that the hairs were almost entirely made up of iron oxide, with a carbon content of less than 2%, and there are no traces of sulphur typical of keratin. This finding indicates that here was complete diagenesis, with destruction of the original proteins and their replacement mainly by iron salts. Each hair was examined microscopically, and one was found to have an egg attached, whose dimensions and position with respect to the hair shaft showed it to be a louse egg. The egg was identical to those of both current forms and ancient specimens (figure). Indeed, the egg from Herculaneum showed no appreciable differences in form or size with even the oldest eggs known (found in the Nahal Herman Cave, Judean Desert, 6900-6300 BC),* or with those found on South American Pre-Columbian mummies, prehistoric north American remains, or Egyptian or Chinese mummies; this similarity confirms that the morphological evolution of lice (and their eggs) has
Scannlng electron mlcrograph of louse egg attached to hair
occurred gradually, following the gradual biological evolution of their human hosts. Above the inion skull E52 displays a flattened area with an oval outline whose maximum transverse diameter is about 20 mm, in which the external tabula is rough and porous. This supra-inion depression3 is an area of superficial bone remodelling produced by irritation of the local periosteum. Anthropologists have correlated this depression with the presence of impetigo, tinea, or pediculosis, which are pathological changes that can produce periostal reaction either directly or through the inflammatory processes that begin as a result of scratching. About 22% of the skulls from Herculaneum show this suprainion depression, with no difference between the sexes or with age. This finding is hardly surprising, and contemporary writers note that lice were quite common in Ancient Rome: both Scilla the Dictator and the Greek poet Alcamon died as a result of their infestation.4 *Luigi Capasso, Gabriella Di rota Department of Anthropology, National Archeological Museum, 66100 Chieti, Italy 1
Grant M. Cities of Vesuvius, Pompeii and Herculonum. New York, The Macmillan Company, 1971. 2 Zias J, Mumcuoglu Y. Pre-Pottery Neolithic B Head Lice from Nahal Hemar Cave. Arigor 1991; 20: 167-68. Jerusalem. 3 Holliday DY. Occipital lesions: a possible cost of cradleboards. Am J Phys Anthr 1993; 90: 283-90. 4 Caii Plinii Secundi, Hisroriee Naturalis, Liber XI, 114, Volumen Sextum.
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