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1.
Am J Kidney Dis ; 38(5): E26, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11684578

RESUMEN

The causal role of aristolochic acid (AA) in the so-called Chinese herbs nephropathy (CHN) has been conclusively demonstrated only in the Belgian epidemic. We report a biopsy-proven hypocellular interstitial fibrosing nephropathy in a Chinese patient who had ingested a Chinese herbal preparation bought in Shanghai. The identification of AA in the preparation and of AA-DNA adducts in the kidney tissue unequivocally demonstrates, for the first time, the causal role of AA outside the Belgian epidemic. Because the ingested preparation is very popular in China as an over-the-counter product, our observation raises the possibility that many such cases due to AA might be currently unrecognized in China. AA should be banned from herbal preparations worldwide. All cases of the so-called CHN, in which the causal role of AA has been thoroughly documented, should be further identified as aristolochic acid nephropathy (AAN). The term phytotherapy-associated interstitial nephritis (PAIN) might refer to the other cases associated with phytotherapy without identification, as yet, of the causal agent.


Asunto(s)
Ácidos Aristolóquicos , Fenantrenos/efectos adversos , Insuficiencia Renal/inducido químicamente , Aductos de ADN , Medicamentos Herbarios Chinos/efectos adversos , Femenino , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/fisiopatología , Persona de Mediana Edad , Terminología como Asunto
2.
Kidney Int ; 59(6): 2164-73, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11380818

RESUMEN

BACKGROUND: Chinese herbs nephropathy (CHN) is a new type of subacute interstitial nephritis that is attributed to aristolochic acid (AA), which inadvertently has been included in slimming pills. The contribution of other simultaneously prescribed drugs remains disputed. In the present study, the effects of a chronic intake of AA given as a single drug was evaluated through renal histology and function in rabbits. METHODS: Female New Zealand White rabbits were injected intraperitoneally with either 0.1 mg AA/kg or with saline 5 days a week for 17 to 21 months. Body weight, renal function, and urinary excretion of glucose and low molecular weight proteins were monitored prior to sacrifice at the end of the study period. RESULTS: All animals given AA developed renal hypocellular interstitial fibrosis, which was classified into three patterns. Fibrosis was confined to medullary rays (MRs) in pattern I (N = 3), extended to the outer cortical labyrinth (OCL) in pattern II (N = 2), and eventually to the inner cortical labyrinth (ICL) in pattern III (N = 6). Fibrosis in MR and OCL was associated with mainly proximal tubular epithelial cell flattening. All treated animals displayed urothelial atypia. Three of them also developed tumors of the urinary tract. No significant pathologic changes were found in control rabbits. AA-treated animals differed from controls by an impaired growth, increased serum creatinine, glucosuria, tubular proteinuria, and anemia. CONCLUSION: The observed pattern of renal histopathological lesions and disorders of the renal function, as well as urothelial atypia and malignancy, are very reminiscent of CHN. Our observations therefore support a causal role of AA alone in the genesis of this new nephropathy.


Asunto(s)
Ácidos Aristolóquicos , Medicamentos Herbarios Chinos/toxicidad , Inhibidores Enzimáticos/toxicidad , Nefritis Intersticial/inducido químicamente , Fenantrenos/toxicidad , Animales , Modelos Animales de Enfermedad , Femenino , Fibrosis , Riñón/patología , Nefritis Intersticial/patología , Tamaño de los Órganos , Conejos , Estómago/patología
3.
Am J Kidney Dis ; 33(6): 1011-7, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10352187

RESUMEN

Rapidly progressive renal fibrosis after a slimming regimen including Chinese herbs containing aristolochic acid (AA) has been identified as Chinese-herb nephropathy (CHN). We reported urothelial atypia in three patients with CHN, with the subsequent development in one patient of overt transitional cell carcinoma (TCC). Therefore, it was decided to remove the native kidneys, as well as the ureters, in all patients with CHN. Nineteen kidneys and ureters removed during and/or after renal transplantation from 10 patients were studied to assess critically urothelial lesions and to characterize the cellular expression of p53, a tumor-suppressor gene overexpressed in several types of malignancies. Multifocal high-grade flat TCC in situ (carcinoma in situ; CiS) was observed, mainly in the upper urinary tract, in four patients, a prevalence of 40%. In one of those patients, a superficially invasive flat TCC of the right upper ureter, as well as two additional foci of noninvasive papillary TCC, were found in the right pelvis and left lower ureter, respectively. This patient also presented recurrent noninvasive papillary TCC of the bladder. Furthermore, in all cases, multifocal, overall moderate atypia was found in the medullary collecting ducts, pelvis, and ureter. All CiS and papillary TCC, as well as urothelial atypia, overexpressed p53. These results show that the intake of Chinese herbs containing AA has a dramatic carcinogenic effect. Carcinogenesis is associated with the overexpression of p53, which suggests a role for a p53 gene mutation. The relationship of this mutation with the reported presence of AA DNA adducts in the kidney remains to be explored.


Asunto(s)
Ácidos Aristolóquicos , Carcinógenos , Carcinoma in Situ/inducido químicamente , Carcinoma de Células Transicionales/inducido químicamente , Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/inducido químicamente , Neoplasias Renales/inducido químicamente , Fenantrenos/efectos adversos , Adulto , Femenino , Humanos , Riñón/patología , Enfermedades Renales/genética , Enfermedades Renales/patología , Persona de Mediana Edad , Proteína p53 Supresora de Tumor/análisis , Uréter/patología , Neoplasias Ureterales/inducido químicamente
8.
Carcinogenesis ; 18(5): 1063-7, 1997 May.
Artículo en Inglés | MEDLINE | ID: mdl-9163697

RESUMEN

Recently, we reported that aristolochic acid (AA) a naturally occurring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). Indeed, we identified the principal aristolochic acid-DNA adduct in the kidney of five such patients. We now extend these observations and demonstrate the presence of additional AA-DNA adducts by the 32P-post-labelling method not only in the kidneys, but also in a ureter obtained after renal transplantation. Using the nuclease P1 version of the assay not only the major DNA adduct of aristolochic acid, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), but also the minor adducts, 7-(deoxyguanosin-N2-yl)-aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)-aristolactam II (dA-AAII) were detected, and identified by cochromatographic analyses with TLC and HPLC. Quantitative analyses of six kidneys revealed relative adduct levels from 0.7 to 5.3/10(7) for dA-AAI, from 0.02 to 0.12/10(7) for dG-AAI and 0.06 to 0.24/ 10(7) nucleotides for dA-AAII. The detection of the dA-AAII adduct is consistent with the occurrence of aristolochic acid II (AAII) in the herb powder imported under the name of Stephania tetrandra and confirms that the patients had indeed ingested the natural mixture of AAI and AAII. 32P-post-labelling analyses of further biopsy samples of one patient showed the known adduct pattern of AA exposure not only in the kidney, but also in the ureter, whereas in skin and muscle tissue no adduct spots were detectable. In an attempt to explain the higher level of the dA-AAI adduct compared to the dG-AAI adduct level in renal tissue even 44 months after the end of regimen, the persistence of these two purine adducts was investigated in the kidney of rats given a single oral dose of pure AAI. In contrast to the dG-AAI adduct, the dA-AAI adduct exhibited a lifelong persistence in the kidney of rats. Our data demonstrate that AA forms DNA adducts in human tissue by the same activation mechanism(s) reported from animal studies. Thus, the carcinogenic/mutagenic activity of AA observed in animals could also be responsible for the urothelial cancers observed in two of the CHN patients.


Asunto(s)
Ácidos Aristolóquicos , Aductos de ADN , Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/genética , Fenantrenos/química , Adulto , Animales , Aductos de ADN/metabolismo , Femenino , Humanos , Enfermedades Renales/inducido químicamente , Masculino , Persona de Mediana Edad , Ratas , Ratas Wistar , Factores de Tiempo
9.
Nephrol Dial Transplant ; 12(1): 81-6, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-9027778

RESUMEN

BACKGROUND: Chinese herbs nephropathy is a new type of subacute interstitial nephropathy reported in women who had followed a slimming regimen including Chinese herbs. METHODS: We report the clinical presentation and follow-up of 15 cases and compare them with a control group of 15 women with interstitial nephropathies of other origins, matched for age, sex, and initial serum creatinine (mean 3 mg/dl). RESULTS: At presentation the Chinese herbs nephropathy group differed from the control group by a lower proteinuria (P = 0.009), a more severe anaemia (P = 0.002), and a higher prevalence of aortic insufficiency (42% vs 0%, P < 0.05). It was further characterized by mild hypertension in 80%, glycosuria and leukocyturia in 40% and asymmetric kidneys in 54% of the cases. During follow-up, deterioration of renal function was faster in the Chinese herbs nephropathy than in the control group (P < 0.05). It was influenced by the duration of Chinese herbs treatment (P = 0.037) and the delay between the end of Chinese herbs ingestion and diagnosis of the disease (P = 0.013). In three cases, renal failure developed 3 years after Chinese herbs ingestion. Complications included severe aortic regurgitation requiring surgery (n = 1), urothelial carcinoma (n = 2), bilateral ureterohydronephrosis due to periureteral fibrosis (n = 1). Five patients with Chinese herbs nephropathy were successfully transplanted, without evidence of recurrence of the disease. CONCLUSIONS: Chinese herbs nephropathy is characterized by a lower proteinuria, more severe anaemia, and a faster progression to renal failure than other interstitial nephropathies. The duration of Chinese herbs treatment and interval between withdrawal of Chinese herbs and diagnosis are correlated with the rate of progression. Severe, unusual extrarenal complications may affect Chinese herbs nephropathy patients.


Asunto(s)
Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/etiología , Enfermedades Renales/cirugía , Trasplante de Riñón , Adulto , Insuficiencia de la Válvula Aórtica/etiología , Estudios de Casos y Controles , Creatinina/sangre , Medicamentos Herbarios Chinos/administración & dosificación , Femenino , Humanos , Hipertensión/etiología , Enfermedades Renales/fisiopatología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/cirugía , Persona de Mediana Edad , Factores de Tiempo
10.
Cancer Res ; 56(9): 2025-8, 1996 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-8616845

RESUMEN

A unique type of rapidly progressive renal fibrosis, designated Chinese herbs nephropathy (CHN), has been described in young Belgian women who had followed a slimming regimen including recently introduced Chinese herbs (Stephania tetrandra and Magnolia officinalis). Aristolochic acid (AA), a known nephrotoxin and carcinogen, was suspected as its causal factor. To substantiate this hypothesis, renal tissue from five patients with CHN and six patients with other renal diseases was analyzed for the presence of AA-derived DNA adducts, a described biomarker of AA exposure associated with its carcinogenic and mutagenic activity. Using the 32P-postlabeling method, a major distinct DNA adduct spot was found in all five cases of CHN and identified by cochromatographic analyses with authentic markers as the deoxyadenosine adduct of AA-I [7-(deoxyadenosin-N6-yl)-aristolactam I], the major component of the plant extract AA. This DNA adduct was absent in the six control cases. The 7-(deoxyadenosin-N6-yl)-aristolactam I adduct levels in CHN ranged from 0.7 to 5.3/10(7) nucleotides. Our data demonstrate that AA is implicated in CHN. They suggest a mechanism for the urothelial atypia and cancers observed in this disease and raise the possibility that a DNA mutation is responsible for the kidney-destructive fibrotic process.


Asunto(s)
Ácidos Aristolóquicos , Aductos de ADN , Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/inducido químicamente , Riñón/efectos de los fármacos , Fenantrenos/efectos adversos , Adulto , Femenino , Humanos , Riñón/metabolismo , Enfermedades Renales/metabolismo , Fenantrenos/metabolismo
11.
Kidney Int ; 48(5): 1571-6, 1995 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-8544416

RESUMEN

Urinary excretion of five low molecular weight proteins (LMWP) [beta 2-microglobulin (beta 2m), cystatin C (cyst C), Clara cell protein (CC16), retinol-binding protein (RBP) and alpha 1-microglobulin (alpha 1m)], albumin and N-acetyl-beta-D-glucosaminidase (NAG) were quantified in 16 patients who followed a weight reduction program which included Chinese herbs, which have been incriminated in the genesis of Chinese herbs nephropathy (CHN). An additional group of four patients transplanted for CHN were investigated. Urinary data were obtained for comparison purpose in five groups of proteinuric patients: two groups with normal serum creatinine (SCr) and glomerular albuminura [12 patients with diabetes mellitus and microalbuminuria (DN), 10 patients with primary nephrotic syndrome (NS)]; two groups with normal SCr and toxic nephropathy [6 patients with analgesic (AN), 9 patients with cadmium nephropathy (CdN)]; and one group of seven patients with glomerular diseases and increased SCr (GN). Patients were classified according to serum level S beta 2m to take into account the possibility of overflow proteinuria at S beta 2m > or = 5 mg/liter. Three patients (CHN0) with a S beta 2m < 5 mg/liter, had a normal urinary protein pattern including NAG and a normal S beta 2m. Eight patients (CHN1) with a S beta 2m < 5 mg/liter had various abnormalities of their urinary protein pattern. In four of them (CHN1a) only beta 2m, RBP and CC16 were increased while total proteinuria and SCr were normal. In the other four (CHN1b and c) albumin, cyst C, alpha 1m and NAG were also elevated, while total proteinuria and SCr were moderately raised. Five patients (CHN2) with a S beta 2m > or = 5 mg/liter had a markedly increased excretion of all LMWP, albumin and NAG (CHN1 vs. CHN2, P < 0.05) as well as a further increase in total proteinuria and SCr. The urinary LMWP/albumin concentration ratio was strikingly higher in CHN patients than in patients with glomerular albuminuria (CHN1 vs. DN and NS, P < 0.01) or moderate renal failure with elevated S beta 2m level (CHN2 vs. GN, P < 0.01), confirming the existence of a tubular proteinuria independent of glomerular albuminuria or overflow proteinuria. A similar proteinuria pattern was present in the two toxic nephropathies (CdN and AN). This pattern was no longer recognizable after transplantation. In conclusion, CHN exhibits various profiles of tubular proteinuria which are the hallmarks of the disease. This pattern is still detectable in patients with renal failure and/or glomerular albuminuria. It is identical to that observed in cadmium and analgesic nephropathies. It does not recur after transplantation. Its most sensitive and reliable marker is a raised urinary level of CC16 or RBP.


Asunto(s)
Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/orina , Proteinuria/sangre , Uteroglobina , Adulto , Analgésicos/efectos adversos , Cadmio/efectos adversos , Femenino , Humanos , Enfermedades Renales/cirugía , Glomérulos Renales , Trasplante de Riñón , Masculino , Peso Molecular , Proteínas/química , Proteínas/metabolismo , Proteínas de Unión al Retinol/orina
13.
15.
Kidney Int ; 45(6): 1680-8, 1994 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-7933816

RESUMEN

Rapidly progressive interstitial renal fibrosis has recently been reported in young women who have been on a slimming regimen including Chinese herbs. We examined four nephroureterectomies performed in three patients prior to or at the time of transplantation to determine the nature and topography of the kidney and urinary tract lesions in Chinese herbs nephropathy (CHN). Extensive, hypocellular, interstitial sclerosis, tubular atrophy and global sclerosis of glomeruli decreasing from the outer to the inner cortex, including the columns of Bertin, were observed in the four kidney specimens, together with severe fibromucoid to fibrous intimal thickening, mainly of interlobular arteries, normal or collapsed residual glomeruli, and mild to moderate atypia and atypical hyperplasia of the urothelium. In addition, bilateral pelvi-ureteric sclerosis was observed in one case. With the exception of the latter, these lesions are very similar to those described in Balkan endemic nephropathy (BEN). The clinical presentation of the patients was also similar to that observed in BEN: normal blood pressure, aseptic leukocyturia, low grade low molecular weight proteinuria, early and severe anemia. In conclusion, on morphological and clinical grounds, CHN appears similar to BEN. A common etiologic agent, aristolochic acid, is suspected. The known carcinogenic potential of this compound, taken together with our finding of multiple foci of cellular atypia of the urothelium suggest that CHN patients should undergo a regular follow-up for urothelial malignancy.


Asunto(s)
Nefropatía de los Balcanes/inducido químicamente , Medicamentos Herbarios Chinos/efectos adversos , Fallo Renal Crónico/inducido químicamente , Adulto , Nefropatía de los Balcanes/patología , Medicamentos Herbarios Chinos/uso terapéutico , Femenino , Fibrosis , Humanos , Riñón/patología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Túbulos Renales/patología , Obesidad/tratamiento farmacológico
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