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.
Similar content being viewed by others
References
Vanherweghem JL, 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
Cosyns JP, Jadoul M, Squifflet JP, et al. Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Int 1994; 45: 1680–8
van Ypersele de Strihou C, Vanherweghem JL. The tragic paradigm of Chinese herbs nephropathy. Nephrol Dial Transplant 1995; 10: 157–60
Reginster F, Jadoul M, van Ypersele de Strihou C. Chinese herbs nephropathy presentation, natural history, and fate after transplantation. Nephrol Dial Transplant 1997; 12: 81–6
Kabanda A, Jadoul M, Lauwerys R, et al. Low molecular weight proteinuria in Chinese herbs nephropathy. Kidney Int 1995; 48: 1571–6
Nortier JL, Deschodt-Lanckman MM, Simon S, et al. Proximal tubular injury in Chinese herbs nephropathy: monitoring by neutral endopeptidase enzymuria. Kidney Int 1997; 51: 288–93
Martinez MC, Nortier J, Vereerstraeten P, et al. Progression rate of Chinese herb nephropathy: impact of Aristolochia fangchi ingested dose. Nephrol Dial Transplant 2002; 17: 408–12
Vanherweghem JL, Abramowicz D, Tielemans C, et al. Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis: a pilot study in Chinese herbs nephropathy. Am J Kidney Dis 1996; 27: 209–15
Depierreux M, Van Damme B, Vanden Houte K, et al. Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 1994; 24: 172–80
Cosyns JP, Jadoul M, Squifflet JP, et al. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999; 33: 1011–7
Nortier JL, Muniz Martinez MC, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi ). N Engl J Med 2000; 342: 1686–92
Cosyns JP, Jadoul M, Squifflet JP, et al. Urothelial malignancy in nephropathy due to Chinese herbs [letter]. Lancet 1994; 344: 188
Vanherweghem JL, Tielemans C, Simon J, et al. Chinese herbs nephropathy and renal pelvic carcinoma. Nephrol Dial Transplant 1995; 10: 270–3
Cosyns JP, Dehoux JP, Guiot Y, et al. Chronic aristolochic acid toxicity in rabbits: a model of Chinese herbs nephropathy? Kidney Int 2001; 59: 2164–73
De Broe ME, Elseviers MM. Analgesic nephropathy. N Engl J Med 1998; 338: 446–52
Duggin GG. Combination analgesic-induced kidney disease: the Australian experience. Am J Kidney Dis 1996; 28(1 Suppl.): 39S–47S
Olsen S. Histopathology of drug and toxin induced kidney lesions. Zentralbl Allg Pathol 1986; 132: 365–83
Elseviers MM, De Broe ME. Combination analgesic involvement in the pathogenesis of analgesic nephropathy: the European perspective. Am J Kidney Dis 1996; 28(1 Suppl.): 48S–55S
Mccredie M, Stewart JH, Carter JJ, et al. Phenacetin and papillary necrosis: independent risk factors for renal pelvic cancer. Kidney Int 1986; 30: 81–4
Blohme I, Johansson S. Renal pelvic neoplasms and atypical urothelium in patients with end-stage analgesic nephropathy. Kidney Int 1981; 20: 671–5
Vogt P, Frei U, Repp H, et al. Malignant tumours in renal transplant recipients receiving cyclosporin: survey of 598 first kidney transplantations. Nephrol Dial Transplant 1990; 5: 282–8
Polenakovic MH, Stefanovic V. Balkan nephropathy. In: Cameron JS, Davison AM, Grünfeld JP, et al., editors. Oxford textbook of clinical nephrology. 2nd ed. New York (NY): Oxford University Press, 1998: 1203–10
Hrabar A, Ceovic S, Aleraj B, et al. Relationship of anemia to Balkan endemic nephropathy. Kidney Int 1991; 40(34 Suppl.): 44S–5S
Raicevic S, Trnacevic S, Hranisavljevic J, et al. Renal function, protein excretion and pathology of Balkan endemic nephropathy: II. Protein excretion. Kidney Int 1991; 40(34 Suppl.): 52S–6S
Stefanovic V. Balkan endemic nephropathy: a need for novel etiological approaches. Q J Med 1998; 91: 457–63
Ferluga D, Hvala A, Vizjak A, et al. Renal function, protein excretion, and pathology of Balkan endemic nephropathy: III. Light and electron microscopic studies. Kidney Int 1991; 40(34 Suppl.): 57S–67S
Petrinska-Venkovska S. Morphologic aspect of endemic nephropathy in Bulgaria. In: Puchlev A, Popov N, Astrug A, et al., editors. International Symposium on Endemic Nephropathy. Sofia: Bulgarian Academy of Sciences Press, 1965: 95–104
Hall III PW, Dammin GJ, Griggs RC, et al. Investigation of chronic endemic nephropathy in Yugoslavia: II. Renal pathology. Am J Med 1965; 39: 210–7
Hall III PW, Dammin GJ. Balkan nephropathy. Nephron 1978; 22: 281–300
Sindjic M. Rezultati autopsijskih i biopsijskih istrazivanjá bubreznih promena u obolelih od endemske nephropatijè. [Doktorska teza]. Beograd: Medicinskom Fakultetu Univerze u Beogradu, 1981
Hall III PW, Dammin GJ. Balkan nephropathy. In: Tisher CG, Brenner BM, editors. Renal pathology with clinical and functional correlations. Philadelphia: JB Lippincott, 1989: 913–24
Ferluga D, Hvala A, Vizjak A, et al. Hantaan nephropathy (HN) and Balkan endemic nephropathy (BEN): tubulointerstitial or vascular renal disease? [abstract]. Pathol Res Pract 1991; 187: 686
Danilovic V, Djurisic M, Mokranjac M, et al. Néphrites chroniques provoquées par l’intoxication au plomb par voie digestive (farine). Presse Med 1957; 65: 2039–40
Cukuranovic R, Ignjatovic M, Stefanovic V. Urinary tract tumours and Balkan nephropathy in the south Morava river basin. Kidney Int 1991; 40(34 Suppl.): 80S–4S
Sindjic M, Calic-Perisic N, Velimirovic D, Anojcic B. Renal vascular changes and their possible role in the pathogenesis and morphogenesis of endemic Balkan nephropathy. In: Strahinjic S, Stefanovic V, editors. Endemic (Balkan) nephropathy. Proceedings of the 4th Symposium on Endemic (Balkan) Nephropathy, Nis: Univ Nis, 1979: 113–22
Mengs U, Stotzem CD. Renal toxicity of aristolochic acid in rats as an example of nephrotoxicity testing in routine toxicology. Arch Toxicol 1993; 67: 307–11
Mengs U. Tumour induction in mice following exposure to aristolochic acid. Arch Toxicol 1988; 61: 504–5
Robisch G, Schimmer O, Göggelmann W. Aristolochic acid is a direct mutagen in Salmonella typhimurium. Mutat Res 1982; 105: 201–4
Maier P, Schawalder HP, Weibel B, et al. Aristolochic acid induces 6-thioguanine-resistant mutants in an extrahepatic tissue in rats after oral application. Mutat Res 1985; 143: 143–8
Frei H, Würgler FE, Juon H, et al. Aristolochic acid is mutagenic and recombinogenic in Drosophila Genotoxicity Test. Arch Toxicol 1985; 56: 158–66
Schmeiser HH, Pool BL, Wiessler M. Mutagenicity of the two main components of commercially available carcinogenic aristolochic acid in Salmonella typhimurium. Cancer Lett 1984; 23: 97–101
Ivic M. The problem of etiology of endemic nephropathy. Acta Fac Med Naiss 1970; 1: 29–37
Stefanovic V, Polenakovic MH. Balkan nephropathy: kidney disease beyond the Balkans? Am J Nephrol 1991; 11: 1–11
Arlt VM, Ferluga D, Stiborova M, et al. Is aristolochic acid a risk factor for Balkan endemic nephropathy-associated urothelial cancer? Int J Cancer 2002; 101: 500–2
Colson CR, De Greef KE, Duymelinck C, et al. Role of serotonin in the development of Chinese herbs nephropathy [abstract]. Nephrol Dial Transplant 1999; 14(4 Suppl.): 16S
Mcintyre M. Chinese herbs: risk, side effects and poisoning: the case for objective reporting and analysis reveals serious misinterpretation. J Altern Complement Med 1998; 4: 15–6
Malak J. Chinese herb nephropathy is not a (dex)fenfluramine nephropathy but a serotonin nephropathy. J Altern Complement Med 1998; 4: 131–2
Arlt VM, Pfohl-Leszkowicz A, Cosyns JP, et al. Analyses of DNA adducts formed by ochratoxin A and aristolochic acid in patients with Chinese herbs nephropathy. Mutat Res 2001; 494: 143–50
But PPH. Need for correct identification of herbs in herbal poisoning [letter]. Lancet 1993; 341: 637
Van Haelen M, Vanhaelen-Fastre R, But P, et al. Identification of aristolochic acid in Chinese herbs [letter]. Lancet 1994; 343: 174
Debelle FD, Nortier JL, De Prez EG, et al. Aristolochic acids induce chronic renal failure with interstitial fibrosis in salt-depleted rats. J Am Soc Nephrol 2002; 13: 431–6
De Smet PAGM. Aristolochia species. In: De Smet PAGM, Keller K, Hänsel R, et al, editors. Adverse effects of herbal drugs. Berlin: Springer-Verlag, 1992: 79–89
Stiborova M, Frei E, Breuer A, et al. Aristolactam Ia metabolite of aristolochic acid I upon activation forms an adduct found in DNA of patients with Chinese herbs nephropathy. Exp Toxicol Pathol 1999; 51: 421–7
Pailer M, Belohlav L, Simonitsch E. Zur Konstitution der Aristolochiasäuren. Monatsh Chem 1955; 86: 676–80
Pailer M, Bergthaller P, Schaden G. Über die Isolierung und Charakterisierung von vier neuen Aristolochiasäuren (aus Aristolochia clematitis L.). Monatsh Chem 1965; 96: 863–83
Pailer M, Bergthaller P. Die Konstitution der Aristolochiasäuren III und IIIa. Monatsh Chem 1966; 97: 484–93
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. Carcinogenesis 1997; 18: 1063–7
Cosyns JP, Goebbels RM, Liberton V, et al. Chinese herbs nephropathy-associated slimming regimen induces tumours in the forestomach but no interstitial nephropathy in rats. Arch Toxicol 1998; 72: 738–43
Krumbiegel G, Hallensleben J, Mennicke WH, et al. Studies on the metabolism of aristolochic acids I and II. Xenobiotica 1987; 17: 981–91
Rücker G, Chung BS. Aristolochic acids from Aristolochia manshuriensis. Planta Med 1975; 27: 68–71
Rosenmund H, Reichstein T. Zur Kenntnis der Aristolochiasäure. Pharm Acta Helv 1943; 18: 243–61
Pailer M, Belohlav L, Simonitsch E. Pflanzliche Naturstoffe mit einer Nitrogruppe. I. Die Konstitution der Aristolochiasäure. Monatsh Chem 1956; 87: 249–68
Kupchan SM, Doskotch RW. Tumor inhibitors: I. Aristolochic acid, the active principle of Aristolochia indica. J Med Pharm Chem 1962; 5: 657–9
Möse JR, Porta J. Weitere Studien über Aristolochiasäure. Drug Res 1974; 24: 52–4
Kluthe R, Vogt A, Batsford S. Doppelblindstudie zur Beeinflussung der Phagozytosefähigkeit von Granulozyten durch Aristolochiasäure. Drug Res 1982; 32: 443–5
Arlt VM, Stiborova M, Schmeiser H. Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis 2002; 17: 265–77
Mehes J, Decsi L, Varga F, et al. Selektive chemische Ausschaltung der Harnkanälchen. I. Ordnung bei Kaninchen. Naunyn-Schmiedeberg’s Arch Exp Path u Pharmak 1958; 234: 548–65
Jackson L, Kofman S, Weiss A, et al. Aristolochic acid (NSC-50413): phase I clinical study. Cancer Chemother Rep 1964; 42: 35–7
Mengs U. Acute toxicity of aristolochic acid in rodents. Arch Toxicol 1987; 59: 328–31
Arlt VM, Wiessler M, Schmeiser HH. Using polymerase arrest to detect DNA binding specificity of aristolochic acid in the mouse H-ras gene. Carcinogenesis 2000; 21: 235–42
Stiborova M, Fernando RC, Schmeiser HH, et al. Characterization of DNA adducts formed by aristolochic acids in the target organ (forestomach) of rats by 32P-postlabelling analysis using different chromatographic procedures. Carcinogenesis 1994; 15: 1187–92
Pfau W, Schmeiser HH, Wiessler M. Aristolochic acid binds covalently to the exocyclic amino group of purine nucleotides in DNA. Carcinogenesis 1990; 11: 313–9
Schmeiser HH, Frei E, Wiessler M, et al. Comparison of DNA adduct formation by aristolochic acids in various in vitro activation systems by 32P-post-labelling: evidence for reductive activation by peroxidases. Carcinogenesis 1997; 18: 1055–62
Fernando RC, Schmeiser HH, Scherf HR, et al. Formation and persistence of specific purine DNA adducts by 32P-post-labelling in target and non-target organs of rats treated with aristolochic acid I. IARC Sci Publ 1993; 124: 167–71
Schmeiser HH, Bieler CA, Wiessler M, et al. Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy. Cancer Res 1996; 56: 2025–8
Schmeiser HH, Janssen JW, Lyons J, et al. Aristolochic acid activates ras genes in rat tumors at deoxyadenosine residues. Cancer Res 1990; 50: 5464–9
Broschard TH, Wiessler M, Von Der Lieth CW, et al. Translesional synthesis on DNA templates containing site-specifically placed deoxyadenosine and deoxyguanosine adducts formed by the plant carcinogen aristolochic acid. Carcinogenesis 1994; 15: 2331–40
Arlt VM, Schmeiser HH, Pfeifer GP. Sequence-specific detection of aristolochic acid-DNA adducts in the human p53 gene by terminal transferase-dependent PCR. Carcinogenesis 2001; 22: 133–40
Olivier M, Eeles R, Hollstein M, et al. The IARC TP53 Database (R6, January 2002): new online mutation analysis and recommendations to users. Hum Mutat 2002; 19: 607–14
Taniere P, Martel-Planche G, Saurin JC, et al. TP53 mutations, amplification of P63 and expression of cell cycle proteins in squamous cell carcinoma of the oesophagus from a low incidence area in Western Europe. Br J Cancer 2001; 85: 721–6
Broschard TH, Wiessler M, Schmeiser HH. Effect of site-specifically located aristolochic acid DNA adducts on in vitro DNA syntheses by human DNA polymerase α. Cancer Lett 1995; 98: 47–56
Zheng F, Zhang X, Huang Q. Establishment of model of aristolochic acid-induced chronic renal interstitial fibrosis in rats. Zhonghua Yi Xue Za Zhi 2001; 81: 1095–100
Lebeau C, Arlt VM, Schmeiser HH, et al. Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cells. Kidney Int 2001; 60: 1332–42
Morrissey JJ, Ishidoya S, McCracke R, et al. The effect of ACE inhibitors on the expression of matrix genes and the role of p53 and p21 (WAF1) in experimental renal fibrosis. Kidney Int 1996; 49(54 Suppl.): 83S–7S
Tanaka A, Nishida R, Maeda K, et al. Chinese herb nephropathy in Japan presents adult-onset Fanconi syndrome: could different components of aristolochic acids cause a different type of Chinese herb nephropathy? Clin Nephrol 2000; 53: 301–6
Yang SS, Chu P, Lin MS, et al. Two clinical variants of Chineseherb nephropathy: case reports and review of the literature. J Med Sci 2001; 21: 217–24
Yang SS, Chu P, Lin YF, et al. Aristolochic acid-induced Fanconi’s syndrome and nephropathy presenting as hypokalemic paralysis. Am J Kidney Dis 2002; 39: E14
Tanaka A, Nishida R, Yoshida T, et al. Outbreak of Chinese herb nephropathy in Japan: are there any differences from Belgium? Intern Med 2001; 40: 296–300
Ubara Y, Hara S, Kobayasi M, et al. A case of Chinese herbs-induced renal interstitial fibrosis associated with fibrosis of salivary glands. Am J Kidney Dis 1999; 33: E6
Krumme B, Endmeir R, Vanhaelen M, et al. Reversible Fanconi syndrome after ingestion of a Chinese herbal ‘remedy’ containing aristolochic acid. Nephrol Dial Transplant 2001; 16: 400–2
van Ypersele de Strihou C. Médecine douce, médecine innocente? Nephrologie 1998; 19: 5–6
Vanherweghem JL. Nephropathy and herbal medicine. Am J Kidney Dis 2000; 35: 330–2
Gillerot G, Jadoul M, Arlt VM, et al. Aristolochic acid nephropathy in a Chinese patient: time to abandon the term ‘Chinese herbs nephropathy’? Am J Kidney Dis 2001; 38: E26
Lord GM, Tagore R, Cook T, et al. Nephropathy caused by Chinese herbs in the UK. Lancet 1999; 354: 481–2
Lord GM, Cook T, Arlt VM, et al. Urothelial malignant disease and Chinese herbal nephropathy. Lancet 2001; 358: 1515–6
Chen HY, Ma B-Y, Grant A, et al. Time to abandon the term ‘Chinese herbs nephropathy’ Kidney Int 2001; 60: 2039–40
Solez K, Daugirdas J, Gregory MC, et al. Is ‘Chinese herbs nephropathy’ a prejudicial term [letter]. Kidney Int 2001; 38: 1141–2
Cosyns JP. When is ‘aristolochic acid nephropathy’ more accurate than ‘Chinese herbs nephropathy’? Kidney Int 2002; 61: 1178–81
van Ypersele de Strihou C. Chinese herbs nephropathy or the evils of nature. Am J Kidney Dis 1998; 32: 1–1ii
Kanaan N, Cosyns JP, Jadoul M, et al. The importance of a histology-based diagnosis of interstitial nephropathy in two patients with renal insufficiency. Nephrol Dial Transplant. In press.
Vanherweghem JL. Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium (Chinese herbs nephropathy). J Altern Complement Med 1998; 4: 9–13
Wolf CR. Individuality in cytochrome P450 expression and its association with the nephrotoxic and carcinogenic effects of chemicals. IARC Sci Publ 1991; 115: 281–7
Li X, Yang L, Yu Y. An analysis of the clinical and pathological characteristics of Mu-Tong (a Chinese herb) induced tubulointerstitial nephropathy. Chin J Intern Med 2001; 40: 681–7
Nishimagi E, Kawaguchi Y, Terai C, et al. Progressive interstitial renal fibrosis due to Chinese herbs in a patient with calcinosis Raynaud esophageal sclerodactyly telangiectasia (CREST) syndrome. Intern Med 2001; 40: 1059–63
Pena JM, Borras M, Ramos J, et al. Rapidly progressive interstitial renal fibrosis due to a chronic intake of a herb (Aristolochia pistolochia) infusion. Nephrol Dial Transplant 1996; 11: 1359–60
Vanherweghem JL, Cuykens JJ, Vandenbergh Ph, et al. Valvular heart disease and Chinese-herb nephropathy [letter]. Lancet 1998; 351: 991
Pourrat J, Montastruc JL, Lacombe L, et al. Néphropathie associée à des herbes chinoises 2 cas [abstract]. Presse Med 1994; 23: 1669
Stengel B, Jones E. Insuffisance rénale terminale associée à la consommation d’herbes chinoises en France. Néphrologie 1998; 19: 15–20
Cronin AJ, Maidment G, Cook T, et al. Aristolochic acid as a causative factor in a case of Chinese herbal nephropathy. Nephrol Dial Transplant 2002; 17: 524–5
Chen W, Chen Y, Li A. The clinical and pathological manifestations of aristolochic acid nephropathy: the report of 58 cases. Zhonghua Yi Xue Za Zhi 2001; 81: 1101–5
Tanaka A, Nishida R, Sawai K, et al. Traditional remedy-induced Chinese herbs nephropathy showing rapid deterioration of renal function. Jpn J Nephrol 1997; 39: 794–7
Tanaka A, Shinkai S, Kasuno K, et al. Chinese herbs nephropathy in the Kansai area: a warning report. Jpn J Nephrol 1997; 39: 438–40
Ng YY, Yu S, Chen TW, et al. Interstitial renal fibrosis in a young woman: association with a Chinese preparation given for irregular menses. Nephrol Dial Transplant 1998; 13: 2115–7
Yang CS, Lin CH, Chang SH, et al. Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs. Am J Kidney Dis 2000; 35: 313–8
Chang CH, Wang YM, Yang AH, et al. Rapidly progressive interstitial renal fibrosis associated with Chinese herbal medications. Am J Nephrol 2001; 21: 441–8
Kessler DA. Cancer and herbs. N Engl J Med 2000; 342: 1742–3
Acknowledgements
The author thanks Professor C. van Ypersele de Strihou for helpful comments, Dr C. de Burbure for the revision of the manuscript, Mrs R.M. Goebbels for technical assistance and Mr S. Lagasse for preparing the photographs.
This research has not been supported by public or private grants. The author has no potential conflict of interest that is directly relevant to the content of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cosyns, JP. Aristolochic Acid and ‘Chinese Herbs Nephropathy’. Drug-Safety 26, 33–48 (2003). https://doi.org/10.2165/00002018-200326010-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-200326010-00004