å¡ CASE REPORT å¡

Delayed Onset Acute Renal Failure Associated with pseudoporphyria HongoIngestion Yoichi IWAFUCHI, Takashi MORITA*, Hideyuki KOBAYASHI, Kensaku KASUGA, Kazuhisa ITO, Osamu NAKAGAWA,Kaoru KUNISADA, Shigeru MlYAZAKI** and Akira KAMIMURA

Abstract smithiana. A 66-year-old manwith diabetes developed acute renal Case History failure after ingestion of Amanita pseudoporphyria Hon- go. Laboratory data showed acute nonoliguric renal fail- In October 2000, a 66-year-old man was admitted; he had ure. A renal biopsy showed acute tubular necrosis with been well until several days before admission when he no- glomerular minor abnormalities. He received hemodialy- ticed general fatigue, facial edema and appetite loss. Six sis treatment for 3 weeks and his renal function normal- months before admission his renal function was normal and ized 2 months after admission. Wediscuss the differences urinary protein was negative. Twoweeks before admission in acute renal failure caused by possible toxins of he picked two mushroomsof Amanita pseudoporphyria Amanita pseudoporphyria Hongo from that caused by Hongo (Fig. 1) with other absolutely edible and other poisonous mushrooms. ate them. Nobody else ate the except for him. He (Internal Medicine 42: 78-81, 2003) was aware of severe fatigue from the following day, but there were no severe gastointestinal symptoms.Onthe day Key words: acute renal failure, Amanita pseudoporphyria of admission, he was seen by a physician and pretibial edema Hongo, mushroompoisoning, nephrotoxin, alle- and renal failure (creatinine 18.0 mg/dl) were pointed out. nic norleucine (2-amino-4, 5-hexadienoic acid) He had a ten-year history of diabetes, and he had taken glibenclamide for five years, but recently he had not taken any other drugs before the occurrence of the abnormal find- ings. Introduction On examination his blood pressure was 186/80 mmHg, pulse 82/min, temperature was 37.4°C. He had gained 5 kg Severe acute renal failure caused by mushroompoisoning in weight in the previous four weeks. Hewas not anemic nor is rare in Japan. Nephrotoxicity is most commonlyreported icteric. His heart and lungs were normal, and lymph nodes due to poisoning in Japan as well as in and were not palpable. Noexanthema was observed but moderate North America. In Europe delayed onset renal failure caused peripheral edema was present. No neurological abnormalities by orellanine poisoning has also been reported. Recently in werenoted. the Pacific Northwest, Amanitasmithiana has been reported Urinalysis showed a 1+ test for protein, a 1+ test for glu- to contain other nephrotoxinsand several cases of acute renal cose and a 1+ test for occult blood; sediment showed 3-5 failure have been reported following ingestion of the mush- erythrocytes, 3-5 leukocytes, and 5-10 hyaline casts per room. Amanita smithiana is possibly being mistaken for the high-power field. Urinary protein was 0.2 g/24 hour and glu- popular matsutake, or " mushroom"Tricholoma magni- cose was 1.5 g/24 hour. The urine p2 microglobulin level velare, to which it bears a superficial resemblance. was 20,640 mg/dl. Stool and urine cultures were negative. Wedescribe the first case report with delayed onset acute Hematocrit was 36.2%, the hemoglobin concentration was renal failure after ingestion of Amanita pseudoporphyria 13.5 g/dl; the platelet count was 157,000/mm3, and the leuko- Hongo that contains the same nephrotoxin as Amanita cyte count was 9,200/mm3.The serum urea nitrogen level

From the Department of Internal Medicine, Koseiren Sanjo General Hospital, Sanjo, *the Department of Pathology, Shinrakuen Hospital, Niigata and **the Department of Internal Medicine, Center, Shinrakuen Hospital, Niigata Received for publication June 17, 2002; Accepted for publication December 2, 2002 Reprint requests should be addressed to Dr. Yoichi Iwafuchi, the Department of Internal Medicine, Koseiren Sanjo General Hospital, 5-1-62 Tsukanome, Sanjo 955-0055

78 Internal Medicine Vol. 42, No. 1 (January 2003) ARFDue to MushroomPoisoning %

.Xt

\1

Figure 2. Renal biopsy reveals prominent tubulointestial le- sions as shown at higher magnification in Fig. 3. A glomeruli appears normal (Periodic acid-silver methenamine stain, x60). Figure 1. Amanita pseudoporphyria Hongo: the mushroomsthat the patient ingested. hospital day, a renal biopsy was performed to elucidate the cause of acute renal failure. Renal histology revealed was 148.7 mg/dl, creatinine, 16.48 mg/dl; uric acid, 8.0 tubulointerstitial lesions and glomerular minor abnormalities. mg/dl; total protein, 6.9 g/dl; and albumin, 4.0 g/dl. The Someproximal tubular cells were vacuolated and the nuclei serumaspartate aminotransferase level was17 IU/Z; alanine were pycnotic. A mitotic figure was also found. In some di- aminotransferase, 37 IU/Z; lactate dehydrogenase, 1,123 IU/Z; lated tubules epithelial cells were stripped off, and the alkaline phosphatase, 166 IU/Z; P-glutamyltranspeptidase, 1 8 lumina were filled with cellular debris. Patchy interstitial cel- IU/Z; and creatine phosphokinase, 459 IU/Z. The serum lular infiltrates, either polynuclear or mononuclear cells were myoglobin level was 496 ng/ml and the urinary myoglobin observed (Figs. 2, 3). level was 980 ng/ml. The serum sodium level was 124 At that time a diagnosis of acute renal failure due to acute mmol/Z, potassium, 6.8 mmol/Z; and chloride, 81 mmol/Z. The tubular necrosis was made. Although rhabdomyolysis ex- glycosylated hemoglobin Ale level was 7.8%. The C reac- isted, it was mild, and not considered as the main cause of tive protein level was 1.87 mg/dl; immunogloblin (Ig) G, renal failure. From the findings of the renal biopsy he had 1,308 mg/dl; IgA, 219 mg/dl; IgM, 84 mg/dl and ferritin, 131 not undertaken steroid therapy. He received homodialysis ng/ml. The total complement level was 74.9 IU/Z; C3, 123 treatment three times a week during the following three mg/dl; and C4, 36 mg/dl. Rheumatoid factor, antistreptolysin weeks. Urine output was over 1,000 ml/24 hour during his O, B virus surface antigen, hepatitis C virus anti- admission and the creatinine level improved rapidly. Onthe body, human immunodeficiency virus antibody, antinuclear antibody and antineutrophil cytoplasmic antibody were all negative. Anarterial blood sample in room air disclosed that the partial oxygen pressure level was 101.9 mmHg;partial dioxide carbon pressure, 19.3 mmHg; HCO3, 9.3 mmol/Z and pH 7.293. There were no cryoglobulin in the serum. The / prothrombin time and activated thromboplastin time were both normal. There were no abnormal findings in ECG. His chest X-ray showed mild cardiomegaly. On computed tomography, slight swelling of the kidneys was observed (longitudinal axis: 12.5 cm). Simple type of diabetic retino- pathy was present. was started on the day of admission. He is 'V** à"å ."- passably conversant with mushrooms. Whenshown a picture of the type of mushroom he ate (Fig. 1) he told us ingestion of Amanita pseudoporphyria Hongo would be poisonous. Other causes, such as and drug use, could not be Figure 3. Interstitial cell infiltration is observed near a dilated found, so wesuspected that acute renal failure was caused by stripped tubule filled with cellular debris (D). Some tubular ingestion of Amanita pseudoporphyria Hongo. As his clini- cells are vacuolated (one of them is indicated by an arrow) (HE cal course was atypical for mushroompoisoning, on the 6th stain, x260).

Internal Medicine Vol. 42, No. 1 (January 2003) 79 Iwafuchi et al

23rd hospital day the patient was discharged without any Table 1. Selected Poisonous Mushrooms and Their Toxins subjective symptoms.Weobserved himat the out-patient de- (1-6) partment; his creatinine level normalized 2 months after ad- Genus and species Toxins mission (creatinine 0.9 mg/dl). I. Cyclopeptide-containing mushrooms Discussion * * The clinical course, laboratory findings and renal histo- Amanita phalloides * logical findings of this patient led to a diagnosis of acute species renal failure due to acute tubular necrosis associated with Lepiota species II. Monomethylhydrazine-containing mushrooms Amanita pseudoporphyria Hongo ingestion. Gyromitra species Monomethlhydrazine Mushroomcollecting is popular in Japan and sometimes III. -containing mushrooms mild mushroompoisoning is reported. Severe acute renal Amanitamuscaria Muscarine failure associated with mushroomingestion is very rare, but Amanita pantherina some kinds of nephrotoxins have been reported (Table 1). Clitocybe dealbata Somecases of acute renal failure associated with amatoxin- Cliocybe dilatata producing mushrooms, such as Amanita virosa, Amanita Cliocybe illudens verna, Amanita phalloides, Galerina species and Lepiota Most species species, have been reported in Japan, Europe and North IV. Coprine-containing mushrooms America (1, 2). Especially Amanita phalloides is known as Coprinus atramentarius Coprine "the death cap", which causes severe illness of the and V. Ibotenic acid- and -containing mushrooms renal failure. This type of organ failure is very severe, with Ibotenic acid a mortality rate of more than 50% (1, 2). In addition Muscimol Amanita pantherina orellanine intoxication has also been reported associated with VI. Psilocybin-containing mushrooms acute renal failure in Europe and Japan (1, 2). Orellanine is caerulipes Psilocybin in the genus Cortinarius, such as Cortinarius speciosissimus Psilocybe cubensis Psilocin (3, 4) Cortinarius orellanus (5) and Cortinarius orellanoides spectabilis (6). Renal failure associated with orellanine has a relatively Psathyrella foenisecii late onset and is severe, often oliguric and improves within VII. Diverse gasrtointestinal toxins a few weeks in 50-70% of cases. Chlorophyllum molybdites Diverse, mostly unknown Recently several cases of poisoning due to Amanita Clitocybe Kebularis smithiana {-Amanita solitaria) have been reported in the Chlorophyllum esculentum Lactarius spesies Pacific Northwest (7-9). First Tulloss and Lidgren reported Paxillus involutus five cases of Amanita smithiana poisoning (7). Two patients VIII. Orelline- and orellanine-containing mushrooms developed acute renal failure and hemodialysis was required Cortinarius orellanus Orelline* for both patients, and one developed both renal and mild Cortinarius speciosissimus Orellanine* . Leathern et al (8) and Warden et al (9) reported Cortinarius orellanoides four cases in which the initial symptoms, such as , IX. Allenic norleucin-containing mushrooms , and dizziness, appeared within 20 minutes Amanita smithiana Allenic norleucine* to 12 hours, and renal failure within 1-6 days after ingestion. Amanita peudoporphyria Hongo Liver damageof these cases was relatively mild and only one of 13 patients fell into mild transient liver failure (7), ( *nephrotoxin). and four of them showed no signs of liver injury. This obser- vation differed from classical amatoxin poisoning which is the mechanismof whythis type of renal failure associated mainly characterized by pronounced liver damage and from with allenic norleucine was delayed is unknown. orellanine poisoning which shows a muchlonger latency pe- On the other hand, Hatanaka reported that allenic norleu- riod of 2-17 days. Amanita smithiana contains allenic cine is isolated from Amanita pseudoporphyria Hongo (13), norleucine (2-amino-4,5-hexadienoic acid) and chloro- which is the same mushroom as in the present case. crotylglycine (10, 1 1) but no amatoxins. Chilton et al proved Although Amanita pseudoporphyria Hongo and Amanita that allenic norleucine is toxic to guinea pigs at doses begin- smithiana belong to the same genus as Amanita phalloides, ning with 33 mg/kg body weight when injected intra- they do not contain any amatoxins (7-9, 13). So ingestion of peritoneally and ascertained to be lethal at a dose of 100 Amanita pseudoporphyria Hongopossibly leads to allenic mg/kg body weight (10). Pelizarri et al reported that when norleucine-induced delayed onset acute renal failure. Such tested in various renal epithelial tissue cultures, allenic relatively delayed onset acute renal failure without severe norleucine caused damage that was morphologically similar liver damage may be characteristic findings of allenic to that produced after Amanita smithiana ingestion (12). But norleucine-associated poisoning. In the present case, the

80 Internal Medicine Vol. 42, No. 1 (January 2003) ARFDue to MushroomPoisoning occurrence of acute renal failure was relatively delayed in needed. comparison with cases of amatoxins, and liver injury was not present. But the exact onset of renal failure is obscure; if our References patient visited a physician as soon as he felt abnormal, renal failure might have been found earlier. Such findings are 1) Gold frank LR. Mushrooms: toxic and hallucinogenic, in: Goldfrank's Toxicologic Emergencies. Gold frank TR, Ed. Appleton & Lange, similar to those of Amanita smithiana poisoning. But in our Norwalk, Conn, 1994: 951-962. case gastrointestinal symptomswere not clear and the period 2) Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J. Diagnosis and from mushroomingestion to hospitalization was longer in Treatment of HumanPoisoning, in: Ellenhorn's Medical Toxicology. comparison with Amanita smithiana poisoning. The differ- Williams & Wilkins, Baltimore, 1997: 1880-1896. 3) Short AI, Watling R, MacDonald MK, Robson JS. Poisoning by ences may be based on age, existence of diabetes, amount of Cortinarius speciosissimus. Lancet 2: 942-944, 1980. the ingested and other toxins contained in addition to 4) Holzl B, Regele H, Kirchmair M, Sandhofer F. Acute renal failure after allenic norleucine. Since there are very few cases reported, ingestion of Cortinarius speciocissimus. Clin Nephrol 48: 260-262, the typical clinical course of this toxic mushroomis still un- 1997. clear, so future cases need to be studied. Renal pathologic 5) Bouget J, Bousser J, Pats B, et al. Acute renal failure following collec- tive intoxication by Cortinarius orellanus. Intensive Care Med16: changes in cases of amatoxins or orellanine poisoning are tu- 506-510, 1990. bular necrosis prominent in the proximal tubules with inter- 6) Benjamin DR. Mushrooms: and Panaceas, in: A Handbook for stitial edema without glomerular changes (4, 5, 14, 15), but Naturalists, Mycologists, and Physicians. W. H. Freeman, NewYork, in the reported cases of Amanita smithiana poisoning renal 1995: 242-263. biopsies were not performed. To our knowledge this is the 7) Tulloss RE, Lindgren JE. Amanita smithiana-, distribution first renal biopsy case of acute renal failure associated with and poisonings. Mycotaxon 45: 373-387, 1992. suspected allenic norleucine poisoning. In our case patho- 8) Leathern AM, Purssell RA, Chan VR, Kroeger PD. Renal failure caused by . J Toxicol Clin Toxicol 35: 67-75, logical changes similar to those of amatoxins or orellanine 1997. poisoning were observed, but it is unclear whether those 9) Warden CR, Benjamin DR. Acute renal failure associated with sus- were the typical renal pathological findings associated with pected Amanita smithiana mushroomingestions: a case series. Acad allenic norluecine poisoning or not. Emerg Med 5: 808-812, 1998. 10) Chilton WS, Tsou G, De Cato L, Malone MH. The unsaturated Acute renal failure caused by allenic norleucine poisoning norleucines of Amanita solitaria. Chemical and pharmacological stud- apparently has a relatively delayed onset, so illness may be ies. Lloydia 36: 169-173, 1973. thought to be due to unknownorigin or pure dehydration due ll) Chilton WS, Ott J. Toxic metabolites of Amanita pantherina, A. to acute gastroenteritis, and the mushroomingestion maygo cothurnata, A. muscaria and other Amanita species. Lloydia 39: 150- unnoticed. For diagnosis of such cases it is important to 157, 1976. question the patient with acute renal failure of uncertain 12) Pelizzari V, Feifel E, Rohrmoser MM,Gstraunthaler G, Moser M. Partial purification and characterization of a toxic component of cause about recent conditions including dietary history. Amanita smithiana. Mycologia 86: 555-560, 1994. Amanita pseudoporphyria Hongogrows on the ground in 13) Hatanaka S. Identification of 2-amino-4,5-hexadienoic acid from forests with broad leaf trees in the summerand autumn in Amanita pseudoporphyria Hongo. Lloydia 38: 273-274, 1975. Japan, but acute renal failure associated with this mushroom 14) Beaudreuil S, Sharobeem R, Maitre F, Karsenti D, Grezard O, Pierre D. has not yet been sufficiently recognized. It is unclear [Kidney toxicity of Amanita phalloides. A case with kidney needle bi- opsy.] Toxicite renale de l'amanite phalloide. Une observation avec whether or not this mushroomgrows in other countries, but ponction biopsie renale. Presse Med 27: 1434, 1998 (in French). ingestion of this mushroommaylead to acute renal failure as 15) Fineschi V, Di Paolo M, Centini F. Histological criteria for diagnosis well as Amanita smithiana, thus further information on its of Amanita phalloides poisoning. J Forensic Sci 41: 429-432, 1996. toxicities and risks to medical and mycological institutions is

Internal Medicine Vol. 42, No. 1 (January 2003) 81