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Amanita Poisonings Resulting in Acute, Reversible Renal Failure: New Cases, New Toxic Amanita Mushrooms
Amanita Poisonings Resulting in Acute, Reversible Renal Failure: New Cases, New Toxic Amanita Mushrooms
Original Article
Martin Kirchmair1,*, Patrı́cia Carrilho2,*, Rudi Pfab3, Bettina Haberl3, Joana Felgueiras2,
Fernanda Carvalho4, José Cardoso5, Ireneia Melo5, José Vinhas2 and Sigrid Neuhauser1
1
Institute of Microbiology, Leopold-Franzens-University of Innsbruck, Innsbruck, Austria, 2Centro Hospitalar de Setubal, Rua Camilo
Castelo Branco, Setubal, Portugal, 3Toxikologische Abt., 2. Med. Klinik, Klinikum rechts der Isar, Technische Universität München,
Abstract Introduction
Background. Renal failure as a consequence of eating
mushrooms has been reported repeatedly after ingestion of Collecting wild mushrooms for food has been a long-
webcaps of the Cortinarius orellanus group. But mushrooms standing tradition in many European countries; however,
of the genus Amanita can also cause renal failure: Amanita edible and toxic species are often confused. Although every
smithiana (North America) and Amanita proxima (Mediterra- ‘mushroom hunters’ guide’ warns its readers against collect-
nean area). Here, we discuss poisonings caused by other white ing unknown or not well-known fungi, several ‘old wives’
amanitas. A German and—independently—two Portuguese tales’ like testing the fruiting bodies with a silver spoon or
patients reported the ingestion of completely white mush- checking for insect damage are still used to distinguish edi-
rooms with ring. Similar to intoxications with A. smithiana
ble and poisonous mushrooms. These practices together
or A. proxima, the clinical picture was characterized by nausea
with tasting unknown edible mushrooms can lead to severe
and vomiting 10–12 h after ingestion, severe acute renal fail-
mushroom poisonings because (i) macro-fungi can hardly
ure and mild hepatitis. Renal biopsy showed acute interstitial
be reliably identified by comparing pictures in a field guide
nephritis and tubular necrosis. Two patients were given
with specimens from the wild, (ii) the ‘gastronomic value’ of
temporary haemodialysis. All have fully recovered their renal
function. Poisonings caused by mushrooms containing the rarer species is often not known and therefore (iii) new
toxin of A. smithiana were suspected. We tested 20 Amanita poisonous species are discovered occasionally such as those
species for the presence of this toxin. described here.
Methods. Thin layer chromatography was applied to detect The fungal genus Amanita is divided into seven sections
A. smithiana nephrotoxin in herbarium specimens using [1]. Mushrooms belonging to the sections Caesareae (Caesar’s
authentic material of A. smithiana as reference. Amanita: Amanita caesaria) and Vaginatae (grisette) are
Results. A. smithiana toxin could be detected in Amanita edible. Poisonous species can be found in all other sections
boudieri, Amanita gracilior and in Amanita echinocephala. of the genus (Table 1). The death caps (Amanita phalloides,
A. boudieri was collected by the Portuguese patients. A. Amanita virosa; section Phalloideae) contain hepatotoxic
echinocephala is the only nephrotoxic Amanita growing cyclopeptides (amatoxins, phalloidin) and cause fulminant
North of the Alps and is suspected to be the cause of renal hepatical and renal failures that are, if at all, treatable only
failure in the German patient. No A. smithiana toxin was symptomatically [2]. The section Amanita contains the quin-
detectable in the nephrotoxic A. proxima. tessential toadstool Amanita muscaria (fly agaric). Toxic
Conclusions. A. boudieri, A. gracilior and A. echinoce- species of the section Amanita contain the neurotoxins
phala are nephrotoxic. These intoxications are clinically ibotenic acid and muscimol. In the section Validae, slightly
similar to that of A. smithiana, with acute reversible renal toxic mushrooms containing bufotenine and/or haemolytic
failure and mild hepatitis but are different in their clinical toxins can be found (false death cap: Amanita citrina, [3]). In
picture from Orellanus syndrome characterized by a sections Lepidella and Amidella, edible and nephrotoxic
delayed onset of severe and often irreversible renal failure. fungi are known. Among the genus Amanita, the North
American Lepidella Amantia smithiana [4–11] and the
Keywords: Amanita boudieri; Amanita echinocephala; mushroom Mediterranean Amidella Amantia proxima are repeatedly
intoxication; thin layer chromatography; toxicology reported to be nephrotoxic [12–17]. Nevertheless, in
Europe, Amanita poisonings resulting in renal failure are
rare. Most severe renal failures can be traced back to
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2 M. Kirchmair et al.
Table 1. Occurrence of Amanita smithiana toxin, amatoxins and allenic norleucine (2-amino-4,5-hexadienoic acid) in Amanita species
2-amino-4,5-hexadienoic
Symptomsa A. smithiana toxin Amatoxins/Phallotoxinsb acidc
Section Lepidella
A. abrupta (h) – – 1
A. boudieri n 1 –
A. chlorinosma g – –
A. echinocephala n 1 –
A. gracilior (n) 1 –
A. singeri n.k. – –
A. smithiana n 1 – 1
A. strobiliformis e – –
A. virgineoidesd n
A. vittatini e – –
Section Amidella
A. lepiotoides (e) – –
A. ovoidea e – –
A. neoovoidead n 1
ingestion of poisonous webcaps (Cortinarius spp., Section NCL 1960): IB 2010/0020 (Austria) IB 1998/0504 (Austria). Amanita vag-
Orellani; [20, 21]). The Portuguese and German patients re- inata (Bull.) Lam.: IB 2005/0647 (Italy). Amanita vittatini (Mor.) Sacc.: IB
1998/0766 (Spain), IB 1998/0830 (Spain).
ported to have eaten mushrooms resembling white Amanita
species. The symptoms were similar to intoxications with A. Thin layer chromatography (TLC)
smithiana or A. proxima but these species could be excluded as
Dried basidiomata (0.1 g) were ground and suspended in 1 mL 50% watery
discussed below. It became evident that there are more neph- methanol for 30 min. This raw extract was filtered through filter paper
rotoxic mushrooms than is currently known. Motivated by (Macherey–Nagel Mn 615¼) and 2 lL were spotted onto TLC plates (silica
these cases, we tested 20 Amanita species for the presence gel 60, Merck 105721) or HPTLC plates (high performance TLC plates;
of the A. smithiana nephrotoxin. silica gel 60, Merck 105631). Chromatograms were developed using meth-
anol–isopropanol–water–acetic acid–acetic acetate (5:8:12:15:40) as solvent
system [22]. The A.smithiana toxin was detected by spraying developed
TLC plates with a ninhydrine solution, Ehrlich reagent, Morgan–Elson
Materials and methods reagent or anisic aldehyde sulphuric acid according to [23] (Table 2). As
reference for the A. smithiana toxin, a raw extract of voucher material of A.
Material examined smithiana [22] was used because the toxin of A. smithiana is not fully
Amanita abrupta Peck: IB 2000/0537 (NC). Amanita boudieri Barla: determined and therefore no purified toxin is available. The toxin of A.
LISU n. 211410 (Portugal). Amanita chlorinosma (Peck) Lloyd: IB smithiana can be detected at an Rf of 0.44 and stains orange–red with
2000/0506 (NC). A. citrina Pers.: no voucher material (Italy). Amanita ninhydrine reagent, yellow with anisic aldehyde—sulphuric acid and yellow
echinocephala (Vitt.) Quel. (¼ Amanita solitaria sensu auct. mult.): IB with Morgan–Elson reagent [24]. The detection of amatoxins and phalloidine
2001/0264 (Italy); IB 1977/0203 (France, Provence); IB 1995/1093 (Aus- was carried out according to [25]: 2 lL fruiting body extract were spotted onto
tria); IB 2010/0110 (Italy). Amanita gemmata (Fr.) Bertill: LISU n. TLC plates (silica gel 60, Merck 105721) using 2-butoxyethanol-25% watery
211411 (Portugal). Amanita gracilior Bas: IB 1996/0255 (France). Ama- ammonium hydroxide (7:3) plus 0.2% v/v cinnamic aldehyde as solvent
nita lepiotoides Barla ss. Gilbert, Cetto: IB 1979/0869 (Italy); IB 1980/ system. Amatoxins can be detected as violet spots at Rf ¼ 0.39 (a-amanitin)
0861 (Italy). A. lepiotoides Barla: IB 1978/0561 (Italy); IB 1977/0311 or Rf ¼ 0.33 (ß-amanitin) after exposing the chromatogram to HCl vapour.
(Italy); IB 1977/0180 (Italy); IB 1976/0480 (Italy). A. muscaria (L.) Lam.
IB 2002/0161 (Austria). Amanita ovoidea (Bull.: Fr.) Quel.: IB 1982/0532
(France); IB 1972/0476 (Israel); MA-Fungi 53355 (Spain); MA-Fungi Results
68917 (Spain). A. phalloides (Vaill.) Secr: IB 2007/0350 (Austria). A. prox-
ima Dumée: MA-Fungi 74268 (Spain), MA-Fungi 69238 (Spain). Amanita
rubescens (Pers. ex Fr.) SF Gray: IB 2005/0624 (Italy). Amanita singeri Bas: Case reports
IB 1986/0540 (Italy). A. smithiana Bas (¼ A. solitaria sensu Hotson 1936):
IB 1995/0357 (OR). IB1991/0995 (OR, voucher material of Pelizzari et al. Portugal. A 51-year-old woman and her 47-year-old
[22]). Amanita strobiliformis (Paulet ex Vittad.) Bertill. (¼ A. solitaria sensu husband, previously healthy, collected mushrooms in a
Amanita poisonings resulting in renal failure 3
Table 2. Spray reagents for TLC [23]
small forest, near Lisbon, in Portugal in April 2010. They evaluation. He was also found to have significant renal
had two consecutive mushroom meals (dinner and next impairment (BUN 50.0 mg dL1, creatinine 8.6 mg
day’s lunch), ingesting ~500 g of mushrooms in total. The dL1) and mild elevations of ALT (69 U L1) and as-
woman complained about anorexia, nausea and vomiting the partate aminotransferase (AST) (32 U L1). Leucocytes
next day. Five days later, as the complaints still persisted and count 7800 lL1. Urinalysis revealed pH 5.5, density
she additionally noticed weakness and a reduction of diure- 1020, trace proteins and some erythrocytes and rare leu-
sis, she went to hospital. On admission, she was normoten- cocytes. Other laboratory tests were normal. His physical
sive, apparently euvolaemic, afebrile, without relevant examination was unremarkable. He was not given dialysis.
findings on physical examination. Initial laboratory tests re- Treatment as described above with prednisone and oral N-
vealed severe renal failure with creatinine 11.7 mg dL1 acetylcysteine was initiated. On the fourth day of admis-
(normal: <1.2), blood urea nitrogen (BUN) 68.18 mg sion, a biopsy of his left kidney was made (Figure 1a and
dL1 (<18) and a mild hepatic cytolysis with elevation of b). It showed marked focal interstitial lymphocytic infil-
alanine aminotransferase (ALT) 64 U L1 (10–35). Urine trate with areas of tubular necrosis. The glomeruli ap-
analysis revealed density 1010, pH 5.5, trace blood and peared normal, apart from one ischaemic glomerulus.
protein. Urine microscopy showed >75 white blood cells Arterioles were normal. Immunofluorescence for immu-
lL1, 10 red blood cells lL1 and no casts. No pathogens noglobulin deposits and complement was negative. These
were detectable in urine or stool. Renal ultrasound showed aspects were compatible with acute interstitial nephritis.
the left kidney to be 123 mm in length and the right kidney His renal function improved, with serum creatinine of
122 mm. Both were echogenic with prominent renal 4.5mg dL1 at day 10 after ingestion of mushrooms.
pyramids and no hydronephrosis. No pathogens grew on Two months later, his serum creatinine was 0.8 mg dL1.
culture of urine or stool. After discharge, the patients re-collected some mush-
Haemodialysis was initiated, through a temporary right rooms at the original place. Specimens were identified at
internal jugular vein dialysis catheter. On the presumption the Botanic Garden (NMNH) of Lisbon University as A.
that they had eaten an orellanine-containing mushroom, ther- boudieri (Figure 2a) and A. gemmata. Later, staff from the
apy was started with antioxidant and steroids, as suggested Botanic Garden accompanied the patients to the field and
by Kilner et al. [26]. The patient was started on prednisolone asked them to point at the mushrooms they had picked.
60 mg once a day and oral N-acetylcysteine 600 mg every Again, the same two species were collected.
6 h. Her renal function improved over the course of the next
days, and she became independent of dialysis 5 days after
admission (10 days after mushroom ingestion; BUN 45.02 Germany. A 55-year-old hitherto healthy woman, native
mg dL1 and a creatinine of 2.2 mg dL1). After 2 months, of Italy, was admitted to a Munich hospital, October 1997,
her BUN was 15.9 mg dL1 and creatinine 1.0 mg dL1. 48 h after a meal of ~500 g fresh mushrooms. She had
The patient’s 47-year-old husband, who had ingested a collected the mushrooms herself in a public park near
smaller amount of the mushroom meals, had mild dyspepsia Munich and sautéed them well before eating. She described
and anorexia, and he did not spontaneously seek for medical the mushrooms as white with a flaked hat, white gills, a
help. He was asked to be submitted to clinical and laboratory white ring and a bulb. She claimed to have eaten this type
4 M. Kirchmair et al.
of mushroom all her life and tested its edibility with a silver examination after 4 weeks showed normal renal and liver
spoon that did not turn black. Starting 6 h after the meal, function tests but no improvement of her visus.
she suffered nausea, vomiting and diarrhoea ~10 h after The cause of the renal failure remained unclear as the
the meal. Orellanus syndrome had to be excluded because of the
As the vomiting did not stop the day after the mushroom negative biopsy sample, the early onset of symptoms and
meal, she was admitted to hospital. There she also com- the fact that the patient ate white mushrooms only (Cortinarius
plained about visual disturbances. Her physical examination orellanus and Cortinarius rubellus are brown). The two white
showed no pathologies except for a slight hypertension (160/ mushrooms that are known to cause similar symptoms—the
90 mmHg) and dry mucous membranes. The first laboratory North American Amanita smithiana and the strict Mediterra-
tests showed normal liver function tests except for bilirubine nean A. proxima—do not grow around Munich but there are
2.3 mg dL1 but an acute renal failure with creatinine 5.2 mg records of A. echinocephala (Figure 2b; [27])—a mushroom
dL1; BUN 48 mg dL1. Other laboratory findings included shown to contain a nephrotoxin in this paper.
lactate dehydrogenase 326 U L1 (<240), C-reactive protein
2.3 mg dL1 (<0.5), potassium 2.01 mmol L1 (3.5–5.0), Detection of A. smithiana toxin in voucher material
leucocytes 12 500 lL1 (400–9000). At the time of admit- of Amanita species
tance, the diarrhoea and vomiting had stopped, but she soon
developed renal failure with preserved water diuresis, mild The toxin of A. smithiana is detectable applying the TLC
proteinuria (0.66 g1) with a tubular protein pattern. Tests for system described above at an Rf of 0.44, stains orange red
anti-nuclear antibodies, extractable nuclear antigen, anti-neu- with ninhydrine and yellow with Morgan–Elson and
trophil cytoplasmic antibody, circulating immunocomplexes, Ehrlich reagent [22,24]. The spot at Rf ¼ 0.4 of extracts
C3-complement, puumula- and hanta-virus were negative. of voucher material used to identify the A. smithiana toxin
A renal biopsy was performed 4 days after the meal and by Pelizzari et al. [22] showed identical reactions. Fruiting
showed massive tubular necrosis with eosinophil casts in body extracts of all A. smithiana collections, A. gracilior, A.
the tubular lumina a minimal lymphphocytic infiltration of boudieri and A. echinocephala reacted like the A. smithiana
the interstitium. No signs of vascular or glomerular damage voucher material (Figure 2c). All these species are closely
were seen. The type of renal lesion may be typical for a toxic related and belong to the section Lepidella. In extracts of the
damage. A kidney biopsy specimen was tested for the pres- edible Lepidella A. strobiliformis, the toxin was not detectable.
ence of orellanine according to Rohrmoser et al. [21]. No The A. smithiana toxin was not detectable in the nephrotoxic
orellanine was detected. The renal function deteriorated so A. proxima, a species of section Amidella and in any other
four sessions of haemodialysis were necessary until the renal species investigated in this study.
function fully recovered within 20 days after the meal. Amatoxins and phalloidin could be detected only in A.
Already at admittance, the patient had reported visual phalloides.
disturbances, which did not improve despite the complete
recovery of the renal failure. An ophthalmologic examina-
tion showed a regular ocular fundus and regular anterior Discussion
chamber. The functional tests revealed a total loss of colour
vision and defects in the upper visual fields in both eyes, Several Amanita spp. of the section Lepidella are known to
fitting for a toxic atrophy of the optic nerve. A follow-up cause renal failure including the North American
Amanita poisonings resulting in renal failure 5
A. smithiana, which is the best known among these neph- cytolysis 5 days after ingestion of the mushrooms. The
rotoxic species [4–11]. The symptoms of our patients con- mushrooms responsible for the intoxication could be iden-
form to those known from A. smithiana intoxications tified as A. boudieri by examining mushrooms re-collected
(Table 3). These symptoms start with nausea and vomiting by the patients. The A. smithiana toxin could be detected in
2–12 h (average 6 h) after the mushroom meal. Renal fail- the dried fruiting bodies. The patient from Germany
ure occurs 2–6 days (average 3.5 days) after ingestion. exhibited similar symptoms as the Portuguese patients.
Patients receive supportive treatment, usually requiring Although from this case, no leftovers were available for
temporary haemodialysis, but their prognosis is good. Sim- examination—it is very likely that A. echinocephala was
ilar symptoms are reported after ingestion of North and the cause of this poisoning. Fruiting bodies of A. echino-
Middle American Amanita thiersii and Amanita nauseosa cephala contain A. smithiana toxin. It is the only white
(both section Lepidella, [1]). There is also a report of renal Lepidella known to occur around Munich [27].
failure after eating Amanita virgineoides [28], although this In contrast to all reported cases of poisonings with
mushroom is sold on Chinese markets [1]. In a case of acute A. smithiana, the German patient suffered from visual dis-
renal failure from Taiwan, a fungus morphologically sim- orders, a symptom that has been reported before only once
ilar to A. smithiana was eaten [29]: 6 h after their meal, the in connection with mushroom poisoning [30]. The authors
two patients suffered abdominal pain, nausea and vomiting. report on an A. phalloides intoxication and discussed inter
One patient became anuric a few days later. Also, the second alia, and thereby provoked taurine depletion as possible
patient developed a minor renal disorder obvious by slightly cause of the visual impairment. The actual significance to
increased creatinine but no haemodialysis was necessary. our case remains speculative as we did not test the amino
Both patients recovered fully. acid levels of the patient.
Until now, no nephrotoxic European species of section Renal failure can also be caused by Amanita spp. section
Lepidella has been identified. The Portuguese patients had Amidella. Most intoxications are reported from Southern
symptoms characterized by reversible severe acute renal Europe where A. proxima can be confused with the mor-
failure due to acute interstitial nephritis and mild hepatic phologically very similar, edible A. ovoidea [12–17].
6 M. Kirchmair et al.
Table 3. Mushroom intoxications accompanied by renal failure (data summarized from [8,10,13–17,31])
Besides the darker volva of A. proxima, the two species are In the hepatotoxic (but not nephrotoxic) A. abrupta [38], the
nearly indistinguishable in their macroscopically and mi- allenic norleucine was detected, but the A. smithiana toxin
croscopically morphological characters. Spores of both could not be detected in our study. The exact nature of
species are elliptical and similar in size. A ‘tennis racket A. smithiana toxin remains unclear. The toxin reacts with
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