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Nephrotoxic Mushroom Poisoning: Global Epidemiology, Clinical Manifestations, and Management

Published:October 07, 2021DOI:https://doi.org/10.1016/j.wem.2021.09.002
      Because mushroom poisonings are increasing worldwide after ingestions of known, newly described, and formerly considered edible species, the objectives of this review are to describe the global epidemiology of nephrotoxic mushroom poisonings, to identify nephrotoxic mushrooms, to present a toxidromic approach to earlier diagnoses of nephrotoxic mushroom poisonings based on the onset of acute renal failure, and to compare the outcomes of renal replacement management strategies. Internet search engines were queried with the keywords to identify scientific articles on nephrotoxic mushroom poisonings and their management during the period of 1957 to the present. Although hepatotoxic, amatoxin-containing mushrooms cause most mushroom poisonings and fatalities, nephrotoxic mushrooms, most commonly Cortinarius species, can cause acute renal insufficiency and failure. Several new species of nephrotoxic mushrooms have been identified, including Amanita proxima and Tricholoma equestre in Europe and Amanita smithiana in the United States and Canada. In addition, the edible, hallucinogenic mushroom Psilocybe cubensis has been noted recently via mass spectrometry as a rare cause of acute renal insufficiency. Renal replacement therapies including hemodialysis are often indicated in the management of nephrotoxic mushroom poisonings, with renal transplantation reserved for extracorporeal treatment failures.

      Keywords

      Introduction

      Increasing Mushroom Poisonings

      Mushroom poisonings are increasing worldwide today for many reasons, including novices mistaking poisonous species for edible ones, recent immigrants mistaking poisonous species for edible ones back home, and adolescents mistaking poisonous species for hallucinogenic ones.
      • Diaz J.H.
      Mistaken mushroom poisonings.
      • Beug M.W.
      Mushroom poisoning in North America.
      • Taylor J.
      • Holzbauer S.M.
      • Wanduragala D.
      • Ivaskovic A.
      • Spinosa R.
      • Smith K.
      • et al.
      Acute intoxications from consumption of Amanita muscaria mushrooms—Minnesota, 2018.
      • Schwartz R.H.
      • Smith D.E.
      Hallucinogenic mushrooms.
      • Hallock R.M.
      • Dean A.
      • Knecht Z.A.
      • Spencer J.
      • Taverna E.C.
      A survey of hallucinogenic mushroom use, factors related to use, and perceptions of use among college students.
      • Brandenburg W.E.
      • Ward K.J.
      Mushroom poisoning epidemiology in the United States.
      The American Mycological Association and the US Centers for Disease Control and Prevention have warned clinicians that mushroom intoxications continue to occur among newly arrived migrant groups accustomed to foraging for edible mushrooms in their home countries who are not familiar with local mushroom ecology.
      • Beug M.W.
      Mushroom poisoning in North America.
      ,
      • Taylor J.
      • Holzbauer S.M.
      • Wanduragala D.
      • Ivaskovic A.
      • Spinosa R.
      • Smith K.
      • et al.
      Acute intoxications from consumption of Amanita muscaria mushrooms—Minnesota, 2018.
      In addition to the risk factors for mushroom poisoning noted among novices and recent immigrants, the recreational ingestion of hallucinogenic mushrooms has become a popular form of substance abuse among adolescents and young adults that can also result in mistaking poisonous mushrooms for hallucinogenic ones.
      • Schwartz R.H.
      • Smith D.E.
      Hallucinogenic mushrooms.
      ,
      • Hallock R.M.
      • Dean A.
      • Knecht Z.A.
      • Spencer J.
      • Taverna E.C.
      A survey of hallucinogenic mushroom use, factors related to use, and perceptions of use among college students.
      Among 174 adolescents previously identified as substance abusers, 45 (26%) reported having ingested psilocybin-containing hallucinogenic mushrooms, often in conjunction with alcohol and other drugs.
      • Schwartz R.H.
      • Smith D.E.
      Hallucinogenic mushrooms.
      In a 2012 survey study of 882 randomly selected college students, 30% of the 409 responders reported having ingested hallucinogenic mushrooms (mean number of ingestions 3.4; mode 1) on several occasions.
      • Hallock R.M.
      • Dean A.
      • Knecht Z.A.
      • Spencer J.
      • Taverna E.C.
      A survey of hallucinogenic mushroom use, factors related to use, and perceptions of use among college students.

      Nephrotoxic Mushroom Poisonings

      Recently, several new species of Amanita mushrooms have been identified as nephrotoxic, including A proxima in Europe, A smithiana in Canada and the United States, A pseudoporphyria in Japan, and A punctata in Korea.
      • Leray H.
      • Canaud B.
      • Andary C.
      • Klouche K.
      • Beraud J.J.
      • Mion C.
      Amanita proxima poisoning: a new cause of renal insufficiency.
      • DeHaro L.
      • Jouglard J.
      • Arditti J.
      • David J.M.
      Acute renal insufficiency caused by Amanita proxima poisoning: experience of the Poison Center of Marseille.
      • Kirchmair M.
      • Carrilho P.
      • Pfab R.
      • Haberl B.
      • Felgueiras J.
      • Carvalho F.
      • et al.
      Amanita poisonings resulting in acute, reversible renal failure: new cases, new toxic Amanita mushrooms.
      • Warden C.R.
      • Benjamin D.R.
      Acute renal failure associated with suspected Amanita smithiana ingestions: a case series.
      • West P.L.
      • Lindgren J.
      • Horowitz B.Z.
      Amanita smithiana mushroom ingestion: a case of delayed renal failure and literature review.
      • Iwafuchi Y.A.
      • Morita T.
      • Kobayashi H.
      • Kesuga K.
      • Ito K.
      • Nakagawa O.
      • et al.
      Delayed onset acute renal failure associated with Amanita pseudoporphyria Hongo ingestion.
      • Kang E.A.
      • Cheong K.-Y.
      • Lee M.-J.
      • Kim S.
      • Shin G.-T.
      • Kim H.
      • et al.
      Severe but reversible acute kidney injury resulting from Amanita punctata poisoning.
      Prior case reports have also suggested, without any laboratory confirmation, that acute renal failure could result from the consumption of hallucinogenic Psilocybe species mushrooms.
      • Raff E.
      • Halloran P.F.
      • Kjellstrand C.M.
      Renal failure after eating “magic” mushrooms.
      ,
      • Franz M.
      • Regele H.
      • Kirchmair M.
      • Kletzmayr J.
      • Sunder-Plassman G.
      • Horl W.H.
      • et al.
      Magic mushrooms: hope for a “cheap” high resulting in end-stage renal failure.
      In 2019, a case of acute kidney injury was reported after consumption of edible, hallucinogenic Psilocybe cubensis mushrooms from a psychedelic mushroom “grow kit” purchased online.
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      A sample from the crop of P cubensis mushrooms consumed in this case was noted via mass spectrometry to contain the hallucinogenic toxin psilocin.
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      In addition to directly nephrotoxic mushrooms, newly recognized myotoxic mushrooms can cause rhabdomyolysis with massive myoglobin release that may indirectly cause acute kidney injury, including the formerly considered edible Tricholoma equestre in Europe and Russula subnigricans in China.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      • Matsura M.
      • Kato S.
      • Saikawa Y.
      • Nakata M.
      • Hashimoto K.
      Identification of cyclopropylacetyl-(R)-carnitine, a unique chemical marker of the fatally toxic mushroom Russula subnigricans.
      Because mushroom poisonings are increasing worldwide after ingestions of known, newly described, and formerly considered edible species, the objectives of this review are to describe the global epidemiology of nephrotoxic mushroom poisonings, to identify nephrotoxic mushrooms, to present a toxidromic approach to earlier diagnoses of nephrotoxic mushroom poisonings based on the onset of acute renal failure, and to compare the frequencies and outcomes of renal replacement management strategies.

      Search Strategy

      Internet search engines and databases including PubMed, Google Scholar, Google, and Ovid Medline were queried with the keywords as medical subject headings to identify scientific articles on nephrotoxic mushroom poisonings and their treatments and outcomes during the search period, 1957 to present. The keywords included mushrooms, poisonous, nephrotoxic; Amanita, poisonous, nephrotoxic; Cortinarius, poisonous, nephrotoxic; orellanus syndrome, orellanine; and allenic norleucine.
      The articles selected to meet the first objective to identify nephrotoxic mushroom species included case reports, case series, and review articles on nephrotoxic mushroom poisonings. The articles selected to meet the second and third objectives to present a toxidromic approach to earlier diagnoses and to compare the frequencies and outcomes of renal replacement treatment strategies included observational studies, retrospective descriptive and analytical epidemiologic studies, and toxicologic investigations. Articles excluded from review included letters to the editor, dispatches, opinion-editorial articles, clinical-pathological case conferences, and abstracts of posters presented at conferences and scientific meetings. These selection methodologies met all recommended criteria for narrative reviews, including use of several keywords, use of 2 or more Internet search engines, a defined study period, and article inclusion and exclusion criteria.
      • Murphy C.M.
      Writing an effective review article.

      The Global Epidemiology of Nephrotoxic Mushroom Poisonings and the Initial Identification of Nephrotoxic Mushrooms

      Nephrotoxic Cortinarius Mushrooms

      Nephrotoxicity and mortality after ingestion of Cortinarius species mushrooms was initially described in Poland in 1957 in a series of 102 cases of acute renal failure with 11 fatalities in patients who had consumed cooked Cortinarius orellanus mushrooms.
      • Grzymala S.
      Massemvergiftungen durch den orangefuchsigen Hautkopf.
      By 1962, Polish investigators had isolated a crude extract from C orellanus, which was named orellanine and which caused renal toxicity when administered orally to experimental animals.
      • Grzymala S.
      L’isolement de l’orellanine poison du Cortinarius orellanis Fries et l’etude de ses effets anatomo-pathologigues.
      In 1990, French investigators reported a case series of 26 healthy young men who developed acute renal failure after ingesting a mushroom soup made with C orellanus.
      • Bouget J.
      • Bousser J.
      • Pats B.
      • Ramee M.P.
      • Chevet D.
      • Rifle G.
      • et al.
      Acute renal failure following collective intoxication by Cortinarius orellanus.
      All patients were hospitalized within 10 to 12 d of ingestion, with 12 patients presenting in acute renal failure with acute tubulointerstitial nephritis on renal biopsy.
      • Bouget J.
      • Bousser J.
      • Pats B.
      • Ramee M.P.
      • Chevet D.
      • Rifle G.
      • et al.
      Acute renal failure following collective intoxication by Cortinarius orellanus.
      Among these 12 patients, 8 required hemodialysis and recovered rapidly.
      • Bouget J.
      • Bousser J.
      • Pats B.
      • Ramee M.P.
      • Chevet D.
      • Rifle G.
      • et al.
      Acute renal failure following collective intoxication by Cortinarius orellanus.
      The remaining 4 patients developed chronic renal failure lasting for months and ultimately required kidney transplants.
      • Bouget J.
      • Bousser J.
      • Pats B.
      • Ramee M.P.
      • Chevet D.
      • Rifle G.
      • et al.
      Acute renal failure following collective intoxication by Cortinarius orellanus.
      Of the remaining 14 patients, 12 developed leukocyturia, and all 12 had normal renal function at 1-y follow-up.
      • Bouget J.
      • Bousser J.
      • Pats B.
      • Ramee M.P.
      • Chevet D.
      • Rifle G.
      • et al.
      Acute renal failure following collective intoxication by Cortinarius orellanus.
      Another group of investigators later followed 12 of the 26 men who had developed renal failure for a period of 13 y after ingestion of the C orellanus mushroom soup.
      • Duvic C.
      • Hertig A.
      • Herody M.
      • Dot J.M.
      • Didelot F.
      • Giudicelli C.P.
      • et al.
      Acute renal failure following ingestion of Cortinarius orellanus in 12 patients. Initial presentation and progress over a period of 13 years.
      Of these 12 patients, 7 recovered normal renal function, 4 underwent kidney transplant for chronic renal failure, and 1 patient on hemodialysis died in a car accident.
      • Duvic C.
      • Hertig A.
      • Herody M.
      • Dot J.M.
      • Didelot F.
      • Giudicelli C.P.
      • et al.
      Acute renal failure following ingestion of Cortinarius orellanus in 12 patients. Initial presentation and progress over a period of 13 years.
      Investigators estimated the incidence of acute renal failure after C orellanus ingestion to range from 30 to 46% depending on individual sensitivity, pre-existing nephropathy, and the cumulated dose of nephrotoxin ingested.
      • Duvic C.
      • Hertig A.
      • Herody M.
      • Dot J.M.
      • Didelot F.
      • Giudicelli C.P.
      • et al.
      Acute renal failure following ingestion of Cortinarius orellanus in 12 patients. Initial presentation and progress over a period of 13 years.
      Investigators also noted that renal failure regressed progressively over several months in 60% of cases.
      • Duvic C.
      • Hertig A.
      • Herody M.
      • Dot J.M.
      • Didelot F.
      • Giudicelli C.P.
      • et al.
      Acute renal failure following ingestion of Cortinarius orellanus in 12 patients. Initial presentation and progress over a period of 13 years.
      Although most Cortinarius poisonings to date have been reported from Poland and France, Cortinarius species mushrooms are widely distributed in the coniferous forests of the Scandinavian countries, Britain, the United States, Canada, and Australia.
      • Holmdahl J.
      • Blohme I.
      Renal transplantations after Cortinarius speciosissimus poisoning.
      In 1995, Swedish investigators reported a case series of 22 patients who were poisoned after consuming cooked C speciosissimus mushrooms during the period of 1979 to 1993 (Figure 1).
      • Holmdahl J.
      • Blohme I.
      Renal transplantations after Cortinarius speciosissimus poisoning.
      Nine patients developed chronic renal failure, and 5 patients required kidney transplants.
      • Holmdahl J.
      • Blohme I.
      Renal transplantations after Cortinarius speciosissimus poisoning.
      Three of these patients underwent transplantation after up to 6 mo of hemodialysis.
      • Holmdahl J.
      • Blohme I.
      Renal transplantations after Cortinarius speciosissimus poisoning.
      Two patients who did regain some renal function restarted hemodialysis 24 and 30 mo later and received kidney transplants.
      • Holmdahl J.
      • Blohme I.
      Renal transplantations after Cortinarius speciosissimus poisoning.
      The investigators concluded that delayed renal failure could follow partial renal recovery by many years and that renal transplantation could guarantee successful outcomes even years after mushroom poisonings.
      • Holmdahl J.
      • Blohme I.
      Renal transplantations after Cortinarius speciosissimus poisoning.
      Figure 1
      Figure 1Cortinarius orellanus has a large orange to rusty brown cap with gills underneath connected to a thick stem without a ring or annulus. It contains highly nephrotoxic orellanine compounds. Source: Wikimedia Commons (public domain). Photographer: Michael 11. Available at https://en.wikipedia.org/wiki/Orellani#/media/File:Corellanus.jpg.

      Nephrotoxic Amanita Mushrooms

      In 1994, French investigators were the first to report 5 cases of acute renal insufficiency after consumption of cooked A proxima mushrooms that were most likely mistaken for the edible Amanita species A ovoidae, which shares the same habitat.
      • Leray H.
      • Canaud B.
      • Andary C.
      • Klouche K.
      • Beraud J.J.
      • Mion C.
      Amanita proxima poisoning: a new cause of renal insufficiency.
      Temporary hemodialysis was required in 4 of the 5 cases, and all patients recovered quickly, with normal renal and hepatic function restored by 3 wk.
      • Leray H.
      • Canaud B.
      • Andary C.
      • Klouche K.
      • Beraud J.J.
      • Mion C.
      Amanita proxima poisoning: a new cause of renal insufficiency.
      In 1998, Canadian investigators in British Columbia reported 4 cases of renal failure in patients who had consumed cooked A smithiana mushrooms and developed gastrointestinal symptoms 5 to 8 h after ingestion (Figure 2).
      • Warden C.R.
      • Benjamin D.R.
      Acute renal failure associated with suspected Amanita smithiana ingestions: a case series.
      One of the patients, an elderly patient with diabetes, presented to an emergency department with renal failure the day after a mushroom meal and required hemodialysis.
      • Warden C.R.
      • Benjamin D.R.
      Acute renal failure associated with suspected Amanita smithiana ingestions: a case series.
      The remaining 3 patients presented to local emergency departments 5 to 6 d after mushroom ingestions and also received supportive care with hemodialysis.
      • Warden C.R.
      • Benjamin D.R.
      Acute renal failure associated with suspected Amanita smithiana ingestions: a case series.
      All patients subsequently regained normal renal function.
      • Warden C.R.
      • Benjamin D.R.
      Acute renal failure associated with suspected Amanita smithiana ingestions: a case series.
      Figure 2
      Figure 2Amanita smithiana is native to the Pacific Northwest of the United States and Canada, where it has been mistaken for the edible pine or matsutake mushroom, Tricholoma magnivalere. It has a large white convex cap with unattached free gills and a thick, shaggy white stem with a torn or absent ring. Source: Wikimedia Commons (public domain). Photographer: Sava Krstic. Available at https://upload.wikimedia.org/wikipedia/commons/8/89/Amanita_smithiana_283102.jpg.
      In 2009, clinicians in Portland, Oregon, reported 4 additional cases of acute renal failure after consumption of cooked A smithiana mushrooms in patients who mistook A smithiana for edible matsutake (Tricholoma matsutake) mushrooms.
      • West P.L.
      • Lindgren J.
      • Horowitz B.Z.
      Amanita smithiana mushroom ingestion: a case of delayed renal failure and literature review.
      All patients presented with gastrointestinal symptoms from 20 min to 12 h after mushroom consumption.
      • West P.L.
      • Lindgren J.
      • Horowitz B.Z.
      Amanita smithiana mushroom ingestion: a case of delayed renal failure and literature review.
      All patients subsequently developed acute renal failure 4 to 6 d post-ingestion, and all received temporary hemodialysis for several weeks before regaining normal renal function.
      • West P.L.
      • Lindgren J.
      • Horowitz B.Z.
      Amanita smithiana mushroom ingestion: a case of delayed renal failure and literature review.
      The laboratory ranges of the presenting serum biomarkers of acute renal failure in these cases included a blood urea nitrogen of 72 to 91 mg‧dL-1 and a creatinine level of 12 to 14 mg‧dL-1.
      • West P.L.
      • Lindgren J.
      • Horowitz B.Z.
      Amanita smithiana mushroom ingestion: a case of delayed renal failure and literature review.
      In addition to A proxima in Europe and A smithiana in North America, delayed onset of acute renal failure was reported from Asia after consumption of other species of Amanita mushrooms, specifically A pseudoporphyria in Japan (2003) and A punctata in Korea (2015).
      • Iwafuchi Y.A.
      • Morita T.
      • Kobayashi H.
      • Kesuga K.
      • Ito K.
      • Nakagawa O.
      • et al.
      Delayed onset acute renal failure associated with Amanita pseudoporphyria Hongo ingestion.
      ,
      • Kang E.A.
      • Cheong K.-Y.
      • Lee M.-J.
      • Kim S.
      • Shin G.-T.
      • Kim H.
      • et al.
      Severe but reversible acute kidney injury resulting from Amanita punctata poisoning.

      Psilocybe Cubensis

      In 2019, the first case of acute kidney injury was reported in a 15-y-old Canadian male who consumed several hallucinogenic P cubensis mushrooms from a psychedelic mushroom “grow kit” purchased online along with 3 of his friends (Figure 3).
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      The suspect mushrooms were identified morphologically by a mycologist, and the serotonergic hallucinogen psilocin was identified by liquid chromatography-mass spectrometry in a sample of the mushroom meal consumed.
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      Figure 3
      Figure 3Psilocybe cubensis hallucinogenic mushrooms cultivated in a home “grow kit” or “grow box” easily purchased online. Source: Wikimedia Commons (public domain). Photographer: Lord Toran. Available at https://commons.wikimedia.iorg/wiki/File:growbox-cubensis,jpg.
      Before identification of the ingested mushrooms, the patient’s initial presentation was consistent with orellanine toxicity after ingestion of Cortinarius mushrooms.
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      However, orellanine was not detected in the mushroom meal sample, and the 3 other boys who ingested mushrooms from the patient’s mushroom meal remained asymptomatic and had normal renal function.
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      In this case, no other cause of acute renal injury was suspected by history or detected by laboratory analyses, including rhabdomyolysis, which was ruled out by normal serum creatine kinase (CK) levels.
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      Hallucinogenic P cubensis mushrooms are frequently consumed recreationally without adverse effects other than negative sensory experiences.
      • Schwartz R.H.
      • Smith D.E.
      Hallucinogenic mushrooms.
      ,
      • Hallock R.M.
      • Dean A.
      • Knecht Z.A.
      • Spencer J.
      • Taverna E.C.
      A survey of hallucinogenic mushroom use, factors related to use, and perceptions of use among college students.
      ,
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      Future case reports and toxicologic studies will be required to document the nephrotoxicity of P cubensis mushrooms.

      Rhabdomyolysis-Causing Mushrooms

      Finally, there are 2 species of myotoxic mushrooms: Tricholoma equestre, first reported as toxic in France in 2001, and Russula subnigricans, first reported as toxic in China in 2015. Both mycotoxins can cause potentially fatal rhabdomyolysis resulting in acute renal failure after consumption.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      • Matsura M.
      • Kato S.
      • Saikawa Y.
      • Nakata M.
      • Hashimoto K.
      Identification of cyclopropylacetyl-(R)-carnitine, a unique chemical marker of the fatally toxic mushroom Russula subnigricans.
      In 2001, French investigators reported 12 cases of delayed rhabdomyolysis with 3 fatalities in patients who had consumed consecutive meals of the edible wild mushroom Tricholoma equestre, harvested from pine forests in coastal southwestern France (Figure 4).
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      After a prodrome of afebrile fatigue and myalgia 24 to 72 h after the last mushroom meal, most (n=8) patients described worsening weakness and stiffness of their legs, accompanied by facial erythema, mild nausea without vomiting, profuse sweating, and darkening urine color over 3 to 4 d.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      Rhabdomyolysis was later confirmed by significantly elevated CK levels without laboratory evidence of cardiac or hepatic injury.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      Muscle biopsy in 6 patients demonstrated histopathologic evidence of acute myopathy.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      In all but 3 of the patients, serum CK levels normalized and most symptoms resolved, but muscular weakness persisted for weeks.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      Figure 4
      Figure 4Tricholoma equestre (synonym T flavovirens), also known as the yellow knight mushroom, has a large flat yellow cap with gills underneath connected to a long thick stem without a ring. T equestre has caused delayed and fatal rhabdomyolysis with acute renal failure. Source: Wikimedia Commons (public domain). Photographer: Matthias Renner. Available at. https://upload.wikimedia.org/wikipedia/commons/8/82/Tricholoma_equestre.jpg.
      In the 3 fatal cases, serum CK levels continued to rise, and all patients developed hyperthermia up to 42°C, cardiac arrhythmias, renal dysfunction (elevated serum creatinine, blood urea nitrogen, and potassium), and cardiovascular collapse.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      Autopsy revealed myocardial lesions identical to the muscle biopsy lesions in 1 patient, renal lesions in 1 patient, and no histopathologic evidence of hepatic damage.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      In 2015, Chinese investigators reported 7 cases of delayed rhabdomyolysis with 1 fatality in a family (age range 18–58 y) who had consumed 1 meal of cooked Russula subnigricans mushrooms harvested from the forests of Guizhou Province in southern China (Figure 5).
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      Twenty hours later, all 7 family members were hospitalized with nausea, vomiting, diarrhea, dizziness, fatigue, and muscle weakness.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      Five patients presented with myalgias in the upper legs.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      No patient was febrile on admission.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      Although serum creatinine and coagulation tests were normal in all patients, serum CK levels were elevated in 6 patients, and all 7 had moderate elevations in serum alanine aminotransferase and aspartate aminotransferase.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      In 4 of the 6 patients with elevated serum CK levels, the CK continued to rise, weakness worsened, and urine color darkened, consistent with rhabdomyolysis.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      All 4 patients received hemodialysis to prevent acute kidney injury, and their serum CK levels began to decline to normal ranges by the third day of hemodialysis.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      In the single fatality, a 50-y-old male, weakness and myalgia with dark urine worsened during the first 12 h after admission, hemodialysis was initiated on the second day after admission, and hyperthermia up to 40°C developed on the third day after admission.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      Cardiac arrhythmias with QRS widening and cardiovascular collapse ensued as the serum CK levels rose to a maximum of 228,750 UL-1 (laboratory normal range 38–174 UL-1), and the patient died 4 d after admission.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      Autopsy was not performed.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      Figure 5
      Figure 5Russula subnigricans mushrooms are native to Asia, with poisonings reported from China, Taiwan, and Japan, where they have been mistaken for edible Russula nigricans mushrooms. R subnigricans has caused delayed and fatal rhabdomyolysis with acute renal failure. Source: Lin et al.
      • Lin S.
      • Mu M.
      • Yang F.
      • Yang C.
      Russula subnigricans poisoning: from gastrointestinal symptoms to rhabdomyolysis.
      In summary, retrospective epidemiologic analyses conducted worldwide have confirmed that nephrotoxic mushrooms can cause both reversible and irreversible acute and delayed-onset renal failure, with some cases progressing to chronic renal failure, and a few species can cause potentially fatal rhabdomyolysis with its indirectly associated risks of renal damage and failure.

      Clinical Manifestations of Nephrotoxic Mushroom Poisoning

      The currently known and suspected nephrotoxic mushroom species stratified by genera are listed in Table 1. The ecologic and morphologic features of nephrotoxic mushrooms and the clinical manifestations of nephrotoxic mushroom poisonings are described in Table 2.
      Table 1Nephrotoxic mushroom species
      CortinariusAmanitaTricholomaRussulaPsilocybe
      C bruneofulvus

      C brunneoincarnata

      C callisteus (suspected)

      C cinnamomeus (suspected)

      C henrici

      C limonius (suspected)

      C ranierensis

      C sanguineus (suspected)

      C speciosissimus (synonym C rubellus)

      C splendens (suspected)
      A boudieri

      A echinocephala

      A gracilor

      A neoovoidea

      A pseudo-porphyria

      A proxima

      A punctata

      A smithiana
      T equestre (synonym T flavovirens)R subnigricansP cubensis
      Table 2Ecology and morphology of nephrotoxic mushroom species and clinical manifestations of poisonings
      Amanita mushroomsCortinarius mushroomsRussula subnigricansTricholoma equestrePsilocybe cubensis
      FamilyAmanitaceaeCortinariaceaeRussulaceaeTricholomataceaeHymenogastraceae
      General descriptionsLarge off-white mushrooms; about 600 species; at least 7 are nephrotoxic; many are edibleLargest mushroom family with 2000–3000 species; at least 8 are nephrotoxic; none are recommended as edible worldwide; more nephrotoxic species likely existA creamy white mushroom native to eastern Asia, where ingestions have resulted in outbreaks of rhabdomyolysis associated with ARFA yellow mushroom also known as the yellow knight; formerly considered edible; rhabdomyolysis-associated nephrotoxicity may follow several mushroom meals; many Tricholoma species are edibleFrequently cultivated for its hallucinogenic effects shortly after ingestion, caused by its primary active serotonergic compound, psilocybin
      Geographic distributionWorldwideWorldwideChina, Japan, Korea, TaiwanWorldwideWorldwide in a semitropical band above and below the equator
      Preferred habitatLeaf and needle litter and decaying wood of coniferous and oak woodlands with chalky (limestone) soilNeedle litter of coniferous woodlands with chalky (limestone) soilLeaf litter of deciduous oak woodlands in mountainous regionsNeedle litter of pine forests with sandy soilMoist, sunny, grassy fields and meadows used for cattle grazing; requires meadow habitats containing cow dung
      Color (adult)Large, white caps that can flatten out from convex to plano-convexLarge orange to rusty brown caps that flatten from convex to flat with ageLarge dull creamy white caps that flatten from convex to flat to concave with ageLarge yellow to yellow-green cap with yellow gillsGolden brown conical to convex cap that flattens with age; gills darken with age
      Color (spore)Rust brownBrownWhiteWhiteDark purple brown
      SmellDescribed as unpleasantSlight radish smellNot distinctiveNot distinctiveDistinctive smell of moist cucumber or watermelon rind
      Distinctive mycologic featuresCap convex to flat with age; free gills; stem (stipe) is shaggy with an easily torn annulus (ring) and a prominent volva (base)Large flat orange to rusty brown caps with gills connected to stems without rings; top of the cap may have a darker umbo (protuberance)Large dull creamy white caps that flatten from convex to flat to an everted umbrella shape with age; gills attached to thick, stems; no annulusLarge yellow to yellow-green cap with yellow gills attached to an even diameter stem without a ringSmall golden brown conical caps that become more convex to flat to slightly everted umbrella shape; dark gills are attached to long, thin stems with a white annulus
      Dimensions (adult)C orellanusA smithianaR subnigricansT equestreP cubensis
      Height, cm6–126–184–107–104–15
      Diameter (cap), cm3–85–175–185–102–8
      Edible species most commonly mistaken forA proxima has been mistaken for edible A ovoidae. A smithiana has been mistaken for edible Tricholoma magnivalere.Cortinarius species mushrooms have been mistaken for edible chanterelles. C speciosissimus (synonym C rubellus) has been mistaken for edible Cratellus tubaeformis and Hygrophorus species.R subnigricans has been mistaken for R nigricans, a less poisonous species that may be consumed.T equestre was formerly considered edible. It has been mistaken for other edible Tricholoma species, such as T aestuans, T auratum, and T sulphureum.Often confused with other Psilocybe species that contain different amounts of psilocybin.
      Clinical toxidromesafter ingestionRapid-onset GI distress in 6–12 h. Lab evidence ARF in <2–4 d.Rapid-onset GI distress in 6–12 h. Lab evidence of ARF in >2–14 d.Delayed-onset GI distress in >24–72 h. Delayed lab evidence of rhabdomyolysis in 3–5 d.Delayed-onset GI distress in >24–72 h. Delayed lab evidence of rhabdomyolysis in 3–5 d.Hallucinations within 20–30 min with facial flushing, mydriasis, tachycardia. Resolves in 4–6 h.
      Associated presenting clinicalfeaturesFever, chills, headache, anorexia, fatigue, abdominal and flank painFever uncommon, oliguria progressing to anuria, abdominal and flank painFever uncommon, dizziness, fatigue, weakness, myalgias in upper legs, vomiting uncommon, darkening urineFever uncommon, weakness and stiffness in lower extremities, facial erythema and edema, profuse sweating, vomiting uncommon, darkening urinePotential for delayed onset of ARF within 36 h that resolves with supportive therapy
      Risk of CRF40%40%20%20%NR
      ARF, acute renal failure; CFR, case fatality rate; CRF, chronic renal failure; GI distress, gastrointestinal distress (nausea, vomiting, diarrhea); NR, not reported.

      Identifying Nephrotoxins in Mushrooms and in Poisoned Patients

      Today, heat-stable nephrotoxins such as orellanine (a tetrahydroxylated-N-oxide bipyridine) in Cortinarius species mushrooms, allenic norleucine (2-amino-4,5-hexadienoic acid) in Amanita species mushrooms, and psilocin in P cubensis mushrooms can be most accurately measured directly in the serum and urine of poisoned patients using immunologic and chromatographic techniques, such as enzyme-linked immunosorbent assay, radioimmunoassay, thin-layer chromatography, high-performance liquid chromatography, and liquid chromatography-mass spectrometry.
      • Leathem A.M.
      • Purssell R.A.
      • Chan V.R.
      • Kroeger P.G.
      Renal failure caused by mushroom poisoning.
      ,
      • Oubrahim H.
      • Richard J.M.
      • Cantin-Esnault D.
      • Seigle-Murandi F.
      • Trécourt F.
      Novel methods for identification and quantification of the mushroom nephrotoxin orellanine. Thin-layer chromatography and electrophoresis screening of mushrooms with electron spin resonance determination of the toxin.
      The mechanisms of orellanine’s toxicity in Cortinarius species mushrooms are unknown but may be the result of an unidentified nephrotoxic metabolite.
      • Oubrahim H.
      • Richard J.M.
      • Cantin-Esnault D.
      • Seigle-Murandi F.
      • Trécourt F.
      Novel methods for identification and quantification of the mushroom nephrotoxin orellanine. Thin-layer chromatography and electrophoresis screening of mushrooms with electron spin resonance determination of the toxin.
      Toxicologists have demonstrated that oxidated orellanine can generate orthosemiquinone anion radicals in vitro that produce oxygen free radicals and deplete glutathione.
      • Oubrahim H.
      • Richard J.M.
      • Cantin-Esnault D.
      • Seigle-Murandi F.
      • Trécourt F.
      Novel methods for identification and quantification of the mushroom nephrotoxin orellanine. Thin-layer chromatography and electrophoresis screening of mushrooms with electron spin resonance determination of the toxin.
      Investigators have postulated that the oxidation of orellanine in the kidneys may result in an accumulation of quinone metabolites that covalently bind to renal tissues and cause cellular damage.
      • Oubrahim H.
      • Richard J.M.
      • Cantin-Esnault D.
      • Seigle-Murandi F.
      • Trécourt F.
      Novel methods for identification and quantification of the mushroom nephrotoxin orellanine. Thin-layer chromatography and electrophoresis screening of mushrooms with electron spin resonance determination of the toxin.
      Portuguese toxicologists used thin-layer chromatography and A smithiana toxin to test several other Amanita species for a suspected nephrotoxin.
      • Kirchmair M.
      • Carrilho P.
      • Pfab R.
      • Haberl B.
      • Felgueiras J.
      • Carvalho F.
      • et al.
      Amanita poisonings resulting in acute, reversible renal failure: new cases, new toxic Amanita mushrooms.
      The A smithiana nephrotoxin, now known as allenic norleucine, was detected in samples of A boudieri, A gracilor, and A echinocephala.
      • Kirchmair M.
      • Carrilho P.
      • Pfab R.
      • Haberl B.
      • Felgueiras J.
      • Carvalho F.
      • et al.
      Amanita poisonings resulting in acute, reversible renal failure: new cases, new toxic Amanita mushrooms.
      The investigators concluded that the intoxications produced by these Amanita mushrooms would resemble the toxidrome that followed the consumption of A smithiana, with a delayed onset of acute, reversible renal failure and mild hepatitis with transaminitis.
      • Kirchmair M.
      • Carrilho P.
      • Pfab R.
      • Haberl B.
      • Felgueiras J.
      • Carvalho F.
      • et al.
      Amanita poisonings resulting in acute, reversible renal failure: new cases, new toxic Amanita mushrooms.
      The mechanisms of allenic norleucine’s toxicity are unknown, but it is a suspected direct nephrotoxin.
      • Kirchmair M.
      • Carrilho P.
      • Pfab R.
      • Haberl B.
      • Felgueiras J.
      • Carvalho F.
      • et al.
      Amanita poisonings resulting in acute, reversible renal failure: new cases, new toxic Amanita mushrooms.
      It causes renal epithelial cell necrosis when cultured with renal tubular epithelium in vitro and does not deplete glutathione as does orellanine.
      • Kirchmair M.
      • Carrilho P.
      • Pfab R.
      • Haberl B.
      • Felgueiras J.
      • Carvalho F.
      • et al.
      Amanita poisonings resulting in acute, reversible renal failure: new cases, new toxic Amanita mushrooms.
      The hallucinogenic nephrotoxin in P cubensis is the tryptamine psilocybin, which is dephosphorylated by hepatic alkaline phosphatase to its active metabolite, psilocin.
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      Both psilocybin and psilocin are multiple serotonin receptor agonists, and their agonism at the 5-HT2A serotonin receptor accounts for most of their hallucinogenic properties.
      • Austin E.
      • Myron H.S.
      • Summerbell R.K.
      • Mackenzie C.A.
      Acute renal failure by confirmed Psilocybe cubensis mushroom ingestion.
      French investigators administered boiled extracts of T equestre to mice, which developed significant increases in CK levels and postmortem histopathologic evidence of striated muscle damage compared to control mice, which received boiled extracts from another species of mushroom and maintained normal CK levels and muscle biopsies.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      The investigators concluded that because most patients with toxic rhabdomyolysis survived, a genetic muscular susceptibility may have triggered the fatal dose-related myotoxic effects after an ingestion threshold of mushrooms was exceeded.
      • Bedry R.
      • Baudrimont I.
      • Deffieux G.
      • Creppy E.E.
      • Pomies J.P.
      • Ragnaud J.M.
      • et al.
      Wild mushroom intoxication as a cause of rhabdomyolysis.
      In 2016, Japanese investigators isolated a unique compound from R subnigricans mushrooms, cyclopropylacetyl-(R)-carnitine, which caused elevated CK levels in mice and was suspected to be the human myotoxin.
      • Matsura M.
      • Kato S.
      • Saikawa Y.
      • Nakata M.
      • Hashimoto K.
      Identification of cyclopropylacetyl-(R)-carnitine, a unique chemical marker of the fatally toxic mushroom Russula subnigricans.
      Visual and microscopic identification of poisonous mushrooms and their spores by experts may offer a more rapid means of identifying mushrooms as potentially nephrotoxic in the field than immunologic and chromatographic techniques in the laboratory. In 2012, Boston-based investigators reported 2 cases of hepatotoxic Amanita mushroom poisoning in Ukrainian immigrants in the Boston area; the authors attributed their successful supportive management to early identification of the ingested mushrooms as containing amatoxin via an initial cellphone image transmitted to a consulting poison control center mycologist.
      • Ward J.
      • Kapadia K.
      • Brush E.
      • Salhanick S.D.
      Amatoxin poisoning: case reports and review of current therapies.
      Nevertheless, there are no specific antidotes for nephrotoxic mushroom poisoning, all treatments are supportive, and precise identification of the causative species is unnecessary in the short term but recommended for epidemiologic and educational purposes in the long term.

      Management of Nephrotoxic Mushroom Poisonings

      The general management of nephrotoxic mushroom poisonings should include fluid resuscitation and oral activated charcoal (1 g‧kg-1) within the first 1 to 4 h after ingestion. A baseline laboratory assessment should include complete blood count; peripheral blood smear; serum glucose and electrolytes, including calcium; liver and renal function tests; and serum CK. Hepatic transaminases, coagulation studies, serum bilirubin, serum glucose, serum creatinine, blood urea nitrogen, and CK will serve as baseline comparative laboratory values over time. Liver and renal function tests should be repeated at least every 12 to 24 h after toxic mushroom ingestion and followed periodically to exclude late-onset hepatotoxicity from cyclopeptide-containing mushroom co-ingestions (Amanita, Galerina, and Lepiota species) and delayed-onset nephrotoxicity from nephrotoxic A proxima and A smithiana mushrooms. Finally, serum CK should be measured every 12 to 24 h in the first 5 to 10 d and every 36 h for 10 to 14 d in delayed-onset myotoxicity with rhabdomyolysis from T equestre or R subnigricans ingestion. All patients with any potential for mushroom nephrotoxin–induced acute renal injury should be referred to medical centers equipped and staffed for hemodialysis and kidney transplantation in the event that conservative supportive care measures fail and severe renal failure ensues.

      Conclusions

      Nephrotoxic mushrooms, most commonly Cortinarius species, can cause acute renal damage and kidney failure. Recently, several new species of nephrotoxic mushrooms have been identified, including A proxima and T equestre in Europe, A smithiana in the Pacific Northwest of the United States and Canada, A pseudoporphyria in Japan, and A punctata in Korea. In rare cases, consumption of the edible, hallucinogenic mushroom P cubensis has caused acute, reversible renal failure. In addition, 2 newly recognized myotoxic mushrooms can cause rhabdomyolysis with massive myoglobin release that indirectly causes acute kidney injury, T equestre in Europe and R subnigricans in China. The management of nephrotoxic mushroom poisonings often requires renal replacement treatments, with renal transplantation reserved for extracorporeal treatment failures.
      Financial/Material Support: Support is from departmental and institutional sources.
      Disclosures: None.

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