Therapeutic Dose of Acetaminophen as a Possible Risk Factor for Acute Kidney Injury: Learning from Two Healthy Young Adult Cases

Kato, Hideki; Fujigaki, Yoshihide; Inoue, Reiko; Asakawa, Shinichiro; Shin, Shoko; Shima, Tomoko; Furunishi, Junko; Higaki, Masato; Tanemoto, Masayuki; Yamaguchi, Yutaka; Hoshimoto, Kazufusa; Uozaki, Hiroshi; Uchida, Shunya

doi:10.2169/internalmedicine.53.1502

Cited by 21 publications

(22 citation statements)

References 10 publications

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“…Moreover, there is evidence that the maximum recommended dose (i.e., 4 g/day) can induce mild to moderate hepatic cytolysis, even in healthy individuals (Watkins et al 2006;Winnike et al 2010). APAP can also induce acute kidney injury in some patients, either after poisoning or at therapeutic doses (Blakely and McDonald 1995;Kato et al 2014). APAP-induced acute nephrotoxicity manifests as acute tubular necrosis with oliguric renal failure, which can occur alone or in association with liver injury (Blakely and McDonald 1995;Jones and Prescott 1997).…”

Section: Acetaminophen (Apap)mentioning

confidence: 99%

“…APAP can also induce acute kidney injury in some patients, either after poisoning or at therapeutic doses (Blakely and McDonald 1995; Kato et al. 2014). APAP‐induced acute nephrotoxicity manifests as acute tubular necrosis with oliguric renal failure, which can occur alone or in association with liver injury (Blakely and McDonald 1995; Jones and Prescott 1997).…”

Section: Introductionmentioning

confidence: 99%

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Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Section: Acetaminophen (Apap)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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“…TIN is also associated with autoimmune diseases such as Sjögren's syndrome and systemic lupus erythematosus, however, these diseases were ruled out in our case. To our knowledge, there have been only four adult cases including our own case of biopsy-confirmed TIN induced by a therapeutic dose of acetaminophen [5,13]. In the cases administrated several medications simultaneously it might be very difficult to specify the causative drug.…”

Section: Discussionmentioning

confidence: 94%

“…Although AKI is thought to be an extremely rare adverse effect of acetaminophen in healthy persons, therapeutic dose of acetaminophen sometimes impairs kidney function in patients who are glutathione depleted (chronic alcoholism, infants, starvation/fasting/malnutrition) or who take drugs that induce p450 proteins (smoking, isoniazid, chronic alcohol ingestion, anticonvulsants) [10]. It has been reported that therapeutic dose of acetaminophen sometimes induces both renal failure and hepatic failure [4,5], but such cases are uncommon. Cases of renal damage induced by a therapeutic dose of acetaminophen without liver damage is very rare and mostly limited to & Ryosuke Usui fzk11643@nifty.com children [6,7], and such cases have hardly ever been reported in adults.…”

Section: Introductionmentioning

confidence: 99%

A case of acetaminophen-induced acute tubulointerstitial nephritis in adult

et al. 2017

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We report a case of allergic acute tubulointerstitial nephritis (TIN) induced by acetaminophen in a 48-year-old Japanese man with no past medical history. Two days after receiving the non-steroidal anti-inflammatory drug (NSAID) loxoprofen for left shoulder pain, he developed cold symptoms such as fever and sore throat. He then took a 300 mg dose of acetaminophen three times a day and a 100 mg dose of minocycline hydrochloride twice a day for 7 days. Because there was no improvement in his symptoms, he consulted a local clinic again, where blood tests revealed renal insufficiency, and he was, then, referred to our hospital for evaluation of kidney function. Renal biopsy revealed acute TIN, and Ga-67 scintigraphy showed diffuse uptake in bilateral kidneys. A drug-induced lymphocyte stimulation test (DLST) was positive for acetaminophen and negative for loxoprofen and minocycline. Based on these findings, we made a diagnosis of acetaminophen-induced TIN. We treated the patient with three courses of semi-pulse steroid therapy, after which his fever went down, and his serum creatinine level recovered from 2.09 to 1.43 mg/dL. Although we medical doctors think that therapeutic dose of acetaminophen retains high safety, it is important to keep in mind that acetaminophen can cause allergic acute TIN.

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“…For example, it was identified as a risk factor for acute renal injury [6] and it can cause onset of Stevens-Johnsons syndrome and toxic epidermal necrolysis [7,8]. Epidemiological studies revealed a link between the use of APAP during pregnancy and the incidence of attention deficit hyperactivity disorder (ADHD) and hyperkinetic disorder in children [9].…”

Section: Introductionmentioning

confidence: 99%

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

Huseinovic¹,

Leeuwen

Welsem

et al. 2017

PLoS ONE

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Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity.

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Therapeutic Dose of Acetaminophen as a Possible Risk Factor for Acute Kidney Injury: Learning from Two Healthy Young Adult Cases

Cited by 21 publications

References 10 publications

Role of endoplasmic reticulum stress in drug‐induced toxicity

Role of endoplasmic reticulum stress in drug‐induced toxicity

A case of acetaminophen-induced acute tubulointerstitial nephritis in adult

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

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