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Acute Renal Failure After Acetaminophen Ingestion
Abstract
Acute renal failure in the absence of severe hepatocellular damage developed in a young woman after ingestion of approximately 30 g of acetaminophen during a 36-hour period. Animal studies suggest that the nephrotoxic effect is due to a toxic oxidative metabolite of acetaminophen that arylates renal macromolecules. This case illustrates the need for detailed drug histories regarding over-the-counter medications. Acetaminophen ingestion should be considered in the differential diagnosis of acute renal failure.(JAMA 1982;247:1012-1014)
... High doses of APAP (acetaminophen) are capable of causing hepatic necrosis and renal tubular necrosis [15][16][17]. The hepatotoxic effect of APAP has been widely studied; however, APAP-induced nephrotoxicity and the actual mechanism of nephrotoxicity are not fully understood. ...
Introduction: Acetaminophen in toxic doses can cause renal failure. The actual mechanism of acetaminophen-induced renal failure is still unknown. The aim of the current study is to investigate the effect of single toxic dose of acetaminophen on renal function and renal histopathological structure. Method: A single toxic dose of acetaminophen (500 mg/kg) was injected intraperitoneally into male Wistar rats. Serum acetaminophen, biochemical markers of renal and liver functions, serum and urine electrolytes were measured at 4, 12 and 24 h after drug injection. The histopathology of renal tissue was investigated. Results: Serum ALT, AST, BUN and creatinine were significantly deteriorated in the experiment group. Acetaminophen injection significantly caused serum sodium retention, hypokalemia and hyperosmolality. In the urine, there was significantly higher excretion of sodium, potassium and phosphate. Renal biopsy showed structural changes resembling acute tubular necrosis. The control group did not show any of the changes observed in the case group. Discussion: Acetaminophen in toxic doses can cause renal injury starting 12 to 24 h post-injection. The histopathological changes in kidney structure resemble acute tubular necrosis. Acetaminophen also alters the renal handling of electrolytes observed by sodium retention, an increase in serum osmolality, hypokalemia and an increase in the urinary excretion of sodium, potassium and phosphate.
APAP poisoning is common, and despite the availability of a specific antidote, fatalities still occur. Early treatment using NAC is highly effective in preventing liver injury, but further study is needed to determine optimum indications, route of administration, dosage, and duration of treatment. Recent advances have changed traditional concepts regarding late treatment and mechanisms of NAC action, but significant gaps in understanding persist. Immediate challenges include refining the diagnosis and treatment of APAP toxicity after repeated ingestions, defining settings in which deviation from standard protocols is appropriate, and improving therapy of APAP-induced hepatic failure.
Paracetamol (PAR) overdose is associated with massive hepatic injury; it may induce kidney toxicity as well. It is essential to measure organ-specific activities of related CYPs for evaluating the overdose cases. Available HPLC-based methods require high amounts of tissue samples. In order to develop liquid chromatography mass spectrometry (LC-MS)-based methods to process small amounts of human tissues, liver and kidney samples were obtained. Individual microsomes were prepared and incubated with PAR (for quantifying bioactivation), with nifedipine (for measuring CYP3A4 activity) and with p-nitrophenol (for measuring CYP2E1 activity). The small amount of tissue microsomes was sufficient to measure both the formation of NAPQI and the activities of CYP enzymes. Although the sample size in group was relatively low, both NAPQI formation and activity of CYP2E1 were significantly higher in males compared to females in kidney. Considerable variations in the metabolic capacity of individuals were observed for both organs.
Acetaminophen (paracetamol) was first discovered in Germany in 1887. It was initially rejected in favor of the structurally related phenacetin, as it was considered too toxic. It was only when restudied in the late 1940s that it was recognized as safer than alternative agents [1]. It was first marketed as an antipyretic and analgesic in the USA, as Tylenol, and UK, as Panadol, in the 1950s [2].
Background:
After decades of worldwide use of paracetamol/acetaminophen as a popular and apparently safe prescription and over-the-counter medicine, the future role of this poorly understood analgesic has been seriously questioned by recent concerns about prenatal, cardiovascular (CV) and hepatic safety, and also about its analgesic efficacy. At the same time the usefulness of codeine in combination products has come under debate.
Methods:
Based on a PubMed database literature search on the terms efficacy, safety, paracetamol, acetaminophen, codeine and their combinations up to and including June 2016, this clinical update reviews the current evidence of the benefit and risks of oral paracetamol alone and with codeine for mild-to-moderate pain in adults, and compares the respective efficacy and safety profiles with those of nonsteroidal anti-inflammatory drugs (NSAIDs).
Results:
Whereas there is a clear strong association of NSAID use and gastrointestinal (GI) and CV morbidity and mortality, evidence for paracetamol with and without codeine supports the recommended use even in most vulnerable individuals, such as the elderly, pregnant women, alcoholics, and compromised GI and CV patients. The controversies and widespread misconceptions about the complex hepatic metabolism and potential hepatotoxicity have been corrected by recent reviews, and paracetamol remains the first-line nonopioid analgesic in patients with liver diseases if notes of caution are applied.
Conclusion:
Due to its safety and tolerability profile paracetamol remained a first-line treatment in many international guidelines. Alone and with codeine it is a safe and effective option in adults, whilst NSAIDs are obviously less safe as alternatives, given the risk of potentially fatal GI and CV adverse effects.
This chapter describes the usage and effects of antipyretic analgesics. There is now incontrovertible evidence that combinations of antipyretic analgesics, taken in large doses over a long period of time, causes a specific form of kidney disease and chronic renal failure. The pathogenesis of analgesic nephropathy involves a direct cytotoxic action of the analgesics on the renal papilla, enhanced by ischemia. Persons so exposed may be more susceptible to the subsequent development of uroepithelial tumors. However, there is no evidence to indicate that single antipyretic analgesic drugs cause chronic renal disease when taken in the small doses usually prescribed by physicians or taken briefly for valid medical reasons. Based on many studies with aspirin-sensitive patients, it now appears likely that in a proportion of patients with reactions, such as urticaria, angioedema, and asthma, pharmacological rather than immunological mechanisms may be responsible, or that both mechanisms may be acting together. When treatment is essential and no alternative drug is available, incremental oral challenge with aspirin can induce a desensitized state, which can be maintained with daily aspirin treatment.
We may define acute renal failure (ARF) as a rapid deterioration of renal function associated with retention of nitrogenous wastes in the body [1]. On the basis of this definition, ARF may occur as result of many different causes, as summarized in table 2-1. In this chapter, only ischemic and toxic forms of ARF in humans are reviewed.
Acetaminophen/paracetamol is the most widely used drug of the world. At the same time, it is probably one of the most dangerous compounds in medical use, causing hundreds of deaths in all industrialized countries due to acute liver failure (ALF). Publications of the last 130 years found in the usual databases were analyzed. Personal contacts existed to renowned researchers having contributed to the medical use of paracetamol and its precursors as H.U. Zollinger, S. Moeschlin, U. Dubach, J. Axelrod and others. Further information is found in earlier reviews by Eichengrün, Rodnan and Benedek, Sneader, Brune; comp. references. The history of the discovery of paracetamol starts with an error (active against worms), continues with a false assumption (paracetamol is safer than phenacetin), describes the first side-effect ‘epidemy’ (phenacetin nephropathy, drug-induced interstitial nephritis) and ends with the discovery of second-generation problems due to the unavoidable production of a highly toxic metabolite of paracetamol N-acetyl-p-benzoquinone imine (NAPQI) that may cause not only ALF and kidney damage but also impaired development of the fetus and the newborn child. It appears timely to reassess the risk/benefit ratio of this compound.
A 29-year-old, 65 kg, Chinese man presented to hospital 10 hours after ingesting 30 g of paracetamol (462 mg/kg body weight). The blood paracetamol level was 145 μ/ml at 10 hours post-ingestion. He had no known risk factors for hepatotoxicity and was treated with intravenous N-acetylcysteine (NAC). Serum creatinine level rose to a maximum of 455 μmol/L on day 8; it gradually declined without the need for dialysis. Little is known of the risk factors for nephrotoxicity, which may occur with or without concurrent liver damage, suggesting possible primary toxic effects on the kidney. The use of NAC in this case may have prevented the progression to liver failure and reduced the severity of the nephrotoxic effects.
Up to 40% of all admissions to hospital with self-poisoning in the UK involve paracetamol. Most deaths are associated with deliberate self-poisoning, but therapeutic misadventures may occur in both adults and children.
In large dosages, acetaminophen (APAP) produces acute kidney necrosis in most mammalian species. High neopterin levels have been accepted as strong indicators for the clinical severity of some diseases. In this study, we aimed to evaluate whether neopterin is a biomarker in the identification of APAP-induced nephrotoxicity.
Thirty adult male Wistar rats were randomly divided into three groups: control, APAP-1, and APAP-2 groups. APAP-1 and APAP-2 group rats were given a single dose of 1 and 2 g/kg body weight of APAP by gastric tube, respectively. Kidney tissues and blood samples were obtained for biochemical and histopathological analyses. Biochemical parameters, serum and kidney neopterin levels, and the grade of tubular injury were compared in the control, APAP-1, and APAP-2 group animals.
APAP treatments caused tubular necrosis in the kidney and increase in serum creatinine concentrations accompanied by elevated serum and kidney neopterin levels. In the rats of groups APAP-1 and APAP-2 when compared with that of the control group (109.1 pmol/mg protein), median kidney neopterin concentrations were 162.1 (p = 0.089) and 222.2 (p < 0.001) pmol/mg protein, respectively. The grade of tubular injury of the APAP-1 and APAP-2 groups was higher than the group of control (both p < 0.001).
Serum and kidney neopterin levels could be sensible alternative to evaluate the risk to have nephrotoxicity because of APAP overdose. The elevated serum and kidney neopterin in the APAP-induced tubular necrosis might be a marker of acute histological kidney injury.
Plectranthus amboinicus (PA), commonly known as country borage, is a folkoric medicinal plant. Juice from its leaves is commonly used for illnesses including liver and renal conditions in the Asian sub-continent. Acetaminophen (APAP), used as an analgesic, produces liver and kidney necrosis in mammals at high doses. The aim of this study was to investigate the nephroprotective, diuretic, and antioxidant activities of the ethanol extract of PA at two doses of 250 and 500 mg/kg bw on APAP-induced toxicity in rats. This study shows that APAP significantly increases the levels of serum urea (UR), hemoglobin (Hb), total leukocyte count, creatinine, raised body weight, and reduced levels of neutrophils, granulocytes, uric acid, and platelet concentration. Ethanol extract of PA rescued these phenotypes by increasing anti-oxidative responses as assessed by biochemistry and histopathology. In addition, the ethanol extract of PA at two doses showed a significant diuretic activity by increased levels of total urine output and urinary elerolytes such as sodium and potassium. In conclusion, these data suggest that the ethanol extract of PA possess nephroprotective and antioxidant effects against APAP-induced nephrotoxicity and strong diuretics effect in rats.
Paracetamol poisoning remains a leading cause of morbidity and mortality. Identifying indices of poor prognosis at first presentation is key to both improving clinical care and determining targets for intervention. Renal failure is a feature of severe paracetamol poisoning. The aim of this study was to investigate the relationship between renal function (serum creatinine, Cr) at first hospital presentation and time of tertiary referral to outcomes in severe paracetamol poisoning.
This was a retrospective cohort analysis of patients referred to the Scottish Liver Transplant Unit due to paracetamol poisoning between 1992 and 2004. The relation between degree of renal injury and outcomes, including worst prothrombin time, Kings College Hospital Criteria (KCHC) and death were examined. The effects of age, nature (single or multiple) and stated size of overdose, hepatic enzyme induction (gamma-glutamyl transpeptidase, GGT), degree of liver injury (aspartate aminotransferase, prothrombin time), blood pressure and renal injury were assessed.
Data from 522 patients were included. Renal impairment (Cr >120 mmol/l) was present in 48.8% of patients with liver injury at time of first presentation. Creatinine at first admission predicted poorer outcome in terms of worse prothrombin time, KCHC and death (p < 0.001). Associated risk factors for renal dysfunction included later presentation, staggered ingestion, increased age, hypotension and elevated GGT at first admission.
Creatinine at first admission appears to be a predictor of poor outcome in paracetamol overdose. A better understanding of mechanisms involved in causing renal dysfunction may offer potential therapeutic targets for improving outcome in this common poisoning.
This report describes a paracetamol overdose in which renal impairment occurred without biochemical evidence of hepatotoxicity. We are aware of only one similar case. However, it is possible this scenario may be seen more frequently with close biochemical follow-up.
The cases of two patients with fulminant hepatic failure after intake of therapeutic doses (4-8 g) of paracetamol, and who were admitted to hospital for assessment for liver transplantation, are described. In both patients starvation, due to abdominal pain, nausea and vomiting or diarrhoea, was probably contributing to the toxic effect of the drug. One of the patients also had an excessive alcohol intake. Paracetamol should not be prescribed for patients with alcoholism or with low food intake.
This is the fourth reported case of acute pancreatitis associated with acetaminophen overdose. The patient had ingested the smallest amount of acetaminophen (9.75 - 13 g) that has been reported to produce acute pancreatitis. This patient also suffered liver and renal impairment and developed an ileus and ascites. Despite late therapy and laboratory tests that indicated a poor prognosis the patient made a complete recovery without sequelae. This is the fourth reported case of acute pancreatitis associated with acetaminophen overdose. This patient had ingested the smallest amount reported to cause pancreatitis. There was allegedly no history of alcohol abuse; coingestion of barbiturates was claimed but not defined. Despite late therapy and laboratory tests that indicated a poor prognosis the patient made a complete recovery. © 1991 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
Renal xenobiotic metabolism can result in production of electrophiles or free radicals that may covalently bind macromolecules or initiate lipid peroxidation. The mechanisms of renal xenobiotic metabolism may vary in different anatomical regions. Kidney cortex contains a cytochrome P-450 system while medulla contains a prostaglandin endoperoxidase. Recently cysteine conjugated-lyase has been implicated in production of reactive intermediates. Metabolic activation may be amplified by accumulation of xenobiotics within renal cells due to tubular concentrating and/or secretory mechanisms. Additionally, renal xenobiotic detoxicification can occur by conjugation with glucuronide, sulfate or glutathione.
The occurrence of hypophosphataemia in paracetamol overdose suggests that nephrotoxicity is common, impaired renal tubular reabsorption of phosphate indicating renal damage. To investigate the potential nephrotoxicity of paracetamol, we studied 148 consecutive patients with paracetamol overdose. Serial clinical and biochemical measurements were made, and a fasting overnight urine collection was obtained for creatinine (Cr), phosphate and retinol-binding protein (RBP) determination. Renal threshold phosphate concentration (TmPO4/GFR) was determined from urinary parameters by an established nomogram. The degree of hypophosphataemia correlated with the severity of overdose, and with TmPO4/GFR. The median RBP/Cr ratio was higher in those patients exhibiting biochemical hepatotoxicity compared with those without hepatotoxicity, in whom median RBP/Cr was not significantly higher than controls. Within the group of patients showing biochemical hepatotoxicity, there was a correlation between log RBP/Cr and TmPO4/GFR. RBP/Cr ratio is a less sensitive marker of renal tubular toxicity than phosphaturia in these patients, and may indicate a different mechanism of toxicity.
Paracetamol overdosage is a common problem, but severe poisoning occurs in only a small percentage of cases. A patient who has suffered paracetamol overdosage should be monitored carefully to ensure that a specialist liver unit can be contacted at the earliest signs of severe poisoning for optimal management and transfer. Paracetamol overdosage remains the most common cause of fulminant hepatic failure in the UK, with a mortality rate of 90%, but survival rates can be improved dramatically by specialist intensive care management, and with the advent of transplantation a previously untreatable group of patients can be treated successfully. However, a patient who is inadequately monitored and treated in the early stages after an overdose may deteriorate to an extent that renders them unsalvable by the time they arrive at the specialist centre.
Our patient experienced acute renal failure but not fulminant hepatic failure from acetaminophen toxicity.
To review the clinical and laboratory characteristics of similar cases of acetaminophen nephrotoxicity.
A MEDLINE search and medical record search at two large teaching hospitals.
We reviewed our index case, a patient at Jackson Memorial Hospital, and 34 additional patients with acetaminophen nephrotoxicity reported in the literature. Oliguria was present in 23 of 31 patients. There was no difference in peak serum creatinine levels between patients treated with N-acetylcysteine and those not treated. The onset of acute renal failure was from 2-5 days after overdose, and peak serum creatinine levels occurred 3-16 days (average 7.3 days) after overdose. Thirteen patients required hemodialysis; all but one were oliguric. Renal failure was spontaneously reversible in all patients.
Although uncommon, it is possible to have acute renal failure due to acetaminophen toxicity in the absence of fulminant hepatic failure.
To determine the rate of acetaminophen related nephrotoxicity in adolescents who present after acute severe acetaminophen intoxication and to identify potential predictors of this outcome.
Retrospective analysis of consecutive patients between the ages of 12 and 18 years who were admitted at a tertiary care children's hospital for treatment of acute severe acetaminophen intoxication with N-acetylcysteine. The main outcome measure was the frequency of acetaminophen-related nephrotoxicity, defined as abnormal blood urea nitrogen (>6.4 mmol/L or > 18 mg/dL) and/or elevated creatinine (97.2 micromol/L or > 1.1 mg/dL) in association with one or both of the following: elevated blood pressure (systolic blood pressure > 140 mm Hg/diastolic blood pressure >85) or abnormal urinalysis (urinalysis with hematuria or proteinuria). Statistical analyses used were measures of central tendency, Student's t-test, Mann-Whitney, and multivariate logistic regression.
Fourty-five patients were included. Acetaminophen-related nephrotoxicity occurred in 4 (8.9%) cases. One victim developed severe renal injury in association with elevated hepatic transaminases. Intergroup analyses revealed no statistically significant association between acetaminophen-related nephrotoxicity and amount/kg of acute severe acetaminophen ingested, delay in treatment with N-acetylcysteine, or measures of hepaticfunction.
Acetaminophen-related nephrotoxicity occurred in 8.9% [95% CI: 4.52, 20.48] of children with severe overdose. There are no obvious predictors of this complication of acetaminophen overdose. Because the occurrence of renal injury can not be predicted, serial blood pressure, blood urea nitrogen/creatinine, and urinalysis should be considered an integral part of the management of children with acute, severe acetaminophen intoxication.
Acetaminophen is frequently used by both physicians and parents for the relief of pain and fever in infants and children of all age groups. It has an excellent safety profile in therapeutic doses, but hepatotoxicity can develop following both intentional or unintentional overdoses. Repetitive doses of acetaminophen, usually in supratherapeutic amounts, but not always, in ill infants have been associated with hepatotoxicity. Acetaminophen toxicity may be very difficult to diagnose in young infants when suspicion for this entity is low. In addition, initial signs and symptoms are nonspecific and biochemical evidence of hepatic damage may not become evident for 24 to 36 hours. We report the case of an infant who received multiple doses of acetaminophen during an illness who developed hepatotoxicity.
Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Recent studies suggest a contributory role for glutathione (GSH)-derived conjugates of APAP in the development of nephrotoxicity. Inhibitors of either gamma-glutamyl transpeptidase (gamma-GT) or the probenecid-sensitive organic anion transporter ameliorate APAP-induced nephrotoxicity but not hepatotoxicity in mice and inhibition of gamma-GT similarly protected rats from APAP nephrotoxicity. Protection against APAP nephrotoxicity by disruption of these GSH conjugate transport and metabolism pathways suggests that GSH conjugates are involved. APAP-induced renal injury may involve the acetaminophen-glutathione (APAP-GSH) conjugate or a metabolite derived from APAP-GSH. Acetaminophen-cysteine (APAP-CYS) is a likely candidate for involvement in APAP nephrotoxicity because it is both a product of the gamma-GT pathway and a probable substrate for the organic anion transporter. The present experiments demonstrated that APAP-CYS treatment alone depleted renal but not hepatic glutathione (GSH) in a dose-responsive manner. This depletion of renal GSH may predispose the kidney to APAP nephrotoxicity by diminishing GSH-mediated detoxification mechanisms. Indeed, pretreatment of male CD-1 mice with APAP-CYS before challenge with a threshold toxic dose of APAP resulted in significant enhancement of APAP-induced nephrotoxicity. This was evidenced by histopathology and plasma blood urea nitrogen (BUN) levels at 24 h after APAP challenge. APAP alone was minimally nephrotoxic and APAP-CYS alone produced no detectable injury. By contrast, APAP-CYS pretreatment did not alter the liver injury induced by APAP challenge. These data are consistent with there being a selective, contributory role for APAP-GSH-derived metabolites in APAP-induced renal injury that may involve renal-selective GSH depletion.
The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. We previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40mg/l) were treated by acetaminophen (APAP, 400mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p<0.01) and AST (p<0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p<0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination.
Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB(1) receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB(1) receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB(1) agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.
Acetaminophen is a commonly used antipyretic and analgesic agent. It is safe when taken at therapeutic doses; however, overdose can lead to serious and even fatal hepatotoxicity. The initial metabolic and biochemical events leading to toxicity have been well described, but the precise mechanism of cell injury and death is unknown. Prompt recognition of overdose, aggressive management, and administration of N-acetylcysteine can minimize hepatotoxicity and prevent liver failure and death. Liver transplantation can be lifesaving for those who develop acute liver failure.
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