Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management

Abstract

Acetaminophen-induced liver necrosis has been studied extensively, but the extrahepatic manifestations of acetaminophen toxicity are currently not described well in the literature. Renal insufficiency occurs in approximately 1-2% of patients with acetaminophen overdose. The pathophysiology of renal toxicity in acetaminophen poisoning has been attributed to cytochrome P-450 mixed function oxidase isoenzymes present in the kidney, although other mechanisms have been elucidated, including the role of prostaglandin synthetase and N-deacetylase enzymes. Paradoxically, glutathione is considered an important element in the detoxification of acetaminophen and its metabolites; however, its conjugates have been implicated in the formation of nephrotoxic compounds. Acetaminophen-induced renal failure becomes evident after hepatotoxicity in most cases, but can be differentiated from the hepatorenal syndrome, which may complicate fulminant hepatic failure. The role of N-acetylcysteine therapy in the setting of acetaminophen-induced renal failure is unclear. This review will focus on the pathophysiology, clinical features, and management of renal insufficiency in the setting of acute acetaminophen toxicity.Case: A 47-year-old female was found lethargic at home and brought by ambulance to an emergency department. History from family members suggested an inadvertent acetaminophen overdose, and she had last been seen a few hours earlier. She reportedly ingested 18 tablets of 500 mg acetaminophen (APAP) over the previous two days because she had run out of her prescription pain medication. Her past medical history was significant for fibromyalgia, arthritis, and a prior gastric bypass procedure. She had no history of alcohol abuse or renal insufficiency. She was lethargic. Vital signs: BP 128/96 mmHg, pulse 112/min, respirations 32/min; pulse oximetry 98% on 2L nasal cannula oxygen. Laboratory studies: BUN 9 mg/dL, creatinine 0.9 mg/dl, acetaminophen 12 mcg/mL, AST 5409 u/L and ALT 1085 u/L. A urinalysis was negative for blood with trace protein and ketones. A urine drug screen was positive for marijuana and opioid metabolites. At the initial hospital, she was treated with N-acetylcysteine (NAC) orally. Subsequently, she developed fulminant hepatic failure with elevated transaminases, hypoglycemia, and coagulopathy (Tables 1A and 1B). She was transferred

Circulating microRNAs, potential biomarkers for drug-induced liver injury

“…1). Tissue injuries other than in the liver have also been reported in acetaminophen overdose (27). Several miRNA species that are predominantly expressed in the brain, heart, lung, and spleen, based on our 6-tissue survey, were also observed at higher levels in acetaminophen-overdosed plasma samples.…”

Acetaminophen Toxicity and 5-Oxoproline (Pyroglutamic Acid)

“…The best characterized of these disorders is hepatic toxicity produced by an acute acetaminophen overdose (1)(2)(3). Acute acetaminophen poisoning can also produce renal injuries that reduce glomerular filtration and cause renal tubule damage characterized by potassium and/or phosphate wasting (4)(5)(6)(7). The pathogenic mechanisms responsible for these acute renal disorders may parallel those responsible for hepatic injury but they are less well characterized.…”

A significant hepatotoxicity associated with paracetamol overdose in the absence of kidney injury in rabbits

“…14 However, important findings obtained from case reports revealed that most cases of nephrotoxicity were diagnosed between 2 and 5 days after PCM overdose ingestion, 20 with a peak S. creatinine to occur at the 1 st week. In the present study, lack of nephrotoxicity, noted after 9 days of PCM treatment cannot definitely rule out late appearance of nephrotoxicity.…”