A case of acetaminophen (paracetamol) causing renal failure without liver damage in a child and review of literature

Abstract

Acetaminophen (paracetamol) is a widely used drug and known as a safety antipyretic and analgesic drug in childhood. Acetaminophen-associated liver damage is more recognized than kidney damage. Nephrotoxicity and hepatotoxicity can be seen together after acetaminophen overdose, but renal damage without liver damage is a rarely seen entity in all age groups being reported more rarely in childhood. We present here a 16-year-old girl with renal failure without liver damage because of acetaminophen toxicity and a review of literature for pathophysiological mechanisms, clinical course, treatment, and outcome.

Keywords:

• children
• acetaminophen
• renal failure
• pathophysiology
• nephrotoxicity

INTRODUCTION

Acetaminophen is a widely used antipyretic and analgesic drug in childhood. Acetaminophen overdose can cause liver and kidney toxicity. Acetaminophen-associated liver damage is more recognized than kidney damage.^1,2 Nephrotoxicity secondary to acetaminophen is frequently seen with hepatotoxicity and is reported as approximately 1–2%.¹ Nephrotoxicity without hepatotoxicity is a rarely seen entity. We present here a 16-year-old girl with acetaminophen-causing renal failure without liver damage.

CASE REPORT

A 16-year-old girl was admitted to the pediatric emergency service with a complaint of abdominal pain. Her medical history revealed that she had taken 25 pills of acetaminophen (12.5 g and 250 mg/kg). Twelve hours after the ingestion of pills, abdominal pain and vomiting had started. She was given intravenous hydration for 24 hours at another medical center with the diagnosis of acetaminophen intoxication. Her biochemical tests were normal and she was discharged the next day because her vomiting and abdominal pain stopped. The patient was admitted to our emergency service when her abdominal pain started again on the third day of drug ingestion. Her physical examination revealed body temperature of 36.5°C, pulse rate of 76/min, respiration rate of 20/min, and blood pressure of 120/70 mmHg. There was no prominent findings of pathological examination. Laboratory studies showed mild anemia (hemoglobin: 9.5 g/dL; white blood cell: 6000/mm³; thrombocyte: 377.000/mm³; mid-corpuscular volume (MCV): 69 fL; peripheral smear: hypochromic microcytic morphology) and impaired renal function tests (blood urea nitrogen: 32.8 mg/dL; creatinine: 5.3 mg/dL). Her liver function tests were within normal range. Urine analysis revealed a pH of 6, density of 1010, 1+ proteinuria, and the absence of glucose, nitrite, or leukocyte. On microscopic examination 10–12 erythrocytes, 4–5 leukocytes, and 2–3 granular casts per high power field were seen. Her blood gases showed pH 7.4, PCO₂ 37.5 mmHg, PO₂ 90 mmHg, HCO₃ 20.3 mmol/L, base excess −4.8, and oxygen saturation 98%. Right and left kidney lengths as revealed by renal ultrasound were 110 × 46 and 104 × 52 mm, respectively. Parenchyma thicknesses were normal, and echogenicity was mildly increased. Tubular phosphorus reabsorption was 78%, fractional sodium excretion was 2.5%, and renal failure index was 2.7. Urine culture was reported as no growth. Complements (C₃, C₄), antinuclear antibody, and hepatitis B surface antigen were negative. The patient was biopsied and focally minimal inflammation and edema in the interstitium were observed. She was accepted to have renal failure secondary to high-dose acetaminophen ingestion, and appropriate fluid therapy without N-acetyl cysteine (NAC) was given. Creatinine levels of the patient decreased to normal levels gradually within 15 days.

DISCUSSION

Nephrotoxicity secondary to acetaminophen usage without hepatotoxicity is rarely seen and generally reversible. In previous reports, nephrotoxicity frequency followed by acetaminophen overdose was reported as 1–2% but subsequent reports revealed more cases than expected.^1,2

Acetaminophen is mostly metabolized through glucuronidation and sulfation whereas lesser portion of drug is metabolized through oxidation by P-450 enzyme system. Metabolites primarily generate in liver and are excreted through kidney. At therapeutic doses, N-acetyl-p-benzoquinoneimine (NAPQI) that is generated from oxidized acetaminophen is reduced to mercapturic acid by glutathione. Overdose of acetaminophen depletes both glutathione and sulfate, then metabolic pathway slides to oxidation. This situation initiates lipid peroxidation that causes cell damage and apoptosis.³ For cases with nephrotoxicity alone, certain damage mechanisms of acetaminophen are controversial at present. Glutathione content may be one of these factors because its quantity is rather more in liver than kidney. Oxidation of paracetamol by cytochrome P-450 system that may result in tubular damage and potentialization of the process by the depletion of glutathione in kidney is also mentioned.⁴ Apoptosis induced by acetaminophen has been shown in murine proximal tubular cells and it is probably increased with endoplasmic reticulum stress. In another study, it is showed that acetaminophen increases reactive oxygen radicals such as nitric oxide and this also contributes to cell damage.^5,6

In our patient, nephrotoxicity without hepatotoxicity occurred after acetaminophen overdose. Some clinical situations such as alcohol ingestion, low protein diets, starvation, and inducing the P-450 enzymatic system with drugs (carbamazepine, phenobarbital, phenytoin, and so on) may enhance the nephrotoxicity of acetaminophen.⁷ Our patient had no risk factor to enhance the nephrotoxicity of acetaminophen.

Histopathological examination reveals tubular necrosis, pigmented tubular casts in tubular lumens, breaks in the tubular basement membrane, normal glomeruli, and vessels. Electron microscopy may show loss of tubular brush border and linear basolateral mitochondrial organization.⁸ A renal biopsy may be required in patients with an unobtainable history or atypical presentation. As our patient did not have hepatotoxicity, we biopsied the patient to exclude other renal pathologies. Histopathological examination revealed only focally minimal inflammation and edema in the interstitium. Electron microscopy could not be examined.

In previously reported cases without hepatotoxicity, urinary findings were appropriate with acute tubular necrosis (ATN). In these cases, ATN should be distinguished from prerenal azotemia and hepatorenal syndrome. Urine analysis shows decreased specific gravity, granular casts with or without red/white blood cells.^2,4,9 The data of published child cases with acetaminophen nephrotoxicity without hepatotoxicity are given in Table 1. Our patient's urine analysis was appropriate for ATN with renal failure index, fractional sodium excretion, and microscopic evaluation.

Table 1.  Previous cases with paracetamol nephrotoxicity without hepatotoxicity

Literature	Age	Dose (mg/kg)	Maximum serum creatinine	Clinical findings	Renal ultrasonography	Renal biopsy	Urine analysis	Urine protein/creatinine	Treatment	Normalization Time (days)
Krause I et al.^4	17.5	63	4.3	Abdominal pain	Normal	Normal	RBC 2–5/HPF	1.22	IV fluid	16
Campbell N. et al.^9	15	∼450	1.92	Mild abdominal pain and nausea	Increased echogenicity of the cortical region of the kidney	No data	Normal microscopy 2+ proteinuria	No data	NAC and IV fluid	5
Boutis K et al.^2	14	588	1.7 mg/dL	No data	No data	No data	3+ Hematuria, 4+ proteinuria	No data	NAC and IV fluid	2–3
	16	282.5	1.39 mg/dL	No data	No data	No data	3+ Hematuria, 3+ proteinuria	No data	NAC and IV fluid	2–3
	17	504	1.5 mg/dL	No data	No data	No data	Normal	No data	NAC and IV fluid	2–3
Our patient	16	250	5.3 mg/dL	Abdominal pain and vomiting	Mildly increased echogenicity	focally minimal inflammation and edema in the interstitium	1+ proteinuria RBC 10–12/HPF, WBC 4–5/HPF, granular casts 2–3 /HPF	0.8	IV fluid	15

Note: IV: intravenous; RBC: red blood cell; WBC: white blood cell; HPF: high power field.

NAC therapy is recommended for the prevention of hepatotoxicity. In the literature it is shown that NAC treatment could protect from hepatotoxicity but this treatment was found to be ineffective to prevent nephrotoxicity and could even increase damage.¹⁰ Our patient was followed without NAC treatment.

In summary, although acetaminophen-induced acute nephrotoxicity is rarely seen, it should be kept in mind that after acetaminophen overdose nephrotoxicity may occur even without hepatotoxicity and these patients should be monitored for nephrotoxicity.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.