Acute interstitial nephritis associated with ondansetron

Abstract

A 16-year-old male presented with seizure to an outside hospital and was found to have severe kidney dysfunction of unknown chronicity. He had dilute urine throughout the hospitalization and a negative serological work-up for acute glomerulonephritis. Exposure history was notable for 1–2 doses of ibuprofen and ondansetron use for nausea for the 3–4 days prior to the admission. All prior medications were discontinued, and he was started on levetiracetam for seizure management. Kidney function markedly improved on hospital day 4, and a planned kidney biopsy was cancelled. Kidney function continued to normalize after discharge. He experienced nausea again 10 days after discharge and took another dose of ondansetron with increased creatinine noted 1 day later. After discontinuation of ondansetron, his kidney function returned to and has remained normal.

Case report

The patient was a generally healthy 16-year-old male (75 kg, 165 cm) of Western Asian descent who began complaining of feeling “not well” and had recurrent emesis 4 days prior to presentation to acute care. He was seen by his primary care provider who prescribed ondansetron 8 mg for symptomatic management of gastritis symptoms. He and his family focused on hydration for the next few days but were unable to quantify fluid intake. He continued to have intermittent emesis requiring ondansetron for 3 days as well as headache and nausea. He was constipated throughout his illness and complained of abdominal bloating. The patient and his family denied changes in urine output, fever, rash, diarrhea, or joint pain. He received 1 dose of ibuprofen at onset of symptoms 4 days prior to admission, but no further doses.

On the morning of admission, he awoke with blurry vision and was taken to the emergency department (ED). Enroute to the hospital he had focal seizure activity in the car, followed by a generalized tonic–clonic seizure after arrival to the ED. Initial labs showed white cell count 12.68 K/cu mm, hemoglobin 14.6 g/dL, Na + 131 mmol/L, K + 4.5 mmol/L, BUN 89 mg/dL, creatinine 12.6 mg/dL, calcium 9.1 mg/dL, with normal transaminases and a creatinine kinase level < 7 U/L. Phosphorus was 5.2 mg/dL on subsequent testing 8 h later. Systolic blood pressure in the ED was elevated in the 140–150’s mmHg range. Urinalysis showed specific gravity 1.008, 2 + protein, blood positive,—but was negative for nitrites, eosinophils, and leukocyte esterase; microscopy showed 5 WBC/HPF, 3 RBC/HPF, and 5 hyaline casts/LPF. The urine protein to creatinine ratio was 0.92 mg/mg of creatinine. Testing for beta-2 microglobulin was unable to be completed by the lab due to sample pH. Urine output was robust with 2.78 l, 3.7 l, 6.1 l, and 6.0 l on the 4 first full days of admission, respectively.

For emergent control of seizure, the patient received levetiracetam 60 mg/kg intravenously and was evaluated with an MRI of the head that showed, “extensive cortical/subcortical edema with mild scattered associated diffusion restriction involving the bilateral cerebral and cerebellar hemispheres and sparing of the deep gray matter, suggestive of posterior reversible encephalopathy syndrome (PRES) in the setting of acute kidney injury (AKI).” A nicardipine infusion was started to control blood pressure with the goal to reduce and maintain systolic pressures in the 130–140 mmHg range for the first 8–12 h. Neurological symptoms did not recur. Imaging of the kidneys was unremarkable with “bilateral (right 10.8 cm, left 11.7 cm) echogenic kidneys with high renal resistive indices, compatible with medical renal disease.”

The differential diagnosis for the etiology of his suspected acute kidney injury included pre-renal from recent acute gastritis, acute glomerulonephritis, acute tubular necrosis, and acute interstitial nephritis (AIN) although previously undetected chronic kidney disease could not immediately be excluded from the differential. High urine output state and the absence of hematuria or granular casts argued against acute tubular necrosis as a potential etiology. He was given intravenous fluids (dextrose 5% 0.9% sodium chloride at 100 mL/h) to address any potential pre-renal component and a serological work-up for acute glomerulonephritis was completed (ANCA-, dsDNA-, ANA-, C3 116 mg/dL, C4 34 mg/dL). Ophthalmological evaluation was negative. He was scheduled to have a kidney biopsy on hospital day 4 when his creatinine markedly improved without intervention (12 → 8.4 mg/dL). The biopsy was cancelled, and he was treated conservatively with blood pressure management and IV fluids as needed. Etiology of presentation was attributed to AIN. However, the suspected causative agent remained uncertain.

Ten days after discharge, the patient experienced 1 episode of nausea after wrestling practice and took a single dose of ondansetron. Previously scheduled labs the following morning after this episode showed a worsening of kidney function BUN and serum creatinine rising from 17 mg/dL and 1.05 mg/dL to 25 mg/dL and 1.95 mg/dL, respectively, 5 days later. At this point, the interstitial nephritis was attributed to ondansetron as it had been the patient’s only known exposure, and he was advised to avoid this medication in the future. With withdrawal of ondansetron, the patient’s kidney function improved and has reached a nadir of creatinine 0.86 mg/dL and cystatin-c 0.79 mg/L, consistent with an estimated GFR = 99 ml/min/1.73 m² (CKiD U25 formula) (Fig. 1). The Naranjo Scale, a method for estimating the probability of adverse drug reaction, was used to assess the likelihood that the reaction was caused by ondansetron and it was determined that causality was probable [1]. Follow-up MRI 2 months after presentation showed complete resolution of prior findings without further seizure activity and levetiracetam was tapered off.

Fig. 1.

Time course of kidney function with known exposure to ondansetron

Discussion

This case highlights a novel causative agent of AIN, ondansetron. Ondansetron is a frequently used medication in both the inpatient and outpatient settings and should be considered a possible culprit in patients with AIN.

Drug-induced acute interstitial nephritis is a delayed hypersensitivity reaction that manifests several days after the exposure to the offending agent. The diagnosis of AIN is made by the combination of acute kidney injury consistent with an interstitial presentation, characteristic morphology on kidney biopsy, and the identification of a causative agent [2]. While in our case, there was no histology available for review; the clinical course is consistent with AIN, especially with the recurrence of kidney dysfunction after re-introduction of ondansetron after hospital discharge. Drug-induced AIN attributed to ondansetron has only been described once previously in a 22-year old man with a similar Western Asian ancestry as our patient [3]. In the reported case, the adverse drug reaction (ADR) Probability Scale score was 9, consistent with the conclusion of “definite” attribution. Recently, a study utilizing the electronic health record database conducted a retrospective evaluation seeking to identify drug-induced kidney injury events and assess which drugs were most implicated. They not only identified some previously known culprits but also showed that children exposed to ondansetron had increased odds for drug-induced kidney injury, OR = 1.49 (95% CI 1.36–1.63) [4]. While the methodology for this study included all changes in estimated GFR and controlled for disease severity, there was no delineation of the mechanism of kidney injury (acute tubular necrosis, pre-renal acute kidney injury, AIN, other causes). This was the first large-scale study to evaluate nephrotoxicity specifically in a pediatric population utilizing electronic health record data.

Conclusion

Ondansetron was probably associated with AIN in this pediatric patient. Clinicians should consider ondansetron as a causative agent when evaluating patients with the appropriate clinical presentation.

Summary.

What is new?

• A case of acute interstitial nephritis resulted from appropriate use of ondansetron to manage symptoms of gastritis. The patient had recovery of kidney function after withdrawal of the agent.