Eun Song Song
Eun Mi Yang*
- Department of Pediatrics, Chonnam National University Hospital and Medical School, Gwangju, Republic of Korea
Background: Calcineurin inhibitors are widely used in organ transplantation and nephrotic syndrome, with chronic toxicities well documented, but acute toxicity is rarely reported.
Case presentation: We report a 3.9-year-old boy with steroid-dependent nephrotic syndrome who accidentally ingested a single dose of cyclosporine A (CsA) at 75 mg/kg (1,500 mg)— over 20 times the intended dose of 3.5 mg/kg (70 mg)—due to medication error. He developed transient abdominal pain, diarrhea, and vomiting, which resolved without treatment. Error was discovered 12 h post-ingestion, and he was hospitalized with a CsA trough level of 1003 ng/mL (measured 13 h after ingestion), yet remained clinically stable. Management included CsA discontinuation, intravenous hydration, rifampin- and phenobarbital-induced cytochrome P450 activation, resulting in normalization of CsA levels within 48 h. A literature review identified 28 pediatric cases of acute CsA overdose, with presentations ranging from asymptomatic to severe neurotoxicity and acute kidney injury. The varied, including supportive care, gastrointestinal decontamination, and enzyme induction, with generally favorable outcomes.
Conclusions: Although rare, acute CsA overdose in children can pose serious risks. This case and review underscore the symptoms of overdose and prompt intervention to prevent complications.
Introduction
Cyclosporine A (CsA), a potent calcineurin inhibitor, is a widely used immunosuppressant the revolutionized organ transplantation and remains a cornerstone in treating pediatric nephrotic syndrome. Due to its narrow therapeutic index, CsA requires regular drug level monitoring and vigilance for adverse effects, particularly chronic toxicities such as nephrotoxicity and neurotoxicity, which are well documented. In contrast, acute CsA overdose, especially in children, is poorly understood.
Pediatric drug ingestion is a major cause of emergency visits, with accidental ingestion common in young children and intentional overdose more frequent among adolescents (1). Acute CsA toxicity presents variably, from asymptomatic to severe, influenced by age, administration route, concurrent use of nephrotoxic drugs, and comorbidities (2). Children, especially premature infants, are more vulnerable, and parenteral overdose carries high morbidity and mortality, often necessitating urgent interventions (2). Symptoms may include headache, nausea, vomiting, hypertension, and in severe cases, kidney injury, tachycardia, hepatitis, seizure (status epilepticus), or death (3). Therapeutic strategies are inconsistently reported but typically involve drug discontinuation, hospitalization, and supportive measurement such as gastric lavage, activated charcoal, and cytochrome 450 enzyme induction. In severe cases, hemodialysis or whole blood exchange may be required (4). We report a case of accidental cyclosporine overdose in a child with nephrotic syndrome, caused by a caregiver error. Despite a markedly elevated cyclosporine level, the patient recovered uneventfully after treatment with enzyme inducers. This case underscores the importance of careful medication administration and reviews current management strategies for acute cyclosporine toxicity.
Case presentation
A 3-year-old boy, diagnosed with nephrotic syndrome at age 2, was referred for frequent relapses. He was diagnosed with steroid-dependent nephrotic syndrome and started on oral CsA. While receiving 70 mg (3.7 mg/kg) twice daily, his outpatient CsA trough levels remained between 61 and 64 ng/mL, and he was relapse-free. Due to a medication error, his grandmother mistakenly administered a 21.4-fold overdose (1,500 mg), confusing CsA with a cold remedy. The dosing error was discovered by his mother 12 h later, before the next scheduled dose, after she noticed the medication bottle was markedly emptier than expected. At dawn, the patient experienced transient gastrointestinal symptoms including abdominal pain, diarrhea, and vomiting. These symptoms emerged during the expected peak early exposure window, which typically occurs within 2–4 h post-administration in children according to previous pharmacokinetic studies. The symptoms resolved spontaneously by morning, and the patient remained asymptomatic at the time of discovery. Consequently, the mother initially questioned the need for a hospital visit, as she was unaware that such a massive overdose could result in severe clinical complications. However, after consulting with the hospital and being advised to seek immediate evaluation, she brought the child to the hospital. On arrival, the patient was clinically stable and no subjective symptoms were reported by himself. A detailed physical examination revealed no abnormalities; his abdomen was soft and non-tender without organomegaly, and his neurological status was unremarkable. Vital signs were within normal limits for his age; blood pressure 102/63 mmHg, heart rate 105 beats/min, and respiratory rate 24 breaths/min. Laboratory studies were largely unremarkable, with the following details: white blood cell count, 13,700/μL; hemoglobin, 11.6 g/dL; platelet count, 447,000/μL; serum sodium, 138 mEq/L; serum potassium, 4.4 mEq/L; serum chloride, 106 mEq/L; serum calcium, 10.0 mg/dL; serum phosphorus, 4.8 mg/dL; blood urea nitrogen, 14.8 mg/dL; serum creatinine, 0.26 mg/dL; serum total protein, 6.3 g/dL; serum albumin, 4.3 g/dL; serum alanine transaminase, 24 U/L; and C-reactive protein, 0.06 mg/dL. The serum lactate level was mildly elevated [2.4 mmol/L (normal range 0.5–2.2 mmol/L)] and normalized within 12 h. Plasma CsA concentration measured 13 h post-ingestion was 1,004 ng/mL. The diagnosis of acute CsA overdose was confirmed by correlating the patient's clinical course with pharmacological data. The rapid resolution of symptoms, combined with the absence of fever or elevated inflammatory marker, allowed for the exclusion of alternative etiologies such as acute infection or an exacerbation of nephrotic syndrome. Furthermore, the markedly elevated plasma CsA concentration, measured 13 h after the reported ingestion, provided definitive objective evidence of a massive acute overdose, even with the delayed hospital presentation. Active charcoal was withheld due to the delay. CsA was discontinued, and intravenous hydration was initiated. Rifampin (10 mg/kg) and intravenous phenobarbital (5 mg/kg every 12 h for 24 h) was administered. He remained asymptomatic with no neurological deficits. Vital signs were stable, and he maintained normal urine output. Repeated laboratory tests, including complete blood count and kidney and liver function tests, remained within normal limits. He was monitored for 36 h; CsA concentration decreased from 1,004 ng/mL to 153 ng/mL within 49 h (Figure 1). After 3 days, the CsA concentration had fallen below 50 ng/mL, and oral CsA was restarted at the regular dose. The patient has since had an uneventful clinical course with normal serum creatinine levels.
Figure 1. Clinical course of cyclosporine levels, therapeutic interventions, and symptoms.
Discussion
Although CsA overdose has been reported in transplant and nephrotic syndrome patients, pediatric cases are less commonly reported. This case describes an accidental acute CsA overdose in children with nephrotic syndrome and the highlights management using enzyme inducers.
CsA, a calcineurin inhibitor (CNI), suppresses immune response by downregulating cytokine gene transcription. It is primarily used to prevent rejection solid organ and bone marrow transplantation and to treat autoimmune and inflammatory conditions, including psoriasis, atopic dermatitis, Crohn's disease, and notably, nephrotic syndrome (5–7). CNIs undergo extensive intestinal and hepatic metabolism via cytochrome P450 enzyme system (CYP) 3A4 (8). Therefore, acute overdose can occur not only form dosing errors but also from CYP downregulation during sepsis, graft failure, or drug interaction (9, 10). Drugs that increase CsA levels include erythromycin, clarithromycin, ketoconazole, voriconazole, itraconazole, corticosteroids, calcium channel blockers, and sex hormones (11, 12). Approximately 80% of CsA overdoses occur in organ transplant patients (2), reflecting its widespread use and frequent co-administration with interacting drugs. In nephrotic syndrome, a recent pediatric case report indicated that CsA overdose was caused by prescription and administration errors (3), as in our case involving caregiver misadministration. Medication errors in children are common yet preventable causes of patient harm, occurring at various stages from prescribing to drug administration. As in our case, most important factor in preventing medication error by caregiver is thorough and repetitive education, with a strong emphasis on precise dosing techniques to ensure patients safety and avoid unnecessary harm.
In most acute CsA overdose cases, symptoms of toxicity are often mild and can be managed solely with supportive care (3, 13, 14). Clinical manifestations appear to be dose-dependent; symptomatic cases involve a significantly higher intake (20.8 ± 28.8 times the usual dose) compared to asymptomatic ones (4.4 ± 3.4 times) (15). While enteral overdoses are generally well-tolerated, intravenous overdoses are poorly tolerated and can be fatal (15). According to a recent systematic review, pediatric patients account for 29.2% of all CsA overdose cases (2). Since the required volume of liquid formulation is generally small, even a 20-fold error may result in a total volume that still appears reasonable to an inexperienced caregiver. This lack of visual disparity makes such medication errors particularly difficult to detect during administration, thereby increasing the risk of significant accidental toxicity (5). Although children tend to metabolize CsA more rapidly and hence require higher dosages to achieve therapeutic levels, they can still be more vulnerable to toxicity as a result of variations in drug absorption, clearance, and tissue susceptibility (16). Acute CsA overdose in children presents as mild to severe, depending on several risk factors. According to recent epidemiological data, gastrointestinal (GI) disturbances are the third most frequent manifestation of CNI intoxication (14.6%), following nephrotoxicity (46.3%) and neurotoxicity (22.0%) (12). Consistently, our review of 29 pediatric cases, including the present case, revealed a broad clinical spectrum: while seven cases remained asymptomatic, the remainder exhibited diverse symptoms ranging from gastrointestinal symptoms (nausea and vomiting) and central nervous system (CNS) manifestations (seizure and coma) to nephrotoxicity and cardiovascular changes, such as hyponatremia, renal failure, and blood pressure fluctuations (Table 1). Cyclosporine toxicity is influenced by multiple risk factors, including young age (particularly prematurity), parenteral administration, and concurrent use of nephrotoxic drugs, and underlying conditions such as prematurity, low birth weight, infection, and renal or respiratory failure (2, 3). One fatal case involved several of these risk factors, including age, parenteral administration, and prematurity (4). Another patient who developed epilepsy had a history of febrile seizures, a known risk factor for neurologic impairments (17). Although no definitive serum concentration threshold for symptom onset has been established, a recent systematic review suggests that oral dose exceeding 400 mg/kg or serum levels above 3,800 ng/mL may be fatal. Seizures have been associated with levels above 500 ng/mL, and coma with levels exceeding 1,000 ng/mL (2). In our case, despite a serum CsA concentration exceeding 1,000 ng/mL at 13 h post-ingestion, no CNS manifestations were observed, and the patient was discharged without adverse outcomes following therapeutic intervention.
Table 1. Summary of clinical manifestations and management strategies in pediatric cyclosporine A intoxication.
Clinical experience regarding the management of acute CsA intoxication is limited (2, 3, 12, 14). Since CNIs are non-dialyzable and there is a lack of antidotes or effective elimination strategies, the primary therapy is to immediately stop the drug and provide supportive care. For oral administration, absorption of CsA from the gastrointestinal tract is reported to be slow and variable, with peak concentration occurring from 1 to 8 h after dosing (2). Thus, gastrointestinal decontamination methods, including gastric lavage, induced vomiting with ipecac syrup, and activated charcoal with sorbitol, can aid oral overdose (4, 18). Ershad et al. suggest that charcoal administration may be effective 5 h or more after an overdose in certain patients (2, 19). In addition, the use of CYP3A4 inducers such as phenobarbital, phenytoin, and rifampicin is a potential treatment option to accelerate the clearance of CNIs (11, 12). By enhancing CsA metabolism, these agents effectively reduce its blood concentrations. Given that neurotoxicity is the most prominent acute symptom of CNIs toxicity, the use of anticonvulsants such as phenytoin and phenobarbital appear to have more benefits than risks. Because the longer half-life and exclusive renal elimination of phenobarbital may increase risk of adverse drug reaction, phenytoin is more commonly the preferred CYP inducer in majority of cases (12). However, some reports have described that phenytoin, owing to its higher affinity for plasma protein compared with phenobarbital, carries the theoretical risk of competing with CNIs and exacerbating toxicity (20). Based on this consideration, we used phenobarbital in our patient. Additionally, rifampicin was added into the treatment regimen, taking advantage of its favorable pharmacokinetic properties, including a shorter half-life, potent induction of both CYP enzymes and intestinal P-glycoprotein, and a predominantly non-renal elimination (12). While various strategies using phenobarbital, phenytoin, and rifampicin have been documented in 34 clinical reports, there is a notable lack of studies comparing isolated CNI withdrawal and active pharmacological induction. In practice, a tailored, patient-centric approach is essential when selecting the induction agent and its administration route. To ensure patient safety, clinicians should implement stringent therapeutic drug monitoring of CNI levels and limit the duration of enzyme-inducing therapy to the minimum necessary period, typically three to four days (12). Additional treatments such as extracorporeal elimination, plasmapheresis, and whole blood exchange have uncertain and minimal benefits in children (2, 4). In our case, rifampin and phenobarbital were used. Following two doses of phenobarbital, the drug concentration dropped below 500, threshold associated with seizure, allowing the discontinuation of the medication. Despite the absence of pharmacodynamic assessments of CsA due to the 12-hour delay in reporting the overdose, the consistent decline in CsA concentrations toward therapeutic ranges without any complications could be contributed to the accelerated systemic clearance facilitated by CYP induction therapy.
This case report has some limitations to consider. Due to the 13-hour delay between the medication error and hospital arrival, we were unable to measure the absolute peak plasma CsA concentration or observe the patient's clinical status during the first few hours of the overdose. Additionally, as this is a single case report, the favorable outcome observed here may not be generalizable to all pediatric patients, particularly those with different underlying comorbidities or those who ingest even higher doses. Despite these limitations, this case holds significant clinical strength as it demonstrates the successful management of a massive CsA overdose in a pediatric patient, even with a delayed diagnosis. This underscores the critical importance of immediate diagnostic recognition followed by intensive observation and proactive management in mitigating the risks of severe accidental toxicity.
In conclusion, while pediatric patients remain vulnerable to cyclosporine overdose, acute overdose may not always lead to severe or life-threatening outcomes. However, early and effective management is critical to prevent serious adverse events.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.
Ethics statement
The studies involving humans were approved by Chonnam National University Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.
Author contributions
ES: Conceptualization, Writing – original draft. EY: Data curation, Investigation, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This study was financially supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00217317) and Chonnam National University (Grant number: 2025-0375-01).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: acute toxicity, children, cyclosporine, nephrotic syndrome, treatment
Citation: Song ES and Yang EM (2026) Acute cyclosporine overdose in a child with nephrotic syndrome: a case report and literature review. Front. Pediatr. 14:1737399. doi: 10.3389/fped.2026.1737399
Received: 1 November 2025; Revised: 1 January 2026;
Accepted: 2 January 2026;
Published: 22 January 2026.
Edited by:
Gian Marco Ghiggeri, Giannina Gaslini Institute (IRCCS), ItalyReviewed by:
Takeshi Ninchoji, Harima Himeji General Medical Hospital, JapanRüveyda Gülmez, Medeniyet Üniversitesi Göztepe Eğitim ve Araştırma Hastanesi, Türkiye
Copyright: © 2026 Song and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Eun Mi Yang, ZW15YW5nQGNob25uYW0uYWMua3I=