Tacrolimus overdosing in lung transplant recipients: clinical manifestations and management

Introduction

Lung transplantation is a life-saving therapy for patients with end-stage lung disease. Advances in surgical techniques and immunosuppressive regimens have led to better outcomes over time. Among immunosuppressants, tacrolimus has become the preferred calcineurin inhibitor due to its superior efficacy in preventing chronic lung allograft dysfunction (CLAD), as shown in recent trials such as ScanCLAD (1-3). However, the narrow therapeutic window and variable pharmacokinetics of tacrolimus complicate its clinical use. Supratherapeutic levels may lead to nephrotoxicity, neurotoxicity, and other complications, while subtherapeutic levels increase the risk of rejection. Factors such as drug interactions, gastrointestinal absorption, hematocrit changes, and genetic polymorphisms contribute to this variability, especially in the early post-transplant period. Although therapeutic drug monitoring is standard practice, there is no universally accepted definition of tacrolimus overdose, nor a structured protocol for its management in lung transplant recipients. The clinical consequences of overdose, including acute kidney injury and neurological complications, remain incompletely characterized. This study aims to systematically assess the frequency, severity, and outcomes of tacrolimus overdose in a real-world cohort of lung transplant recipients. We also propose a pragmatic severity classification and introduce a structured protocol for prevention and management. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1253/rc).

Methods

We conducted a retrospective analysis on the medical records of 61 individuals who had undergone single or bilateral lung transplantation between January 2022 and December 2023 at the University Hospital Zurich in Zurich, Switzerland. The study population consisted solely of adults aged 18 years or older; all patients under 18 years were excluded. Tacrolimus was exclusively administered orally at 0.05 mg/kg BID in all patients; no intravenous formulations were used during the study period. Administration occurred 1 hour before or 2 hours after meals. Trough levels were measured daily post-transplant and then adjusted based on clinical stability.

The primary outcome was the frequency and severity of tacrolimus overdose episodes. Trough levels were measured daily during the first postoperative week, then every other day until stabilization, followed by weekly monitoring. Most overdoses occurred within the first three months post-transplantation. Tacrolimus overdose was defined as a level at least 2 µg/L above the highest point of the target range. The definition of overdose applied in this study is arbitrary and based on clinical judgment and institutional practice. While no universally accepted threshold exists, a cut-off of ≥15 µg/L was selected to enable systematic evaluation of supratherapeutic levels. Overdose severity was classified as mild for tacrolimus levels of 15–<20 µg/L, moderate for levels of 20–<25 µg/L, and severe for levels exceeding 25 µg/L.

Secondary outcomes included the effect of tacrolimus overdose on renal function, the frequency of other medical complications (gastrointestinal, neurological, etc.) and the time to normalization of the trough level after an overdose episode.

The preexisting relevant comorbidity was also documented, including pre-transplant chronic kidney disease (CKD), diabetes mellitus and arterial hypertension. Renal function was assessed through creatinine levels and estimated glomerular filtration rate (eGFR).

Given the distinct gastrointestinal absorption characteristics in cystic fibrosis (CF) patients compared to those with other conditions requiring lung transplantation, we specifically examined tacrolimus overdose in CF versus non-CF patients. This differentiation allows for a more accurate assessment of tacrolimus overdose risk within these distinct groups. Patients with CF typically require higher tacrolimus doses to achieve therapeutic levels (4). Concurrent medications known to interact with tacrolimus, such as itraconazole, macrolides, statins, and proton pump inhibitors, were also documented. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Canton of Zurich (Kantonale Ethikkommission Zürich, KEK-ZH) (No. 2024-00697). Written informed consent for the use of clinical data was obtained from all patients.

Tacrolimus overdose prevention and management protocol

Inconsistent tacrolimus dosing during the early post-transplant period remains a clinical challenge. Many centers rely on empirical dose titration, which leads to significant variability in drug exposure. This increases the risk of both acute cellular rejection due to subtherapeutic levels and toxicity when levels become excessive. While therapeutic drug monitoring is standard practice, a structured clinical response to tacrolimus overdose is lacking in most transplant programs.

To address this gap, we implemented a two-part clinical tool at our center in early 2023: (I) a severity grading system for tacrolimus overdose, and (II) a structured management algorithm that guides both prevention and intervention. The grading system is summarized in Figure 1.

Figure 1 Tacrolimus overdose severity grading and management cues.

Overdose severity classification

The tacrolimus overdose classification (mild, moderate, and severe) reflects institutional practice and serves to standardize the response to elevated levels. It should be emphasized that these thresholds are not based on prospective outcome data but are derived from pragmatic clinical use and internal consistency.

Prevention protocol

Preventive strategies focus on minimizing pharmacokinetic variability and include:

• Strict timing of tacrolimus administration in relation to meals (1 hour before or 2 hours after food).
• Avoidance or close monitoring of drug interactions (notably with itraconazole, macrolides, and proton pump inhibitors).
• Regular review of hematocrit levels and gastrointestinal symptoms, especially in the early postoperative period.
• Consistent and protocolized therapeutic drug monitoring, with daily trough levels during the first post-transplant week and stepwise extension thereafter.

Management protocol

In the event of overdose, management is adapted to severity:

• Mild overdose (15–<20 µg/L): Reduce tacrolimus dose by 30–50%, monitor trough levels daily or every other day. No additional interventions are usually required.
• Moderate overdose (20–<25 µg/L): Temporarily withhold 1–2 doses, resume at a reduced dose when trough level is <15 µg/L. Close renal function monitoring is recommended.
• Severe overdose (≥25 µg/L): Stop tacrolimus immediately. Initiate close clinical observation, including daily neurologic examination and renal function tests. Consider temporary conversion to cyclosporine in cases of persistent toxicity or significant symptoms (e.g., neurotoxicity, AKI). In rare cases, activated charcoal or hemoadsorption may be considered in consultation with toxicology.

Since its implementation in early 2023, this protocol has been applied to all lung transplant recipients at our center. While no formal statistical comparison was performed, a numerical decrease in the incidence of overdose has been observed. Prospective validation is planned.

Statistical analysis

Categorical variables were summarized as counts and percentages. Between-group comparisons (tacrolimus overdose vs. no overdose) were performed using Fisher’s exact test, with two-sided P values <0.05 considered statistically significant. Because of the retrospective and exploratory design, no formal sample-size calculation was undertaken, and no multivariable, subgroup, or sensitivity analyses were performed. No missing data occurred; therefore, no imputation was required. In an exploratory post hoc analysis, we estimated the odds ratio (with exact 95% confidence interval) for acute kidney injury comparing patients with at least one overdose episode versus none; the P value for this comparison was obtained from Fisher’s exact test.

Results

Table 1 summarizes the baseline demographic and clinical characteristics of the 61 lung transplant recipients included in the study. Tacrolimus overdose occurred in almost 90% of patients, with all cases deemed unintentional and without any signs of suicidal intent (standardly assessed in such contexts). Tacrolimus overdose typically occurred during the early postoperative phase, with a median onset at 81 days post-transplantation. The cohort showed a male predominance, with a male-to-female ratio of nearly 2:1. Nearly all patients received maintenance therapy with itraconazole and proton pump inhibitors, and a subset was additionally treated with macrolides (azithromycin) for their immunomodulatory properties.

Among the 61 transplant recipients, four patients (7%) had CF, and all experienced at least one episode of tacrolimus overdose. One CF patient had six episodes (four mild, one moderate, one severe), another had four (one mild, two moderate, one severe), one had three mild episodes, and one had a single mild episode. Tacrolimus overdose was a frequent occurrence in the cohort, typically presenting within the first three months after transplantation. Most episodes were mild, though moderate and severe cases also occurred. On average, normalization of tacrolimus levels required just over a week. Normalization was defined as the return of tacrolimus trough levels to the institutional target range. The observed variation in duration reflects differences in comorbidities, metabolism, and concurrent medication use. Full details are provided in Table 2.

Renal complications were common, with acute kidney injury occurring in over a third of patients. While CKD was less frequent, no patients progressed to end-stage renal disease. Other complications, such as hyperkalemia, gastrointestinal symptoms, neurological issues, and C-reactive protein (CRP) elevation, were observed sporadically. A detailed summary is presented in Table 3. Gastrointestinal symptoms, including nausea, vomiting, or diarrhea, were reported in 13% of patients with tacrolimus overdose but were absent in the non-overdose group. A single case of posterior reversible encephalopathy syndrome (PRES) was identified in one patient (2%), who presented with new-onset, right-sided visual disturbances. Ophthalmological evaluation confirmed visual impairment without an identifiable cause, and intraocular pressure was normal. Neurological assessment revealed impaired coordination, and magnetic resonance imaging (MRI) findings were consistent with PRES. The patient also exhibited uncontrolled, non-dipping hypertension. Two tacrolimus trough levels were elevated at 26.8 and 32.5 µg/L in the days preceding PRES, following a recent switch from cyclosporine in this patient, suggesting calcineurin inhibitor toxicity as the likely trigger. Tacrolimus was subsequently replaced with cyclosporine, and the patient underwent neurological rehabilitation with close monitoring and recovery was protracted over several months.

Discussion

This study examined the frequency and clinical implications of tacrolimus overdose in lung transplant recipients, highlighting several key findings.

Unintentional overdose was common, occurring in 88.5% of patients (Table 1). Overdoses were most often mild, though moderate and severe cases were also frequent enough to warrant concern. Given the absence of a standardized definition for tacrolimus overdose in the literature, the threshold used in this study reflects a pragmatic, institution-specific approach. While this enabled internal consistency, it may affect the generalizability of our findings. Notably, all patients with CF experienced one or more overdose episodes (Table 2), and male patients predominated in the affected group.

Renal complications

Although tacrolimus overdose and AKI frequently co-occurred, our analysis did not demonstrate a statistically significant association. These findings suggest a potential link, but should be interpreted with caution due to the limited sample size. This reflects findings from previous studies, where up to 50% of tacrolimus-treated patients developed nephrotoxicity. AKI is a known complication post-lung transplantation, and when persistent, can progress to CKD, contributing poorer long-term outcomes (5). Elevated tacrolimus trough levels have been linked to early AKI development (5), though additional factors—such as circulatory shock, systemic inflammation, and concurrent nephrotoxic drugs—also play a role. Recovery from AKI in this setting is often limited (5). Therefore, close monitoring and careful dose adjustments are essential, particularly in the early post-transplant period (5). Determining the exact contribution of tacrolimus to renal dysfunction can be complex, given the presence of other nephrotoxic agents (e.g., co-trimoxazole, valganciclovir) and comorbidities like diabetes (6).

CRP elevation and infection risk

CRP elevations were observed in both groups (71.4% in non-overdose vs. 63% in overdose group). Our data do not support a causal link between inflammation and tacrolimus overdose. Although tacrolimus levels may affect the risk of infection and rejection, these outcomes were not systematically assessed in this study. Prospective studies are needed to clarify these associations. Tacrolimus primarily suppresses cell-mediated immunity but can also impair humoral responses to a lesser extent. Non-infectious inflammatory reactions in the context of tacrolimus overdose have not been reported in the literature to date.

Studies have linked plasma tacrolimus levels to an increased risk of peripheral leukopenia (7) and identified hypogammaglobulinemia as a frequent finding in transplant recipients (8-11). However, the exact relationship between these immunological changes and susceptibility to inflammation or infection remains debated (12). In our cohort, although nephrotoxicity and elevated CRP were observed in a notable number of patients with tacrolimus overdose, these associations did not reach statistical significance—likely due to the limited sample size. As such, while our findings suggest a potential link between tacrolimus toxicity and these complications, larger studies are needed to validate and better define their clinical relevance and underlying mechanisms.

Neurological manifestations

Though uncommon, neurotoxicity remains a serious complication of tacrolimus overdose. It can occur even with tacrolimus trough levels in the therapeutic range, but severe manifestations are more often linked to elevated brain concentrations of tacrolimus. Tacrolimus inhibits p-glycoprotein expression in brain endothelial cells, compromising the blood-brain barrier and promoting vasogenic edema (13,14). Animal studies support a correlation between tacrolimus brain concentration and symptom severity (15). Neurotoxic effects are more frequent in lung transplant recipients than in renal transplant recipients and are often associated with sustained levels above 15 µg/L (14,16).

PRES, first described in 1996 (17), is a rare but recognized complication of tacrolimus or ciclosporin therapy. While high tacrolimus levels are commonly implicated, other factors such as hypomagnesemia, hypercalcemia, hypercholesterolemia, renal failure, hypertension and sepsis may also contribute (18).

PRES presents with nonspecific symptoms such as headache, visual disturbances (in 39%), seizures (in up to 87%), and encephalopathy ranging from lethargy to coma (19).

Focal deficits, such as aphasia or hemiparesis, are reported in 19% of cases (18).

MRI is the preferred diagnostic modality due to superior sensitivity, though CT can also be diagnostic (18). While rare, PRES has been reported following intravenous immunoglobulin therapy and cytotoxic drugs (20,21). Accurate diagnosis requires clinical suspicion and the exclusion of alternative causes of acute neurological symptoms. Encephalopathy is typically defined as a disturbance of attention and orientation lasting ≥24 hours or causing significant clinical impact, excluding delayed awakening from anesthesia (22). In rare cases, PRES is lethal, so prompt therapeutic measures are mandatory. Given the potentially serious complications of tacrolimus toxicity, including neurotoxicity such as PRES, a structured protocol was introduced at our center to guide prevention and management. This protocol has been in routine use since early 2023 and is described in detail in the Methods section. The majority of patients in this cohort (92%) were transplanted before its implementation (23). While prospective validation is pending, initial experience suggests it may help reduce complication rates.

Study limitations

This study is limited by its retrospective design and relatively small cohort, which may reduce statistical power. Additionally, we did not assess genetic polymorphisms (e.g., CYP3A5 variants), which are known to influence tacrolimus metabolism and could provide further insights into interindividual variability. Another limitation is that the proposed management protocol for tacrolimus overdose has not been prospectively validated, and its clinical application requires further investigation in larger, independent cohorts.

Future prospective studies with larger cohorts are needed to allow for more robust statistical modeling, including adjusted risk estimates and effect size interpretation with confidence intervals. Although suggestive of a mild increase in risk, the wide confidence interval and nonsignificant P value reflect the limited statistical power of this retrospective cohort. As such, these findings should be interpreted cautiously and warrant validation in larger, prospective studies using adjusted models.

Conclusions

Tacrolimus overdose is a frequent occurrence after lung transplantation, typically within the first three postoperative months. While acute kidney injury and neurotoxicity were observed, severe complications remain uncommon. Our findings underscore the need for vigilant monitoring, individualized dosing, and a structured management approach. Prospective multicenter studies are warranted to validate the proposed classification and protocol.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1253/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1253/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1253/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1253/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Canton of Zurich (Kantonale Ethikkommission Zürich, KEK-ZH) (No. 2024-00697). Written informed consent for use of clinical data was obtained from all patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dellgren G, Lund TK, Raivio P, et al. Effect of once-per-day tacrolimus versus twice-per-day ciclosporin on 3-year incidence of chronic lung allograft dysfunction after lung transplantation in Scandinavia (ScanCLAD): a multicentre randomised controlled trial. Lancet Respir Med 2024;12:34-44. [Crossref] [PubMed]
2. Nelson J, Alvey N, Bowman L, et al. Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation. Pharmacotherapy 2022;42:599-633. [Crossref] [PubMed]
3. Combs MP. Once-per-day tacrolimus to reduce chronic lung transplant rejection. Lancet Respir Med 2024;12:3-5. [Crossref] [PubMed]
4. Saint-Marcoux F, Knoop C, Debord J, et al. Pharmacokinetic study of tacrolimus in cystic fibrosis and non-cystic fibrosis lung transplant patients and design of Bayesian estimators using limited sampling strategies. Clin Pharmacokinet 2005;44:1317-28. [Crossref] [PubMed]
5. Sikma MA, Hunault CC, van de Graaf EA, et al. High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury. Eur J Clin Pharmacol 2017;73:573-80. [Crossref] [PubMed]
6. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004;43:623-53. [Crossref] [PubMed]
7. Urbanowicz T, Straburzyńska-Migaj E, Klotzka A, et al. Induction therapy, tacrolimus plasma concentration, and duration if intensive care unit stay are risk factors for peripheral leucopenia following heart transplantation. Ann Transplant 2014;19:494-8. [Crossref] [PubMed]
8. Legris T, Picard C, Moal V, et al. Humoral immunity after kidney transplantation: impact of two randomized immunosuppressive protocols. Ann Transplant 2013;18:622-34. [Crossref] [PubMed]
9. Sarmiento E, Rodríguez-Molina J, Muñoz P, et al. Decreased levels of serum immunoglobulins as a risk factor for infection after heart transplantation. Transplant Proc 2005;37:4046-9. [Crossref] [PubMed]
10. Fernández-Ruiz M, López-Medrano F, Varela-Peña P, et al. Monitoring of immunoglobulin levels identifies kidney transplant recipients at high risk of infection. Am J Transplant 2012;12:2763-73. [Crossref] [PubMed]
11. Kawut SM, Shah L, Wilt JS, et al. Risk factors and outcomes of hypogammaglobulinemia after lung transplantation. Transplantation 2005;79:1723-6. [Crossref] [PubMed]
12. Lavríková P, Sečník P, Kubíček Z, et al. Tacrolimus has immunosuppressive effects on heavy/light chain pairs and free light chains in patients after heart transplantation: A relationship with infection. Transpl Immunol 2018;50:43-7. [Crossref] [PubMed]
13. Wu G, Weng FL, Balaraman V. Tacrolimus-induced encephalopathy and polyneuropathy in a renal transplant recipient. BMJ Case Rep 2013;2013:bcr2013201099. [Crossref] [PubMed]
14. Jin B, Kim GY, Cheon SM. Tacrolimus-induced neurotoxicity from bipolar disorder to status epilepticus under the therapeutic serum level: a case report. BMC Neurol 2021;21:448. [Crossref] [PubMed]
15. Sakamoto Y. Correlation between neurotoxic events and intracerebral concentration of tacrolimus in rats. Biol Pharm Bull 2000;23:1008-10. [Crossref] [PubMed]
16. Chegounchi M, Hanna MG, Neild GH. Progressive neurological disease induced by tacrolimus in a renal transplant recipient: case presentation. BMC Nephrol 2006;7:7. [Crossref] [PubMed]
17. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494-500. [Crossref] [PubMed]
18. Triplett JD, Kutlubaev MA, Kermode AG, et al. Posterior reversible encephalopathy syndrome (PRES): diagnosis and management. Pract Neurol 2022;22:183-9. [Crossref] [PubMed]
19. Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc 1991;23:3175-8.
20. Belmouaz S, Desport E, Leroy F, et al. Posterior reversible encephalopathy induced by intravenous immunoglobulin. Nephrol Dial Transplant 2008;23:417-9. [Crossref] [PubMed]
21. Mathy I, Gille M, Van Raemdonck F, et al. Neurological complications of intravenous immunoglobulin (IVIg) therapy: an illustrative case of acute encephalopathy following IVIg therapy and a review of the literature. Acta Neurol Belg 1998;98:347-51.
22. Mateen FJ, Dierkhising RA, Rabinstein AA, et al. Neurological complications following adult lung transplantation. Am J Transplant 2010;10:908-14. [Crossref] [PubMed]
23. Schuurmans MM, Raeber ME, Roeder M, et al. Adaptive Immunosuppression in Lung Transplant Recipients Applying Complementary Biomarkers: The Zurich Protocol. Medicina (Kaunas) 2023;59:488. [Crossref] [PubMed]