Identifying the association between tacrolimus exposure and toxicity in heart and lung transplant recipients: A systematic review

Abstract

Aims: Tacrolimus is the cornerstone of immunosuppression management in heart and lung transplant recipients, improving overall survival. However, tacrolimus-associated toxicities, including nephrotoxicity, neurotoxicity, new-onset diabetes mellitus after transplant (NODAT), and gastrointestinal toxicity, are known contributors to increased post-transplant morbidity outcomes and reduced graft and recipient survival rates. The aim of this systematic review was to identify correlations between pharmacokinetic measures of tacrolimus exposure in heart and lung recipients and tacrolimus toxicities.

Methods: MEDLINE, Embase, the Cochrane Library, CENTRAL and WHO Clinical Trial Registries were searched for published studies evaluating tacrolimus toxicities and their correlation to pharmacokinetic monitoring parameters in thoracic transplant recipients. Studies were reviewed by two authors, with data extracted for evaluation. Risk of bias was assessed using the PEDro scale for randomised control trials and the Newcastle Ottawa Scale for non-randomised cohort studies.

Results: Eighteen studies were eligible; a randomised control trial, 11 observational cohort studies, and 6 case series or studies. Of these, 9 studies were in heart transplant recipients alone and 5 in lung transplant recipients alone, 2 studies were in heart and lung transplant recipients and 2 were heart, lung, liver or renal transplant recipients. Studies used variable criteria to define toxicities. Tacrolimus trough concentration (C₀) was the marker of tacrolimus exposure most commonly used. Ten studies reported on nephrotoxicity. Elevated tacrolimus C₀ was associated with acute kidney injury occurrence and severity in three observational studies. Increasing C₀ was a predictor of renal impairment in 6 studies. One study found that for each 5 ng/mL per year of tacrolimus exposure, defined by consecutive AUC, eGFR declined by 1.3 mL/min/1.73m² (p < 0.001). Comparatively, 2 studies failed to find a significant association between nephrotoxicity and tacrolimus exposure. Seven studies reported on neurotoxicity, including neuro-encephalopathies, polyneuropathies and symptomatic change in neurological status. Neurotoxicity occurred both with tacrolimus C₀ within therapeutic range and with supratherapeutic C₀. No significant association was found between NODAT and tacrolimus C₀ in two studies. One study reported on gastrointestinal toxicity, with supratherapeutic C₀ and elevated peak concentration in one lung transplant recipient three days prior to symptom development.

Conclusion: No clearly defined relationship between tacrolimus exposure and toxicities is described in the literature. Studies with clear toxicity criteria and pharmacokinetic markers of tacrolimus exposure are required to provide valuable information that may optimise tacrolimus therapy, helping to reduce toxicities in heart and lung transplant recipients.

Keywords: Gastrointestinal toxicity; Heart transplantation; Lung transplantation; NODAT; Nephrotoxicity; Neurotoxicity; Tacrolimus.