Carcinogenicity risk associated with tacrolimus use in kidney transplant recipients: a systematic review and meta-analysis

BACKGROUND: Currently, tacrolimus is the preferred anti-rejection therapy for kidney transplant recipients due to its greater protection against acute rejections compared to cyclosporin A (CsA). Despite the advantages of kidney transplantation, it has been associated with an increased incidence of de novo malignancies. Furthermore, a systematic review in 2005 revealed no statistical difference in tumorigenicity between tacrolimus and CsA. This report provides an up to date systematic review and evaluation of all relevant studies in the literature to determine the risk of malignancy in kidney transplant recipients exposed to tacrolimus. METHODS: A systematic literature search was performed using the Medline (PubMed and Ovid), Embase, Clinical Trials, and Cochrane databases (from creation to May 2021). We performed a meta-analysis of 11 studies with 36,985 kidney transplant recipients that compared the tacrolimus group with the control group. Outcomes of this study were incidence of malignancies and skin cancer risk. Risk of Bias was assessed in terms of whether there was random sequence generation, allocation concealment, blinding, completeness of results, selective reporting, etc. This meta-analysis was performed in accordance with PRISMA guidelines. RESULTS: Of the 11 included studies, 8 were high quality studies, 1 was assessed as medium quality, and 2 were low quality studies. The results showed a significantly increased risk of overall malignancy associated with tacrolimus exposure compared to non-tacrolimus therapy [risk ratio (RR) =1.59; 95% confidence interval (CI): 1.19–2.11; P=0.002], and especially with sirolimus (SRL) (RR =2.58; 95% CI: 1.62–4.09; P<0.0001). The incidence of skin cancer was consistent with the overall study (RR =2.03; 95% CI: 1.25–3.28; P=0.004). However, there was no significant difference in the incidence of tumors between tacrolimus and cyclosporine A treatment (RR =1.12; 95% CI: 0.80–1.56; P=0.52), even in studies with long follow-up periods of more than 3 years. DISCUSSION: The data demonstrated that patients treated with tacrolimus had a higher risk of carcinogenicity compared to patients treated with SRL. However, patients treated with tacrolimus had a similar incidence of carcinogenicity compared to patients treated with CsA. Further clinical studies are warranted to confirm these findings.