Torque Teno virus is predictive for malignancies after kidney transplantation

BACKGROUND AND HYPOTHESIS: Malignancy, driven by the effects of immunosuppression, is a major complication following kidney transplantation. The widespread and non-pathogenic TT virus (TTV) has emerged as a surrogate of the immune status of its host, with prior studies linking TTV load to insufficient and excessive immunosuppression and thus indirectly to graft rejection and infection. Its relationship to malignancy in kidney transplant recipients is unknown. METHODS: This prospective observational single center study evaluated 428 patients who underwent kidney transplantation between 2016 and 2019. TTV was quantified by qPCR in plasma and the primary outcome was the incidence of the first malignancy during years 2-5 post-transplant. RESULTS: In total 53 patients developed a malignancy (53% cutaneous keratinocyte cancer). The mean log10 TTV load during months 4 to 12 post-transplant (logTTVm4-12) was associated with increased malignancy risk with a hazard ratio (HR) of 1.25 (95% CI 1.02-1.54) in unadjusted analysis and 1.20 (95% CI 0.97-1.48) after adjustment for age, sex, smoking, and body mass index. In a subgroup, the result remained consistent after additional adjustment for tacrolimus and mycophenolate exposure (HR 1.31, 95% CI 1.03-1.67). Patients with logTTVm4-12 > 8, a cut-off we previously proposed to indicate infection risk, had a HR of 2.10 (95% CI 1.22-3.60). CONCLUSIONS: These findings suggest that a high TTV load-indicating a state of intense immunosuppression-predicts malignancy after kidney transplantation. Monitoring TTV as a marker of immunosuppression may offer a novel strategy for personalizing immunosuppressive therapy and reducing cancer risk.