Sebastian Kapps

Background and hypothesis: Malignancy, driven by the effects of immunosuppression, is a major complication following kidney transplantation. The widespread and non-pathogenic Torque Teno 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 at the General Hospital of Vienna, Austria. TTV was measured by quantitative polymerase chain reaction 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 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% confidence interval (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 an 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.

Background: After kidney transplantation adherence to immunosuppressive medication is crucial for graft survival and its assessment requires valid measurements. The Basel Assessment of Adherence-to Immunosuppressive Medications Scale (BAASIS) is a validated self-report tool to detect non-adherence, however, its ability to predict clinically relevant outcomes remains to be established. Methods: In this prospective cohort study including 226 consecutive kidney graft recipients transplanted at the Medical University of Vienna between 2018 and 2019 the adherence toward immunosuppressive medication was monitored for 2 years after transplantation. The BAASIS was applied at the first outpatient visit and at months 3, 6, 9, 12, and 24 post-transplant to assess the implementation and persistence phase of adherence. Non-adherence was defined by any positive response to one of the BAASIS-items. The primary endpoint was biopsy-proven allograft rejection defined by the Banff meeting report during a maximum follow-up of 4 years. Results: Of the total study cohort [median age 56 years (IQR 46–63), 75 (33%) female], 125 recipients (55%) reported non-adherence at least once. Self-reported non-adherence increased within the first 3 months from 11% to 31% and remained between 27% and 32% at months 6 to 24 post-transplant. Non-adherent recipients experienced more allograft rejections than adherent patients (24%, n = 30 vs. 7%, n = 7; P < .001) during a median follow-up of 3.7 years (IQR 1.0–4.0). Using a time-dependent Cox regression model, the adjusted hazard ratio for allograft rejection associated with previously reported non-adherence was 2.90 (95% confidence interval (CI) 1.51–5.58; P = .001) accounting for recipient sex, age at transplantation, and history of previous transplantation. Conclusion: Our findings support the clinical value of the BAASIS. Its implementation into routine post-transplant care may facilitate the identification of clinically relevant medication non-adherence, enabling timely interventions.

Torque Teno virus (TTV) load is linked with the functionality of its host's immune system and has been proposed as a potential monitoring tool for immune‐modulating therapy. However, the immunological mechanisms of TTV control are incompletely understood. To assess the effect of the classical complement pathway on TTV, 64 healthy volunteers and 10 kidney transplant recipients treated with the anti‐C1s antibody sutimlimab were analyzed for serum TTV copy numbers (c/mL) by qPCR. Overall, a correlation was observed between the decrease in complement activity caused by sutimlimab and the TTV load increase ( ρ = −0.367, p < 0.001). Subgroup analysis indicated a trend toward TTV load increase in healthy volunteers following the highest sutimlimab dose compared to baseline (100 mg/kg body weight; median 3.5 log ₁₀ c/mL, interquartile range [IQR] 2.8–4.4 vs. 2.9 log ₁₀ c/mL, 0.8–3.5; p = 0.063). Administering multiple lower doses (30 mg/kg) also showed a trend toward TTV load increase in healthy volunteers (1.8 log ₁₀ c/mL, 0–2.3 vs. 1.9, 1.3–2.8; p = 0.054) and a significant increase in transplant recipients (3.5 log ₁₀ c/mL, 3.0–6.1 vs. 4.1, 3.5–6.4; p = 0.004). This report suggests a role for the classical complement pathway in controlling TTV load.

Torque Teno virus (TTV) load is linked with the functionality of its host’s immune system and has been proposed as a potential monitoring tool for immune-modulating therapy. However, the immunological mechanisms of TTV control are incompletely understood. To assess the effect of the classical complement pathway on TTV, 64 healthy volunteers and 10 kidney transplant recipients treated with the anti-C1s antibody sutimlimab were analyzed for serum TTV copy numbers (c/mL) by qPCR. Overall, a correlation was observed between the decrease in complement activity caused by sutimlimab and the TTV load increase (ρ = −0.367, p < 0.001). Subgroup analysis indicated a trend toward TTV load increase in healthy volunteers following the highest sutimlimab dose compared to baseline (100 mg/kg body weight; median 3.5 log ₁₀ c/mL, interquartile range [IQR] 2.8–4.4 versus 2.9 log ₁₀ c/mL, 0.8–3.5; p = 0.063). Administering multiple lower doses (30 mg/kg) also showed a trend toward TTV load increase in healthy volunteers (1.8 log ₁₀ c/mL, 0–2.3 versus 1.9, 1.3–2.8; p = 0.054) and a significant increase in transplant recipients (3.5 log ₁₀ c/mL, 3.0–6.1 versus 4.1, 3.5–6.4; p = 0.004). This report suggests a role for the classical complement pathway in controlling TTV load.

Torque Teno virus (TTV) is nonpathogenic, highly prevalent, and reflects the immune status of its host. Thus, TTV plasma load was suggested for the guidance of immunosuppression post solid organ transplantation. The present study was designed to determine the kinetics of TTV following changes in calcineurin inhibitor (CNI) dose. A total of 48 adult recipients of a kidney graft transplanted at the Medical University of Vienna between 2018 and 2019 with isolated changes in CNI dose were selected from the prospective TTV‐POET trial. TTV plasma load was quantified by in‐house PCR. At Day 30 following CNI dose adaptation (median 33% of daily dose) no changes in TTV load were noted. However, at Day 60, following CNI dose reduction a lower TTV load of 6.4 log₁₀ c/mL (median; interquartile range [IQR] 4.9–8.1) compared with the baseline of 7.1 log₁₀ c/mL (IQR 5.3–8.9) was noted (p = 0.001); there was also a trend toward a higher TTV load following CNI increase (6.6 log₁₀ c/mL, IQR 4.1–9.7 vs. 5.2 log₁₀ c/mL, IQR 4.5–6.8; p = 0.09). The data suggested that TTV load changes become noticeable only 2 months after CNI dose adaptation, which might be the ideal time point for TTV load monitoring.