The Plasma Virome Post-Kidney Transplantation Predicts Clinical Outcome

Abstract

Background: Long-term immunosuppression following solid organ transplantation is associated with increased morbidity and mortality. Viral infections as a result of immunosuppression are a major cause of prolonged hospitalization and poor prognostic outcome post-transplantation. Additionally, changes in the viral populations inhabiting these patients (the virome) may affect the immune response, with implications for graft survival. Methods: We performed metagenomic sequencing of RNA and DNA extracted from paired plasma samples taken from patients pre- and post-renal transplant. This untargeted approach was used to detect changes in the virome following immunosuppression and to determine viral targets for further characterisation. Correlations between viral presence, viral load and clinical outcome were established to determine the relevance of these viruses to patient outcomes. Findings: Anellovirus load was found to be a strong predictor of immunosuppression-related infectious complications, especially viral reactivation events, in the first year post-transplant. Anellovirus load was increased in patients who had been treated for acute graft rejection 1-2 months prior to sampling, revealing additional immunosuppressive measures can have a prolonged negative impact on a patient. Interpretation: Currently no assays exist for predicting infection risk in immunosuppressed patients, meaning that potentially life-threatening infections must be dealt with retrospectively. Our observations support the possibility of a viral marker being used to monitor immunosuppressive protocols, pre-emptively minimizing risk of severe infections including viral re-activation events, reducing hospitalization and improving long-term allotransplant success rates. Funding Statement: This work was funded by Wellcome Programme Grant number WT091501/Z/10/Z, which provided funding for sequencing, reagents and computing infrastructure. MRC programme grant number MR/L019027/1 provided funding for collection of the samples. MRC CASE Studentship MR/K017071/1 provided funding for reagents and the PhD studentship of SS, of which this study formed a part. LW is funded by a Wellcome Clinical Training Fellowship and ECJ received funding from an MRC Clinical Research Fellowship, Sackler Studentship and Evelyn Trust funding. Declaration of Interests: SS reports an MRC CASE studentship in collaboration with GlaxoSmithKline, outside of the submitted work. GSK did not influence any aspect of this study including data collection, analysis, writing of the manuscript or decision to submit for publication. All other authors have nothing to disclose. Ethics Approval Statement: All samples were anonymized and obtained with informed written consent under the approval of the Cambridge Local Research Ethical Committee (reference 08/H0308/176).