BKV, CMV, and EBV Interactions and their Effect on Graft Function One Year Post-Renal Transplantation: Results from a Large Multi-Centre Study

Abstract

Background: BK virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivations are common after kidney transplantation and associated with increased morbidity and mortality. Although CMV might be a risk factor for BKV and EBV, the effects of combined reactivations remain unknown. The purpose of this study is to ascertain the interaction and effects on graft function of these reactivations.

Methods: 3715 serum samples from 540 kidney transplant recipients were analysed for viral load by qPCR. Measurements were performed throughout eight visits during the first post-transplantation year. Clinical characteristics, including graft function (GFR), were collected in parallel.

Findings: BKV had the highest prevalence and viral loads. BKV or CMV viral loads over 10,000 copies·mL^-1 led to significant GFR impairment. 57 patients had BKV-CMV combined reactivation, both reactivations were significantly associated (p = 0.005). Combined reactivation was associated with a significant GFR reduction one year post-transplantation of 11.7 mL·min^-1·1.73 m^-2 (p = 0.02) at relatively low thresholds (BKV > 1000 and CMV > 4000 copies·mL^-1). For EBV, a significant association was found with CMV reactivation (p = 0.02), but no GFR reduction was found. Long cold ischaemia times were a further risk factor for high CMV load.

Interpretation: BKV-CMV combined reactivation has a deep impact on renal function one year post-transplantation and therefore most likely on long-term allograft function, even at low viral loads. Frequent viral monitoring and subsequent interventions for low BKV and/or CMV viraemia levels and/or long cold ischaemia time are recommended. FUND: Investigator Initiated Trial; financial support by German Federal Ministry of Education and Research (BMBF).

Keywords: BK virus; Combined reactivation; Cytomegalovirus; Epstein-Barr virus; Graft function; Kidney transplantation.

Fig. 1

Trial profile.

Fig. 2

Viral dynamics of BKV, CMV, and EBV during the first post-transplantation year. Prevalence and viral load levels for BKV (blue), CMV (red), and EBV (green) are plotted for the eight visits of the study. The size of the points is a function of the prevalence of positive measurements (viral load over detection level). The height of the points represents the median viral load (copies·mL⁻¹) of positive measurements; the bars indicate the interquartile range. Asterisks indicate a significant difference calculated with the Mann-Whitney test (* p < 0·05; ** p < 0·01; *** p < 0·001) in viral load (only samples with detectable viral load) for each virus.

Fig. 3

Frequency of triple, combined and mono-reactivations of BKV, CMV, and EBV during the first post-transplantation year. Number of patients with reactivations and all their possible combinations are plotted as a Venn diagram. Fig. 3a depicts the combinations of BKV⁺, CMV⁺, and EBV⁺, i.e. viral load over detection level. Fig. 3b depicts the combinations of elevated viral load sub-groups (eBKV, eCMV, and eEBV, > 2000 copies·mL⁻¹). Fig. 3c depicts the combinations of high-level viral load sub-groups (hBKV, hCMV, and hEBV, > 10,000 copies·mL⁻¹).

Fig. 4

Graft function dynamics of patients with BKV and CMV mono-reactivations and combined reactivations, in comparison to non-reactivating patients. Median GFR (mL·min⁻¹·1·73 m⁻²) for patients with BKV-CMV combined reactivation (red; N = 16), hBKV (blue; N = 59), hCMV (green; N = 18) and non-reactivating (black; N = 208) for the last seven visits is plotted. Coloured groups are not mutually exclusive – a patient might belong to more than one sub-group. The bars indicate the interquartile range. Coloured asterisks indicate a significant difference calculated with the Mann-Whitney test (* p < 0·05; ** p < 0·01) in GFR of the corresponding group with respect to the non-reactivating group. Day 0 is not shown, as it is pre-transplantation.