Torquetenovirus viremia for early prediction of graft rejection after kidney transplantation

doi:10.1016/j.jinf.2019.05.010

Journal of Infection

Volume 79, Issue 1, July 2019, Pages 56-60

https://doi.org/10.1016/j.jinf.2019.05.010 Get rights and content

Summary

Objectives

New biomarkers reflecting the degree of immunosuppression in transplant recipients are needed to provide an optimal personalized balance between rejection and infection risks.

Methods

For this purpose, we investigated TTV viremia dynamics in 66 kidney transplant recipients followed up for two years after transplantation, in relation to BK virus infection and graft rejection.

Results

After transplantation, TTV viremia rose by ≥2 log₁₀ copies/mL from baseline to month 3, then declined by ≥1 log₁₀ copies/mL thereafter. Higher TTV viremia was associated with recipients of a deceased donor, a lower count of CD8+ T cells and a higher BKV viremia. Importantly, TTV loads were significantly lower in KTR who would later display graft rejection; indeed, patients with TTV viremia lower than 3.4 log₁₀ copies/mL at transplantation or lower than 4.2 log₁₀ copies/mL at month 1 had a higher risk of developing graft rejection in the two following years (hazard ratio (HR) at D0 = 7.30, p = 0.0007 and HR at M1 = 6.16, p = 0.001).

Conclusions

TTV viremia measurement at early times post transplantation predicts graft rejection and would represent a useful tool to improve kidney transplant monitoring.

Introduction

Long-term graft function and survival after kidney transplantation relies on suitable immunosuppressive treatment to provide an optimal balance between rejection and infection risks. BK virus (BKV)-associated nephropathy (BKVAN) and graft rejection are major causes of graft dysfunction and loss in kidney transplant recipients (KTR).¹ The disruption of the balance between BKV replication and host immune control is a key element of viral pathogenesis.² Torquetenovirus (TTV) is a small, non-enveloped, single-stranded DNA virus of the Anelloviridae family which has not been linked to any specific human illness but represents a major component of the human virome.³ Indeed, immunocompetent hosts display low-level viremia while TTV loads are substantially higher in immunocompromised patients.⁴ In lung and heart transplant recipients, high TTV loads correlate with high doses of immunosuppressive drugs and are associated with microbial infection occurrence,5, 6 while low levels of TTV viremia are observed in patients with graft rejection episodes.³ These data suggest that TTV viremia may be linked to BKV replication and/or graft rejection in KTR. In this work, we investigated long-term TTV load kinetics at transplantation and over 24 months in a well-characterized KTR cohort. We analyzed TTV loads according to patient characteristics, immunosuppressive drugs, BKV replication status and rejection episodes, in order to determine if TTV viremia may adequately reflect the degree of immunosuppression and represent a useful predictor of BKV replication and/or graft rejection.

Section snippets

Patients

Sixty-six adult patients who underwent kidney transplantation between July 2012 and July 2014 in Strasbourg University Hospitals were enrolled in this study. The present study was based on a prospective longitudinal study on anti-BKV neutralizing antibodies (Clinical Trials.gov identifier: NCT02826811). The design of the study has earlier been reported in detail.⁷ Briefly, all patients who displayed BKV replication in urine in the first two years post-transplantation (n = 50) were included.

TTV load kinetics

Patient characteristics are presented in Table 1. Positive TTV viremia was detected in 86% of KTR on the day of transplantation (D0) with a mean load of 3.06 log₁₀ copies/mL, and in 96% of patients during follow-up. Only TTV-positive patients were subsequently considered for the analysis of TTV loads (n = 63). TTV kinetics showed an increasing phase up until M (month) 3 (M1 mean TTV load: 4.35 log₁₀ copies/mL, M3 mean TTV load: 6.79 log₁₀ copies/mL) with a 98% probability for TTV viremia to

Discussion

In this long-term longitudinal study on KTR, for the first time, we (i) describe a relationship between TTV and BKV viremia and (ii) determine cutoff values of TTV viremia allowing to identify, as early as in the first month after transplantation, the patients who are at high risk of graft rejection.

Longitudinal TTV load dynamics in KTR are characterized by a first increasing phase from baseline to M3, and a decreasing phase from M3 to M24. Some shorter-term studies in KTR have been published

Acknowledgments

The TTV R-GENE^® kits used in this study were kindly provided by Philippe Bourgeois and Carole Janis, bioMérieux, Marcy l'Etoile, France.

Declarations of interest

None

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Cited by (41)

Evaluation of Torque Teno Virus DNA Load as a Predictive Biomarker in Kidney Transplant Recipients Converted from Calcineurin Inhibitors to Belatacept
2024, Kidney International Reports
Belatacept is a relevant alternative to calcineurin inhibitors (CNIs) after kidney transplantation (KT). Circulating Torque Teno virus (TTV) DNA load is correlated to infections and rejection risks post-KT in patients treated with CNIs. The aim of this study was to assess the TTV DNA load profile in kidney transplant recipients converted from CNIs to belatacept and explore its use as a predictive biomarker.
Sixty-eight single-center kidney transplanted recipients who were converted from CNIs to belatacept between June, 2015 and December, 2020 were included in this study. Whole blood TTV DNA load was measured before, at 3, 6, and 12 months post-belatacept conversion. Our primary end point was to assess the TTV DNA load profile and correlate the results with rejection and opportunistic infection (OPI).
TTV DNA load remained stable after belatacept conversion, that is, 3.8 (3.1–4.9), 4.4 (3.2–5.4), 4.0 (3.0–5.7) and 4.2 (3.0–5.2) log₁₀ copies/ml at baseline, 3, 6, and 12 months, respectively. No correlation was found between TTV DNA load and post-KT complications. Chronic allograft dysfunction at 1 year postconversion was associated with a lower TTV DNA load after 6 and 12-months (P = 0.014 and P = 0.021, respectively). A higher TTV DNA load was found in older patients and in those with higher body mass index (BMI) (P = 0.023 and P = 0.005, respectively).
Conversion from CNIs to belatacept did not affect TTV DNA load. OPIs or acute rejection occurrences were not associated with TTV DNA load. However, low TTV (lTTV) DNA load after 6 months postconversion may be a promising tool to predict graft dysfunction risk at 1-year postconversion.
Prospective cohort study of Torque Teno Virus (TTV) viral load kinetics and the association with graft rejection in renal transplant patients
2023, Journal of Clinical Virology
Graft survival is mainly determined by rejections and infectious complications in transplant recipients. Torque Teno Virus (TTV), a nonpathogenic and ubiquitous single-stranded DNA virus, has been proposed as a biomarker of the immune status in transplant patients. This study aimed to determine the correlation between a Home-Brew TTV PCR and R-GENE®PCR; the TTV viral load kinetics in renal transplant recipients and the association with graft rejection.
Prospective cohort study on 107 adult renal transplant recipients. TTV viral load was determined in 746 plasma samples collected before and after renal transplantation by a Home-Brew PCR and a commercial PCR (R-GENE®PCR). Associations of TTV viral load with graft rejections were analyzed.
Agreement of both PCR assays was 93.2% and Pearson correlation coefficient was r: 0.902 (95%CI: 0.8881–0.9149, p < 0.0001). TTV viral load kinetics showed an initial gradual increase reaching a peak at 3 months. This highest value was followed by a slight decrease, reaching a plateau significantly higher than the initial baseline at 6 months (p < 0.0001). Between (181–270) days post-transplantation, TTV median viral load in patients with graft rejection was significantly lower, 3.59 Log₁₀ copies/mL (by Home-Brew PCR) and 3.10 Log₁₀ copies/mL (by R-GENE®PCR) compared to patients without graft rejection (6.14 and 5.96 Log₁₀ copies/mL, respectively).
Significantly lower TTV viral load was observed in patients with renal rejection occurring at a median of 243 days post-transplantation. Given the dynamic behavior of TTV viral load post-transplantation, cut-off values for risk stratification to predict rejection might be determined in relation to the post-transplant period.
High torque tenovirus (TTV) load before first vaccine dose is associated with poor serological response to COVID-19 vaccination in lung transplant recipients
2022, Journal of Heart and Lung Transplantation
Citation Excerpt :
Qualitative results and index values were used for analysis, with the cut-off for positive set at 1.4 S/CO. DNA extraction from serum samples, and amplification of DNA was performed as previously described.21, 28 In brief, DNA extraction was carried out using the eMAG Nucleic Acid Extraction System (BioMerieux, Marcy, France).
Serological responses to COVID-19 vaccination are diminished in recipients of solid organ transplants, especially in lung transplant recipients (LTR), probably as result of immunosuppressive treatment. There is currently no marker of immunosuppression that can be used to predict the COVID-19 vaccination response. Here, we study whether torque tenovirus (TTV), a highly prevalent virus can be used as an indicator of immunosuppression.
The humoral response to the mRNA 1273 vaccine was assessed in 103 LTR, who received a transplant between 4 and 237 months prior to vaccination, by measuring Spike (S)-specific IgG levels at baseline, 28 days after first, and 28 days after the second vaccination. TTV loads were determined by RT-PCR and Pearson's correlation coefficient was calculated to correlate serological responses to TTV load.
Humoral responses to COVID-19 vaccination were observed in 41 of 103 (40%) LTR at 28 days after the second vaccination. Sixty-two of 103 (60%) were non-responders. Lower TTV loads at baseline (significantly) correlated with higher S-specific antibodies and a higher percentage of responders. Lower TTV loads also strongly correlated with longer time since transplantation, indicating that participants with lower TTV loads were longer after transplantation.
This study shows a better humoral response to the SARS-CoV-2 vaccine in subjects with a lower TTV load pre-vaccination. In addition, TTV load correlates with the time after transplantation. Further studies on the use of TTV load in vaccination efficacy studies in immunocompromised cohorts should provide leads for the potential use of this marker for optimizing vaccination response.
Combining predictive markers for severe COVID-19: Torquetenovirus DNA load and SARS-CoV-2 RNAemia
2022, Journal of Clinical Virology
Citation Excerpt :
Its replication increases with age and is higher in males than females [8], and has been demonstrated to be associated with the immune status of the host. Immunocompetent individuals display low and stable TTV DNA loads, typically under 10,000 copies/mL [9], whereas immunocompromised patients, especially transplant patients, show much higher TTV DNA loads correlating with the intensity of their immunosuppression [10]. Low TTV DNA load, mirroring strong immune levels, is a marker of graft rejection risk [10,11] in these populations, whereas high TTV DNA load, reflecting poor immunity, is associated with microbial infection occurrence [12].
SARS-CoV-2 is the cause of worldwide COVID-19, which severity has been linked to the immune and inflammatory response. Here, we investigate Torquetenovirus (TTV) DNA load - a marker reflecting the intensity of the overall immune response - as well as SARS-CoV-2 RNAemia and IgM/IgG antibodies in COVID-19-positive patients.
Two hundred and fifteen COVID-19-positive patients were enrolled, including 87 severe cases and 128 mild-moderate cases. SARS-CoV-2 RNAemia and IgM/IgG antibodies, as well as TTV DNA loads, were measured on longitudinal plasma samples.
The rate of severe cases was higher in patients with low TTV DNA load in plasma considering a threshold of 700 copies/mL. In severe patients, SARS-CoV-2 RNAemia positivity rates were higher than those in mild-moderate cases at any timepoint. When combined, TTV DNA load and SARS-CoV-2 RNAemia allowed to predict the outcome of COVID-19 infection, with a higher risk (HR=12.4) of ICU admission in patients with low TTV DNA load and positive SARS-CoV-2 RNAemia.
TTV DNA load and SARS-CoV-2 RNAemia may be effective, non-invasive markers reflecting disease severity and poor outcome that could be conveniently measured in a clinical laboratory setting, as soon as COVID-19 diagnosis is made.
Non-invasive molecular biomarkers for monitoring solid organ transplantation: A comprehensive overview
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Torquetenovirus viremia for early prediction of graft rejection after kidney transplantation

Summary

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Patients

TTV load kinetics

Discussion

Acknowledgments

Declarations of interest

Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg

Cell

Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis

J Heart Lung Transplant Off Publ Int Soc Heart Transplant

J Clin Virol Off Publ Pan Am Soc Clin Virol

Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg

J Clin Virol Off Publ Pan Am Soc Clin Virol

Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg

45 years after the discovery of human polyomaviruses BK and JC: time to speed up the understanding of associated diseases and treatment approaches

Crit Rev Microbiol