Torquetenovirus Serum Load and Long-Term Outcomes in Renal Transplant Recipients
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. TTV Viral Load Measurements
2.3. Clinical End Points
2.4. Data Analysis
3. Results
3.1. Recipient Demographics
3.2. TTV and All-Cause Mortality
3.3. TTV and Death Due to a Cause
3.4. TTV and Graft Failure
3.5. Time since Transplantation and TTV
4. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Meier-Kriesche, H.-U.; Schold, J.D.; Srinivas, T.R.; Kaplan, B. Lack of Improvement in Renal Allograft Survival Despite a Marked Decrease in Acute Rejection Rates Over the Most Recent Era. Am. J. Transplant. 2004, 4, 378–383. [Google Scholar] [CrossRef] [PubMed]
- Chand, S.; Atkinson, D.; Collins, C.; Briggs, D.; Ball, S.; Sharif, A.; Skordilis, K.; Vydianath, B.; Neil, D.; Borrows, R. The Spectrum of Renal Allograft Failure. PLoS ONE 2016, 11, e0162278. [Google Scholar] [CrossRef] [PubMed]
- Morrissey, P.E.; Reinert, S.; Yango, A.; Gautam, A.; Monaco, A.; Gohh, R. Factors Contributing to Acute Rejection in Renal Transplantation: The Role of Noncompliance. Transplant. Proc. 2005, 37, 2044–2047. [Google Scholar] [CrossRef] [PubMed]
- Maggi, F.; Bendinelli, M. Human Anelloviruses and the Central Nervous System. Rev. Med. Virol. 2010, 20, 392–407. [Google Scholar] [CrossRef] [PubMed]
- Nishizawa, T.; Okamoto, H.; Konishi, K.; Yoshizawa, H.; Miyakawa, Y.; Mayumi, M. A Novel DNA Virus (TTV) Associated with Elevated Transaminase Levels in Posttransfusion Hepatitis of Unknown Etiology. Biochem. Biophys. Res. Commun. 1997, 241, 92–97. [Google Scholar] [CrossRef] [PubMed]
- Okamoto, H.; Nishizawa, T.; Ukita, M. A Novel Unenveloped DNA Virus (TT Virus) Associated with Acute and Chronic Non-A to G Hepatitis. Intervirology 1999, 42, 196–204. [Google Scholar] [CrossRef]
- Spandole, S.; Cimponeriu, D.; Berca, L.M.; Mihaescu, G. Human Anelloviruses: An Update of Molecular, Epidemiological and Clinical Aspects. Arch. Virol. 2015, 160, 893–908. [Google Scholar] [CrossRef]
- Focosi, D.; Antonelli, G.; Pistello, M.; Maggi, F. Torquetenovirus: The Human Virome from Bench to Bedside. Clin. Microbiol. Infect. 2016, 22, 589–593. [Google Scholar] [CrossRef]
- Ott, C.; Duret, L.; Chemin, I.; Trepo, C.; Mandrand, B.; Komurian-Pradel, F. Use of a TT Virus ORF1 Recombinant Protein to Detect Anti-TT Virus Antibodies in Human Sera. J. Gen. Virol. 2000, 81, 2949–2958. [Google Scholar] [CrossRef][Green Version]
- Mankotia, D.S.; Irshad, M. Cloning and Expression of N22 Region of Torque Teno Virus (TTV) Genome and Use of Peptide in Developing Immunoassay for TTV Antibodies. Virol. J. 2014, 11, 96. [Google Scholar] [CrossRef]
- Nishizawa, T.; Okamoto, H.; Tsuda, F.; Aikawa, T.; Sugai, Y.; Konishi, K.; Akahane, Y.; Ukita, M.; Tanaka, T.; Miyakawa, Y.; et al. Quasispecies of TT Virus (TTV) with Sequence Divergence in Hypervariable Regions of the Capsid Protein in Chronic TTV Infection. J. Virol. 1999, 73, 9604–9608. [Google Scholar] [CrossRef] [PubMed]
- Kulifaj, D.; Essig, M.; Meynier, F.; Pichon, N.; Munteanu, E.; Moulinas, R.; Joannes, M.; Heckel, D.; Combrissson, J.; Barranger, C.; et al. Torque Teno Virus (TTV) in Immunosuppressed Host: Performances Studies of TTV R-Gene Registered Kit and Donors and Recipients Kidney Samples Genotyping: Presentation at ESCV 2016: Poster 166. J. Clin. Virol. 2016, 82, S103–S104. [Google Scholar] [CrossRef]
- Rezahosseini, O.; Drabe, C.H.; Sørensen, S.S.; Rasmussen, A.; Perch, M.; Ostrowski, S.R.; Nielsen, S.D. Torque-Teno Virus Viral Load as a Potential Endogenous Marker of Immune Function in Solid Organ Transplantation. Transplant. Rev. 2019, 33, 137–144. [Google Scholar] [CrossRef] [PubMed]
- Minović, I.; Eisenga, M.F.; Riphagen, I.J.; van den Berg, E.; Kootstra-Ros, J.E.; Frenay, A.-R.S.; van Goor, H.; Rimbach, G.; Esatbeyoglu, T.; Levy, A.P.; et al. Circulating Haptoglobin and Metabolic Syndrome in Renal Transplant Recipients. Sci. Rep. 2017, 7, 14264. [Google Scholar] [CrossRef]
- Eisenga, M.F.; Kieneker, L.M.; Soedamah-Muthu, S.S.; van den Berg, E.; Deetman, P.E.; Navis, G.J.; Gans, R.O.B.; Gaillard, C.A.J.M.; Bakker, S.J.L.; Joosten, M.M. Urinary Potassium Excretion, Renal Ammoniagenesis, and Risk of Graft Failure and Mortality in Renal Transplant Recipients. Am. J. Clin. Nutr. 2016, 104, 1703–1711. [Google Scholar] [CrossRef]
- Kulifaj, D.; Durgueil-Lariviere, B.; Meynier, F.; Munteanu, E.; Pichon, N.; Dubé, M.; Joannes, M.; Essig, M.; Hantz, S.; Barranger, C.; et al. Development of a Standardized Real Time PCR for Torque Teno Viruses (TTV) Viral Load Detection and Quantification: A New Tool for Immune Monitoring. J. Clin. Virol. 2018, 105, 118–127. [Google Scholar] [CrossRef]
- Solis, M.; Velay, A.; Gantner, P.; Bausson, J.; Filiputti, A.; Freitag, R.; Moulin, B.; Caillard, S.; Fafi-Kremer, S. Torquetenovirus Viremia for Early Prediction of Graft Rejection after Kidney Transplantation. J. Infect. 2019, 79, 56–60. [Google Scholar] [CrossRef]
- Macera, L.; Spezia, P.G.; Medici, C.; Rofi, E.; Re, M.D.; Focosi, D.; Mazzetti, P.; Navarro, D.; Antonelli, G.; Danesi, R.; et al. Comparative Evaluation of Molecular Methods for the Quantitative Measure of Torquetenovirus Viremia, the New Surrogate Marker of Immune Competence. J. Med. Virol. 2019. [Google Scholar] [CrossRef]
- World Health Organisation; Centre for Disease Control; Prevention. ICD-9-CM CDC Copy; National Center for Health Statistics: Hyattsville, MD, USA, 2015.
- World Health Organisation. ICD 9 001-139; Pan American Health Organization: Washington, DC, USA, 2012; ISBN 9241540044. [Google Scholar]
- Youden, W.J. Index for Rating Diagnostic Tests. Cancer 1950, 3, 32. [Google Scholar] [CrossRef]
- Görzer, I.; Haloschan, M.; Jaksch, P.; Klepetko, W.; Puchhammer-Stöckl, E. Plasma DNA Levels of Torque Teno Virus and Immunosuppression after Lung Transplantation. J. Hear. Lung Transplant. 2014, 33, 320–323. [Google Scholar] [CrossRef]
- Walton, A.H.; Muenzer, J.T.; Rasche, D.; Boomer, J.S.; Sato, B.; Brownstein, B.H.; Pachot, A.; Brooks, T.L.; Deych, E.; Shannon, W.D.; et al. Reactivation of Multiple Viruses in Patients with Sepsis. PLoS ONE 2014, 9, e98819. [Google Scholar] [CrossRef] [PubMed]
- Maggi, F.; Focosi, D.; Statzu, M.; Bianco, G.; Costa, C.; Macera, L.; Spezia, P.G.; Medici, C.; Albert, E.; Navarro, D.; et al. Early Post-Transplant Torquetenovirus Viremia Predicts Cytomegalovirus Reactivations In Solid Organ Transplant Recipients. Sci. Rep. 2018, 8, 15490–15498. [Google Scholar] [CrossRef] [PubMed]
- Maggi, F.; Pifferi, M.; Fornai, C.; Andreoli, E.; Tempestini, E.; Vatteroni, M.; Presciuttini, S.; Marchi, S.; Pietrobelli, A.; Boner, A.; et al. TT Virus in the Nasal Secretions of Children with Acute Respiratory Diseases: Relations to Viremia and Disease Severity. J. Virol. 2003, 77, 2418–2425. [Google Scholar] [CrossRef] [PubMed]
- Nordén, R.; Magnusson, J.; Lundin, A.; Tang, K.-W.; Nilsson, S.; Lindh, M.; Andersson, L.-M.; Riise, G.C.; Westin, J. Quantification of Torque Teno Virus and Epstein-Barr Virus Is of Limited Value for Predicting the Net State of Immunosuppression After Lung Transplantation. Open Forum Infect. Dis. 2018, 5, ofy050. [Google Scholar] [CrossRef] [PubMed]
- Shang, D.; Lin, Y.H.; Rigopoulou, I.; Chen, B.; Alexander, G.J.M.; Allain, J.-P. Detection of TT Virus DNA in Patients with Liver Disease and Recipients of Liver Transplant. J. Med. Virol. 2000, 61, 455–461. [Google Scholar] [CrossRef]
- Burra, P.; Masier, A.; Boldrin, C.; Calistri, A.; Andreoli, E.; Senzolo, M.; Zorzi, M.; Sgarabotto, D.; Guido, M.; Cillo, U.; et al. Torque Teno Virus: Any Pathological Role in Liver Transplanted Patients? Transpl. Int. 2008, 21, 972–979. [Google Scholar] [CrossRef]
- Béland, K.; Dore-Nguyen, M.; Gagné, M.-J.; Patey, N.; Brassard, J.; Alvarez, F.; Halac, U. Torque Teno Virus in Children Who Underwent Orthotopic Liver Transplantation: New Insights About a Common Pathogen. J. Infect. Dis. 2014, 209, 247–254. [Google Scholar] [CrossRef]
- Görzer, I.; Jaksch, P.; Kundi, M.; Seitz, T.; Klepetko, W.; Puchhammer-Stöckl, E. Pre-Transplant Plasma Torque Teno Virus Load and Increase Dynamics after Lung Transplantation. PLoS ONE 2015, 10, e0122975. [Google Scholar] [CrossRef]
- Görzer, I.; Jaksch, P.; Strassl, R.; Klepetko, W.; Puchhammer-Stöckl, E. Association between Plasma Torque Teno Virus Level and Chronic Lung Allograft Dysfunction after Lung Transplantation. J. Hear. Lung Transplant. 2017, 36, 366–368. [Google Scholar] [CrossRef]
- Schiemann, M.; Puchhammer-Stöckl, E.; Eskandary, F.; Kohlbeck, P.; Rasoul-Rockenschaub, S.; Heilos, A.; Kozakowski, N.; Görzer, I.; Kikić, Ž.; Herkner, H.; et al. Torque Teno Virus Load-Inverse Association with Antibody-Mediated Rejection after Kidney Transplantation. Transplantation 2017, 101, 360–367. [Google Scholar] [CrossRef]
- Strassl, R.; Doberer, K.; Rasoul-Rockenschaub, S.; Herkner, H.; Görzer, I.; Kläger, J.P.; Schmidt, R.; Haslacher, H.; Schiemann, M.; Eskandary, F.A.; et al. Torque Teno Virus for Risk Stratification of Acute Biopsyproven Alloreactivity in Kidney Transplant Recipients. J. Infect. Dis. 2019, 219, 1934–1939. [Google Scholar] [CrossRef] [PubMed]
- El-Zoghby, Z.M.; Stegall, M.D.; Lager, D.J.; Kremers, W.K.; Amer, H.; Gloor, J.M.; Cosio, F.G. Identifying Specific Causes of Kidney Allograft Loss. Am. J. Transplant. 2009, 9, 527–535. [Google Scholar] [CrossRef] [PubMed]
- Sellarés, J.; De Freitas, D.G.; Mengel, M.; Reeve, J.; Einecke, G.; Sis, B.; Hidalgo, L.G.; Famulski, K.; Matas, A.; Halloran, P.F. Understanding the Causes of Kidney Transplant Failure: The Dominant Role of Antibody-Mediated Rejection and Nonadherence. Am. J. Transplant. 2012, 12, 388–399. [Google Scholar] [CrossRef] [PubMed]
- Fernández-Ruiz, M.; Albert, E.; Giménez, E.; Ruiz-Merlo, T.; Parra, P.; López-Medrano, F.; San Juan, R.; Polanco, N.; Andrés, A.; Navarro, D.; et al. Monitoring of Alphatorquevirus DNA Levels for the Prediction of Immunosuppression-Related Complications after Kidney Transplantation. Am. J. Transplant. 2019, 19, 1139–1149. [Google Scholar] [CrossRef] [PubMed]
- Strassl, R.; Schiemann, M.; Doberer, K.; Görzer, I.; Puchhammer-Stöckl, E.; Eskandary, F.; Kikic, Ž.; Gualdoni, G.A.; Vossen, M.G.; Rasoul-Rockenschaub, S.; et al. Quantification of Torque Teno Virus Viremia as a Prospective Biomarker for Infectious Disease in Kidney Allograft Recipients. J. Infect. Dis. 2018, 218, 1191–1199. [Google Scholar] [CrossRef]
- Rocchi, J.; Ricci, V.; Albani, M.; Lanini, L.; Andreoli, E.; Macera, L.; Pistello, M.; Ceccherini-Nelli, L.; Bendinelli, M.; Maggi, F. Torquetenovirus DNA Drives Proinflammatory Cytokines Production and Secretion by Immune Cells via Toll-like Receptor 9. Virology 2009, 394, 235–242. [Google Scholar] [CrossRef]
Undetectable TTV | Low | Medium | High | p | |
---|---|---|---|---|---|
Number of Patients (%) | 117 (18) | 183 (27) | 184 (28) | 182 (27) | |
Age (years) | 49 ± 14 *a | 53 ± 16 | 53 ± 13 | 55 ± 12 | 0.01 * |
Male (%) | 57 (49) | 103 (56) | 106 (58) | 112 (62) | 0.18 |
Weight (Kg) | 77 ± 15 | 81 ± 16 | 81 ± 16 | 81 ± 18 | 0.15 |
BMI (Kg/m2) | 26.0 ± 4.3 | 26.6 ± 4.5 | 27.0 ± 5.1 | 26.8 ± 5.0 | 0.33 |
Renal Function | |||||
Serum creatine (umol/L) | 132 ± 67 | 135 ± 63 | 138 ± 57 | 145 ± 54 | 0.23 |
eGFR (mL/1.73 m2) | 50 ± 20 *b | 47 ± 20 *b | 45 ± 18 | 40 ± 16 *b | <0.001 * |
Urinary protein excretion (g/24 h) | 0.18 (0.00–0.27) | 0.20 (0.00–0.41) | 0.19 (0.00–0.47) | 0.19 (0.00–0.47) | 0.49 |
Proteinuria present, n (%) | 21 (18) | 42 (23) | 46 (25) | 40 (22) | 0.57 |
Albuminuria (mg/24 h) | 41 (8–144) | 43 (11–189) | 42 (12–235) | 36 (9–202) | 0.94 |
Transplantation | |||||
Living Donation, n (%) | 45 (39) | 62 (34) | 69 (38) | 56 (31) | 0.45 |
Warm Ischemic Time (minutes) | 42 ± 17 | 43 ± 15 | 43 ± 16 | 44 ± 13 | 0.53 |
Cold Ischaemic Time (hours) | 13 ± 10 | 14 ± 10 | 14 ± 11 | 15 ± 10 | 0.56 |
HLA I Antibodies, n (%) | 9 (8) | 33 (18) | 26 (14) | 33 (18) | 0.05 |
HLA II Antibodies, n (%) | 20 (17) | 37 (20) | 33 (18) | 25 (14) | 0.43 |
Transplant vintage (years) | 7.1 (4.0–12.4) | 6.4 (3.1–11.0) | 5.3 (2.2–14.3) | 3.2 (1.0–9.0) | <0.001 |
Acute rejection, n (%) | 24 (21) | 54 (30) | 58 (32) | 38 (21) | 0.04 |
Medication | |||||
Mono-therapy, n (%) | 4 (3) | 11 (6) | 4 (2) | 4 (2) | 0.15 |
Dual-therapy, n (%) | 82 (70) | 107 (59) | 94 (51) | 78 (43) | 0.01 |
Triple-therapy, n (%) | 31 (27) | 65 (36) | 86 (47) | 100 (55) | <0.001 |
Prednisolone dose (mg/day) | 7.5 (7.5–10) | 10 (7.5–10) | 10 (7.5–10) | 10 (7.5–10) | 0.02 |
MTOR inhibitors, n (%) | 3 (3) | 9 (5) | 3 (2) | 3 (2) | 0.17 |
Cyclosporin, n (%) | 24 (21) | 62 (34) | 82 (45) | 91 (50) | <0.001 |
Tacrolimus, n (%) | 18 (15) | 24 (13) | 30 (16) | 46 (25) | 0.03 |
Azathioprine, n (%) | 25 (21) | 27 (15) | 38 (21) | 23 (13) | 0.15 |
Mycophenolate, n (%) | 79 (68) | 126 (69) | 117 (64) | 120 (66) | 0.94 |
End Points | |||||
All-cause mortality | 6.3 (6.1–6.5) | 6.2 (6.0–6.4) | 6.0 (5.7–6.2) | 5.7 (5.4–6.0) | 0.001 |
Infectious Death | 6.6 (6.5–6.8) | 6.6 (6.5–6.8) | 6.7 (6.5–6.8) | 6.4 (6.2–6.6) | 0.08 |
Graft Failure | 6.1 (5.8–6.4) | 6.5 (6.3–6.6) | 6.3 (6.0–6.5) | 6.3 (6.0–6.5) | 0.5 |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Gore, E.J.; Gomes-Neto, A.W.; Wang, L.; Bakker, S.J.L.; Niesters, H.G.M.; de Joode, A.A.E.; Verschuuren, E.A.M.; Westra, J.; Leer-Buter, C.V. Torquetenovirus Serum Load and Long-Term Outcomes in Renal Transplant Recipients. J. Clin. Med. 2020, 9, 440. https://doi.org/10.3390/jcm9020440
Gore EJ, Gomes-Neto AW, Wang L, Bakker SJL, Niesters HGM, de Joode AAE, Verschuuren EAM, Westra J, Leer-Buter CV. Torquetenovirus Serum Load and Long-Term Outcomes in Renal Transplant Recipients. Journal of Clinical Medicine. 2020; 9(2):440. https://doi.org/10.3390/jcm9020440
Chicago/Turabian StyleGore, Edmund J., António W. Gomes-Neto, Lei Wang, Stephan J. L. Bakker, Hubert G. M. Niesters, Anoek A. E. de Joode, Erik A. M. Verschuuren, Johanna Westra, and Coretta Van Leer-Buter. 2020. "Torquetenovirus Serum Load and Long-Term Outcomes in Renal Transplant Recipients" Journal of Clinical Medicine 9, no. 2: 440. https://doi.org/10.3390/jcm9020440
APA StyleGore, E. J., Gomes-Neto, A. W., Wang, L., Bakker, S. J. L., Niesters, H. G. M., de Joode, A. A. E., Verschuuren, E. A. M., Westra, J., & Leer-Buter, C. V. (2020). Torquetenovirus Serum Load and Long-Term Outcomes in Renal Transplant Recipients. Journal of Clinical Medicine, 9(2), 440. https://doi.org/10.3390/jcm9020440