Top

Published in:

Open Access 01-12-2021 | Kidney Transplantation | Mini review

Novel ways to monitor immunosuppression in pediatric kidney transplant recipients—underlying concepts and emerging data

Authors: Thurid Ahlenstiel-Grunow, Lars Pape

Published in: Molecular and Cellular Pediatrics | Issue 1/2021

Abstract

After pediatric kidney transplantation, immunosuppressive therapy is given to avoid acute and chronic rejections. However, the immunosuppression causes an increased risk of severe viral complications and bacterial infections and is associated with serious side effects. It is therefore crucial to achieve the optimal individual balance between over- and under-immunosuppression and thereby avoid unnecessary exposure to immunosuppressive drugs. In routine use, steering of immunosuppressants is performed primarily by monitoring of trough levels that mirror pharmacokinetics (although not, however, pharmacodynamics). Other diagnostic and prognostic markers to assess the individual intensity of immunosuppression are missing. Potential methods to determine immune function and grade of immunosuppression, such as analysis of the torque teno virus (TTV) load, QuantiFERON Monitor®, and ImmuKnow® as well as virus-specific T cells (Tvis), are currently being evaluated. In some studies TTV load, QuantiFERON Monitor® and ImmuKnow® were associated with the risk for post-transplant rejections and infections, but randomized controlled trials after pediatric kidney transplantation are not available. Post-transplant monitoring of Tvis levels seem to be promising because Tvis control virus replication and have been shown to correlate with virus-specific as well as general cellular immune defense, which represents the individual’s susceptibility to infections. Additional Tvis-monitoring provides an innovative opportunity to personalize the antiviral management and the dosing of the immunosuppressive therapy after pediatric kidney transplantation to avoid unnecessary therapeutic interventions and identify over-immunosuppression.

Trompeter R, Filler G, Webb NJ, Watson AR, Milford DV, Tyden G, Grenda R, Janda J, Hughes D, Ehrich JH, Klare B, Zacchello G, Bjorn Brekke I, McGraw M, Perner F, Ghio L, Balzar E, Friman S, Gusmano R, Stolpe J (2002) Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 17(3):141–149. https://doi.org/10.1007/s00467-001-0795-9CrossRefPubMed

Naesens M, Kuypers DR, Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4(2):481–508. https://doi.org/10.2215/CJN.04800908CrossRefPubMed

Franke D, Thomas L, Steffens R, Pavicic L, Gellermann J, Froede K, Querfeld U, Haffner D, Zivicnjak M (2015) Patterns of growth after kidney transplantation among children with ESRD. Clin J Am Soc Nephrol 10(1):127–134. https://doi.org/10.2215/CJN.02180314CrossRefPubMed

Zhang H, Zheng Y, Liu L, Fu Q, Li J, Huang Q, Liu H, Deng R, Wang C (2016) Steroid avoidance or withdrawal regimens in paediatric kidney transplantation: a meta-analysis of randomised controlled trials. Plos One 11(3):e0146523. https://doi.org/10.1371/journal.pone.0146523CrossRefPubMedPubMedCentral

Tsampalieros A, Knoll GA, Molnar AO, Fergusson N, Fergusson DA (2017) Corticosteroid use and growth after pediatric solid organ transplantation: a systematic review and meta-analysis. Transplantation 101(4):694–703. https://doi.org/10.1097/TP.0000000000001320CrossRefPubMedPubMedCentral

Schober T, Framke T, Kreipe H, Schulz TF, Grosshennig A, Hussein K, Baumann U, Pape L, Schubert S, Wingen AM, Jack T, Koch A, Klein C, Maecker-Kolhoff B (2013) Characteristics of early and late PTLD development in pediatric solid organ transplant recipients. Transplantation 95(1):240–246. https://doi.org/10.1097/TP.0b013e318277e344CrossRefPubMed

Hocker B, Zencke S, Pape L, Krupka K, Koster L, Fichtner A, Dello Strologo L, Guzzo I, Topaloglu R, Kranz B, Konig J, Bald M, Webb NJ, Noyan A, Dursun H, Marks S, Ozcakar ZB, Thiel F, Billing H, Pohl M, Fehrenbach H, Schnitzler P, Bruckner T, Ahlenstiel-Grunow T, Tonshoff B (2016) Impact of everolimus and low-dose cyclosporin on cytomegalovirus replication and disease in pediatric renal transplantation. Am J Transplant 16(3):921–929. https://doi.org/10.1111/ajt.13649CrossRefPubMed

Hocker B, Zencke S, Krupka K, Fichtner A, Pape L, Dello Strologo L, Guzzo I, Topaloglu R, Kranz B, Konig J, Bald M, Webb NJ, Noyan A, Dursun H, Marks S, Yalcinkaya F, Thiel F, Billing H, Pohl M, Fehrenbach H, Bruckner T, Tonshoff B (2016) Cytomegalovirus infection in pediatric renal transplantation and the impact of chemoprophylaxis with (val-)ganciclovir. Transplantation 100(4):862–870. https://doi.org/10.1097/TP.0000000000000888CrossRefPubMed

Josephson MA, Williams JW, Chandraker A, Randhawa PS (2006) Polyomavirus-associated nephropathy: update on antiviral strategies. Transpl Infect Dis 8(2):95–101. https://doi.org/10.1111/j.1399-3062.2006.00150.xCrossRefPubMed

10.

Hocker B, Schneble L, Murer L, Carraro A, Pape L, Kranz B, Oh J, Zirngibl M, Dello Strologo L, Buscher A, Weber LT, Awan A, Pohl M, Bald M, Printza N, Rusai K, Peruzzi L, Topaloglu R, Fichtner A, Krupka K, Koster L, Bruckner T, Schnitzler P, Hirsch HH, Tonshoff B (2019) Epidemiology of and risk factors for BK polyomavirus replication and nephropathy in pediatric renal transplant recipients: an international CERTAIN registry study. Transplantation 103(6):1224–1233. https://doi.org/10.1097/TP.0000000000002414CrossRefPubMed

11.

Laurent A, Klich A, Roy P, Lina B, Kassai B, Bacchetta J, Cochat P (2018) Pediatric renal transplantation: a retrospective single-center study on epidemiology and morbidity due to EBV. Pediatr Transplant 22(3):e13151. https://doi.org/10.1111/petr.13151CrossRefPubMed

12.

Preiksaitis JK, Brennan DC, Fishman J, Allen U (2005) Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transplant 5(2):218–227. https://doi.org/10.1111/j.1600-6143.2004.00692.xCrossRefPubMed

13.

Comoli P, Maccario R, Locatelli F, Valente U, Basso S, Garaventa A, Toma P, Botti G, Melioli G, Baldanti F, Nocera A, Perfumo F, Ginevri F (2005) Treatment of EBV-related post-renal transplant lymphoproliferative disease with a tailored regimen including EBV-specific T cells. Am J Transplant 5(6):1415–1422. https://doi.org/10.1111/j.1600-6143.2005.00854.xCrossRefPubMed

14.

Kanzelmeyer NK, Maecker-Kolhoff B, Zierhut H, Lerch C, Verboom M, Haffner D, Pape L (2018) Graft outcomes following diagnosis of post-transplant lymphoproliferative disease in pediatric kidney recipients: a retrospective study. Transpl Int 31(4):367–376. https://doi.org/10.1111/tri.13071CrossRefPubMed

15.

Danger R, Sawitzki B, Brouard S (2016) Immune monitoring in renal transplantation: the search for biomarkers. Eur J Immunol 46(12):2695–2704. https://doi.org/10.1002/eji.201545963CrossRefPubMed

16.

Solis M, Velay A, Gantner P, Bausson J, Filipputtu A, Freitag R, Moulin B, Caillard S, Fafi-Kremer S (2019) Torquetenovirus viremia for early prediction of graft rejection after kidney transplantation. J Infect 79(1):56–60. https://doi.org/10.1016/j.jinf.2019.05.010CrossRefPubMed

17.

He J, Li Y, Zhang H, Wei X, Zheng H, Xu C, Bao X, Yuan X, Hou J (2013) Immune function assay (ImmuKnow) as a predictor of allograft rejection and infection in kidney transplantation. Clin Transplant 27:351CrossRef

18.

Sageshima J, Ciancio G, Chen L, Dohi T, El-Hinnawi A, Paloyo S, Gaynor JJ, Mattiazzi A, Guerra G, Kupin W, Roth D, Ruiz P, Burke GW (2014) Lack of clinical association and effect of peripheral WBC counts on immune cell function test in kidney transplant recipients with T-cell depleting induction and steroid-sparing maintenance therapy. Transpl Immunol 30(2-3):88–92. https://doi.org/10.1016/j.trim.2014.01.003CrossRefPubMed

19.

Ravaioli M, Neri F, Lazzarotto T, Bertuzzo VR, Di Gioia P, Stacchini G, Morelli MC, Ercolani G, Cescon M, Chiereghin A, Del Gaudio M, Cucchetti A, Pinna AD (2015) Immunosuppression modifications based on an immune response assay: results of a randomized, controlled trial. Transplantation 99(8):1625–1632. https://doi.org/10.1097/TP.0000000000000650CrossRefPubMed

20.

Wang Z, Liu X, Lu P, Han Z, Tao J, Wang J, Liu K, Wu B, Yin C, Tan R, Gu M (2014) Performance of the ImmuKnow assay in differentiating infection and acute rejection after kidney transplantation: a meta-analysis. Transplant Proc 46(10):3343–3351. https://doi.org/10.1016/j.transproceed.2014.09.109CrossRefPubMed

21.

Mian M, Natori Y, Ferreira V, Selzner N, Husain S, Singer L, Kim SJ, Humar A, Kumar D (2018) Evaluation of a novel global immunity assay to predict infection in organ transplant recipients. Clin Infect Dis 66(9):1392–1397. https://doi.org/10.1093/cid/cix1008CrossRefPubMed

22.

Rezahosseini O, Drabe CH, Sorensen SS, Rasmussen A, Perch M, Ostrowski SR, Nielsen SD (2019) Torque-teno virus viral load as a potential endogenous marker of immune function in solid organ transplantation. Transplant Rev (Orlando) 33(3):137–144. https://doi.org/10.1016/j.trre.2019.03.004CrossRef

23.

Focosi D, Macera L, Pistello M, Maggi F (2014) Torque teno virus viremia correlates with intensity of maintenance immunosuppression in adult orthotopic liver transplant. J Infect Dis 210(4):667–668. https://doi.org/10.1093/infdis/jiu209CrossRefPubMed

24.

Christensen JK, Eugen-Olsen J, SLrensen M, Ullum H, Gjedde SB, Pedersen BK, Nielsen JO, Krogsgaard K (2000) Prevalence and prognostic significance of infection with TT virus in patients infected with human immunodeficiency virus. J Infect Dis 181(5):1796–1799. https://doi.org/10.1086/315440CrossRefPubMed

25.

Fernandez-Ruiz M, Albert E, Gimenez E, Ruiz-Merlo T, Parra P, Lopez-Medrano F, San Juan R, Polanco N, Andres A, Navarro D, Aguado JM (2019) Monitoring of alphatorquevirus DNA levels for the prediction of immunosuppression-related complications after kidney transplantation. Am J Transplant 19(4):1139–1149. https://doi.org/10.1111/ajt.15145CrossRefPubMed

26.

Strassl R, Doberer K, Rasoul-Rockenschaub S, Herkner H, Gorzer I, Klager JP, Schmidt R, Haslacher H, Schiemann M, Eskandary FA, Kikic Z, Reindl-Schwaighofer R, Puchhammer-Stockl E, Bohmig GA, Bond G (2019) Torque teno virus for risk stratification of acute biopsy-proven alloreactivity in kidney transplant recipients. J Infect Dis 219(12):1934–1939. https://doi.org/10.1093/infdis/jiz039CrossRefPubMedPubMedCentral

27.

Strassl R, Schiemann M, Doberer K, Gorzer I, Puchhammer-Stockl E, Eskandary F, Kikic Z, Gualdoni GA, Vossen MG, Rasoul-Rockenschaub S, Herkner H, Bohmig GA, Bond G (2018) Quantification of torque teno virus viremia as a prospective biomarker for infectious disease in kidney allograft recipients. J Infect Dis 218(8):1191–1199. https://doi.org/10.1093/infdis/jiy306CrossRefPubMedPubMedCentral

28.

Doberer K, Haupenthal F, Nackenhorst M, Bauernfeind F, Dermuth F, Eigenschink M, Schiemann M, Klager J, Gorzer I, Eskandary F, Reindl-Schwaighofer R, Kikic Z, Bohmig G, Strassl R, Regele H, Puchhammer-Stockl E, Bond G (2020) Torque teno virus load is associated with sub-clinical alloreactivity in kidney transplant recipients: a prospective observational trial. Transplantation. https://doi.org/10.1097/TP.0000000000003619

29.

Beland K, Dore-Nguyen M, Gagne MJ, Patey N, Brassard J, Alvarez F, Halac U (2014) Torque teno virus in children who underwent orthotopic liver transplantation: new insights about a common pathogen. J Infect Dis 209(2):247–254. https://doi.org/10.1093/infdis/jit423CrossRefPubMed

30.

Schachtner T, Stein M, Reinke P (2017) CMV-specific T cell monitoring offers superior risk stratification of CMV-seronegative kidney transplant recipients of a CMV-seropositive donor. Transplantation 101(10):e315–e325. https://doi.org/10.1097/TP.0000000000001825CrossRefPubMed

31.

Schultze-Florey RE, Tischer S, Schwerk N, Heim A, Eiz-Vesper B, Maecker-Kolhoff B (2016) Monitoring of adenovirus (ADV)-specific T cells in a boy with ADV pneumonia and disseminated disease after lung transplantation. Transpl Infect Dis 18(5):756–760. https://doi.org/10.1111/tid.12569CrossRefPubMed

32.

Falco DA, Nepomuceno RR, Krams SM, Lee PP, Davis MM, Salvatierra O, Alexander SR, Esquivel CO, Cox KL, Frankel LR, Martinez OM (2002) Identification of epstein-barr virus-specific CD8+ T lymphocytes in the circulation of pediatric transplant recipients. Transplantation 74(4):501–510. https://doi.org/10.1097/00007890-200208270-00012CrossRefPubMed

33.

Comoli P, Azzi A, Maccario R, Basso S, Botti G, Basile G, Fontana I, Labirio M, Cometa A, Poli F, Perfumo F, Locatelli F, Ginevri F (2004) Polyomavirus BK-specific immunity after kidney transplantation. Transplantation 78(8):1229–1232. https://doi.org/10.1097/01.TP.0000137932.44791.D3CrossRefPubMed

34.

Ahlenstiel-Grunow T, Liu X, Schild R, Oh J, Taylan C, Weber LT, Staude H, Verboom M, Schroder C, Sabau R, Grosshennig A, Pape L (2021) Steering transplant immunosuppression by measuring virus-specific T cell levels: the randomized, controlled IVIST trial. J Am Soc Nephrol 32(2):502–516. https://doi.org/10.1681/ASN.2020050645. Epub 2020 Dec 15.

35.

Borsum N, Verboom M, Ahlenstiel-Grunow T, Pape L (2019) Cytokine profiles in children after pediatric kidney transplantation with acute cellular compared to chronic antibody-mediated rejection and stable patients: a pilot study. Transplant Direct 5(11):e501. https://doi.org/10.1097/TXD.0000000000000943CrossRefPubMedPubMedCentral

36.

Sester M, Leboeuf C, Schmidt T, Hirsch HH (2016) The “ABC” of virus-specific T cell immunity in solid organ transplantation. Am J Transplant 16(6):1697–1706. https://doi.org/10.1111/ajt.13684CrossRefPubMed

37.

Ahlenstiel-Grunow T, Pape L (2021) Virus-specific T cells in pediatric renal transplantation. Pediatr Nephrol 36(4):789–796. https://doi.org/10.1007/s00467-020-04522-6CrossRefPubMed

38.

Ahlenstiel-Grunow T, Koch A, Grosshennig A, Fromke C, Sester M, Sester U, Schroder C, Pape L (2014) A multicenter, randomized, open-labeled study to steer immunosuppressive and antiviral therapy by measurement of virus (CMV, ADV, HSV)-specific T cells in addition to determination of trough levels of immunosuppressants in pediatric kidney allograft recipients (IVIST01-trial): study protocol for a randomized controlled trial. Trials 15:324CrossRef

Title: Novel ways to monitor immunosuppression in pediatric kidney transplant recipients—underlying concepts and emerging data
Authors: Thurid Ahlenstiel-Grunow
Lars Pape
Publication date: 01-12-2021
Publisher: Springer Berlin Heidelberg
Keywords: Kidney Transplantation
Kidney Transplantation
Kidney Transplantation
Kidney Transplantation
Kidney Transplantation
Kidney Transplantation
Biomarkers
Published in: Molecular and Cellular Pediatrics / Issue 1/2021
Electronic ISSN: 2194-7791
DOI: https://doi.org/10.1186/s40348-021-00118-8

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Novel ways to monitor immunosuppression in pediatric kidney transplant recipients—underlying concepts and emerging data

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

A fresh look to the phenotype in mono-allelic likely pathogenic variants of the leptin and the leptin receptor gene

Combined RT-qPCR and pyrosequencing of a Spike glycoprotein polybasic cleavage motif can uncover pediatric SARS-CoV-2 infections associated with heterogeneous presentation

Perinatal origins of chronic lung disease: mechanisms–prevention–therapy—sphingolipid metabolism and the genetic and perinatal origins of childhood asthma

Translational research approaches to study pediatric polycystic kidney disease

ESPED survey on newly diagnosed immune thrombocytopenia in childhood: how much treatment do we give?

The role of the immune system in idiopathic nephrotic syndrome