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  • Review Article
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Liquid biopsies: donor-derived cell-free DNA for the detection of kidney allograft injury

Nature Reviews Nephrology volume 17, pages 591–603 (2021)Cite this article

Subjects

Abstract

In kidney transplantation, the use of minimally invasive damage biomarkers that are more sensitive and specific than plasma creatinine will be crucial to enable early, actionable detection or exclusion of structural kidney damage due to acute or chronic rejection. Donor-derived cell-free DNA (dd-cfDNA), which can be quantified, for example, through next-generation sequencing, droplet digital PCR and quantitative PCR, is a candidate biomarker with great potential for enabling comprehensive monitoring of allograft injury. dd-cfDNA has a favourable overall diagnostic performance for the detection of rejection and its high negative predictive value might be especially useful for avoiding unnecessary biopsies. Elevated dd-cfDNA levels have been shown to be detectable before graft injury can be clinically identified using current diagnostic methods. Moreover, dd-cfDNA falls rapidly to baseline levels after successful treatment for rejection owing to its short half-life. dd-cfDNA can detect graft injury caused by immune activation owing to insufficient immunosuppression and might therefore also help guide immunosuppression dosing. The fractional abundance of dd-cfDNA can be affected by changes in the recipient cfDNA (for example, due to infection or physical exercise) but the use of absolute quantification of dd-cfDNA overcomes this limitation. Serial dd-cfDNA determinations might therefore facilitate cost-effective personalized clinical management of kidney transplant recipients to reduce premature graft loss.

Key points

  • Novel approaches that can improve the detection, monitoring and treatment of graft injury, especially due to rejection, are crucially needed in kidney transplantation.

  • Plasma creatinine is an insensitive, non-specific and delayed graft injury biomarker as detectable increases generally only occur 24–48 hours after injury; immunosuppressive drug monitoring can also predict potential toxicity but is not a biomarker of graft damage.

  • Donor-derived cell-free DNA (dd-cfDNA) has been shown to be a useful biomarker for comprehensive monitoring of allograft injury that overcomes the limitations of traditional approaches.

  • Serial dd-cfDNA determinations can suggest or rule out acute and chronic rejection, as well as other graft injuries, early, avoiding unnecessary biopsies.

  • dd-cfDNA determination allows detection of under-immunosuppression and is therefore useful for guiding immunosuppression minimization.

  • As a biomarker, dd-cfDNA has the potential to enable cost-effective close surveillance of transplant recipients to decrease both re-transplantation and premature graft loss.

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Fig. 1: Pathophysiological mechanisms of T cell-mediated and antibody-mediated rejection.
Fig. 2: Origin and fragmentation of blood and urinary dd-cfDNA after kidney transplantation.
Fig. 3: Efficiency of PCR amplification of fragmented cfDNA templates.
Fig. 4: Individualized therapy in kidney transplant recipients.

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References

  1. Eikmans, M. et al. Non-invasive biomarkers of acute rejection in kidney transplantation: novel targets and strategies. Front. Med. 5, 358 (2018).

    Article  Google Scholar 

  2. Held, P. J., McCormick, F., Ojo, A. & Roberts, J. P. A cost-benefit analysis of government compensation of kidney donors. Am. J. Transplant. 16, 877–885 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Australia and New Zealand Dialysis and Transplant Registry. ANZDATA 43rd Annual Report 2020 Ch. 7 (ANZDATA, 2020).

  4. Hart, A. et al. OPTN/SRTR 2019 annual data report: kidney. Am. J. Transplant. 21 (Suppl. 2), 21–137 (2021).

    Article  PubMed  Google Scholar 

  5. Desanti De Oliveira, B. et al. Molecular nephrology: types of acute tubular injury. Nat. Rev. Nephrol. 15, 599–612 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. American Society of Nephrology. American Society of Nephrology Renal Research Report. J. Am. Soc. Nephrol. 16, 1886–1903 (2005).

    Article  Google Scholar 

  7. First, M. R., Lee, D., Lewis, P. & Rose, S. An economic analysis of the cost effectiveness of blood gene expression profiling in kidney transplant recipients. J. Health Med. Econ. 3, 3 (2017).

    Article  Google Scholar 

  8. Van Loon, E. et al. Diagnostic performance of kSORT, a blood-based mRNA assay for noninvasive detection of rejection after kidney transplantation: a retrospective multicenter cohort study. Am. J. Transplant. 21, 740–750 (2021).

    Article  PubMed  CAS  Google Scholar 

  9. Patel, R. & Terasaki, P. I. Significance of the positive crossmatch test in kidney transplantation. N. Engl. J. Med. 280, 735–739 (1969).

    Article  CAS  PubMed  Google Scholar 

  10. Parajuli, S. et al. Subclinical antibody-mediated rejection after kidney transplantation: treatment outcomes. Transplantation 103, 1722–1729 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Schwarz, A. et al. Safety and adequacy of renal transplant protocol biopsies. Am. J. Transplant. 5, 1992–1996 (2005).

    Article  PubMed  Google Scholar 

  12. Miller, C. A. et al. Non-invasive approaches for the diagnosis of acute cardiac allograft rejection. Heart 99, 445–453 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Sellares, J. et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am. J. Transplant. 12, 388–399 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Friedewald, J. J. et al. Development and clinical validity of a novel blood-based molecular biomarker for subclinical acute rejection following kidney transplant. Am. J. Transplant. 19, 98–109 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Bouatou, Y. et al. Response to treatment and long-term outcomes in kidney transplant recipients with acute T cell-mediated rejection. Am. J. Transplant. 19, 1972–1988 (2019).

    CAS  PubMed  Google Scholar 

  16. Kim, M., Martin, S. T., Townsend, K. R. & Gabardi, S. Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options. Pharmacotherapy 34, 733–744 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Cornell, L. D., Smith, R. N. & Colvin, R. B. Kidney transplantation: mechanisms of rejection and acceptance. Annu. Rev. Pathol. 3, 189–220 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Roufosse, C. et al. A 2018 reference guide to the Banff classification of renal allograft pathology. Transplantation 102, 1795–1814 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yang, J. Y. & Sarwal, M. M. Transplant genetics and genomics. Nat. Rev. Genet. 18, 309–326 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Robinson, J. et al. The IMGT/HLA database. Nucleic Acids Res. 41, D1222–D1227 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. El-Awar, N., Jucaud, V. & Nguyen, A. HLA epitopes: the targets of monoclonal and alloantibodies defined. J. Immunol. Res. 2017, 3406230 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Marino, J., Paster, J. & Benichou, G. Allorecognition by T lymphocytes and allograft rejection. Front. Immunol. 7, 582 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Geneugelijk, K. & Spierings, E. PIRCHE-II: an algorithm to predict indirectly recognizable HLA epitopes in solid organ transplantation. Immunogenetics 72, 119–129 (2020).

    Article  PubMed  Google Scholar 

  24. Duquesnoy, R. J. Epitope-based human leukocyte antigen matching for transplantation: a personal perspective of its future. Curr. Opin. Organ Transplant. 23, 486–492 (2018).

    PubMed  Google Scholar 

  25. Geneugelijk, K. et al. Exploratory study of predicted indirectly recognizable HLA epitopes in mismatched hematopoietic cell transplantations. Front. Immunol. 10, 880 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wiebe, C. et al. Class II HLA epitope matching – A strategy to minimize de novo donor-specific antibody development and improve outcomes. Am. J. Transplant. 13, 3114–3122 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Sapir-Pichhadze, R. et al. HLA-DR and -DQ eplet mismatches and transplant glomerulopathy: a nested case-control study. Am. J. Transplant. 15, 137–148 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Moreau, A., Varey, E., Anegon, I. & Cuturi, M. C. Effector mechanisms of rejection. Cold Spring Harb. Perspect. Med. 3, a015461 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Haas, M. et al. The Banff 2017 kidney meeting report: revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am. J. Transplant. 18, 293–307 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Loupy, A. & Lefaucheur, C. Antibody-mediated rejection of solid-organ allografts. N. Engl. J. Med. 379, 1150–1160 (2018).

    Article  CAS  PubMed  Google Scholar 

  31. Baldwin, W. M. 3rd, Valujskikh, A. & Fairchild, R. L. Mechanisms of antibody-mediated acute and chronic rejection of kidney allografts. Curr. Opin. Organ Transplant. 21, 7–14 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Montgomery, R. A., Loupy, A. & Segev, D. L. Antibody-mediated rejection: new approaches in prevention and management. Am. J. Transplant. 18 (Suppl. 3), 3–17 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Wiebe, C. et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am. J. Transplant. 12, 1157–1167 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Zhang, Q. & Reed, E. F. The importance of non-HLA antibodies in transplantation. Nat. Rev. Nephrol. 12, 484–495 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cornaby, C. et al. B cell epitope spreading: mechanisms and contribution to autoimmune diseases. Immunol. Lett. 163, 56–68 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Allen, G. et al. Rapid accomodation of an A1 renal allograft after preconditioning for ABO-incompatible transplantation. Contrib. Nephrol. 162, 35–46 (2009).

    Article  PubMed  Google Scholar 

  37. Valenzuela, N. M. & Reed, E. F. Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies. J. Clin. Invest. 127, 2492–2504 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Levine, M. H. & Abt, P. L. Treatment options and strategies for antibody mediated rejection after renal transplantation. Semin. Immunol. 24, 136–142 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Wan, S. S. et al. The treatment of antibody-mediated rejection in kidney transplantation: an updated systematic review and meta-analysis. Transplantation 102, 557–568 (2018).

    Article  PubMed  Google Scholar 

  40. Loupy, A. et al. Subclinical rejection phenotypes at 1 year post-transplant and outcome of kidney allografts. J. Am. Soc. Nephrol. 26, 1721–1731 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Filippone, E. J., McCue, P. A. & Farber, J. L. Transplant glomerulopathy. Mod. Pathol. 31, 235–252 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Kovacs, G. et al. Association between transplant glomerulopathy and graft outcomes following kidney transplantation: a meta-analysis. PLoS ONE 15, e0231646 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. De Vlaminck, I. et al. Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci. Transl Med. 6, 241ra277 (2014).

    Article  CAS  Google Scholar 

  44. Lo, Y. M. et al. Presence of donor-specific DNA in plasma of kidney and liver-transplant recipients. Lancet 351, 1329–1330 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Han, D. S. C. et al. The biology of cell-free DNA fragmentation and the roles of DNASE1, DNASE1L3, and DFFB. Am. J. Hum. Genet. 106, 202–214 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sun, K. et al. Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc. Natl Acad. Sci. USA 112, E5503–E5512 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Beck, J., Urnovitz, H. B., Riggert, J., Clerici, M. & Schutz, E. Profile of the circulating DNA in apparently healthy individuals. Clin. Chem. 55, 730–738 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Sherwood, K. & Weimer, E. T. Characteristics, properties, and potential applications of circulating cell-free DNA in clinical diagnostics: a focus on transplantation. J. Immunol. Methods 463, 27–38 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Leung, F. et al. Circulating tumor DNA as a cancer biomarker: fact or fiction? Clin. Chem. 62, 1054–1060 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sanchez, C., Snyder, M. W., Tanos, R., Shendure, J. & Thierry, A. R. New insights into structural features and optimal detection of circulating tumor DNA determined by single-strand DNA analysis. NPJ Genom. Med. 3, 31 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Zheng, Y. W. et al. Nonhematopoietically derived DNA is shorter than hematopoietically derived DNA in plasma: a transplantation model. Clin. Chem. 58, 549–558 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Sharon, E. et al. Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype. PLoS Comput. Biol. 13, e1005629 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Snyder, T. M., Khush, K. K., Valantine, H. A. & Quake, S. R. Universal noninvasive detection of solid organ transplant rejection. Proc. Natl Acad. Sci. USA 108, 6229–6234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Beck, J. et al. Digital droplet PCR for rapid quantification of donor DNA in the circulation of transplant recipients as a potential universal biomarker of graft injury. Clin. Chem. 59, 1732–1741 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Grskovic, M. et al. Validation of a clinical-grade assay to measure donor-derived cell-free DNA in solid organ transplant recipients. J. Mol. Diagn. 18, 890–902 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Sigdel, T. K. et al. Optimizing detection of kidney transplant injury by assessment of donor-derived cell-free DNA via massively multiplex PCR. J. Clin. Med. 8, 19 (2019).

    Article  CAS  Google Scholar 

  57. Dauber, E. M. et al. Quantitative PCR of INDELs to measure donor-derived cell-free DNA–a potential method to detect acute rejection in kidney transplantation: a pilot study. Transpl. Int. 33, 298–309 (2020).

    Article  CAS  PubMed  Google Scholar 

  58. Goh, S. K., Muralidharan, V., Christophi, C., Do, H. & Dobrovic, A. Probe-free digital PCR quantitative methodology to measure donor-specific cell-free DNA after solid-organ transplantation. Clin. Chem. 63, 742–750 (2017).

    Article  CAS  PubMed  Google Scholar 

  59. Oellerich, M. et al. Donor-derived cell-free DNA testing in solid organ transplantation: a value proposition. J. Appl. Lab. Med. 5, 993–1004 (2020).

    Article  PubMed  Google Scholar 

  60. Zhou, Y. et al. A noninvasive and donor-independent method simultaneously monitors rejection and infection in patients with organ transplant. Transplant. Proc. 51, 1699–1705 (2019).

    Article  CAS  PubMed  Google Scholar 

  61. Macher, H. C. et al. Donor-specific circulating cell free DNA as a noninvasive biomarker of graft injury in heart transplantation. Clin. Chim. Acta 495, 590–597 (2019).

    Article  CAS  PubMed  Google Scholar 

  62. Whitlam, J. B. et al. Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction. Am. J. Transplant. 19, 1037–1049 (2019).

    Article  CAS  PubMed  Google Scholar 

  63. Oellerich, M. et al. Absolute quantification of donor-derived cell-free DNA as a marker of rejection and graft injury in kidney transplantation: results from a prospective observational study. Am. J. Transplant. 19, 3087–3099 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. De Vlaminck, I. The proportion of donor-specific cell-free DNA in blood as a marker of transplant rejection: not an absolute. Clin. Chem. 66, 1257–1258 (2020).

    Article  PubMed  Google Scholar 

  65. Garcia Moreira, V., Prieto Garcia, B., Baltar Martin, J. M., Ortega Suarez, F. & Alvarez, F. V. Cell-free DNA as a noninvasive acute rejection marker in renal transplantation. Clin. Chem. 55, 1958–1966 (2009).

    Article  PubMed  CAS  Google Scholar 

  66. Hummel, E. M. et al. Cell-free DNA release under psychosocial and physical stress conditions. Transl Psychiatry 8, 236 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rhodes, A., Wort, S. J., Thomas, H., Collinson, P. & Bennett, E. D. Plasma DNA concentration as a predictor of mortality and sepsis in critically ill patients. Crit. Care 10, R60 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Tug, S. et al. Exercise-induced increases in cell free DNA in human plasma originate predominantly from cells of the haematopoietic lineage. Exerc. Immunol. Rev. 21, 164–173 (2015).

    PubMed  Google Scholar 

  69. Knight, S. R., Thorne, A. & Lo Faro, M. L. Donor-specific cell-free DNA as a biomarker in solid organ transplantation. A systematic review. Transplantation 103, 273–283 (2019).

    Article  CAS  PubMed  Google Scholar 

  70. Wijtvliet, V. P. W. M. et al. Donor-derived cell-free DNA as a biomarker for rejection after kidney transplantation: a systematic review and meta-analysis. Transpl. Int. 33, 1626–1642 (2020).

    Article  CAS  PubMed  Google Scholar 

  71. Gielis, E. M. et al. Plasma donor-derived cell-free DNA kinetics after kidney transplantation using a single tube multiplex PCR assay. PLoS ONE 13, e0208207 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. De Vlaminck, I. et al. Noninvasive monitoring of infection and rejection after lung transplantation. Proc. Natl Acad. Sci. USA 112, 13336–13341 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Bloom, R. D. et al. Cell-free DNA and active rejection in kidney allografts. J. Am. Soc. Nephrol. 28, 2221–2232 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bromberg, J. S. et al. Biological variation of donor-derived cell-free DNA in renal transplant recipients: clinical implications. J. Appl. Lab. Med. 2, 309–321 (2017).

    Article  CAS  PubMed  Google Scholar 

  75. Schutz, E. et al. Time-dependent apparent increase in dd-cfDNA percentage in clinically stable patients between one and five years following kidney transplantation. Clin. Chem. 66, 1290–1299 (2020).

    Article  PubMed  Google Scholar 

  76. Lee, H. et al. Evaluation of digital PCR as a technique for monitoring acute rejection in kidney transplantation. Genomics Inform. 15, 2–10 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Agbor-Enoh, S. et al. Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: evidence from cell-free DNA analysis. J. Heart Lung Transpl. 37, 925–932 (2018).

    Article  Google Scholar 

  78. Gielis, E. M. et al. The use of plasma donor-derived, cell-free DNA to monitor acute rejection after kidney transplantation. Nephrol. Dial. Transplant. 35, 714–721 (2020).

    Article  CAS  PubMed  Google Scholar 

  79. Schutz, E. et al. Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: a prospective, observational, multicenter cohort study. PLoS Med. 14, e1002286 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Stoltz, D., Brubaker, A., Grskovic, M., Woodward, R. N. & A., G. Donor-derived cell-free DNA predicts biopsy-proven acute cellular rejection in pediatric kidney transplant recipients [abstract]. Am. J. Transplant. 17, 483 (2017).

    Google Scholar 

  81. Jordan, S. C. et al. Donor-derived cell-free DNA identifies antibody-mediated rejection in donor specific antibody positive kidney transplant recipients. Transplant. Direct 4, e379 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Stites, E. et al. High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury. Am. J. Transplant. 20, 2491–2498 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Beck, J. et al. Donor-derived cell-free DNA is a novel universal biomarker for allograft rejection in solid organ transplantation. Transplant. Proc. 47, 2400–2403 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Hidestrand, M. et al. Highly sensitive noninvasive cardiac transplant rejection monitoring using targeted quantification of donor-specific cell-free deoxyribonucleic acid. J. Am. Coll. Cardiol. 63, 1224–1226 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Kanzow, P. et al. Graft-derived cell-free DNA as an early organ integrity biomarker after transplantation of a marginal HELLP syndrome donor liver. Transplantation 98, e43–e45 (2014).

    Article  PubMed  Google Scholar 

  86. Agbor-Enoh, S. 2018 ATS BEAR cage winning proposal: cell-free DNA to improve lung transplant outcomes. Am. J. Respir. Crit. Care Med. 199, 1058–1060 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Agbor-Enoh, S. et al. Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation. J. Heart Lung Transpl. 36, 1004–1012 (2017).

    Article  Google Scholar 

  88. Huang, E. et al. Early clinical experience using donor-derived cell-free DNA to detect rejection in kidney transplant recipients. Am. J. Transplant. 19, 1663–1670 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Zhang, H. et al. Diagnostic performance of donor-derived plasma cell-free DNA fraction for antibody-mediated rejection in post renal transplant recipients: a prospective observational study. Front. Immunol. 11, 342 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Garg, N., Samaniego, M. D., Clark, D. & Djamali, A. Defining the phenotype of antibody-mediated rejection in kidney transplantation: advances in diagnosis of antibody injury. Transplant. Rev. 31, 257–267 (2017).

    Article  Google Scholar 

  91. Hoshino, J., Kaneku, H., Everly, M. J., Greenland, S. & Terasaki, P. I. Using donor-specific antibodies to monitor the need for immunosuppression. Transplantation 93, 1173–1178 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Johnson, K. M., Belfer, J. J., Peterson, G. R., Boelkins, M. R. & Dumkow, L. E. Managing COVID-19 in renal transplant recipients: a review of recent literature and case supporting corticosteroid-sparing immunosuppression. Pharmacotherapy 40, 517–524 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Oellerich, M. et al. Use of graft-derived cell-free DNA as an organ integrity biomarker to reexamine effective tacrolimus trough concentrations after liver transplantation. Ther. Drug Monit. 36, 136–140 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Hucker, A. et al. Non-adherence to immunosuppressants following renal transplantation: a protocol for a systematic review. BMJ Open 7, e015411 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Sigdel, T. K. et al. A rapid noninvasive assay for the detection of renal transplant injury. Transplantation 96, 97–101 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sawinski, D. et al. Persistent BK viremia does not increase intermediate-term graft loss but is associated with de novo donor-specific antibodies. J. Am. Soc. Nephrol. 26, 966–975 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Goussous, N. et al. Donor-derived cell-free DNA in infections in kidney transplant recipients: case series. Transplant. Direct 6, e568 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Hirsch, H. H. & Randhawa, P. S. AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation–guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin. Transpl. 33, e13528 (2019).

    Google Scholar 

  99. Shah, A. et al. Native kidney BK virus nephropathy, a systematic review. Transpl. Infect. Dis. 21, e13083 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Watkins, N. A. & Charames, G. S. Implementing next-generation sequencing in clinical practice. J. Appl. Lab. Med. 3, 338–341 (2018).

    Article  PubMed  Google Scholar 

  101. Milosevic, D. et al. Applying standard clinical chemistry assay validation to droplet digital PCR quantitative liquid biopsy testing. Clin. Chem. 64, 1732–1742 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Crescioli, C. Chemokines and transplant outcome. Clin. Biochem. 49, 355–362 (2016).

    Article  CAS  PubMed  Google Scholar 

  103. Brunet, M. et al. Barcelona consensus on biomarker-based immunosuppressive drugs management in solid organ transplantation. Ther. Drug Monit. 38 (Suppl. 1), S1–S20 (2016).

    Article  PubMed  Google Scholar 

  104. Yang, J. Y. C. et al. A urine score for noninvasive accurate diagnosis and prediction of kidney transplant rejection. Sci. Transl Med. 12, eaba2501 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ledeganck, K. J. et al. MicroRNAs in AKI and kidney transplantation. Clin. J. Am. Soc. Nephrol. 14, 454–468 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the very professional secretarial support provided by C. Zimara.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, University Medical Center Goettingen, Goettingen, Germany

    Michael Oellerich & Philip D. Walson

  2. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

    Karen Sherwood & Paul Keown

  3. Department of Medicine, University of British Columbia, Vancouver, BC, Canada

    Paul Keown

  4. Chronix Biomedical, Goettingen, Germany

    Ekkehard Schütz & Julia Beck

  5. Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Johannes Stegbauer & Lars Christian Rump

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All authors researched data for the article, made substantial contributions to discussions of the content, wrote the manuscript, and reviewed or edited the manuscript before submission.

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Competing interests

M.O. acts as consultant and scientific advisor to Chronix Biomedical and Liquid Biopsy Center (LBC) GmbH. E.S. and J.B. are employees of and own stock and intellectual property rights at Chronix Biomedical. P.D.W. receives reimbursement to travel from Hannover to University Medical Center Goettingen from the Liquid Biopsy Center (LBC) GmbH. The other authors declare no competing interests.

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Glossary

Class switching

A biological mechanism by which antibody isotypes change following B cell activation; each antibody isotype (IgA, IgD, IgE, IgG and IgM) has distinct properties and biological functions.

Affinity maturation

A biological mechanism by which antibodies produced by activated B cells develop increasing affinity for a specific antigen following repeated exposures to the antigen.

Antigen spreading

A mechanism by which the diversity of epitope recognition increases to enable broader antigen recognition during the immune response (also known as epitope spread or antigen cascade).

SNP-chip technology

A technology that uses immobilized probes and fluorescent labels to obtain genotypes for a large number of single-nucleotide polymorphisms (SNPs).

Shallow sequencing

A method of next-generation sequencing that produces a relatively low read number per sample resulting in a lower coverage than ‘deep’ sequencing methods.

Minor allele population frequency

The frequency of uncommon alleles in a population.

Limit of quantification

The lowest or highest analyte concentration at which the measurement procedure fulfils specifications for precision and accuracy.

Dynamic range

The range between the lower and upper limit of quantification

Limit of blank

The highest apparent analyte concentration obtained from measuring replicates of a sample without analyte.

Limit of detection

The smallest detectable amount of an analyte.

Bayesian approach

An approach to test result interpretation that takes the pre-test probability into account.

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Oellerich, M., Sherwood, K., Keown, P. et al. Liquid biopsies: donor-derived cell-free DNA for the detection of kidney allograft injury. Nat Rev Nephrol 17, 591–603 (2021). https://doi.org/10.1038/s41581-021-00428-0

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