Expanding the Non-Invasive Diagnosis of Acute Rejection in Kidney Transplants Through Detection of Donor-Derived DNA in Urine: Proof-of-Concept Study
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background: Approximately 10%–20% of kidney transplant (KT) recipients suffer from acute rejection (AR); thus, sensitive and accurate monitoring of allograft status is recommended. We evaluated the clinical utility of donor-derived DNA (dd-DNA) detection in the urine of KT recipients as a non-invasive means for diagnosing AR. Methods: Urine samples serially collected from 39 KT recipients were tested for 39 single-nucleotide variant loci selected according to technical criteria (i.e., high minor allele frequency and low analytical error) using next-generation sequencing. The fraction of dd-DNA was calculated and normalized by the urine creatinine (UCr) level (%dd-DNA/UCr). The diagnostic performance of %dd-DNA/UCr for AR was assessed by ROC curve analysis. Results: There was an increasing trend of %dd-DNA/UCr in the AR group before subsequent graft injury, which occurred before (median of 52 days) histological rejection. The serum creatinine (SCr) level differed significantly between the AR and non-AR groups at two and four months of follow-up, whereas %dd-DNA/UCr differed between the groups at six months of follow-up. The combination of %dd-DNA/UCr, SCr, and spot urine protein (UPtn)/UCr showed high discriminating power, with an area under the ROC curve of 0.93 (95% confidence interval: 0.81–1.00) and a high negative predictive value of 100.0%. Conclusions: Although the dd-DNA–based test cannot eliminate the need for biopsy, the high negative predictive value of this marker could increase the prebiopsy probability of detecting treatable injury to make biopsy an even more effective diagnostic tool.
Abstract
Background: Approximately 10%–20% of kidney transplant (KT) recipients suffer from acute rejection (AR); thus, sensitive and accurate monitoring of allograft status is recommended. We evaluated the clinical utility of donor-derived DNA (dd-DNA) detection in the urine of KT recipients as a non-invasive means for diagnosing AR. Methods: Urine samples serially collected from 39 KT recipients were tested for 39 single-nucleotide variant loci selected according to technical criteria (i.e., high minor allele frequency and low analytical error) using next-generation sequencing. The fraction of dd-DNA was calculated and normalized by the urine creatinine (UCr) level (%dd-DNA/UCr). The diagnostic performance of %dd-DNA/UCr for AR was assessed by ROC curve analysis. Results: There was an increasing trend of %dd-DNA/UCr in the AR group before subsequent graft injury, which occurred before (median of 52 days) histological rejection. The serum creatinine (SCr) level differed significantly between the AR and non-AR groups at two and four months of follow-up, whereas %dd-DNA/UCr differed between the groups at six months of follow-up. The combination of %dd-DNA/UCr, SCr, and spot urine protein (UPtn)/UCr showed high discriminating power, with an area under the ROC curve of 0.93 (95% confidence interval: 0.81–1.00) and a high negative predictive value of 100.0%. Conclusions: Although the dd-DNA–based test cannot eliminate the need for biopsy, the high negative predictive value of this marker could increase the prebiopsy probability of detecting treatable injury to make biopsy an even more effective diagnostic tool.
참고문헌 (34)
- Harada KM, "Risk factors associated with graft loss and patient survival after kidney transplantation", Transplant Proc, 41, pp.3667~3670 (2009)
- Thomas ME, "The definition of acute kidney injury and its use in practice", Kidney Int, 87, pp.62~73 (2015)
- Lachenbruch PA, "Biomarkers and surrogate endpoints in renal transplantation: present status and considerations for clinical trial design", Am J Transplant, 4, pp.451~457 (2004)
- Josephson MA, "Monitoring and managing graft health in the kidney transplant recipient", Clin J Am Soc Nephrol, 6, pp.1774~1780 (2011)
- Devadass CW, "Evaluation of renal allograft biopsies for graft dysfunction and relevance of C4d staining in antibody mediated rejection", J Clin Diagn Res, 10, pp.EC11~EC15 (2016)
- Held PJ, "A cost-benefit analysis of government compensation of kidney donors", Am J Transplant, 16, pp.877~875 (2016)
- Shahbaz SK, "High expression of TIM-3 and KIM-1 in blood and urine of renal allograft rejection patients", Transpl Immunol, 43-44, pp.11~20 (2017)
- Lorenzen JM, "Urinary miR-210 as a mediator of acute T-cell mediated rejection in renal allograft recipients", Am J Transplant, 11, pp.2221~2227 (2011)
- Lorenzen JM, "Long noncoding RNAs in urine are detectable and may enable early detection of acute T cell-mediated rejection of renal allografts", Clin Chem, 61, pp.1505~1514 (2015)
- Srinivasan M, "Effect of fixatives and tissue processing on the content and integrity of nucleic acids", Am J Pathol, 161, pp.1961~1971 (2002)
- Vaidya VS, "Biomarkers of acute kidney injury", Annu Rev Pharmacol Toxicol, 48, pp.463~493 (2008)
- Lo YM, "Presence of donor-specific DNA in plasma of kidney and liver-transplant recipients", Lancet, 351, pp.1329~1330 (1998)
- Beck J, "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, pp.1732~1741 (2013)
- Whitlam JB, "Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction", Am J Transplant, 19, pp.1037~1049 (2019)
- Bloom RD, "Cell-free DNA and active rejection in kidney allografts", J Am Soc Nephrol, 28, pp.2221~2232 (2017)
- Knight SR, "Donor-specific cell-free DNA as a biomarker in solid organ transplantation. A systematic review", Transplantation, 103, pp.273~283 (2019)
- Nissaisorakarn V, "Urine biomarkers informative of human kidney allograft rejection and tolerance", Hum Immunol, 79, pp.343~355 (2018)
- Zhang Z, "Analysis of urinary donor-derived DNA in renal transplant recipients with acute rejection", Clin Transpl, 16(S8), pp.45~50 (2002)
- Buderer NMF, "Statistical methodology: I. Incorporating the prevalence of disease into the sample size calculation for sensitivity and specificity", Acad Emerg Med, 3, pp.895~900 (1996)
- Solez K, "Banff 07 classification of renal allograft pathology: updates and future directions", Am J Transplant, 8, pp.753~760 (2008)
- Jhang JS, "Evaluation of linearity in the clinical laboratory", Arch Pathol Lab Med, 128, pp.44~48 (2004)
- Kim J, "SNP-based next-generation sequencing reveals low-level mixed chimerism after allogeneic hematopoietic stem cell transplantation", Ann Hematol, 97, pp.1731~1734 (2018)
- Sigdel TK, "A rapid noninvasive assay for the detection of renal transplant injury", Transplantation, 96, pp.97~101 (2013)
- 정병하, "Changing Donor Source Pattern for Kidney Transplantation over 40 Years: A Single-Center Experience", The Korean Journal of Internal Medicine, 25(3), pp.288~293 (2010), 대한내과학회
- Huggett JF, "Considerations for digital PCR as an accurate molecular diagnostic tool", Clin Chem, 61, pp.79~88 (2015)
- Aird D, "Analyzing and minimizing PCR amplification bias in Illumina sequencing libraries", Genome Biol, 12, pp.R18~ (2011)
- Augustus E, "The art of obtaining a high yield of cell-free DNA from urine", PloS One, 15, pp.e0231058~ (2020)
- Grskovic M, "Validation of a clinical-grade assay to measure donor-derived cell-free DNA in solid organ transplant recipients", J Mol Diagn, 18, pp.890~902 (2016)
- Jordan SC, "Donor-derived cell-free DNA identifies antibody-mediated rejection in donor specific antibody positive kidney transplant recipients", Transplant Direct, 4, pp.e379~ (2018)
- 이혜선, "Evaluation of Digital PCR as a Technique for Monitoring Acute Rejection in Kidney Transplantation", Genomics & Informatics, 15(1), pp.2~10 (2017), 한국유전체학회[DOI]
- Gielis EM, "Plasma donor-derived cell-free DNA kinetics after kidney transplantation using a single tube multiplex PCR assay", PloS One, 13, pp.e0208207~ (2018)
- Johansson G, "Considerations and quality controls when analyzing cell-free tumor DNA", Biomol Detect Quantif, 17, pp.100078~ (2019)
- Hung ECW, "Presence of donor-derived DNA and cells in the urine of sex-mismatched hematopoietic stem cell transplant recipients: implication for the transrenal hypothesis", Clin Chem, 55, pp.715~722 (2009)
- Franquesa M, "Kidney regeneration and repair after transplantation", Curr Opin Organ Transplant, 18, pp.191~196 (2013)