Donor-derived cell-free DNA in the diagnosis of postoperative lung transplantation complications

doi:10.3877/cma.j.issn.1674-3903.2025.01.007

Abstract

Abstract:

The occurrence of postoperative lung transplantaion complications severely affect the patient's quality of life and prognosis. Accurate diagnosis of allograft rejection and pulmonary infection is crucial for the treatment and outcome of patients. Traditional histopathological examination by lung biopsies is the gold standard for the diagnosis of rejection, but it has drawbacks such as invasiveness,low positivity rate, high operational difficulty, and delayed results. Cell-free DNA in plasma,especially donor-derived cell-free DNA (dd-cfDNA), as a sensitive biomarker, has been increasingly used for monitoring rejection after solid organ transplantation such as kidney and liver transplantation.This article reviews application value of dd-cfDNA as an potential tool for post-transplant management,in the management of complications after lung transplantation.

Key words: Donor-derived cell-free DNA, Lung transplantation, Allograft rejection, Pulmonary infection

Dong Xiang, Xiaohua Wang, Peihang Xu, Chunrong Ju. Donor-derived cell-free DNA in the diagnosis of postoperative lung transplantation complications[J]. Chinese Journal of Transplantation(Electronic Edition), 2025, 19(01): 37-42.

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References 47

1	Singh TP, Cherikh WS, Hsich E, et al. Graft survival in primary thoracic organ transplant recipients： a special report from the International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation[J]. J Heart Lung Transplant, 2023,42 (10)：1321-1333.
2	Levine DJ, Hachem RR. Lung allograft rejection[J]. Thorac Surg Clin, 2022,32 (2)：221-229.
3	Parulekar AD, Kao CC. Detection, classification, and management of rejection after lung transplantation[J]. J Thorac Dis, 2019,11(Suppl 14)：S1732-S1739.
4	Trachuk P, Bartash R, Abbasi M, et al. Infectious complications in lung transplant recipients[J]. Lung, 2020,198(6)：879-887.
5	Chen-Yoshikawa TF. Ischemia-reperfusion injury in lung transplantation[J]. Cells, 2021,10(6)：1333.
6	Evans RA, Walter KS, Lobo LJ, et al. Pharmacotherapy of chronic lung allograft dysfunction post lung transplantation[J]. Clin Transplant, 2022,36(8)：e14770.
7	Mondoni M, Rinaldo RF, Solidoro P, et al. Interventional pulmonology techniques in lung transplantation[J]. Respir Med,2023,211：107212.
8	Keating DT, Taverner J.Transbronchial cryobiopsy in lung transplantation： risk, reward and relevance[J]. Eur Respir J, 2023,61(1)：2201942.
9	Kataria A, Kumar D, Gupta G. Donor-derived cell-free DNA in solid-organ transplant diagnostics： indications, limitations, and future directions[J]. Transplantation, 2021,105(6)：1203-1211.
10	Knight SR, Thorne A, Lo Faro ML. Donor-specific cell-free DNA as a biomarker in solid organ transplantation. A systematic review[J].Transplantation, 2019,103(2)：273-283.
11	Martuszewski A, Paluszkiewicz P, Król M, et al. Donor-derived cell-free DNA in kidney transplantation as a potential rejection biomarker： a systematic literature review[J]. J Clin Med, 2021,10(2)：193.
12	Lo YM, Tein MS, Pang CC, et al. Presence of donor-specific DNA in plasma of kidney and liver-transplant recipients[J]. Lancet,1998,351(9112)：1329-1330.
13	Mouliere F, Robert B, Arnau Peyrotte E, et al. High fragmentation characterizes tumour-derived circulating DNA[J]. PLoS One, 2011,6(9)：e23418.
14	Mouliere F, Chandrananda D, Piskorz AM, et al. Enhanced detection of circulating tumor DNA by fragment size analysis[J]. Sci Transl Med, 2018,10(466)：eaat4921.
15	Gall TMH, Belete S, Khanderia E, et al. Circulating tumor cells and cell-free DNA in pancreatic ductal adenocarcinoma[J]. Am J Pathol, 2019,189(1)：71-81.
16	Bronkhorst AJ, Ungerer V, Holdenrieder S. The emerging role of cell-free DNA as a molecular marker for cancer management[J].Biomol Detect Quantif, 2019,17：100087.
17	Alekseeva LA, Mironova NL, Brenner EV, et al. Alteration of the exDNA profile in blood serum of LLC-bearing mice under the decrease of tumour invasion potential by bovine pancreatic DNase I treatment[J]. PLoS One, 2017,12(2)：e0171988.
18	Tamkovich SN, Cherepanova AV,Kolesnikova EV,et al.Circulating DNA and DNase activity in human blood[J]. Ann N Y Acad Sci, 2006,1075：191-196.
19	Reckamp KL, Melnikova VO, Karlovich C, et al. A highly sensitive and quantitative test platform for detection of NSCLC EGFR mutations in urine and plasma[J]. J Thorac Oncol, 2016,11(10)：1690-1700.
20	Miranda KC, Bond DT, McKee M, et al. Nucleic acids within urinary exosomes/microvesicles are potential biomarkers for renal disease[J]. Kidney Int, 2010,78(2)：191-199.
21	Botezatu I, Serdyuk O, Potapova G, et al. Genetic analysis of DNA excreted in urine： a new approach for detecting specific genomic DNA sequences from cells dying in an organism[J]. Clin Chem, 2000,46(8 Pt 1)：1078-1084.
22	Diehl F, Li M, Dressman D, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors[J]. Proc Natl Acad Sci U S A, 2005,102(45)：16368-16373.
23	Keller M, Agbor-Enoh S. Donor-derived cell-free DNA for acute rejection monitoring in heart and lung transplantation[J]. Curr Transplant Rep, 2021,8(4)：351-358.
24	Agbor-Enoh S, Wang Y, Tunc I, et al. Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation[J]. EbioMedicine, 2019,40：541-553.
25	Keller M, Bush E, Diamond JM, et al. Use of donor-derived-cellfree DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD)[J]. J Heart Lung Transplant, 2021,40(6)：488-493.
26	De Vlaminck I, Martin L, Kertesz M, et al. Noninvasive monitoring of infection and rejection after lung transplantation[J]. Proc Natl Acad Sci U S A, 2015,112(43)：13336-13341.
27	Jang MK, Tunc I, Berry GJ, et al. Donor-derived cell-free DNA accurately detects acute rejection in lung transplant patients, a multicenter cohort study[J]. J Heart Lung Transplant, 2021,40(8)：822-830.
28	Levine DJ, Ross DJ, Sako E. Single center "snapshot" experience with donor-derived cell-free DNA after lung transplantation[J].Biomark Insights, 2020,15：1177271920958704.
29	Ju C, Xu X, Zhang J, et al. Application of plasma donor-derived cell free DNA for lung allograft rejection diagnosis in lung transplant recipients[J]. BMC Pulm Med, 2023,23(1)：37.
30	Bazemore K, Rohly M, Permpalung N, et al. Donor derived cell free DNA% is elevated with pathogens that are risk factors for acute and chronic lung allograft injury[J]. J Heart Lung Transplant, 2021,40(11)：1454-1462.
31	Sayah D, Weigt SS, Ramsey A, et al. Plasma donor-derived cellfree DNA levels are increased during acute cellular rejection after lung transplant： pilot data[J]. Transplant Direct, 2020,6(10)：e608.
32	Tanaka S, Sugimoto S, Kurosaki T, et al. Donor-derived cell-free DNA is associated with acute rejection and decreased oxygenation in primary graft dysfunction after living donor-lobar lung transplantation[J]. Sci Rep, 2018,8(1)：15366.
33	Khush KK, De Vlaminck I, Luikart H, et al. Donor-derived, cellfree DNA levels by next-generation targeted sequencing are elevated in allograft rejection after lung transplantation[J]. ERJ Open Res,2021,7(1)：00462-2020.
34	Keller M, Sun J, Mutebi C, et al. Donor-derived cell-free DNA as a composite marker of acute lung allograft dysfunction in clinical care[J]. J Heart Lung Transplant, 2022,41(4)：458-466.
35	中国肾移植供体来源游离DNA应用与研究专家组, 中国医药生物技术协会移植技术分会.供体来源游离DNA检测在肾移植中临床应用的专家共识(2022版)[J/CD]. 中华移植杂志：电子版, 2022,16(5)：257-265.
36	Urosevic N, Merritt AJ, Inglis TJJ. Plasma cfDNA predictors of established bacteraemic infection[J]. Access Microbiol, 2022,4(6)：acmi000373.
37	Mondelo-Macía P, Castro-Santos P, Castillo-García A, et al.Circulating free DNA and its emerging role in autoimmune diseases[J]. J Pers Med, 2021,11(2)：151.
38	Truszewska A, Foroncewicz B, Pᶏczek L. The role and diagnostic value of cell-free DNA in systemic lupus erythematosus[J]. Clin Exp Rheumatol, 2017,35(2)：330-336.
39	Tug S, Helmig S, Deichmann ER, et al. Exercise-induced increases in cell free DNA in human plasma originate predominantly from cells of the haematopoietic lineage[J]. Exerc Immunol Rev, 2015,21：164-173.
40	Keller MB, Meda R, Fu S, et al. Comparison of donor-derived cellfree DNA between single versus double lung transplant recipients[J].Am J Transplant, 2022,22(10)：2451-2457.
41	Ju C, Wang L, Xu P, et al. Differentiation between lung allograft rejection and infection using donor-derived cell-free DNA and pathogen detection by metagenomic next-generation sequencing[J].Heliyon, 2023,9(11)：e22274.
42	Assadiasl S, Nicknam MH. Cytokines in lung transplantation[J].Lung, 2022,200(6)：793-806.
43	García Moreira V, Prieto García B, Baltar Martín JM, et al. Cellfree DNA as a noninvasive acute rejection marker in renal transplantation[J]. Clin Chem, 2009,55(11)：1958-1966.
44	Speck NE, Schuurmans MM, Murer C, et al. Diagnostic value of plasma and bronchoalveolar lavage samples in acute lung allograft rejection： differential cytology[J]. Respir Res, 2016,17(1)：74.
45	McNamara ME, Jain SS, Oza K, et al. Circulating, cell-free methylated DNA indicates cellular sources of allograft injury after liver transplant[J]. bioRxiv, 2024. [Preprint]
46	Snyder MW, Kircher M, Hill AJ, et al. Cell-free DNA comprises an invivo nucleosome footprint that informs its tissues-of-origin[J].Cell, 2016,164(1-2)：57-68.
47	Tsuji N, Agbor-Enoh S. Cell-free DNA beyond a biomarker for rejection： biological trigger of tissue injury and potential therapeutics[J]. J Heart Lung Transplant, 2021,40(6)：405-413.

类型	潜在应用
循环线粒体DNA	各种疾病的诊断和预测标志物,细胞死亡和非特异性组织损伤标志物
循环肿瘤DNA	肿瘤诊断中的标志物,监测肿瘤发展
胎儿游离DNA	产前诊断,检测胎儿缺陷
供体来源游离DNA	评估移植后并发症

类型	潜在应用
循环线粒体DNA	各种疾病的诊断和预测标志物,细胞死亡和非特异性组织损伤标志物
循环肿瘤DNA	肿瘤诊断中的标志物,监测肿瘤发展
胎儿游离DNA	产前诊断,检测胎儿缺陷
供体来源游离DNA	评估移植后并发症

识别方法	定量方法
性别不匹配	霰弹枪测序
目标单核苷酸多态性位点识别	目标序列捕获测序
单基因组基因分型	定量PCR 技术
双基因组基因分型	数字液滴PCR

识别方法	定量方法
性别不匹配	霰弹枪测序
目标单核苷酸多态性位点识别	目标序列捕获测序
单基因组基因分型	定量PCR 技术
双基因组基因分型	数字液滴PCR

作者	研究设计	样本量(例)	dd-cfDNA%阈值	分组	术后时间	诊断效能
作者	研究设计	样本量(例)	dd-cfDNA%阈值	分组	术后时间	敏感度(%)	特异度(%)	NPV(%)	PPV(%)	AUC
De Vlaminck 等^[26]	单中心前瞻性	51	1	ACR/ 稳定组	＞2 个月	100	73	-	-	0. 9
Jang 等^[27]	多中心前瞻性	148	1	AR/ 稳定组	＞45 d	77	84	90	64	0. 89
Levine 等^[28]	单中心前瞻性	48	0. 51	(CLAD+AR) / 稳定组	3 个月至12 年	81	100	-	-	0. 98
Ju 等^[29]	单中心回顾性	170	0. 89	CLAD/ 稳定组	＞14 d	95	77	98. 8	42.2	0. 847
Sayah 等^[31]	多中心前瞻性	69	0. 85	AR/ 稳定组	＞14 d 至＜1 年	73	53	85. 5	34.1	0. 72
Khush 等^[33]	单中心前瞻性	38	0. 85	(AR+CLAD) / 稳定组	＞14 d	56	76	84	43	0. 67
Keller 等^[34]	多中心回顾性	175	1	(AR+INF) / 稳定组	＞1 个月至＜3 年	74	88	97	43	0. 82

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