外泌体在高血压供肾功能评估中的应用进展

Progress on the application of exosomes in function assessment of hypertensive donor kidneys

摘要

高血压供肾已成为我国肾移植的重要供肾来源，由于合并慢性肾脏病变，此类供肾常被归属于边缘供肾。目前缺乏精准、无创的供肾质量评估手段，导致此类供肾弃用率居高不下，进一步加剧了器官短缺问题。外泌体是一种细胞外囊泡，富含细胞特异性的蛋白质、核酸及脂类等物质，参与了细胞间的信号传递，在循环与组织液中稳定性良好，有望作为评估肾损伤的新型生物标志物。因此，本文就高血压供肾的应用现状与挑战进行综述，分析现有评估方法的优势与局限，并从蛋白质组学以及转录组学层面探讨外泌体在高血压肾损伤与供肾质量评估中的应用价值，以期寻找一种早期、无创、精准的供肾质量评估方法，降低供肾弃用率，提升临床移植疗效，优化高血压供肾的临床应用策略。

Abstract

Hypertensive donor kidneys have become a major source for kidney transplantation in China. Due to the complication of chronic kidney lesions, such organs are usually classified as marginal grafts. At present, the lack of accurate and non-invasive methods for evaluating donor kidney quality leads to a high discard rate of such kidneys, which further exacerbates the problem of organ shortage. Exosomes are extracellular vesicles that are rich in cell-specific proteins, nucleic acids, lipids and other substances. They participate in intercellular signal transmission and have good stability in circulation and tissue fluid, making them promising novel biomarkers for evaluating renal injury. Therefore, this article reviews the application status and challenges of hypertensive donor kidneys, analyzes the advantages and limitations of existing evaluation methods, and discusses the application value of exosomes in hypertensive renal injury and donor kidney quality evaluation from the perspectives of proteomics and transcriptomics. The aim is to find an early, non-invasive and accurate method for donor kidney quality evaluation, reduce the discard rate of donor kidneys, improve the efficacy of clinical transplantation, and optimize the clinical application strategy of hypertensive donor kidneys.

关键词

肾移植 / 扩大标准供者 / 高血压 / 外泌体 / 供肾功能评估 / 肾损伤 / 蛋白组学 / 转录组学

Key words

Kidney transplantation / Expanded criteria donor / Hypertension / Exosome / Donor kidney function assessment / Kidney injury / Proteomics / Transcriptomics

参考文献

[1] 黄洁夫 . 中国器官捐献和移植发展报告-2023[M]. 北京: 清华大学出版社, 2025.

[2] DIENA D, ALLESINA A, FOP F, et al. Relationship between cytomegalovirus viremia and long-term outcomes in kidney transplant recipients with different donor ages[J]. Microorganisms, 2023, 11(2): 458. DOI: 10.3390/microorganisms11020458.

[3] GOMES V M, DOS SANTOS L I, DE CARVALHO SILVA B D P, et al. Impact of donor expanded criteria kidney transplantation on clinical outcomes and survival: a single-center experience[J]. Transpl Immunol, 2024, 86: 102116. DOI: 10.1016/j.trim.2024.102116.

[4] 孙平平, 陈好雨, 贾志缃, 等 . 高血压脑出血供者供肾评估及肾移植预后分析[J]. 中华器官移植杂志, 2019, 40(10): 591-594. DOI: 10.3760/cma.j.issn.0254-1785.2019.10.003.

[5] SUN P P, CHEN H Y, JIA Z X, et al. Evaluations of kidney from hypertensive cerebral hemorrhage donor and prognosis of renal transplantation[J]. Chin J Organ Transplant, 2019, 40(10): 591-594. DOI: 10.3760/cma.j.issn.0254-1785.2019.10.003.

[6] CICEK S K, AKINCI O, ERGUN S, et al. Comparison of survival in recipients of marginal and standard cadaveric donor kidneys[J]. Transplant Proc, 2023, 55(1): 87-92. DOI: 10.1016/j.transproceed.2022.10.052.

[7] DIONNE J C, CAMPBELL P, CARDINAL H, et al. Optimizing the use of deceased donor kidneys at risk of discard: a clinical practice guideline[J]. Transpl Int, 2025, 38: 14596. DOI: 10.3389/ti.2025.14596.

[8] SCURT F G, FISCHER-FRÖHLICH C L, WASSERMANN T, et al. Histological and clinical evaluation of discarded kidneys in a European cohort of deceased brain death donor kidneys of marginal quality[J]. J Nephrol, 2023, 36(9): 2587-2600. DOI: 10.1007/s40620-023-01785-8.

[9] KRYLOVA S V, FENG D. The machinery of exosomes: biogenesis, release, and uptake[J]. Int J Mol Sci, 2023, 24(2): 1337. DOI: 10.3390/ijms24021337.

[10] PIRONTI G, STRACHAN R T, ABRAHAM D, et al. Circulating exosomes induced by cardiac pressure overload contain functional angiotensin II type 1 receptors[J]. Circulation, 2015, 131(24): 2120-2130. DOI: 10.1161/CIRCULATIONAHA.115.015687.

[11] SONG R, CHOU Y I S, KONG J, et al. Association of endothelial microparticle with NO, eNOS, ET-1, and fractional flow reserve in patients with coronary intermediate lesions[J]. Biomarkers, 2015, 20(6/7): 429-435. DOI: 10.3109/1354750x.2015.1094140.

[12] GONZALEZ-CALERO L, MARTÍNEZ P J, MARTIN-LORENZO M, et al. Urinary exosomes reveal protein signatures in hypertensive patients with albuminuria[J]. Oncotarget, 2017, 8(27): 44217-44231. DOI: 10.18632/oncotarget.17787.

[13] MALEK S K. Procurement biopsies in kidneys retrieved for transplantation[J]. Clin J Am Soc Nephrol, 2014, 9(3): 443-444. DOI: 10.2215/cjn.00470114.

[14] EMMONS B R, BATAL I, KING K L, et al. Association of implantation biopsy findings in living donor kidneys with donor and recipient outcomes[J]. Am J Kidney Dis, 2024, 83(3): 306-317. DOI: 10.1053/j.ajkd.2023.08.022.

[15] WANG M, LV J, ZHAO J, et al. Postreperfusion renal allograft biopsy predicts outcome of single-kidney transplantation: a 10-year observational study in China[J]. Kidney Int Rep, 2023, 9(1): 96-107. DOI: 10.1016/j.ekir.2023.10.021.

[16] EMMONS B R, ALI HUSAIN S, KING K L, et al. Variations in deceased donor kidney procurement biopsy practice patterns: a survey of U.S. organ procurement organizations[J]. Clin Transplant, 2021, 35(9): e14411. DOI: 10.1111/ctr.14411.

[17] ANTONIETA AZANCOT M, MORESO F, SALCEDO M, et al. The reproducibility and predictive value on outcome of renal biopsies from expanded criteria donors[J]. Kidney Int, 2014, 85(5): 1161-1168. DOI: 10.1038/ki.2013.461.

[18] SCHNUELLE P. Renal biopsy for diagnosis in kidney disease: indication, technique, and safety[J]. J Clin Med, 2023, 12(19): 6424. DOI: 10.3390/jcm12196424.

[19] MOEIN M, GOLKARIEH A, VLASSIS I, et al. Comparative analysis of outcomes in high KDPI spectrum kidney transplants using unsupervised machine learning algorithm[J]. PLoS One, 2025, 20(8): e0324265. DOI: 10.1371/journal.pone.0324265.

[20] VILLANEGO F, VIGARA L A, CAZORLA J M, et al. Evaluation of expanded criteria donors using the kidney donor profile index and the preimplantation renal biopsy[J]. Transpl Int, 2022, 35: 10056. DOI: 10.3389/ti.2022.10056.

[21] 中华医学会器官移植学分会, 中国医师协会器官移植医师分会, 中国医疗保健国际交流促进会肾脏移植学分会. 中国遗体器官捐献供肾体外低温机械灌注保存指南[J]. 器官移植, 2024, 15(6): 837-845. DOI: 10.3969/j.issn.1674-7445.2024171.

[22] Branch of Organ Transplantation of Chinese Medical Association, Branch of Organ Transplantation Physician of Chinese Medical Doctor Association, Branch of Kidney Transplantation of China International Exchange and Promotive Association for Medical and Health Care . Guidelines for ex vivo hypothermic machine perfusion preservation of donor kidney from deceased organ donation in China[J]. Organ Transplant, 2024, 15(6): 837-845. DOI: 10.3969/j.issn.1674-7445.2024171.

[23] FONSECA BUITRAGO L, VERSTRAETEN L, FIEUWS S, et al. Renal resistance during hypothermic machine perfusion: a scoping review of variability and determinants, with a meta-analysis of predictive value for transplant outcomes[J]. Transplant Rev, 2025, 39(4): 100956. DOI: 10.1016/j.trre.2025.100956.

[24] VERSTRAETEN L, FIEUWS S, HOFKER H S, et al. Renal resistance trajectories during hypothermic machine perfusion in kidneys donated after circulatory death: associations with donor characteristics and posttransplant outcomes-an analysis of COMPARE trial data[J]. Am J Transplant, 2025, 25(10): 2161-2172. DOI: 10.1016/j.ajt.2025.06.014.

[25] HAMELINK T L, OGURLU B, JAYNES C L, et al. Perfusate biomarker comparison during renal hypothermic and normothermic machine perfusion: do these techniques provide similar insights?[J]. Transplantation, 2025, 109(10): e554-e566. DOI: 10.1097/TP.0000000000005440.

[26] MULVEY J F, SHAHEED S U, CHARLES P D, et al. Perfusate proteomes provide biological insight into oxygenated versus standard hypothermic machine perfusion in kidney transplantation[J]. Ann Surg, 2023, 278(5): 676-682. DOI: 10.1097/SLA.0000000000006046.

[27] DE ALMEIDA LEITE R R, LEITE M, EINICKER-LAMAS M, et al. Clinical outcomes prediction in kidney transplantation by use of biomarkers from hypothermic machine perfusion[J]. Int Braz J Urol, 2024, 50(4): 470-479. DOI: 10.1590/s1677-5538.ibju.2024.0166.

[28] MINOR T, MALKUS L, ZLATEV H, et al. Noninvasive measurement of¹³Carbon turnover for evaluation of porcine renal grafts during ex vivo machine perfusion [J]. Commun Med, 2023, 3: 192. DOI: 10.1038/s43856-023-00422-6.

[29] NIKOLAEV A V, FANG Y, ESSERS J, et al. Pre-transplant kidney quality evaluation using photoacoustic imaging during normothermic machine perfusion[J]. Photoacoustics, 2024, 36: 100596. DOI: 10.1016/j.pacs.2024.100596.

[30] HAMELINK T L, OGURLU B, PAMPLONA C C, et al. Magnetic resonance imaging as a noninvasive adjunct to conventional assessment of functional differences between kidneys in vivo and during ex vivo normothermic machine perfusion[J]. Am J Transplant, 2024, 24(10): 1761-1771. DOI: 10.1016/j.ajt.2024.04.001.

[31] TINGLE S J, CONNELLY C, GLOVER E K, et al. Contrast-enhanced ultrasound to assess kidney quality during ex situ normothermic machine perfusion[J]. Transpl Int, 2025, 38: 14268. DOI: 10.3389/ti.2025.14268.

[32] NOMURA S, NAKAMURA T, CONE J, et al. Cytometric analysis of high shear-induced platelet microparticles and effect of cytokines on microparticle generation[J]. Cytometry, 2000, 40(3): 173-181.

[33] JIMENEZ-TRINIDAD F R, CALVO-GOMEZ S, SABATÉ M, et al. Extracellular vesicles as mediators of endothelial dysfunction in cardiovascular diseases[J]. Int J Mol Sci, 2025, 26(3): 1008. DOI: 10.3390/ijms26031008.

[34] ZHONG D, CHEN Y, ZHANG Y, et al. Emerging exosomal biomarkers for essential hypertension: a systematic review[J]. Cardiovasc Diagn Ther, 2025, 15(4): 915-926. DOI: 10.21037/cdt-2025-76.

[35] TONG Y, YE C, REN X S, et al. Exosome-mediated transfer of ACE (angiotensin-converting enzyme) from adventitial fibroblasts of spontaneously hypertensive rats promotes vascular smooth muscle cell migration[J]. Hypertension, 2018, 72(4): 881-888. DOI: 10.1161/HYPERTENSIONAHA.118.11375.

[36] DE LA CUESTA F, BALDAN-MARTIN M, MORENO-LUNA R, et al. Kalirin and CHD7: novel endothelial dysfunction indicators in circulating extracellular vesicles from hypertensive patients with albuminuria[J]. Oncotarget, 2017, 8(9): 15553-15562. DOI: 10.18632/oncotarget.14948.

[37] DAMKJAER M, JENSEN P H, SCHWÄMMLE V, et al. Selective renal vasoconstriction, exaggerated natriuresis and excretion rates of exosomic proteins in essential hypertension[J]. Acta Physiol (Oxf), 2014, 212(1): 106-118. DOI: 10.1111/apha.12345.

[38] CAPPUCCI I P, TREMOLI E, ZAVAN B, et al. Circulating extracellular vesicles in cardiovascular disease[J]. Int J Mol Sci, 2025, 26(14): 6817. DOI: 10.3390/ijms26146817.

[39] REN X S, TONG Y, QIU Y, et al. MiR155-5p in adventitial fibroblasts-derived extracellular vesicles inhibits vascular smooth muscle cell proliferation via suppressing angiotensin-converting enzyme expression[J]. J Extracell Vesicles, 2019, 9(1): 1698795. DOI: 10.1080/20013078.2019.1698795.

[40] ZOU X, WANG J, CHEN C, et al. Secreted monocyte miR-27a, via mesenteric arterial mas receptor-eNOS pathway, causes hypertension[J]. Am J Hypertens, 2020, 33(1): 31-42. DOI: 10.1093/ajh/hpz112.

[41] BAO H, CHEN Y X, HUANG K, et al. Platelet-derived microparticles promote endothelial cell proliferation in hypertension via miR-142-3p[J]. FASEB J, 2018, 32(7): 3912-3923. DOI: 10.1096/fj.201701073r.

[42] HE L, LIU Y, WIDLANSKY M E, et al. MicroRNA and hypertension[J]. Hypertension, 2025, 82(2): 181-184. DOI: 10.1161/hypertensionaha.124.21728.

[43] LIU X, YUAN W, YANG L, et al. miRNA profiling of exosomes from spontaneous hypertensive rats using next-generation sequencing[J]. J Cardiovasc Transl Res, 2019, 12(1): 75-83. DOI: 10.1007/s12265-017-9784-7.

[44] WU Q, YUAN X, LI B, et al. Differential miRNA expression analysis of extracellular vesicles from brain microvascular pericytes in spontaneous hypertensive rats[J]. Biotechnol Lett, 2020, 42(3): 389-401. DOI: 10.1007/s10529-019-02788-x.

[45] 陈冠廷, 张琳琪, 李清茹. 外泌体在慢性肾脏病诊疗中的研究热点与趋势[J]. 中国组织工程研究, 2024, 28(1): 86-92. DOI: 10.12307/2023.765.

[46] CHEN G Y, ZHANG L Q, LI Q R . Research hot spots and trends of exosomes in theranostic application for chronic kidney disease[J]. Chin J Tissue Eng Res, 2024, 28(1): 86-92. DOI: 10.12307/2023.765.

[47] VERDUGO-MOLINARES M G, KU-CENTURION M, CORTES-SANABRIA L, et al. Potential kidney biomarkers in urinary extracellular vesicles from end stage renal disease and post-transplant patients[J]. J Proteomics, 2025, 321: 105523. DOI: 10.1016/j.jprot.2025.105523.

[48] 李柠, 朱婷婷, 吕林莉. 尿液细胞外囊泡生物标志物研究新进展与挑战[J]. 中华检验医学杂志, 2024, 47(8): 969-974. DOI: 10.3760/cma.j.cn114452-20240502-00221.

[49] LI N, ZHU T T, LÜ L L . Progress and challenges in the research of urinary extracellular vesicles as disease biomarkers[J]. Chin J Lab Med, 2024, 47(8): 969-974. DOI: 10.3760/cma.j.cn114452-20240502-00221.

[50] BLIJDORP C J, HARTJES T A, WEI K Y, et al. Nephron mass determines the excretion rate of urinary extracellular vesicles[J]. J Extracell Vesicles, 2022, 11(1): e12181. DOI: 10.1002/jev2.12181.

[51] DIMUCCIO V, RANGHINO A, PRATICÒ BARBATO L, et al. Urinary CD133⁺ extracellular vesicles are decreased in kidney transplanted patients with slow graft function and vascular damage [J]. PLoS One, 2014, 9(8): e104490. DOI: 10.1371/journal.pone.0104490.

[52] SVENNINGSEN P, MASLAUSKIENE R, PALARASAH Y, et al. Urinary extracellular vesicles for non-invasive quantification of principal cell damage in kidney transplant recipients[J]. Biomolecules, 2024, 14(9): 1124. DOI: 10.3390/biom14091124.

[53] GILDEA J J, CARLSON J M, SCHOEFFEL C D, et al. Urinary exosome miRNome analysis and its applications to salt sensitivity of blood pressure[J]. Clin Biochem, 2013, 46(12): 1131-1134. DOI: 10.1016/j.clinbiochem.2013.05.052.

[54] PEREZ-HERNANDEZ J, OLIVARES D, FORNER M J, et al. Urinary exosome miR-146a is a potential marker of albuminuria in essential hypertension[J]. J Transl Med, 2018, 16(1): 228. DOI: 10.1186/s12967-018-1604-6.

[55] LV L L, CAO Y H, NI H F, et al. microRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis[J]. Am J Physiol Renal Physiol, 2013, 305(8): F1220-F1227. DOI: 10.1152/ajprenal.00148.2013.

[56] PEREZ-HERNANDEZ J, RIFFO-CAMPOS A L, ORTEGA A, et al. Urinary- and plasma-derived exosomes reveal a distinct microRNA signature associated with albuminuria in hypertension[J]. Hypertension, 2021, 77(3): 960-971. DOI: 10.1161/HYPERTENSIONAHA.120.16598.

[57] MARTINEZ-ARROYO O, FLORES-CHOVA A, MENDEZ-DEBAETS M, et al. Inhibiting miR-200a-3p increases sirtuin 1 and mitigates kidney injury in a tubular cell model of diabetes and hypertension-related renal damage[J]. Biomolecules, 2025, 15(7): 995. DOI: 10.3390/biom15070995.

[58] KIM M J, KWON H E, JANG H W, et al. Multicenter, prospective, observational study for urinary exosomal biomarkers of kidney allograft fibrosis[J]. Sci Rep, 2024, 14(1): 20319. DOI: 10.1038/s41598-024-71279-5.

[59] EL FEKIH R, FRANZEN K, HURLEY J, et al. An exosomal mRNA urine test for detection and risk stratification of human kidney transplant rejection[J]. Kidney Int Rep, 2025, 10(4): 1131-1142. DOI: 10.1016/j.ekir.2025.01.036.

[60] 赵盈, 刁波, 杨莹莹, 等 . 细胞外囊泡在系统性红斑狼疮中的研究新进展[J]. 中国免疫学杂志, 2024, 40(6): 1307-1314. DOI: 10.3969/j.issn.1000-484X.2024.06.032.

[61] ZHAO Y, DIAO B, YANG Y Y, et al. Role of extracellular vesicles in treatment of systemic lupus erythematosus[J]. Chin J Immunol, 2024, 40(6): 1307-1314. DOI: 10.3969/j.issn.1000-484X.2024.06.032.

[62] DA-SILVA C C S, ANAUATE A C, GUIRAO T P, et al. Analysis of exosome-derived microRNAs as early biomarkers of lipopolysaccharide-induced acute kidney injury in rats[J]. Front Physiol, 2022, 13: 944864. DOI: 10.3389/fphys.2022.944864.

[63] WANG J, LI X, WU X, et al. Expression profiling of exosomal miRNAs derived from the peripheral blood of kidney recipients with DGF using high-throughput sequencing[J]. Biomed Res Int, 2019: 1759697. DOI: 10.1155/2019/1759697.

[64] CHEN Y, HAN X, SUN Y, et al. A circulating exosomal microRNA panel as a novel biomarker for monitoring post-transplant renal graft function[J]. J Cell Mol Med, 2020, 24(20): 12154-12163. DOI: 10.1111/jcmm.15861.

[65] GREMMELS H, DE JONG O G, TOOROP R J, et al. The small RNA repertoire of small extracellular vesicles isolated from donor kidney preservation fluid provides a source for biomarker discovery for organ quality and posttransplantation graft function[J]. Transplant Direct, 2019, 5(9): e484. DOI: 10.1097/TXD.0000000000000929.

[66] SZEBENI B, VERES-SZÉKELY A, PAP D, et al. Extracellular vesicles of patients on peritoneal dialysis inhibit the TGF-β- and PDGF-B-mediated fibrotic processes[J]. Cells, 2024, 13(7): 605. DOI: 10.3390/cells13070605.

[67] RAMALHETE L, ARAÚJO R, FERREIRA A, et al. Exosomes and microvesicles in kidney transplantation: the long road from trash to gold[J]. Pathology, 2024, 56(1): 1-10. DOI: 10.1016/j.pathol.2023.10.004.

基金资助

国家自然科学基金面上项目(82470103)

广州市科学技术局基础研究计划(SL2022A03J00629)