Accessible Requires Authentication Published by De Gruyter April 22, 2021

Urinary exosomal CD26 is associated with recovery from acute kidney injury in intensive care units: a prospective cohort study

Juan Du, Yihui Li, Qiang Sun, Zhihao Wang, Feng Wang, Fangfang Chen, Hao Wang, Yirui Liu, Huimin Zhou, Guokai Shang, Xiaomei Chen, Shifang Ding, Chen Li, Dawei Wu, Wei Zhang and Ming Zhong

Abstract

Objectives

Currently there is no validated method to predict renal reversal and recovery after acute kidney injury (AKI). As exosomes have the potential for AKI prognosis and CD26 is involved in the mechanisms in AKI, this study aims to investigate whether urinary exosomal CD26 is associated with renal-related outcomes and explore its prospect as a novel prognosis biomarker.

Methods

This was a single-center, prospective cohort study. A total of 133 AKI patients and 68 non-AKI patients admitted to ICU in Qilu Hospital Shandong University from January 2017 to January 2018. Urine samples were collected at enrollment and the relative expression of CD26 (CD26 percentage) in urinary exosomes was examined, that was then categorized into a low-CD26 level and a high-CD26 level.

Results

CD26 percentage was significantly lower in the AKI cohort than in the control cohort. Within the AKI cohort, a high-CD26 level was associated with lower incidence of major adverse kidney events within 90 days, but higher incidence of reversal within 28 days. In AKI survivors, a high-CD26 level had a 4.67-, 3.50- and 4.66-fold higher odds than a low-CD26 level for early reversal, recovery and reversal, respectively, after adjustment for clinical factors. Prediction performance was moderate for AKI survivors but improved for non-septic AKI survivors.

Conclusions

Urinary exosomal CD26 is associated with renal reversal and recovery from AKI and is thus a promising prognosis biomarker.


Corresponding author: Ming Zhong, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107, Wen Hua Xi Road, 250012, Jinan, Shandong, P.R. China, Phone: +86 531 82169339, Fax: +86 531 86169356, E-mail:

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 81470560

Award Identifier / Grant number: 81873534

Award Identifier / Grant number: 81570400

Award Identifier / Grant number: 81801953

Award Identifier / Grant number: 81670411

Award Identifier / Grant number: 81471036

Award Identifier / Grant number: 81600633

Award Identifier / Grant number: 81702194

Funding source: Key Research and Development Program of Shandong Province

Award Identifier / Grant number: 2019GSF108041

Award Identifier / Grant number: 2018GSF118002

Award Identifier / Grant number: 2017GSF18156

Funding source: Natural Science Foundation of Shandong Province

Award Identifier / Grant number: ZR2019BH064

Acknowledgments

We give special thanks to my friend Luying Hou for her endeavor in improving the writing of this paper.

  1. Research funding: Ming Zhong received funding from the National Natural Science Foundation of China (81470560) and 10 Key Research and Development Program of Shandong Province (2019GSF108041). Wei Zhang received 11 funding from the National Natural Science Foundation of China (81873534 and 81570400) and from the 12 Key Research and Development Program of Shandong Province (2018GSF118002). Yihui Li received 13 funding from the National Natural Science Foundation of China (81801953 and 81670411) and the 14 Natural Science Foundation of Shandong Province (ZR2019BH064). Zhihao Wang received funding 15 from the National Natural Science Foundation of China (81471036 and 81600633) and Key Research 16 and Development Program of Shandong Province (2017GSF18156). Guokai Shang received funding 17 from the National Natural Science Foundation of China (81702194).

  2. Author contributions: J.D. and M.Z. designed and performed the experiments; collected, analyzed and interpreted the data; and wrote the manuscript. Y.L. designed and performed the experiments and analyzed and interpreted the data. F.W., F.C., H.Z. and G.S. performed the experiments. Q.S., H.W., Y.L., C.L. and S.D. collected, analyzed and interpreted the data. Z.W., D.W., X.C. and W.Z. helped to design and write the manuscript. All authors read and approved the final manuscript.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The study protocol was approved by the Ethics Committee of Qilu Hospital, Shandong University (IERB: 2017074).

References

1. Chawla, LS, Bellomo, R, Bihorac, A, Goldstein, SL, Siew, ED, Bagshaw, SM. Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nat Rev Nephrol 2017;13:241–57. https://doi.org/10.1038/nrneph.2017.2. Search in Google Scholar

2. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012;2:1–138. Search in Google Scholar

3. Kellum, JA, Sileanu, FE, Bihorac, A, Hoste, EA, Chawla, LS. Recovery after acute kidney injury. Am J Respir Crit Care Med 2017;195:784–91. https://doi.org/10.1164/rccm.201604-0799oc. Search in Google Scholar

4. Chawla, LS, Eggers, PW, Star, RA, Kimmel, PL. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 2014;371:58–66. https://doi.org/10.1056/nejmra1214243. Search in Google Scholar

5. Brown, JR, Kramer, RS, Coca, SG, Parikh, CR. Duration of acute kidney injury impacts long-term survival after cardiac surgery. Ann Thorac Surg 2010;90:1142–8. https://doi.org/10.1016/j.athoracsur.2010.04.039. Search in Google Scholar

6. Hobson, CE, Yavas, S, Segal, MS, Schold, JD, Tribble, CG, Layon, AJ. Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation 2009;119:2444–53. https://doi.org/10.1161/circulationaha.108.800011. Search in Google Scholar

7. Bravi, CA, Vertosick, E, Benfante, N, Tin, A, Sjoberg, D, Hakimi, AA. Impact of acute kidney injury and its duration on long-term renal function after partial nephrectomy. Eur Urol 2019;76:398–403. https://doi.org/10.1016/j.eururo.2019.04.040. Search in Google Scholar

8. Perinel, S, Vincent, F, Lautrette, A, Dellamonica, J, Mariat, C, Zeni, F. Transient and persistent acute kidney injury and the risk of hospital mortality in critically ill patients: results of a Multicenter Cohort Study. Crit Care Med 2015;43:e269–75. https://doi.org/10.1097/ccm.0000000000001077. Search in Google Scholar

9. Cao, H, Cheng, Y, Gao, H, Zhuang, J, Zhang, W, Bian, Q. In vivo tracking of mesenchymal stem cell-derived extracellular vesicles improving mitochondrial function in renal ischemia-reperfusion injury. ACS Nano 2020;14:4014–26. https://doi.org/10.1021/acsnano.9b08207. Search in Google Scholar

10. Asvapromtada, S, Sonoda, H, Kinouchi, M, Oshikawa, S, Takahashi, S, Hoshino, Y. Characterization of urinary exosomal release of aquaporin-1 and -2 after renal ischemia-reperfusion in rats. Am J Physiol Ren Physiol 2018;314:F584–601. https://doi.org/10.1152/ajprenal.00184.2017. Search in Google Scholar

11. Panich, T, Chancharoenthana, W, Somparn, P, Issara-Amphorn, J, Hirankarn, N, Leelahavanichkul, A. Urinary exosomal activating transcriptional factor 3 as the early diagnostic biomarker for sepsis-induced acute kidney injury. BMC Nephrol 2017;18:10. https://doi.org/10.1186/s12882-016-0415-3. Search in Google Scholar

12. Zhou, H, Pisitkun, T, Aponte, A, Yuen, PS, Hoffert, JD, Yasuda, H. Exosomal Fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury. Kidney Int 2006;70:1847–57. https://doi.org/10.1038/sj.ki.5001874. Search in Google Scholar

13. Dominguez, JH, Liu, Y, Gao, H, Dominguez, JM2nd, Xie, D, Kelly, KJ. Renal tubular cell-derived extracellular vesicles accelerate the recovery of established renal ischemia reperfusion injury. J Am Soc Nephrol 2017;28:3533–44. https://doi.org/10.1681/asn.2016121278. Search in Google Scholar

14. Boonacker, E, Van Noorden, CJ. The multifunctional or moonlighting protein CD26/DPPIV. Eur J Cell Biol 2003;82:53–73. https://doi.org/10.1078/0171-9335-00302. Search in Google Scholar

15. Morimoto, C, Schlossman, SF. The structure and function of CD26 in the T-cell immune response. Immunol Rev 1998;161:55–70. https://doi.org/10.1111/j.1600-065x.1998.tb01571.x. Search in Google Scholar

16. Morimoto, C, Lord, CI, Zhang, C, Duke-Cohan, JS, Letvin, NL, Schlossman, SF. Role of CD26/dipeptidyl peptidase IV in human immunodeficiency virus type 1 infection and apoptosis. Proc Natl Acad Sci U S A 1994;91:9960–4. https://doi.org/10.1073/pnas.91.21.9960. Search in Google Scholar

17. Sun, AL, Deng, JT, Guan, GJ, Chen, SH, Liu, YT, Cheng, J. Dipeptidyl peptidase-IV is a potential molecular biomarker in diabetic kidney disease. Diabetes Vasc Dis Res 2012;9:301–8. https://doi.org/10.1177/1479164111434318. Search in Google Scholar

18. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1–150. Search in Google Scholar

19. Melo, SA, Luecke, LB, Kahlert, C, Fernandez, AF, Gammon, ST, Kaye, J. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015;523:177–82. https://doi.org/10.1038/nature14581. Search in Google Scholar

20. Semler, MW, Self, WH, Wanderer, JP, Ehrenfeld, JM, Wang, L, Byrne, DW. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018;378:829–39. https://doi.org/10.1056/nejmoa1711584. Search in Google Scholar

21. Bagshaw, SM, Uchino, S, Bellomo, R, Morimatsu, H, Morgera, S, Schetz, M. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol 2007;2:431–9. https://doi.org/10.2215/cjn.03681106. Search in Google Scholar

22. Bagshaw, SM, George, C, Bellomo, R, Committee, ADM. Early acute kidney injury and sepsis: a multicentre evaluation. Crit Care 2008;12:R47. https://doi.org/10.1186/cc6863. Search in Google Scholar

23. Song, T, Eirin, A, Zhu, X, Zhao, Y, Krier, JD, Tang, H. Mesenchymal stem cell-derived extracellular vesicles induce regulatory T cells to ameliorate chronic kidney injury. Hypertension 2020;75:1223–32. https://doi.org/10.1161/hypertensionaha.119.14546. Search in Google Scholar

24. Moreno, E, Canet, J, Gracia, E, Lluis, C, Mallol, J, Canela, EI. Molecular evidence of adenosine deaminase linking adenosine A2A receptor and CD26 proteins. Front Pharmacol 2018;9:106. https://doi.org/10.3389/fphar.2018.00106. Search in Google Scholar

25. Yap, SC, Lee, HT. Adenosine and protection from acute kidney injury. Curr Opin Nephrol Hypertens 2012;21:24–32. https://doi.org/10.1097/mnh.0b013e32834d2ec9. Search in Google Scholar

26. Day, YJ, Huang, L, Ye, H, Li, L, Linden, J, Okusa, MD. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: the role of CD4+ T cells and IFN-gamma. J Immunol 2006;176:3108–14. https://doi.org/10.4049/jimmunol.176.5.3108. Search in Google Scholar

27. Antonioli, L, Colucci, R, La Motta, C, Tuccori, M, Awwad, O, Da Settimo, F. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 2012;13:842–62. https://doi.org/10.2174/138945012800564095. Search in Google Scholar

28. Proost, P, Struyf, S, Schols, D, Durinx, C, Wuyts, A, Lenaerts, JP. Processing by CD26/dipeptidyl-peptidase IV reduces the chemotactic and anti-HIV-1 activity of stromal-cell-derived factor-1alpha. FEBS Lett 1998;432:73–6. https://doi.org/10.1016/s0014-5793(98)00830-8. Search in Google Scholar

29. Busso, N, Wagtmann, N, Herling, C, Chobaz-Peclat, V, Bischof-Delaloye, A, So, A. Circulating CD26 is negatively associated with inflammation in human and experimental arthritis. Am J Pathol 2005;166:433–42. https://doi.org/10.1016/s0002-9440(10)62266-3. Search in Google Scholar

30. Bauvois, B, Sanceau, J, Wietzerbin, J. Human U937 cell surface peptidase activities: characterization and degradative effect on tumor necrosis factor-alpha. Eur J Immunol 1992;22:923–30. https://doi.org/10.1002/eji.1830220407. Search in Google Scholar

31. Pinheiro, A, Silva, AM, Teixeira, JH, Goncalves, RM, Almeida, MI, Barbosa, MA. Extracellular vesicles: intelligent delivery strategies for therapeutic applications. J Contr Release 2018;289:56–69. https://doi.org/10.1016/j.jconrel.2018.09.019. Search in Google Scholar

32. Thakar, CV, Christianson, A, Himmelfarb, J, Leonard, AC. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am Soc Nephrol 2011;6:2567–72. https://doi.org/10.2215/cjn.01120211. Search in Google Scholar

33. Kellum, JA, Prowle, JR. Paradigms of acute kidney injury in the intensive care setting. Nat Rev Nephrol 2018;14:217–30. https://doi.org/10.1038/nrneph.2017.184. Search in Google Scholar

34. Darmon, M, Schortgen, F, Vargas, F, Liazydi, A, Schlemmer, B, Brun-Buisson, C. Diagnostic accuracy of Doppler renal resistive index for reversibility of acute kidney injury in critically ill patients. Intensive Care Med 2011;37:68–76. https://doi.org/10.1007/s00134-010-2050-y. Search in Google Scholar

35. Brown, JR, Kramer, RS, MacKenzie, TA, Coca, SG, Sint, K, Parikh, CR. Determinants of acute kidney injury duration after cardiac surgery: an externally validated tool. Ann Thorac Surg 2012;93:570–6. https://doi.org/10.1016/j.athoracsur.2011.11.004. Search in Google Scholar

36. Schnell, D, Deruddre, S, Harrois, A, Pottecher, J, Cosson, C, Adoui, N. Renal resistive index better predicts the occurrence of acute kidney injury than cystatin C. Shock 2012;38:592–7. https://doi.org/10.1097/shk.0b013e318271a39c. Search in Google Scholar

37. Chawla, LS, Davison, DL, Brasha-Mitchell, E, Koyner, JL, Arthur, JM, Shaw, AD. Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Crit Care 2013;17:R207. https://doi.org/10.1186/cc13015. Search in Google Scholar

38. Hoste, E, Bihorac, A, Al-Khafaji, A, Ortega, LM, Ostermann, M, Haase, M. Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study. Intensive Care Med 2020;46:943–53. https://doi.org/10.1007/s00134-019-05919-0. Search in Google Scholar

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2021-0040).

Received: 2021-01-10
Accepted: 2021-03-30
Published Online: 2021-04-22
Published in Print: 2021-08-26

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