Skip to main content
SpringerLink
Log in

Intravenous infusion of ulinastatin attenuates acute kidney injury after cold ischemia/reperfusion

  • Nephrology - Original Paper
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Background

Administration of ulinastatin was proved to protect many organs from ischemia/reperfusion (I/R) induced injury, yet its protective effects on renal I/R injury under cold condition and mechanism still remain unclear.

Aims

In the present study, the protective effects of ulinastatin on renal cold I/R injury as well as its mechanism were investigated.

Methods and results

Renal cold I/R model was constructed via cross-clamping of left renal artery and vein at 4 °C. The ulinastatin was administrated and multi-methods were performed to evaluate the protective effects. The results showed that ulinastatin could mitigate the renal cold I/R injury. In addition, the attenuated kidney cold I/R injury by ulinastatin was also accompanied with its regulating capability of the microenvironment, such as decreased acute inflammatory response, oxidative stress damage and apoptosis, as well as attenuation of vasculature levels decrease, as evidence by reduced TNF-α, IL-6 mRNA expression, MDA levels and apoptosis, higher levels of SOD activity and CD31/α-SMA expression.

Conclusion

The present study suggested that ulinastatin might be clinically useful in reducing preservation injury induced by cold I/R during renal transplantation surgery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Wekerle T, Segev D, Lechler R, Oberbauer R (2017) Strategies for long-term preservation of kidney graft function. Lancet 389:2152–2162

    Article  Google Scholar 

  2. Liyanage T, Ninomiya T, Jha V, Neal B, Patrice HM, Okpechi I et al (2015) Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet 385:1975

    Article  Google Scholar 

  3. Lindell SL, Muir H, Brassil J, Mangino MJ (2013) Hypothermic machine perfusion preservation of the DCD kidney: machine effects. J Transplant 2013:802618

    Article  Google Scholar 

  4. Kosieradzki M, Rowiński W (2008) Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention. Transplantation proceedings. Elsevier, Amsterdam, pp 3279–3288

    Google Scholar 

  5. Henry SD, Guarrera JV (2012) Protective effects of hypothermic ex vivo perfusion on ischemia/reperfusion injury and transplant outcomes. Transplant Rev 26:163–175

    Article  Google Scholar 

  6. Yuan X, Theruvath AJ, Ge X, Floerchinger B, Jurisch A, García-Cardeña G et al (2010) Machine perfusion or cold storage in organ transplantation: indication, mechanisms, and future perspectives. Transpl Int 23:561–570

    Article  Google Scholar 

  7. Siedlecki A, Irish W, Brennan DC (2011) Delayed graft function in the kidney transplant. Am J Transplant 11:2279–2296

    Article  CAS  Google Scholar 

  8. Schröppel B, Legendre C (2014) Delayed kidney graft function: from mechanism to translation. Kidney Int 86:251–258

    Article  Google Scholar 

  9. Pan Y, Fang H, Lu F, Pan M, Chen F, Xiong P et al (2017) Ulinastatin ameliorates tissue damage of severe acute pancreatitis through modulating regulatory T cells. J Inflamm 14:7

    Article  Google Scholar 

  10. Shin I-W, Jang I-S, Lee S-M, Park K-E, Ok S-H, Sohn J-T et al (2011) Myocardial protective effect by ulinastatin via an anti-inflammatory response after regional ischemia/reperfusion injury in an in vivo rat heart model. Korean J Anesthesiol 61:499–505

    Article  CAS  Google Scholar 

  11. Umeadi C, Kandeel F, Alabdullah IH (2008) Ulinastatin is a novel protease inhibitor and neutral protease activator. Transplant Proc 40:387–389

    Article  CAS  Google Scholar 

  12. Chen Q, Hu C, Liu Y, Liu Y, Wang W, Zheng H et al (2017) Safety and tolerability of high-dose ulinastatin after 2-hour intravenous infusion in adult healthy Chinese volunteers: a randomized, double-blind, placebo-controlled, ascending-dose study. PLoS One 12:e0177425

    Article  Google Scholar 

  13. Zhong DF, Xu Q (2011) The clinical observation of high-dose ulinastatin in septic shock. Chin J Clin Ration Drug Use 4:41–42

    Google Scholar 

  14. Zhang A, Dong XJ (2008) Clinical trial of combined ulinastatin and octreotide in treatment of severe acute pancreatitis. Chin J Clin Pharmacol 24:104

    Google Scholar 

  15. Xu L, Ren B, Li M, Jiang F, Zhanng Z, Hu J (2008) Ulinastatin suppresses systemic inflammatory response following lung ischemia-reperfusion injury in rats. Transplantation proceedings. Elsevier, Amsterdam, pp 1310–1311

    Google Scholar 

  16. Cao Z-L, Okazaki Y, Naito K, Ueno T, Natsuaki M, Itoh T (2000) Ulinastatin attenuates reperfusion injury in the isolated blood-perfused rabbit heart. Ann Thorac Surg 69:1121–1126

    Article  CAS  Google Scholar 

  17. Okuhama Y, Shiraishi M, Higa T, Tomori H, Taira K, Mamadi T et al (1999) Protective effects of ulinastatin against ischemia–reperfusion injury. J Surg Res 82:34–42

    Article  CAS  Google Scholar 

  18. Xiaoqiao Z, Rong M, Zhigang Y, Yong D, Xihong F, Jingzhong S (2004) Protective effect of ulinastatin against ischemia-reperfusion injury in rat small bowel transplantation. Transplantation proceedings. Elsevier, Amsterdam, pp 1564–1566

    Google Scholar 

  19. Xu M, Wen X, Chen S, An X, Xu H (2011) Addition of ulinastatin to preservation solution promotes protection against ischemia-reperfusion injury in rabbit lung. Chin Med J 124:2179–2183

    CAS  PubMed  Google Scholar 

  20. Chen C-C, Liu Z-M, Wang H-H, He W, Wang Y, Wu W-D (2004) Effects of ulinastatin on renal ischemia-reperfusion injury in rats. Acta Pharmacol Sin. 2004(25):1334

    Google Scholar 

  21. Wang Y-L, Li G, Zou X-F, Chen X-B, Liu T, Shen Z-Y (2013) Effect of autologous adipose-derived stem cells in renal cold ischemia and reperfusion injury. Transplantation proceedings. Elsevier, Amsterdam, pp 3198–3202

    Google Scholar 

  22. Ayala A, Munoz MF, Arguelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014:360438

    Article  Google Scholar 

  23. Vieira SA, Zhang G, Decker EA (2017) Biological implications of lipid oxidation products. J Am Oil Chem Soc 94:339–351

    Article  CAS  Google Scholar 

  24. Schneider MP, Sullivan JC, Wach PF, Boesen EI, Yamamoto T, Fukai T et al (2010) Protective role of extracellular superoxide dismutase in renal ischemia/reperfusion injury. Kidney Int 78:374–381

    Article  CAS  Google Scholar 

  25. Rao PS, Ojo A (2009) The alphabet soup of kidney transplantation: SCD, DCD, ECD—fundamentals for the practicing nephrologist. Clin J Am Soc Nephrol 4:1827–1831

    Article  Google Scholar 

  26. Matas A, Smith J, Skeans M, Thompson B, Gustafson S, Schnitzler M et al (2014) OPTN/SRTR 2012 annual data report: kidney. Am J Transplant 14:11–44

    Article  Google Scholar 

  27. Lutz J, Thürmel K, Heemann U (2010) Anti-inflammatory treatment strategies for ischemia/reperfusion injury in transplantation. J Inflamm 7:27

    Article  Google Scholar 

  28. Mahmoud MF, El Shazly SM, Barakat W (2012) Inhibition of TNF-α protects against hepatic ischemia–reperfusion injury in rats via NF-κB dependent pathway. Naunyn-Schmiedeberg’s Arch Pharmacol 385:465–471

    Article  CAS  Google Scholar 

  29. Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR (1999) Early kidney TNF-α expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol-Regul Integr Compar Physiol 277:R922–R929

    Article  CAS  Google Scholar 

  30. Torre-Amione G, Kapadia S, Lee J, Bies RD, Lebovitz R, Mann DL (1995) Expression and functional significance of tumor necrosis factor receptors in human myocardium. Circulation 92:1487–1493

    Article  CAS  Google Scholar 

  31. Sack MN (2002) Tumor necrosis factor-α in cardiovascular biology and the potential role for anti-tumor necrosis factor-α therapy in heart disease. Pharmacol Ther 94:123–135

    Article  CAS  Google Scholar 

  32. Chen W, Shen X, Hu Y, Xu K, Ran Q, Yu Y et al (2017) Surface functionalization of titanium implants with chitosan-catechol conjugate for suppression of ROS-induced cells damage and improvement of osteogenesis. Biomaterials 114:82–96

    Article  CAS  Google Scholar 

  33. Cuzzocrea S, Riley DP, Caputi AP, Salvemini D (2001) Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev 53:135–159

    CAS  PubMed  Google Scholar 

  34. Li J, Shu Y, Hao T, Wang Y, Qian Y, Duan C et al (2013) A chitosan–glutathione based injectable hydrogel for suppression of oxidative stress damage in cardiomyocytes. Biomaterials 34:9071–9081

    Article  CAS  Google Scholar 

  35. Lin M, Li L, Li L, Pokhrel G, Qi G, Rong R et al (2014) The protective effect of baicalin against renal ischemia-reperfusion injury through inhibition of inflammation and apoptosis. BMC Complement Altern Med. 14:19

    Article  Google Scholar 

  36. Yang M, Antoine DJ, Weemhoff JL, Jenkins RE, Farhood A, Park BK et al (2014) Biomarkers distinguish apoptotic and necrotic cell death during hepatic ischemia/reperfusion injury in mice. Liver Transpl 20:1372–1382

    Article  Google Scholar 

  37. Scarabelli T, Stephanou A, Rayment N, Pasini E, Comini L, Curello S et al (2001) Apoptosis of endothelial cells precedes myocyte cell apoptosis in ischemia/reperfusion injury. Circulation 104:253–256

    Article  CAS  Google Scholar 

  38. Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63

    Article  CAS  Google Scholar 

  39. Borghetti G, Yamaguchi AA, Aikawa J, Yamazaki RK, Brito GAP, Fernandes LC (2015) Fish oil administration mediates apoptosis of Walker 256 tumor cells by modulation of p53, Bcl-2, caspase-7 and caspase-3 protein expression. Lipids Health Dis 14:94

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, Chinese People’s Liberation Army General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of China

    Yunpeng Wang, Cheng Peng, Zheng Zhang, Jing Shi, Yingli Lin, Liangyou Gu & Hongzhao Li

  2. School of Basic Medical Science, Beijing University of Chinese Medicine, No. 11 North Third Ring Road, Chaoyang District, Beijing, 100029, People’s Republic of China

    Xin Ma

Authors
  1. Yunpeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cheng Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yingli Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liangyou Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xin Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hongzhao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongzhao Li.

Ethics declarations

Conflict of interest

The authors declare no competing financial interests in the present study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Peng, C., Zhang, Z. et al. Intravenous infusion of ulinastatin attenuates acute kidney injury after cold ischemia/reperfusion. Int Urol Nephrol 51, 1873–1881 (2019). https://doi.org/10.1007/s11255-019-02204-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-019-02204-3

Keywords

Search

Navigation