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Human Atrial Natriuretic Peptide in Cold Storage of Donation After Circulatory Death Rat Livers

An Old but New Agent for Protecting Vascular Endothelia?

Nigmet, Yermek, MD1; Hata, Koichiro, MD, PhD1; Tamaki, Ichiro, MD1; Okamura, Yusuke, MD, PhD1; Tsuruyama, Tatsuaki, MD, PhD2; Miyauchi, Hidetaka, MD, PhD1; Kusakabe, Jiro, MD1; Tajima, Tetsuya, MD1; Hirao, Hirofumi, MD, PhD1; Kubota, Toyonari, MD1; Inamoto, Osamu, MD1; Yoshikawa, Junichi, MD1; Goto, Toru, MD1; Tanaka, Hirokazu, MD1; Uemoto, Shinji, MD, PhD1

doi: 10.1097/TP.0000000000002552
Original Basic Science—Liver

Background. Current critical shortage of donor organs has increased the use of donation after circulatory death (DCD) livers for transplantation, despite higher risk for primary nonfunction or ischemic cholangiopathy. Human atrial natriuretic peptide (hANP) is a cardiovascular hormone that possesses protective action to vascular endothelia. We aimed to clarify the therapeutic potential of hANP in cold storage of DCD livers.

Methods. Male Wistar rats were exposed to 30-minute warm ischemia in situ. Livers were then retrieved and cold-preserved for 6 hours with or without hANP supplementation. Functional and morphological integrity of the livers was evaluated by oxygenated ex vivo reperfusion at 37°C.

Results. hANP supplementation resulted in significant reduction of portal venous pressure (12.2 ± 0.5 versus 22.5 ± 3.5 mm Hg, P < 0.001). As underlying mechanisms, hANP supplementation significantly increased tissue adenosine concentration (P = 0.008), resulting in significant upregulation of endothelial nitric oxide synthase and significant downregulation of endothelin-1 (P = 0.01 and P = 0.004 vs. the controls, respectively). Consequently, hANP significantly decreased transaminase release (P < 0.001) and increased bile production (96.2 ± 18.2 versus 36.2 ± 15.2 μL/g-liver/h, P < 0.001). Morphologically, hepatocytes and sinusoidal endothelia were both better maintained by hANP (P = 0.021). Electron microscopy also revealed that sinusoidal ultrastructures and microvilli formation in bile canaliculi were both better preserved by hANP supplementation. Silver staining also demonstrated that hANP significantly preserved reticulin fibers in Disse space (P = 0.017), representing significant protection of sinusoidal frameworks/architectures.

Conclusions. Supplementation of hANP during cold storage significantly attenuated cold ischemia/warm reperfusion injury of DCD livers.

1Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

2Center for Anatomical, Pathological, and Forensic Medical Research, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Received 5 August 2018. Revision received 27 October 2018.

Accepted 6 November 2018.

This work was supported by Grants-in-Aid for Scientific Research B (K.H. and S.U., No. 17H04271) and by another Grants-in-Aid for Scientific Research B (S.U. and K.H., No. 15H04019) from the Japan Society for the Promotion of Science, Tokyo, Japan.

The authors declare no conflicts of interest.

Y.N. mainly performed the experiments and wrote the draft. K.H. obtained the grant, designed the study protocol, participated in performing the research, analyzed the data, and wrote the draft. T.T. performed and supervised histological assays and analyses. I.T., Y.O., H.M., J.K., T.T., H.H., T.K., O.I., J.Y., T.G., and H.T. participated in performing the research and assays. S.U. supervised the research, participated in data analyses, and revised the draft.

Correspondence: Koichiro Hata, MD, PhD, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. (

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