Non-Invasive Magnetic Resonance Imaging in Rats for Prediction of the Fate of Grafted Kidneys from Cardiac Death Donors Jun-Ya Kaimori 1,3 , Satomi Iwai 2 , Masaki Hatanaka 3 , Takumi Teratani 4 , Yoshitsugu Obi 3 , Hidetoshi Tsuda 1 , Yoshitaka Isaka 3 *, Takashi Yokawa 5 , Kagayaki Kuroda 6 , Naotsugu Ichimaru 1 , Masayoshi Okumi 7 , Koji Yazawa 7 , Hiromi Rakugi 3 , Norio Nonomura 7 , Shiro Takahara 1 , Eiji Kobayashi 4 1 Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan, 2 Laboratory of Small Animal Surgery I, School of Veterinary Medicine, Kitasato University, Aomori, Japan, 3 Department of Geriatrics and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan, 4 Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan, 5 BioView, Tokyo, Japan, 6 Tokai University School of Information Science and Technology Department of Human and Information Science, Kanagawa, Japan, 7 Department of Specific Organ Regulation(Urology), Osaka University Graduate School of Medicine, Osaka, Japan Abstract The main objective of this study was to assess cardiac death (CD) kidney grafts before transplantation to determine whether blood oxygen level-dependent (BOLD) and diffusion MRI techniques can predict damage to these grafts after transplantation. We assessed CD kidney tissue by BOLD and diffusion MRI. We also examined pathological and gene expression changes in CD kidney grafts before and after transplantation. Although there was significantly more red cell congestion (RCC) in the inner stripe of the outer medulla (IS) in both 1 h after cardiac death (CD1h) and CD2h kidneys destined for grafts before transplantation compared with CD0h (p,0.05), CD2h, but not CD1h, kidney grafts had significantly different RCC in the IS 2 days after transplantation (p,0.05). Consistent with these pathological findings, tissue plasminogen activator (tPA) gene expression was increased only in the cortex and medulla of CD2h kidney grafts after transplantation. BOLD MRI successfully and non-invasively imaged and quantified RCC in the IS in both CD1h and CD2h kidney grafts (p,0.05). Diffusion MRI also non-invasively assessed increased the apparent diffusion coefficient in the IS and decreased it in the outer stripe (OS) of CD2h grafts, in concordance with interstitial edema in the IS and tubule cellular edema in the OS. These two types of edema in the outer medulla could explain the prolonged RCC in the IS only of CD2h kidney grafts, creating part of a vicious cycle inhibiting red cells coming out of capillary vessels in the IS. Perfusion with University of Wisconsin solution before MRI measurements did not diminish the difference in tissue damage between CD1h and CD2h kidney grafts. BOLD and diffusion MRI, which are readily available non-invasive tools for evaluating CD kidney grafts tissue damage, can predict prolonged organ damage, and therefore the outcome, of transplanted CD kidney grafts. Citation: Kaimori J-Y, Iwai S, Hatanaka M, Teratani T, Obi Y, et al. (2013) Non-Invasive Magnetic Resonance Imaging in Rats for Prediction of the Fate of Grafted Kidneys from Cardiac Death Donors. PLoS ONE 8(5): e63573. doi:10.1371/journal.pone.0063573 Editor: Emmanuel A. Burdmann, University of Sao Paulo Medical School, Brazil Received October 18, 2012; Accepted April 3, 2013; Published May 7, 2013 Copyright: ß 2013 Kaimori et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was suported by a Grant-in-Aid for Progressive Renal Disease Research from the Ministry of Health, Labor, and Welfare of Japan, a research promoting grant of the Japan Society for Organ Preservation, Medical Biology and JSPS Grant-in-Aid for Challenging Exploratory Research Grant Number 24659714. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Takashi Yokawa, Ph.D., belongs to a private company, BioView, Inc. However, BioView, Inc has nothing to do with this paper’s competing interest. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: isaka@kid.med.osaka-u.ac.jp Introduction The worldwide shortage of organs for transplantation has highlighted expanded criteria donors (ECDs) and donation after cardiac death (DCD) as new organ sources. Because kidney grafts from ECDs and DCD are more susceptible to additional ischemia- reperfusion injuries than are those from living or brain-dead donors, these grafts are more likely to develop primary dysfunction and delayed graft loss[1]. In spite of considerable efforts to protect such marginal donor kidneys, conventional static cold storage combined with intra-cellular type solution has remained the primary option, even for damaged kidneys [2]. However, recent evidence has shown that the use of normothermic recirculation (NR) has protective effects on ECD and DCD organs. Most of this evidence has focused on NR prior to DCD liver transplantation [3–5]. In the case of renal transplantation, one clinical study reported significant improvements in delayed graft function and graft survival after transplantation using NR compared with conventional organ cooling methods [6]. One of the common features of ischemic kidney damage, congestion of blood in the capillaries of the inner stripe(IS) of the outer medulla, is thought to possibly impair both circulation and tubular flow [7]. Although its pathogenesis is still obscure, it is proposed that dramatic capillary PLOS ONE | www.plosone.org 1 May 2013 | Volume 8 | Issue 5 | e63573