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Am J Physiol Renal Physiol 290: F324-F334, 2006. First published August 30, 2005; doi:10.1152/ajprenal.00026.2005
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Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy

Joao Seda Neto,1,3 Atsunori Nakao,1,3 Hideyoshi Toyokawa,1,3 Michael A. Nalesnik,1,5 Anna Jeanine Romanosky,2 Kei Kimizuka,1,3 Takashi Kaizu,1,3 Naoki Hashimoto,1,3 Olga Azhipa,1,3 Donna B. Stolz,2 Augustine M. K. Choi,4 and Noriko Murase1,3

1Thomas E. Starzl Transplantation Institute, 2Center for Biological Imaging, Departments of 3Surgery, 4Pulmonary Allergy and Critical Care Medicine, and 5Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Submitted 24 January 2005 ; accepted in final form 22 August 2005

Chronic allograft nephropathy (CAN) is the primary cause for late kidney allograft loss. Carbon monoxide (CO), a product of heme metabolism by heme oxygenases, is known to impart protection against various stresses. We hypothesized that CO could minimize the chronic fibroinflammatory process and protect kidney allografts from CAN. Lewis kidney grafts were orthotopically transplanted into binephrectomized Brown-Norway rats under short-course tacrolimus. Recipients were maintained in room air or exposed to CO at 20 parts/million for 30 days after transplant. Efficacy of inhaled CO was studied at day 30 and day 80. Isografts maintained normal kidney function throughout the experiment with creatinine clearance of ~1.5 ml/min. Renal allograft function in air controls progressively deteriorated, and creatinine clearance declined to 0.2 ± 0.1 ml/min by day 80 with substantial proteinuria. CO-treated animals had significantly better creatinine clearance (1.3 ± 0.2 ml/min) with minimal proteinuria. Histological examination revealed the development of progressive CAN in air-exposed grafts, whereas CO-treated grafts had minimal tubular atrophy and interstitial fibrosis, with negligible collagen IV deposition. In vitro analyses revealed that CO-treated recipients had significantly less T cell proliferation against donor peptides via the indirect allorecognition pathway and less anti-donor IgG antibodies compared with air controls. Intragraft mRNA levels for chemokines (regulated on activation normal T cell expressed and secreted, macrophage inflammatory protein-1{alpha}, chemokine receptors (CCR1, CXCR3, CXCR5), IL-2, and intercellular adhesion molecule-1 were significantly decreased in CO-treated than in air-treated allografts. Furthermore, reduction of blood flow in air-treated allografts was prevented with CO. In conclusion, inhaled CO at a low concentration efficiently abrogates chronic fibroinflammatory changes associated with CAN and improves long-term renal allograft function.

kidney transplantation; cytoprotection; anti-inflammatory effect


Address for reprint requests and other correspondence: N. Murase, Thomas E. Starzl Transplantation Institute, Dept. of Surgery, E1555 Biomedical Science Tower, Univ. of Pittsburgh, Pittsburgh, PA 15213 (e-mail: murase{at}pitt.edu)




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