Submitted on December 5, 2008
Revised on March 24, 2009
Accepted on April 14, 2009
LOW DOSE CARBON MONOXIDE INHIBITS PROGRESSIVE CHRONIC ALLOGRAFT NEPHROPATHY AND RESTORES RENAL ALLOGRAFT FUNCTION
Atsunori Nakao1, Gaetano Faleo1, Michael A. Nalesnik1, Joao Seda Neto1, Junichi Kohmoto1, and Noriko Murase1*
1 University of Pittsburgh, Thomas E. Starzl Transplantation Institute
* To whom correspondence should be addressed. E-mail: murase{at}pitt.edu.
Chronic allograft nephropathy (CAN) represents progressive deterioration of renal allograft function with fibroinflammatory changes. CAN, recently reclassified as interstitial fibrosis and tubular atrophy with no known specific etiology (IF/TA) is a major cause of late renal allograft loss and remains a significant deleterious factor of successful renal transplantation. Carbon monoxide (CO), an effector byproduct of heme oxygenase pathway, is known to have potent anti-inflammatory and anti-fibrotic functions. We hypothesized that inhaled CO would inhibit fibroinflammatory process of CAN and restore renal allograft function, even when the treatment was initiated after CAN was established. Methods: Lewis rat kidney grafts were orthotopically transplanted into binephrectomized allogenic BN rats under brief tacrolimus (0.5 mg/kg, d0-6, im). At d60, CO 20 ppm inhalation was initiated to recipients and continued until d150 or animal death. Results: Development of CAN was confirmed at d60 with decreased creatinine clearance (CCr), significant proteinuria, and histopathological findings of tubular atrophy, interstitial fibrosis and intimal arteritis. Air-treated control recipients continued to deteriorate with further declines of CCr and increases of urinary protein excretion and died with a median survival of 82 days. In contrast, progression of CAN was decelerated when recipients received CO on d60-150, showing markedly improved graft histopathology, restored renal function and improved recipient survival to a median of >150 days. CO significantly reduced intragraft mRNA levels for IFN-
and TNF-
at d90. Expression of profibrotic TGF-
/Smad was significantly suppressed with CO, together with downregulation of ERK MAPK pathways. Continuous CO 20 ppm treatment for d0-30, d30-60, or d0-90, or daily 1 hr CO 250 ppm treatment for d0-90 also showed efficacy in inhibiting CAN. Conclusions: The study demonstrates that CO is able to inhibit progression of fibroinflammatory process of CAN, restore renal allograft function, and improve survival even when the treatment is started after CAN is diagnosed.
