Low level carbon monoxide exposure as a therapeutic approach to improving transplant outcome
SummaryDailyUpdates 24th August, 2004: Heme oxygenase-1 (HO-1), one of the enzymes responsible for the production of carbon monoxide, is induced under conditions of ischemic stress. Clinical data has previously demonstrated that increased expression of HO-1 may limit post-transplant ischemia reperfusion injury, a major cause of reduced graft survival. Now researchers have reported that maintaining transplant recipients in an atmosphere of elevated carbon monoxide promotes extended graft survival
Since the first successful kidney transplantation more than 40 years ago, the treatment of end-stage organ failure has dramatically improved. Many organs are now transplanted, the most common of which include (procedures performed in the in 2001) the kidney (14,000), heart (2,000), liver (5,000) and lung (1,000). Despite these figures transplantation is still somewhat limited by availability of human donor organs.
Although about 14,000 people in the receive a donor kidney each year, more than four times that number end up on organ transplant waiting list and almost 3,000 die before a match could be found.
When organs are available, the successful use of immunomodulatory agents means that nowadays the major problem in organ transplantation is not acute graft rejection but chronic graft deterioration. In addition to alloantigen-specific events, alloantigen independent factors including perioperative ischemia-reperfusion injury have a major impact on long-term graft function.
A shortage of donor kidneys has prompted clinicians to consider the use of organs from people who had high blood pressure or other health problems, as well as kidneys from non-heart beating donors. These marginal kidneys once were presumed to have higher failures rates, but research now suggests that the majority of them fare as well as any other transplanted organ. Such kidneys may however be more prone to ischemia-reperfusion injury, tissue damage that occurs when blood flow to an organ is stopped, then started again after a period of time. The injury is common in all kidney transplants, but may be particularly severe in patients who receive marginal kidneys. The use of marginal kidneys as a donor alternative may be more common today, but they still accounted for less than 2% of all organ transplants. Addressing the issue of ischemia-reperfusion injury is expected to improve the outcome of transplantation in general and particularly so in situations when marginal organs are used. This may in turn make physicians less wary of using such organs thereby reducing the wait for transplants.
Heme oxygenase (HO), an essential enzyme in heme catabolism, cleaves heme to form biliverdin and carbon monoxide (CO), a putative neurotransmitter. HO is expressed in two forms, constitutive HO-2 and inducible HO-1. Induction of the later occurs in response to ischemic stress and CO which is elevated as a result, is known to impart protection against oxidative stress.
At the end of last year clinical data was published by Dutch researchers, Lemos et al reporting a correlation between renal function at the first week post-transplantation and HO-1 expression. More recently the same group has shown that kidneys donated by carriers of the HO-1 S-allele, which is associated with higher expression of HO-1, survived better in graft recipients (Baan et al, 2004). These data suggest that increasing CO levels may improve the survival of transplanted kidneys. In rodent studies, transfer of the HO-1 gene into kidneys prior to transplant has been shown to increase their subsequent survival (Blydt-Hansen et al, 2003). Using a similar rat kidney transplant model, researchers now have found that exposing transplant recipients to an atmosphere of increased CO levels also promotes extended graft survival.
In their study published in this month's edition of the American Journal of Physiology, Neto et al report exposing rats to CO (250 ppm) in air for 1 hour before and 24 hours after transplantation reduced the expression of inflammatory mediators and improved renal cortical blood flow in transplanted kidenys. Further detailed morphological analyses revealed that CO preserved the glomerular vascular architecture and podocyte viability with less apoptosis of tubular epithelial cells and less macrophage infiltration. CO inhalation resulted in improved serum creatinine levels and clearance, and animal survival was over twice as long compared to control animals. This study demonstrates that exposure of kidney graft recipients to CO at a low concentration can impart significant protective effects against renal ishemia-reperfusion injury and improve function of renal grafts.
Source: Protection Of Transplant-Induced Renal Ischemia/Reperfusion Injury With Carbon Monoxide. Am J Physiol Renal Physiol. 2004 Aug 3 [Epub ahead of print]
This article is highlighted in the August 24th edition of DailyUpdates-Internal Medicine, LeadDiscovery’s unique bulletin of breaking journal articles and press releases for the drug discovery community. To access the article and to view today’s bulletin click here