Abstract
BackgroundMatrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in ischemic injury to the heart, yet it is not known if these MMPs are involved in the injury that occurs to the transplant kidney. We therefore studied the pharmacologic protection of transplant kidneys during machine cold perfusion.MethodsHuman kidney perfusates were analyzed for the presence of injury markers such as cytochrome c oxidase, lactate dehydrogenase, and neutrophil-gelatinase associated lipocalin (NGAL), and MMP-2 and MMP-9 were measured. The effects of MMP inhibitors MMP-2 siRNA and doxycycline were studied in an animal model of donation after circulatory determination of death (DCDD).ResultsMarkers of injury were present in all analyzed perfusates, with higher levels seen in perfusates from human kidneys donated after controlled DCDD compared to brain death and in perfusate from kidneys with delayed graft function. When rat kidneys were perfused at 4°C for 22 hours with the addition of MMP inhibitors, this resulted in markedly reduced levels of MMP-2, MMP-9 and analyzed injury markers.ConclusionsBased on our study, MMPs are involved in preservation injury and the supplementation of preservation solution with MMP inhibitors is a potential novel strategy in protecting the transplant kidney from preservation injury.
Highlights
In an effort to increase the number of kidneys available for transplantation in the face of ongoing donor organ shortage, the use of kidneys from more marginal donors has been increasing
The funders had Markers of injury were present in all analyzed perfusates, with higher levels seen in perfusates from human kidneys donated after controlled donation after circulatory determination of death (DCDD) compared to brain death and in perfusate from kidneys with delayed graft function
When rat kidneys were perfused at 4°C for 22 hours with the addition of Matrix metalloproteinases (MMPs) inhibitors, this resulted in markedly reduced levels of MMP-2, MMP-9 and analyzed injury markers
Summary
In an effort to increase the number of kidneys available for transplantation in the face of ongoing donor organ shortage, the use of kidneys from more marginal donors has been increasing. This includes the use of kidneys from older donors and those with hypertension [Expanded Criteria Donors (ECD)] as well as Donation after Circulatory Determination of Death donors (DCDD). Both ECD and DCDD donated kidneys are associated with a higher rate of Delayed Graft Function (DGF) and poorer function at one year [1]. We studied the pharmacologic protection of transplant kidneys during machine cold perfusion.
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