Protection of the Transplant Kidney from Preservation Injury by Inhibition of Matrix Metalloproteinases.
BACKGROUND
Matrix 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.


METHODS
Human 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).


RESULTS
Markers 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.


CONCLUSIONS
Based 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.
Department of Surgery and Saskatchewan Renal Transplant Program, Saskatoon, Saskatchewan.
Michael A J
http://orcid.org/0000-0003-0735-199X
MA
Moser
Department of Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Steve
S
Arcand
Department of Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.|University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Han-Bin
HB
Lin
Prairie Diagnostic Services, Department of Veterinary Pathology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Chris
C
Wojnarowicz
Department of Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Jolanta
J
Sawicka
Department of Laboratory Medicine and Pathology, Saskatoon Health Region, Saskatoon, Saskatchewan, Canada.
Tamalina
T
Banerjee
Department of Surgery and Saskatchewan Renal Transplant Program, Saskatoon, Saskatchewan.
Yigang
Y
Luo
Department of Surgery and Saskatchewan Renal Transplant Program, Saskatoon, Saskatchewan.
Gavin R
GR
Beck
Multi Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada.
Patrick P
PP
Luke
Department of Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.|Department of Clinical Chemistry, Medical University of Wroclaw, Wroclaw, Poland.
Grzegorz
G
Sawicki
D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D051799:Delayed Graft Function / Q000201:enzymology / Q000473:pathology; D004318:Doxycycline / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000293:injuries* / Q000473:pathology / Q000648:ultrastructure; D016030:Kidney Transplantation; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000071068:Lipocalin-2 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D009926:Organ Preservation; D010477:Perfusion; D051381:Rats
D015415:Biomarkers; D000071068:Lipocalin-2; D061965:Matrix Metalloproteinase Inhibitors; D007770:L-Lactate Dehydrogenase; D003576:Electron Transport Complex IV; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline