Effect of synthetic protease inhibitor gabexate mesilate on the attenuation of ischemia/reperfusion injury in canine kidney autotransplantation.
BACKGROUND
Kidneys from non-heart-beating donors are associated with delayed graft function and a high rejection rate due to the long period of warm ischemia. Gabexate mesilate (GM), a synthetic serine protease inhibitor, has been shown to improve organ function by suppressing cytokine activity and neutrophil function after ischemia/reperfusion. In this study, we evaluated the effect of GM on renal function after warm ischemia in a canine kidney autotransplantation model.


METHODS
After 60 minutes of warm ischemia, the left kidney was transplanted into the iliac fossa, and the right kidney was removed. The control group (n = 7) and GM group (n = 7) were evaluated for serum creatinine and blood urea nitrogen (BUN) concentrations, renal tissue blood flow, resistive index, pulsatility index, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha mRNA expression levels in peripheral blood mononuclear cells, apoptotic index, CD10 immunolabeling as an indicator of brush border injury, and standard histopathology.


RESULTS
Compared with controls, administration of GM resulted in lower serum creatinine concentrations (11.3 +/- 2.4 vs 5.2 +/- 3.3 mg/dL at 72 hours; P = .04) and BUN concentrations (188 +/- 26 mg/dL vs 98 +/- 41 mg/dL at 72 hours; P = .04), as well as better tissue blood flow, improvement of brush border injury and apoptotic index (each P < .05). The expression of IL-1beta and TNF-alpha mRNA did not change after administration of GM.


CONCLUSIONS
The present study shows that GM protected renal function after warm ischemia/reperfusion by inhibition of serine proteases, maintenance of tissue blood flow, and amelioration of tubular apoptosis.
Inoue
Shigetaka
S
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Sugitani
Atsushi
A
Yamamoto
Hirofumi
H
Kitada
Hidehisa
H
Motoyama
Kentaro
K
Okabe
Yasuhiro
Y
Ohta
Morihito
M
Yoshida
Jun-ichi
J
Nishiyama
Ken-ichi
K
Tanaka
Masao
M
D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000235:genetics; D004285:Dogs; D016670:Gabexate / Q000627:therapeutic use*; D015870:Gene Expression; D007668:Kidney / Q000187:drug effects / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000473:pathology / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D014182:Transplantation, Autologous; D014655:Vascular Resistance / Q000187:drug effects
D016207:Cytokines; D015842:Serine Proteinase Inhibitors; D016670:Gabexate; D003404:Creatinine