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Castellano, G.; Melchiorre, R.; Loverre, A.; Ditonno, P.; Montinaro, V.; Rossini, M.; ... ; Grandaliano, G. (2010)

Therapeutic Targeting of Classical and Lectin Pathways of Complement Protects from Ischemia-Reperfusion-Induced Renal Damage

Article / Letter to editor
Ischemia-reperfusion injury is the major cause of delayed graft function in transplanted kidneys, an early event significantly affecting long-term graft function and survival. Several studies in rodents suggest that the alternative pathway of the complement system plays a pivotal role in renal ischemia-reperfusion injury. However, limited information is currently available from humans and larger animals. Here we demonstrated that 30 minutes of ischemia resulted in the induction of C4d/C1q, C4d/MLB, and MBL/MASP-2 deposits in a swine model of ischemia-reperfusion injury. The infusion of Cl-inhibitor led to a significant reduction in peritubular capillary and glomerular C4d and C5b-9 deposition. Moreover, complement-inhibiting treatment significantly reduced the numbers of infiltrating CD163(+), SWC3a(+), CD4a(+), and CD8a(+) cells. Cl-inhibitor administration led to significant inhibition of tubular damage and tubular epithelial cells apoptosis. Interestingly, we report that focal...Show moreIschemia-reperfusion injury is the major cause of delayed graft function in transplanted kidneys, an early event significantly affecting long-term graft function and survival. Several studies in rodents suggest that the alternative pathway of the complement system plays a pivotal role in renal ischemia-reperfusion injury. However, limited information is currently available from humans and larger animals. Here we demonstrated that 30 minutes of ischemia resulted in the induction of C4d/C1q, C4d/MLB, and MBL/MASP-2 deposits in a swine model of ischemia-reperfusion injury. The infusion of Cl-inhibitor led to a significant reduction in peritubular capillary and glomerular C4d and C5b-9 deposition. Moreover, complement-inhibiting treatment significantly reduced the numbers of infiltrating CD163(+), SWC3a(+), CD4a(+), and CD8a(+) cells. Cl-inhibitor administration led to significant inhibition of tubular damage and tubular epithelial cells apoptosis. Interestingly, we report that focal C4d-deposition colocalizes with C1q and MBL at the peritubular and glomerular capillary levels also in patients with delayed graft function. In conclusion, we demonstrated the activation and a pathogenic role of classical and lectin pathways of complement in a swine model of ischemia-reperfusion induced renal damage. Therefore, inhibition of these two pathways might represent a novel therapeutic approach in the prevention of delayed graft function in kidney transplant recipients. (Am J Pathol 2010, 176:1648-1659; DOI: 10.2353/ajpath.2010.090276)Show less
membrane attack complex delayed graft function human c1 inhibitor ischemia/reperfusion injury kidney-transplantation brain ischemia c1-inhibitor activation c4d mice
All authors
Castellano, G.; Melchiorre, R.; Loverre, A.; Ditonno, P.; Montinaro, V.; Rossini, M.; Divella, C.; Battaglia, M.; Lucarelli, G.; Annunziata, G.; Palazzo, S.; Selvaggi, F.P.; Staffieri, F.; Crovace, A.; Daha, M.R.; Mannesse, M.; Wetering, S. van; Schena, F.P.; Grandaliano, G.
Date
2010-04-30
Journal
American Journal of Pathology
Volume
176
Issue
4
Pages
1648 - 1659
DOI
doi:10.2353/ajpath.2010.090276