Therapeutic targeting of classical and lectin pathways of complement protects from ischemia-reperfusion-induced renal damage

Am J Pathol. 2010 Apr;176(4):1648-59. doi: 10.2353/ajpath.2010.090276. Epub 2010 Feb 11.


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 C1-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. C1-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Complement C1 Inhibitor Protein / biosynthesis
  • Complement C1q / metabolism
  • Complement C4b / metabolism
  • Complement System Proteins / metabolism*
  • Disease Models, Animal
  • Female
  • Graft Survival
  • Humans
  • Immunohistochemistry / methods
  • Ischemia / pathology
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology*
  • Lectins / chemistry*
  • Peptide Fragments / metabolism
  • Reperfusion Injury / metabolism*
  • Swine


  • Complement C1 Inhibitor Protein
  • Lectins
  • Peptide Fragments
  • Complement C1q
  • Complement C4b
  • complement C4d
  • Complement System Proteins