Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation

Abstract

BackgroundIschemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Complement and contact system activation are among its key mechanisms.Study designWe investigated the benefits of pre-reperfusion treatment with recombinant human C1INH (rhC1INH), inhibitor of both complement and contact activation, in a pig model of kidney autotransplantation, subjecting the organ to 60 min warm ischemia prior to 24 h static preservation to maximize damage.ResultsSerum creatinine measurement showed that treated animals recovered glomerular function quicker than the Vehicle group. However, no difference was observed in tubular function recovery, and elevated level of urinary NGal (Neutrophil gelatinase-associated lipocalin) and plasma AST (Aspartate Aminotransferase) were detected, indicating that treatment did not influence IRI-mediated tubular cell necrosis. Regarding chronic graft outcome, rhC1INH significantly prevented fibrosis development and improved function. Immunohistochemistry and western blot showed decreased invasion by macrophages and T lymphocytes, and reduction of epithelial to mesenchymal transition. We determined the effect of treatment on complement activation with immunofluorescence analyses at 30 min post reperfusion, showing an inhibition of C4d deposition and MBL staining in treated animals.ConclusionsIn this model, the inhibition of complement activation by rhC1INH at reperfusion, while not completely counteracting IRI, limited immune system activation, significantly improving graft outcome on the short and long term.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1013-7) contains supplementary material, which is available to authorized users.

Efficacy of the natural oxygen transporter HEMO 2 life ® in cold preservation in a preclinical porcine model of donation after cardiac death

“…The present study aimed at confirming the benefits of using M101 in organ transplantation, in organs that are particularly sensitive to IRI. Thus, we subjected kidneys to 60‐min warm ischemia prior to preservation, a protocol previously demonstrated to increase post‐transplant complications to levels encountered in ECD and DCD transplantation . As clinical practice increasingly includes MP in the management of such organs, we separated our study into two preservation arms: static cold storage (CS) and hypothermic MP.…”

Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation

“…C1 inhibitor plays a central role in the modulation of inflammation by upstream regulation of the complement, coagulation, and contact systems. Although the mechanisms leading to complement activation during BD remain unclear, studies using knock‐out technology and other complement‐intervention strategies during IRI and BD have shown reduced tissue inflammation and improved renal function after reperfusion in multiple models . Poppelaars et al showed that treatment of BD rats with rhC1INH resulted in reduced renal mRNA expression and serum levels of IL‐6, improved renal function, and reduced renal injury prior to transplantation.…”

“…It acts as a major regulator by inhibiting the CP and LP of complement activation and preventing amplification of the inflammatory response . In renal IRI and kidney transplant models, C1 inhibition has shown protective effects on vessel/organ integrity and reduced IRI and progression to AMR after renal transplantation . The objective of this study was to determine the impact of rhC1INH as a donor treatment strategy in BD conditions for the prevention of early posttransplant kidney dysfunction and modulation of immune responses.…”

Donor anti-complement therapy: Complement-ing the protection array?

“…First against warm ischemia, it demonstrated the ability to reduce complement deposition and innate immune cell recruitment, which were associated with tubulointerstitial damage 1 . Further testing took place in a pig kidney transplantation model, with treatment at reperfusion following a severe course of ischemia (60 minutes warm followed by 24 hours cold) 2 . Unsurprisingly, the timing of the treatment did not protect the tubular cells against necrosis; however, it did improve functional recovery, translating at the end of the 3‐month follow‐up into long‐term protection against loss of function, immune cell infiltration, epithelial to mesenchymal transition, and interstitial fibrosis.…”