Effect of human natural xenoantibody depletion and complement inactivationon early pig kidney function

Preformed xenoreactive natural antibodies (XNA) and complement mediate hype racute xenograft rejection (HXR) in pig-to-human discordant xenotransplanta tion. In a pig kidney-human blood xenoperfusion model, we investigated whet her XNA depletion and/or human complement inactivation preserved early pig kidney function. Pig kidneys were perfused for 180 min with pig blood (AUTO group, n = 8), human blood (HETER group, n = 6), complement-inactivated hu man blood (COMI group, n = 5), XNA-depleted human blood (ABd group, n = 5) or complement-inactivated and XNP-depleted human blood (ABd&COMi group, n = 5). METER kidneys were rejected after 15-30 min and showed vascular microt hrombi and interstitial hemorrhages. XNA depletion and/or complement inacti vation prevented MXR. The glomerular filtration rate in ABd, COMi and ABd&C OMi groups was significantly lower than in the AUTO group. Also, beyond 60 min, the COMI group showed a significantly lower glomerular filtration rate than that observed in ABd and ABd&COMi groups. Kidneys from ABd, COMI and ABd&COMi groups displayed endothelial cell edema, as well as higher soluble P-selectin levels and a higher renal myeloperoxidase content than the AUTO group kidneys. COMI and ABd&COMi groups had a significantly lower renal my eloperoxidase level than the METER group. Also, in contrast to METER and AB d groups, these complement-inactivated groups failed to show a positive cor relation between P-selectin and renal myeloperoxidase. We also investigated platelet-activating factor (PAF) as possible mediator for these functional and pathologic changes. We found that blood PAF levels were similar in MET ER, ABd, COMI and ABd&COMi groups and significantly higher than in the AUTO group. Also, when PAF was added to porcine endothelial cell monolayers, mo rphological changes due to cytoskeleton contraction were observed, and thes e changes were prevented by preincubation with a PAF receptor antagonist. I n conclusion, although depletion of XNA and/or complement inactivation prev ent MXR, the pig kidney function is not preserved at the level of the autol ogous combination. The PAF overproduction observed in the xenogenic combina tion, which is independent of the presence of XNA and complement, may be, a t least in part, responsible for early endothelial cell morphological chang es still present when MXR is prevented.