Clinical analysis of perioperative complement activity during ischemia/reperfusion injury following renal transplantation

Abstract

Background and objectives: The complement cascade seems to be an important mediator modulating renal ischemia/reperfusion injury. This study analyzed whether significant changes occur in the levels of a terminal panel of complement molecules (C3a, C5a, and C5b-9/membrane attack complex) during the early phase of human kidney allograft reperfusion and evaluated the potential association of these changes with clinical post-transplant graft function in kidney transplant recipients.

Design, setting, participants, & measurements: Seventy-five renal transplant recipients undergoing transplantation between 2004 and 2006 were enrolled in the study and divided into early, slow, and delayed graft function groups. Blood samples were collected perioperatively during consecutive minutes of allograft reperfusion from the renal vein. Levels of complement molecules were measured using ELISA.

Results: Analysis revealed no significant changes in C3a and C5a levels throughout reperfusion. The main complement molecule that was significantly associated with post-transplant graft function was C5b-9/membrane attack complex; throughout the reperfusion period, perioperative levels of C5b-9/membrane attack complex were around two to three times higher in delayed graft function patients than early and slow graft function individuals (P<0.005). In addition, C5b-9/membrane attack complex levels had a relatively high clinical sensitivity and specificity (70%-87.5%) for the prediction of early and long-term (1 year) post-transplant allograft function.

Conclusions: This clinical study supports a role for the complement cascade in delayed graft function development. However, additional studies are needed to elucidate the exact mechanisms responsible for this phenomenon. In addition, perioperative measurements of C5b-9/membrane attack complex are highlighted as promising potential clinical markers of post-transplant renal allograft function.

Figures

Figure 1.

Perioperative concentrations of examined complement anaphylatoxins measured in kidney allograft recipients. The figure depicts mean (A) C3a, (B) C5a, and (C) C5b-9/membrane attack complex (MAC) concentrations stated in consecutive minutes of kidney allograft reperfusion in particular groups of kidney transplant recipients. Circles (for early graft function [EGF]), squares (for slow graft function [SGF]), and triangles (for delayed graft function [DGF]) with solid vertical lines represent means ± SD. P values in parentheses represent results of Friedmann ANOVA test for appropriate group. *P<0.005 (versus EGF and versus SGF); #P<0.05 (versus SGF). Results are from the Mann–Whitney test for comparison of mean values between analyzed groups.

Figure 2.

Diagnostic value of examined molecular and clinical markers for prediction of early post-transplant allograft function. Receiver operating characteristics (ROCs) curves of newly introduced molecular markers (A–C) and surgical revascularization time (D) as indicators of early post-transplant allograft function. Calculated sensitivity (y axis) is plotted against the one-specificity formula (x axis) for newly introduced molecular markers (that is, MAC[0] as an indicator of SGF/DGF [A] or just DGF [B], MAC∆[1–0] as an indicator of DGF [C], and best clinical marker [surgical revascularization time parameter] as an indicator of post-transplant SGF/DGF [D]). Precise description of these parameters is presented in Table 4.

Figure 3.

Comparison of long-term (1 year) allograft function between the groups created according to newly introduced markers. Comparison of graft function between the groups created according to the suggested cutoff values of newly introduced markers (that is, [A] MAC[0] as indicator for SGF/DGF, [B] MAC[0 just for DGF, and [C] MAC∆[1–0]). Calculated estimated GFR values according to the Modification of Diet in Renal Disease formula (y axis) are plotted against months of follow-up post-transplantation (x axis). Each dot/square with solid vertical lines represents mean ± SD. P values were derived from linear mixed models by repeated measures, and they showed that groups created by division according to results of newly introduced markers significantly differ in post-transplant graft function.