Original ArticlesRenal Transplantation

Clinical Analysis of Perioperative Complement Activity during Ischemia/Reperfusion Injury following Renal Transplantation

Wojciech Błogowski, Barbara Dołęgowska, Daria Sałata, Marta Budkowska, Leszek Domański and Teresa Starzyńska
CJASN November 2012, 7 (11) 1843-1851; DOI: https://doi.org/10.2215/CJN.02200312

Summary

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.

Introduction

Ischemia/reperfusion injury (I/R) exerts a profound influence on post-transplant kidney allograft function, and despite several attempts to exclude or at least ameliorate the consequences of this process, I/R remains an inseparable aspect of transplantation medicine. According to recent studies, temporary I/R injury may lead to significant damage of kidney allograft architecture, which in turn, results in defective clinical function in the recipient. Among various mechanisms involved in renal I/R, activation of the complement cascade (CC) is especially emphasized; however, thus far, its importance in determining post-transplant outcome has only been moderately verified in clinical studies (1,2).

The complement system is a central mediator linking innate and adaptive immunity. Complement activation after various types of tissue/organ injuries may occur through three different pathways (classic, alternative, or lectin) through the interaction of antibodies, proinflammatory proteins, or mannose-binding lectin fragments (2–4). Recent experimental studies have shown that, in terms of heart, intestinal, or liver I/R injury, the classic route of CC activation plays the most important role in causing cellular damage within the architecture of a transplanted organ. However, in terms of experimental kidney I/R injury, it seems likely that the alternative and lectin pathways of CC activation may be of greatest significance (2,5,6). Nevertheless, independent of the mechanism, activation of CC leads to generation of the terminal panel of the complement anaphylatoxins, C3a, C5a, and C5b-9 (membrane attack complex [MAC]) molecules, with actions that enhance mobilization of inflammatory cells and/or intensify cellular lysis within the site of tissue or organ injury.

Recent experimental studies have shown that selected CC anaphylatoxins may interact with alloreactive T lymphocytes, attract them to the site of a renal allograft, and induce acute rejection of transplanted kidneys (7–10). However, although these experiments clearly show the importance of CC anaphylatoxins in the regulation of the I/R injury scenario after kidney transplantation, the clinical significance and translation of these observations have not been verified and examined in actual human renal transplantation settings. To address this discrepancy, we comprehensively examined changes in the levels of the terminal panel of CC effector molecules C3a, C5a, and C5b-9/MAC during the early phase of kidney allograft reperfusion and verified their association with post-transplant clinical allograft function in recipients. Our hypothesis is that, during the early phase of kidney allograft reperfusion, significant changes occur in the levels of complement molecules, and these changes are associated with early and long-term (1 year) post-transplant allograft function.

Materials and Methods

Patients

This study included 75 consecutive recipients transplanted in our University Center (Department of General and Transplantation Surgery) who were retrospectively divided into three groups depending on graft reactivation: early (immediate; EGF), slow (SGF), and delayed (DGF) graft function according to previously described criteria (Table 1) (11–15). In brief, patients with immediate allograft activation, defined by serum creatinine levels below 3 mg/dl on postoperative day 5, were assigned to the EGF group. Individuals with graft reactivation problems were divided into SGF (creatinine level higher than 3 mg/dl on postoperative day 5 and not requiring dialysis treatment) and DGF (dialysis was required within the first week after transplantation) groups. All patients were primary recipients and have been treated using hemodialysis for at least several months before transplantation. Renal allografts were received only from brain death deceased donors. Grafts were stored cold and perfused with EuroCollins preservation solutions. Allocation of donor kidneys to individual recipients was centrally directed by the Poltransplant system. In addition, a group of age- and sex-matched healthy controls and patients undergoing hemodialysis treatment was examined in the study (detailed description in Supplemental Material and Methods). The general characteristics of the patients and transplantation procedure are presented in Table 1 and Supplemental Table 1.

View this table:
Table 1.

General characteristics of the donors and patients enrolled in the study as well as the transplantation procedure [presented as means ± SD or medians (interquartile range)]

Perioperative and Post-Transplant Treatment

All patients received a standard immunosuppressive protocol with triple drug therapy, including cyclosporine A, azathioprine, and steroids. Cyclosporine administration was initiated on the day of transplantation with a dose of 5 mg/kg (per os). From day 2 and daily thereafter, patients received 10 mg/kg cyclosporine. In cases where allograft reactivation problems occurred, the dose was reduced to 50%. During follow-up, cyclosporine doses were adjusted to achieve troughs of 200–250 ng/ml for the first 3–6 months, with maintenance levels of 120–180 ng/ml afterward. The dose of prednisolone was gradually reduced to 5 mg/d over 3–6 months.

Material

Blood samples were collected according to a previously described protocol (16). To determine prereperfusion levels/activity of analyzed parameters, a blood sample was taken from the iliac vein before anastomosing kidney vessels with the recipient’s iliac vessels (time 0). Next, to analyze changes in CC parameters activity/levels, after the transplant renal vein was cannulated, additional blood samples were taken at minutes 1, 3, and 5 after reperfusion. Reperfusion of the transplanted kidney was monitored with the ThermaCAM SC500 (AGEMA; Infrared System AB, Danderyd, Sweden) thermovision camera, which detects infrared radiation and records digital images representing the surface temperature distribution from the tested objects. The process of total reperfusion was considered complete when scans from the thermovision camera showed that the whole organ was filled with the recipient’s blood.

For the assessment of changes in CC parameter levels/activity, 5-ml blood samples were collected and mixed with 109 mM K3EDTA (9:1; vol/vol). Then, blood was centrifuged (10 minutes at 20°C at 3824 × g), and plasma was transferred to a fresh test tube and stored at −80°C until assays were performed.

Biochemical Assays

Plasma was defrosted at room temperature, and C3a, C5a, and C5b-9/MAC levels were measured using ELISA kits (BD Bioscience OptEIA ELISA Kits, BD Bioscience) according to the manufacturer’s instructions.

Clinical Parameters of Allograft Function

To determine allograft function, creatinine levels were measured during perioperative periods (i.e., on post-transplant days 1, 5, and 10) and follow-up visits during the first year after transplantation. Values of estimated GFRs were calculated according to the Modification of Diet in Renal Disease equation (17).

Clinical Predictive Value of Examined Parameters

Application of cutoff limits enabled classification of patients into four categories: true positive, true negative, false positive, and false negative. Sensitivity, specificity, and positive and negative predictive values were calculated.

Statistical Analyses

To determine the distribution of variables, a Shapiro–Wilk test was used. For comparison of the mean parameter values between the examined groups, t test was used (for normally distributed variables). Abnormally distributed variables were log-transformed. If normal distribution was achieved, variables were also compared using t test. However, if this transformation did not change the distribution, the Mann–Whitney test was performed. Differences between concentrations of analyzed parameters in consecutive minutes of reperfusion were assessed by the Friedmann ANOVA test. To evaluate the effects of continuous variables on determination of post-transplant allograft function, multivariate regression analyses were performed with a stepwise selection method. Variables excluded from the initial model were re-entered individually to exclude residual confounding. During development of multivariate regression models, the number of inserted independent variables did not exceed 10% of the total number of analyzed patients. Constructed models were verified using the Akaike information criterion, and wrongly constructed matrices resulted in rejection of the model. Receiver operating characteristics (ROCs) curves were constructed for all analyzed parameters as diagnostics for graft activation problems (i.e., SGF and DGF), and the area under each ROC curve was calculated. Linear mixed-effects models were used for evaluation of repeated measures for clinical allograft function comparison. To adjust for multiple comparisons, Bonferroni correction was applied when appropriate Statistical analysis was performed using SPSS statistical analysis software. Statistical significance was defined when P values were less than 0.05. The study protocol was approved by the Bioethical Committee of the Pomeranian Medical University in Szczecin, Poland, and all patients provided informed written consent before participation.

Results

Patients’ and Donors’ Characteristics

Statistical comparison of initial donors’ and patients’ characteristic features showed no significant differences between the examined groups (Table 1). However, in this analysis, comparison of such parameters as duration of hemodialysis treatment before transplantation and cold ischemia time between SDG and DGF patients revealed values close to the statistical significance (P=0.09 and P=0.07, respectively).

Perioperative Activation of the CC

Statistical analysis revealed no significant differences in C3a or C5a concentrations immediately before and during the analyzed reperfusion period in all recruited patients as well as the particular analyzed group (Figure 1, A and B and Supplemental Figure 1, A and B). Moreover, we could not show any significant differences in mean C3a and C5a levels at appropriate time points between patients classified into different groups. Prereperfusion concentrations of these complement anaphylatoxins were significantly higher in all examined groups than in healthy controls and age- and sex-matched patients on hemodialysis (Supplemental Table 2).

Figure 1.
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.

In contrast, several significant differences were observed with respect to perioperative C5b-9/MAC levels (Figure 1C). Namely, prereperfusion C5b-9/MAC levels were significantly higher in all examined groups than in age- and sex-matched patients on hemodialysis (Supplemental Table 2), and although no statistically significant differences in MAC levels were observed within the reperfusion period in the general population of kidney transplant recipients (Supplemental Figure 1C), analysis between each group revealed that significantly higher MAC levels were constantly observed in DGF individuals. In this group of kidney transplant recipients, C5b-9 concentrations significantly decreased during the reperfusion time. In addition, analysis of the dynamics of MAC changes during the reperfusion period showed significant differences between DGF individuals and EGF/SGF patients (Supplemental Table 3). However, in our study, we could not establish any correlation between perioperative MAC levels and patient characteristics or the transplantation procedure.

Clinical Associations Between Perioperative Levels of Complement Anaphylatoxins and Post-Transplant Kidney Allograft Function—Potential Predictive and Practical Value

Multivariate regression analyses were used to strengthen our observations that, indeed, the associations between perioperative activity/levels of complement molecules and post-transplant renal allograft function occur (Tables 2 and 3). These results showed that perioperative levels of the analyzed complement molecules (mainly C5b-9/MAC), together with such clinical parameters as elder donors’ age, duration of cold ischemia time, and dialysis treatment before transplantation, are strongly associated with post-transplant allograft function.

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Table 2.

Clinical and molecular parameters associated with early (first week) post-transplant renal allograft graft function (modeling using multivariate regression analysis)

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Table 3.

Clinical and molecular parameters associated with long-term (first 6 month) post-transplant renal allograft graft function (modeling using multivariate regression analysis)

To determine whether perioperative activity/levels of complement molecules may serve as novel predictors of post-transplant graft function (EGF, SGF, or DGF prediction), we constructed ROCs and determined the approximate area under each ROC curve value to assess the suitability of these parameters as a diagnostic tool. Among all clinical and newly examined parameters, only those parameters with 95% confidence interval lower bound value exceeding 0.50 are presented and precisely described (Figure 2 and Table 4).

Figure 2.
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.

View this table:
Table 4.

Diagnostic value of examined parameters to discriminate delayed and slow allograft function from immediate allograft function

In addition, we addressed whether measurement of these new markers may be of prognostic value for early (first 1 year) post-transplant graft function. Our study highlighted that perioperative analysis of MAC levels may also be of benefit for the prognosis of the first 6–12 months of graft function (Figure 3), whereas the clinical parameter of surgical revascularization time was not associated with long-term (first 12 months) post-transplant allograft function (P=0.25). When the study population was divided according to suggested cutoff values, we could not show any significant differences between groups with regard to the frequency of occurrence of acute rejection episodes observed during the first 1 year after transplantation (Supplemental Figure 2).

Figure 3.
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.

Discussion

For over 30 years, it has been known that the actions of the complement system contribute to organ I/R injury; however, the precise role of the CC in human renal I/R is not fully understood (2). Hence, we decided to address this important question by comprehensively analyzing changes in the levels of the terminal panel of CC effector molecules during the early phase of renal allograft reperfusion and verifying their potential associations with both early and long-term clinical allograft function in renal transplant recipients.

We found that, during the early phase of kidney allograft reperfusion, no significant changes occur in C3a and C5a anaphylatoxins levels. This finding is in accordance with results of previous experimental studies, in which changes in renal C3 gene expression were examined during reperfusion in mice subjected to renal transplantation (18). The study by Damman et al. (18) showed that the most pronounced local renal activation of the CC occurs during brain death in experimental animals and that the CC remains at the same high level during the transplantation procedure. Results of our study support these previous experimental observations. However, although in our study, C3a and C5a levels in plasma did not change, we hypothesize that these anaphylatoxins may be, in fact, the most important mediators of inflammation causing DGF, which was suggested in experimental models (19,20). One of the reasons why no significant changes in the levels of C3a and C5a anaphylatoxins were observed in our study may be the fact that these complement anaphylatoxins have a very short half-life. Hence, the direct levels of these CC anaphylatoxins in plasma may not necessarily reflect tissue injury.

However, in our study, perioperative C5b-9/MAC levels seemed to be strongly associated with post-transplant allograft function, and significant differences in concentrations of this complement derivative were detected between analyzed groups. C5b-9/MAC itself is a very powerful molecule, and its action may directly induce cellular injury and necrosis within a transplanted allograft. Relatively small amounts of MAC have proved to be sufficient to attract neutrophils, increase expression of adhesion molecules on endothelium, and activate platelets (21–23). The work by Zhou et al. (5) showed that C5b-9/MAC action most evidently contributes to the determination of renal function after injurious stimuli, such as in I/R. In our study, we observed that, although in the general population of renal transplant recipients, perioperative MAC levels did not significantly change (similarly reported in the work by de Vries et al. [24] in the clinical setting of living donation), C5b-9/MAC levels were constantly significantly higher (even already before reperfusion) in DGF patients than EGF/SGF individuals. Interestingly, observed MAC values were not associated with either recipient characteristics or factors related to the transplantation procedure. Our results are, therefore, in agreement with previous laboratory observations indicating that human C5b-9/MAC levels are not related to anthropometric or biochemical factors specific for a particular donor and that, in response to injurious/stimulating factors, C5b-9/MAC generation is relatively unpredictable and individual-specific (21,25). Although we cannot definitively state the mechanisms responsible for observed phenomenon at this stage of our research, we hypothesize that various factors related to individual patient’s response to pretransplant hemodialysis treatment and the surgery itself may be responsible for this tendency. Because of the fact that CC activation on cell surfaces is regulated by multiple factors, such as decay accelerating factor, membrane cofactor protein, and/or protectin (reviewed in detail in ref. 26), individual variations in their activity/genetic polymorphisms may be responsible for observed phenomenon. What is also important to highlight is that observed MAC concentrations may be a manifestation of an intensified CC activation rather than the cause of injury, because complement functions as a cascade amplifying the amount of C5b-9/MAC, which is more stable than CC anaphylatoxins and farther downstream (hence, easier to detect). Nevertheless, these hypotheses should be verified in additional cohort studies, in which patients undergoing hemodialysis treatment and living donation transplantations should be examined.

Finally, the clinical value of CC molecule activity/levels as diagnostic markers for SGF/DGF prediction needs to be evaluated. Our results show that recipients with high MAC levels (either specific for a particular recipient or generated in response to the surgical procedure) are very likely to develop DGF after transplantation and may also present with worse allograft function during the first year after transplantation. Although our mixed model analyses revealed significant differences in clinical allograft function during the first year after transplantation in patients with lower C5b-9/MAC levels, these statistics could benefit from more pronounced differences in kidney allograft function that were observed during the first 3–6 months between analyzed groups of patients. Nevertheless, our preliminary analysis suggests that this proinflammatory molecule possesses the potential to differentiate between EGF and SGF/DGF. Although several studies expended great effort to discover clinically suitable early post-transplant markers for SGF/DGF prediction, our team concentrates on finding perioperative SGF/DGF predictors (27–31). Within the current study, we propose and preliminarily describe novel perioperative markers with sensitivity that reaches 80%–90% that seem to be promising tools for future post-transplant graft function prediction. Unfortunately, at this stage, these markers do not seem suitable for independent decision-making because of their low specificity; also, their diagnostic value was determined based on a relatively small sample size. In addition, their cutoff and predictive values must be further verified in cohort studies.

In summary, our clinical study supports a role of the complement in DGF development in humans. However, additional studies are needed to elucidate the exact molecular mechanisms responsible for this phenomenon. In addition, perioperative measurements of C5b-9/MAC are highlighted as a promising potential clinical marker of post-transplant renal allograft function.

Disclosures

None.

Acknowledgments

This study was fully financed from the grant funds awarded by the Polish National Science Center (2011/01/N/NZ5/01398) to W.B.

Parts of these results were presented during the 7th International Federation of Shock Societies Conference, June 9–13, 2012, Miami, Florida, and the 24th International Congress of The Transplantation Society, July, 15–19, 2012, Berlin, Germany.

There are no potential personal or financial conflicts of interest affecting any author.

Footnotes

  • Received March 2, 2012.
  • Accepted July 8, 2012.

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Clinical Analysis of Perioperative Complement Activity during Ischemia/Reperfusion Injury following Renal Transplantation
Wojciech Błogowski, Barbara Dołęgowska, Daria Sałata, Marta Budkowska, Leszek Domański, Teresa Starzyńska
CJASN Nov 2012, 7 (11) 1843-1851; DOI: 10.2215/CJN.02200312
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