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NDT Advance Access originally published online on September 12, 2006
Nephrology Dialysis Transplantation 2006 21(12):3371-3373; doi:10.1093/ndt/gfl480
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Complement-ary matching: a definite maybe*

Duska Dragun

Department of Nephrology and Center for Cardiovascular Research, Charité University Medicine Berlin, Berlin, Germany

Correspondence and offprint requests to: Dr Duska Dragun, Department of Nephrology and Critical Care Medicine, Charité CVK, Augustenburger, Platz 1, 133353 Berlin, Germany. Email: duska.dragun{at}charite.de

Keywords: complement; C3; C3F/S allotypes; kidney transplantation

The mammalian complement system has evolved as an important bridge between the innate and adaptive immune system, with responsibility for host defense against pyogenic bacteria, disposal of immune complexes and the products of inflammatory injury [1]. Three different pathways (Figure 1, panel A) lead to activation of the complement system [2]. First discovered was the classical, antigen-antibody binding-initiated pathway. Of no lesser importance is the mannose-binding lectin-mediated pathway. The evolutionarily oldest complement defense is the alternative pathway [1]. The central complement protein C3 represents the point of convergence for all three recognized activation pathways and plays a decisive role in a variety of physiological and pathological processes pivotal to the complement cascade. Sequential proteolytic cleavages of a large C3 (187 kDa) protein, which moves through the bloodstream in an inactive form and first becomes activated after encountering with foreign targets, lead to the production of terminal pathway effector products analogous to the coagulation/fibrinolysis pathways. Three main types of C3 effector products are the anaphylotoxins C3a and C5a, the membrane attack complex C5b-9 and covalently bound C3b, along with its metabolites iC3b and C3d [3]. The membrane attack complex (Figure 1, panel B) leads directly to inflammatory transcription factor activation [4].


Figure 1
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  		Fig. 1. Three different pathways lead to activation of complement system that converges at C3. C3 effector products are the anaphylatoxins C3a and C5a, the membrane attack complex C5b-9 and covalently bound C3b. The membrane attack complex leads directly to inflammatory transcription factor activation.

 
C3 is not only involved in the regulation of specific immune responses in infection, but also contributes to various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosis [5]. Although most circulating C3 is produced in the liver, local synthesis in the extravascular tissues is no less important, since endogenous activators of complement can be found in injured mammalian tissues. Most extrahepatic C3 is located in the kidney [6]. Increased local C3 synthesis and/or defective regulation of C3 may contribute to a wide variety of complement-mediated intrarenal processes ranging from ischaemia-reperfusion injury to responses against urinary tract bacterial pathogens [7], as well as alloantigen-dependent and alloantigen-independent conditions associated with renal transplantation [8]. Already during the immediate post-operative period after transplantation, C3 mediates reaction to heat and cold stress associated with organ preservation and reperfusion [9].

Another important C3-related issue is antibody-mediated rejection, because the switching of alloantibody to high-affinity IgG responses is also highly C3-dependent [10]. Furthermore, recent experimental studies provide important evidence that renal-tissue-derived C3 is essential for the regulation of transplant rejection and that local production of C3 exerts effects on T-cell allo-responses in the functional mouse renal transplant model [11]. Pratt et al. [11] from the Sacks laboratory showed that transplants from C3-deficient mouse donors had less inflammation and generated a weaker recipient immune response than transplants from wild-type donors.

After impressive animal and cellular studies on the importance of C3 in regulating systemic and intrarenal responses to various stimuli, the same group next moved to address human renal transplantation and investigated C3 in terms of genetic diversity [12]. Human C3 exists as two common allotypic variants, the less common C3F (fast) and more common C3S (slow) variant. The two can be discriminated on the basis of electrophoretic mobility [13]. The two alleles probably have functional differences, as shown in association studies for many autoimmune and inflammatory diseases [14]. In their recent report, Brown et al. [12] observed that the C3F allotype of the donor is associated with better long-term kidney allograft survival. Data on C3 allotypes and their influence on the outcome after renal transplantation were derived from 501 pairs of white donors and renal transplant recipients, who were divided into four groups according to the presence or absence of the C3F allele in the donor and the recipient.

The very fact that the authors even considered genetic variability of both the donor and the recipient makes this study remarkable. Until recently, the attention of transplant investigators has been primarily focused on recipient genetic polymorphisms. With significant improvement in immunosuppressive regimens and satisfying short-term survival, the attention of the transplant community is now shifting towards the long-term follow-up. As a result, problems with organ shortage that force utilization of expanded donor criteria are increasing in importance as outcome variables. In the last decade, we have learned that donor-associated factors involving age, gender, diabetes, hypertension, pre-existing atherosclerosis and the systemic effects of brain death can alone or in combination negatively influence long-term graft survival [15]. Genetic polymorphisms within a donor kidney may thus represent important additional modulating variables [16]. Brown et al. [12] found that the presence of C3F allele in a renal allograft was associated with a better long-term outcome and that C3F allografts did particularly well in C3S recipients. Moreover, their results also implied that C3F kidneys may be ‘injury-resistant kidneys’ or C3S recipients may be ‘suitable recipients’ of C3F ‘injury-resistant kidneys’. In this group, there were more kidneys with donor-related risk factors such as advancing donor age and extended preservation times, and fewer kidneys from living donors. Nevertheless, this potentially disadvantaged group had a better outcome [12].

However, the C3F allele frequency differs significantly between Caucasian and non-Caucasian populations, with the highest frequency in Caucasians (20%) and the lowest in Asians (1%) [17]. Another confounding variable is the fact that the study did not delineate mechanisms by which the C3F allotype may determine the long-term graft outcome. Although some older data exist on binding characteristics of allotypic variants to complement receptors [18,19], the issue is controversial because the site of the C3F/S polymorphism is remote from the known binding sites of complement receptors. Furthermore, many binding domains on C3 are unknown. The recently published structure of C3 [20] will certainly aid in predicting how these allotypes may affect protein–protein interactions that could be responsible for functional consequences in the many settings involving C3. We eagerly await further developments in this area.

Should we begin thinking about ‘complementary matching’ at the C3 locus if future research confirms and extends the findings by Brown et al.? Selecting appropriate donor–recipient combinations based on the ability to identify those at risk for faster functional deterioration and thereby minimizing allograft loss is one of the allocation algorithm goals. For example, Eurotransplant relies on allocation algorithms that take into account factors such as age, human leucocyte antigen match, waiting time and clinical urgency. Yet the schemes are flexible and can be changed based on scientific data [21]. Although complementary matching that considers the C3 allotypes is not very likely in the immediate future, the recent study by Brown et al. [12] establishes a working paradigm for further research. Improved donor–recipient risk-profiling can optimize long-term allograft survival.

Conflict of interest statement. None declared.



   Notes
 
* Comment on Brown KM, Kondeatis E, Vaughan R et al. Influence of Donor C3 allotype on late renal-transplantation outcome. N Engl J Med 2006; 354: 2014–2024 Back



   References
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Received for publication: 29. 6.06
Accepted in revised form: 14. 7.06


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