Influence of Graft Characteristics on the Outcome of Kidney Transplantation
http://www.100md.com
《新英格兰医药杂志》
The characteristics of renal allografts before transplantation present a multifaceted puzzle that in large part predetermines the outcome of kidney transplantation. Compatibility at the major-histocompatibility-complex (MHC) loci, the age of the donor, cold-ischemia times, and nephron mass1,2 all contribute to long-term results through interacting effects involving initial damage to parenchymal or vascular cells and possible hyperfiltration. Many factors are involved in chronic allograft dysfunction, in which immune-mediated lesions caused by chronic rejection are only one component.3
In this issue of the Journal, Brown et al.4 report on a newly identified donor factor, an allotype of the C3 complement molecule that may be associated with better long-term outcomes for cadaveric kidney grafts. The C3 allotypes may be distinguished because they can be visualized by their distinct electrophoretic migration patterns: C3F (fast), which is present in about 20 percent of white patients, and C3S (slow). The authors raise the possibility that the presence of the C3F allele in a kidney allograft is associated with a better outcome. Their study provides yet another example of how a single mutation, or polymorphism, of a molecule (or of its regulatory elements) with potentially key functions may affect graft outcome. As is usual for a new and potentially significant finding, the study poses several unresolved questions.
Although Brown et al. stress the importance of the donor's allotype, it is noteworthy that the outcome of kidney grafts from donors with the C3F or C3F/S allele differs from that of grafts from donors with the C3S/S allele only when the recipient has the C3S/S allele. Recipients with the C3F allele who receive grafts with the C3S/S allele have no substantial effect from their native C3F allele. This suggests that the allotypes of donor and recipient interact and that the C3S/S phenotype of the recipient is also important. In addition, at 10 years of follow-up, the apparent 25 percent advantage of C3S/S recipients of a kidney from a donor with the C3F allele is based on a low number of at-risk patients, making a definitive conclusion premature. However, in support of the findings of Brown et al., the various known ("classic") risk factors — such as prolonged cold-ischemia time, older age of the donor, and cadaveric origin of the grafts — were all more frequent in the study group that had a more favorable outcome (i.e., a donor with the C3F allele and a recipient with the C3S/S allele). Thus, although the results are potentially promising, the small sample size means that confirmation on a larger scale is needed.5
The mechanisms by which the C3F allotype may affect the long-term graft outcome also need to be elucidated. C3 is a key component of the complement cascade, a fundamental innate defense system. C3 is situated at the crossroads of three major complement activation pathways, yielding several effector molecules with powerful inflammatory effects.6 The classic pathway of complement activation is initiated by antibody binding to antigens, the alternative pathway is directly activated by the foreign surface of microorganisms, and the mannose-binding lectin pathway is activated by bacterial walls with terminal mannose groups. Although the complement cascade is primarily involved in host defense, it also promotes clearance of antibody-coated microorganisms and antigens, and several C-component deficiencies of the classic pathway (C1q, C1r, C1s, and C4) are associated with autoimmune diseases, such as lupus erythematosus.
Complement is well documented to play a role in the reactivity of kidney allografts, particularly through the binding of complement-fixing preexisting antibodies to graft endothelial cells, as well as antibodies induced by transplantation (as seen in hyperacute or acute humoral rejection) or appearing later, often preceding chronic rejection and transplant glomerulopathy.7 The more frequent detection of C4d (molecular evidence of previous complement activation) in chronic humoral rejection provides clear evidence that complement plays a role in chronic rejection. Indeed, the observation made back in the 1970s8 that complement also boosts the production of T-cell–dependent antibodies opened a new area of investigation in the field of transplantation.
More recent data that document the effects of complement on several stages of adaptive T-cell immunity (alloresponses and antivirus or antitumor responses) have expanded the field of study. Transplants from animals in which the C3 gene has been knocked out resist rejection.9 The absence of complement-regulatory molecules, such as decay-accelerating factor, increases T-cell immunity.10 Although circulating complement molecules are likely to be instrumental in the formation of microvascular lesions (through reperfusion and the immunoglobulin-mediated classic pathway), the local production of C3 by proximal-tubule epithelial cells, endothelial cells, and mesenchymal glomerular cells — production that is up-regulated by ischemia, inflammation, and rejection — may have a greater effect on chronic cellular responses. Thus, complement from both the donor and the recipient can contribute to the development of graft lesions.
Whereas evidence for a possible role of kidney graft–derived complement would raise the possibility of a potential long-term effect on allograft survival, the observations of Brown et al. do not unambiguously show that a difference in allotype is linked to a difference in function. Recently, a comprehensive crystallographic description of human C3 molecules was reported.11 The amino acid difference that discriminates between the C3F and the C3S allele lies in the first 2-macroglobulin domain (MG1) at the C3 terminal part of the C3 light chain (Figure 3 in the article by Brown et al. and Figure 1 of this editorial).11
Figure 1. The Differentiation in Amino Acids between C3F and C3S.
Human C3 exists as two allotypic variants, C3F (fast) and C3S (slow), according to electrophoretic mobility. The arginine substitution to glycine at position 80, which distinguishes the C3F allele from the C3S allele, lies at the C3 terminal part of the C3 light chain in the first 2-macroglobulin domain (MG1). Currently, MG1 does not appear to be critical for the C3 functional domain. (Reprinted with the permission of Macmillan Publishers.11)
In our current understanding of the molecular portrait of C3, MG1, which is conserved in C3, C4, C5, and other members of the 2-macroglobulin superfamily, does not appear to be a critical C3 functional domain, as is the case for the thioester, the anaphylatoxin (which recruits inflammatory cells), or the proteolytic cascade sites in the molecule. Differences that are not yet understood could affect binding to complement receptor on antigen-presenting cells, B cells, or T cells. The effect of an unknown gene proximal to the C3 gene cannot be excluded, but research has not yielded pertinent candidates. No information is yet available on possible differences in the production of alloantibody (or C3F antibody) in the at-risk population of transplant recipients. A partial histologic analysis of late-deteriorating transplants did not reveal C4d deposition in the C3S/S grafts — a finding that does not suggest chronic stimulation of T-cell–dependent alloantibody. The lack of undelineated functional differences between the two alleles warrants further confirmation of this observation in larger studies, which the study by Brown et al. will clearly engender.
The effect of the single-mutation polymorphism described in the context of the study by Brown et al. may contribute to global allograft survival, but as yet the full clinical implications remain to be defined. At present, the study suggests that complement should be considered a factor that may affect long-term allograft outcome, and future studies to explore this hypothesis will no doubt be stimulated by these data.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Centre Hospitalier Universitaire de Nantes and INSERM Unité 643 (J.-P.S., M.G.) and Université de Nantes (J.-P.S.) — all in Nantes, France.
References
Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med 1994;331:365-376.
Giral M, Nguyen JM, Karam G, et al. Impact of graft mass on the clinical outcome of kidney transplants. J Am Soc Nephrol 2005;16:261-268.
Nankivell BJ, Borrows RJ, Fung CL-S, O'Connell PJ, Allen RDM, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2326-2333.
Brown KM, Kondeatis E, Vaughan RW, et al. Influence of donor C3 allotype on late renal-transplantation outcome. N Engl J Med 2006;354:2014-2023.
Colhoun HM, McKeigue PM, Davey Smith G. Problems of reporting genetic associations with complex outcomes. Lancet 2003;361:865-872.
Walport M. Complement at the interface between innate and adaptative immunity. N Engl J Med 2001;344:1140-1145.
Terasaki PI. Humoral theory of transplantation. Am J Transplant 2003;3:665-673.
Pepys MB. Role of complement in induction of antibody production in vivo: effect of cobra factor and other C3-reactive agents on thymus-dependent and thymus-independent antibody responses. J Exp Med 1974;140:126-145.
Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002;8:582-587.
Liu J, Miwa T, Hilliard B, et al. The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. J Exp Med 2005;201:567-577.
Janssen BJ, Huizinga EG, Raaijmakers HC, et al. Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 2005;437:505-512.(Jean-Paul Soulillou, M.D.)
In this issue of the Journal, Brown et al.4 report on a newly identified donor factor, an allotype of the C3 complement molecule that may be associated with better long-term outcomes for cadaveric kidney grafts. The C3 allotypes may be distinguished because they can be visualized by their distinct electrophoretic migration patterns: C3F (fast), which is present in about 20 percent of white patients, and C3S (slow). The authors raise the possibility that the presence of the C3F allele in a kidney allograft is associated with a better outcome. Their study provides yet another example of how a single mutation, or polymorphism, of a molecule (or of its regulatory elements) with potentially key functions may affect graft outcome. As is usual for a new and potentially significant finding, the study poses several unresolved questions.
Although Brown et al. stress the importance of the donor's allotype, it is noteworthy that the outcome of kidney grafts from donors with the C3F or C3F/S allele differs from that of grafts from donors with the C3S/S allele only when the recipient has the C3S/S allele. Recipients with the C3F allele who receive grafts with the C3S/S allele have no substantial effect from their native C3F allele. This suggests that the allotypes of donor and recipient interact and that the C3S/S phenotype of the recipient is also important. In addition, at 10 years of follow-up, the apparent 25 percent advantage of C3S/S recipients of a kidney from a donor with the C3F allele is based on a low number of at-risk patients, making a definitive conclusion premature. However, in support of the findings of Brown et al., the various known ("classic") risk factors — such as prolonged cold-ischemia time, older age of the donor, and cadaveric origin of the grafts — were all more frequent in the study group that had a more favorable outcome (i.e., a donor with the C3F allele and a recipient with the C3S/S allele). Thus, although the results are potentially promising, the small sample size means that confirmation on a larger scale is needed.5
The mechanisms by which the C3F allotype may affect the long-term graft outcome also need to be elucidated. C3 is a key component of the complement cascade, a fundamental innate defense system. C3 is situated at the crossroads of three major complement activation pathways, yielding several effector molecules with powerful inflammatory effects.6 The classic pathway of complement activation is initiated by antibody binding to antigens, the alternative pathway is directly activated by the foreign surface of microorganisms, and the mannose-binding lectin pathway is activated by bacterial walls with terminal mannose groups. Although the complement cascade is primarily involved in host defense, it also promotes clearance of antibody-coated microorganisms and antigens, and several C-component deficiencies of the classic pathway (C1q, C1r, C1s, and C4) are associated with autoimmune diseases, such as lupus erythematosus.
Complement is well documented to play a role in the reactivity of kidney allografts, particularly through the binding of complement-fixing preexisting antibodies to graft endothelial cells, as well as antibodies induced by transplantation (as seen in hyperacute or acute humoral rejection) or appearing later, often preceding chronic rejection and transplant glomerulopathy.7 The more frequent detection of C4d (molecular evidence of previous complement activation) in chronic humoral rejection provides clear evidence that complement plays a role in chronic rejection. Indeed, the observation made back in the 1970s8 that complement also boosts the production of T-cell–dependent antibodies opened a new area of investigation in the field of transplantation.
More recent data that document the effects of complement on several stages of adaptive T-cell immunity (alloresponses and antivirus or antitumor responses) have expanded the field of study. Transplants from animals in which the C3 gene has been knocked out resist rejection.9 The absence of complement-regulatory molecules, such as decay-accelerating factor, increases T-cell immunity.10 Although circulating complement molecules are likely to be instrumental in the formation of microvascular lesions (through reperfusion and the immunoglobulin-mediated classic pathway), the local production of C3 by proximal-tubule epithelial cells, endothelial cells, and mesenchymal glomerular cells — production that is up-regulated by ischemia, inflammation, and rejection — may have a greater effect on chronic cellular responses. Thus, complement from both the donor and the recipient can contribute to the development of graft lesions.
Whereas evidence for a possible role of kidney graft–derived complement would raise the possibility of a potential long-term effect on allograft survival, the observations of Brown et al. do not unambiguously show that a difference in allotype is linked to a difference in function. Recently, a comprehensive crystallographic description of human C3 molecules was reported.11 The amino acid difference that discriminates between the C3F and the C3S allele lies in the first 2-macroglobulin domain (MG1) at the C3 terminal part of the C3 light chain (Figure 3 in the article by Brown et al. and Figure 1 of this editorial).11
Figure 1. The Differentiation in Amino Acids between C3F and C3S.
Human C3 exists as two allotypic variants, C3F (fast) and C3S (slow), according to electrophoretic mobility. The arginine substitution to glycine at position 80, which distinguishes the C3F allele from the C3S allele, lies at the C3 terminal part of the C3 light chain in the first 2-macroglobulin domain (MG1). Currently, MG1 does not appear to be critical for the C3 functional domain. (Reprinted with the permission of Macmillan Publishers.11)
In our current understanding of the molecular portrait of C3, MG1, which is conserved in C3, C4, C5, and other members of the 2-macroglobulin superfamily, does not appear to be a critical C3 functional domain, as is the case for the thioester, the anaphylatoxin (which recruits inflammatory cells), or the proteolytic cascade sites in the molecule. Differences that are not yet understood could affect binding to complement receptor on antigen-presenting cells, B cells, or T cells. The effect of an unknown gene proximal to the C3 gene cannot be excluded, but research has not yielded pertinent candidates. No information is yet available on possible differences in the production of alloantibody (or C3F antibody) in the at-risk population of transplant recipients. A partial histologic analysis of late-deteriorating transplants did not reveal C4d deposition in the C3S/S grafts — a finding that does not suggest chronic stimulation of T-cell–dependent alloantibody. The lack of undelineated functional differences between the two alleles warrants further confirmation of this observation in larger studies, which the study by Brown et al. will clearly engender.
The effect of the single-mutation polymorphism described in the context of the study by Brown et al. may contribute to global allograft survival, but as yet the full clinical implications remain to be defined. At present, the study suggests that complement should be considered a factor that may affect long-term allograft outcome, and future studies to explore this hypothesis will no doubt be stimulated by these data.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Centre Hospitalier Universitaire de Nantes and INSERM Unité 643 (J.-P.S., M.G.) and Université de Nantes (J.-P.S.) — all in Nantes, France.
References
Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med 1994;331:365-376.
Giral M, Nguyen JM, Karam G, et al. Impact of graft mass on the clinical outcome of kidney transplants. J Am Soc Nephrol 2005;16:261-268.
Nankivell BJ, Borrows RJ, Fung CL-S, O'Connell PJ, Allen RDM, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2326-2333.
Brown KM, Kondeatis E, Vaughan RW, et al. Influence of donor C3 allotype on late renal-transplantation outcome. N Engl J Med 2006;354:2014-2023.
Colhoun HM, McKeigue PM, Davey Smith G. Problems of reporting genetic associations with complex outcomes. Lancet 2003;361:865-872.
Walport M. Complement at the interface between innate and adaptative immunity. N Engl J Med 2001;344:1140-1145.
Terasaki PI. Humoral theory of transplantation. Am J Transplant 2003;3:665-673.
Pepys MB. Role of complement in induction of antibody production in vivo: effect of cobra factor and other C3-reactive agents on thymus-dependent and thymus-independent antibody responses. J Exp Med 1974;140:126-145.
Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002;8:582-587.
Liu J, Miwa T, Hilliard B, et al. The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. J Exp Med 2005;201:567-577.
Janssen BJ, Huizinga EG, Raaijmakers HC, et al. Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 2005;437:505-512.(Jean-Paul Soulillou, M.D.)