The role of complement in antibody-mediated rejection in kidney transplantation

Nature

The role of complement in antibody-mediated rejection in kidney transplantation"


Play all audios:

Loading...

ABSTRACT Over the past decade, several studies have suggested that the complement system has an active role in both acute and chronic allograft rejection. These studies have been facilitated


by improved techniques to detect antibody-mediated organ rejection, including immunohistological staining for C4d deposition in the allograft and solid-phase assays that identify


donor-specific alloantibodies (DSAs) in the serum of transplant recipients. Studies with eculizumab, a humanized monoclonal antibody directed against complement component C5, have shown that


activation of the terminal complement pathway is necessary for the development of acute antibody-mediated rejection in recipients of living-donor kidney allografts who have high levels of


DSAs. The extent to which complement activation drives chronic antibody-mediated injury leading to organ rejection is less clear. In chronic antibody-mediated injury, early complement


activation might facilitate chemotaxis of inflammatory cells into the allograft in a process that later becomes somewhat independent of DSA levels and complement factors. In this Review, we


discuss the different roles that the complement system might have in antibody-mediated allograft rejection, with specific emphasis on renal transplantation. KEY POINTS * Activation of the


complement cascade by donor-specific alloantibodies (DSAs) might be the primary mechanism of acute antibody-mediated rejection (AMR) in sensitized kidney transplant recipients * Complement


activation might cause injury by enhancing cellular infiltration and inflammation or by directly damaging the allograft * Blockade of complement component C5 with eculizumab reduces the


incidence of early AMR in sensitized renal transplant recipients * The role of complement activation in chronic antibody-mediated injury is not yet clear: complement probably initiates


intragraft inflammation, but might not be necessary for maintaining it. * Complement components might modulate T-cell activity and adaptive immune responses involved in allograft rejection


Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this


journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now


Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer


support SIMILAR CONTENT BEING VIEWED BY OTHERS THE ROLE OF COMPLEMENT IN KIDNEY DISEASE Article 21 September 2023 C3 COMPLEMENT INHIBITION PREVENTS ANTIBODY-MEDIATED REJECTION AND PROLONGS


RENAL ALLOGRAFT SURVIVAL IN SENSITIZED NON-HUMAN PRIMATES Article Open access 15 September 2021 TRANSLATING B CELL IMMUNOLOGY TO THE TREATMENT OF ANTIBODY-MEDIATED ALLOGRAFT REJECTION


Article 02 January 2024 REFERENCES * Starzl, T. E. _ et al_. The use of cyclosporine A and prednisone in cadaver kidney transplantation. _Surg. Gynecol. Obstet._ 151, 17–26 (1980). CAS 


PubMed  PubMed Central  Google Scholar  * Ferguson, R. Acute rejection episodes—best predictor of longterm primary cadaveric renal transplant survival. _Clin. Transplant._ 8, 328–331 (1994).


CAS  PubMed  Google Scholar  * Tantravahi, J. R., Womer K. L. & Kaplan, B. Why hasn't eliminating acute rejection improved graft survival? _Ann. Rev. Med._ 58, 369–385 (2007).


Article  CAS  Google Scholar  * Cosio, F. G. _ et al_. Significance and implications of capillaritis during acute rejection of kidney allografts. _Transplantation_ 89, 1088–1094 (2010).


Article  Google Scholar  * Stegall, M. D., Gloor, J., Winters, J. L., Moore, S. B. & Degoey, S. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft


recipients with high levels of donor specific alloantibody. _Am. J. Transplant._ 6, 346–351 (2006). Article  CAS  Google Scholar  * Patel, R. & Terasaki P. I. Significance of the


positive crossmatch test in kidney transplantation. _N. Engl. J. Med._ 280, 735–739 (1969). Article  CAS  Google Scholar  * Issa, N. _ et al_. Transplant glomerulopathy: risk and prognosis


related to anti-human leukocyte antigen class II antibody levels. _Transplantation_ 15, 681–685 (2008). Article  Google Scholar  * Feucht, H. E. _ et al_. Vascular deposition of


complement-split products in kidney allografts with cell-mediated rejection. _Clin. Exp. Immunol._ 86, 464–470 (1991). Article  CAS  Google Scholar  * Cohen, D. _ et al_. Pros and cons for


C4d as a biomarker. _Kidney Int._ 81, 628–639 (2012). Article  CAS  Google Scholar  * Trpkov, K. _ et al_. Pathologic features of acute renal allograft rejection associated with


donor-specific alloantibody: analysis using the Banff grading schema. _Transplantation_ 61, 1586–1592 (1996). Article  CAS  Google Scholar  * Pei, R., Lee, J., Chen, T., Rojo, S. &


Terasaki, P. I. Flow cytometric detection of HLA antibodies using a spectrum of microbeads. _Hum. Immunol._ 60, 1293–1302 (1999). Article  CAS  Google Scholar  * Solez, K. _ et al_. Banff 07


classification of renal allograft pathology: updates and future directions. _Am. J. Transplant._ 8, 753–760 (2008). Article  CAS  Google Scholar  * Montgomery, R. A. & Zachary, A. A.


Transplanting patients with a positive donor-specific crossmatch: a single center's perspective. _Pediatr. Transplant._ 8, 535–542 (2004). Article  Google Scholar  * Bartel, G. _ et


al_. Peritransplant immunoadsorption for positive crossmatch deceased donor kidney transplantation. _Am. J. Transplant._ 10, 2033–2042 (2010). Article  CAS  Google Scholar  * Vo, A. A. _ et


al_. Rituximab and intravenous immune globulin for desensitization during renal transplantation. _N. Engl. J. Med._ 359, 242–251 (2008). Article  CAS  Google Scholar  * Burns, J. M. _ et


al_. Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation. _Am. J. Transplant._ 8, 2684–2694 (2008). Article  CAS  Google Scholar  * Rother,


R. P., Rollins, S. A., Mojcik, C. F., Brodsky R. A. & Bell, L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria.


_Nat. Biotechnol._ 25, 1256–1264 (2007). Article  CAS  Google Scholar  * Hillmen, P. _ et al_. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. _N. Engl. J. Med._


355, 1233–1243 (2006). Article  CAS  Google Scholar  * Stegall, M. D. _ et al_. Terminal complement decreases antibody-mediated rejection in sensitized renal transplant recipients. _Am. J.


Transplant._ 11, 2405–2413 (2011). Article  CAS  Google Scholar  * US National Library of Medicine. ClinicalTrials.gov [online], (2012). * Lee, P.-C. _ et al_. All chronic rejection failures


of kidney transplants were preceded by the development of HLA antibodies. _Transplantation_ 74, 1192–1194 (2003). Article  Google Scholar  * Gaston, R. S. _ et al_. Evidence for antibody


mediated injury as a major determinant of late kidney allograft failure. _Transplantation_ 90, 68–74 (2010). Article  CAS  Google Scholar  * Sellares, J. _ et al_. Understanding the causes


of kidney transplant failure: the dominant role of antibody mediated rejection and nonadherence. _Am. J. Transplant._ 12, 388–399 (2012). Article  CAS  Google Scholar  * Haririan, A. _ et


al_. Positive cross-match living donor kidney transplantation: longer-term outcomes. _Am. J. Transplant._ 9, 536–542 (2009). Article  CAS  Google Scholar  * Lefaucheur, C. _ et al_.


Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. _J. Am. Soc. Nephrol._ 21, 1398–1406 (2010). Article  Google Scholar  * Stegall, M. D. _ et al_. The


histology of solitary renal allografts at 1 and 5 years after transplantation. _Am. J. Transplant._ 11, 698–707 (2011). Article  CAS  Google Scholar  * Lamb, K. E., Lodhi, S. &


Meier-Kriesche, H. U. Long-term renal allograft survival in the United States: a critical reappraisal. _Am. J. Transplant._ 11, 450–462 (2011). Article  CAS  Google Scholar  * Cornell, L.


D., Smith, R. N. & Colvin, R. B. Kidney transplantation: mechanisms of rejection and acceptance. _Annu. Rev. Pathol._ 3, 189–220 (2008). Article  CAS  Google Scholar  * Loupy, A., Hill,


G. S., Nochy, D. & Legendre, C. Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. _Am. J. Transplant._ 10, 952; author reply 953 (2010).


Article  CAS  Google Scholar  * Cosio, F. G. _ et al_. Predicting subsequent decline in kidney allograft function from early surveillance biopsies. _Am. J. Transplant._ 5, 2464–2472 (2005).


Article  Google Scholar  * Gloor, J. M. _ et al_. Baseline donor-specific antibody levels and outcomes in positive crossmatch kidney transplantation. _Am. J. Transplant._ 10, 582–589 (2010).


Article  CAS  Google Scholar  * Bentall, A. J. _ et al_. Five-year outcomes in living donor kidney transplants with a positive crossmatch. _Am. J. Transplant._ (in press). * Haas, M. _ et


al_. Subclinical acute antibody-mediated rejection in positive crossmatch renal allografts. _Am. J. Transplant._ 7, 576–585 (2007). Article  CAS  Google Scholar  * Lerut, E., Naesens, M.,


Kuypers, D. R., Vanrenterghem, Y. & Van Damme, B. Subclinical peritubular capillaritis at 3 months is associated with chronic rejection at 1 year. _Transplantation_ 83, 1416–1422 (2007).


Article  Google Scholar  * Hidalgo, L. G. _ et al_. Interpreting NK cell transcripts versus T cell transcripts in renal transplant biopsies. _Am. J. Transplant._ 12, 1180–1191 (2012).


Article  CAS  Google Scholar  * Zhang, X., Rozengurt, E. & Reed, E. F. HLA class I molecules partner with integrin β4 to stimulate endothelial cell proliferation and migration. _Sci.


Signal._ 3, ra85 (2010). CAS  PubMed  Google Scholar  * Li, F., Zhang, X., Jin, Y. P., Mulder, A. & Reed, E. F. Antibody ligation of human leukocyte antigen class I molecules stimulates


migration and proliferation of smooth muscle cells in a focal adhesion kinase-dependent manner. _Hum. Immunol._ 72, 1150–1159 (2011). Article  CAS  Google Scholar  * Katsushige, A. _ et al_.


Enhanced expression of complement C5a receptor mRNA in human diseased kidney assessed by _in situ_ hybridization. _Kidney Int._ 60, 137–146 (2001). Article  Google Scholar  * Shankland, S.


J., Pippin, J. W. & Couser, W. G. Complement (C5b-9) induces glomerular epithelial cell DNA synthesis but not proliferation _in vitro_. _Kidney Int._ 56, 538–548 (1999). Article  CAS 


Google Scholar  * Wavamunno, M. D. _ et al_. Transplant glomerulopathy: ultrastructural abnormalities occur early in longitudinal analysis of protocol biopsies. _Am. J. Transplant._ 7,


2757–2768 (2007). Article  CAS  Google Scholar  * Dean, P. G., Park, W. D., Cornell, L. D., Gloor, J. M. & Stegall, M. D. Intragraft gene expression in positive crossmatch kidney


allografts: ongoing inflammation mediates chronic antibody-mediated injury. _Am. J. Transplant._ 6, 1551–1563 (2012). Article  Google Scholar  * Sis, B. _ et al_. Endothelial gene expression


in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. _Am. J. Transplant._ 9, 2312–2323 (2009). Article  CAS  Google Scholar  * Sis, B.


& Halloran, P. F. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. _Curr. Opin. Organ Transplant._ 15, 42–48 (2010). Article 


Google Scholar  * Sis, B. _ et al_. A new diagnostic algorithm for antibody-mediated microcirculation inflammation in kidney transplants. _Am. J. Transplant._ 12, 1168–1179 (2012). Article 


CAS  Google Scholar  * Everly, M. J. _ et al_. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. _Transplantation_ 86, 1754–1761 (2008). Article  CAS 


Google Scholar  * Locke, J. E. _ et al_. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection. _Am. J. Transplant._ 9, 231–235 (2009).


Article  CAS  Google Scholar  * Worthington, J. E., Martin, S., Al-Husseini, D. M., Dyer, P. A. & Johnson, R. W. Posttransplantation production of donor HLA-specific antibodies as a


predictor of renal transplant outcome. _Transplantation_ 15, 1034–1040 (2003). Article  Google Scholar  * Lee, P.-C., Zhu, L., Terasaki, P. I. & Everly, M. J. HLA-specific antibodies


developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. _Transplantation_ 88, 568–574 (2009). Article  CAS  Google Scholar  * Everly, M. J. _ et


al_. Survival after the onset of _de novo_ donor specific anti-HLA antibodies in a consecutive series of “low risk” renal transplant patients [abstract #180, 80]. _Am. J. Transplant._ 12


(Suppl. 3) 27–542 (2012). Google Scholar  * Sacks, S. H. & Zhou, W. The role of complement in the early immune response to transplantation. _Nat. Rev. Immunol._ 21, 431–442 (2012).


Article  Google Scholar  * Sutherland, S. M. _ et al_. Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss. _Pediatr. Transplant._


16, 12–17 (2012). Article  CAS  Google Scholar  * Yabu, J. M. _ et al_. C1q-fixing human leukocyte antigen antibodies are specific for predicting transplant glomerulopathy and late graft


failure after kidney transplantation. _Transplantation_ 91, 342–347 (2011). Article  CAS  Google Scholar  * Wahrmann, M. _ et al_. Pivotal role of complement-fixing HLA alloantibodies in


presensitized kidney allograft recipients. _Am. J. Transplant._ 6, 1033–1041 (2006). Article  CAS  Google Scholar  * Wahrmann, M. _ et al_. Clinical relevance of preformed C4d-fixing and


non-C4d-fixing HLA single antigen reactivity in renal allograft recipients. _Transpl. Int._ 22, 982–989 (2009). Article  CAS  Google Scholar  * Marcén, R. _ et al_. Immunoglobulin class and


specificity of lymphocytotoxic antibodies after kidney transplantation. _Nephrol. Dial. Transplant._ 3, 809–813 (1988). PubMed  Google Scholar  * Bryan, C. F. _ et al_. IgM antibodies


identified by a DTT-ameliorated positive crossmatch do not influence renal graft outcome but the strength of the IgM lymphocytotoxicity is associated with DR phenotype. _Clin. Transplant._


15 (Suppl. 6), 28–35 (2001). Article  Google Scholar  * Taylor, C. J., Chapman, J. R., Ting, A. & Morris, P. J. Characterization of lymphocytotoxic antibodies causing a positive


crossmatch in renal transplantation. Relationship to primary and regraft outcome. _Transplantation_ 48, 953–958 (1989). Article  CAS  Google Scholar  * Barger, B. _ et al_. Successful renal


allografts in recipients with crossmatch-positive, dithioerythritol-treated negative sera. Race, transplant history, and HLA-DR1 phenotype. _Transplantation_ 47, 240–245 (1989). Article  CAS


  Google Scholar  * Stastny, P. _ et al_. Role of immunoglobulin (Ig)-G and IgM antibodies against donor human leukocyte antigens in organ transplant recipients. _Hum. Immunol._ 70, 600–604


(2009). Article  CAS  Google Scholar  * Brodsky, S. V. _ et al_. Expression of the decay-accelerating factor (CD55) in renal transplants--a possible prediction marker of allograft survival.


_Transplantation_ 88, 457–464 (2009). Article  CAS  Google Scholar  * Chen Song, S. _ et al_. Complement inhibition enables renal allograft accommodation and long-term engraftment in


presensitized nonhuman primates. _Am. J. Transplant._ 11, 2057–2066 (2011). Article  CAS  Google Scholar  * US National Library of Medicine. ClinicalTrials.gov [online], (2012). *


Ferraresso, M. _ et al_. Posttransplant ischemia-reperfusion injury in transplanted heart is prevented by a minibody to the fifth component of complement. _Transplantation_ 86, 1445–1451


(2008). Article  CAS  Google Scholar  * Jang, J. H. _ et al_. Increased local concentration of complement C5a contributes to incisional pain in mice. _J. Neuroinflammation_ 7, 80 (2011).


Article  Google Scholar  * Iyer, A. _ et al_. Inhibition of inflammation and fibrosis by a complement C5a receptor antagonist in DOCA-salt hypertensive rats. _J. Cardiovasc. Pharmacol._ 58,


479–486 (2011). Article  CAS  Google Scholar  * Heeger, P. S. & Kemper, C. Novel roles of complement in T effector cell regulation. _Immunobiology_ 217, 216–224 (2012). Article  CAS 


Google Scholar  * Molina, H. _ et al_. Markedly impaired humoral immune responses in mice deficient in complement receptors 1 and 2. _Proc. Natl Acad. Sci. USA_ 93, 3357–3361 (1996). Article


  CAS  Google Scholar  * Fang, Y., Xu, C., Fu, Y., Holer, V. M. & Molina, H. Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a


strong antigen-specific IgG response. _J. Immunol._ 160, 5273–5279 (1998). CAS  PubMed  Google Scholar  * Carter, R. H., Spycher, M. O., Ng, Y. C., Hoffman, R. & Fearon, D. T.


Synergistic interaction between complement receptor type 2 and membrane IgM on B lymphocytes. _J. Immunol._ 141, 457–467 (1988). CAS  PubMed  Google Scholar  Download references AUTHOR


INFORMATION AUTHORS AND AFFILIATIONS * Department of Surgery, Division of Transplantation Surgery and von Liebig Transplant Center, 200 First Street SW, Mayo Clinic, Rochester, 55905, MN,


USA Mark D. Stegall & Marcio F. Chedid * Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, 200 First Street SW, Mayo Clinic, Rochester, 55905, MN, USA Lynn


D. Cornell Authors * Mark D. Stegall View author publications You can also search for this author inPubMed Google Scholar * Marcio F. Chedid View author publications You can also search for


this author inPubMed Google Scholar * Lynn D. Cornell View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS M. D. Stegall, M. F. Chedid and L.


D. Cornell contributed equally to researching data for the article, discussions of the content, writing the article and review and/or editing of the manuscript before submission.


CORRESPONDING AUTHOR Correspondence to Mark D. Stegall. ETHICS DECLARATIONS COMPETING INTERESTS M. D. Stegall and L. D. Cornell have received grant support from Alexion Pharmaceuticals. M.


D. Stegall has also received grant support from Millennium Pharmaceuticals. M. F. Chedid declares no competing interests. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE


CITE THIS ARTICLE Stegall, M., Chedid, M. & Cornell, L. The role of complement in antibody-mediated rejection in kidney transplantation. _Nat Rev Nephrol_ 8, 670–678 (2012).


https://doi.org/10.1038/nrneph.2012.212 Download citation * Published: 02 October 2012 * Issue Date: November 2012 * DOI: https://doi.org/10.1038/nrneph.2012.212 SHARE THIS ARTICLE Anyone


you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the


Springer Nature SharedIt content-sharing initiative


Trending News

'my lover transformed our bedroom into sex cave - the ceiling mirror is freaky'

JUST JANE: TODAY OUR AGONY AUNT JANE O'GORMAN HELPS OUR DAILY STAR READERS WITH A NUMBER OF WOES - INCLUDING A BOOZ...

'i tried the melitta purista's no-fuss espresso machine – it gets the job done'

YOU CAN GO FROM BEAN TO CUP IN JUST A MINUTE OR TWO, WHICH IS GREAT WHEN YOU'RE IN A HURRY - IT’S ESPECIALLY WELL-S...

New covid variant spiking in china hits major nations as who adds to watchlist

OFFICIALS HAVE RELEASED STATEMENTS WARNING THE PUBLIC TO STAY VIGILANT AS A NEW HIGHLY 'CONTAGIOUS' VARIANT OF...

Viktor gyokeres transfer message as arsenal get answer from sporting lisbon

ARSENAL HAVE BEEN LINKED WITH A MOVE FOR SPORTING FORWARD VIKTOR GYOKERES, WHO IS UNDERSTOOD TO BE OPEN TO A MOVE TO THE...

Scammers will bombard oasis fans with 9m fake tickets to con cash this summer

WHILE LONDON SEES HIGH VOLUMES, SCAMMERS ARE INCREASINGLY TARGETING FANS IN LEEDS, BIRMINGHAM AND MANCHESTER, WHICH ARE ...

Latests News

The role of complement in antibody-mediated rejection in kidney transplantation

ABSTRACT Over the past decade, several studies have suggested that the complement system has an active role in both acut...

Book Review | Nature

ARTICLE PDF RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Book Review. _Nature_ 3...

Crystal structure of the breakage–reunion domain of dna gyrase

ABSTRACT DNA gyrase is a type II DNA topoisomerase from bacteria that introduces supercoils into DNA1,2. It catalyses th...

We can’t afford to lose sight of a ceasefire for peace — scottish national party

CONTACT Scottish National Party Gordon Lamb House 3 Jackson's Entry Edinburgh, Scotland EH8 8PJ tel: 0800 633 5432 ...

Quantum sensing at the megabar frontier

Access through your institution Buy or subscribe The typical hallmarks of superconductivity are a sharp drop in resistan...

Top