Journal Article
. 2002 Aug; 13(9):2371-80.
doi: 10.1097/01.asn.0000025780.03790.0f.

Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection

Heinz Regele 1 Georg A Böhmig  Antje Habicht  Daniela Gollowitzer  Martin Schillinger  Susanne Rockenschaub  Bruno Watschinger  Dontscho Kerjaschki  Markus Exner  
  • PMID: 12191982
  •     72 citations


Endothelial deposition of the complement split product C4d is an established marker of antibody-mediated acute renal allograft rejection. A contribution of alloantibody-dependent immune reactions to chronic rejection is under discussion. In this study, the association of immunohistochemically detected endothelial C4d deposition in peritubular capillaries (PTC) with morphologic features of chronic renal allograft injury was investigated in a large study cohort. C4d deposits in PTC were detected in 73 (34%) of 213 late allograft biopsies performed in 213 patients more than 12 mo after transplantation (median, 4.9 yr) because of chronic allograft dysfunction. Endothelial C4d deposition was found to be associated with chronic transplant glomerulopathy (CG) (P < 0.0001), with basement membrane multilayering in PTC (P = 0.01), and with an accumulation of mononuclear inflammatory cells in PTC (P < 0,001). Furthermore, C4d deposits in PTC (in biopsies with normal glomerular morphology) were associated with development of CG in follow-up biopsies. Other morphologic features of chronic allograft nephropathy (with exception of tubular atrophy) were not associated with C4d deposits in PTC. Analyses of previous and follow-up biopsies revealed that C4d deposits may occur de novo and may also disappear at any time after transplantation. In conclusion, the data suggest that complement activation in renal microvasculature, indicating humoral alloreactivity, contributes to chronic rejection characterized by chronic transplant glomerulopathy and basement membrane multilayering in PTC.

Combating chronic renal allograft dysfunction : optimal immunosuppressive regimens.
Pierre Merville.
Drugs, 2005 Mar 08; 65(5). PMID: 15748097
[Alloantibodies-mediated kidney transplant rejection: a pair of continuing approaches, and with nonetheless many open questions].
Georg Böhmig.
Wien Klin Wochenschr, 2006 Jul 26; 118(13-14). PMID: 16865640
Rescue therapy with tacrolimus and mycophenolate mofetil does not prevent deterioration of graft function in C4d-positive chronic allograft nephropathy.
Christoph Schwarz, Heinz Regele, +6 authors, Georg A Böhmig.
Wien Klin Wochenschr, 2006 Jul 26; 118(13-14). PMID: 16865644
Newer developments in immunohistology.
A S-Y Leong, T Y-M Leong.
J Clin Pathol, 2006 Oct 31; 59(11). PMID: 17071800    Free PMC article.
Late kidney allograft loss: what we know about it, and what we can do about it.
Anthony M Jevnikar, Roslyn B Mannon.
Clin J Am Soc Nephrol, 2008 Mar 20; 3 Suppl 2. PMID: 18309004    Free PMC article.
Tribbles-1 as a novel biomarker of chronic antibody-mediated rejection.
Joanna Ashton-Chess, Magali Giral, +12 authors, Sophie Brouard.
J Am Soc Nephrol, 2008 Mar 29; 19(6). PMID: 18369086    Free PMC article.
Four stages and lack of stable accommodation in chronic alloantibody-mediated renal allograft rejection in Cynomolgus monkeys.
R N Smith, T Kawai, +4 authors, R B Colvin.
Am J Transplant, 2008 Jun 19; 8(8). PMID: 18557724    Free PMC article.
C4d deposition without rejection correlates with reduced early scarring in ABO-incompatible renal allografts.
Mark Haas, Dorry L Segev, +8 authors, Robert A Montgomery.
J Am Soc Nephrol, 2008 Sep 09; 20(1). PMID: 18776120    Free PMC article.
Focal C4d+ in renal allografts is associated with the presence of donor-specific antibodies and decreased allograft survival.
R L Kedainis, M J Koch, D C Brennan, H Liapis.
Am J Transplant, 2009 Apr 07; 9(4). PMID: 19344468    Free PMC article.
The role of antibodies in transplantation.
Alexander T Chang, Jeffrey L Platt.
Transplant Rev (Orlando), 2009 Jul 25; 23(4). PMID: 19628382    Free PMC article.
Combination of peritubular c4d and transplant glomerulopathy predicts late renal allograft failure.
Niamh Kieran, Xiaotong Wang, +11 authors, Jolanta Kowalewska.
J Am Soc Nephrol, 2009 Sep 05; 20(10). PMID: 19729438    Free PMC article.
Complement independent antibody-mediated endarteritis and transplant arteriopathy in mice.
T Hirohashi, S Uehara, +4 authors, R B Colvin.
Am J Transplant, 2010 Jan 09; 10(3). PMID: 20055805    Free PMC article.
Advances in immunosuppression for renal transplantation.
Antoine Durrbach, Helene Francois, +2 authors, Bernard Charpentier.
Nat Rev Nephrol, 2010 Feb 04; 6(3). PMID: 20125095
Antibody-mediated rejection: emergence of animal models to answer clinical questions.
William M Baldwin, Anna Valujskikh, Robert L Fairchild.
Am J Transplant, 2010 Mar 30; 10(5). PMID: 20346069    Free PMC article.
Chronic humoral rejection of human kidney allografts associates with broad autoantibody responses.
Fabrice Porcheray, Julie DeVito, +8 authors, Emmanuel Zorn.
Transplantation, 2010 May 07; 89(10). PMID: 20445487    Free PMC article.
Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation.
Carmen Lefaucheur, Alexandre Loupy, +7 authors, Caroline Suberbielle-Boissel.
J Am Soc Nephrol, 2010 Jul 17; 21(8). PMID: 20634297    Free PMC article.
Highly Cited.
Probabilistic (Bayesian) modeling of gene expression in transplant glomerulopathy.
Eric A Elster, Jason S Hawksworth, +7 authors, Roslyn B Mannon.
J Mol Diagn, 2010 Aug 07; 12(5). PMID: 20688906    Free PMC article.
Antibodies in transplantation.
Jeffrey L Platt.
Discov Med, 2010 Sep 03; 10(51). PMID: 20807473    Free PMC article.
Emerging role of B cells in chronic allograft dysfunction.
Robert B Colvin, Tsutomu Hirohashi, +3 authors, R Neal Smith.
Kidney Int Suppl, 2010 Dec 01; (119). PMID: 21116310    Free PMC article.
Optimal cutoff point for immunoperoxidase detection of C4d in the renal allograft: results from a multicenter study.
Gretchen S Crary, Yassaman Raissian, +5 authors, Joseph P Grande.
Transplantation, 2011 Mar 25; 90(10). PMID: 21430605    Free PMC article.
Digital pathology evaluation of complement C4d component deposition in the kidney allograft biopsies is a useful tool to improve reproducibility of the scoring.
Ernesta Brazdziute, Arvydas Laurinavicius.
Diagn Pathol, 2011 Apr 22; 6 Suppl 1. PMID: 21489200    Free PMC article.
Diminished met signaling in podocytes contributes to the development of podocytopenia in transplant glomerulopathy.
Putri A Agustian, Mario Schiffer, +10 authors, Jan U Becker.
Am J Pathol, 2011 Apr 26; 178(5). PMID: 21514418    Free PMC article.
Antibodies reactive to non-HLA antigens in transplant glomerulopathy.
Rajani Dinavahi, Ajish George, +15 authors, Peter S Heeger.
J Am Soc Nephrol, 2011 May 14; 22(6). PMID: 21566057    Free PMC article.
Peritubular capillary basement membrane changes in chronic renal allograft rejection: Comparison of light microscopic and ultrastructural observations.
Bela Ivanyi, Eva Kemeny, +5 authors, Edit Szederkenyi.
Virchows Arch, 2011 Jul 02; 459(3). PMID: 21720964
Chronic alloantibody mediated rejection.
R Neal Smith, Robert B Colvin.
Semin Immunol, 2011 Nov 05; 24(2). PMID: 22051115    Free PMC article.
Clinical role of the renal transplant biopsy.
Winfred W Williams, Diana Taheri, Nina Tolkoff-Rubin, Robert B Colvin.
Nat Rev Nephrol, 2012 Jan 11; 8(2). PMID: 22231130    Free PMC article.
Pros and cons for C4d as a biomarker.
Danielle Cohen, Robert B Colvin, +8 authors, Ingeborg M Bajema.
Kidney Int, 2012 Feb 03; 81(7). PMID: 22297669    Free PMC article.
Diagnostic challenges in chronic antibody-mediated rejection.
Evan A Farkash, Robert B Colvin.
Nat Rev Nephrol, 2012 Mar 28; 8(5). PMID: 22450441    Free PMC article.
The impact of donor-specific anti-HLA antibodies on late kidney allograft failure.
Alexandre Loupy, Gary S Hill, Stanley C Jordan.
Nat Rev Nephrol, 2012 Apr 18; 8(6). PMID: 22508180
Highly Cited. Review.
Antibody-mediated rejection in kidney transplantation: a review.
Chethan Puttarajappa, Ron Shapiro, Henkie P Tan.
J Transplant, 2012 May 12; 2012. PMID: 22577514    Free PMC article.
Enhanced de novo alloantibody and antibody-mediated injury in rhesus macaques.
E K Page, A J Page, +8 authors, S J Knechtle.
Am J Transplant, 2012 Jul 11; 12(9). PMID: 22776408    Free PMC article.
Role of complement and NK cells in antibody mediated rejection.
Takurin Akiyoshi, Tsutomu Hirohashi, +6 authors, Robert B Colvin.
Hum Immunol, 2012 Aug 02; 73(12). PMID: 22850181    Free PMC article.
Diagnostic significance of peritubular capillary basement membrane multilaminations in kidney allografts: old concepts revisited.
George Liapis, Harsharan K Singh, +3 authors, Volker Nickeleit.
Transplantation, 2012 Sep 01; 94(6). PMID: 22936037    Free PMC article.
Partial therapeutic response to Rituximab for the treatment of chronic alloantibody mediated rejection of kidney allografts.
R Neal Smith, Fahim Malik, +6 authors, Waichi Wong.
Transpl Immunol, 2012 Sep 11; 27(2-3). PMID: 22960786    Free PMC article.
The importance of C4d in biopsies of kidney transplant recipients.
Rosana Rosa Miranda Corrêa, Juliana Reis Machado, +5 authors, Marlene Antônia dos Reis.
Clin Dev Immunol, 2013 Aug 13; 2013. PMID: 23935649    Free PMC article.
The specificity of acute and chronic microvascular alterations in renal allografts.
Edward J Filippone, John L Farber.
Clin Transplant, 2013 Oct 15; 27(6). PMID: 24118527    Free PMC article.
Sensitive solid-phase detection of donor-specific antibodies as an aid highly relevant to improving allograft outcomes.
Gerald Schlaf, Beatrix Pollok-Kopp, Wolfgang W Altermann.
Mol Diagn Ther, 2013 Oct 31; 18(2). PMID: 24170304
Effector mechanisms of rejection.
Aurélie Moreau, Emilie Varey, Ignacio Anegon, Maria-Cristina Cuturi.
Cold Spring Harb Perspect Med, 2013 Nov 05; 3(11). PMID: 24186491    Free PMC article.
Diagnosis and management of antibody-mediated rejection: current status and novel approaches.
A Djamali, D B Kaufman, +3 authors, M Samaniego.
Am J Transplant, 2014 Jan 10; 14(2). PMID: 24401076    Free PMC article.
Highly Cited. Review.
Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy.
Maurizio Salvadori, Elisabetta Bertoni.
World J Transplant, 2014 Mar 29; 4(1). PMID: 24669363    Free PMC article.
Bortezomib in late antibody-mediated kidney transplant rejection (BORTEJECT Study): study protocol for a randomized controlled trial.
Farsad Eskandary, Gregor Bond, +8 authors, Georg A Böhmig.
Trials, 2014 Apr 09; 15. PMID: 24708575    Free PMC article.
Transplant glomerulopathy: the interaction of HLA antibodies and endothelium.
William Hanf, Claudine S Bonder, P Toby H Coates.
J Immunol Res, 2014 Apr 18; 2014. PMID: 24741606    Free PMC article.
Issues in solid-organ transplantation in children: translational research from bench to bedside.
Steven E Lipshultz, Jayanthi J Chandar, +10 authors, James D Wilkinson.
Clinics (Sao Paulo), 2014 May 27; 69 Suppl 1. PMID: 24860861    Free PMC article.
Pretransplant IgG reactivity to apoptotic cells correlates with late kidney allograft loss.
B Gao, C Moore, +14 authors, E Zorn.
Am J Transplant, 2014 Jun 18; 14(7). PMID: 24935695    Free PMC article.
Three-dimensional structure of axonal mitochondria reflects the age of drosophila.
Honglian Zhu, Xiaojiang Sun.
Neural Regen Res, 2013 Mar 05; 8(7). PMID: 25206706    Free PMC article.
Personalization of the immunosuppressive treatment in renal transplant recipients: the great challenge in "omics" medicine.
Gianluigi Zaza, Simona Granata, +2 authors, Antonio Lupo.
Int J Mol Sci, 2015 Feb 19; 16(2). PMID: 25690039    Free PMC article.
Anti-huCD20 antibody therapy for antibody-mediated rejection of renal allografts in a mouse model.
T Abe, D Ishii, +9 authors, R L Fairchild.
Am J Transplant, 2015 Mar 04; 15(5). PMID: 25731734    Free PMC article.
The diffuse extent of peritubular capillaritis in renal allograft rejection is an independent risk factor for graft loss.
Nicolas Kozakowski, Harald Herkner, +4 authors, Željko Kikić.
Kidney Int, 2015 Mar 05; 88(2). PMID: 25738252
Capillary deposition of complement C4d and C3d in Chinese renal allograft biopsies.
Rong Lv, Wei Zhang, +3 authors, Jianghua Chen.
Dis Markers, 2015 Mar 31; 2015. PMID: 25821339    Free PMC article.
Novel solid phase-based ELISA assays contribute to an improved detection of anti-HLA antibodies and to an increased reliability of pre- and post-transplant crossmatching.
Gerald Schlaf, Beatrix Pollok-Kopp, +2 authors, Wolfgang Altermann.
NDT Plus, 2010 Dec 01; 3(6). PMID: 25949460    Free PMC article.
Nanoparticle enhanced MRI scanning to detect cellular inflammation in experimental chronic renal allograft rejection.
S R Alam, G H Tse, +6 authors, P A Henriksen.
Int J Mol Imaging, 2015 May 09; 2015. PMID: 25954516    Free PMC article.
Capillary C4d and Kidney Allograft Outcome in Relation to Morphologic Lesions Suggestive of Antibody-Mediated Rejection.
Željko Kikić, Alexander Kainz, +4 authors, Georg A Böhmig.
Clin J Am Soc Nephrol, 2015 Jun 14; 10(8). PMID: 26071493    Free PMC article.
Recent advances in renal transplantation: antibody-mediated rejection takes center stage.
Eric Pouliquen, Alice Koenig, +5 authors, Olivier Thaunat.
F1000Prime Rep, 2015 Jun 23; 7. PMID: 26097724    Free PMC article.
Autoimmune Liver Disease Post-Liver Transplantation: A Summary and Proposed Areas for Future Research.
Catherine Edmunds, Udeme D Ekong.
Transplantation, 2015 Oct 09; 100(3). PMID: 26447505    Free PMC article.
Tolerogenic Dendritic Cells on Transplantation: Immunotherapy Based on Second Signal Blockage.
Priscila de Matos Silva, Julia Bier, +5 authors, Patricia Ucelli Simioni.
J Immunol Res, 2015 Nov 07; 2015. PMID: 26543876    Free PMC article.
Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation.
Tobias Bergler, Bettina Jung, +5 authors, Bernhard Banas.
PLoS One, 2016 Jun 11; 11(6). PMID: 27285579    Free PMC article.
The clinical implications of the unique glomerular complement deposition pattern in transplant glomerulopathy.
Priya S Verghese, Robin C Reed, +2 authors, Youngki Kim.
J Nephrol, 2016 Nov 17; 31(1). PMID: 27848227
Rethinking peritubular capillary basement membrane multilayering in renal transplant pathology: a case report.
Diana Maria Lopategui, Evelyne Lerut, +3 authors, Noël Knops.
Pediatr Nephrol, 2016 Nov 20; 32(4). PMID: 27858192
Transplant glomerulopathy.
Edward J Filippone, Peter A McCue, John L Farber.
Mod Pathol, 2017 Oct 14; 31(2). PMID: 29027535
Multicolor Flow Cytometry and Cytokine Analysis Provides Enhanced Information on Kidney Transplant Biopsies.
Kimberly A Muczynski, Nicolae Leca, +2 authors, Susan K Anderson.
Kidney Int Rep, 2018 Jul 11; 3(4). PMID: 29989006    Free PMC article.
A Fully Automated System Using A Convolutional Neural Network to Predict Renal Allograft Rejection: Extra-validation with Giga-pixel Immunostained Slides.
Young-Gon Kim, Gyuheon Choi, +5 authors, Namkug Kim.
Sci Rep, 2019 Mar 28; 9(1). PMID: 30914690    Free PMC article.
Germinal Center Alloantibody Responses Mediate Progression of Chronic Allograft Injury.
Manu Chhabra, Jawaher Alsughayyir, +10 authors, Gavin J Pettigrew.
Front Immunol, 2019 Feb 08; 9. PMID: 30728823    Free PMC article.
Clinical significance of C4d deposition in renal tissues from patients with primary Sjögren's syndrome-a preliminary study.
Wenli Xia, Bixia Gao, +6 authors, Mingxi Li.
BMC Nephrol, 2019 May 30; 20(1). PMID: 31138153    Free PMC article.
Potential Roles for C1 Inhibitor in Transplantation.
Mel Berger, William M Baldwin, Stanley C Jordan.
Transplantation, 2015 Nov 26; 100(7). PMID: 26599489    Free PMC article.
Molecular Assessment of C4d-Positive Renal Transplant Biopsies Without Evidence of Rejection.
Katherine M Dominy, Michelle Willicombe, +7 authors, Candice Roufosse.
Kidney Int Rep, 2019 Jan 01; 4(1). PMID: 30596178    Free PMC article.
Glomerular C3 Deposition Is an Independent Risk Factor for Allograft Failure in Kidney Transplant Recipients With Transplant Glomerulopathy.
Sarah E Panzer, Emily Joachim, +3 authors, Arjang Djamali.
Kidney Int Rep, 2019 Apr 18; 4(4). PMID: 30993233    Free PMC article.
Glomerular C4d in Post-Transplant IgA Nephropathy is associated with decreased allograft survival.
Michael Eder, Nicolas Kozakowski, +7 authors, Željko Kikić.
J Nephrol, 2020 Dec 12; 34(3). PMID: 33306182    Free PMC article.
Shiga Toxin 2a Binds to Complement Components C3b and C5 and Upregulates Their Gene Expression in Human Cell Lines.
Sára Kellnerová, Sneha Chatterjee, +8 authors, Reinhard Würzner.
Toxins (Basel), 2020 Dec 31; 13(1). PMID: 33374102    Free PMC article.
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Hengcheng Zhang, Zijie Wang, +10 authors, Min Gu.
Front Immunol, 2021 Mar 19; 12. PMID: 33732243    Free PMC article.
Acute Kidney Injury, Microvascular Rarefaction, and Estimated Glomerular Filtration Rate in Kidney Transplant Recipients.
Alice Doreille, Féryel Azzi, +6 authors, Héloïse Cardinal.
Clin J Am Soc Nephrol, 2021 Mar 03; 16(3). PMID: 33648972    Free PMC article.
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Shannon R Reese, Nancy A Wilson, +6 authors, Sarah E Panzer.
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