Case Control Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Nephrol. Oct 27, 2019; 8(6): 95-108
Published online Oct 27, 2019. doi: 10.5527/wjn.v8.i6.95
Complement activation and long-term graft function in ABO-incompatible kidney transplantation
Marit S van Sandwijk, Astrid Klooster, Ineke JM ten Berge, Arjan Diepstra, Sandrine Florquin, Joris J Hoelbeek, Frederike J Bemelman, Jan-Stephan Sanders
Marit S van Sandwijk, Ineke JM ten Berge, Frederike J Bemelman, Department of Nephrology, Amsterdam University Medical Centers, Amsterdam NL-1105 AZ, Netherlands
Marit S van Sandwijk, Dianet Dialysis Center, Amsterdam NL-1105 AZ, Netherlands
Astrid Klooster, Arjan Diepstra, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen NL-9700 RB, Netherlands
Astrid Klooster, Department of Pathology, Pathology Friesland, Leeuwarden NL-8917 EN, Netherlands
Sandrine Florquin, Joris J Hoelbeek, Department of Pathology, Amsterdam University Medical Centers, Amsterdam NL-1105 AZ, Netherlands
Jan-Stephan Sanders, Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen NL-9700 RB, Netherlands
Author contributions: van Sandwijk MS, Klooster A, Bemelman FJ, and Sanders JS designed the study; van Sandwijk MS and Klooster A collected and analyzed the clinical data; Diepstra A, Florquin S, and Hoelbeek JJ collected and analyzed the biopsy data; van Sandwijk MS wrote the first draft of the article; all other authors reviewed the draft, provided expertise for revisions, and approved the final version of the manuscript.
Institutional review board statement: In this study, anonymized patient information was retrospectively obtained and analyzed. This information was available from the Dutch Organ Transplantation Registry. All subjects consented to being included in this Registry at the time of transplantation. All subjects of this study were treated according to standard clinical practice, and their treatment or clinical outcomes were not in any way affected by their retrospective inclusion in this study. As the subjects of this study were not subjected to procedures nor were required to follow rules of behaviour, Institutional Review Board approval was not required according to Dutch law.
Informed consent statement: Patient consent was not obtained but the presented data are anonymized and risk of identification is low.
Conflict-of-interest statement: All authors declare no potential conflicts of interest.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at m.s.vansandwijk@amsterdamumc.nl.
STROBE statement: The authors have read the STROBE Statement – checklist of items, and the manuscript was prepared and revised according to the STROBE Statement – checklist of items.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Marit S van Sandwijk, MD, Staff Physician, Internist-Nephrologist, Department of Nephrology, Amsterdam University Medical Centers, location AMC, Meibergdreef 9, Amsterdam NL-1105 AZ, Netherlands. m.s.vansandwijk@amsterdamumc.nl
Telephone: +31-20-5662596
Received: May 22, 2019
Peer-review started: May 23, 2019
First decision: August 1, 2019
Revised: August 29, 2019
Accepted: October 18, 2019
Article in press: October 18, 2019
Published online: October 27, 2019
Abstract
BACKGROUND

ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABO-incompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.

AIM

To unravel the relationship between pre-transplant anti-ABO antibodies, complement activation, and long-term graft function.

METHODS

We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex, and transplantation date.

RESULTS

Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABO-incompatible recipients did have a lower kidney function at three months (creatinine clearance 58 vs 69 mL/min, P = 0.02, Modification of Diet in Renal Disease 46 vs 52 mL/min/1.73 m2, P = 0.08), due to a high rate of early rejection (33% vs 15%, P = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO IgG titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.

CONCLUSION

Co-stimulation of T-cell activation by ongoing complement activation by anti-ABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.

Keywords: ABO-incompatible, Kidney transplantation, Complement, Graft function, Rejection

Core tip: This retrospective case-control study was designed to unravel the relationship between complement activation, pre-transplant anti-ABO antibodies, and renal graft function. In this study, the slope of kidney function during a five-year follow up was not significantly different compared to matched ABO-compatible transplant recipients, but ABO-incompatible kidney transplant recipients did have a lower kidney function at three months, due to a high rate of early T-cell mediated rejection. Based on several complement staining results, we argue that this may be due to co-stimulation of T-cell activation by ongoing complement activation by anti-ABO antibodies.