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      Anti-Angiotensin II Type 1 Receptor and Anti-Endothelial Cell Antibodies: A Cross-Sectional Analysis of Pathological Findings in Allograft Biopsies

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          Abstract

          Background

          This is a cross-sectional study designed to evaluate the histologic characteristics of graft injury in the presence of anti-angiotensin II type 1 receptor antibody (AT1R-Ab) and anti-endothelial cell antibody (AECA).

          Methods

          Non-HLA antibody testing was included in the posttransplant evaluation for 70 kidney recipients. Biopsies were performed for cause for 47 patients and as protocol for the remaining 23 patients. Biopsy-proven rejection was defined according to the Banff 2009-2013 criteria. AT1R-Ab was measured on an ELISA platform. Patients were divided into 3 groups based on AT1R-Ab levels (>17, 10-17, and <10 U/ml). AECA was evaluated using an endothelial cell crossmatch (ECXM) in patients whose HLA antibody level was insufficient to cause a positive flow cytometric crossmatch.

          Results

          AT1R-Ab levels were higher in patients diagnosed with antibody mediated rejection compared to those with no rejection ( P = 0.004). Glomerulitis (g) and peritubular capillaritis (ptc) scores were independently correlated with increased AT1R-Ab concentrations in the presence or absence of HLA-DSA ( P = 0.007 and 0.03 for g scores; p = 0.005 and 0.03 for ptc scores). Patients with a positive ECXM had higher AT1R-Ab levels compared to those with a negative ECXM ( P = 0.005). Microcirculation inflammation (MCI = g + ptc score) was higher in patients with a positive ECXM and with AT1R-Ab >17 U/ml, although this did not reach statistical significance ( P = 0.07).

          Conclusions

          The data show an association between non-HLA antibodies detected in the ECXM and AT1R ELISA and microvascular injury observed in antibody mediated rejection.

          Abstract

          The histologic characteristics of kidney graft injury are examined in terms of the presence of anti-angiotensin II type 1 receptor antibody (AT1R-Ab) and anti-endothelial cell antibody (AECA). The presence of AECA or AT1R-Ab correlates with microvascular injury observed in antibody-mediated rejection.

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          Most cited references28

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          Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.

          Matthew Campbell, Bernard P. Halloran, B Sis … (2009)
          We studied the phenotype of late kidney graft failure in a prospective study of unselected kidney transplant biopsies taken for clinical indications. We analyzed histopathology, HLA antibodies and death-censored graft survival in 234 consecutive biopsies from 173 patients, taken 6 days to 31 years posttransplant. Patients with late biopsies (>1 year) frequently displayed donor-specific HLA antibody (particularly class II) and microcirculation changes, including glomerulitis, glomerulopathy, capillaritis, capillary multilayering and C4d staining. Grafts biopsied early rarely failed (1/68), whereas grafts biopsied late often progressed to failure (27/105) within 3 years. T-cell-mediated rejection and its lesions were not associated with an increased risk of failure after biopsy. In multivariable analysis, graft failure correlated with microcirculation inflammation and scarring, but C4d staining was not significant. When microcirculation changes and HLA antibody were used to define antibody-mediated rejection, 17/27 (63%) of late kidney failures after biopsy were attributable to antibody-mediated rejection, but many were C4d negative and missed by current diagnostic criteria. Glomerulonephritis accounted for 6/27 late losses, whereas T-cell-mediated rejection, drug toxicity and unexplained scarring were uncommon. The major cause of late kidney transplant failure is antibody-mediated microcirculation injury, but detection of this phenotype requires new diagnostic criteria.
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            Banff 2011 Meeting report: new concepts in antibody-mediated rejection.

            M Mengel, B Sis, M. Haas … (2012)
            The 11th Banff meeting was held in Paris, France, from June 5 to 10, 2011, with a focus on refining diagnostic criteria for antibody-mediated rejection (ABMR). The major outcome was the acknowledgment of C4d-negative ABMR in kidney transplants. Diagnostic criteria for ABMR have also been revisited in other types of transplants. It was recognized that ABMR is associated with heterogeneous phenotypes even within the same type of transplant. This highlights the necessity of further refining the respective diagnostic criteria, and is of particular significance for the design of randomized clinical trials. A reliable phenotyping will allow for definition of robust end-points. To address this unmet need and to allow for an evidence-based refinement of the Banff classification, Banff Working Groups presented multicenter data regarding the reproducibility of features relevant to the diagnosis of ABMR. However, the consensus was that more data are necessary and further Banff Working Group activities were initiated. A new Banff working group was created to define diagnostic criteria for ABMR in kidneys independent of C4d. Results are expected to be presented at the 12th Banff meeting to be held in 2013 in Brazil. No change to the Banff classification occurred in 2011. © copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.
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              Antibody-mediated renal allograft rejection: diagnosis and pathogenesis.

              Robert B Colvin (2007)
              Alloantibodies to HLA class I or II and other antigens expressed by endothelium cause a variety of effects on renal transplants, ranging from acute to chronic rejection, and even apparent graft acceptance (accommodation). Recognition of these conditions and appropriate therapy requires demonstration of C4d in biopsies, commonly confirmed by tests for circulating alloantibody. Substantial practical experience by pathologists in the interpretation and pitfalls of C4d stains are reviewed along with considerations of the clinical significance and pathologic mechanisms of the different effects of antibody on the endothelium of the renal allograft. Clinical trials will be needed to ascertain the optimal treatment for the newly appreciated conditions chronic humoral rejection and accommodation.
              Article 0 comments Cited 81 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Transplantation
                Journal ID (iso-abbrev): Transplantation
                Journal ID (publisher-id): TP
                Title: Transplantation
                Publisher: Lippincott Williams & Wilkins
                ISSN (Print): 0041-1337
                ISSN (Electronic): 1534-6080
                Publication date (Print): March 2017
                Publication date (Electronic): 19 May 2016
                Volume: 101
                Issue: 3
                Pages: 608-615
                Affiliations
                [1] 1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
                [2] 2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
                [3] 3 Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
                [4] 4 Clinic of Nephrology and Intensive Care Medicine Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charite, Berlin, Germany.
                Author notes
                Correspondence: Mary Carmelle Philogene, PhD, Immunogenetics Laboratory, 2041 E. Monument Street, Baltimore, MD 21205. ( mphilogene@ 123456jhmi.edu ).
                Article
                Publisher ID: TP500508 Accession ID: 00026
                DOI: 10.1097/TP.0000000000001231
                PMC ID: 5319389
                PubMed ID: 27222934
                SO-VID: 9d0989fc-4345-40a2-a6d4-228337ce441c
                Copyright © Copyright © 2016 Wolters Kluwer Health, Inc.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                Date received : 19 November 2015
                Date revision received : 18 February 2016
                Date accepted : 8 March 2016
                Page count
                Pages: 0
                Categories
                Subject: Original Clinical Science—General
                Custom metadata
                OPEN-ACCESS TRUE

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