|
1
|
Sorohan BM, Tacu D, Gîngu C, Guler-Margaritis S, Obrișcă B, Tănăsescu MD, Ismail G, Baston C. Complement in Antibody-Mediated Rejection of the Kidney Graft: From Pathophysiology to Clinical Practice. J Clin Med 2025; 14:2810. [PMID: 40283639 PMCID: PMC12027593 DOI: 10.3390/jcm14082810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/14/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Antibody-mediated rejection (AMR) is a leading cause of kidney graft failure. Complement activation is involved in the AMR process. Our aim is to provide the current understanding of the pathophysiology related to complement-mediated injury in AMR, to present the current evidence regarding complement blockade in AMR management, and to point out emerging therapies and future directions in this area. The complement system plays an important role in the onset and progression of AMR. There is a balance between complement-dependent and -independent mechanisms in the development of rejection lesions. Classic and leptin pathways are involved in this process. C4d positivity is no longer a mandatory feature for AMR diagnosis but remains an independent predictor of negative outcomes. The current evidence regarding AMR treatment is limited. Terminal and proximal complement blockade has gained recognition in clinical practice. Eculizumab and C1 inhibitors are effective in the treatment of AMR as adjuvant therapies to the standard of care. The availability of novel complement inhibitors will lead to more effective and tailored treatment strategies.
Collapse
Affiliation(s)
- Bogdan Marian Sorohan
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.G.); (S.G.-M.); (B.O.); (M.-D.T.); (G.I.); (C.B.)
- Department of Kidney Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Dorina Tacu
- Department of Kidney Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Constantin Gîngu
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.G.); (S.G.-M.); (B.O.); (M.-D.T.); (G.I.); (C.B.)
- Department of Kidney Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Silviu Guler-Margaritis
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.G.); (S.G.-M.); (B.O.); (M.-D.T.); (G.I.); (C.B.)
- Department of Kidney Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Bogdan Obrișcă
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.G.); (S.G.-M.); (B.O.); (M.-D.T.); (G.I.); (C.B.)
- Department of Nephrology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Maria-Daniela Tănăsescu
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.G.); (S.G.-M.); (B.O.); (M.-D.T.); (G.I.); (C.B.)
- Department of Nephrology, Emergency University Hospital, 022328 Bucharest, Romania
| | - Gener Ismail
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.G.); (S.G.-M.); (B.O.); (M.-D.T.); (G.I.); (C.B.)
- Department of Nephrology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Cătălin Baston
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.G.); (S.G.-M.); (B.O.); (M.-D.T.); (G.I.); (C.B.)
- Department of Kidney Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| |
Collapse
|
|
2
|
Nankivell BJ, Viswanathan S. Early and Late Microvascular Inflammation Have Differing Etiological Causes and Clinical Expression. Transplantation 2025; 109:376-385. [PMID: 39344003 DOI: 10.1097/tp.0000000000005224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
BACKGROUND Microvascular inflammation (MVI) is an important pathological feature of antibody-mediated rejection (AMR). How posttransplant time affects its clinicopathological expression is little understood. METHODS This retrospective, single-center study screened 3398 kidney transplant biopsies and dichotomized 202 MVI ≥ 2 (Banff glomerulitis + peritubular capillaritis ≥ 2) samples by 9-mo median incidence time for comparison. RESULTS The prevalence of MVI ≥ 2 was 12.4% in transplant kidneys, which failed more frequently than propensity-matched normal controls (n = 202; P < 0.001). Epidemiological risk factors for early MVI ≥ 2 were delayed graft function, prior AMR, and circulating donor-specific antibodies (DSAs+). Prior recipient sensitization occurred in 72.3%. Early MVI ≥ 2 was classified AMR in 65.3% and cellular rejection in 34.7%, and demonstrated excellent functional recovery and graft survival comparable to normal control kidneys. Late MVI ≥ 2 was predicted by younger (18 = 29 y) age, female recipient, living-donation, prior methylprednisolone, cyclosporine (versus tacrolimus, levels <5 ng/mL), absent antiproliferative therapy, and DSA+ using multivariable epidemiological modeling. Nonadherence caused 49.5%, with iatrogenic minimization responsible for 47.5%, usually for recipient infection. Late MVI ≥ 2 was because of AMR in 93.1%, and characterized by greater interstitial fibrosis, tubular atrophy, complement degradation split-product 4d (C4d) staining of peritubular capillaries+, endothelial C4d staining of glomerular capillaries+, transplant glomerulopathy and vasculopathy scores, DSA strength, and graft failure than early MVI ≥ 2 or normal transplant kidneys. Death-censored graft survival in 149 unique MVI ≥ 2 kidneys was independently determined by nonadherence, serum creatinine, proteinuria, DSA+, Banff C4d staining of peritubular capillaries+, and chronic interstitial fibrosis scores. MVI score and time lost significance using multivariable Cox regression. CONCLUSIONS The changing expression of MVI ≥ 2 over time is best explained by differences in underimmunosuppression and microvascular injury from AMR impacting allograft function and survival.
Collapse
Affiliation(s)
- Brian J Nankivell
- Department of Renal Medicine, Westmead Hospital, Westmead, NSW, Australia
| | - Seethalakshmi Viswanathan
- Department of Tissue Pathology and Diagnostic Oncology, ICPMR, Westmead Hospital, Westmead, NSW, Australia
| |
Collapse
|
|
3
|
Nankivell BJ, Taverniti A, Viswanathan S, Ronquillo J, Carroll R, Sharma A. The relationship of microvascular inflammation with antibody-mediated rejection in kidney transplantation. Am J Transplant 2025; 25:115-126. [PMID: 39084463 DOI: 10.1016/j.ajt.2024.07.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024]
Abstract
Microvascular inflammation (MVI) is a key diagnostic feature of antibody-mediated rejection (AMR); however, recipients without donor-specific antibodies (DSA) defy etiologic classification using C4d staining of peritubular capillaries (C4dptc) and conventional DSA assignment. We evaluated MVI ≥ 2 (Banff g + ptc ≥ 2) using Banff 2019 AMR (independent of MVI ≥ 2 but including C4dptc) with unconventional endothelial C4d staining of glomerular capillaries (C4dglom) and - arterial endothelium and/or intima (C4dart) using tissue immunoperoxidase, shared-eplet and subthreshold DSA (median fluorescence intensity, [MFI] 100-499), and capillary ultrastructure from 3398 kidney transplant samples for evidence of AMR. MVI ≥ 2 (n = 202 biopsies) from 149 kidneys (12.4% prevalence) correlated with DSA+, C4dptc+, C4dglom+, Banff cg, i, t, ti scores, serum creatinine, proteinuria, and graft failure compared with 202 propensity score matched normal controls. The laboratory reported DSA- MVI ≥ 2 (MFI ≥500) occurred in 34.7%; however, subthreshold (28.6%), eplet-directed (51.4%), and/or misclassified anti-Human leukocyte antigen (HLA) DSA (12.9%) were identified in 67.1% by forensic reanalysis, with vascular C4d+ staining in 67.1%, and endothelial abnormalities in 57.1%, totaling 87.1%. Etiologic analysis attributed 62.9% to AMR (77.8% for MVI with negative reported DSA [DSA- MVI ≥2] with glomerulitis) and pure T cellular rejection in 37.1%. C4dptc-DSA- MVI ≥ 2 was unrecognized AMR in 48.0%. Functional outcomes and graft survival were comparable to normal controls. We concluded that DSA- MVI ≥ 2 frequently signified a mild "borderline" phenotype of AMR which was recognizable using novel serologic and pathological techniques.
Collapse
Affiliation(s)
- Brian J Nankivell
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
| | - Anne Taverniti
- New South Wales Transplantation and Immunogenetics, Australian Red Cross, LifeBlood, New South Wales, Australia
| | | | - John Ronquillo
- Tissue Pathology and Diagnostic Oncology, ICPMR, Sydney, Australia
| | - Robert Carroll
- New South Wales Transplantation and Immunogenetics, Australian Red Cross, LifeBlood, New South Wales, Australia
| | - Ankit Sharma
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| |
Collapse
|
|
4
|
Zhang J, Yu X, Xie Z, Wang R, Li H, Tang Z, Na N. A bibliometric and knowledge-map analysis of antibody-mediated rejection in kidney transplantation. Ren Fail 2023; 45:2257804. [PMID: 37724568 PMCID: PMC10512841 DOI: 10.1080/0886022x.2023.2257804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 09/06/2023] [Indexed: 09/21/2023] Open
Abstract
OBJECTIVES Antibody-mediated rejection (AMR) is a large obstacle to the long-term survival of allograft kidneys. It is urgent to find novel strategies for its prevention and treatment. Bibliometric analysis is helpful in understanding the directions of one field. Hence, this study aims to analyze the state and emerging trends of AMR in kidney transplantation. METHODS Literature on AMR in kidney transplantation from 1999 to 2022 was collected from the Web of Science Core Collection. HistCite (version 12.03.17), CiteSpace (version 6.2.R2), Bibliometrix 4.1.0 Package from R language, and Gephi (https://gephi.org) were applied to the bibliometric analysis of the annual publications, leading countries/regions, core journals, references, keywords, and trend topics. RESULTS A total of 2522 articles related to AMR in kidney transplantation were included in the analysis and the annual publications increased year by year. There were 10874 authors from 118 institutions located in 70 countries/regions contributing to AMR studies, and the United States took the leading position in both articles and citation scores. Halloran PF from Canada made the most contribution to AMR in kidney transplantation. The top 3 productive journals, American Journal of Transplantation, Transplantation, and Transplantation Proceedings, were associated with transplantation. Moreover, the recent trend topics mainly focused on transplant outcomes, survival, and clinical research. CONCLUSIONS North American and European countries/regions played central roles in AMR of kidney transplantation. Importantly, the prognosis of AMR is the hotspot in the future. Noninvasive strategies like plasma and urine dd-cfDNA may be the most potential direction in the AMR field.
Collapse
Affiliation(s)
- Jinhua Zhang
- Department of kidney transplantation, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaowen Yu
- Department of General Surgery, Kunming Municipal Hospital of Traditional Chinese Medicine, the Third Affiliated Hospital of Yunnan University of Chinese Medicine, Kunming, China
| | - Zhenwei Xie
- Department of kidney transplantation, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ruojiao Wang
- Department of kidney transplantation, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Heng Li
- Department of kidney transplantation, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - ZuoFu Tang
- Department of kidney transplantation, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ning Na
- Department of kidney transplantation, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
5
|
Mubarak M, Raza A, Rashid R, Shakeel S. Evolution of human kidney allograft pathology diagnostics through 30 years of the Banff classification process. World J Transplant 2023; 13:221-238. [PMID: 37746037 PMCID: PMC10514746 DOI: 10.5500/wjt.v13.i5.221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 09/15/2023] Open
Abstract
The second half of the previous century witnessed a tremendous rise in the number of clinical kidney transplants worldwide. This activity was, however, accompanied by many issues and challenges. An accurate diagnosis and appropriate management of causes of graft dysfunction were and still are, a big challenge. Kidney allograft biopsy played a vital role in addressing the above challenge. However, its interpretation was not standardized for many years until, in 1991, the Banff process was started to fill this void. Thereafter, regular Banff meetings took place every 2 years for the past 30 years. Marked changes have taken place in the interpretation of kidney allograft biopsies, diagnosis, and classification of rejection and other non-rejection pathologies from the original Banff 93 classification. This review attempts to summarize those changes for increasing the awareness and understanding of kidney allograft pathology through the eyes of the Banff process. It will interest the transplant surgeons, physicians, pathologists, and allied professionals associated with the care of kidney transplant patients.
Collapse
Affiliation(s)
- Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Amber Raza
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Rahma Rashid
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Shaheera Shakeel
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| |
Collapse
|
|
6
|
Böhmig GA, Halloran PF, Feucht HE. On a Long and Winding Road: Alloantibodies in Organ Transplantation. Transplantation 2023; 107:1027-1041. [PMID: 36944603 DOI: 10.1097/tp.0000000000004550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
Today we know that both the humoral and the cellular arm of the immune system are engaged in severe immunological challenges. A close interaction between B and T cells can be observed in most "natural" challenges, including infections, malignancies, and autoimmune diseases. The importance and power of humoral immunity are impressively demonstrated by the current coronavirus disease 2019 pandemic. Organ transplant rejection is a normal immune response to a completely "artificial" challenge. It took a long time before the multifaceted action of different immunological forces was recognized and a unified, generally accepted opinion could be formed. Here, we address prominent paradigms and paradigm shifts in the field of transplantation immunology. We identify several instances in which the transplant community missed a timely paradigm shift because essential, available knowledge was ignored. Moreover, we discuss key findings that critically contributed to our understanding of transplant immunology but sometimes developed with delay and in a roundabout way, as was the case with antibody-mediated rejection-a main focus of this article. These include the discovery of the molecular principles of histocompatibility, the recognition of the microcirculation as a key interface of immune damage, the refinement of alloantibody detection, the description of C4d as a footmark of endothelium-bound antibody, and last but not least, the developments in biopsy-based diagnostics beyond conventional morphology, which only now give us a glimpse of the enormous complexity and pathogenetic diversity of rejection.
Collapse
Affiliation(s)
- Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Centre, ATAGC, University of Alberta, Edmonton, AB, Canada
| | | |
Collapse
|
|
7
|
Rosales IA, Mahowald GK, Tomaszewski K, Hotta K, Iwahara N, Otsuka T, Tsuji T, Takada Y, Acheampong E, Araujo-Medina M, Bruce A, Rios A, Cosimi AB, Elias N, Kawai T, Gilligan H, Safa K, Riella LV, Tolkoff-Rubin NE, Williams WW, Smith RN, Colvin RB. Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection. J Am Soc Nephrol 2022; 33:2306-2319. [PMID: 36450597 PMCID: PMC9731628 DOI: 10.1681/asn.2022040444] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 07/19/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. METHODS We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes. RESULTS The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. CONCLUSIONS Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.
Collapse
Affiliation(s)
- Ivy A. Rosales
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Grace K. Mahowald
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kristen Tomaszewski
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kiyohiko Hotta
- Department of Urology, Hokkaido University Hospital, Hokkaido, Japan
| | - Naoya Iwahara
- Department of Urology, Hokkaido University Hospital, Hokkaido, Japan
| | - Takuya Otsuka
- Department of Surgical Pathology, Hokkaido University Hospital, Hokkaido, Japan
| | - Takahiro Tsuji
- Department of Pathology, Sapporo City General Hospital, Hokkaido, Japan
| | - Yusuke Takada
- Department of Kidney Transplant Surgery, Sapporo City General Hospital, Hokkaido, Japan
| | - Ellen Acheampong
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Milagros Araujo-Medina
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Amy Bruce
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrea Rios
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Anthony Benedict Cosimi
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nahel Elias
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Tatsuo Kawai
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Hannah Gilligan
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kassem Safa
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Leonardo V. Riella
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nina E. Tolkoff-Rubin
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Winfred W. Williams
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rex Neal Smith
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Robert B. Colvin
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
8
|
Halloran PF, Madill‐Thomsen KS, Pon S, Sikosana MLN, Böhmig GA, Bromberg J, Einecke G, Eskandary F, Gupta G, Hidalgo LG, Myslak M, Viklicky O, Perkowska‐Ptasinska A. Molecular diagnosis of ABMR with or without donor-specific antibody in kidney transplant biopsies: Differences in timing and intensity but similar mechanisms and outcomes. Am J Transplant 2022; 22:1976-1991. [PMID: 35575435 PMCID: PMC9540308 DOI: 10.1111/ajt.17092] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We studied the clinical, histologic, and molecular features distinguishing DSA-negative from DSA-positive molecularly defined antibody-mediated rejection (mABMR). We analyzed mABMR biopsies with available DSA assessments from the INTERCOMEX study: 148 DSA-negative versus 248 DSA-positive, compared with 864 no rejection (excluding TCMR and Mixed). DSA-positivity varied with mABMR stage: early-stage (EABMR) 56%; fully developed (FABMR) 70%; and late-stage (LABMR) 58%. DSA-negative patients with mABMR were usually sensitized, 60% being HLA antibody-positive. Compared with DSA-positive mABMR, DSA-negative mABMR was more often C4d-negative; earlier by 1.5 years (average 2.4 vs. 3.9 years); and had lower ABMR activity and earlier stage in molecular and histology features. However, the top ABMR-associated transcripts were identical in DSA-negative versus DSA-positive mABMR, for example, NK-associated (e.g., KLRD1 and GZMB) and IFNG-inducible (e.g., PLA1A). Genome-wide class comparison between DSA-negative and DSA-positive mABMR showed no significant differences in transcript expression except those related to lower intensity and earlier time of DSA-negative ABMR. Three-year graft loss in DSA-negative mABMR was the same as DSA-positive mABMR, even after adjusting for ABMR stage. Thus, compared with DSA-positive mABMR, DSA-negative mABMR is on average earlier, less active, and more often C4d-negative but has similar graft loss, and genome-wide analysis suggests that it involves the same mechanisms. SUMMARY SENTENCE: In 398 kidney transplant biopsies with molecular antibody-mediated rejection, the 150 DSA-negative cases are earlier, less intense, and mostly C4d-negative, but use identical molecular mechanisms and have the same risk of graft loss as the 248 DSA-positive cases.
Collapse
Affiliation(s)
- Philip F. Halloran
- Alberta Transplant Applied Genomics CentreEdmontonAlbertaCanada,Department of Medicine, Division of Nephrology and Transplant ImmunologyUniversity of AlbertaEdmontonAlbertaCanada
| | | | - Shane Pon
- Alberta Transplant Applied Genomics CentreEdmontonAlbertaCanada
| | | | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine IIIMedical University of ViennaViennaAustria
| | | | - Gunilla Einecke
- Department of NephrologyHannover Medical SchoolHannoverGermany
| | - Farsad Eskandary
- Division of Nephrology and Dialysis, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Gaurav Gupta
- Division of NephrologyVirginia Commonwealth UniversityRichmondVirginiaUSA
| | | | - Marek Myslak
- Department of Clinical Interventions, Department of Nephrology and Kidney Transplantation SPWSZ HospitalPomeranian Medical UniversitySzczecinPoland
| | - Ondrej Viklicky
- Department of Nephrology and Transplant CenterInstitute for Clinical and Experimental MedicinePragueCzech Republic
| | | | | |
Collapse
|
|
9
|
Nankivell BJ, Shingde M, P’Ng CH, Sharma A. The Clinical and Pathological Phenotype of Antibody-Mediated Vascular Rejection Diagnosed using Arterial C4d Immunoperoxidase. Kidney Int Rep 2022; 7:1653-1664. [PMID: 35812292 PMCID: PMC9263238 DOI: 10.1016/j.ekir.2022.04.097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/19/2022] [Accepted: 04/22/2022] [Indexed: 12/02/2022] Open
Abstract
Introduction The diagnosis of antibody-mediated vascular rejection (AM-VR) should be reliable and accurate. We hypothesized that arterial C4d (C4dart) immunoperoxidase deposition represents endothelial interaction with antibody. Methods From 3309 consecutive, kidney transplant biopsies from a single center, 100 vascular rejection (VR) cases were compared against rejection without arteritis (n = 540) and normal controls (n = 1108). The clinical utility of C4dart for diagnosis and classification of AM-VR was evaluated against an independent reference test. Results C4dart occurred in 20.4% of acute, 11.0% of subclinical, and 46% of VR episodes. Semiquantitative C4dart score significantly correlated with immunodominant donor-specific antibodies (DSAs) (rho = 0.500, P < 0.001), peritubular capillary C4d (C4dptc), microvascular inflammation, and Banff v scores. Banff v3 arteritis suggested AM-VR. Addition of C4dart to Banff antibody-mediated rejection (AMR) schema increased diagnostic sensitivity for AM-VR from 57.9% to 93.0%, accuracy 74.0% to 92.0%, and specificity 95.4% to 90.2% versus Banff 2019 (using C4dptc). Death-censored graft failure was associated with C4dart AM-VR criteria using Cox regression (adjusted hazard ratio [HR] 4.310, 95% CI 1.322–14.052, P = 0.015). VR was then etiologically classified into AM-VR (n = 57, including 36 mixed VR) or “pure” (TCM-VR, n = 43). AM-VR occurred within all post-transplant periods, characterized by greater total, interstitial, and microvascular inflammation, arterial and peritubular C4d, DSA levels, and graft failure rates compared with TCM-VR. Mixed VR kidneys had the greatest inflammatory burden and graft loss (P < 0.001). Conclusion C4dart is a suggestive biomarker of the humoral alloresponse toward muscular arteries. Inclusion of C4dart into the Banff schema improved its diagnostic performance for detection of AM-VR and etiologic classification of arteritis.
Collapse
Affiliation(s)
- Brian J. Nankivell
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
- Correspondence: Brian J. Nankivell, Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales 2145, Australia.
| | - Meena Shingde
- Department of Tissue Pathology and Diagnostic Oncology, Institute of Clinical Pathology and Medical Research, Sydney, Australia
| | - Chow H. P’Ng
- Department of Tissue Pathology and Diagnostic Oncology, Institute of Clinical Pathology and Medical Research, Sydney, Australia
| | - Ankit Sharma
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| |
Collapse
|
|
10
|
Nankivell BJ, P’Ng CH, Shingde M. Glomerular C4d Immunoperoxidase in Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy. Kidney Int Rep 2022; 7:1594-1607. [PMID: 35812271 PMCID: PMC9263257 DOI: 10.1016/j.ekir.2022.04.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/24/2022] [Accepted: 04/11/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction The diagnosis of late antibody-mediated rejection (AMR) is compromised by frequent absence of C4d in peritubular capillaries (C4dptc), termed “C4d-negative” AMR. We hypothesized that glomerular capillary C4d (C4dglom) reflected endothelial interaction with antibody and could improve immunologic classification of transplant glomerulopathy (TG). Methods We evaluated C4d using immunoperoxidase in 3524 consecutive, kidney transplant biopsies from a single center. Results C4dglom was detected in 16.5% and C4dptc in 9.9% of biopsies. C4dglom occurred in 60.3% of TG (n = 174) and was absent in normal glomeruli. Epidemiologic risk factors for C4dglom were younger, female, living-donor recipients with early AMR, prior treated rejection, and late presentation using multivariable analysis. Semiquantitative C4dglom score correlated with donor specific antibody (DSA) level, C4dptc, microvascular inflammation (MVI), Banff cg scores, renal dysfunction, and proteinuria. Principal component analysis colocalized C4dglom with histologic AMR. Multivariable analysis of TG found DSA, C4dptc, and post-transplant time associated with C4dglom. Addition of C4dglom into Banff chronic AMR schema improved its diagnostic sensitivity for TG (verified by electron microscopy [EM]) from 22.2% to 82.4% and accuracy from 59.6% to 93.9%, compared with Banff 2019 using only C4dptc. Tissue C4dglom and chronic AMR diagnosis incorporating C4dglom were associated with death-censored allograft failure in TG (P < 0.001), independent of the severity of glomerulopathy and chronic interstitial fibrosis. Conclusion C4dglom is a promising diagnostic biomarker of endothelial interaction with antibody which substantially improved test performance of the Banff schema to correctly classify TG by pathophysiology and prognosticate graft loss. We recommend routine C4d immunoperoxidase to minimize underdiagnosis of late AMR in TG.
Collapse
Affiliation(s)
- Brian J. Nankivell
- Department of Renal Medicine, Westmead Hospital, Sydney, New South Wales, Australia
- Correspondence: Brian J. Nankivell, Department of Renal Medicine, Westmead Hospital, Westmead, Sydney, 2145 New South Wales, Australia.
| | - Chow H. P’Ng
- Department of Tissue Pathology and Diagnostic Oncology, Institute of Clinical Pathology and Medical Research, Sydney, New South Wales, Australia
| | - Meena Shingde
- Department of Tissue Pathology and Diagnostic Oncology, Institute of Clinical Pathology and Medical Research, Sydney, New South Wales, Australia
| |
Collapse
|
|
11
|
Halloran PF, Einecke G, Sikosana MLN, Madill-Thomsen K. The Biology and Molecular Basis of Organ Transplant Rejection. Handb Exp Pharmacol 2022; 272:1-26. [PMID: 35091823 DOI: 10.1007/164_2021_557] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Allograft rejection is defined as tissue injury in a transplanted allogeneic organ produced by the effector mechanisms of the adaptive alloimmune response. Effector T lymphocytes and IgG alloantibodies cause two different types of rejection that can occur either individually or simultaneously: T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). In TCMR, cognate effector T cells infiltrate the graft and orchestrate an interstitial inflammatory response in the kidney interstitium in which effector T cells engage antigen-presenting myeloid cells, activating the T cells, antigen-presenting cells, and macrophages. The result is intense expression of IFNG and IFNG-induced molecules, expression of effector T cell molecules and macrophage molecules and checkpoints, and deterioration of parenchymal function. The diagnostic lesions of TCMR follow, i.e. interstitial inflammation, parenchymal deterioration, and intimal arteritis. In ABMR, HLA IgG alloantibodies produced by plasma cells bind to the donor antigens on graft microcirculation, leading to complement activation, margination, and activation of NK cells and neutrophils and monocytes, and endothelial injury, sometimes with intimal arteritis. TCMR becomes infrequent after 5-10 years post-transplant, probably reflecting adaptive mechanisms such as checkpoints, but ABMR can present even decades post-transplant. Some rejection is triggered by inadequate immunosuppression and non-adherence, challenging the clinician to target effective immunosuppression even decades post-transplant.
Collapse
Affiliation(s)
- Philip F Halloran
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
| | - Gunilla Einecke
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Majid L N Sikosana
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | | |
Collapse
|
|
12
|
Loupy A, Mengel M, Haas M. 30 years of the International Banff Classification for Allograft Pathology: The Past, Present and Future of Kidney Transplant Diagnostics. Kidney Int 2021; 101:678-691. [DOI: 10.1016/j.kint.2021.11.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/06/2021] [Accepted: 11/05/2021] [Indexed: 10/19/2022]
|
|
13
|
Caveolin-1 in Kidney Chronic Antibody-Mediated Rejection: An Integrated Immunohistochemical and Transcriptomic Analysis Based on the Banff Human Organ Transplant (B-HOT) Gene Panel. Biomedicines 2021; 9:biomedicines9101318. [PMID: 34680435 PMCID: PMC8533527 DOI: 10.3390/biomedicines9101318] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/13/2021] [Accepted: 09/22/2021] [Indexed: 02/07/2023] Open
Abstract
Caveolin-1 overexpression has previously been reported as a marker of endothelial injury in kidney chronic antibody-mediated rejection (c-ABMR), but conclusive evidence supporting its use for daily diagnostic practice is missing. This study aims to evaluate if Caveolin-1 can be considered an immunohistochemical surrogate marker of c-ABMR. Caveolin-1 expression was analyzed in a selected series of 22 c-ABMR samples and 11 controls. Caveolin-1 immunohistochemistry proved positive in peritubular and glomerular capillaries of c-ABMR specimens, irrespective of C4d status whereas all controls were negative. Multiplex gene expression profiling in c-ABMR cases confirmed Caveolin-1 overexpression and identified additional genes (n = 220) and pathways, including MHC Class II antigen presentation and Type II interferon signaling. No differences in terms of gene expression (including Caveolin-1 gene) were observed according to C4d status. Conversely, immune cell signatures showed a NK-cell prevalence in C4d-negative samples compared with a B-cell predominance in C4d-positive cases, a finding confirmed by immunohistochemical assessment. Finally, differentially expressed genes were observed between c-ABMR and controls in pathways associated with Caveolin-1 functions (angiogenesis, cell metabolism and cell–ECM interaction). Based on our findings, Caveolin-1 resulted as a key player in c-ABMR, supporting its role as a marker of this condition irrespective of C4d status.
Collapse
|
|
14
|
Reese SR, Wilson NA, Huang Y, Ptak L, Degner KR, Xiang D, Redfield RR, Zhong W, Panzer SE. B-cell Deficiency Attenuates Transplant Glomerulopathy in a Rat Model of Chronic Active Antibody-mediated Rejection. Transplantation 2021; 105:1516-1529. [PMID: 33273321 PMCID: PMC8106694 DOI: 10.1097/tp.0000000000003530] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Transplant glomerulopathy (TG) is a pathological feature of chronic active antibody-mediated rejection (cAMR) and is associated with renal allograft failure. The specific role of B cells in the pathogenesis of TG is unclear. METHODS We used a minor mismatched rat kidney transplant model with B cell-deficient recipients, generated by clustered regularly interspaced short palindromic repeats/Cas9 technology, to investigate the impact of B-cell depletion on the pathogenesis of TG. We hypothesized that B-cell deficiency would prevent TG in the rat kidney transplant model of cAMR. Treatment groups included syngeneic, allogeneic, sensitized allogeneic, and B cell-deficient allogeneic transplant recipients. RESULTS B cell-deficient recipients demonstrated reduced TG lesions, decreased microvascular inflammation, reduced allograft infiltrating macrophages, and reduced interferon gamma transcripts within the allograft. Allograft transcript levels of interferon gamma, monocyte chemoattractant protein-1, and interleukin-1β correlated with numbers of intragraft macrophages. B cell-deficient recipients lacked circulating donor-specific antibodies and had an increased splenic regulatory T-cell population. CONCLUSIONS In this model of cAMR, B-cell depletion attenuated the development of TG with effects on T cell and innate immunity.
Collapse
Affiliation(s)
- Shannon R. Reese
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
| | - Nancy A. Wilson
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
| | - Yabing Huang
- Department of Pathology, Renmin Hospital of Wuhan University, China
| | - Lucille Ptak
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
| | - Kenna R. Degner
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
| | - Ding Xiang
- Department of Organ Transplantation, Xiangya Hospital, Central South University, China
| | - Robert R. Redfield
- Department of Surgery, Division of Transplant Surgery, University of Wisconsin, Madison, WI, United States
| | - Weixiong Zhong
- Department of Pathology, University of Wisconsin, Madison, WI, United States
| | - Sarah E. Panzer
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
| |
Collapse
|
|
15
|
Doreille A, Azzi F, Larivière-Beaudoin S, Karakeussian-Rimbaud A, Trudel D, Hébert MJ, Dieudé M, Patey N, Cardinal H. Acute Kidney Injury, Microvascular Rarefaction, and Estimated Glomerular Filtration Rate in Kidney Transplant Recipients. Clin J Am Soc Nephrol 2021; 16:415-426. [PMID: 33648972 PMCID: PMC8011007 DOI: 10.2215/cjn.07270520] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 01/14/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVES Animal studies suggest that microvascular rarefaction is a key factor in the acute kidney disease to CKD transition. Hence, delayed graft function appears as a unique human model of AKI to further explore the role of microvascular rarefaction in kidney transplant recipients. Here, we assessed whether delayed graft function is associated with peritubular capillary loss and evaluated the association between this loss and long-term kidney graft function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This observational, retrospective cohort study included 61 participants who experienced delayed graft function and 130 who had immediate graft function. We used linear regression models to evaluate associations between delayed graft function and peritubular capillary density expressed as the percentage of efficient cortical area occupied by peritubular capillaries in pre- and post-transplant graft biopsies. eGFRs 1 and 3 years post-transplant were secondary outcomes. RESULTS Post-transplant biopsies were performed at a median of 113 days (interquartile range, 101-128) after transplantation. Peritubular capillary density went from 15.4% to 11.5% in patients with delayed graft function (median change, -3.7%; interquartile range, -6.6% to -0.8%) and from 19.7% to 15.1% in those with immediate graft function (median change, -4.5%; interquartile range, -8.0% to -0.8%). Although the unadjusted change in peritubular capillary density was similar between patients with and without delayed graft function, delayed graft function was associated with more peritubular capillary loss in the multivariable analysis (adjusted difference in change, -2.9%; 95% confidence interval, -4.0 to -1.8). Pretransplant peritubular capillary density and change in peritubular capillary density were associated with eGFR 1 and 3 years post-transplantation. CONCLUSIONS Perioperative AKI is associated with lower density in peritubular capillaries before transplantation and with loss of peritubular capillaries following transplantation. Lower peritubular capillary density is linked to lower long-term eGFR.
Collapse
Affiliation(s)
- Alice Doreille
- Centre de recherche du Centre hospitalier de l’Université de Montréal, Immunopathology axis, Montreal, Quebec, Canada,Faculté de Médecine, Université Paris-Sud, Paris, France
| | - Féryel Azzi
- Institut du cancer de Montréal, Montreal, Quebec, Canada
| | - Stéphanie Larivière-Beaudoin
- Centre de recherche du Centre hospitalier de l’Université de Montréal, Immunopathology axis, Montreal, Quebec, Canada,Canadian Donation and Transplantation Research Program, Edmonton, Alberta, Canada
| | - Annie Karakeussian-Rimbaud
- Centre de recherche du Centre hospitalier de l’Université de Montréal, Immunopathology axis, Montreal, Quebec, Canada,Canadian Donation and Transplantation Research Program, Edmonton, Alberta, Canada
| | - Dominique Trudel
- Institut du cancer de Montréal, Montreal, Quebec, Canada,Pathology Department, Centre hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
| | - Marie-Josée Hébert
- Centre de recherche du Centre hospitalier de l’Université de Montréal, Immunopathology axis, Montreal, Quebec, Canada,Canadian Donation and Transplantation Research Program, Edmonton, Alberta, Canada,Nephrology Department, Centre hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
| | - Mélanie Dieudé
- Centre de recherche du Centre hospitalier de l’Université de Montréal, Immunopathology axis, Montreal, Quebec, Canada,Canadian Donation and Transplantation Research Program, Edmonton, Alberta, Canada
| | - Natacha Patey
- Centre de recherche du Centre hospitalier de l’Université de Montréal, Immunopathology axis, Montreal, Quebec, Canada,Pathology Department, Sainte-Justine Hospital, Montreal, Quebec, Canada
| | - Héloïse Cardinal
- Centre de recherche du Centre hospitalier de l’Université de Montréal, Immunopathology axis, Montreal, Quebec, Canada,Canadian Donation and Transplantation Research Program, Edmonton, Alberta, Canada,Nephrology Department, Centre hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
| |
Collapse
|
|
16
|
Zhang H, Wang Z, Zhang J, Gui Z, Han Z, Tao J, Chen H, Sun L, Fei S, Yang H, Tan R, Chandraker A, Gu M. Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation. Front Immunol 2021; 12:618737. [PMID: 33732243 PMCID: PMC7959759 DOI: 10.3389/fimmu.2021.618737] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 01/14/2021] [Indexed: 01/11/2023] Open
Abstract
Background Costimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. The adoption of the novel immunosuppressant Belatacept has been limited, partly due to concerns regarding higher rates and grades of acute rejection in clinical trials. In this study, we hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation. Materials and Methods The rat kidney transplantation model was used to investigate graft rejection in single and combined therapy. Graft function was analyzed by detecting serum creatinine. Pathological staining was used to observe histological changes in grafts. The expression of T cells was observed by immunohistochemistry and flow cytometry. In vitro, we constructed an antigen-stimulated immune response by mixed lymphocyte culture, treated with or without Belatacept and BTLA-overexpression adenovirus, to observe the proliferation of receptor cells and the expression of cytokines. In addition, western blot and qRT-PCR analyses were performed to evaluate the expression of CTLA-4 and BTLA at various time points during the immune response. Results In rat models, combined therapy reduced the serum creatinine levels and prolonged graft survival compared to single therapy and control groups. Mixed acute rejection was shown in the allogeneic group and inhibited by combination treatment. Belatacept reduced the production of DSA and the deposition of C4d in grafts. Belatacept combined with BTLA overexpression downregulated the secretion of IL-2 and IFN-γ, as well as increasing IL-4 and IL-10 expression. We also found that Belatacept combined with BTLA overexpression inhibited the proliferation of spleen lymphocytes. The duration of the elevated expression levels of CTLA-4 and BTLA differentially affected the immune response. Conclusion Belatacept combined with BTLA overexpression attenuated acute rejection after kidney transplantation and prolonged kidney graft survival, which suggests a new approach for the optimization of early immunosuppression after kidney transplantation.
Collapse
Affiliation(s)
- Hengcheng Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jiayi Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zeping Gui
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhijian Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Sun
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuang Fei
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haiwei Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ruoyun Tan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Anil Chandraker
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Min Gu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
17
|
O'Neill MA, Hidalgo LG. NK cells in antibody-mediated rejection - Key effector cells in microvascular graft damage. Int J Immunogenet 2021; 48:110-119. [PMID: 33586864 DOI: 10.1111/iji.12532] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/12/2021] [Accepted: 01/31/2021] [Indexed: 12/14/2022]
Abstract
Antibody-mediated rejection (ABMR) stands as the major limitation to long-term transplant outcome. The immunologic understanding of ABMR continues to progress and has identified natural killer (NK) cells as key effector cells promoting and coordinating the immune attack on the graft microvascular endothelium. This review discusses the current concepts outlining the different ways that allow for NK cell recognition of graft endothelial cells which includes antibody-dependent as well as independent processes.
Collapse
Affiliation(s)
- Megan A O'Neill
- Department of Surgery, University of Wisconsin School of Medicine and Public Health (UWSMPH), Madison, WI, USA
| | - Luis G Hidalgo
- Department of Surgery, University of Wisconsin School of Medicine and Public Health (UWSMPH), Madison, WI, USA
| |
Collapse
|
|
18
|
Shiga Toxin 2a Binds to Complement Components C3b and C5 and Upregulates Their Gene Expression in Human Cell Lines. Toxins (Basel) 2020; 13:toxins13010008. [PMID: 33374102 PMCID: PMC7824702 DOI: 10.3390/toxins13010008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/16/2020] [Accepted: 12/22/2020] [Indexed: 01/06/2023] Open
Abstract
Enterohemorrhagic Escherichia coli (EHEC) infections can cause EHEC-associated hemolytic uremic syndrome (eHUS) via its main virulent factor, Shiga toxins (Stxs). Complement has been reported to be involved in the progression of eHUS. The aim of this study was to investigate the interactions of the most effective subtype of the toxin, Stx2a, with pivotal complement proteins C3b and C5. The study further examined the effect of Stx2a stimulation on the transcription and synthesis of these complement proteins in human target cell lines. Binding of Stx2a to C3b and C5 was evaluated by ELISA. Kidney and gut cell lines (HK-2 and HCT-8) were stimulated with varied concentrations of Stx2a. Subsequent evaluation of complement gene transcription was studied by real-time PCR (qPCR), and ELISAs and Western blots were performed to examine protein synthesis of C3 and C5 in supernatants and lysates of stimulated HK-2 cells. Stx2a showed a specific binding to C3b and C5. Gene transcription of C3 and C5 was upregulated with increasing concentrations of Stx2a in both cell lines, but protein synthesis was not. This study demonstrates the binding of Stx2a to complement proteins C3b and C5, which could potentially be involved in regulating complement during eHUS infection, supporting further investigations into elucidating the role of complement in eHUS pathogenesis.
Collapse
|
|
19
|
Glomerular C4d in Post-Transplant IgA Nephropathy is associated with decreased allograft survival. J Nephrol 2020; 34:839-849. [PMID: 33306182 PMCID: PMC8192385 DOI: 10.1007/s40620-020-00914-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/11/2020] [Indexed: 11/23/2022]
Abstract
Background Glomerulonephritis (GN), including post-transplant IgAN (post-Tx IgAN) is an important contributor to decreased long-term allograft survival. The immunopathological detection of the complement degradation product C4d in glomeruli (C4dG) has been recently described as a risk factor in native kidney IgAN, however little is known about C4dG deposition in post-Tx IgAN. We hypothesized that glomerular C4d may indicate a more aggressive disease course and worse allograft survival in patients with post-Tx IgAN. Methods In this retrospective study we assessed the presence and clinical relevance of C4dG in patients with post-transplant IgAN. We analyzed 885 renal allograft recipients, including 84 patients with post-transplant GN. All patients were transplanted between January 1999 and April 2006 and underwent at least one biopsy for differnt causes. The primary endpoint was death-censored graft survival, with a median follow-up of 9.6 (IQR 3.8–13.2) years. Results The prevalence of post-Tx GN was 9.5%. Twenty-seven patients with post-Tx IgAN were included. C4dG positive patients (N = 18, 66.7%) had significantly worse allograft survival compared to C4dG negative post-Tx IgAN patients and patients without post-Tx IgAN [C4dG positive: 27.8% vs. 55.6% and 66.0%; log-rank: p = 0.01]. C4dG remained a significant risk factor (HR 2.22, 95% CI 1.27–3.87) for allograft loss even after adjustment for T cell mediated rejection (TCMR) and antibody mediated rejection. Conclusion Glomerular C4d deposition is an independent risk factor for worse graft-survival in patients with post-Tx IgAN, even after adjusting for other risk factors such as antibody mediated rejection. Assessment of glomerular C4d deposition may provide a valuable prognostic risk assessment tool to identify high risk patients in post-Tx IgAN. Graphic abstract ![]()
Electronic supplementary material The online version of this article (10.1007/s40620-020-00914-x) contains supplementary material, which is available to authorized users.
Collapse
|
|
20
|
Tsalouchos A, Salvadori M. Rigetto anticorpo-mediato nel trapianto di rene: fisiopatologia, clinica e terapia. GIORNALE DI CLINICA NEFROLOGICA E DIALISI 2020; 32:131-134. [DOI: 10.33393/gcnd.2020.2182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Introduction. Over the past two decades, our thinking has changed from considering rejection as primarily a T-cell mediated process to the realization that insufficient control of the humoral arm of a recipient’s immune system is the factor primarily responsible for the allograft dysfunction and loss. Acute Antibody Mediated Rejection (ABMR) in kidney transplantation is a severe complication that frequently occurs after transplantation and is due either to pre-transplant Donor Specific Antibodies (DSAs) or to de novo DSAs. New techniques to detect DSAs in the recipient serum and advances in the assessment of graft pathology have allowed us to recognize this entity in recent years.
Methods. The treatment of ABMR is a multistep process consisting in the desensitization of the patients with preformed antibodies to prevent acute ABMR: in case of acute ABMR, the antibodies are removed from the serum and anti-B cells immunosuppressants are used.
Results and Discussion. Along with our knowledge on acute ABMR, a distinct entity has been recognized: the chronic AMBR. Chronic ABMR is a frequent cause of late graft dysfunction and is characterized by a typical histopathologic feature. The treatment is often difficult and new drugs are now tested to control the disease.
Collapse
|
|
21
|
Clinical Relevance of Arteriolar C4d Staining in Patients With Chronic-active Antibody-mediated Rejection: A Pilot Study. Transplantation 2020; 104:1085-1094. [PMID: 31517782 DOI: 10.1097/tp.0000000000002957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND C4d staining in peritubular capillaries is a well-established feature of antibody-mediated rejection (AMR). The relevance of C4d staining outside peritubular capillaries is not well understood. We investigated the significance of arteriolar C4d staining in chronic-active AMR (c-aAMR). METHODS All for-cause renal allograft biopsies performed in 2007-2014 at the Erasmus MC and meeting the criteria for suspicious/diagnostic c-aAMR using the Banff Classification 2015 were included. For comparison, renal allograft biopsies from a matched control group and native renal biopsies were analyzed. Arteriolar C4d staining was semiquantitatively scored as negative (0), small deposits in 1 arteriole (1+), small/large deposits in >1 arterioles (2+), or at least extensive deposits in most arterioles (3+). RESULTS Thirty-four of 40 (85%) patients with c-aAMR showed arteriolar C4d staining. A significant difference in arteriolar C4d score was observed between cases and matched controls (P = 0.01) and a trend toward significance difference between cases and native renal biopsies (P = 0.05). In the cases, arteriolar C4d staining was significantly associated with severity of arteriolar hyalinosis (P = 0.004) and ≥2 arteriolar C4d staining was independently associated with better graft outcome in a multivariate Cox regression analysis (hazard ratio, 0.260; 95% CI, 0.104-0.650; P = 0.004). CONCLUSIONS This pilot study shows that arteriolar C4d staining is more common in biopsies with c-aAMR compared with those without and that it is associated with arteriolar hyalinosis and ≥2 arteriolar C4d staining is associated with superior graft outcome. However, larger studies are needed to examine these findings in more detail to asses if arteriolar C4d staining is truly related to antibody-mediated injury.
Collapse
|
|
22
|
Metter C, Torrealba JR. Pathology of the kidney allograft. Semin Diagn Pathol 2020; 37:148-153. [PMID: 32249077 DOI: 10.1053/j.semdp.2020.03.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 11/11/2022]
Abstract
The kidney biopsy still represents the best approach to diagnose renal transplant complications. It is considered the gold standard in the diagnosis of rejection and non-rejection complications. Although invasive, it is a safe procedure with a very low complication rate. With adequate sampling, changes related to antibody-mediated rejection (ABMR) and T-cell mediated rejection (TCMR) can be identified. However, the pathologist needs to be aware of the many other complications, not related to rejection, that can affect the allograft function. Examples include viral infections, drug toxicity, systemic diseases such as hypertension and diabetes, and recurrent or de novo glomerulopathy, among others. In this article, we review the recent classification of pathology of the kidney allograft, with reference to recent consensus reached at the most recent Banff renal allograft classification meetings, and also highlight common non-rejection complications of the kidney transplant.
Collapse
Affiliation(s)
- Christopher Metter
- Department of Pathology, University of Texas Southwestern Medical Center, Professional Office Building I, 3rd Floor Suite HP3.370, Room HP3.392 ,5959 Harry Hines Blvd, Dallas, TX 75390, TX, United States
| | - Jose R Torrealba
- Department of Pathology, University of Texas Southwestern Medical Center, Professional Office Building I, 3rd Floor Suite HP3.370, Room HP3.392 ,5959 Harry Hines Blvd, Dallas, TX 75390, TX, United States.
| |
Collapse
|
|
23
|
Khairwa A. The relevance of complement C4d staining in renal allograft biopsies. INDIAN JOURNAL OF TRANSPLANTATION 2020. [DOI: 10.4103/ijot.ijot_60_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
24
|
Roy S, Nalwa A, Keith J, Weck K, Singh H, Nickeleit V. Pseudolinear C4d deposits in a hereditary glomerulopathy caused by a rare NC1 collagen-4-alpha-5 missense mutation: a "new disease entity"? Ultrastruct Pathol 2019; 43:209-215. [PMID: 31682783 DOI: 10.1080/01913123.2019.1683666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
C4d positive glomerulopathies with pseudolinear capillary wall deposits caused by basement membrane (GBM) remodeling have sporadically been reported in renal transplants. Here we describe the case of a hypertensive 60 year-old male with a 5 month history of nephrotic range proteinuria in the setting of normal serum creatinine, complement and ANA levels. Work-up showed MGUS (IgG/kappa restricted). A diagnostic renal biopsy to search for monoclonal gammopathy of renal significance demonstrated thickened glomerular capillary walls with strong pseudolinear complement factor C4d deposits by immunofluorescence microscopy (IF); all other IF studies including stains for Col4A3 were unrevealing with only minor abnormalities seen for Col4A5. The strong and unusual C4d staining of undetermined direct diagnostic significance triggered additional electron microscopic studies uncovering marked structural GBM changes suggestive of a hereditary nephropathy. Further genetic testing revealed a very rare X-linked single missense mutation in the NC1 domain of Col4A5 (exon 51) with a single amino acid substitution (COL4A5 p.A1581S) that has thus far not been reported in hereditary nephropathies. Our case provides further support for pseudolinear glomerular C4d deposits as general markers of GBM remodeling, in our case an unexpected hereditary nephropathy in an older male. Pseudolinear C4d: a general signpost for architectural GBM disturbance and a stimulus for in-depth studies including electron microscopy.
Collapse
Affiliation(s)
- Sanjeet Roy
- Department of Pathology, Division of Nephropathology, University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Aasma Nalwa
- Department of Pathology, Division of Nephropathology, University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Jared Keith
- Blue Ridge Nephrology and Hypertension Center, Boone, NC, USA
| | - Karen Weck
- Department of Pathology, Molecular Genetics Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, USA
| | - Harsharan Singh
- Department of Pathology, Division of Nephropathology, University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Volker Nickeleit
- Department of Pathology, Division of Nephropathology, University of North Carolina at Chapel Hill, Chapel Hill, United States
| |
Collapse
|
|
25
|
Xia W, Gao B, Duan L, Li Y, Wen Y, Chen L, Li X, Zheng F, Li M. Clinical significance of C4d deposition in renal tissues from patients with primary Sjögren's syndrome-a preliminary study. BMC Nephrol 2019; 20:189. [PMID: 31138153 PMCID: PMC6540533 DOI: 10.1186/s12882-019-1341-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 04/17/2019] [Indexed: 01/06/2023] Open
Abstract
Background To evaluate renal expression of C4d, a complement component in the classical/mannose binding lectin (MBL) pathway, in patients with primary Sjögren’s syndrome (pSS)-associated renal impairments. Methods We retrospectively reviewed the clinical and pathological data from 39 patients with pSS presenting with renal impairments. C4d was examined in paraffin-embedded biopsy tissues using immunohistochemistry. Glomerular C4d positive was defined when > 75% glomeruli were globally stained. Tubulointerstitial C4d (TI-C4d) were scored semi-quantitatively as 0 (absent), 1 (spotty or weak), 2 (patchy) and 3 (diffuse). A TI-C4d score ≥ 2 was considered TI-C4d positive and included in the TI-C4d+ group and vice versa. Peritubular capillary (PTC) C4d was scored as 0 (absent), 1 (0~10%, minimal), 2 (10%~ 50%, focal), and 3 (> 50%, diffuse). Results Glomerular C4d deposition was observed in all 8 patients with pSS-related membranous nephropathy (MN) without obvious C1q deposition. Two of 5 patients with mesangial proliferative glomerulonephritis and 1 of 2 patients with IgA nephropathy had mild mesangial C4d deposition. Sixteen patients (6 glomerular dominant and 10 tubulointerstitial dominant) presented TI-C4d score ≥ 2. Patients in the TI-C4d+ group exhibited a higher serum creatinine level at the time of renal biopsy (TI-C4d+ 132.5 [89.7, 165.5] vs. TI-C4d− 83.0 [70.7, 102.0] μmol/L, P = 0.008). PTC C4d was observed in 12 patients, with each of minimal, focal and diffuse staining being noted in 4 patients. Conclusions The MBL pathway of complement activation was potentially involved in pSS-related MN. Tubulointerstitial C4d might be a pathological marker of severe renal injury in patients with pSS-related renal impairments. Electronic supplementary material The online version of this article (10.1186/s12882-019-1341-y) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Wenli Xia
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.,Department of Nephrology, Beijing Jishuitan Hospital, Fourth Clinical College, Peking University, Beijing, 100035, China
| | - Bixia Gao
- Renal Division, Department of Medicine, Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University First Hospital, Peking University, Beijing, 100034, China
| | - Lin Duan
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Yan Li
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Yubing Wen
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Limeng Chen
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Xuemei Li
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Falei Zheng
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Mingxi Li
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.
| |
Collapse
|
|
26
|
Anglicheau D, Delville M, Lamarthee B. Non anti-HLA antibodies and acute rejection: A critical viewpoint. Nephrol Ther 2019; 15 Suppl 1:S53-S59. [PMID: 30981396 DOI: 10.1016/j.nephro.2019.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 03/04/2019] [Indexed: 10/27/2022]
Abstract
In solid organ transplantation, the deleterious effect of antibodies directed against donor HLA antigens, whether preformed or de novo, is well established. Anti-HLA antibodies have been associated not only with the risk of antibody-mediated rejection but also with late graft dysfunction and are now considered to be the leading cause of allograft loss after renal transplantation. In addition to HLA antibodies, the possible involvement of non-HLA antibodies targeting donor endothelial cells has long been the subject of intense research. The purpose of this review is to discuss current knowledge and remaining issues related to the involvement of non-HLA antibodies in solid organ transplantation. More specifically, the clinical data underlying the hypothesis of the role of non-HLA antibodies will be discussed, as well as the different techniques for antibody detection, their clinical relevance and their antigenic targets.
Collapse
Affiliation(s)
- Dany Anglicheau
- Service de néphrologie et transplantation rénale adulte, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Inserm, U1151, 149, rue de Sèvres, 75015 Paris, France.
| | - Marianne Delville
- Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Service de biothérapie, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Inserm, U1163, 24, boulevard de Montparnasse, 75015 Paris, France
| | - Baptiste Lamarthee
- Service de néphrologie et transplantation rénale adulte, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Inserm, U1151, 149, rue de Sèvres, 75015 Paris, France
| |
Collapse
|
|
27
|
Panzer SE, Joachim E, Parajuli S, Zhong W, Astor BC, Djamali A. Glomerular C3 Deposition Is an Independent Risk Factor for Allograft Failure in Kidney Transplant Recipients With Transplant Glomerulopathy. Kidney Int Rep 2019; 4:582-593. [PMID: 30993233 PMCID: PMC6451156 DOI: 10.1016/j.ekir.2019.01.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 01/22/2019] [Accepted: 01/28/2019] [Indexed: 01/09/2023] Open
Abstract
INTRODUCTION Transplant glomerulopathy (TG) becomes increasingly prevalent in kidney transplant recipients over time, and it is strongly associated with allograft failure. To date, our prognostic biomarkers and understanding of the processes of immunologic injury in TG are limited. METHODS This is a retrospective cohort analysis of kidney transplant recipients with TG (double contours of the glomerular basement membrane as defined by the chronic glomerulopathy score). Glomerular deposition of the complement protein C3 was determined, and its association with allograft survival was analyzed by Cox regression analysis. RESULTS Of the 111 patients with TG, 72 (65%) had allograft failure, with a median follow-up time of 3 years from biopsy diagnosis of TG. C3-positive compared to C3-negative patients did not differ with respect to cause of end-stage renal disease, induction or maintenance immunosuppression, or sensitization. A greater proportion of patients with glomerular C3 deposition developed allograft failure compared to those with no C3 deposition (78% vs. 55%, P = 0.01). C3 deposition was independently associated with allograft failure in multivariate analyses (adjusted hazard ratio [HR] = 1.38, 95% confidence interval [CI] = 1.13-1.69, P = 0.002). There was no association between C4d or C1q deposition and allograft failure. Chronicity score was also associated with allograft failure in multivariate analysis (adjusted HR 1.26, 95% CI 1.12-1.41, P = 0.0001). CONCLUSION In this cohort of patients with TG, glomerular C3 deposition was independently associated with a higher risk of allograft failure. These findings identify glomerular C3 as a novel prognostic indicator in patients with TG.
Collapse
Affiliation(s)
- Sarah E. Panzer
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, Wisconsin, USA
| | - Emily Joachim
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, Wisconsin, USA
| | - Sandesh Parajuli
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, Wisconsin, USA
| | - Weixiong Zhong
- Department of Pathology, University of Wisconsin, Madison, Wisconsin, USA
| | - Brad C. Astor
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, Wisconsin, USA
- Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin, USA
| | - Arjang Djamali
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, Wisconsin, USA
- Department of Surgery, Division of Transplant Surgery, University of Wisconsin, Madison, Wisconsin, USA
| |
Collapse
|
|
28
|
Kim YG, Choi G, Go H, Cho Y, Lee H, Lee AR, Park B, Kim N. A Fully Automated System Using A Convolutional Neural Network to Predict Renal Allograft Rejection: Extra-validation with Giga-pixel Immunostained Slides. Sci Rep 2019; 9:5123. [PMID: 30914690 PMCID: PMC6435691 DOI: 10.1038/s41598-019-41479-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 03/04/2019] [Indexed: 12/20/2022] Open
Abstract
Pathologic diagnoses mainly depend on visual scoring by pathologists, a process that can be time-consuming, laborious, and susceptible to inter- and/or intra-observer variations. This study proposes a novel method to enhance pathologic scoring of renal allograft rejection. A fully automated system using a convolutional neural network (CNN) was developed to identify regions of interest (ROIs) and to detect C4d positive and negative peritubular capillaries (PTCs) in giga-pixel immunostained slides. The performance of faster R-CNN was evaluated using optimal parameters of the novel method to enlarge the size of labeled masks. Fifty and forty pixels of the enlarged size images showed the best performance in detecting C4d positive and negative PTCs, respectively. Additionally, the feasibility of deep-learning-assisted labeling as independent dataset to enhance detection in this model was evaluated. Based on these two CNN methods, a fully automated system for renal allograft rejection was developed. This system was highly reliable, efficient, and effective, making it applicable to real clinical workflow.
Collapse
Affiliation(s)
- Young-Gon Kim
- Department of Biomedical Engineering, Asan Institute of Life Science, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea
- Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea
- Center for Superintelligence, Seoul National University, 08826, Seoul, South Korea
| | - Gyuheon Choi
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea
| | - Heounjeong Go
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea.
| | - Yongwon Cho
- Department of Biomedical Engineering, Asan Institute of Life Science, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea
- Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea
- Center for Superintelligence, Seoul National University, 08826, Seoul, South Korea
| | - Hyunna Lee
- Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea
- Center for Superintelligence, Seoul National University, 08826, Seoul, South Korea
| | - A-Reum Lee
- Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea
- Center for Superintelligence, Seoul National University, 08826, Seoul, South Korea
| | - Beomhee Park
- Department of Biomedical Engineering, Asan Institute of Life Science, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea
- Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea
- Center for Superintelligence, Seoul National University, 08826, Seoul, South Korea
| | - Namkug Kim
- Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea.
- Center for Superintelligence, Seoul National University, 08826, Seoul, South Korea.
| |
Collapse
|
|
29
|
Luque S, Lúcia M, Melilli E, Lefaucheur C, Crespo M, Loupy A, Bernal-Casas D, Gomà M, Jarque M, Crespo E, Montero N, Manonelles A, Cruzado JM, Gil-Vernet S, Grinyó JM, Bestard O. Value of monitoring circulating donor-reactive memory B cells to characterize antibody-mediated rejection after kidney transplantation. Am J Transplant 2019; 19:368-380. [PMID: 30085394 DOI: 10.1111/ajt.15055] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/06/2018] [Accepted: 07/29/2018] [Indexed: 01/25/2023]
Abstract
Antibody-mediated rejection (ABMR) is defined by specific histopathological lesions and evidence of circulating donor-specific antibodies (DSA). Although DSA are not always detectable, monitoring donor-reactive memory B cells (mBC) could identify patients at risk of developing ABMR. Peripheral donor-reactive mBC using a novel HLA B cell ELISpot assay, serum DSA, and numbers of different B cell subsets were assessed in 175 consecutive kidney transplants undergoing either for-cause or 6- and 24-month surveillance biopsies for their association with main histological lesions of ABMR and impact on allograft outcome. In 85 incident for-cause biopsies, high frequencies of donor-reactive mBC were detected in all 16 (100%) acute ABMR/DSA+ and most chronic ABMR, with or without DSA (24/30[80%] and 21/29[72.4%], respectively). In a longitudinal cohort of 90 nonsensitized patients, a progressively higher expansion of donor-reactive mBC than de novo DSA was observed at 6 and 24 months (8.8% vs 7.7% and 15.5% vs 11.1%, respectively) and accurately identified patients with ongoing subclinical ABMR (area under the curve = 0.917 and area under the curve = 0.809, respectively). An unsupervised hierarchical cluster analysis revealed a strong association between donor-reactive mBC with main fundamental allograft lesions associated with ABMR and conferred a significant deleterious impact on graft outcome. Monitoring donor-reactive mBC may be useful to further characterize humoral rejection after kidney transplantation.
Collapse
Affiliation(s)
- Sergi Luque
- Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain
| | - Marc Lúcia
- Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain
| | - Edoardo Melilli
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Carmen Lefaucheur
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, UMR-S970, Paris, France
| | - Marta Crespo
- Kidney Transplant Unit, Nephrology Department, Hospital del Mar, Barcelona, Spain
| | - Alex Loupy
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, UMR-S970, Paris, France
| | - David Bernal-Casas
- Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain.,Department of Genetics, Microbiology and Statistics, Section of Statistics, University of Barcelona, Barcelona, Spain
| | - Montse Gomà
- Pathology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Marta Jarque
- Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain
| | - Elena Crespo
- Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain
| | - Núria Montero
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Anna Manonelles
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Josep M Cruzado
- Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain.,Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Salvador Gil-Vernet
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Josep M Grinyó
- Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain.,Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Oriol Bestard
- Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain.,Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain
| |
Collapse
|
|
30
|
Chhabra M, Alsughayyir J, Qureshi MS, Mallik M, Ali JM, Gamper I, Moseley EL, Peacock S, Kosmoliaptsis V, Goddard MJ, Linterman MA, Motallebzadeh R, Pettigrew GJ. Germinal Center Alloantibody Responses Mediate Progression of Chronic Allograft Injury. Front Immunol 2019; 9:3038. [PMID: 30728823 PMCID: PMC6351502 DOI: 10.3389/fimmu.2018.03038] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 12/07/2018] [Indexed: 02/02/2023] Open
Abstract
Different profiles of alloantibody responses are observed in the clinic, with those that persist, often despite targeted treatment, associated with poorer long-term transplant outcomes. Although such responses would suggest an underlying germinal center (GC) response, the relationship to cellular events within the allospecific B cell population is unclear. Here we examine the contribution of germinal center (GC) humoral alloimmunity to chronic antibody mediated rejection (AMR). A murine model of chronic AMR was developed in which T cell deficient (Tcrbd-/-) C57BL/6 recipients were challenged with MHC-mismatched BALB/c heart allografts and T cell help provided by reconstituting with 103 "TCR75" CD4 T cells that recognize self-restricted allopeptide derived from the H-2Kd MHC class I alloantigen. Reconstituted recipients developed Ig-switched anti-Kd alloantibody responses that were slow to develop, but long-lived, with confocal immunofluorescence and flow cytometric characterization of responding H-2Kd-allospecific B cells confirming persistent splenic GC activity. This was associated with T follicular helper (TFH) cell differentiation of the transferred TCR75 CD4 T cells. Heart grafts developed progressive allograft vasculopathy, and were rejected chronically (MST 50 days), with explanted allografts displaying features of humoral vascular rejection. Critically, late alloantibody responses were abolished, and heart grafts survived indefinitely, in recipients reconstituted with Sh2d1a-/- TCR75 CD4 T cells that were genetically incapable of providing TFH cell function. The GC response was associated with affinity maturation of the anti-Kd alloantibody response, and its contribution to progression of allograft vasculopathy related principally to secretion of alloantibody, rather than to enhanced alloreactive T cell priming, because grafts survived long-term when B cells could present alloantigen, but not secrete alloantibody. Similarly, sera sampled at late time points from chronically-rejecting recipients induced more vigorous donor endothelial responses in vitro than sera sampled earlier after transplantation. In summary, our results suggest that chronic AMR and progression of allograft vasculopathy is dependent upon allospecific GC activity, with critical help provided by TFH cells. Clinical strategies that target the TFH cell subset may hold therapeutic potential. This work is composed of two parts, of which this is Part II. Please read also Part I: Alsughayyir et al., 2019.
Collapse
Affiliation(s)
- Manu Chhabra
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Jawaher Alsughayyir
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - M. Saeed Qureshi
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Mekhola Mallik
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Jason M. Ali
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Ivonne Gamper
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Ellen L. Moseley
- Department of Pathology, Papworth Hospital, Papworth Everard, United Kingdom
| | - Sarah Peacock
- Histocompatibility and Immunogenetics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | | | - Martin J. Goddard
- Department of Pathology, Papworth Hospital, Papworth Everard, United Kingdom
| | - Michelle A. Linterman
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Reza Motallebzadeh
- Division of Surgery and Interventional Science, University College London, London, United Kingdom
- Centre for Transplantation, Department of Renal Medicine, University College London, London, United Kingdom
- Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Gavin J. Pettigrew
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| |
Collapse
|
|
31
|
Liao T, Zhang Y, Ren J, Zheng H, Zhang H, Li X, Liu X, Yin T, Sun Q. Noninvasive quantification of intrarenal allograft C4d deposition with targeted ultrasound imaging. Am J Transplant 2019; 19:259-268. [PMID: 30171802 DOI: 10.1111/ajt.15105] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 08/08/2018] [Accepted: 08/27/2018] [Indexed: 01/25/2023]
Abstract
Antibody-mediated rejection (AMR) has emerged as a major cause of renal allograft dysfunction. C4d, a specific marker for AMR diagnosis, was strongly recommended for routine surveillance; however, currently, C4d detection is dependent upon tissue biopsy, which is invasive and provides only local semi-quantitative data. Targeted ultrasound imaging has been used extensively for noninvasive and real-time molecular detection with advantages of high specificity and sensitivity. In this study, we designed C4d-targeted microbubbles (MBC4d ) using a streptavidin-biotin conjugated method and detected C4d deposition in vivo in a rat model of AMR by enhanced ultrasound imaging. This noninvasive procedure allowed successful acquisition of the first qualitative image of C4d deposition in a wide renal allograft section, which reflected real-time C4d distribution in grafts. Moreover, we introduced normal intensity difference for quantitative analysis, which exhibited a nearly linear correlation with the grade of C4d deposition according to pathologic analysis. In addition, this approach showed no influence on survival rates and pathologic features in the microbubble injection groups, thereby demonstrating its safety. These findings demonstrated a simple, noninvasive, quantitative, and safe evaluation method for C4d, with the utility of this approach potentially preventing patients from having to undergo an invasive biopsy.
Collapse
Affiliation(s)
- Tao Liao
- Organ Transplantation Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yannan Zhang
- Organ Transplantation Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jie Ren
- Department of Medical Ultrasound, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Haofeng Zheng
- Organ Transplantation Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hongjun Zhang
- Department of Medical Ultrasound, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiujie Li
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaonan Liu
- Organ Transplantation Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tinghui Yin
- Department of Medical Ultrasound, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qiquan Sun
- Organ Transplantation Research Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| |
Collapse
|
|
32
|
Molecular Assessment of C4d-Positive Renal Transplant Biopsies Without Evidence of Rejection. Kidney Int Rep 2018; 4:148-158. [PMID: 30596178 PMCID: PMC6308373 DOI: 10.1016/j.ekir.2018.09.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/17/2018] [Accepted: 09/10/2018] [Indexed: 12/28/2022] Open
Abstract
Introduction Immunohistochemical staining for C4d in peritubular capillaries has been part of antibody-mediated rejection (AbMR) definition in the Banff Classification for Allograft Pathology since 2003. However, it has limited sensitivity and specificity, therefore the clinical significance of C4d-positive biopsies without evidence of rejection (C4d+ WER) is unknown. We investigated the transcript levels of genes associated with AbMR in C4d+ WER biopsies from both ABO-compatible and incompatible renal transplant patients. Methods RNA was extracted from formalin-fixed paraffin-embedded renal transplant biopsies (n = 125) and gene expression analysis of 35 AbMR-associated transcripts carried out using the NanoString nCounter system. Results AbMR-associated transcripts were significantly increased in samples with AbMR or suspicious AbMR. A subgroup of 17 of 35 transcripts that best distinguished AbMR from C4d-negative biopsies without evidence of rejection was used to study C4d+ WER samples. There was no differential expression between C4d-negative and C4d+ WER from both ABO-incompatible and -compatible transplants. The geometric mean of 17 differentially expressed genes was used to assign the C4d+ WER biopsies a high- or low-AbMR transcript score. Follow-up biopsies showed AbMR within 1 year of initial biopsy in 5 of 7 high-AbMR transcript patients but only 2 of 46 low-AbMR transcript patients. In multivariate logistic regression analysis, elevated transcript levels in a C4d+ WER biopsy were associated with increased odds for biopsy-proven AbMR on follow-up (P = 0.032, odds ratio 16.318), whereas factors including donor-specific antibody (DSA) status and time since transplantation were not. Conclusion Gene expression analysis in C4d+ WER samples has the potential to identify patients at higher risk of developing AbMR.
Collapse
|
|
33
|
Eskandary F, Jilma B, Mühlbacher J, Wahrmann M, Regele H, Kozakowski N, Firbas C, Panicker S, Parry GC, Gilbert JC, Halloran PF, Böhmig GA. Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection-results from a first-in-patient phase 1 trial. Am J Transplant 2018; 18:916-926. [PMID: 28980446 DOI: 10.1111/ajt.14528] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 09/03/2017] [Accepted: 09/24/2017] [Indexed: 01/25/2023]
Abstract
The classical pathway (CP) of complement may contribute to the pathogenesis of antibody-mediated rejection (ABMR). Selective CP blockade may be a promising strategy to counteract rejection. The objective of this first-in-patient phase 1b trial was to evaluate the safety/tolerability and CP-blocking potential of 4 weekly doses (60 mg/kg) of the anti-C1s antibody BIVV009 in complement-mediated disorders. Here we describe the results in a cohort of 10 stable kidney transplant recipients (median of 4.3 years posttransplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement-fixing donor-specific antibodies (DSA). During 7 weeks follow-up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA-triggered CP activation in serum. Five of 8 C4d-positive recipients turned C4d-negative in 5-week follow-up biopsies, while another 2 recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody-triggered CP activation, even though short-course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials.gov NCT#02502903.
Collapse
Affiliation(s)
- F Eskandary
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - B Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - J Mühlbacher
- Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - M Wahrmann
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - H Regele
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - N Kozakowski
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - C Firbas
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - S Panicker
- Bioverativ Therapeutics, Inc, South San Francisco, CA, USA
| | - G C Parry
- Bioverativ Therapeutics, Inc, South San Francisco, CA, USA
| | - J C Gilbert
- True North Therapeutics, Inc, South San Francisco, CA, USA
| | - P F Halloran
- Alberta Transplant Applied Genomics Centre, ATAGC, University of Alberta, Edmonton, AB, Canada
| | - G A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
34
|
Vazquez Martul E. [The pathology of renal transplants]. REVISTA ESPAÑOLA DE PATOLOGÍA : PUBLICACIÓN OFICIAL DE LA SOCIEDAD ESPAÑOLA DE ANATOMÍA PATOLÓGICA Y DE LA SOCIEDAD ESPAÑOLA DE CITOLOGÍA 2018; 51:110-123. [PMID: 29602372 DOI: 10.1016/j.patol.2017.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 10/01/2017] [Indexed: 11/15/2022]
Abstract
In order to make an objective assessment of the histopathology of a renal biopsy during a kidney transplant, all the various elements involved in the process must be understood. It is important to know the characteristics of the donor organ, especially if the donor is older than 65. The histopathological features of the donor biopsy, especially its vascular status, are often related to an initial poor function of the transplanted kidney. The T lymphocyte inflammatory response is characteristic in acute cellular rejection; the degree of tubulitis, together with the amount of affected parenchyme, are important factors. The proportion of cellular sub-populations, such as plasma cells and macrophages, is also important, as they can be related to antibody-mediated humoral rejection. Immunofluorescent or immunohistochemical studies are necessary to rule out C4d deposits or immunogloblulins. The presence of abundant deposits of C4d in tubular basement membranes supports a diagnosis of humoral rejection, as does the presence of capillaritis, glomerulitis which, together with vasculitis, are typical diagnostic findings in C4d negative cases. Interstitial fibrosis, tubular atrophy and glomerular sclerosis, although non-specific, imply a chronic phase. Transplant glomerulopathy and multilamination in more than 6 layers of the tubular and glomerular basement membranes are quasi-specific characteristics of chronic humoral rejection. Electron microscopy is essential to identify of these pathologies as well as to demonstrate the presence of other glomerular renal diseases.
Collapse
Affiliation(s)
- Eduardo Vazquez Martul
- Ex Jefe de Servicio de Anatomía Patológica, Hospital Universitario A Coruña (retirado), A Coruña, España; Ex profesor asociado de la Facultad de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, A Coruña, España; Miembro del Club de Nefropatología (Sociedad Española de Nefrología), España.
| |
Collapse
|
|
35
|
Muczynski KA, Leca N, Anderson AE, Kieran N, Anderson SK. Multicolor Flow Cytometry and Cytokine Analysis Provides Enhanced Information on Kidney Transplant Biopsies. Kidney Int Rep 2018; 3:956-969. [PMID: 29989006 PMCID: PMC6035131 DOI: 10.1016/j.ekir.2018.02.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 02/26/2018] [Indexed: 12/31/2022] Open
Abstract
Introduction Current processing of renal biopsy samples provides limited information about immune mechanisms causing kidney injury and disease activity. We used flow cytometry with transplanted kidney biopsy samples to provide more information on the immune status of the kidney. Methods To enhance the information available from a biopsy, we developed a technique for reducing a fraction of a renal biopsy sample to single cells for multicolor flow cytometry and quantitation of secreted cytokines present within the biopsy sample. As proof of concept, we used our technique with transplant kidney biopsy samples to provide examples of clinically relevant immune information obtainable with cytometry. Results A ratio of CD8+ to CD4+ lymphocytes greater than or equal to 1.2 in transplanted allografts is associated with rejection, even before it is apparent by microscopy. Elevated numbers of CD45 leukocytes and higher levels of interleukin (IL)−6, IL-8, and IL-10 indicate more severe injury. Antibody binding to renal microvascular endothelial cells can be measured and corresponds to antibody-mediated forms of allograft rejection. Eculizumab binding to endothelial cells suggests complement activation, which may be independent of bound antibody. We compared intrarenal leukocyte subsets and activation states to those of peripheral blood from the same donor at the time of biopsy and found significant differences; thus the need for new techniques to evaluate immune responses within the kidney. Conclusion Assessment of leukocyte subsets, renal microvascular endothelial properties, and measurement of cytokines within a renal biopsy by flow cytometry enhance understanding of pathogenesis, indicate disease activity, and identify potential targets for therapy.
Collapse
Affiliation(s)
| | - Nicolae Leca
- Division of Nephrology, University of Washington, Seattle, Washington, USA
| | - Arthur E Anderson
- Division of Nephrology, University of Washington, Seattle, Washington, USA
| | - Niamh Kieran
- Division of Nephrology, University of Washington, Seattle, Washington, USA
| | - Susan K Anderson
- Division of Nephrology, University of Washington, Seattle, Washington, USA
| |
Collapse
|
|
36
|
Transplant glomerulopathy. Mod Pathol 2018; 31:235-252. [PMID: 29027535 DOI: 10.1038/modpathol.2017.123] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/28/2017] [Accepted: 08/10/2017] [Indexed: 12/13/2022]
Abstract
In the renal allograft, transplant glomerulopathy represents a morphologic lesion and not a specific diagnosis. The hallmark pathologic feature is glomerular basement membrane reduplication by light microscopy or electron microscopy in the absence of immune complex deposits. Transplant glomerulopathy results from chronic, recurring endothelial cell injury that can be mediated by HLA alloantibodies (donor-specific antibodies), various autoantibodies, cell-mediated immune injury, thrombotic microangiopathy, or chronic hepatitis C. Clinically, transplant glomerulopathy may be silent, detectable on protocol biopsy, or present with overt manifestations, including up to nephrotic range proteinuria, hypertension, and declining glomerular filtration rate. In either case, transplant glomerulopathy is associated with reduced graft survival. This review details the morphologic features of transplant glomerulopathy found on light microscopy, immunofluorescence microscopy, and electron microscopy. The pathophysiology of the causes and risk factors are discussed. Clinical manifestations are emphasized and potential therapeutic modalities are examined.
Collapse
|
|
37
|
Reindl-Schwaighofer R, Heinzel A, Signorini L, Thaunat O, Oberbauer R. Mechanisms underlying human genetic diversity: consequence for antigraft antibody responses. Transpl Int 2017; 31:239-250. [DOI: 10.1111/tri.13059] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 07/28/2017] [Accepted: 08/30/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Roman Reindl-Schwaighofer
- Division of Nephrology and Dialysis; Department of Internal Medicine III; Medical University of Vienna; Vienna Austria
| | - Andreas Heinzel
- Division of Nephrology and Dialysis; Department of Internal Medicine III; Medical University of Vienna; Vienna Austria
| | - Lorenzo Signorini
- Renal and Dialysis Unit; Department of Medicine; University of Verona; Verona Italy
| | - Olivier Thaunat
- Hospices Civils de Lyon; Hôpital Edouard Herriot; Service de Transplantation; Néphrologie et Immunologie Clinique; INSERM U1111; Université Lyon-I; Lyon France
| | - Rainer Oberbauer
- Division of Nephrology and Dialysis; Department of Internal Medicine III; Medical University of Vienna; Vienna Austria
| |
Collapse
|
|
38
|
Kozakowski N, Eskandary F, Herkner H, Bond G, Oberbauer R, Regele H, Böhmig GA, Kikić Ž. Diffuse Extent of Peritubular Capillaritis in Late Antibody-Mediated Rejection: Associations With Levels of Donor-Specific Antibodies and Chronic Allograft Injury. Transplantation 2017; 101:e178-e187. [PMID: 28252564 DOI: 10.1097/tp.0000000000001707] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Recently, diffuse peritubular capillaritis (ptc) has been suggested to independently predict chronic transplant injury and loss, and although the ptc score is a diagnostic criterion for antibody-mediated rejection, the utility of diffuse ptc is under debate. METHODS We evaluated the diagnostic value of ptc characteristics in this cross-sectional study including 85 biopsies of patients with donor-specific antibodies (DSA). Biopsies were reevaluated for the extent (diffuse vs focal), score and leukocytic composition in relation to DSA binding strength (mean fluorescence intensity [MFI]_max). Chronic allograft injury (transplant chronic glomerulopathy [cg] or chronic lesion score CLS]) were associated with ptc features. RESULTS Peritubular capillaritis was detected in 50% (76% mononuclear ptc). Peritubular capillaritis scores 1, 2, and 3 were present in 36%, 55%, and 9%, and focal or diffuse ptc in 36% or 64%. Diffuse ptc was associated with DSA MFI_max (median: 4407 vs 2419 [focal ptc; P = 0.04] or 1946 [no ptc; P = 0.004]), cg (58% vs no ptc 24% [P = 0.02]), and higher CLS (mean: 6.81 vs 4.67 [focal ptc, P = 0.01] or 5.18 [no ptc, P = 0.001]), respectively. The association of ptc score of 2 or greater with cg was slightly better than with diffuse ptc. Diffuse ptc and ptc score of 2 or greater remained independently related to cg after adjusting for DSA_MFI_max, C4d, or previous rejection episodes, however lost their independent relation after adjusting for total microcirculation scores. Diffuse ptc was the only ptc characteristic independently related to CLS. CONCLUSIONS Our results emphasize the clinical relevance of reporting diffuse ptc, which may relate to DSA binding strength and potentially to chronic graft injury.
Collapse
Affiliation(s)
- Nicolas Kozakowski
- 1 Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria. 2 Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria. 3 Department of Emergency Medicine, Medical University Vienna, Vienna, Austria
| | | | | | | | | | | | | | | |
Collapse
|
|
39
|
The Diagnostic Impact of C4d, CD68, and NF-κB Expression in the Differentiation Between Recurrent Hepatitis C and Acute Cellular Rejection After Liver Transplantation. Appl Immunohistochem Mol Morphol 2017; 24:639-647. [PMID: 26469325 DOI: 10.1097/pai.0000000000000245] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Liver transplantation is the selected treatment for patients with advanced liver disease and cirrhosis, mostly as a complication of hepatitis C virus (HCV). Recurrent HCV and acute cellular rejection (ACR) of the graft are the most common causes of graft failure. The distinction between the 2 conditions is essential because they are managed differently. In some cases, the clinical and histopathologic features may overlap between recurrent hepatitis C and ACR, making differentiation difficult. The aim of this study was to investigate the role of C4d, CD68, and nuclear factor kappa-B (NF-κB) in the differentiation between ACR and recurrent HCV in the post-liver-transplant biopsy using immunohistochemistry. C4d expression in endothelial cells of portal or central veins (P=0.001) and the number of macrophages highlighted by CD68 (P=0.02) were in favor of ACR, whereas NF-κB expression by hepatocytes was in favor of recurrent hepatitis C. Vascular injury demonstrated by endothelial expression of C4d and prominent macrophage infiltration identified by CD68 expression were the distinguishing criteria for ACR and representing humoral and cellular-mediated immunity as evoking factors for graft injury. The upregulation of NF-κB in the hepatocytes of recurrent hepatitis C could be an immune response to infection or it may be induced by HCV itself.
Collapse
|
|
40
|
Sullivan HC, Gebel HM, Bray RA. Understanding solid-phase HLA antibody assays and the value of MFI. Hum Immunol 2017; 78:471-480. [DOI: 10.1016/j.humimm.2017.05.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 05/26/2017] [Accepted: 05/29/2017] [Indexed: 01/10/2023]
|
|
41
|
Memarnejadian A, Meilleur CE, Mazzuca DM, Welch ID, Haeryfar SMM. Quantification of Alloantibody-Mediated Cytotoxicity In Vivo. Transplantation 2017; 100:1041-51. [PMID: 26985743 DOI: 10.1097/tp.0000000000001154] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Preexisting, donor-specific antibodies (DSAs) are culprits of hyperacute rejection. Donor-specific antibodies are also formed de novo, and their role in acute and chronic rejection is increasingly appreciated. However, it is difficult to assess damage inflicted exclusively by DSAs when alloreactive T cell and B cell responses coincide. We reasoned that allosensitization with "costimulation-deficient" cells should induce DSA synthesis but not naive cytotoxic T lymphocyte (CTL) precursors' priming via direct allorecognition. Accordingly, we have developed a novel model to quantify DSA-mediated cytotoxicity in vivo. METHODS C57BL/6 (H-2b) mice were sensitized with H-2 kidney epithelial cells, and a cytofluorimetric killing assay was tailored to the measurement of allocytotoxicity. We took cell/complement depletion, costimulation blockade, and serum transfer approaches to reveal the mediators of cytotoxicity. "Third-party" controls and a skin allotransplantation model were used to confirm DSAs' specificity for allo-major histocompatibility complex. We validated our experimental approach in other mouse strains primed with different allogeneic cell types, including endothelial cells. To demonstrate the usefulness of our model/method for drug efficacy testing, we examined the effect of CTLA4-Ig and rapamycin on DSA-mediated cytolysis. RESULTS Allosensitization of MHC-disparate mouse strains with costimulation-deficient cells led to robust cytotoxicity mediated by complement-fixing DSAs and phagocytic cells. This response was independent of CTLs, natural killer or natural killer T cells. It required CD4 T cell help, CD40 signaling and CD28-based costimulation during allosensitization and could be reversed by sustained rapamycin treatment. CONCLUSIONS The unique model described herein should enable mechanistic studies on sensitization and effector phases of humoral alloreactivity as well as efficacy testing of future immunotherapies to prevent DSA-induced pathology.
Collapse
Affiliation(s)
- Arash Memarnejadian
- 1 Department of Microbiology and Immunology, Western University, London, Ontario, Canada. 2 Animal Care and Veterinary Services, Western University, London, Ontario, Canada. 3 Division of Clinical Immunology & Allergy, Department of Medicine, Western University, London, Ontario, Canada. 4 Centre for Human Immunology, Western University, London, Ontario, Canada. 5 Lawson Health Research Institute, London, Ontario, Canada
| | | | | | | | | |
Collapse
|
|
42
|
Abstract
Complement is a major contributor to inflammation and graft injury. This system is especially important in ischemia-reperfusion injury/delayed graft function as well as in acute and chronic antibody-mediated rejection (AMR). The latter is increasingly recognized as a major cause of late graft loss, for which we have few effective therapies. C1 inhibitor (C1-INH) regulates several pathways which contribute to both acute and chronic graft injuries. However, C1-INH spares the alternative pathway and the membrane attack complex (C5–9) so innate antibacterial defenses remain intact. Plasma-derived C1-INH has been used to treat hereditary angioedema for more than 30 years with excellent safety. Studies with C1-INH in transplant recipients are limited, but have not revealed any unique toxicity or serious adverse events attributed to the protein. Extensive data from animal and ex vivo models suggest that C1-INH ameliorates ischemia-reperfusion injury. Initial clinical studies suggest this effect may allow transplantation of donor organs which are now discarded because the risk of primary graft dysfunction is considered too great. Although the incidence of severe early AMR is declining, accumulating evidence strongly suggests that complement is an important mediator of chronic AMR, a major cause of late graft loss. Thus, C1-INH may also be helpful in preserving function of established grafts. Early clinical studies in transplantation suggest significant beneficial effects of C1-INH with minimal toxicity. Recent results encourage continued investigation of this already-available therapeutic agent.
Collapse
|
|
43
|
Diagnostic Contribution of Donor-Specific Antibody Characteristics to Uncover Late Silent Antibody-Mediated Rejection-Results of a Cross-Sectional Screening Study. Transplantation 2017; 101:631-641. [PMID: 27120452 DOI: 10.1097/tp.0000000000001195] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Circulating donor-specific antibodies (DSA) detected on bead arrays may not inevitably indicate ongoing antibody-mediated rejection (AMR). Here, we investigated whether detection of complement-fixation, in parallel to IgG mean fluorescence intensity (MFI), allows for improved prediction of AMR. METHODS Our study included 86 DSA+ kidney transplant recipients subjected to protocol biopsy, who were identified upon cross-sectional antibody screening of 741 recipients with stable graft function at 6 months or longer after transplantation. IgG MFI was analyzed after elimination of prozone effect, and complement-fixation was determined using C1q, C4d, or C3d assays. RESULTS Among DSA+ study patients, 44 recipients (51%) had AMR, 24 of them showing C4d-positive rejection. Although DSA number or HLA class specificity were not different, patients with AMR or C4d + AMR showed significantly higher IgG, C1q, and C3d DSA MFI than nonrejecting or C4d-negative patients, respectively. Overall, the predictive value of DSA characteristics was moderate, whereby the highest accuracy was computed for peak IgG MFI (AMR, 0.73; C4d + AMR, 0.71). Combined analysis of antibody characteristics in multivariate models did not improve AMR prediction. CONCLUSIONS We estimate a 50% prevalence of silent AMR in DSA+ long-term recipients and conclude that assessment of IgG MFI may add predictive accuracy, without an independent diagnostic advantage of detecting complement-fixation.
Collapse
|
|
44
|
Lopategui DM, Lerut E, Naesens M, Van Damme-Lombaerts R, Levtchenko E, Knops N. Rethinking peritubular capillary basement membrane multilayering in renal transplant pathology: a case report. Pediatr Nephrol 2017; 32:697-701. [PMID: 27858192 DOI: 10.1007/s00467-016-3541-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 09/26/2016] [Accepted: 10/11/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND Severe multilayering (ML) of the peritubular capillary basement membranes in kidney allografts is considered to be an ultrastructural hallmark of chronic antibody-mediated rejection (CAMR). We describe here the unexpected findings in a young male adolescent with underlying focal segmental glomerulosclerosis who underwent a living-related donor transplant procedure, a case which brought into question the specificity of ML. METHODS The patient received a kidney from his mother, whose donor screening was unremarkable. He developed nephrotic-range proteinuria shortly after the procedure. Biopsies performed within the first 6 months after transplantation demonstrated ML (5-6 layers). RESULTS Since there were no other criteria for CAMR, electron microscopic analysis of the baseline biopsy was performed, which in retrospect also demonstrated ML. The donor is still asymptomatic after 7 years of follow-up, with normal renal function and no proteinuria. CONCLUSIONS We discuss the phenomenon of ML in renal disease and together with the findings in our case would like to draw attention to the fact that ML in the setting of renal transplantation is not specific to CAMR, as it can exist in several kidney diseases and even in asymptomatic donors.
Collapse
Affiliation(s)
- Diana Maria Lopategui
- University of Barcelona, Barcelona, Spain. .,Department of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Leuven, Belgium.
| | - Evelyne Lerut
- Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.,Department of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Rita Van Damme-Lombaerts
- Department of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Elena Levtchenko
- Department of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Noël Knops
- Department of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
|
45
|
Gasim AH, Chua JS, Wolterbeek R, Schmitz J, Weimer E, Singh HK, Nickeleit V. Glomerular C4d deposits can mark structural capillary wall remodelling in thrombotic microangiopathy and transplant glomerulopathy: C4d beyond active antibody-mediated injury: a retrospective study. Transpl Int 2017; 30:519-532. [PMID: 28207978 DOI: 10.1111/tri.12936] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 09/06/2017] [Accepted: 02/10/2017] [Indexed: 01/05/2023]
Abstract
Peritubular capillary C4d (ptc-C4d) usually marks active antibody-mediated rejection, while pseudolinear glomerular capillary C4d (GBM-C4d) is of undetermined diagnostic significance, especially when seen in isolation without concurrent ptc-C4d. We correlated GBM-C4d with structural GBM abnormalities and active antibody-mediated rejection in 319 renal transplant and 35 control native kidney biopsies. In kidney transplants, ptc-C4d was associated with GBM-C4d in 97% by immunofluorescence microscopy (IF) and 61% by immunohistochemistry (IHC; P < 0.001). Transplant glomerulopathy correlated with GBM-C4d (P < 0.001) and presented with isolated GBM-C4d lacking ptc-C4d in 69% by IF and 40% by IHC. Strong isolated GBM-C4d was found post year-1 in repeat biopsies with transplant glomerulopathy. GBM-C4d staining intensity correlated with Banff cg scores (rs = 0.45, P < 0.001). Stepwise exclusion and multivariate logistic regression corrected for active antibody-mediated rejection showed significant correlations between GBM duplication and GBM-C4d (P = 0.001). Native control biopsies with thrombotic microangiopathies demonstrated GBM-C4d in 92% (IF, P < 0.001) and 35% (IHC). In conclusion, pseudolinear GBM-C4d staining can reflect two phenomena: (i) structural GBM changes with duplication in native and transplant kidneys or (ii) active antibody-mediated rejection typically accompanied by ptc-C4d. While ptc-C4d is a dynamic 'etiologic' marker for active antibody-mediated rejection, isolated strong GBM-C4d can highlight architectural glomerular remodelling.
Collapse
Affiliation(s)
- Adil H Gasim
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Jamie S Chua
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.,Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ron Wolterbeek
- Department of Medical Statistics and Bio-Informatics, Leiden University Medical Center, Leiden, The Netherlands
| | - John Schmitz
- Department of Pathology and Laboratory Medicine, McLendon Clinical Laboratories, The University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Eric Weimer
- Department of Pathology and Laboratory Medicine, McLendon Clinical Laboratories, The University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Harsharan K Singh
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Volker Nickeleit
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC, USA
| |
Collapse
|
|
46
|
Go H, Shin S, Kim YH, Han DJ, Cho YM. Refinement of the criteria for ultrastructural peritubular capillary basement membrane multilayering in the diagnosis of chronic active/acute antibody-mediated rejection. Transpl Int 2017; 30:398-409. [PMID: 28109026 DOI: 10.1111/tri.12921] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/06/2016] [Accepted: 01/12/2017] [Indexed: 12/17/2022]
Abstract
Chronic active/acute antibody-mediated rejection (cABMR) is the main cause of late renal allograft loss. Severe peritubular capillary basement membrane multilayering (PTCML) assessed on electron microscopy is one diagnostic feature of cABMR according to the Banff 2013 classification. We aimed to refine the PTCML criteria for an earlier diagnosis of cABMR. We retrospectively investigated ultrastructural features of 159 consecutive renal allografts and 44 nonallografts. The presence of serum donor-specific antibodies at the time of biopsy of allografts was also examined. Forty-three patients (27.0%) fulfilled the criteria of cABMR, regardless of PTCML, and comprised the cABMR group. Forty-one patients (25.8%) did not exhibit cABMR features and comprised the non-cABMR allograft control group. In addition, 15 zero-day wedge resections and 29 native kidney biopsies comprised the nonallograft control group. When the diagnostic accuracies of various PTCML features were assessed using the cABMR and non-cABMR allograft control groups, ≥4 PTCML, either circumferential or partial, in ≥2 peritubular capillaries of the three most affected capillaries exhibited the highest AUC value (0.885), greater than the Banff 2013 classification (0.640). None of the nonallograft control groups exhibited PTCML features. We suggest that ≥4 PTCML in ≥2 peritubular capillaries of the three most affected cortical capillaries represents the proper cutoff for cABMR.
Collapse
Affiliation(s)
- Heounjeong Go
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung Shin
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Hoon Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Duck Jong Han
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yong Mee Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| |
Collapse
|
|
47
|
Katsuma A, Yamakawa T, Nakada Y, Yamamoto I, Yokoo T. Histopathological findings in transplanted kidneys. RENAL REPLACEMENT THERAPY 2017. [DOI: 10.1186/s41100-016-0089-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
|
|
48
|
Halloran PF, Famulski KS, Chang J. A Probabilistic Approach to Histologic Diagnosis of Antibody-Mediated Rejection in Kidney Transplant Biopsies. Am J Transplant 2017; 17:129-139. [PMID: 27340822 DOI: 10.1111/ajt.13934] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 06/07/2016] [Accepted: 06/08/2016] [Indexed: 01/25/2023]
Abstract
Histologic diagnosis of antibody-mediated rejection (ABMR) in kidney transplant biopsies uses lesion score cutoffs such as 0 versus >0 rather than actual scores and requires donor-specific antibody (DSA); however, cutoffs lose information, and DSA is not always reliable. Using microarray-derived molecular ABMR scores as a histology-independent estimate of ABMR in 703 biopsies, we reassessed criteria for ABMR to determine relative importance of various lesions, the utility of equations using actual scores rather than cutoffs, and the potential for diagnosing ABMR when DSA is unknown or negative. We confirmed that the important features for ABMR diagnosis were peritubular capillaritis (ptc), glomerulitis (g), glomerular double contours, DSA and C4d staining, but we questioned some features: arterial fibrosis, vasculitis, acute tubular injury, and sum of ptc+g scores. Regression equations using lesion scores predicted molecular ABMR more accurately than score cutoffs (area under the curve 0.85-0.86 vs. 0.75). DSA positivity improved accuracy, but regression equations predicted ABMR with moderate accuracy when DSA was unknown. Some biopsies without detectable DSA had high probability of ABMR by regression, although most had HLA antibody. We concluded that regression equations using lesion scores plus DSA maximized diagnostic accuracy and can estimate probable ABMR when DSA is unknown or undetectable.
Collapse
Affiliation(s)
- P F Halloran
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada.,Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, AB, Canada
| | - K S Famulski
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada.,Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - J Chang
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada
| |
Collapse
|
|
49
|
Verghese PS, Reed RC, Lihong B, Matas AJ, Kim Y. The clinical implications of the unique glomerular complement deposition pattern in transplant glomerulopathy. J Nephrol 2016; 31:157-164. [PMID: 27848227 DOI: 10.1007/s40620-016-0365-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 11/05/2016] [Indexed: 11/25/2022]
Abstract
The etiology and treatment of transplant glomerulopathy (TG) is not clear. TG is associated with donor-specific antibodies but the lack of C4d deposition in the peritubular capillaries (ptc-C4d) in some cases has caused the role of complement in the pathogenesis of TG to be debated. There is however, little information on C4d deposition in the glomerulus itself. We retrieved random frozen sections from 25 cases with well-established TG by light microscopy (LM) and 25 cases without TG as controls and reviewed the LM and immunofluorescence (nine biopsies were excluded due to inadequate samples). Glomerular complement deposition was assessed in all included biopsies. Glomerular C3d and C4d deposition occurred in a distinct pattern in all TG biopsies: segmental or global double linear staining of the glomerular capillary wall in 23 (100%). This pattern was not present in any NON-TG biopsies. The distinct glomerular complement deposition patterns in all TG cases are suggestive that TG is a proximal complement-mediated process and therapies should focus on proximal complement inhibition.
Collapse
Affiliation(s)
- Priya S Verghese
- Division of Pediatric Nephrology, University of Minnesota, Minneapolis, USA.
| | - Robin C Reed
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, USA
| | - Bu Lihong
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, USA
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, USA
| | - Youngki Kim
- Division of Pediatric Nephrology, University of Minnesota, Minneapolis, USA
| |
Collapse
|
|
50
|
Abstract
This review paper discusses the impact of de novo donor-specific antibodies (DSA) to donor HLA antigens in kidney transplantation and summarizes the benefits and challenges that exist with DSA monitoring. Post-transplant DSA is associated with worse allograft outcomes and its detection may precede or coincide with clinical, biochemical, and histologic allograft dysfunction. There are no absolute features of DSA testing results that perfectly discriminate between states of disease and health. In a state of antibody-associated graft dysfunction, removal or reduction in DSA may only provide clinical benefit for some. Furthermore, various factors influence test results, and detection of HLA antibodies must be interpreted within the appropriate clinical and laboratory context. The utility of DSA monitoring is further affected by the limited effectiveness of treatment for antibody-mediated rejection. Although DSA monitoring is potentially beneficial in some circumstances, the optimal screening and treatment strategies are still to be defined.
Collapse
|