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Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: the 2019 Expert Consensus From the Transplant Society Working Group

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Abstract and Figures

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low level evidence. The number of prospective randomized trials for the treatment of AMR is small and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated.At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes and outcomes were discussed. The evidence for different treatments was reviewed and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented.Whilst it was agreed that the aims of treatment are to preserve renal function, reduce histological injury and reduce the titer of donor specific antibody (DSA), there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.
Transplantation May 2020 Volume 104 Number 5 www.transplantjournal.com 911
Received 7 October 2019. Revision received 20 November 2019.
Accepted 3 December 2019.
C.A.S. and R.B.M. are equal first author.
1 Mayo Clinic William J. von Liebig Center for Transplantation and Clinical
Regeneration, Mayo Clinic, Rochester, MN.
2 Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL.
3 Department of Nephrology and Medical Intensive Care, Charité
Universitätsmedizin Berlin, Berlin, Germany.
4 Section of Transplantation, Department of Surgery, The University of Chicago,
Chicago, IL.
5 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical
Center, Los Angeles, CA.
Recommended Treatment for Antibody-mediated
Rejection After Kidney Transplantation: The 2019
Expert Consensus From the Transplantion Society
Working Group
Carrie A. Schinstock, MD,1 Roslyn B. Mannon, MD,2 Klemens Budde, MD,3 Anita S. Chong, PhD,4
Mark Haas, MD,5 Stuart Knechtle, MD,6 Carmen Lefaucheur, MD, PhD,7 Robert A. Montgomery, MD,8
Peter Nickerson, MD,9 Stefan G. Tullius, MD, PhD,10 Curie Ahn, MD, PhD,11,12 Medhat Askar, MD, PhD,13
Marta Crespo, MD, PhD,14 Steven J. Chadban, PhD,15 Sandy Feng, MD, PhD,16 Stanley C. Jordan, MD,17
Kwan Man, PhD,18 Michael Mengel, MD,19 Randall E. Morris, MD,20 Inish O’Doherty, PhD,21
Binnaz H. Ozdemir, MD, PhD,22 Daniel Seron, MD, PhD,23 Anat R. Tambur, PhD,24 Kazunari Tanabe, MD, PhD,25
Jean-Luc Taupin, PhD,26,27 and Philip J. O’Connell, PhD28
INTRODUCTION
Despite modern immunosuppression, ongoing kidney
injury and graft loss due to alloantibody-induced immu-
nity remains an important issue.1-4 Driving this response
are polymorphic HLA antigens. While the impact of
antibodies to HLA on kidney allograft survival has been
known for some time, only recently, with the advent of
sensitive solid-phase assays to detect donor-specic anti-
HLA antibodies (DSA) and the development of the Banff
diagnostic criteria for antibody-mediated rejection (AMR),
has the size of the problem been realized. By 10 years, after
kidney transplant, up to 25% have developed de novo
DSA (dnDSA).5 Thus, it is not surprising that AMR was
the most common cause of allograft failure in a cohort of
Review
Abstract. With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histo-
logical classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of
kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The
number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard
for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society
convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and
chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be
evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes
were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of
care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are
to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive
evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion.
It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed
to improve patient outcomes.
(Transplantation 2020;104: 911–922).
6 Duke Transplant Center, Department of Surgery, Duke University School of
Medicine, Durham, NC.
7 Université de Paris, Department of Transplantation, Saint Louis Hospital, Paris,
France.
8 NYU Langone Transplant Institute, New York, NY.
9 Transplant Immunology Laboratory, Shared Health and Rady Faculty of Health
Sciences, University of Manitoba, Winnipeg, MB, Canada.
10 Division of Transplant Surgery and Transplant Surgery Research Laboratory,
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
11 Transplantation Center, Seoul National University Hospital, Seoul, Korea.
12 Department of Internal Medicine, Seoul National University College of
Medicine, Seoul, Korea.
912 Transplantation May 2020 Volume 104 Number 5 www.transplantjournal.com
renal transplant recipients with indication biopsies before
graft failure.3 Moreover, in a multicenter cohort study,
antibody-mediated damage caused allograft dysfunction
late posttransplant in nearly 60% of renal transplant
recipients.4
Given the scope and severity of the problem, it is
unfortunate that there are no commonly accepted guide-
lines for treatment. To date, clinical trials of AMR have
been small or inconclusive, and there are no Federal
Drug Administration (FDA)-approved therapies for the
prevention and treatment of the condition.6 The lack of
an accepted common standard for the treatment of AMR
has been an impediment to the development of new ther-
apies because it is difcult for industry to initiate phase
2 and 3 clinical trials for novel treatments or preven-
tion of AMR. To overcome this lack of evidence-based
guidelines, The Transplantation Society brought together
a group of experts from around the globe for a 1.5-day
meeting, with the aim of producing a consensus docu-
ment that outlined recommended treatments for active
and chronic active AMR, based on the best available evi-
dence. This publication is a summary of that meeting and
includes up-to-date information about the pathogenesis
of the condition, the criteria for diagnosis, prognosis, and
long-term outcome.
BIOLOGY OF THE ALLOIMMUNE RESPONSE
A general appreciation of the complex immunologic
processes underlying antibody production in immuno-
logically naive and presensitized individuals is central to
understanding the varied presentations of AMR and poten-
tial treatment options (Figure1). In alloimmune naive indi-
viduals, the generation of antibody-secreting cells follows
a scripted series of checkpoint events, starting with the
initial encounter of alloantigen with B cells expressing the
appropriate B-cell antigen receptor. This event activates
B-cell migration to the T- and B-cell interface in the lymph
node, where it receives help from alloreactive T cells that
encountered alloantigen presented indirectly on recipient
dendritic cells. Some of B cells differentiate into memory
B cells or short-lived plasmablasts, while the rest enter
into germinal centers to emerge as high-afnity and class-
switched memory B cells, plasmablasts, and long-lived
plasma cells.7,8 In the context of transplantation, presen-
sitized individuals have a robust long-lived plasma cells
constitutively secreting anti-HLA antibodies and resting
memory B cells primed to secrete large amounts of anti-
body upon antigen reexposure leading to a rapid anamnes-
tic antibody response.
Some features of the alloimmune response complicate
our understanding of DSA production, limiting our ability
13 Baylor University Medical Center, Transplant Immunology, Dallas, TX.
14 Department of Nephrology, Hospital del Mar and Institute Hospital del Mar for
Medical Research, Barcelona, Spain.
15 Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia.
16 Department of Surgery, University of California San Francisco, San Francisco, CA.
17 Comprehensive Transplant Center, Cedars-Sinai Medical Center, West
Hollywood, CA.
18 Department of Surgery, The University of Hong Kong, Hong Kong, People's
Republic of China.
19 Department of Laboratory Medicine and Pathology, University of Alberta,
Edmonton, AB, Canada.
20 Stanford University School of Medicine, Stanford, CA.
21 Critical Path Institute, Tucson, AZ.
22 Department of Pathology, Baskent University, School of Medicine, Ankara, Turkey.
23 Nephrology Department, Hospital Vall d’Hebron, Autonomous University of
Barcelona, Catalonia, Spain.
24 Comprehensive Transplant Center, Northwestern University, Chicago, IL.
25 Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan.
26 Laboratory of Immunology and Histocompatibility, Hôpital Saint-Louis APHP,
Paris, France.
27 INSERM U976 Institut de Recherche Saint-Louis, Université Paris Diderot,
Paris, France.
28 Centre for Transplant and Renal Research, Westmead Institute of Medical
Research, University of Sydney and Renal Unit, Westmead Hospital, NSW,
Australia.
This meeting was organized by The Transplantation Society with the assistance
of an unconditional education grant from CSL Behring. CSL Behring had no
involvement in the development of the program, the choice of speakers, nor in
the writing of the manuscript. The manuscript was written by the authors.
P.J.O. is an advisory board member for CSL Behring, eGenesis, Qihan Biotech,
and Renalytix AI and received research funding from CSL Behring. C.A.S. involved
in current contracts with CSL Bering and negotiating research contracts with
Vitaeris. R.B.M. has received research grants from CSL Behring, Alexion, and
Mallinckrodt and honoraria from Novartis and Hansa. He serves on the Medical
Steering Committee for Vitaeris Imagine Trial. K.B. has received research funds
and honoraria from Abbvie, Alexion, Astellas, Bristol-Meyer Squibb, Chiesi,
CSL, Behring, Fresenius, Genetech, Hexal, Novartis, Otsuka, Pfizer, Roche,
Shire, Siemens, Veloxis, and Vitaeris. M.H. serves as a paid consultant on
pathology adjudication committees for industry-sponsored clinical trials by Shire
ViroPharma and AstraZeneca. He received honoraria for serving as a speaker
and advisor for CareDx and Novartis. M.M. has research funding from Roche
Diagnostics and advisory board membership from Novartis and Vitaeris. C.L.
has a research grant from CSL Behring. R.A.M. served on advisory boards for
Genentech Scientific/ROCHE, Alexion, Novartis, CSL Behring, eGenesis, Sanofi,
Viela Bio, Vitaeris Bio, and Hansa Medical. He received consulting fees or travel
expenses from Alexion, Hansa Medical, CLS Behring, Viela Bio, Vitaeris Bio,
and Shire/Takeda. He received research grants from ViroPharma/Shire, Hansa
Medical, United Therapeutics, and Alexion. P.N. is a consultant for Vitaeris Inc.,
Astellas Pharma, Vielo Bio, Paladin, and Renalytix AI Inc. and received honoraria
from Astellas and Thermo Fisher Scientific.
M.A. is an advisory board member for Immucor. S.J.C. has received travel
support, speakers fees, or advisory board payments from Novartis, Astellas,
Vitaeris, Alexion, and AstraZeneca. S.F. is an advisory board member for
Novartis. S.C.J. is a consultant for CSL Behring, Vitaeris, and Hansa Medical
and has received research grants from CSL Behring, Vitaeris, and Hansa
Medical. I.O. works for the Critical Path Institute that received funding from the
FDA and member companies. D.S. received grants from Astellas, TEVA, and
Chiesi and is an advisory board member for Astellas, Novartis, CSL Behring,
and Vitaeris. A.R.T. is an advisory board member for Astellas and Viela Bio and
is the central lab for HLA testing for an Astellas study. The other authors declare
no conflicts of interest.
P.J.O. proposed and organized the meeting and was primarily responsible
for the development of the program and overall editing of the manuscript.
C.A.S. and R.B.M. delivered presentations at the meeting, were involved in
discussion, and undertook a major role in writing the manuscript. K.B., A.S.C.,
M.H., S.K., C.L., R.A.M., P.N., and S.G.T. were responsible for writing sections
of the manuscript. All other authors either delivered presentations or chaired
sessions, were involved in discussions, and participated in the development of
the consensus. All authors reviewed and edited the manuscript and agreed with
the final document.
Correspondence: Philip J. O’Connell, MBBS, PhD, Centre for Transplant and
Renal Research, Westmead Institute of Medical Research, Westmead, NSW
2145,Australia. (philip.oconnell@sydney.edu.au).
Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. This
is an open-access article distributed under the terms of the Creative Commons
Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it
is permissible to download and share the work provided it is properly cited. The
work cannot be changed in any way or used commercially without permission
from the journal.
ISSN: 0041-1337/20/1045-911
DOI: 10.1097/TP.0000000000003095
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. 913
Schinstock et al
to predict and develop therapeutic approaches for AMR. In
general, memory B cells are derived from B cells with recep-
tors that are less mutated and of lower afnity than those
that are destined to become plasma cells.9-11 As a result, the
repertoire of plasma cells and memory B cells are not iden-
tical. Furthermore, the repertoire of plasma cells and the
antibodies they produce are up to 100-fold more restricted
compared with the repertoire of memory B cells.12 These
differences between memory B cells and plasma cell genera-
tion predict that treatment aiming to prevent plasma cell
generation and subsequent DSA production may not stop
the generation of memory B cells. Likewise, the absence of
DSA does not imply the lack of memory B cells and the
potential for an anamnestic response. Thus, the ability to
quantify donor-specic memory B cells may aid in risk
stratication and treatment of presensitized recipients sus-
ceptible for an active AMR early posttransplant.
The diversity at the level of antibodies presents an
additional challenge. Antibodies have different Fc regions
corresponding to their isotype and subclasses, each with
nonoverlapping functions including their ability to bind
to Fc receptors and activate complement. Less appreci-
ated is heterogeneity in the anti-HLA antibody repertoire,
which comprise antibodies that bind to private specici-
ties on HLA molecules and thus are highly donor specic.
Alternatively, cross-reactive alloantibodies may be donor
reactive but not donor specic, and some may bind mul-
tiple HLA molecules. As a result, the breadth of the circu-
lating antibody with HLA reactivity may not be a direct
readout of the plasma cell repertoire.
DIAGNOSTIC CRITERIA AND HISTOLOGICAL
FEATURES OF AMR
AMR is a clinicopathological diagnosis that was
rst formally described in a 2003 addition to the 1997
International Banff Classication of kidney allograft rejec-
tion13 but has continually evolved with our increased
understanding of AMR particularly with regards to the
relevance of C4d-negative AMR and the utility of molecu-
lar diagnostics. The salient features of active AMR based
on the Banff 2017 classication14 are (1) histological
evidence of graft injury via microvascular inammation
(MVI), intimal or transmural arteritis (v >0), acute throm-
botic microangiopathy in the absence of any other cause,
or acute tubular injury in the absence of any other appar-
ent cause; (2) histological evidence of antibody-endothelial
interactions either by C4d deposition or at least moderate
MVI; and (3) the presence of circulating DSA, predomi-
nantly anti-HLA antibody (Table1). Clearly, the main his-
tological manifestation of active AMR in renal allografts is
MVI in the form of glomerulitis (g) and peritubular capil-
laritis (ptc). The presence of either (g + ptc >0) satises
criterion 1, and a (g + ptc) sum score of ≥2 also satises
criterion 2. The exception is that peritubular capillari-
tis alone is insufcient for diagnosis in the presence of
T-cell–mediated rejection (TCMR), including borderline
rejection. Recurrent or de novo glomerulonephritis must
be considered as a differential diagnosis, especially in the
context of glomerulitis and thrombotic microangiopathy.
To diagnose chronic active AMR, morphological features
of chronic tissue injury are present in addition to crite-
ria 2 and 3 for active AMR. Signs of chronic tissue injury
include transplant glomerulopathy (Banff chronic glomer-
ulitis [cg] score >0), severe peritubular capillary basement
membrane multilayering on electron microscopy, or new
arterial intimal brosis without another obvious cause.
CLINICAL PHENOTYPES OF AMR
The Banff classication has been a major advancement in
the eld of transplantation to increase the awareness of AMR
and standardize denitions. However, a classication schema
based on histological features oversimplies the complexity
of AMR. The Banff classication has 3 AMR diagnostic cat-
egories (including chronic AMR with transplant glomeru-
lopathy and current or prior DSA but no MVI or C4d): the
clinical reality is that AMR is frequently a chronic progres-
sive disease process. This chronic disease process starts with
the formation of DSA. The DSA may or may not lead to
active AMR with histological features that often include but
are not limited to MVI. Moreover, not all active AMR will
progress to chronic active AMR. Over time, chronic histo-
logical features such as transplant glomerulopathy become
evident, and eventually, the patient develops allograft dys-
function, proteinuria, and probable allograft loss. Thus, nd-
ing an active versus chronic active AMR on the biopsy may
be more reective of the timing of the biopsy rather than the
underlying pathological process itself.
Further complicating the diagnosis and management of
AMR are various clinical phenotypes. AMR can present
with abrupt allograft dysfunction early posttransplant but
can also have an insidious or subclinical onset, presenting
later posttransplant. Anti-HLA antibody can also be pre-
sent before transplant (preexisting DSA) or develop after
transplant (dnDSA) in the setting of under-immunosuppres-
sion. In some circumstances, the histological features sug-
gestive of AMR are present, but anti-HLA antibody is not
detected. Incorporating these clinical features of AMR into
the current Banff classication while considering the likely
underlying immunologic mechanisms is critical to appro-
priately guide therapeutic decisions and ultimately design
FIGURE 1. Kinetics of memory B cells and plasma cell generation relative to the germinal center (GC) reaction following transplantation.
Following encounter with alloantigen, activated B cells migrate to the T- and B-cell interface and receive T-cell help. Some of the helped
B cells differentiate into memory B cells or plasma cells, while the rest enter into a germinal center to emerge as high-affinity and class-
switched memory B cells and plasma cells. Memory B cells tend to have low levels of somatic hypermutations and lower B-cell receptor
(BCR) affinity compared with plasma cells, and cells generated pre-GC tend to be of lower affinity than cells generated post-GC.
914 Transplantation May 2020 Volume 104 Number 5 www.transplantjournal.com
efcient and effective therapeutic clinical trials. Therefore,
we recommend considering the timing of presentation, and
type of DSA (preexisting or de novo), in relation to the his-
tological classication as discussed below (Table2).
Early Posttransplant (<30 Days) Active AMR
In patients who have measurable DSA at the time of
kidney transplant or who have an immunologic amnes-
tic response due to previous exposure to allo-HLA, active
AMR can occur within the rst 30 days posttransplant.
The risk of early posttransplant AMR increases with
growing DSA strength or breadth at the time of transplant
as determined by DSA mean uorescence intensity (MFI),
the degree of ow cytometric crossmatch positivity, and
the number or breadth of cross-reactive DSA specici-
ties.15,16 In general, this form of AMR is uncommon, as it
is common practice to avoid allocating kidneys to patients
with known preformed DSA, as early posttransplant AMR
occurs in up to 40% of patients with preformed DSA and
a positive ow cytometric crossmatch.38,39 This aggres-
sive form of active AMR typically presents with an abrupt
increase in DSA accompanied by allograft dysfunction
(increased creatinine and oliguria with or without pro-
teinuria). If not recognized and treated quickly, it can lead
to cortical necrosis and allograft loss within days. From
a histological perspective, the criteria for Banff active
AMR are met and C4d is usually positive.40 There is often
interstitial hemorrhage, glomerular brin thrombi, and
microvascular coagulative necrosis. With prompt diagno-
sis and treatment, patients can recover allograft function
and histological features of active AMR frequently resolve
completely.40,41 In other cases, the histological features of
active AMR persist and chronic active AMR, allograft dys-
function, and ultimate allograft failure ensues.
Late (>30 Days) Posttransplant AMR With
Preexisting DSA
While many patients with preexisting DSA do not
develop an aggressive early AMR as described above, they
can develop an indolent and progressive form of AMR that
is usually initially detected on a surveillance biopsy (in the
setting of stable function) or on a for-cause biopsy for mild
allograft dysfunction.42,43 Histological ndings are depend-
ent on the timing of the biopsy. When detected early, MVI
in glomeruli and peritubular capillaries is the predominant
nding and C4d staining may or may not be present. MVI
tends to persist and is later accompanied by chronic his-
tological features including transplant glomerulopathy and
peritubular basement membrane multilayering.17,44,45 At
diagnosis, there is often minimal if any reduction in glomer-
ular ltration rate (GFR) or proteinuria even when mild
chronic features are present. Overtime, however, the GFR
declines and the patient becomes proteinuric39 with graft
failure often occurring several years after transplant.18,21 In
an observational prospective cohort study of >100 renal
transplant recipients who underwent surveillance biopsy at
1 year, patients with AMR were the most likely to experi-
ence allograft failure.21 Allograft survival was only 56% at
8 years posttransplant compared with 88% if subclinical
TCMR was present, and 90% if the biopsy was normal.21
Late (>30 Days) AMR Associated With dnDSA
In the current era of sensitive DSA testing and a general
avoidance of preexisting DSA, the most common form of
AMR is associated with dnDSA. In general, dnDSA is a new
DSA detected after >3 months posttransplant in the context of
inadequate immunosuppression which is either due to patient
nonadherence, physician directed, or genetically determined
variability in metabolism of immunosuppressive drugs. This
TABLE 1.
Banff 2017 classification of AMR in renal allografts14
Active AMR All 3 criteria must be met for diagnosis
1 Histological evidence of acute tissue injury, including 1 or more of the following:
(a) Microvascular inflammation (g > 0 or ptc > 0), in the absence of recurrent or de novo glomerulonephritis. In the presence
of acute T-cell–mediated rejection, borderline infiltrate, or infection, ptc >1 alone is not sufficient.
(b) Intimal or transmural arteritis (v > 0)
(c) Acute thrombotic microangiopathy, in the absence of any other cause
(d) Acute tubular injury, in the absence of any other apparent cause
2 Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more the following:
(a) Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d >0 by IHC
on paraffin sections)
(b) At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis,
although in the presence of a T-cell–mediated rejection, borderline infiltrate, or infection, ptc ≥2 alone is not sufficient.
(c) Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with AMR, if thoroughly vali-
dated.
3 Serological evidence of donor-specific antibodies (DSA to HLA or other antigens); C4d staining or expression of validated tran-
scripts/classifiers as noted in criterion 2 may substitute for DSA
Chronic active
AMR
Morphological evidence of chronic tissue injury, including 1 or more the following, plus criteria 2 and 3 for Active AMR:
Transplant glomerulopathy (cg >0) if no evidence of chronic thrombotic microangiopathy or chronic recurrent/de novo glo-
merulonephritis; includes changes evident by electron microscopy alone
Severe peritubular capillary basement membrane multilayering on electron microscopy
Arterial intimal fibrosis of new onset, excluding other causes
AMR, antibody-mediated rejection; cg, chronic glomerulitis; DSA, donor-specific antibody; g, glomerulitis; IHC, immunohistochemistry; ptc, peritubular capillaritis; v, vasculitis score.
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. 915
Schinstock et al
TABLE 2.
Antibody-mediated rejection phenotypes
Timing DSA HistologyaClinical presentation Pathophysiology Prognosis Features associated with reduced allograft survival
Earlya Acute
(<30 days
posttransplant)
Preexisting DSA
(or nonimmuno-
logically naive)
Banff 2017 active AMR
Usually C4d+
Thrombotic microangiopathy
often present
Abrupt allograft dysfunction
correlating with increased
DSA MFI or titer usually
7–10 days posttransplant15
Memory B-cell
response
Graft loss
within
days if not
treated15
Pretransplant crossmatch (+T-AHG-CDC+15 or high-flow cytometric
crossmatch)15
Late (>30 days
posttransplant)
Preexisting DSA Banff 2017 active or
chronic active AMR
May be C4d±
± Allograft dysfunction and
proteinuria
Preexisting plasma
cell response
Graft loss
within
months to
ys16-20
Histological
Banff cg >0 lesion19,21,22
Degree of IFTA23-25
Concomitant TCMR22-24,26,27
Banff cv score >024
C4d positivity28-30
Clinical
Proteinuria19,25,31,32
Allograft dysfunction19,22,24,25,31,33
Ys posttransplant24,25
Patient nonadherence or physician-directed immunosuppression
reduction22,25
DSA characteristics
C1q-positive DSA24,34,35
High DSA MFI or titer and pretransplant crossmatch16,18,31,36,37
Anticlass II DSA17,36
De novo DSA Banff 2017 active or
chronic active AMR
May be C4d±
Concomitant TCMR
often present
± allograft dysfunction and
proteinuria
Under-immuno-
suppression
Graft loss
within
months
to ys
28-30,32
aHyperacute rejection is associated with very high DSA (positive complement-dependent cytotoxicity crossmatch) at the time of transplant and results in graft loss within minutes to hours posttransplant. This type of AMR is virtually nonexistent in the current era and not addressed
in this article.
AMR, antibody-mediated rejection; CDC, complement-dependent cytotoxicity; cg, chronic glomerulitis; cv, chronic vasculopathy; DSA, donor-specific antibody; IFTA, interstitial fibrosis and tubular atrophy; MFI, mean fluorescence intensity; TCMR, T-cell mediated rejection.
916 Transplantation May 2020 Volume 104 Number 5 www.transplantjournal.com
form of AMR often presents with allograft dysfunction and
concomitant or preexisting TCMR.3,46,47 In patients who
have routine surveillance DSA testing or surveillance biopsies,
the presentation can be more indolent and is similar to that
of late posttransplant AMR in patients with preexisting DSA
(subclinical AMR associated with dnDSA).46
Results from 2 recent studies have suggested that AMR
with dnDSA is associated with inferior allograft survival
when compared with AMR from preexisting DSA after
adjusting for clinical, histological, and immunologic char-
acteristics.19,23 Allograft survival was 63% in patients with
preexisting DSA and only 34% in patients with dnDSA
8 years after the rejection diagnosis.19 Despite these nd-
ings, it remains unclear whether it is the dnDSA itself that
is associated with inferior allograft survival or a delay in
AMR diagnosis. Compared with patients with preexisting
DSA, those with dnDSA tend to have increased proteinuria
and increased expression of interferon-γ–inducible, natu-
ral killer cell, and T-cell transcripts at presentation.19
FEATURES ASSOCIATED WITH REDUCED
ALLOGRAFT SURVIVAL IN LATE AMR
(PREEXISTING OR DNDSA)
Although there are differences in the initial presentation of
AMR and pace of clinical deterioration depending on whether
the DSA is formed before the transplant, or is dnDSA, the his-
tological, clinical, and alloantibody features associated with
reduced allograft survival are similar (Table 2). Allograft
histology is key to document the chronicity and extent of
injury. Chronic histological features such as the presence of
transplant glomerulopathy (Banff cg score >0)19,21,22 and the
degree of interstitial brosis and tubular atrophy23-25 are pre-
dictive of allograft failure. Other histological features asso-
ciated with inferior allograft survival include concomitant
TCMR,22-24,26,27 C4d positivity,28-30,48 and vascular lesions
(Banff cv score >0).24 Not surprisingly, clinical factors are
also predictive of outcome including allograft dysfunction
at diagnosis,19,22,24,25,31,49 proteinuria,19,25,31,32 and time of
diagnosis posttransplant.24,25 To illustrate the relevance of
having allograft dysfunction at presentation: time to 50%
graft failure was 3.3 years in patients with allograft dysfunc-
tion versus 8.3 years in patients without allograft dysfunc-
tion among 47 patients with dnDSA.22 Although it is clear
that under-immunosuppression is a major risk factor for
dnDSA, prior studies have also shown that a history of medi-
cation nonadherence is independently associated with infe-
rior allograft survival among patients with dnDSA.22,25,50,51
Lastly, several alloantibody characteristics have been
associated with outcome including the presence of C1q-
positive DSA34,35,52 and anticlass II DSA.17,36 Additionally,
the level or strength of DSA correlates with graft failure
as determined by DSA titer or ow cytometric crossmatch
positivity. Notably, several studies have correlated DSA
titer and MFI with C1q positivity53; thus, it is unclear
whether complement binding characteristics or levels of
alloantibody determine outcomes.
CONSENSUS FOR MEASURING AND MONITORING
OF DSA
Initial Assessment for Anti-HLA DSA
The initial assessment of a renal transplant candidate
involves donor and recipient HLA typing, anti-HLA
antibody screening, and obtaining a history of allosensi-
tizing events (previous transplant, blood transfusion, and
pregnancy) (strength of recommendations and level of evi-
dence 1A).54-56 Molecular HLA typing ideally includes A;
B; C; DRB1; DRB3, 4, 5; DQA1/DQB1; and DPA1/DPB1
(2B). For anti-HLA–sensitized recipients, a high-resolution
level of typing, approaching or even reaching the allelic
level (ie, the so-called “4-digit” typing), should be under-
taken as often as possible on the potential donor, to match
the resolution of the alloantibody identication assays.
The rst-line screening for alloantibody would be with
single-antigen bead (SAB) solid-phase assays (LABScreen
[one Lambda] or LifeScreen [LifeCodes-Immucor]), but
multiantigen beads can also be used (1A). Patients with
no history of allosensitizing events and with negative anti-
HLA antibody testing using single-antigen or multiantigen
bead solid-phase assays are at low risk for AMR.
Monitoring for De Novo DSA
Immunosuppression reduction either as a result of non-
adherence or under physician direction is associated with
development of dnDSA.46,47,51 Monitoring for dnDSA is
recommended in the following settings: immunosuppres-
sion reduction by physician for any reason, known patient
medication nonadherence, or at the time of rejection epi-
sode (T cell or antibody mediated) (2B). The presence of
dnDSA is a general indicator of under-immunosuppression
and signals the need to reevaluate maintenance immu-
nosuppression. Based on the strong relationship between
dnDSA, AMR, and graft loss, transplant patients with
dnDSA should undergo close monitoring of allograft func-
tion19,22,47 (1B). A kidney biopsy is also recommended to
detect T-cell or AMR (clinically evident or subclinical).6
Interpreting Positive DSA Results
The SAB test detecting DSA has been an important
advancement to the eld; however, the test has limitations
that must be identied for correct interpretation. First, the
SAB test has a high coefcient of variation, and thus, the posi-
tive cutoff varies among and within laboratories. In general,
a positive cutoff MFI of 1000–1500 is associated with the
detection of specic anti-HLA antibodies.57 SAB tests are also
prone to interference from external substances, bead satura-
tion, and “shared-epitope” phenomenon, which can lead to a
falsely low MFI.53,58,59 Methods to identify interference and
bead saturation include performing serum dilution or using
ethylenediaminetetraacetic acid. We recommend the routine
use of these methods in the following situations: transplant
candidates/recipients who are not immunologically naive,
unexpected positive crossmatch, or AMR with unexpectedly
low DSA MFI (2B).
Additional DSA Testing for Risk Stratification
All patients with DSA are at some risk for AMR.
Crossmatch testing can be used with SAB testing for AMR
risk stratication. The risks of AMR from highest to low-
est based on crossmatch and SAB-positive testing are the
following: positive complement-dependent cytotoxicity
(CDC) crossmatch, positive ow cytometric crossmatch,
and negative crossmatch.60 Importantly, hyperacute AMR
is also associated with having a positive CDC crossmatch.
Testing to assess the complement binding ability of DSA
(C1q or C3d) is commercially available, and positive results
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. 917
Schinstock et al
are associated with AMR and allograft loss.34,52 However,
C1q and C3d binding positivity is associated with a high
DSA titer.53 It remains unclear whether complement bind-
ing assays outperform antibody titers for AMR risk strati-
cation. For this reason, we do not recommend routine use
of complement binding assays unless it is used as a means
of predicting high strength DSA. Lastly, DSA IgG subclass
testing has been used for research purposes. This testing
has not been thoroughly validated for clinical use and at
the moment cannot be recommended.
AVAILABLE EVIDENCE FOR THE TREATMENT OF
ACTIVE AND CHRONIC ACTIVE AMR
Most reports on the treatment of AMR are small and
include heterogeneous patient populations. These studies
frequently include mixed antibody and TCMRs, do not dif-
ferentiate responses based on the timing of AMR detection,
and make no distinction between dnDSA and preformed
DSA, although all these factors have an impact on out-
come.61 The heterogeneity of available studies makes it dif-
cult to draw meaningful conclusions about treatment effects.
As recommended by guidelines,56 most studies describe the
use of a variable mix of interventions (eg, variable intensity
of plasmapheresis, different doses of intravenous immune
globulins [IVIG], variable use of steroid pulses together with
or without different T-cell–depleting and B-cell–depleting
antibodies). Obviously, these different interventions create a
challenge in the interpretation of treatment effects. As a con-
sequence, treatment studies for AMR are rarely comparable,
and the available evidence is generally of low quality.55,62
Plasma Exchange and IVIG
The primary aims of nearly all therapeutic approaches
for AMR are removing circulating DSA and reducing DSA
production. In this sense, the strongholds for contemporary
treatment of AMR are represented by plasma exchange
(PLEX) and IVIG, although neither of these have FDA
approval. This treatment regimen is most commonly used
to treat active AMR, although frequency, modality, and dos-
ing may vary14,55,56,61,62 (Table 3). On those grounds, the
expert consensus at the FDA Antibody-Mediated Rejection
Workshop in 201767 as well as Kidney Disease: Improving
Global Outcomes (KDIGO) in 201068 was that PLEX and
IVIG could be regarded as a standard of care for acute active
AMR, despite the weakness of evidence in support of efcacy.
In particular, their ability to improve short-term outcomes
has been demonstrated by several studies,65,66,70,71 while
their results on long-term effects remain variable, emphasiz-
ing the need for new alternatives or adjunctive therapy for
the treatment of AMR. In addition, there is a need to better
dene the amount of PLEX and dosing of IVIG.
The rationale for using PLEX and IVIG is to combine
removal of circulating DSA with immunomodulation of the
antigraft immune response and in particular modulation
of the B-cell response. In experimental models, IVIG has
been shown to inhibit B-cell responses by the Fc portion
of the Ig binding the Fc fragment of IgG2b receptor on B
cells, and sialylated IVIG binds CD22, inducing apoptosis
of mature B cells.72 It also functions as a scavenger of acti-
vated complement.72 While PLEX and IVIG have formed
the mainstay of treatment for acute active AMR, the evi-
dence consists largely of case series and poorly controlled
randomized trials. Well-designed clinical trials in this
area have proven difcult. One of the best-designed trials
recruited only 10 patients (5 in each arm) and consisted of
immunoabsorption without IVIG. While all of the patients
receiving immunoabsorption responded to treatment, the
trial was ceased at the rst interim analysis because of 80%
graft loss in the control arm, which suggests that immuno-
absorption was benecial in this setting.71
Complement Inhibitors
Over the last decade, the complement system has
attracted increasing attention as an important contributor
to AMR. Hence, several studies have been undertaken to
evaluate the ability of various complement inhibitors to
prevent and treat AMR. The main goal of using comple-
ment inhibitors is to avoid the downstream damage to the
allograft from DSA.
Eculizumab results in terminal complement blockade
as a monoclonal antibody targeting C5. A single-center
TABLE 3.
Evidence for use of plasma exchange and intravenous immune globulins as SOC in active AMR
Criterion Evidence Reference
Biological rationale Anti-HLA antibodies activate complement and interact with Fc receptors and endothelium.
Removal of anti-HLA Ab via plasma exchange correlates with better clinical response in kidney
transplant recipients.
Intravenous immune globulins have pleiotropic effects including neutralization of antibodies/
cytokines/activated components of complement, effects on B cells, T cells, and Fc receptors.
Akiyoshi et al63
Gelfand64
Benefit in clinical
(observational)
studies
Humoral rejection treated with PE/IVIG results in improved renal function.
The combination PE/IVIG leads to better removal of anti-HLA antibodies and correlates with better
graft survival.
Rocha et al65
Lefaucheur et al66
International
recommendations
FDA 2017 Public workshop: Antibody removal therapies, generally in combination with low- or
high-dose IVIG (immunomodulation) form the SOC in many institutions.
KDIGO 2010: Recommendation for PE and IVIG in association with corticosteroids.
Velidedeoglu et al67
Kasiske et al68
Most used combination
in clinical practice
American Society of Transplantation survey: Most centers utilize a combination of IVIG and plas-
mapheresis for treatment.
The treatment of AMR in kidney transplant recipients: a systematic review.
Burton et al69
Roberts et al55
Ab, antibody; AMR, antibody-mediated rejection; Fc, fragment crystallizable; IVIG, intravenous immune globulins; PE, plasma exchange; FDA, Federal Drug Administration; KDIGO, Kidney Disease:
Improving Global Outcomes; SOC, standard of care.
918 Transplantation May 2020 Volume 104 Number 5 www.transplantjournal.com
study showed that among patients who received positive
crossmatch HLA-incompatible transplants, the incidence
of early active AMR was decreased from approximately
40% in historical controls to 7% among treated patients.
Furthermore, 2 multicenter randomized phase 2 trials con-
rmed the protective effect of eculizumab for preventing
early active AMR in positive crossmatch HLA-incompatible
living73 and deceased74 donor populations. A single-center
small case series has also shown that eculizumab has effec-
tiveness in treating early active AMR that occurs within
the rst month posttransplant.40 Despite these promising
results, long-term follow-up of eculizumab-treated posi-
tive crossmatch patients in a single-center study has shown
that despite prevention of early active AMR, the long-term
incidence of chronic AMR and allograft survival is compa-
rable to historical controls.18,45
Proximal complement inhibition has also been studied
as a therapeutic target. The plasma C1 esterase inhibi-
tors Berinert (CSL Behring) and Cinryze (Takeda/Shire/
ViroPharma) have been tested in 2 pilot studies and indi-
cate a possible improvement in allograft function in kid-
ney recipients with AMR.75,76 An additional clinical trial
evaluating a C1 esterase inhibitor for the treatment of
AMR that is resistant to PLEX and IVIG (NCT03221842)
in renal transplant recipients is ongoing.
Rituximab
Rituximab, a B-cell–depleting agent, was suggested as a
treatment option by KDIGO guidelines.56 Despite its fre-
quent use,69 the evidence is low and 3 small randomized
trials have investigated its utility without demonstrating
a clear benet.55,62,77 A small study in 20 children inves-
tigated the effect of Rituximab compared with standard
of care (pulse steroids) in B-cell–rich rejections (of whom
40% in the control group and 80% in treatment group
had DSA).78 There were no major differences in outcome,
and Rituximab had a reasonable safety prole. However,
small numbers, demographic, and baseline differences as
well as an unclear AMR denition preclude meaningful
conclusions. The second trial was a French prospective,
double-blind, multicenter, randomized study investigating
38 patients with active AMR in the rst year after trans-
plantation. All patients received treatment with steroids,
IVIG, and PLEX and were randomized to either rituxi-
mab or placebo. There was no difference in any outcome
parameter, except side effects.79 More recently, there was a
Spanish prospective, randomized, placebo-controlled, dou-
ble-blinded clinical trial where patients were randomized
to receive IVIG plus Rituximab or IVIG plus saline infu-
sion. Only 50% enrollment was achieved (25 patients),
and at 12 months, there were no differences between treat-
ment and control groups in estimated glomerular ltration
rate decline, level of proteinuria, Banff score on biopsy, or
MFI of the immunodominant DSA.80 In contrast to these
prospective RCTs, several retrospective analyses have sug-
gested some positive effects of rituximab in multimodal
treatment regimens together with steroids, plasmapher-
esis, and high-dose IVIG, especially on patients with vas-
cular AMR.55,62,81 A recent study developed a prognostic
score on the basis of a treatment response to a regimen
with Rituximab in the context of multimodal therapy.
Moreover, a single-center nonrandomized study suggests
that Rituximab as an add-on therapy may prevent DSA
rebound as part of a desensitization protocol in highly
sensitized patients.82 However, optimal doses, number
of treatment cycles, and the effect on patients without
a vascular component remain unclear, as is the need for
Rituximab within a multimodal regimen.83
Imlifidase
Imlidase (Hansa Biopharma AB), an IgG-degrading
enzyme of Streptococcus pyogenes (IdeS), can rapidly
reduce or even eliminate anti-HLA DSA and is undergo-
ing clinical trials in AMR.84 IdeS cleaves human IgG at a
highly specic amino acid sequence within the hinge region
producing Fc and F(ab)2 fragments and effectively block-
ing CDC and antibody-dependent cellular cytotoxicity.85
Although data are lacking for using IdeS in AMR, this
agent has been used safely in highly sensitized individuals
for desensitization. After administration of IdeS, all previ-
ously positive crossmatches became negative and all stud-
ied patients received a transplant.86 Unfortunately within
7–10 days of administration, patients often experience a
rebound in DSA and anti-IdeS antibodies develop after 1
or 2 doses, thereby preventing repeated administrations.
Thus, IdeS will unlikely be an isolated treatment for active
or chronic active AMR, but rather an adjunct to other ther-
apies aiming to reduce DSA in the long term. The unique
feature of this drug is that it permits any highly sensitized
patient to undergo transplantation within hours of a donor
being identied regardless of the crossmatch status.
Antithymocyte Globulin
Since its introduction, antithymocyte globulin (ATG)
or other T-cell–depleting antibodies have been used for
treatment of refractory rejection, vascular rejection, mixed
rejections, and AMR.69,87 Although depleting antibodies
were proposed by KDIGO guidelines as potential treatment
options,56 no benet has been demonstrated for treatment
of pure AMR with T-cell–depleting therapy.55,62,87 No pro-
spective trial with ATG for AMR had been performed, and
a large retrospective series suggests that T-cell depletion in
combination with steroids has no effect on the outcome
in vascular AMR.81 Side effects are well described with
a higher risk of infectious-associated death, particularly
when ATG was combined with B-cell depletion.88
Splenectomy
There are several case series of surgical splenectomy,
splenic embolization, and splenic radiation being used as a
salvage procedure for severe early AMR.89,90 It must be per-
formed rapidly after the onset of early AMR to be effective.
Designing a proper study would be challenging and patients
who have undergone splenectomy are known to be sensi-
tized, have preformed antibody, or have undergone desen-
sitization therapy. Most of these AMR cases occur in the
rst week after transplantation and result in profound graft
dysfunction and a sudden rise in DSA strength, usually from
an anamnestic response. Some patients who recover develop
transplant glomerulopathy and premature graft loss.
Proteasome Inhibitor: Bortezomib
Bortezomib is a proteasome inhibitor approved for
the treatment of multiple myeloma that directly targets
antibody-producing plasma cells making it an attractive
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. 919
Schinstock et al
candidate for the treatment of active AMR.91 Data sup-
porting its use are limited to case series suggesting a posi-
tive effect within a multimodal treatment regimen of
PLEX, IVIG, steroids, and depleting antibodies.55,62,91 The
only prospective randomized, double-blind, placebo-con-
trolled trial was in “late” AMR and did not demonstrate
any benecial effect of bortezomib alone.92 The drug has
well-documented side effects, and at the present time, there
are no trial data to support its use.93
Cyclophosphamide
Cyclophosphamide is used for the treatment of antibody-
mediated diseases such as anti-neutrophil cytoplasmic anti-
body vasculitis or lupus nephritis. Previous anecdotal reports
describe its use within a multimodal treatment regimen for
the treatment of refractory rejections.62,94 While it is rela-
tively inexpensive, there are no trial data to support its use.
Interleukin-6 Inhibitors
A single-center, nonrandomized trial of tocilizumab
(anti-interleukin-6 receptor monoclonal antibody) was
undertaken in 36 patients with chronic active AMR that
had failed IVIG plus rituximab. Patient and graft survival
at 6 years (91% and 80%, respectively) were found to be
superior to historical controls, with signicant reductions
in DSA and stabilization of renal function.95 Partly based
on these encouraging results, a small investigator-initiated
randomized control trial has begun recruitment and a large
multicenter randomized control trial has been initiated to
evaluate Clazakizumab, an anti-interleukin-6 monoclonal
antibody, for the treatment of chronic active AMR.96
CONSENSUS FOR TREATMENT OF EARLY ACTIVE
AMR (≤30 DAYS POSTTRANSPLANT)
The current evidence for treatment options in active
AMR is of limited quality. The consensus view was that
the combination of PLEX, IVIG with corticosteroids could
be regarded as standard of care, consistent with the con-
clusions of the FDA workshop and KDIGO guidelines
(Table4).6,56 However, in some centers, the use of corticos-
teroids is reserved for patients with concompetant TCMR.
While adjunctive therapy with other agents has been used
in specic settings, there have been only 3 (underpow-
ered) prospective randomized trials for treatment of active
AMR.78,79,92 These trials had many limitations, and most
evidence comes from small retrospective studies with dif-
ferent combination therapies using different AMR deni-
tions in different populations.40,55,62,83 Thus, the available
evidence supporting the use of any adjunctive agents is of
low quality with the best evidence relating to drug toxicity
and costs. Nevertheless, these rejections are relatively rare
with a high incidence of graft loss and a randomized clini-
cal trial would be difcult to achieve. Hence, in the absence
of trial data, the consensus was that adjunctive therapy
may be warranted especially when the risk of graft loss
is considered high. The recommended adjunctive therapies
include complement inhibitors, rituximab, or splenectomy
depending on availability (Table 4). Where concomitant
TCMR is present, it should be treated.
CONSENSUS FOR TREATMENT OF LATE
ACTIVE AND CHRONIC ACTIVE AMR (≥30 DAYS
POSTTRANSPLANT)
Preexisting DSA
As described above, the transition from active to chronic
active AMR should be considered a continuum, and the
DSA may have been present at the time of transplant or
appear de novo. Among patients with known preexisting
DSA and active AMR without chronic features, the con-
sensus treatment recommendations include PLEX, IVIG,
and corticosteroids.
TABLE 4.
Consensus treatment recommendations based on available evidence and expert opinion
Timing DSA
Histology
(Banff 2017) Standard of careaConsider adjunctive
therapies
Earlya Acute
(<30 days
posttransplant)
Preexisting DSA (or
nonimmunologi-
cally naive)
Active AMR Plasmapheresis (daily or alternative day × 6 based on
DSA titer) (1C)b
IVIG 100 mg/kg after each plasmapheresis treatment or
IVIG 2 g/kg at end of plasmapheresis treatments (1C)
Corticosteroids (EO)
Complement inhibitors (2B)
Rituximab 375 mg/m2 (2B)
Splenectomy (3C)
Late (>30 days
posttransplant)
Preexisting DSA Active AMR Plasmapheresis (daily or alternative day × 4–6 based on
DSA titer) (2C)b
IVIG 100 mg/kg after each plasmapheresis treatment or
IVIG 2 g/kg at end of plasmapheresis treatments (2C)
Corticosteroids (EO)
Rituximab 375 mg/m2 (2B)
Chronic AMR Optimize baseline immunosuppression (eg, add steroids if
on a steroid-free regimen) (1C)
IVIG (3C)
De novo DSA Active AMR Optimize baseline immunosuppression (eg, add steroids if
on a steroid-free regimen) (1C)
Evaluate and manage nonadherence
Plasmapheresis and IVIG (3C)
Rituximab (3C)
Chronic AMR IVIG (3C)
aFor all cases, treatment of concomitant T-cell–mediated rejection (≥borderline) and optimizing immunosuppression is recommended. Optimizing immunosuppression includes the use of tacrolimus
with goal trough of >5 and use of maintenance steroid equivalent to prednisone 5 mg daily.
bFresh-frozen plasma to be used for replacement fluid for plasmapheresis if a biopsy was performed within 24–48 h. The codes for grades of evidence have been taken from KDIGO.54,56
AMR, antibody-mediated rejection; DSA, donor-specific antibody; EO, expert opinion; IVIG, intravenous immune globulins; KDIGO, Kidney Disease: Improving Global Outcomes.
920 Transplantation May 2020 Volume 104 Number 5 www.transplantjournal.com
In cases of chronic active AMR or chronic transplant
vasculopathy, goals of therapy should be to stabilize or
reduce the rate of decline in GFR, proteinuria, histological
injury score, and titer of DSA while minimizing drug toxic-
ity. The use of IVIG and PLEX, with or without Rituximab,
has not been shown to improve outcomes in patients with
chronic active AMR (as distinct from acute active AMR)
and has to be balanced against increased risk of adverse
events such as infection and cost. The consensus opinion
was that treatment should focus on optimizing immuno-
suppression and supportive care, with reintroduction of
steroids (if on a steroid-free regimen), maintaining trough
tacrolimus levels >5 ng/mL, and optimizing medical man-
agement with focus on blood pressure, blood glucose, and
lipid control.
De Novo DSA
dnDSA generally occurs in the context of reduced immu-
nosuppression whether from patient nonadherence or a
physician-directed change in immunosuppression. AMR in
this setting is also often initially detected with concomi-
tant TCMR. Therefore, the standard for managing AMR
in this setting (active or chronic active) is to optimize base-
line immunosuppression and manage potential medica-
tion nonadherence. Treatment of concomitant TCMR is
recommended in all cases of AMR but is particularly rel-
evant in these cases. Similar to patients with chronic active
AMR in the context of preexisting antibodies, treatment
with PLEX, IVIG, and Rituximab is used in some centers,
although the evidence level (3C) is low.
CONCLUSIONS
Despite the severity of the problem and poor outcomes
for patients who develop AMR, there is very little high-
level evidence to support the use of any therapy. Most
trials in this area have been small investigator-initiated
studies with small numbers of participants, lacking appro-
priate controls. As a result, there were no clear treatment
regimens to recommend and there are no approved treat-
ments. The consensus opinion of those present at the meet-
ing was based largely on observational studies, low-level
evidence, and expert opinion. Despite the clear lack of evi-
dence, it was considered important to dene a standard of
care for AMR, which could be used as a benchmark for
future studies and prospective trials. It is obvious that new
agents and clinical trials are needed urgently. Future direc-
tions in this eld will require new trial designs and large
transnational trial consortia to undertake these studies.97
In addition, better characterization of the different forms
of AMR based on pathophysiology, histology, as well as
clinical and genetic phenotypes is needed.
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... 13 These changes in Fc glycosylation are correlated with disease activity 7,14 and precede disease recurrence. 15,16 The role of DSA glycosylation in the incidence of ABMR has been poorly investigated to date. ...
... 2,4,5 A decrease in IgG sialylation has been associated with the severity and the risk of relapse in various auto-immune diseases such as in SLE or ANCA vasculitis. 10,15,29,48 In our study, IgG1 hypogalactosylation, high bisecting-GlcNAc IgG3 and IgG3 hyposialylation of DSA were independent factors associated with ABMR risk. As previously demonstrated in autoimmune disease, we confirmed that the proinflammatory profile of Fc glycosylation also plays a major role in alloimmune response. ...
... La survie des greffons à 8 ans était à 88% pour les patients avec rejet cellulaire sans ABMR, à 90% pour les patients ayant une biopsie normale mais seulement à 56% pour les patients présentant un ABMR infraclinique. 14 Les ABMR infra-cliniques affectent très significativement la survie des greffons rénaux à long terme.Plus récemment une classification phénotypique de l'ABMR a été proposée en fonction du délai de survenue post-transplantation, du type de DSA (préformés ou de novo) et de la classification histologique de BANFF dans le but de guider la stratégie thérapeutique.15 Cette Un ABMR précoce peut survenir chez les patients présentant des DSA détectables le jour de la greffe (DSA préformés) ou des DSA historiques liés à une exposition préalable aux antigènes HLA lors de transfusions, de grossesses ou de transplantations antérieures. ...
Thesis
Le rejet à médiation humorale (ABMR) est aujourd’hui reconnu comme la première cause de perte du greffon rénal au-delà de la première année. Les anticorps anti-HLA spécifiques du donneur de novo (DSAdn) sont le facteur de risque principal d’ABMR après transplantation rénale. Ils sont au centre des mécanismes physiopathologiques impliqués au cours de cette pathologie. Cependant, l’évolution clinique après la détection d’un DSAdn est extrêmement hétérogène suggérant que tous n’ont pas la même pathogénicité. Plusieurs caractéristiques des DSAdn ont été identifiées comme étant associées à un risque plus élevé d’ABMR ou de perte du greffon comme la « force » des anticorps (évaluée par la MFI au test Luminex Single Antigen), leur capacité à fixer et activer la voie classique du complément et la détection d’une sous-classe IgG3. Dans ce travail de thèse, j’ai étudié le rôle de la répartition des différentes sous-classe IgG et du profil de glycosylation des DSA au cours de l’ABMR, grâce à la mise au point d’une technique innovante basée sur la spectrométrie de masse.Dans la première partie de ce travail, nous avons mis en évidence que les DSA étaient toujours composés des quatre sous-classes d’IgG mais avec une répartition variable selon les patients. La distribution des sous-classes des DSA était différente de celle des IgG totales avec plus d’IgG1, plus d’IgG3, plus d’IgG4 mais moins d’IgG2. Une proportion élevée d’IgG3 (>6.4%) était significativement associée à la présence d’un ABMR, à la sévérité histologique de l’ABMR avec plus de dépôts de complément et plus d’inflammation de la microcirculation (glomérulite et capillarite péri-tubulaire) et au déclin du débit de filtration glomérulaire, indépendamment des autres caractéristiques du DSA, en particulier de la valeur de MFI.Dans la deuxième partie de ce travail, nous avons montré pour la première fois une association entre le profil de glycosylation des DSA et le risque d’ABMR. Le groupe de patients présentant un ABMR avaient des DSA dont les sous-classes IgG1 et IgG3 exhibaient un profil de glycosylation pro-inflammatoire associant une plus faible galactosylation des IgG1, une plus faible sialylation des IgG3 et une proportion plus élevée de GlcNAc en position bissectrice. L’hyposialylation des IgG3 semble un facteur prometteur pour prédire du risque d’ABMR. Ces résultats ouvrent aussi potentiellement la voie à de nouvelles stratégies thérapeutiques qui sont particulièrement attendues, l’efficacité des thérapeutiques utilisées actuellement étant souvent décevante.
... Treatment of ABMR relies mainly on retrospective studies and empirical treatment guidelines [367]. Consensus is that it is important to classify the clinical and histological phenotype of the rejection in order to make adequate treatment decisions [367]. ...
... Treatment of ABMR relies mainly on retrospective studies and empirical treatment guidelines [367]. Consensus is that it is important to classify the clinical and histological phenotype of the rejection in order to make adequate treatment decisions [367]. Important clinical factors are time of rejection (early acute < 30 days post-transplant vs. late), preformed vs. de novo donor-specific antibodies (DSA), and histology (active vs. chronic rejection). ...
... Moreover, in the context of AMR HLA-DSA after kidney transplantation were measured with various cut-offs. 12,13 Interestingly, most previous studies analyzing the impact of HLA antibodies on transplantation outcome did not consider cumulative MFI values. The pretransplant HLA antibody status is still an important issue because the percentage of HLA antibody positive immunized kidney transplant candidates is increasing on the waiting lists and there is an emerging need to serve these patients adequately. ...
Article
Full-text available
It is still not fully elucidated which pretransplant donor‐specific human leukocyte antigen (HLA) antibodies (DSA) are harmful after kidney transplantation. In particular, it needs to be clarified whether cumulative mean fluorescence intensities (MFI) against multiple HLA specificities have a predictive value for allograft function. Our retrospective single centre study analysed preformed HLA antibodies determined by Luminex™ Single Antigen Bead (SAB) assay, including C1q addition, in relation to rejection and clinical outcome in 255 cross match negative kidney allograft recipients. Only 33 recipients (13%) of the total cohort showed early AMR during the first year posttransplant, but in patients with pre‐transplant DSA the rate was increased to 15 out of 40 (38%). Three year graft survival was significantly shorter in patients with histological signs of AMR compared to patients without AMR or with no biopsy (74%, 92% and 97%, respectively, p<0.0001). In patients with HLA‐DSA, a cumulative MFI value of all HLA antibodies of more than 103.000 indicated the highest risk for AMR posttransplant (p=0.01). In conclusion, in patients with HLA‐DSA, the cumulative MFI value may help to further stratify the risk of AMR after kidney transplantation. This article is protected by copyright. All rights reserved.
... At this moment, the immunological risk evaluation of KT recipients is based on the alloimmunity and anti-HLA antibody evaluation [100,101]. ABMR due to anti-HLA antibodies benefits from some evidence regarding evaluation and treatment, and new randomized clinical trials testing molecules such as interleukin-6 antagonism, CD38-targeting antibodies and selective complement inhibitors are in progress [100,102]. However, it is quite clear that the immunological risk assessment focused only on anti-HLA donor-specific antibodies is insufficient. ...
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Full-text available
The polymorphic human leukocyte antigen (HLA) system has been considered the main target for alloimmunity, but the non-HLA antibodies and autoimmunity have gained importance in kidney transplantation (KT). Apart from the endothelial injury, secondary self-antigen exposure and the presence of polymorphic alloantigens, respectively, auto- and allo- non-HLA antibodies shared common steps in their development, such as: antigen recognition via indirect pathway by recipient antigen presenting cells, autoreactive T cell activation, autoreactive B cell activation, T helper 17 cell differentiation, loss of self-tolerance and epitope spreading phenomena. Both alloimmunity and autoimmunity play a synergic role in the formation of non-HLA antibodies, and the emergence of transcriptomics and genome-wide evaluation techniques has led to important progress in understanding the mechanistic features. Among them, non-HLA mismatches between donors and recipients provide valuable information regarding the role of genetics in non-HLA antibody immunity and development.
Chapter
During its lifetime, the renal allograft is at continuous risk for the development of rejection due to HLA and non-HLA incompatibility with the recipient which is why lifelong immunosuppressive therapy is required. The goal of immunosuppressive therapy posttransplantation in pediatric renal transplant recipients is to prevent acute and chronic rejection and support adherence while minimizing drug side effects and infectious complications. Most therapies alter immune response mechanisms but are not immunologically specific, and a careful balance is required to find the dose that prevents rejection of the graft, while minimizing the risks of over-immunosuppression leading to increased morbidity and mortality from infection and cancer. Although data from adult renal transplantation trials are used to help guide management decisions in pediatric patients, immunosuppressive therapy in pediatric renal transplant recipients is often modified due to the unique dosage requirements and clinical effects of these agents on the growth and development of children, who are less likely to have had prior exposure to pathogens. The optimal immunosuppressive therapy posttransplant has to be individualized to patient characteristics, and ideally should be titrated to the specific immune-risk thresholds of the recipient and to minimize any negative impact on growth. Evaluation of risk factors involves a comprehensive evaluation of clinical, biopsy, HLA mismatch, and viral findings, and the potential for recurrence of certain primary renal diseases such as lupus nephritis or focal segmental glomerular sclerosis. Allograft survival rates vary among the various immunosuppressive agents due to patient-specific clinical characteristics, such as age, obesity, ethnicity, hyperlipidemia, arterial hypertension, proteinuria and/or delayed allograft function. The “one size fits all” strategy needs to evolve into tailored strategies based upon a child’s medical history and circumstances.
Article
Objective Antibodies against donor human leukocyte antigen are a risk factor for chronic immune injury (CII) following renal transplantation; however, it is often not detectable. The main goal of this study is to gain new insights into the kinetics of exosome release and content in sensitized vs non-sensitized recipients. Towards this, we investigated the role for circulating exosomes with allo and self-antigens as well as immunoregulatory molecules in the development of CII and acute rejection. Methods Using murine kidney allograft rejection models, we investigated the role of exosomes on immune responses leading to allo- and auto-immunity to self-antigens resulting in rejection. Exosomes were analyzed for kidney self-antigens (Collagen-IV, fibronectin, angiotensin II receptor type 1), and immune-regulatory molecules (PD-L1, CD73) using western blot. Antibodies to donor MHC in serum samples were detected by immunofluorescence, self-antigens by enzyme-linked immunosorbent assay and kidney tissue infiltrating cells were determined by immunohistochemistry. Results BALB/c; H2d to C57BL/6; H2b renal transplantation (BALB/c), resulted in tubulitis and cellular infiltration by day 14, suggestive of acute inflammation, that was self-limiting with functioning graft. This contributed to CII on post-transplant day >100, which was preceded by induction of exosomes with donor and self-antigens leading to antibodies and immune-regulatory molecules. The absence of acute rejection in this allogenic transplant model is likely due to the induction of splenic and, graft-infiltrating CD4 + FoxP3+ T regulatory cells. In contrast, prior sensitization by skin graft followed by kidney transplantation induced antibodies to MHC and self-antigens leading to acute rejection. Conclusion We demonstrate a pivotal role for induction of exosomes with immune-regulatory molecules, allo- and auto-immunity to self-antigens leading to chronic immune injury following murine kidney transplantation.
Article
Background: Blockade of interleukin-6 (IL-6) has emerged as a promising therapeutic option for antibody-mediated rejection. Subtherapeutic anti-IL-6 antibody level or treatment cessation following prolonged cytokine neutralization may result in proinflammatory rebound phenomena via accumulation of IL-6 and/or modulated gene expression of major components of the IL-6/IL-6 receptor (IL-6R) axis. Methods: We evaluated biologic material obtained from a randomized controlled, double-blind phase 2 trial designed to evaluate the safety and efficacy of the anti-IL-6 monoclonal antibody clazakizumab in late antibody-mediated rejection. Twenty kidney transplant recipients, allocated to clazakizumab or placebo, received 4-weekly doses over 12 wks, followed by a 40-wk extension where all recipients received clazakizumab. Serum proteins were detected using bead-based immunoassays and RNA transcripts using quantitative real-time polymerase chain reaction (peripheral blood) or microarray analysis (serial allograft biopsies). Results: Clazakizumab treatment resulted in a substantial increase in median total (bound and unbound to drug) serum IL-6 level (1.4, 8015, and 13 600 pg/mL at 0, 12, and 52 wks), but median level of free (unbound to drug) IL-6 did not increase (3.0, 2.3, and 2.3 pg/mL, respectively). Neutralization of IL-6 did not boost soluble IL-6R or leukocyte or allograft expression of IL-6, IL-6R, and glycoprotein 130 mRNA. Cessation of treatment at the end of the trial did not result in a meaningful increase in C-reactive protein or accelerated progression of graft dysfunction during 12 mo of follow-up. Conclusion: Our results argue against clinically relevant rebound phenomena and modulation of major components of the IL-6/IL-6R axis following prolonged IL-6 neutralization with clazakizumab.
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Purpose of review: Antibody-mediated rejection (AMR) has emerged as the leading cause of late graft loss in kidney transplant recipients. Donor-specific antibodies are an independent risk factor for AMR and graft loss. However, not all donor-specific antibodies are pathogenic. AMR treatment is heterogeneous due to the lack of robust trials to support clinical decisions. This review provides an overview and comments on practical but relevant dilemmas physicians experience in managing kidney transplant recipients with AMR. Recent findings: Active AMR with donor-specific antibodies may be treated with plasmapheresis, intravenous immunoglobulin and corticosteroids with additional therapies considered on a case-by-case basis. On the contrary, no treatment has been shown to be effective against chronic active AMR. Various biomarkers and prediction models to assess the individual risk of graft failure and response to rejection treatment show promise. Summary: The ability to personalize management for a given kidney transplant recipient and identify treatments that will improve their long-term outcome remains a critical unmet need. Earlier identification of AMR with noninvasive biomarkers and prediction models to assess the individual risk of graft failure should be considered. Enrolling patients with AMR in clinical trials to assess novel therapeutic agents is highly encouraged.
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Chronic active antibody-mediated rejection is the leading cause of kidney transplant failure. Although various immunosuppressive agents have been tested, rituximab included, presently there is no effective treatment. There are reports about the beneficial role of certain immunosuppressive protocols that include rituximab to reduce donor-specific antibodies, the cause of chronic active antibody-mediated rejection. If an immunosuppressive agent reduces donor-specific antibodies, its administration before the occurrence of chronic active antibody-mediated rejection may be beneficial. We describe a case of a renaltransplantrecipient with recurrent membranous nephropathy and recent development of donor-specific antibodies but without histological evidence of active antibody-mediated rejection. The patient received 3 weekly doses of rituximab for recurrent membranous nephropathy, and complete remission was achieved. One year after, he has preserved an excellentrenal function without proteinuria. However, repeated measurements of donor-specific antibodies revealed that rituximab only modestly reduced donor-specific antibodies. Donor-specific antibody levels remained considerably higher than the laboratory reference value. Thus,rituximab alone may not have a role to prevent chronic active antibody- mediated rejection in patients with donor-specific antibodies.
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Purpose of review: The present review describes the clinical relevance of human leukocyte antigen (HLA) donor-specific antibodies (HLA-DSAs) as biomarkers of alloimmunity and summarizes recent improvements in their characterization that provide insights into immune risk assessment, precision diagnosis, and prognostication in transplantation. Recent findings: Recent studies have addressed the clinical utility of HLA-DSAs as biomarkers for immune risk assessment in pretransplant and peritransplant, diagnosis and treatment evaluation of antibody-mediated rejection, immune monitoring posttransplant, and risk stratification. Summary: HLA-DSAs have proved to be the most advanced immune biomarkers in solid organ transplantation in terms of analytical validity, clinical validity and clinical utility. Recent studies are integrating multiple HLA-DSA characteristics including antibody specificity, HLA class, quantity, immunoglobulin G subclass, and complement-binding capacity to improve risk assessment peritransplant, diagnosis and treatment evaluation of antibody-mediated rejection, immune monitoring posttransplant, and transplant prognosis evaluation. In addition, integration of HLA-DSAs to clinical, functional and histological transplant parameters has further consolidated the utility of HLA-DSAs as robust biomarkers and allows to build new tools for monitoring, precision diagnosis, and risk stratification for individual patients. However, prospective and randomized-controlled studies addressing the clinical benefit and cost-effectiveness of HLA-DSA-based monitoring and patient management strategies are required to demonstrate that the use of HLA-DSAs as biomarkers can improve current clinical practice and transplant outcomes.
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The presence of preformed donor‐specific antibodies (DSAs) in transplant recipients increases risk of acute antibody‐mediated rejection (AMR). Results of an open‐label, single‐arm trial to evaluate safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased‐donor kidney transplants with preformed DSAs are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion, 900 mg on posttransplantation days 1, 7, 14, 21 and 28, and 1200 mg at weeks 5, 7 and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. Primary end point was treatment failure rate, a composite of biopsy‐proven grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow‐up, within 9 weeks posttransplantation. Eighty patients received transplants (48 women); median age was 52 years (range, 24–70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P < .001). By 9 weeks, 3/80 patients had experienced AMR and 4/80 experienced graft loss. At 36 months, graft and patient survival were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has potential to provide prophylaxis against injury caused by acute AMR in such patients. (EudraCT 2010‐019631‐35). This article is protected by copyright. All rights reserved.
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We report results of a phase 2, randomized, multicenter, open‐label, two‐arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody‐mediated rejection (AMR) in sensitized recipients of living‐donor kidney transplants requiring pretransplantation desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplantation, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplantation treatment failure rate, a composite of: biopsy‐proven acute AMR (Banff 2007 grades II or III; assessed by blinded central pathology); graft loss; death; or loss to follow‐up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living‐donor kidney transplants. (EudraCT 2010‐019630‐28). This article is protected by copyright. All rights reserved.
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Background Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials (RCT) have failed to demonstrate the efficacy of widely used therapies, such as rituximab plus intravenous immunoglobulin or proteasome inhibition (bortezomib), reinforcing a great need for new therapeutic concepts. One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity. Methods This investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR ≥ 365 days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charité University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25 mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4–12), all patients will receive clazakizumab at 25 mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival. Discussion Currently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection. Trial registration ClinicalTrials.gov, NCT03444103. Registered on 23 February 2018 (retrospective registration). Electronic supplementary material The online version of this article (10.1186/s13063-018-3158-6) contains supplementary material, which is available to authorized users.
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We aimed to determine long‐term outcomes for eculizumab‐treated, positive crossmatch (+XM) kidney transplant recipients compared with +XM and age‐matched negative crossmatch (−XM) controls. We performed an observational retrospective study and examined allograft survival, histologic findings, long‐term B‐cell flow cytometric XM (BFXM), and allograft‐loss–associated factors. The mean (SD) posttransplant follow‐up was 6.3 (2.5) years in the eculizumab group; 7.6 (3.5), +XM control group; 7.9 (2.5), −XM control group. Overall and death‐censored allograft survival were similar in +XM groups (P=.73, P=.48) but reduced compared with −XM control patients (P<.001, P<.001). In the eculizumab‐treated group, 57.9% (11/19) of allografts had chronic antibody‐mediated rejection, but death‐censored allograft survival was 76.6%, 5 years; 75.4%, 7 years. Baseline IgG3 positivity and BFXM ≥300 were associated with allograft loss. C1q positivity was also associated with allograft loss but did not reach statistical significance. Donor‐specific antibodies appeared to decrease in eculizumab‐treated patients. After excluding patients with posttransplant plasmapheresis, 42.3% (9/21) had negative BFXMs; 31.8% (7/22), completely negative single‐antigen beads 1 year posttransplant. Eculizumab‐treated +XM patients had reduced allograft survival compared with −XM controls but similar survival to +XM controls. BFXM and complement‐activating DSA (by IgG3 and C1q testing) may be used for risk stratification in +XM transplantation. This article is protected by copyright. All rights reserved.
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Background Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients’ access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations. Methods and findings To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55–3.74, P = 0.001; I² = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05–6.87, P = 0.001; I² = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection. Conclusions In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification. Trial registration National Clinical Trial protocol ID: NCT03438058.
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The presence of pre‐existing (memory) or de novo donor specific HLA antibodies (DSA) is a known barrier to successful long‐term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA varies markedly between centers. A collaborative effort between ASHI and the AST provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as renal, liver, heart and lung transplantation. The goal was to perform a critical review of biologically driven, state‐of‐the‐art, clinical diagnostics literature; and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the STAR (Sensitization in Transplantation: Assessment of Risk) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, as well as highlighted gaps in knowledge are intended to spur research that will inform the next STAR working group meeting in 2019. This article is protected by copyright. All rights reserved.
Article
Background: Active antibody-mediated rejection (AMR) that occurs during the amnestic response within the first month post-transplant is a rare but devastating cause of early allograft loss after kidney transplant. Prior reports of eculizumab treatment for AMR have been in heterogeneous patient groups needing salvage therapy or presenting at varied time points. We investigated the role of Eculizumab as primary therapy for active AMR early post-transplant. Methods: We performed a retrospective observational study of a consecutive cohort of solitary kidney transplant recipients who were transplanted between January 1, 2014 and January 31, 2018 and had AMR within the first 30 days post-transplant and treated with eculizumab ± plasmapheresis. Results: Fifteen patients had early active AMR at a median [IQR] of 10 [7-11] days post-transplant and were treated with eculizumab ± plasmapheresis. Thirteen cases were biopsy proven and 2 cases were presumed based on donor specific antibody trends and allograft function. Within 1 week of treatment the median estimated glomerular filtration rate (eGFR) increased from 21 mL/min to 34 mL/min (P = .001); and persistent active AMR was only found in 16.7% (2/12) of biopsied patients within 4-6 months. No graft losses occurred and at last follow-up (median [IQR] of 13 [12-19] months) the median IQR eGFR increased to 52 (46-60) mL/min. Conclusions: Prompt eculizumab treatment as primary therapy is safe and effective for early active AMR after kidney transplant or abrupt increases in donor-specific antibodies when biopsy cannot be performed for diagnosis confirmation.
Article
We aimed to evaluate patient factors including nonadherence and viral infection and de novo donor specific antibody (dnDSA) characteristics [Total IgG, C1q, IgG3, and IgG4] as predictors of renal allograft failure in a multicenter cohort with dnDSA. We performed a retrospective observational study of 113 kidney transplant recipients with dnDSA and stored sera for analysis. Predictors of death‐censored allograft loss were assessed by Cox‐proportional modeling Death censored allograft survival was 77.0%(87/113) during a median follow‐up of 2.2(IQR 1.2‐3.7) years after dnDSA detection. Predictors of allograft failure included: medication nonadherence [HR 6.5 (95% CI 2.6‐15.9)], prior viral infection requiring immunosuppression reduction [HR 5.3 (95% CI 2.1‐13.5)], IgG3 positivity [HR 3.8(95%CI 1.5, 9.3)], and time post‐transplant (years) until DSA detection [HR 1.2 (95% CI 1.0,1.3)]. In the 67 patients who were biopsied at dnDSA detection; chronic antibody mediated rejection [HR 11.4(95% CI 2.3, 56.0)] and mixed rejection [HR 7.4(95% CI 2.2, 24.8)] were associated with allograft failure. We conclude that patient factors, including a history of viral infection requiring immunosuppression reduction or medication nonadherence, combined with DSA and histologic parameters must be considered to understand the risk of allograft failure in patients with dnDSA. This article is protected by copyright. All rights reserved.
Article
This review focuses on current standards for management of antibody-mediated rejection in solid-organ transplant recipients and emphasizes advances that may ultimately lead to the development of precise, pathogenesis-based therapeutic approaches.
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Objectives: The presence of a donor-specific positive crossmatch has been considered to be a contraindication to kidney transplantation because of the risk of hyperacute rejection. Desensitization is the process of removing hazardous preformed donor-specific antibody (DSA) in order to safely proceed with transplant. Traditionally, this involves plasmapheresis and intravenous immune globulin treatments that occur over days to weeks, and has been feasible when there is a living donor and the date of the transplant is known, allowing time for pre-emptive treatments. For sensitized patients without a living donor, transplantation has been historically difficult. Summary of background data: IdeS (imlifidase) is an endopeptidase derived from Streptococcus pyogenes which has specificity for human IgG, and when infused intravenously results in rapid cleavage of IgG. Methods: Here we present our single-center's experience with 7 highly sensitized (cPRA98-100%) kidney transplant candidates who had DSA resulting in positive crossmatches with their donors (5 deceased, 2 living) who received IdeS within 24 hours prior to transplant. Results: All pre-IdeS crossmatches were positive and would have been prohibitive for transplantation. All crossmatches became negative post-IdeS and the patients underwent successful transplantation. Three patients had DSA rebound and antibody-mediated rejection, which responded to standard of care therapies. Three patients had delayed graft function, which ultimately resolved. No serious adverse events were associated with IdeS. All patients have functioning renal allografts at a median follow-up of 235 days. Conclusion: IdeS may represent a groundbreaking new method of desensitization for patients who otherwise might have no hope for receiving a lifesaving transplant.