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,
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
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
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-specic 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
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,
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
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 difcult 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
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 (Figure1). 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-afnity 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
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,
27 INSERM U976 Institut de Recherche Saint-Louis, Université Paris Diderot,
28 Centre for Transplant and Renal Research, Westmead Institute of Medical
Research, University of Sydney and Renal Unit, Westmead Hospital, NSW,
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
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.
© 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 afnity 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-specic memory B cells may aid in risk
stratication 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 specici-
ties on HLA molecules and thus are highly donor specic.
Alternatively, cross-reactive alloantibodies may be donor
reactive but not donor specic, 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 Classication 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 classication14 are (1) histological
evidence of graft injury via microvascular inammation
(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 (Table1). 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) satises
criterion 1, and a (g + ptc) sum score of ≥2 also satises
criterion 2. The exception is that peritubular capillari-
tis alone is insufcient 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 classication has been a major advancement in
the eld of transplantation to increase the awareness of AMR
and standardize denitions. However, a classication schema
based on histological features oversimplies the complexity
of AMR. The Banff classication 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 reective 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 classication 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
efcient 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 classication as discussed below (Table2).
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 specici-
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
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
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-
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
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
Antibody-mediated rejection phenotypes
Timing DSA HistologyaClinical presentation Pathophysiology Prognosis Features associated with reduced allograft survival
Banff 2017 active AMR
Abrupt allograft dysfunction
correlating with increased
DSA MFI or titer usually
7–10 days posttransplant15
days if not
Pretransplant crossmatch (+T-AHG-CDC+15 or high-ﬂow cytometric
Late (>30 days
Preexisting DSA Banff 2017 active or
chronic active AMR
May be C4d±
± Allograft dysfunction and
Banff cg >0 lesion19,21,22
Degree of IFTA23-25
Banff cv score >024
Patient nonadherence or physician-directed immunosuppression
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±
± allograft dysfunction and
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
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 identication 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 identied for correct interpretation. First, the
SAB test has a high coefcient 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 specic 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 stratication. 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 efcacy.
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
dene 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 difcult. 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 benecial in this setting.71
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
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
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
Beneﬁt in clinical
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
Rocha et al65
Lefaucheur et al66
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, 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 benet.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 prole. However,
small numbers, demographic, and baseline differences as
well as an unclear AMR denition 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
Imlidase (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 specic 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 identied regardless of the crossmatch status.
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 benet 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
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 benecial 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 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.
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 signicant 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
(Table4).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 specic 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 deni-
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 difcult 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
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,
Consensus treatment recommendations based on available evidence and expert opinion
(Banff 2017) Standard of careaConsider adjunctive
Preexisting DSA (or
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)
Complement inhibitors (2B)
Rituximab 375 mg/m2 (2B)
Late (>30 days
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)
Rituximab 375 mg/m2 (2B)
Chronic AMR Optimize baseline immunosuppression (eg, add steroids if
on a steroid-free regimen) (1C)
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)
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
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.
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 dene 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.
1. Meier-Kriesche HU, Ojo AO, Hanson JA, et al. Increased impact of
acute rejection on chronic allograft failure in recent era. Transplantation.
2. El-Zoghby ZM, Stegall MD, Lager DJ, et al. Identifying speciﬁc causes
of kidney allograft loss. Am J Transplant. 2009;9:527–535.
3. Sellarés J, de Freitas DG, Mengel M, et al. Understanding the causes
of kidney transplant failure: the dominant role of antibody-mediated
rejection and nonadherence. Am J Transplant. 2012;12:388–399.
4. Gaston RS, Cecka JM, Kasiske BL, et al. Evidence for antibody-
mediated injury as a major determinant of late kidney allograft failure.
5. Everly MJ, Rebellato LM, Haisch CE, et al. Incidence and impact
of de novo donor-speciﬁc alloantibody in primary renal allografts.
6. Archdeacon P, Chan M, Neuland C, et al. Summary of FDA Antibody-
Mediated Rejection Workshop. Am J Transplant. 2011;11:896–906.
7. Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol.
8. Nutt SL, Hodgkin PD, Tarlinton DM, et al. The generation of antibody-
secreting plasma cells. Nat Rev Immunol. 2015;15:160–171.
9. Sciammas R, Shaffer AL, Schatz JH, et al. Graded expression of inter-
feron regulatory factor-4 coordinates isotype switching with plasma
cell differentiation. Immunity. 2006;25:225–236.
10. Ochiai K, Maienschein-Cline M, Simonetti G, et al. Transcriptional
regulation of germinal center B and plasma cell fates by dynamical
control of IRF4. Immunity. 2013;38:918–929.
11. Shinnakasu R, Inoue T, Kometani K, et al. Regulated selection of ger-
minal-center cells into the memory B cell compartment. Nat Immunol.
12. Lavinder JJ, Horton AP, Georgiou G, et al. Next-generation sequenc-
ing and protein mass spectrometry for the comprehensive analysis of
human cellular and serum antibody repertoires. Curr Opin Chem Biol.
13. Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working clas-
siﬁcation of renal allograft pathology. Kidney Int. 1999;55:713–723.
14. Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney Meeting
Report: revised diagnostic criteria for chronic active T cell-mediated
rejection, antibody-mediated rejection, and prospects for integra-
tive endpoints for next-generation clinical trials. Am J Transplant.
15. Gloor JM, Winters JL, Cornell LD, et al. Baseline donor-speciﬁc anti-
body levels and outcomes in positive crossmatch kidney transplanta-
tion. Am J Transplant. 2010;10:582–589.
16. Schinstock CA, Gandhi M, Cheungpasitporn W, et al. Kidney trans-
plant with low levels of DSA or low positive B-ﬂow crossmatch: an
underappreciated option for highly sensitized transplant candidates.
17. Bentall A, Cornell LD, Gloor JM, et al. Five-year outcomes in living
donor kidney transplants with a positive crossmatch. Am J Transplant.
18. Schinstock CA, Bentall AJ, Smith BH, et al. Long-term outcomes of
eculizumab-treated positive crossmatch recipients: allograft survival,
histologic ﬁndings, and natural history of the donor-speciﬁc antibod-
ies. Am J Transplant. 2019;19:1671–1683.
19. Aubert O, Loupy A, Hidalgo L, et al. Antibody-mediated rejection due
to preexisting versus de novo donor-speciﬁc antibodies in kidney allo-
graft recipients. J Am Soc Nephrol. 2017;28:1912–1923.
20. Amrouche L, Aubert O, Suberbielle C, et al. Long-term outcomes
of kidney transplantation in patients with high levels of preformed
DSA: the Necker high-risk transplant program. Transplantation.
21. Loupy A, Vernerey D, Tinel C, et al. Subclinical rejection phenotypes
at 1 year post-transplant and outcome of kidney allografts. J Am Soc
22. Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Rates and determinants
of progression to graft failure in kidney allograft recipients with de novo
donor-speciﬁc antibody. Am J Transplant. 2015;15:2921–2930.
23. Haas M, Mirocha J, Reinsmoen NL, et al. Differences in pathologic
features and graft outcomes in antibody-mediated rejection of renal
allografts due to persistent/recurrent versus de novo donor-speciﬁc
antibodies. Kidney Int. 2017;91:729–737.
24. Viglietti D, Loupy A, Aubert O, et al. Dynamic prognostic score to
predict kidney allograft survival in patients with antibody-mediated
rejection. J Am Soc Nephrol. 2018;29:606–619.
25. Malheiro J, Santos S, Tafulo S, et al. Correlations between donor-
speciﬁc antibodies and non-adherence with chronic active antibody-
mediated rejection phenotypes and their impact on kidney graft
survival. Hum Immunol. 2018;79:413–423.
26. Krisl JC, Alloway RR, Shield AR, et al. Acute rejection clinically
deﬁned phenotypes correlate with long-term renal allograft survival.
27. Matignon M, Muthukumar T, Seshan SV, et al. Concurrent acute
cellular rejection is an independent risk factor for renal allograft
failure in patients with c4d-positive antibody-mediated rejection.
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. 921
Schinstock et al
28. Loupy A, Hill GS, Suberbielle C, et al. Signiﬁcance of C4D Banff
scores in early protocol biopsies of kidney transplant recipients
with preformed donor-speciﬁc antibodies (DSA). Am J Transplant.
29. Mokteﬁ A, Parisot J, Desvaux D, et al. C1Q binding is not an inde-
pendent risk factor for kidney allograft loss after an acute antibody-
mediated rejection episode: a retrospective cohort study. Transpl Int.
30. Issa N, Cosio FG, Gloor JM, et al. Transplant glomerulopathy: risk and
prognosis related to anti-human leukocyte antigen class II antibody
levels. Transplantation. 2008;86:681–685.
31. Redﬁeld RR, Ellis TM, Zhong W, et al. Current outcomes of chronic
active antibody mediated rejection - a large single center retrospec-
tive review using the updated BANFF 2013 criteria. Hum Immunol.
32. Naesens M, Lerut E, Emonds MP, et al. Proteinuria as a noninvasive
marker for renal allograft histology and failure: an observational cohort
study. J Am Soc Nephrol. 2016;27:281–292.
33. Orandi BJ, Chow EH, Hsu A, et al. Quantifying renal allograft loss
following early antibody-mediated rejection. Am J Transplant.
34. Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding
anti-HLA antibodies and kidney-allograft survival. N Engl J Med.
35. Bailly E, Anglicheau D, Blancho G, et al. Prognostic value of the
persistence of c1q-binding anti-HLA antibodies in acute antibody-
mediated rejection in kidney transplantation. Transplantation.
36. Willicombe M, Brookes P, Santos-Nunez E, et al. Outcome of
patients with preformed donor-speciﬁc antibodies following alem-
tuzumab induction and tacrolimus monotherapy. Am J Transplant.
37. Lefaucheur C, Loupy A, Hill GS, et al. Preexisting donor-speciﬁc
HLA antibodies predict outcome in kidney transplantation. J Am Soc
38. Vo AA, Peng A, Toyoda M, et al. Use of intravenous immune globu-
lin and rituximab for desensitization of highly HLA-sensitized patients
awaiting kidney transplantation. Transplantation. 2010;89:1095–1102.
39. Stegall MD, Diwan T, Raghavaiah S, et al. Terminal complement inhibi-
tion decreases antibody-mediated rejection in sensitized renal trans-
plant recipients. Am J Transplant. 2011;11:2405–2413.
40. Tan EK, Bentall A, Dean PG, et al. Use of eculizumab for active
antibody-mediated rejection that occurs early post-kidney trans-
plantation: a consecutive series of 15 cases. Transplantation.
41. Orandi BJ, Zachary AA, Dagher NN, et al. Eculizumab and sple-
nectomy as salvage therapy for severe antibody-mediated rejec-
tion after HLA-incompatible kidney transplantation. Transplantation.
42. Loupy A, Hill GS, Jordan SC. The impact of donor-speciﬁc anti-
HLA antibodies on late kidney allograft failure. Nat Rev Nephrol.
43. Gloor JM, Cosio FG, Rea DJ, et al. Histologic ﬁndings one year after
positive crossmatch or ABO blood group incompatible living donor
kidney transplantation. Am J Transplant. 2006;6:1841–1847.
44. Wavamunno MD, O’Connell PJ, Vitalone M, et al. Transplant glomeru-
lopathy: ultrastructural abnormalities occur early in longitudinal analy-
sis of protocol biopsies. Am J Transplant. 2007;7:2757–2768.
45. Cornell LD, Schinstock CA, Gandhi MJ, et al. Positive crossmatch
kidney transplant recipients treated with eculizumab: outcomes
beyond 1 year. Am J Transplant. 2015;15:1293–1302.
46. Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical
pathologic correlations of de novo donor-speciﬁc HLA antibody post
kidney transplant. Am J Transplant. 2012;12:1157–1167.
47. Schinstock CA, Cosio F, Cheungpasitporn W, et al. The value of proto-
col biopsies to identify patients with de novo donor-speciﬁc antibody
at high risk for allograft loss. Am J Transplant. 2017;17:1574–1584.
48. Orandi BJ, Alachkar N, Kraus ES, et al. Presentation and outcomes
of c4d-negative antibody-mediated rejection after kidney transplanta-
tion. Am J Transplant. 2016;16:213–220.
49. Orandi BJ, Garonzik-Wang JM, Massie AB, et al. Quantifying the risk
of incompatible kidney transplantation: a multicenter study. Am J
50. Wiebe C, Nevins TE, Robiner WN, et al. The synergistic effect of class
II HLA epitope-mismatch and nonadherence on acute rejection and
graft survival. Am J Transplant. 2015;15:2197–2202.
51. Schinstock CA, Dadhania DM, Everly MJ, et al. Factors at de novo
donor-speciﬁc antibody initial detection associated with allograft loss:
a multicenter study. Transpl Int. 2019;32:502–515.
52. Bouquegneau A, Loheac C, Aubert O, et al. Complement-activating
donor-speciﬁc anti-HLA antibodies and solid organ transplant survival:
a systematic review and meta-analysis. Plos Med. 2018;15:e1002572.
53. Tambur AR, Herrera ND, Haarberg KM, et al. Assessing antibody
strength: comparison of MFI, c1q, and titer information. Am J
54. Uhlig K, Macleod A, Craig J, et al. Grading evidence and recom-
mendations for clinical practice guidelines in nephrology. A position
statement from kidney disease: improving global outcomes (KDIGO).
Kidney Int. 2006;70:2058–2065.
55. Roberts DM, Jiang SH, Chadban SJ. The treatment of acute anti-
body-mediated rejection in kidney transplant recipients-a systematic
review. Transplantation. 2012;94:775–783.
56. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant
Work Group. KDIGO clinical practice guideline for the care of kidney
transplant recipients. Am J Transplant. 2009;9(Suppl 3):S1–S155.
57. Reed EF, Rao P, Zhang Z, et al. Comprehensive assessment and
standardization of solid phase multiplex-bead arrays for the detection
of antibodies to HLA. Am J Transplant. 2013;13:1859–1870.
58. Visentin J, Vigata M, Daburon S, et al. Deciphering complement inter-
ference in anti-human leukocyte antigen antibody detection with ﬂow
beads assays. Transplantation. 2014;98:625–631.
59. Tambur AR, Campbell P, Claas FH, et al. Sensitization in transplanta-
tion: assessment of risk (STAR) 2017 working group meeting report.
Am J Transplant. 2018;18:1604–1614.
60. Montgomery RA, Warren DS, Segev DL, et al. HLA incompatible renal
transplantation. Curr Opin Organ Transplant. 2012;17:386–392.
61. Loupy A, Lefaucheur C. Antibody-mediated rejection of solid-organ
allografts. N Engl J Med. 2018;379:1150–1160.
62. Wan SS, Ying TD, Wyburn K, et al. The treatment of antibody-medi-
ated rejection in kidney transplantation: an updated systematic review
and meta-analysis. Transplantation. 2018;102:557–568.
63. Akiyoshi T, Hirohashi T, Alessandrini A, et al. Role of comple-
ment and NK cells in antibody mediated rejection. Hum Immunol.
64. Gelfand EW. Intravenous immune globulin in autoimmune and inﬂam-
matory diseases. N Engl J Med. 2012;367:2015–2025.
65. Rocha PN, Butterly DW, Greenberg A, et al. Beneﬁcial effect of
plasmapheresis and intravenous immunoglobulin on renal allograft
survival of patients with acute humoral rejection. Transplantation.
66. Lefaucheur C, Nochy D, Andrade J, et al. Comparison of combi-
nation plasmapheresis/IVIG/anti-CD20 versus high-dose IVIG in
the treatment of antibody-mediated rejection. Am J Transplant.
67. Velidedeoglu E, Cavaillé-Coll MW, Bala S, et al. Summary of 2017
FDA public workshop: antibody-mediated rejection in kidney trans-
plantation. Transplantation. 2018;102:e257–e264.
68. Kasiske BL, Zeier MG, Chapman JR, et al; Kidney Disease: Improving
Global Outcomes. KDIGO clinical practice guideline for the care of kid-
ney transplant recipients: a summary. Kidney Int. 2010;77:299–311.
69. Burton SA, Amir N, Asbury A, et al. Treatment of antibody-mediated
rejection in renal transplant patients: a clinical practice survey. Clin
70. Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis
and intravenous immune globulin provides effective rescue therapy
for refractory humoral rejection and allows kidneys to be successfully
transplanted into cross-match-positive recipients. Transplantation.
71. Böhmig GA, Wahrmann M, Regele H, et al. Immunoadsorption in
severe c4d-positive acute kidney allograft rejection: a randomized
controlled trial. Am J Transplant. 2007;7:117–121.
72. Fehr T, Gaspert A. Antibody-mediated kidney allograft rejection:
therapeutic options and their experimental rationale. Transpl Int.
73. Marks WH, Mamode N, Montgomery RA, et al; C10-001 Study
Group. Safety and efﬁcacy of eculizumab in the prevention of anti-
body-mediated rejection in living-donor kidney transplant recipients
requiring desensitization therapy: a randomized trial. Am J Transplant.
74. Glotz D, Russ G, Rostaing L, et al; C10-002 Study Group. Safety
and efﬁcacy of eculizumab for the prevention of antibody-mediated
rejection after deceased-donor kidney transplantation in patients
922 Transplantation ■ May 2020 ■ Volume 104 ■ Number 5 www.transplantjournal.com
with preformed donor-speciﬁc antibodies. Am J Transplant.
75. Viglietti D, Gosset C, Loupy A, et al. C1 inhibitor in acute anti-
body-mediated rejection nonresponsive to conventional therapy
in kidney transplant recipients: a pilot study. Am J Transplant.
76. Montgomery RA, Orandi BJ, Racusen L, et al. Plasma-derived
C1 esterase inhibitor for acute antibody-mediated rejection fol-
lowing kidney transplantation: results of a randomized double-
blind placebo-controlled pilot study. Am J Transplant. 2016;16:
77. Macklin PS, Morris PJ, Knight SR. A systematic review of the use
of rituximab for the treatment of antibody-mediated renal transplant
rejection. Transplant Rev (Orlando). 2017;31:87–95.
78. Zarkhin V, Li L, Kambham N, et al. A randomized, prospective trial of
rituximab for acute rejection in pediatric renal transplantation. Am J
79. Sautenet B, Blancho G, Büchler M, et al. One-year results of the
effects of rituximab on acute antibody-mediated rejection in renal
transplantation: RITUX ERAH, a multicenter double-blind randomized
placebo-controlled trial. Transplantation. 2016;100:391–399.
80. Moreso F, Crespo M, Ruiz JC, et al. Treatment of chronic antibody
mediated rejection with intravenous immunoglobulins and rituximab:
a multicenter, prospective, randomized, double-blind clinical trial. Am
J Transplant. 2018;18:927–935.
81. Lefaucheur C, Loupy A, Vernerey D, et al. Antibody-mediated vascu-
lar rejection of kidney allografts: a population-based study. Lancet.
82. Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous
immune globulin for desensitization during renal transplantation. N
Engl J Med. 2008;359:242–251.
83. Budde K, Dürr M. Any progress in the treatment of antibody-mediated
rejection? J Am Soc Nephrol. 2018;29:350–352.
84. Jordan SC, Lorant T, Choi J, et al. IgG endopeptidase in highly
sensitized patients undergoing transplantation. N Engl J Med.
85. Winstedt L, Järnum S, Nordahl EA, et al. Complete removal of extra-
cellular IgG antibodies in a randomized dose-escalation phase I study
with the bacterial enzyme ides–a novel therapeutic opportunity. PLoS
86. Lonze BE, Tatapudi VS, Weldon EP, et al. Ides (imliﬁdase): a novel
agent that cleaves human IgG and permits successful kidney trans-
plantation across high-strength donor-speciﬁc antibody. Ann Surg.
87. Bamoulid J, Staeck O, Crépin T, et al. Anti-thymocyte globulins in kid-
ney transplantation: focus on current indications and long-term immu-
nological side effects. Nephrol Dial Transplant. 2017;32:1601–1608.
88. Kamar N, Milioto O, Puissant-Lubrano B, et al. Incidence and predic-
tive factors for infectious disease after rituximab therapy in kidney-
transplant patients. Am J Transplant. 2010;10:89–98.
89. Locke JE, Zachary AA, Haas M, et al. The utility of splenectomy as
rescue treatment for severe acute antibody mediated rejection. Am J
90. Kaplan B, Gangemi A, Thielke J, et al. Successful rescue of refractory,
severe antibody mediated rejection with splenectomy. Transplantation.
91. Ejaz NS, Alloway RR, Halleck F, et al. Review of bortezomib treat-
ment of antibody-mediated rejection in renal transplantation. Antioxid
Redox Signal. 2014;21:2401–2418.
92. Eskandary F, Regele H, Baumann L, et al. A randomized trial of bort-
ezomib in late antibody-mediated kidney transplant rejection. J Am
Soc Nephrol. 2018;29:591–605.
93. Moreno Gonzales MA, Gandhi MJ, Schinstock CA, et al. 32 doses of
bortezomib for desensitization is not well tolerated and is associated
with only modest reductions in anti-HLA antibody. Transplantation.
94. Waiser J, Duerr M, Budde K, et al. Treatment of acute antibody-medi-
ated renal allograft rejection with cyclophosphamide. Transplantation.
95. Choi J, Aubert O, Vo A, et al. Assessment of tocilizumab (anti-
interleukin-6 receptor monoclonal) as a potential treatment for
chronic antibody-mediated rejection and transplant glomerulopa-
thy in HLA-sensitized renal allograft recipients. Am J Transplant.
96. Eskandary F, Dürr M, Budde K, et al. Clazakizumab in late antibody-
mediated rejection: study protocol of a randomized controlled pilot
trial. Trials. 2019;20:37.
97. OʼConnell PJ, Kuypers DR, Mannon RB, et al. Clinical trials for immu-
nosuppression in transplantation: the case for reform and change in
direction. Transplantation. 2017;101:1527–1534.