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Case Rep Nephrol Dial
DOI: 10.1159/000503951
© 2019 The Author(s)
Published by S. Karger AG, Basel
www.karger.com/cnd
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Patricia Hirt-Minkowski, MD
Clinic for Transplantation Immunology and Nephrology, University Hospital Basel
Petersgraben 4
CH–4031 Basel (Switzerland)
E-Mail patricia.hirt-minkowski@usb.ch
Case Report
Daratumumab for Treatment of
Antibody-Mediated Rejection after
ABO-Incompatible Kidney
Transplantation
Davide Spicaa Till Junkerb Michael Dickenmanna Stefan Schauba, c, d
Jürg Steigera, c Tanja Rüflie Jörg Halterb Helmut Hopferf
Andreas Holbrob, e Patricia Hirt-Minkowskia
aTransplantation Immunology and Nephrology, University Hospital Basel,
Basel, Switzerland; bDivision of Hematology, Department of Medicine, University Hospital
Basel, Basel, Switzerland; cTransplantation Immunology, Department of Biomedicine,
University of Basel, Basel, Switzerland; dHLA-Diagnostic and Immunogenetics, Department
of Laboratory Medicine, University Hospital Basel, Basel, Switzerland; eBlood Transfusion
Service, Swiss Red Cross, Basel, Switzerland; fInstitute for Pathology, University Hospital
Basel, Basel, Switzerland
Keywords
Antibody-mediated rejection · ABO-incompatible kidney transplantation · Anti-rejection
therapy · Daratumumab
Abstract
We report the effectiveness of daratumumab, a human IgGκ monoclonal antibody targeting
CD38 on plasma cells, for therapy-refractory antibody-mediated rejection (AMR) due to blood
group antibodies in a 59-year-old man who received a living ABO-incompatible kidney trans-
plantation. Standard treatment options for AMR due to blood group antibodies including im-
munoadsorption, lymphocyte depletion with anti-human T-lymphocyte globulins, intravenous
methylprednisolone pulses and eculizumab limited tissue injury, however failed to sufficiently
suppress blood group antibody production. After administration of daratumumab as a rescue
Case Rep Nephrol Dial
DOI: 10.1159/000503951
© 2019 The Author(s). Published by S. Karger AG, Basel
www.karger.com/cnd
Spica et al.: Daratumumab for Treatment of Antibody-Mediated Rejection after ABO-
Incompatible Kidney Transplantation
138
therapy, blood group antibody titers decreased and remained at low levels without further
immunoadsorption and allowed kidney graft function to recover.
© 2019 The Author(s)
Published by S. Karger AG, Basel
Introduction
Kidney transplantation is the therapy of choice for many patients with end-stage renal
disease. Pretransplant risk stratification and modern immunosuppression have led to striking
advances over the past decades, resulting in better long-term graft survival [1–4]. Neverthe-
less, there still exist important unmet clinical needs and problems to be solved for kidney
transplant recipients [5–7]. Antibody-mediated rejection (AMR) has been recognized as one
of the most important causes of graft loss [8–10]. Although less frequent than antibodies di-
rected against human leukocyte antigens (i.e., donor specific HLA-antibodies [DSA]) [11], an-
tibodies against ABO blood group antigens can be the cause of AMR [12]. In a meta-analysis,
which included 26 centers, describing 1,346 ABO-incompatible kidney transplant patients,
AMR within the first year post-transplant was more common and occurred with a fourfold
risk compared to 4,943 center-matched controls, who were ABO-compatible [12]. To date,
there are no US Food and Drug Administration (FDA)-approved immunosuppressive drugs
for either prevention or treatment of AMR [13]. The only FDA-approved drugs for treatment
of acute rejection are polyclonal anti-T lymphocyte globulins [6]. Several additional agents
have been employed as off-label for the treatment of AMR with variable effectiveness such as
intravenous immunoglobulins, rituximab, bortezomib, and eculizumab as well as removing of
circulating anti-HLA antibodies and blood group antibodies by plasmapheresis/plasma ex-
change or immunoadsorption [13, 14]. Thus, our armamentarium to treat AMR is still incom-
plete. For this reason, new therapeutic options to reduce the burden of AMR are urgently
needed.
Daratumumab is a human monoclonal IgGκ antibody targeting the glycoprotein CD38
which is expressed on plasma cells and induces cell death and apoptosis through different
immune effector mechanisms such as complement-mediated cytotoxicity, antibody-mediated
cytotoxicity, antibody-dependent phagocytosis and direct induction of apoptosis [15]. Based
on data of the MMY2002 (SIRIUS) [16] and the GEN501 [17] studies, daratumumab has
emerged as a new option in therapy-refractory multiple myeloma and was approved for treat-
ment of multiple myeloma in 2015 [18]. As CD38 is also expressed on nonmalignant plasma
cells, it seems obvious to test daratumumab as a rescue therapy in other diseases with patho-
genetically involved, antibody-producing plasma cells after failure of established therapies.
Thus, daratumumab has been used in other settings where antibody production by plasma
cells is the pathophysiologic key feature. The effective treatment of refractory post-transplant
autoimmune hemolytic anemia after allogenic hematopoietic stem cell transplantation
(HSCT) was reported by Schuetz et al. [19] in a small case series of 3 patients (1 adult, 2 pedi-
atric cases). Furthermore, daratumumab was used successfully for treatment of delayed red-
cell engraftment (i.e., pure red cell aplasia) due to ABO incompatibility after allogenic HSCT
[20]. These conditions share the central role of deleterious blood group antibodies produced
by nonmalignant plasma cells that target and destroy allogenic tissue. In all reported cases,
depletion of the plasma cells by daratumumab resulted in resolution of red blood cell destruc-
tion [19, 20].
Case Rep Nephrol Dial
DOI: 10.1159/000503951
© 2019 The Author(s). Published by S. Karger AG, Basel
www.karger.com/cnd
Spica et al.: Daratumumab for Treatment of Antibody-Mediated Rejection after ABO-
Incompatible Kidney Transplantation
139
As therapeutic options for AMR are limited, an anti-CD38 agent such as daratumumab
may be a new treatment option to be evaluated in patients with no response to so far utilized
anti-rejection therapies for AMR.
Case Report
A 59-year-old man with end-stage renal disease due to IgA nephropathy received a living
kidney donation from his 64-year-old HLA-haploidentical sister. HLA antibody screening be-
fore transplantation performed by Luminex single HLA antigen beads (LabScreen SA; One
Lambda Inc., CA, USA) showed no DSA. Because of major ABO incompatibility (i.e., recipient
with blood group B and donor with blood group A), the recipient was treated with rituximab
375 mg/m2 for B-cell depletion 4 weeks before transplantation. Baseline immunosuppressive
therapy with tacrolimus (tac) with a goal to reach a trough level of 8−10 µg/L and mycophe-
nolate mofetil (MMF) twice daily 500 mg was started 2 weeks before transplantation and ex-
tended by prednisone with an initial dose of 30 mg per day on day −6 (i.e., 6 days before trans-
plantation). During the in-hospital stay, tac trough levels were measured three times per week
(i.e., within the first 37 days post-transplant), followed by weekly measurements thereafter.
In addition, from day −5 to −1 (i.e., from 5 days to 1 day before transplantation) the patient
received five sessions of immunoadsorption with a Glycosorb® column (Glycorex Transplan-
tation AB, Lund, Sweden) to remove circulating anti-A blood group antibodies. When starting
immunoadsorption, anti-A IgM isohemagglutinin and anti-A IgG titers were 1:8 and 1:32, re-
spectively. On the day of transplantation, anti-A IgM isohemagglutinin and anti-A IgG titers
had been reduced to 1:2 and 1:4, respectively (Fig. 1). Induction immunosuppression con-
sisted of basiliximab (i.e., 20 mg at day 0, followed by 20 mg at day 4) and baseline immuno-
suppressive therapy with tac, MMF, and prednisone was continued during the whole course.
This treatment approach reflects the standard procedure in ABO-incompatible kidney trans-
plantation at our center as described before [21]. Serum creatinine levels dropped from 604
to 189 µmol/L at day 4 (Fig. 1), reaching an adequate baseline estimated GFR (eGFR) of 33
mL/min/1.73 m2 calculated by CKD-EPI formula, taking into account the patient’s/donor’s
age, weight mismatch, and kidney function of the sister before donation (i.e., eGFR of 94
mL/min/1.73 m2).
In the first days after transplantation, anti-A IgM and anti-A IgG isohemagglutinin titers
remained low (maximal 1:2 and 1:4, respectively). On day 6, both titers began to rise and
reached a maximum of 1:64, which was followed by a sudden drop in kidney graft function
(decrease in eGFR from 33 to 14 mL/min/1.73 m2 on day 10) (Fig. 1). A biopsy on day 7
showed mild diffuse acute tubular damage (Fig. 2a). By immunofluorescence, both IgM and
C3c deposition was seen in the peritubular capillaries in addition to the C4d positivity usually
seen in AB0-incompatible graft biopsies suggesting very recent antibody-mediated comple-
ment activation (Fig. 2b–d). In the context of rising anti-A isohemagglutinins and declining
graft function, these findings were interpreted as a very early episode of AMR due to anti-A
blood group antibodies. Immunoadsorption was restarted on day 8, effectively removing the
circulating anti-A blood group antibodies (Fig. 1). To suppress further antibody production,
anti-human T-lymphocyte globulins (i.e., totally seven infusions with a dosage between 2 and
4 mg/kg of body weight on day 9, from day 14 to 18, and on day 20) as well as high-dose
intravenous methylprednisolone (i.e., totally five pulses between day 7 and 11) were admin-
istrated. Afterwards, prednisone dosed 0.5 mg/kg body weight was continued. Additionally,
eculizumab, a monoclonal antibody that targets complement C5 (i.e., three infusions of 900
Case Rep Nephrol Dial
DOI: 10.1159/000503951
© 2019 The Author(s). Published by S. Karger AG, Basel
www.karger.com/cnd
Spica et al.: Daratumumab for Treatment of Antibody-Mediated Rejection after ABO-
Incompatible Kidney Transplantation
140
mg per week on days 12, 19 and 26, respectively), was administrated to limit destruction of
endothelial cells by complement-dependent cytotoxicity. So far, our approach for treatment
of AMR stabilized kidney graft function with low eGFR levels between 18 and 20 mL/min/1.73
m2. Unfortunately, anti-A antibody titers immediately rose again after discontinuation of im-
munoadsorption on day 19 to IgM isohemagglutinin titers of 1:32 and IgG of 1:32 on day 23
post-transplant. Thus, immunoadsorption of anti-A blood group antibodies was resumed and
anti-A antibodies could successfully be removed. When immunoadsorption was stopped once
again on day 26, anti-A antibody titers rose repeatedly, reaching IgM isohemagglutinin titers
of 1:16 and IgG of 1:16, respectively on day 29, as summarized in Figure 1.
To prevent long-term dependence of immunoadsorption and eventually graft failure and
due to the lack of effectiveness of the so far established combined therapy, daratumumab was
administrated as a rescue therapy at a dose of 16 mg per kg of body weight in weekly intervals
beginning on day 30 after kidney transplantation. The patient gave his consent after infor-
mation about the experimental approach. Eculizumab was discontinued avoiding interference
with daratumumab by possibly blocking complement-mediated cytotoxicity of the targeted
plasma cells, which is considered an important mechanism of action of daratumumab. Within
72 h after the first dose of daratumumab, the pathogenic IgM isohemagglutinins started to fall
continuously without any further immunoadsorption. In total, the patient received six infu-
sions of daratumumab, without any severe drug-related adverse event. Two weeks after ad-
ministration of the last daratumumab infusion on day 65, the anti-A IgM isohemagglutinin and
anti-A IgG titers were 1:1 and 1:2, respectively and persisted at low levels the following weeks.
As binding of daratumumab to CD38 on red blood cells can affect measurement of anti-A IgG
antibodies, anti-A IgG titers were validated after incubation with dithiothreitol as described
previously [22]. A biopsy of the kidney graft on day 73 post-transplant showed no signs of
acute rejection (image not shown). The patient’s graft function nearly recovered to baseline
with eGFR levels at 27–32 mL/min/1.73 m2. To note, no further immunoadsorption was nec-
essary after initiation of daratumumab.
Discussion
To the best of our knowledge, this is the first report of successful administration of dara-
tumumab for treatment of therapy-refractory AMR in kidney transplantation. In the context
of rising anti-A isohemagglutinin titers right before graft function deterioration, early active
ABO blood group AMR was strongly suggested. In this case, it was confirmed by the histologic
findings of tissue injury (unexplained acute tubular injury) and evidence of interaction of IgM
antibodies with vascular endothelial cells on the peritubular capillaries with concomitant ac-
tivation and deposition of complement factor C3c. This provided the pathogenetic linkage be-
tween the rising anti-A isohemagglutinins and kidney transplant injury. Thus, we interpreted
the early rise in anti-A isohemagglutinin titers as clinically relevant. Because of the evidence
for early anti-A isohemagglutinins-mediated tissue injury, we did not screen for de novo DSA
in this patient, who was tested negative for pre-transplant DSA timely before transplantation
and treated with rituximab for desensitization 4 weeks prior to transplantation.
In summary, our patient developed early active AMR caused by anti-A IgM isohemagglu-
tinins after kidney transplantation from his ABO-incompatible sister despite following estab-
lished therapeutic strategies for ABO-incompatible kidney transplantation [21], and immedi-
ate treatment with anti-human T-lymphocyte globulins, high-dose methylprednisolone,
blocking the complement-mediated effector mechanisms of tissue injury by eculizumab and
Case Rep Nephrol Dial
DOI: 10.1159/000503951
© 2019 The Author(s). Published by S. Karger AG, Basel
www.karger.com/cnd
Spica et al.: Daratumumab for Treatment of Antibody-Mediated Rejection after ABO-
Incompatible Kidney Transplantation
141
immunoadsorption for the removal of circulating blood group antibodies. Although this ap-
proach prevented further decrease in allograft function and possibly graft loss, it did not in-
duce resolution of the rejection process due to the ongoing production of anti-A blood group
antibodies.
Based on the efficacy of daratumumab in the treatment of post-HSCT autoimmune hemo-
lytic anemia and pure red cell aplasia following ABO-incompatible HSCT, we hypothesized
that direct targeting and depletion of the antibody-producing plasma cells by daratumumab
could be a treatment option for our patient in order to avoid graft failure. Bortezomib has been
described for the treatment of refractory AMR in kidney transplantation in several cases [23,
24], which is a less directed approach to target plasma cells. However, we were reluctant to
give bortezomib because of the risk of severe peripheral neuropathy as a limiting side effect
in a patient who had been operated for spinal stenosis prior to kidney transplantation.
In fact, after the first dose of daratumumab, the suspected pathogenic IgM isohemagglu-
tinins continuously fell without any additional immunoadsorption. The rapid response could
be explained by the relatively short half-life of IgM antibodies of approximately 5 days. Al-
though we cannot prove the causality between daratumumab and the reduction in antibody
titers – which could also be part of the natural course after ABO-incompatible kidney trans-
plantation – the timely coincidence suggests the decrease in antibody titers to be a direct con-
sequence of daratumumab. Further, rising blood group antibody titers after transplantation
do not necessarily need to reflect subsequent allograft dysfunction or AMR, because allograft
tolerance of the blood group antibodies can be observed after ABO-incompatible kidney trans-
plantation. Even though a rise in blood group antibody titers can occur early in the post-trans-
plant course (i.e., from the first week ongoing), titers normally rise within 4–6 weeks after
transplantation, and “pure rebound” is typically not associated with graft dysfunction and his-
tologic signs of early active AMR [25–27].
Moreover, there could be an influence of the complex antirejection therapy (steroid
pulses, anti-thymocyte globulins, eculizumab) administrated prior to daratumumab on the re-
duction of anti-A blood group antibodies and resolution of tissue damage. In a complex clinical
situation where a new therapeutic option is evaluated as a rescue therapy, it is impossible in
a single case to prove causality of the rescue therapy (i.e., therapeutic effect of a specific treat-
ment). One explanation in our case may be the fact that, despite those initial treatments, anti-
A IgM titers rose again two times immediately after discontinuation of immunoadsorption
and, in contrary, fell right after the first daratumumab administration without further immu-
noadsorption assuming a much greater effect of daratumumab on anti-A blood group anti-
body suppression. In addition, the level of blood group antibodies measured in the blood does
not necessarily reflect the burden of antibodies bound to the graft. However, the second allo-
graft biopsy performed on day 73 post-transplant showed no signs of acute rejection, includ-
ing no more deposition of IgM and complement C3c. Concerns about immunomodulatory ef-
fects of daratumumab occurred before infusion, as the drug targets CD38-expressing cells
through a variety of immune-mediated mechanisms [15]. Krejcik et al. [28] studied peripheral
blood and bone marrow of patients with relapsed/refractory myeloma which were treated
with daratumumab from two different monotherapy studies. They showed that daratumumab
depleted CD38-positive immune regulatory cells and promoted T-cell expansion, and demon-
strated further T-cell changes, which they highlighted as “skew of T-cell repertoire in multiple
myeloma” [28]. In transplantation, these immunomodulatory effects of the anti-CD38 drug
could represent additional mechanisms of interaction which may trigger cellular rejection
and, thus, act against the allograft. Thus, it is important to mention that the patient developed
no acute cellular rejection during the course and after treatment with daratumumab proven
Case Rep Nephrol Dial
DOI: 10.1159/000503951
© 2019 The Author(s). Published by S. Karger AG, Basel
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Spica et al.: Daratumumab for Treatment of Antibody-Mediated Rejection after ABO-
Incompatible Kidney Transplantation
142
by biopsy. Further, the medication was well tolerated by the patient, and no severe infections
were observed.
Conclusion
Our case report suggests that daratumumab may be a promising option as a rescue ther-
apy for therapy-refractory AMR in the context of ABO-incompatible kidney transplantation.
As large clinical trials evaluating new treatment regimens for AMR are unlikely to be per-
formed in the near future, case reports may be a more practical way to evaluate treatment
response. Furthermore, daratumumab may also be considered part of the preparative regi-
men before ABO-incompatible kidney transplantation with or without rituximab in order to
directly target blood group antibody-producing plasma cells with the potential to avoid im-
munoadsorption. Nevertheless, the immunomodulatory effects of daratumumab need to be
taken into account. To address this issue, further studies are warranted.
Statement of Ethics
The research was conducted in accordance with the World Medical Association Declara-
tion of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-
principles-for-medical-research-involving-human-subjects/). The participant gave written
informed consent for publication of this case report.
Disclosure Statement
The authors of this article declare no conflicts of interest as described by Karger Case Re-
ports in Nephrology and Dialysis.
Funding Sources
Daratumumab therapy was funded by Janssen-Cilag AG, Zug, Switzerland. P.H.-M. is sup-
ported by the Alfred und Erika Bär-Spycher-Stiftung.
Author Contributions
All authors contributed equally to the literature review and the text of the manuscript.
D.S., P.H.-M. and A.H. were responsible for the patient care and treatment.
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A. Holbro and P. Hirt-Minkowski contributed equally to this article
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Incompatible Kidney Transplantation
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Fig. 1. Course of the 59-year-old patient treated with daratumumab for antibody-mediated acute rejection
after ABO-incompatible kidney transplantation. Daratumumab was administered at a dose of 16 mg per
kg of body weight in weekly intervals. MP, methylprednisolone (pulse doses between 250–500 mg). Ecu-
lizumab (three infusions of 900 mg per week on days 12, 19, and 26, respectively). ATG, anti-human T-
lymphocyte globulins (i.e., totally seven infusions with a dosage between 2–4 mg/kg of body weight). Tac,
tacrolimus (goal trough level of 8−10 µg/L). Tac trough levels are indicated bi-weekly ±4 days and illus-
trate selected time points of measurement post-transplant. MMF, mycophenolate mofetil (twice daily 500
mg). Prednisone (30–50 mg daily).
Case Rep Nephrol Dial
DOI: 10.1159/000503951
© 2019 The Author(s). Published by S. Karger AG, Basel
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Spica et al.: Daratumumab for Treatment of Antibody-Mediated Rejection after ABO-
Incompatible Kidney Transplantation
145
Fig. 2. Kidney transplant biopsy on day 7. a Conventional histology showed diffuse mild acute tubular
damage with widened tubular lumina and mild interstitial edema. PAS stain, original magnification ×100.
b–d Immunofluorescence of cryosections demonstrated diffuse linear complement C4d staining along the
peritubular capillaries (b), but also a more granular deposition of IgM (c) and complement C3c (d), indi-
cating a very recent antibody interaction with the endothelium. Incubations for IgA and IgG were negative
(not shown). Indirect (b) and direct (c, d) immunofluorescence with FITC-labeled antibodies. Original
magnification ×200.
