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7 The Sensitized Patient Awaiting Heart Transplantation
83
Fig. 7.2 Mechanism of Intravenous Immunoglobulin
(IVIg) activity. Reused with permission from Inessa
Schwab et al., Intravenous immunoglobulin therapy: how
[66]. In a study of sensitized LVAD recipients
awaiting HTx [67], patients received monthly
courses of either IVIg or plasmapheresis in conjunction with cyclophosphamide. Prolongation
in transplant waiting time was related to the
presence of Class I antibodies. Infusion of IVIg
(2 g/kg) caused a mean reduction of 33% in
anti-HLA class I alloreactivity within 1 week.
Waiting time to transplantation was significantly
reduced by IVIg therapy and subsequently
matched non-sensitized patients. Although plasmapheresis caused a similar reduction in antibodies, this effect was achieved after longer
treatment. Plasmapheresis was associated with
does IgG modulate the immune system? Nature Reviews
Immunology, 13(3), 176–189, 2013, Springer Nature.
https://doi.org/10.1038/nri3401
an unacceptably high frequency of infectious
complications. In this study, IVIg appeared to be
more effective than plasmapheresis in reducing
PRA with a superior safety profile.
Rituximab
Rituximab is a chimeric monoclonal antibody
against CD20 expressed on pre-B and mature
B lymphocytes and was developed for the treatment of lymphoma. CD20 has an important
role in B-cell maturation, regulating the early
stages of cell cycle initiation and differentiation.
84 J. Patel and K. Patel
Rituximab causes B-cell depletion by complement and antibody-dependent cytotoxicity and
apoptosis. In sensitized patients awaiting renal
transplantation, rituximab in conjunction with
IVIg has been shown to significantly reduce
PRA, shorten time to transplant, and provide
excellent 12-month graft and patient survival
[68]. In HTx [69], 21 patients treated with a
combination of plasmapheresis, IVIG, and rituximab had a mean reduction of PRA from 70.5
to 30.2%, resulting in a negative prospective
donor-specific crossmatch and successful HTx.
Compared with the control group (PRA < 10%),
the treated sensitized group had similar 5-year
survival and freedom from cardiac allograft
vasculopathy. In a prospective study, 14 sensitized pediatric patients awaiting HTx underwent desensitization with high-dose IVIg and
rituximab [70]. Eight patients had a significant
decrease in cPRA, although 6 required multiple
doses for a response. The total number of unacceptable antigens decreased for all 8 responders,
leading to a median increase in the percentage
of potential donors in the overall population
from 10% pre-treatment to 85% post-treatment.
Obinutuzumab is a second-generation fully
humanized CD20 monoclonal antibody that may
be more effective in depleting B cells, with published reports of use in desensitization limited to
renal transplant candidates [71, 72].
Proteasome Inhibitors
Although plasmapheresis, IVIg, and rituximab variably reduce antibody burden, these
modalities have no suppressive effect on the cell
responsible for antibody production, the mature
plasma cell. Bortezomib is a selective, reversible
26S proteasome inhibitor used in the treatment
of multiple myeloma, a plasma cell neoplasm.
In vitro, bortezomib demonstrated plasma cell
apoptosis and blocked anti-HLA antibody production [73]. In contrast, IVIG, rituximab, and
anti-thymocyte globulin had no effect on suppressing antibody production by plasma cells. In
one study, 34 highly sensitized patients awaiting
living-related donor renal transplant underwent
desensitization with a combination of plasmapheresis, bortezomib, rabbit-ATG, mycophenolate mofetil (MMF) and IVIg [74]. In total,
29/34 patients responded within one month with
a significant reduction in AHG-CDC and flow
cytometry crossmatches. Side effects were noted
in 38% of patients and were manageable. Two
patients lost a graft at one year, and acute rejections were noted in a quarter of the patients who
responded to steroids and rATG.
In HTx, bortezomib, in conjunction with
plasmapheresis, has been described by several
centers [75, 76]. The response to this combination was noted mainly in class I antibodies
(Class I cPRA 90–74% in Brinkley et al., 60.5–
54.9% in Dhillon et al.). The primary route of
synthesis of HLA class I molecules is dependent on peptide generation by the proteasome,
whereas that of class II is not. Nevertheless, the
majority of patients were able to undergo transplants with one-year survival rates comparable
to non-sensitized patients. The most common
side effects were thrombocytopenia, neutropenia, and peripheral neuropathy.
Carfilzomib is a second-generation proteasome inhibitor that is also approved for multiple myeloma and leads to irreversible inhibition
of plasma cells. There has been a single center
report describing the experience of 9 patients
undergoing carfilzomib therapy combined
with plasmapheresis and IVIg, demonstrating effectiveness in class I antibody reduction
(total cPRA 76–40% and C1q-fixing antibodies 56–4%) and facilitation of transplant in
6 patients with acceptable outcomes [77]. It
should be noted, though, that the majority of
these patients had LVADs who may have a more
benign phenotype of sensitization and that there
has been significant cardiotoxicity associated
with carfilzomib in patients with hematologic
malignancies [78].
The combination of plasmapheresis with
proteasome inhibitors may be more effective
than plasmapheresis monotherapy because the
removal of circulating antibodies by plasmapheresis results in increased metabolic demands
on B-cells, memory B-cells, and plasma cells to
produce more antibodies. This metabolic stress
857 The Sensitized Patient Awaiting Heart Transplantation
enhances the sensitivity of plasma cells to proteasome inhibition. Plasmapheresis during proteasome inhibitor therapy also provides the
additional benefit of removing pre-existing circulating antibodies. This combination is primarily used in the inpatient setting.
Emerging Desensitization Strategies
The CD38 monoclonal antibody daratumumab
was similarly also originally developed for multiple myeloma but has shown utility in desensitization. CD38 is present on plasma cells and
other immune cells. Experience in HTx candidates has been limited to case reports/series
[79, 80].
Animal models have demonstrated the potential utility of antibodies against CTLA4 in inhibiting de novo DSA production [81]. Belatacept,
which is a T-cell costimulation blocker that
functions as an antibody against CD80/CD86
fused with CTLA4, has been trialed in conjunction with proteasome inhibitors in highly
sensitized patients, demonstrating significant
reductions in both HLA class I and II antibodies, including those that were previously C1qbinding [82].
Tocilizumab is an IL-6 inhibitor, which
downregulates T and B cell differentiation and
proliferation. In an early phase study of kidney
transplant candidates who were unresponsive
to desensitization with IVIg, rituximab, and/
or plasma exchange, tocilizumab with IVIg led
to a fall in class I/II cPRAs from 74 ± 31% and
93 ± 5% to 59 ± 41% and 89 ± 9%, respectively,
and 5/10 patients went onto successful transplant, all of which were free of AMR [83]. A
humanized IL-6 inhibitor, clazakizumab, is also
under investigation.
Splenectomy
Splenectomy reduces plasma and precursor cells
and impairs B-cell immune surveillance. It can
be performed using minimally invasive techniques. It is, however, associated with a life-long
risk of sepsis from encapsulated bacteria, and its
effect on the immune system is permanent. This
significantly limits its use in highly sensitized
patients already at increased infection risk due
to other desensitization therapies. Splenectomy
has been shown to be effective in permitting
ABO and HLA incompatible renal transplantation against a positive crossmatch when used in
conjunction with plasmapheresis and immunoglobulin [84]. However, the use of this modality
has waned due to potential complications and
unintended consequences.
Eculizumab
Antibody-mediated injury predominantly relies
on the activation of complement. The complement system may be activated by 3 separate
pathways that converge to C5, and the subsequent formation of the membrane attack complex (C5b-C9), which has proinflammatory and
chemotactic properties and, importantly, promotes cell lysis. An approach preventing complement activation may, therefore, be effective
in preventing AMR in sensitized patients after
HTx. Eculizumab is a monoclonal antibody that
specifically binds to the complement protein C5
with high affinity and inhibits its cleavage to
C5a and C5b, thus preventing the generation of
the terminal membrane attack complex C5b-9.
C5a is also a potent immunomodulator involved
in chemotaxis, macrophage cytokine production,
and ischemia–reperfusion injury. One potential advantage of targeting the terminal components of the complement system is that the
early components are preserved to remain active
in immune defense. For example, C3b is an
important opsonin against microbial infection.
Eculizumab is approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical
hemolytic uremic syndrome.
In renal transplantation, the incidence of
biopsy-proven AMR in the first 3 months in 26
highly sensitized recipients treated with eculizumab was significantly reduced compared
to a matched historical cohort (7.7 vs 41.2%;
p = 0.003) [85]. A single-center pilot study of
86 J. Patel and K. Patel
Table 7.2 Key takeaways from the 2023 Consensus Conference on Emerging Understanding of Antibodies and
Antibody-Mediated Rejection in Heart Transplantation
1. Stratify antibody risk by Mean Fluorescent Intensity (MFI) in the undiluted assay:
• Low risk < 5,000 MFI
• Moderate risk 5,000-8,000 MFI
• High risk > 8,000 MFI.
2. Consider desensitizing if the calculated panel reactive antibody (cPRA) is >50%, depending on patient/
3. There is a need for precision in defining ABO-related histocompatibility between donor and recipient to
4. Induction therapy (antithymocyte globulin (ATG) or basiliximab) may be considered peri-transplant for
5. Crossing donor-specific antibodies (DSA) in experienced centers may be considered for sensitized patients
6. If crossing DSA at the time of heart transplant, induction therapy (ATG) or IVIG/plasmapheresis are
7. Several variables should be considered to treat patients with post-transplant DSA, including cardiac
8. Endomyocardial biopsy is not mandated in patients with asymptomatic post-transplant DSA but should be
9. Testing and treatment of non-HLA antibodies have not been recommended until a causal role in graft
10. Sensitization should be factored into donor heart allocation policy.
antibody characteristics and center support/infrastructure. The goal of pre-transplant desensitization therapy is to lower the cPRA to broaden the donor pool and minimize the risk of post-transplant AMR.
enable clinicians to carefully analyze risk and benefit while expanding this platform from infants to older
children and select adults.
sensitized patients.
but should take into account patient characteristics, antibody attributes, and their biological significance.
common therapies.
dysfunction by imaging, abnormal hemodynamics, an increasing MFI trend in DSA, the presence of early
DSA, antibody attributes (C1q+ binding, detection of DSA in dilution assay), biopsy-proven pAMR ≥ 2,
and abnormal molecular findings (dd-cfDNA and/or the MMDx) as available. However, the clinical utility
of treating asymptomatic post-transplant DSA remains unclear.
performed when DSA are associated with signs of clinical or subclinical graft dysfunction or graft injury.
injury and defined thresholds are established.
the use of eculizumab at the time of transplantation and two months afterward in 20 highly
sensitized patients demonstrated that despite
positive B cell and T cell flow crossmatches in
14 and 11 patients, only 4 patients went onto
have pAMR2 or greater and/or left ventricular
dysfunction. Survival was 90% at 1 year [86].
Monitoring of Sensitized Patients While Awaiting Transplantation
Antibodies may potentially rebound following
the completion of desensitization therapy, and
additional treatment may need to be considered.
Further opportunities for sensitization may also
present in patients receiving blood products,
MCS, or developing infection. Circulating
antibodies, therefore, need to be periodically
monitored while awaiting HTx. For sensitized
patients (PRA > 10%), circulating antibodies
should be checked at 6–12 month intervals and/
or if sensitizing events (blood transfusions) have
occurred.
Consensus conferences took place in 2008 [46],
2016 [87], and 2023 [88, 89] to assess the prevalence of sensitization in patients awaiting HTx,
the use and efficacy of desensitization therapies,
and the outcomes of desensitized patients after
HTx. Recently published key takeaways from
the 2023 Consensus Conference on Emerging
Understanding of Antibodies and AntibodyMediated Rejection in Heart Transplantation are
summarized in Table 7.2 [88, 89].
877 The Sensitized Patient Awaiting Heart Transplantation
Conclusions
HTx waitlists continue to grow as demand for
organs has vastly out-stripped the donor pool
despite expansion made possible by the use of
Hepatitis C donors and donation after cardiac
death. In this scenario, sensitized patients awaiting HTx represent a particular challenge. Due to
a limited donor supply, an increasing number of
patients awaiting HTx are on MCS, and these
patients are at particular risk for sensitization.
Pre-transplant sensitization is associated with an
increased waiting time to transplant, increased
wait-list mortality, and increased risk of rejection after transplant. Solid-phase immunoassays
offer increased sensitivity and specificity for
HLA antibody detection. These high-resolution
tests allow patients to be listed for transplant
by virtual cross-match, thereby increasing the
donor pool. However, unlike the CDC assay,
these assays do not distinguish complement fixing from non-complement fixing antibodies,
and antibody strength and serial dilution serve
as surrogates for cytotoxicity. The C1q binding assay further distinguishes HLA antibodies
that can bind the first component of complement and may further help expand the donor
pool by identifying the most pathogenic antibodies. Treatment options for sensitized patients
remain an area of active investigation and focus
on antibody removal (plasmapheresis and immunoadsorption), targeting B cells and immunomodulation (rituximab and IVIg), plasma cell
depletion (proteasome inhibitors) and complement blockade (eculizumab). The most effective
approach for reducing alloantibodies requires a
combination of therapies.
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Donor Organ Procurement and Preservation
Pedro Catarino
Abstract
With the expanding burden of advanced heart
failure and the scarcity of donor hearts, several innovations in organ procurement and
preservation have emerged to help facilitate
and improve the clinical outcomes of heart
transplantation. This chapter explores donor
referral and evaluation, focusing on both
brain death and circulatory death donors. In
addition, this chapter covers donor heart procurement and preservation techniques.
Keywords
Heart transplantation · Donor · Procurement ·
Brain death · Circulatory death · Organ
preservation
Clinical Pearls
• Intermediary organizations take responsibility for the process of consent, donor management and evaluation, and donor allocation,
removing any conflict of interest from both
those caring for potential donors and those
providing transplants to potential recipients.
P. Catarino (*)
Cedars-Sinai Smidt Heart Institute, Los Angeles,
CA, USA
e-mail: pedro.catarino@cshs.org
•
For potential donors it is essential to obtain
as complete a picture as possible regarding their social and medical history and any
condition that might be a contra-indication to
organ donation.
• Goal-directed intensive care management
with attention to hemodynamics, fluid and
electrolyte management, and ventilatory
parameters are important to optimize the viability of all organs.
• The use of normothermic or hypothermic
ex vivo machine perfusion has been shown
to mitigate risk in extended criteria donors,
more complex recipients, and predicted long
ischemic times.
• The consideration of any donor's heart needs
to be made in the context of the recipient's
situation, with individual risk–benefit analyses carried out in each case. This requires an
understanding of the overall availability and
quality of donors.
•
Donation after circulatory death (DCD) has
significantly increased the donor pool by
including patients who are not braindead but
have a determination of futility of further
active treatment. In these patients, there has
been a planned withdrawal oflife-supporting
therapies (WLST) resulting in irreversible
cessation of circulatory function, at which
time they are declared deadand can become
organ donors (after a 5-minute standoff
period).
8
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
J. Kobashigawa (ed.), Clinical Guide to Heart Transplantation, https://doi.org/10.1007/978-3-031-88290-6_8
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