Transcript Overcoming Antibody Barriers in Renal Transplantation

Overcoming Antibody Barriers in
Renal Transplantation
Reference: Montgomery MA. Renal
transplantation across HLA and ABO antibody
barriers: Integrating paired donation into
desensitization protocols.
Am J Transplant. 2010;10:449–457.
• All patients in need of renal transplantation face the
crisis of organ availability, particularly, those who are
disadvantaged by human leukocyte antigen (HLA)
sensitization or hard-to-match blood types and will
have to wait for prolonged periods.
• At present, there are three options available to patients
who have an incompatible live donor—desensitization,
kidney paired donation (KPD) and a combination of the
two modalities.
• Figure 1 outlines a transplant modality algorithm that
takes into account the clinical phenotypes that are
likely to benefit from the different options.
Desensitization
• Two desensitization protocols have demonstrated clinical
efficacy—Plasmapheresis (or immunoadsorption) and highdose intravenous immunoglobulin (IVIg) with low-dose IVIg
(PP/IVIg).
• Within days of discontinuing plasmapheresis, the anti-HLA
antibody rebounds whereas the transplantation benefit of
high-dose IVIg can continue for several months after the drug
is administered.
• However, both the protocols are designed to lower donorspecific alloantibody (DSA) strength to a level that is safe for
transplantation; besides the immunoregulartory mechanisms
can promote maintenance of reduced antibody reactivity
following preconditioning and transplantation.
High-Dose IVIg
• Similar protocols exist for both live and deceased
donor transplants.
• The protocol consists of monthly infusions of 2
g/kg IVIg until either the crossmatch is deemed
safe or a total of four doses are administered.
• The Mayo group, after performing a head-tohead comparison between a single high-dose of
IVIg and PP/IVIg in live donor recipients, reported
that PP/IVIg was more effective in abrogating a
positive crossmatch particularly when the
strength of the crossmatch was higher.
PP/IVIg
• Effective reduction of HLA antibody and isohemagglutinin via
plasmapheresis helps in the preparation for an incompatible live
donor transplant (see Fig. 2).
• After transplantation, at least two PP/IVIg sessions are performed,
beyond which the duration of treatment is predicated by DSA
levels.
• Low-dose IVIg (100 mg/kg) serves to reduce the synthesis and
release of endogenous antibody that occurs after plasma exchange
otherwise it can have immunomodulatory effects similar to highdose protocols.
• Anti-CD20 has been used selectively in patients with high-risk
donor/recipient phenotypes (combined ABOi and +XM, high XM
starting titer, multiple DSAs and multiple repeat mismatches).
Kidney Paired Donation
• Currently, computer modeling and mathematical
algorithms have helped to simulate incompatible
donor pools.
• When compared to the general donor/recipient
population, incompatible pools contain a
dramatic blood type skewing towards a greater
percentage of hard-to-match O recipients and
fewer valuable O donors.
• However, several of the hard-to-match patients
who are less likely to find matches can be
considered for desensitization.
KPD versus Desensitization
• Two important questions can help to determine
the best option for an individual pair; they are
(1) how difficult will they be to match in a KPD?
and (2) how difficult will they be to desensitize?
• The first question can be addressed using
mathematical simulations to impute the
probability of matching in a KPD based on the
donor blood type, recipient blood type, degree of
sensitization and the size of the KPD pool (see
Table 1).
KPD versus Desensitization
• Once the immunologic profile of the donor/recipient has been
determined, it becomes possible to predict who will be either difficult-todesensitize or at risk for antibody-mediated acute rejection (AMR).
• The strength of the recipient’s antibody reactivity to the donor in positive
crossmatch patients is a good predictor of the length of the
desensitization therapy as well as the risk of AMR after the transplant.
• Broadly sensitized patients will have variable strengths of antibody
reactivity against different HLA molecules.
• Very broadly sensitized patients with high HLA reactivity that are both
difficult-to-match and difficult-to-desensitize can be transplanted by
combining KPD and desensitization (see Fig. 1C).
• Figure 3 reveals that this can be accomplished by raising the threshold for
the antibody strength that defines unacceptable antigens and then search
the KPD database for genotypes that would permit a positive crossmatch
with a low strength.
Conclusion
• Several different interventions with proven
efficacy exist that can be used to avoid or
confront antibody incompatibilities.
• Considering the strengths and limitations of
these interventions can help to apply a more
rational application of therapeutic modalities
that have the potential to add several
thousand additional transplants each year.