Overcoming Antibody Barriers in Renal Transplantation

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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. 201010449457.

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• 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
  donordesensitization, 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.

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Desensitization

• Two desensitization protocols have demonstrated
  clinical efficacyPlasmapheresis (or
  immunoadsorption) and high-dose 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
  donor-specific 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.

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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-to-head
  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.

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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
  high-dose 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).

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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.

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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).

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KPD versus Desensitization

• Once the immunologic profile of the
  donor/recipient has been determined, it becomes
  possible to predict who will be either
  difficult-to-desensitize or at risk for
  antibody-mediated acute rejection (AMR).
• The strength of the recipients 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.

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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.