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 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.

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.

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).

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-to desensitize 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.