Sensitized Candidates - Professor Richard Kirk 2023

Cardiac Transplantation
Evaluation	Listing	Candidate Follow Up	Donor Offer	Peri Tx Issues	Transplant Week 1	Transplant Follow Up	Rejection	Graft Failure	Drug Interactions	Dallas Guidelines

Sensitised Candidates

Transplant candidates may have preformed HLA antibodies to potential donors which may put them at risk of acute antibody mediated rejection in the post transplant period. Quantifying the risk can be difficult. The HLA laboratory report usually details the individual antibodies and strength (MFI) and the overall chance of finding a donor who has none of the antigens to which the candidate has antibodies (calculated Panel Reactive Antibodies- cPRA). Class I antibodies have the greatest significance at the time of transplant, but other classes may also cause rejection, especially if strong. It is also important to know that the laboratory information, for various technical reasons, may not truly reflect the immunological reaction between donor and recipient - it is therefore a very helpful guide, but surprises occur.

When a candidate has a large number of antibodies thus a high cPRA the options range from not transplanting, taking the first donor to be offered regardless of the antibodies or something between these 2 approaches. A reasonable approach to listing a candidate with HLA antibodies is to look at the strength of individual antibodies - those that are < 5,000 are unlikely to cause immediate rejection, those > 10,000 will likely cause rejection.

When a candidate has many antibodies with a range of MFIs commonly found in the potential donor population (a high cPRA) there are various options. Either the candidate can be listed and donors with any of the antigens against the candidate antibodies (donor specific antibodies - DSA) avoided in which case transplant may be unlikely or donors with antigens against high MFI candidate antibodies can be excluded but donors with low MFI candidate antibodies can be accepted. This allows a much greater chance of a transplant occurring.

There are online calculators to predict the cPRA but it is preferable to ask the HLA laboratory what the cPRA would be if certain strong MFI antigens are avoided.

Online cPRA Calculators
Eurotransplant Reference Laboratory	NMDP CPRA Calculator	Organ Procurement Transplant Network	Allele Frequencies

To take a simple example. A candidate may have lots of HLA antibodies with a cPRA of 100%, but only the A2 antibody has a high MFI, the others are all low. If a donor is sought to which the candidate has no antibodies, then they will never be transplanted. However, an A2 antibody is usually present in half the population so the candidate could be listed, donors with an A2 genotype rejected, but other donors accepted. This would mean that 50% of donor offers would be acceptable for the candidate.

Taking this approach makes it possible to decide an individual strategy to balance the risk of rejection against the risk of dying on the wait-list. When a sensitised candidate is listed for transplant the risk of crossing various antigens is balanced against the patient condition and the antibody strength. Below is a suggested strategy at the time of transplant.

Finally if there is time it may be possible to reduce HLA antibodies pre transplant by desensitisation but this generally takes months and current techniques are imperfect. It is also possible to block the effects of antibodies, currently either by blocking the complement cascade (eculizumab) or by cleaving the antibodies (infliximab) however these tend to only gain time to try and reduce the antibody production and are currently not a long term solution.

Strategy for Sensitized Candidates
Antibody Strength	Desensitisation	Action
MFI > 10,000	Consider desensitisation	Avoid if possible, otherwise CTOTc plus consider eculizumab, infliximab
MFI 5,000-10,000	Consider desensitisation	Avoid unless patient condition severe, otherwise CTOTc protocol
MFI < 5,000		Cross if necessary, CTOTc protocol

CTOTc Protocol

When the virtual crossmatch is positive, the 1-3 plasma volume exchanges are undertaken in the OR prior to Xclamp release
If the subsequent "wet" complement dependent cytotoxic crossmatch (CDC) is negative, normal post operative care is given
If the CDC crossmatch is positive then

Undertake 1-1.5 plasma changes daily for the first 5 days
IVIG 2 g/kg IV within 24 hours of the last planned plasmapheresis. Five additional doses will be given commencing one month post transplant,and monthly thereafter
Usual treatment with tacrolimus and MMF
Corticosteroids 0.25 mg/kg/day, enteral route, with a maximum dose of 20 mg per day. Tapering of 0.05 mg/kg at monthly intervals if possible. Steroids to be maintained for a minimum of six months