Highly Sensitized Patients Are Well Served by Receiving a Compatible Organ Offer Based on Acceptable Mismatches

Abstract

Highly sensitized kidney patients accrue on the transplant waiting list due to their broad immunization against non-self Human Leucocyte Antigens (HLA). Although challenging, the best option for highly sensitized patients is transplantation with a crossmatch negative donor without any additional therapeutic intervention. The Eurotransplant Acceptable Mismatch (AM) program was initiated more than 30 years ago with the intention to increase the chance for highly sensitized patients to be transplanted with such a compatible donor. The AM program allows for enhanced transplantation to this difficult to transplant patient group by allocating deceased donor kidneys on the basis of a match with the recipient's own HLA antigens in combination with predefined acceptable antigens. Acceptable antigens are those HLA antigens towards which the patients has never formed antibodies, as determined by extensive laboratory testing. By using this extended HLA phenotype for allocation and giving priority whenever a compatible donor organ becomes available, organ offers are made for roughly 80% of patients in this program. Up till now, more than 1700 highly sensitized patients have been transplanted through the AM program. Recent studies have shown that the concept of acceptable mismatches being truly immunologically acceptable holds true for both rejection rates and long-term graft survival. Patients that were transplanted through the AM program had a similar rejection incidence and long-term graft survival rates identical to non-sensitized patients transplanted through regular allocation. However, a subset of patients included in the AM program does not receive an organ offer within a reasonable time frame. As these are often patients with a rare HLA phenotype in comparison to the Eurotransplant donor population, extension of the donor pool for these specific patients through further European collaboration would significantly increase their chances of being transplanted. For those patients that will not benefit from such strategy, desensitization is the ultimate solution.

Keywords: HLA; acceptable antigen; desensitization; donor specific antibodies; donor specific antibody (DSA); histocompatibility; kidney transplanation; organ allocation.

Figure 1

Characteristics of patients enrolled in the AM program. (A) The number of patients included in the AM program and transplanted through the AM program from 1989 to 2020. (B) Country of origin of patients transplanted through the AM program. (C) Percentage of transplants through the AM program within all renal transplants from deceased donors within Eurotransplant in the last 10 years.

Figure 2

Organ offers and effectuated transplants in the AM program. A time period of 01-01-2015 to 31-21-2016 was selected for inclusion of AM patients (n = 417). (A) Rate of first organ offer to patients on the AM waiting list. (B) Rate of first organ offer to patients on the AM waiting list stratified for the chance of an organ offer within the AM program. (C) Rate of transplantation of patients on the AM waiting list. (D) Rate of transplantation of patients on the AM waiting list stratified for the chance of an organ offer within the AM program.

Figure 3

The 15-year death censored graft survival of AM patients is similar to that of unsensitized patients. Selection was based on criteria described prior (16) and included: transplantation from 1996 onwards (start ETKAS allocation), minimum 1 HLA mismatch, kidney only, repeat transplants (since the vast majority of AM patients are repeat transplant candidates). Patients transplanted through ETKAS are subdivided into 0-5% PRA (non-sensitized), 6-85% PRA (intermediately sensitized), >85% PRA (highly sensitized, transplanted outside the AM program).