Doc, I am very sensitized!

Another day of transplant clinic… I heard from my attending that a couple is here for a second opinion about a kidney transplant. The husband is a 60 yo male with ESRD 2/2 PKD who had a previous transplanted kidney about 10 years ago that failed last year. Due to persistent fevers, he underwent a nephrectomy of his allograft recently. On revaluation for a second transplant 1 month later, he was found to have a PRA of 98% and also positive cross-match for B and T cells against his son. His physician was not very excited about attempting another transplant and he was looking for additional recommendations.

I feel that dealing with highly sensitized patients have become very common and UNOS reports that more than 25% of patients on the waiting list are sensitized and of those with PRA >80%, only 8% of patients will ever be transplanted! Today, we will discuss some of the terms used in describing sensitized patients and on my next blog will focus on the management of these patients.

The Panel of reactive Antibody (PRA) is a screening test that can tell you how sensitized a potential transplant recipient is to HLA antigens in general. The source of HLA antigens are usually a combination of B and T cells from a panel of donors selected to represent commonly found HLA antigens in the local population. Once the serum of the recipient is added followed by complement, cell lysis detection is performed and the results are represented as the percentage of panel cells that are killed by the serum. The PRA does not tell you if you have antibody against any specific donor, but it can estimate how sensitized you might be to potential donors in your community and predict the likelihood of finding a compatible donor. For example, a PRA 70% suggests that 70% of donors will likely be unacceptable for the tested patient due to the presence of anti-HLA antibodies.

On the other hand, the crossmatch can specifically test if the recipient has any antibodies against the donor. Our patient above was very sensitized with a PRA of 98% and also had specific anti-HLA antibody against his donor. A positive crossmatch against B and T cells suggest class I anti-HLA Ab, while the presence of only Abs against B cells indicates class II. IgG antibodies against class I are the most important for transplantation. IgM antibodies usually represent autoantibodies and are not considered true sensitization. Their activity can be removed either by heating the serum to 55 degrees C or by using DTT reducing agent. If crossmatch is positive, the lab will also usually run recipients' serum with his/her own cells to rule out auto-antibodies.

The crossmatch assays available differ in their sensitivity to detect Abs and most centers perform the classic cytotoxicity (CDC) assay, while others also perform a flow cross-match and/or luminex. In addition to determining the positivity, these assays can tell you how strong the reaction is by reporting the titer. Regardless of the test used, highly sensitized patients are often crossmatch positive to multiple potential donors and require a zero antigen mismatch allograft to increase success. These patients are therefore relegated to the deceased donor waiting list and have a very low rate of eventual transplantation.

For this reason, desensitization against preformed HLA antibodies should be considered. The titers of antibodies are important in determining how feasible a desensitization might be. We will discuss on the next blog the current recommended desensitization protocols according to anti-HLA titer levels and other potential options, focusing on our case above as an example.

Addendum: Your lab might perform additional modifications of the CDC assay: Amos-modified CDC to eliminate clinically irrelevant Abs and AHG-modified CDC, in which anti-human globulin (AHG) is added to induce cross linking and increase sensitivity.