Desensitization in kidney transplantation: a clear survival benefit

I would like to direct your attention to a landmark paper in transplantation just published on the NEJM two weeks ago.

We have previously discussed the terms used to characterize sensitized patients and the most common protocols to overcome this barrier to transplantation. Briefly, more than 30% of patients on the waiting list for a kidney transplant are sensitized to HLA antibodies, with more than 8,000 patients being highly sensitized. Sensitized patients have 3 options to undergo kidney tx:

- stay on the waiting list (hoping to get a matched kidney - annual transplantation is below 7%);
- enroll in a paired kidney donation (improves chances but still low rate); or
- undergo a desensitization protocol.

Desensitization usually involves plasmapheresis, IVIg and high dose immunosuppressive drugs (+/- rituximab) in order to decrease circulating anti-HLA antibodies. These patients have a high risk of complications, including bleeding, cancer, infection and antibody-mediated rejection (which is associated with poor allograft function). Moreover, these patients are very expensive to the hospital’s transplant program. More recently, with the spread of quality of measures in transplantation, having many sensitized patients on a program can significantly reduce the successful statistical outcomes of transplantation and consequently deteriorate the image of the program. Therefore, many programs just avoid taking highly sensitized patients.

Despite all the potential complications, whether undergoing desensitization leads to significant long-term survival benefit is unknown. Montgomery et al. analyzed a single-center cohort of 211 sensitized patients who underwent desensitization (IVIg+plasmapheresis) followed by renal transplantation, comparing with two carefully matched control groups of patients on a waiting list for kidney tx who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group). During the 11-year study period, 98% of the sensitized patients underwent successful transplantation and this study included patients with different detection methods of anti-HLA antibodies, such as positive cross-match by cytotoxicity assay, flow cytometry and/or bead assay (Luminex).

In the desensitized group, rates of survival were 90.6% at 1 year, 85.7% at 3 years and 80.6% at 8 years, compared with 91.1%, 67.2% and 30.5% in the dialysis-only group (view figure). Among the different levels of anti-HLA antibodies, patients with positive cross-match by cytotoxicity assay carried the worst outcome. Nonetheless, the survival benefit curve crossed at 18 months even in that group. Combining all sensitized groups, the survival benefit was clear after 12 months.

Overall, major adverse events during desensitization treatment occurred in less than 5% of patients, including anaphylaxis or bleeding. The most common cause of death was cardiovascular disease (~16% patients) and there were 6 deaths related to infection (~3%), which were likely secondary to the intensive immunosuppression produced by the desensitization protocol. In summary, sensitized patients can obtain a significant survival benefit by undergoing desensitization followed by kidney transplantation compared to alternative options, but risks of infection are higher and more studies are needed to help identify patients at greatest risk of dying and suffering from complications like malignancy or cardiovascular disease.