Even Low Levels of Donor-Specific Antibodies Adversely Affect Kidney Allograft Outcomes

/kidneynews/5_1/1/graphic/1f1.jpg

The presence of donor-specific antibodies in kidney recipients is a significant hurdle to successful organ transplantation with good long-term outcomes. Although this is a well-accepted fact, the clinical significance of different levels of these antibodies has been unclear. Now, new research indicates that recipients who have even very low levels of preformed antibodies directed against a donated kidney have a significantly increased risk of acute rejection and graft failure. The findings, which are published in the Journal of the American Society of Nephrology, could help physicians determine better donor-recipient matches and tailor recipients’ immunosuppressive therapy after transplantation.

“Our study reviews disparate findings across different patient cohorts of varying levels of immunological risk and for the first time demonstrates a universally applicable risk stratification using the results of the various currently available immunological testing,” said first author Sumit Mohan, MD, of Columbia University.

Detecting antibodies

Transplant recipients who have had previous transplants, blood transfusions, and other sensitizing events often have antibodies directed against a particular donor’s kidney. Many studies have examined the risks associated with the presence of such donor-specific antibodies in transplant recipients, and there are conflicting reports of the clinical significance of antibodies detected by newer, more sensitive solid-phase assays, especially when the results of more traditional tests such as flow cytometry crossmatching are negative.

“This has been confusing and has limited our ability to understand and develop standard clinical management for patients with donor-specific antibodies at the time of transplantation while at the same time potentially preventing transplantation of certain donor-recipient pairs,” said Mohan. Understanding the true level of risk in patients with antibodies detected by different techniques is essential to optimizing outcomes after transplantation.

To determine this risk, Mohan and his colleagues sifted through the medical literature to find studies that assessed donor-specific antibodies and health outcomes in kidney transplant recipients. Their search identified seven retrospective cohort studies that included 1119 patients. These studies included patients who were shown to be negative for donor-specific antibodies by flow cytometry crossmatching. They compared patients with and without donor-specific antibodies detected by solid-phase assays at the time of transplantation. The analysis allowed the investigators to define the level of risk of acute antibody-mediated rejection and allograft failure in patients with donor-specific antibodies relative to patients without.

Determining risk

After analyzing the results of these studies, the investigators determined that the detection of donor-specific antibodies by newer solid-phase assays—despite negative results from older tests—nearly doubles the risk for acute antibody-mediated rejection and increases the risk of graft failure by 76 percent. (The absolute risk of failure in the first year in the United States is currently about 8.2 percent for first-time recipients and about 10.7 percent for recipients of repeated transplants.)

Previously reported cohorts of patients who were tested only with the most recent solid-phase assays were more heterogeneous than previously thought, the authors found. These cohorts included patients who would have been identified as being at risk by flow cytometry; as a result, these cohorts tended to have a much higher risk of acute antibody-mediated rejection (odds ratio of 7.8) and similar graft failure (odds ratio of 1.7). The researchers were also able to demonstrate differences in relative risk in patients with and without donor-specific antibodies by solid-phase assays when the cohorts were defined by flow cytometry results.

“Our findings allow clinicians to use the results of various tests available to measure the presence of antibodies in recipients for both prognostication and potential identification of those patients who would benefit from more aggressive immunosuppression at the time of transplantation,” said Mohan. The findings also suggest the need for increased vigilance in patients with donor-specific antibodies detected by solid-phase assay with a negative crossmatch—and perhaps more so in patients with donor-specific antibodies detected by solid-phase assays at centers that have foregone flow crossmatching tests.

Mohan noted that the study was limited by the quality of the current literature; the included studies tended to have very different immunosuppression treatment protocols, and they reported outcomes after different lengths of follow-up. Nonetheless, the results were consistent and confirmed differences of patient outcomes based on differences in the measurement of immunological risk by flow cytometry and solid-phase assays regardless of the immunosuppression protocol used.

“This article is an important reminder that donor-specific antibodies are clinically relevant, the treatment protocols are heterogeneous, and the available evidence is limited,” said Dorry Segev, MD, PhD, who was not involved with the research and is a transplant surgeon at the Johns Hopkins School of Medicine. Segev is an expert in issues related to incompatible kidney transplantation and organ allocation. “The problem of sensitization to donor-specific antibodies is not going away, but rather is getting worse, and will not be solved by paired donation alone. The findings provide strong motivation for the creation of large multicenter cohorts to better study treatment protocols and center-specific effects in kidney transplantation across donor-specific antibody barriers,” he added.

Nearly 17,000 kidney transplantations take place each year in the United States.

Notes

[1] Study coauthors include Demetra Tsapepas, PharmD, Bekir Tanriover, MD, R. John Crew, MD, Geoffrey Dube, MD, Lloyd E. Ratner, MD, David Cohen, MD, and Jai Radhakrishnan, MD.

[2] Disclosures: The authors reported no financial disclosures.

[3] The article, entitled “Donor-Specific Antibodies Adversely Impact Kidney Allograft Outcomes,” is online at http://jasn.asnjournals.org/, doi: 10.1681/2012070664.

January 2013 (Vol. 5, Number 1)