Identifying Patients at Lower Risk for Kidney Transplant Rejection

A new risk stratification model developed by Northwestern Medicine scientists may help better identify patients who have a lower risk of kidney transplant rejection, which can inform more personalized treatment and care strategies that present fewer adverse side effects, as detailed in a recent study published in Nature Communications.

Anat Roitberg-Tambur, DMD, PhD, research professor of Surgery in the Division of Organ Transplantation, was senior author of the study.

An estimated 100,000 kidney transplants are performed each year globally in patients with kidney failure, according to data from the Global Observatory on Donation and Transplantation.

Despite the procedure’s initial success, patients remain at risk of organ transplant rejection, which can occur if the recipient develops antibodies that attack mismatched proteins called human leukocyte antigens (HLAs) that are carried by the donor kidney.

The most effective approach to mitigate this HLA incompatibility is to find an HLA-matched organ donor, however, the likelihood of finding such a match is very low. Quantification tools have also been proposed to allow the identification of lower risk donors, as demonstrated by correlation between HLA mismatches and risk of developing de-novo donor-specific antibodies in previous retrospective studies.

Nonetheless, these approaches were not always effective when a physician had to make a decision for an individual patient. Therefore, there remains a need for approaches that are tailored to support informed personalized treatment strategies.

To better identify the biological reasons as to why some HLA mismatches are more incompatible than others, the scientists analyzed patient data from more than 3,000 kidney transplant recipients from five transplant centers in the U.S., Belgium, the Netherlands and Spain.

The scientists used a variety of techniques, including hierarchical clustering based on HLA evolutionary divergence and amino acid physiochemical unique qualities, to evaluate the specific cell surface proteins that trigger the generation of antibodies.

From their analysis, they discovered that HLA-DQ alleles separate into two main groups that were separated during evolution, such that mismatches across these two main groups led to increased risk of developing HLA-DQ de-novo donor-specific antibodies

The scientists then further divided the HLA-DQ alleles into six functional groups and developed a qualitative risk stratification that is associated with increased risk to develop de-novo donor-specific antibodies, antibody-mediated rejection and graft loss.

Using this risk stratification model could help better identify patients with lower risk of organ transplant rejection and, therefore, determine which patients may benefit from less post-transplant immunosuppressive medications, which generally have severe side effects, according to Roitberg-Tambur.

“The most important thing will be the immediate post-transplant management of patients. Right now, after a patient goes through transplantation, they’re bombarded with immunosuppression medications. But if you can risk-stratify those patients, you can determine which patients can have their immunosuppression dialed down, and which patients must remain on a high level of immunosuppression medications,” said Roitberg-Tambur, who is also a member of the Center for Human Immunobiology.

Going forward, the scientists aim to validate their new risk stratification model using patient data from different geographic areas.

“Our biologically grounded model offers a practical tool that can be implemented in clinical decision-making peri- and post-transplantation, including choice of maintenance immunosuppression or insights regarding the safety of stepwise immunosuppression tapering. Critically, risk stratification of donor mismatches can guide the frequency of immune monitoring both for de novo donor-specific antibodies and invasive biopsies,” the authors wrote.

Co-authors of the study include Akansha Agrawal, MD, assistant professor of Medicine in the Division of Nephrology and Hypertension, Aleksandar Senev, MD, PhD, research assistant professor of Surgery in the Division of Organ Transplantation.

This work was funded in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant RO1A170728).

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