New study refines understanding of kidney transplant rejection

Rutgers Health researchers and other medical scientists involved in a large international study have identified new signs of kidney transplant rejection that could lead to more precise diagnosis and treatment for transplant recipients.

The research, published in The New England Journal of Medicine, examined more than 16,000 kidney transplant biopsies and found that certain results previously thought to be of questionable significance actually indicate an increased risk of transplant failure.

"This study reveals that inflammation in even the smaller blood vessels around the kidneys predicts trouble down the road," said Vikas Dharnidharka, the chair of pediatrics at Rutgers Robert Wood Johnson Medical School and one of the study authors.

Transplantation typically provides patients with nonworking kidneys longer and better lives than dialysis, but many transplants fail because patient bodies reject the new organ and direct their immune systems against it.

Doctors reduce rejection risk by giving transplant patients medications that suppress their immune systems. They adjust medication levels by using blood tests and biopsies to monitor transplanted kidneys.

Post-transplant treatment is a delicate balance between protecting the transplanted organ from immune system attack and protecting the patient against infectious diseases that attack an overly suppressed immune system.

"If you try to treat a rejection with stronger immunosuppression medicines, you run the risk of life-threatening infections occurring,” Dharnidharka said. “So, it's not a trivial decision that we make because there is a risk involved.”

The study examined kidney biopsies performed between 2004 and 2023 at more than 30 transplant centers in Europe and North America. Researchers used the latest criteria from the Banff Classification, an international standard for diagnosing transplant rejection, to categorize the biopsy results.

A key focus was on microvascular inflammation – damage to the small blood vessels in the transplanted kidney. The 2022 update to the Banff Classification added two new categories related to this type of inflammation. The first, called "microvascular inflammation/injury, DSA-negative, C4d-negative," or MVI, describes inflammation without other typical signs of antibody-mediated rejection. The second, "probable antibody-mediated rejection," indicates milder inflammation with some antibody presence.

The study asked whether these new categories provide useful information about likely outcomes for transplant patients. The answer was a resounding “yes.”

The researchers found 503 of 16,293 biopsies in the MVI category and 285 in the probable antibody-mediated rejection category. Previous classification criteria would have labeled these as nonrejections, but the latest study tied such results to elevated rejection risk.

Patients with MVI had more than twice the five-year graft-failure risk as patients with no signs of rejection. Patients with antibody-mediated rejection were nearly three times as likely to experience graft failure than patients with no signs of rejection.

The study also found patients with these newly categorized types of inflammation were at higher risk of developing more severe rejection or chronic kidney damage over time.

Such results strongly validate the diagnostic utility of the new classification and pave the way for future trials that improve care for patients who fall into them.

"These data indicate that we should be treating patients who fall into these categories differently," said Dharnidharka, who is also physician-in-chief of the Bristol-Myers Squibb Children’s Hospital at Robert Wood Johnson University Hospital. "What is the right treatment? How much is the right treatment? We should be doing tests that compare different strategies."

Clinical trials comparing different treatment approaches for these inflammation types would likely start with adult patients before expanding to pediatric transplant recipients, said Dharnidharka, who specializes in pediatric cases. Kidney failure is much more common in adults than children, so it is easier to recruit large numbers of adult patients for large research projects.

Looking forward, the implications of the study’s findings may extend beyond kidney transplants to those of hearts, lungs and other organs, where similar types of inflammation may occur. About 25,000 Americans receive kidney transplants each year, while another 20,000 receive transplants of other organs.