New study refines understanding of kidney transplant rejection

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

The research, published in The New England Journal of Medicineexamined 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 shows that inflammation in even the smaller blood vessels around the kidneys portends long-term problems,” said Vikas Dharnidharka, chairman of pediatrics at Rutgers Robert Wood Johnson Medical School and one of the study authors.

Transplantation typically gives patients with non-functioning kidneys a longer and better life than dialysis, but many transplants fail because patients’ bodies reject the new organ and turn their immune systems against it.

Doctors reduce the risk of rejection 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 attack by the immune system and protecting the patient from infectious diseases that attack an overly suppressed immune system.

“If you try to treat rejection with stronger immunosuppressive drugs, you run the risk of developing life-threatening infections,” Dharnidharka said. “So it is 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 Classificationan international standard for diagnosing transplant rejection, to categorize biopsy results.

A major 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 these types 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 presence of antibodies.

The survey 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 non-rejections, but the latest study linked such results to an increased risk of rejection.

Patients with MVI had more than twice the risk of graft failure as patients without signs of rejection. Patients with antibody-mediated rejection were almost three times more likely to experience graft failure than patients without signs of rejection.

The study also found that patients with these newly categorized types of inflammation were at greater 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 studies that improve care for patients falling into this classification.

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

Clinical trials comparing different treatment methods for these types of inflammation 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 in children, making it easier to recruit large numbers of adult patients for large research projects.

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