A new study advances understanding of kidney transplant rejection

Rutgers Health researchers and other medical scientists involved in a major international effort test identified new signs of kidney transplant rejection that may lead to more accurate diagnosis and treatment of transplant recipients.

Research published in New England Journal of Medicineexamined more than 16,000 kidney transplant biopsies and found that some results previously considered questionable actually indicate an increased risk of graft failure.

“This study shows that inflammation of even the smaller blood vessels around the kidneys is a precursor to future problems,” said Vikas Dharnidharka, chair of pediatrics at Rutgers Robert Wood Johnson Medical School and one of the study’s authors.

A transplant usually gives patients failing kidneys a longer, better life than dialysis, but many transplants fail because the patient’s body rejects the new organ and turns its immune system against it.

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

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

“If you try to treat rejection with stronger immunosuppressive drugs, you risk developing life-threatening infections,” Dharnidharka said. “So it’s not a trivial decision that we make because there are risks 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 Banff classificationinternational standard for diagnosing transplant rejection, enabling categorization of biopsy results.

The main focus was on microvascular inflammation – damage to small blood vessels in the transplanted kidney. The 2022 Banff classification update added two new categories related to this type of inflammation. The first, called “DSA-negative, C4d-negative microvascular inflammation/injury” or MVI, describes inflammation without other typical symptoms 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 the likely outcomes of transplant patients. The answer was a resounding “yes.”

Investigators found 503 of 16,293 biopsies in the MVI category and 285 in the probable antibody-mediated rejection category. Previous classification criteria would have marked these cases as no rejection, but the latest study linked such findings to an increased risk of rejection.

Patients with MVI were more than twice as likely to have graft failure at five years than those without symptoms of rejection. Patients with antibody-mediated rejection had almost three times the risk of graft failure compared with patients without symptoms of rejection.

The study also found that patients with newly classified types of inflammation were more likely to develop more severe transplant rejection or chronic kidney damage over time.

Such results strongly support the diagnostic utility of the new classification and pave the way for future research that will improve the care of patients who fall within it.

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

Clinical trials comparing different approaches to treating this type of inflammation will likely start with adult patients and then expand to pediatric transplant recipients, says Dharnidharka, who specializes in pediatric cases. Renal failure is much more common in adults than in children, so it is 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 heart, lung and other organ transplants where similar types of inflammation may occur. Each year, about 25,000 Americans receive kidney transplants, and another 20,000 receive other organ transplants.