Non-Specific Graft Injury and Inflammation Associated with Early Acute Cellular Rejection in Pediatric Liver Transplant Recipients

A new analysis presented by UPMC Children’s Hospital of Pittsburgh physicians and researchers at the 2025 World Transplant Congress explored non-immune system factors that could be related to the development of acute cellular rejection in the first year posttransplant in pediatric liver transplant recipients.

UPMC Children’s co-authors included Rakesh Sindhi, MD, FACS, director, pediatric transplantation research and George V. Mazariegos, MD, FACS, chief, pediatric transplantation, Kyle Soltys, MD, Simon Horslen, MD, director, pediatric hepatology, and James E. Squires, MD, associate director, pediatric hepatology.

Previous research has shown an association between primed pre-transplant memory T-cells and early acute cellular rejection in pediatric liver transplant recipients. The research team explored the association between tissue inflammation and injury and the development of acute cellular rejection within the first year posttransplant.

Researchers retrospectively examined posttransplant biopsies in 283 pediatric liver transplants performed at UPMC Children’s between 2014 and 2023. There were 281 transplant recipients because 5 of the 283 transplants were retransplants.

Disease indications for liver transplant included metabolic disease (138), cholestatic disease (98), unresectable malignancy (19), acute liver failure (13), hepatopulmonary/portopulmonary syndrome (3), and benign tumor (1).

Although the original subject group included 283 liver transplants, 79 grafts were not biopsied within 12 months after transplant. Biopsies were performed when recipients’ aminotransferase (liver enzyme) blood tests indicated potential liver injury, but liver blood flow appeared normal in ultrasound imaging.

The remaining 204 grafts varied in the number of biopsies performed within the one year posttransplant period. 70 of the 204 grafts (34%) were biopsied once in the first year posttransplant, 46 (23%) were biopsied twice, and 34 (17%) were biopsied three times. 19 (9%) grafts were biopsied four times, and 35 (17%) were biopsied between 5 and 11 times.

Acute cellular rejection was detected in the first biopsy of 109 grafts (53.4%). Acute cellular rejection with bile duct obstruction was detected in the first biopsy of 3 grafts (1.5%). The median number of days between the liver transplant and the first biopsy was 25.5 (3-350).

Non-specific inflammation and injury were detected in the first biopsy of 47 grafts. 28 of 204 grafts (13.7%) indicated non-specific inflammation. 19 of 204 grafts (9.3%) indicated a cholangitic (bile duct) pattern of inflammation.

31 of 204 recipients (15%) were diagnosed with acute cellular rejection in their second or later biopsy. The median number of days between the liver transplant and the second or later biopsy was 67.5 (17-349). The grafts that later progressed to acute cellular rejection had varied results at their first biopsy, including indeterminate for acute cellular rejection, non-specific inflammation and bile duct inflammation.

Implications

Researchers found that non-specific inflammation and injury could precede the diagnosis of acute cellular rejection in the first year after pediatric liver transplant.

Future research is needed to better understand the relationship between the non-specific inflammation and injury detected at the tissue level and the development of acute cellular rejection in pediatric liver transplant recipients. If non-specific tissue swelling or injury is a potential warning sign of future acute cellular rejection, posttransplant surveillance protocols could be adjusted to enable earlier treatment and improve patient outcomes.

Read the full abstract.