Dr. Alexander Wiseman and Dr. Carrie A Schinstock are paid partners of Biogen. In addition, Dr. Schinstock is a principal investigator for ongoing research in AMR and MVI.
Each year, approximately 23,000 people in the U.S. are diagnosed with antibody-mediated rejection (AMR) after a kidney transplant,1 making it a driving force of transplant failure and the leading cause of long-term graft loss. When transplants fail due to rejection, the consequences are far-reaching: patients are forced to rejoin an overburdened transplant waitlist and go back onto dialysis, confronting the physical and emotional toll of starting over.
While there are therapies used to manage certain aspects of AMR, no treatments are currently approved by the U.S. Food and Drug Administration to treat it, largely due to a lack of established efficacy in clinical studies. This was in part due to our limited grasp of the underlying cause. However, a deeper understanding of the mechanistic drivers of AMR is opening new possibilities, advancing both therapeutic development and our fundamental understanding of rejection biology itself.
Uncovering a Hidden Driver of Rejection
For years, AMR was understood primarily as an antibody-driven disease, where the body produces antibodies against the donor graft, referred to as donor specific antibodies (DSAs), which can set off a cascade of events that result in graft injury. The standard of care has focused on trying to remove antibodies and increasing broad immunosuppression. This approach has significant limitations. However, recent research has revealed that AMR is more complex than DSA alone. While CD38-positive plasma cells are responsible for producing antibodies, other immune cells, including CD38-positive natural killer (NK) cells, contribute to kidney damage through antibody-independent mechanisms, such as "missing self" recognition and recognizing the graft as foreign. These can cause direct cellular damage and drive microvascular inflammation (MVI), a strong predictor of transplant outcomes. This means that current approaches, which focus primarily on managing antibody levels, often miss a critical piece of the disease puzzle.
