Rewriting What We Know About Kidney Transplant Rejection

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.

“AMR remains one of the biggest challenges in kidney transplantation, because our current options lack specificity against the primary mediators of graft injury,” explains Dr. Alexander Wiseman, Executive Director, Kidney Transplantation at AdventHealth Porter Adventist Hospital in Denver, Colorado.

“Targeting the specific CD38-expressing cells that drive disease represents an important shift toward addressing the biology that can cause ongoing damage to the transplant and may give physicians a long sought-after tool to manage or even prevent rejection.”

CD38: Targeting the Root Causes of AMR

To meet this need, a new treatment philosophy is emerging. By targeting certain CD38-expressing cells, it may become possible to address both antibody-dependent and antibody-independent drivers of transplant rejection. Rather than broadly suppressing the immune system or temporarily reducing antibody levels, this unique approach aims to selectively target and deplete disease-causing cells that express CD38, with the goal of slowing down or halting progression at its source.

Recent research revealing CD38-positive NK cells as potentially an entirely new driver of disease enables novel avenues of study and clinical trials in patients without pathogenic antibodies.

Studies have further determined that NK cells are likely the primary driver of MVI in patients who lack detectable donor-specific antibodies, a population that has previously been excluded from trials and currently have no treatment options. This evolving understanding directly informed the Phase 2 TRANSPIRE study, the first clinical trial to study patients affected by this.

“The ongoing TRANSPIRE study reflects a growing recognition that MVI can be harmful to the graft, even in the absence of a full diagnosis of AMR. Studying patients with MVI, including those who are DSA-negative, may help us to better treat the biology that’s driving injury in a transplanted kidney,” shares Dr. Carrie A Schinstock, Medical Director of Kidney Transplantation at Mayo Clinic in Rochester, Minnesota.

The Broader Hope of CD38

As researchers deepen their understanding of how certain CD38-expressing cells promote inflammation, broader insights are emerging about how the immune system contributes to kidney disease. This approach is now being explored in other immune-mediated kidney diseases, including IgA nephropathy (IgAN), the most prevalent chronic glomerular disease worldwide. And the potential applications extend even further. Targeting CD38-expressing cells may have relevance across multiple therapeutic areas where harmful antibody production drives disease.

Despite the complexity of transplant rejection and kidney disease, meaningful innovation is possible with the understanding of what drives disease at the cellular level. Directly targeting the cellular infiltrate (i.e., natural killer cells) associated with disease progression can potentially serve as a new approach to transplant management.

Biogen is currently pursuing investigational research into a therapeutic CD38 target via Phase 2 and Phase 3 clinical studies to address this critical unmet need. To learn more about this emerging research, visit https://www.biogen.com/disease-areas/kidney-disease.html.

References:

1. SRTR; National Institute of Diabetes and Digestive and Kidney Diseases; Department of Health; Hart, Singh. Clin Transplant 2021; Crew. Am J. Transplant. 2016

The MedPage Today Editorial team was not involved in the creation of this content.

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