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Felzartamab and the Hidden Injury of Isolated MVI, With Yasir Qazi, MD
TRANSPIRE investigator Yasir Qazi, MD, explains how isolated MVI can signal kidney transplant injury before creatinine rises.
Isolated microvascular inflammation (MVI) can signal injury in a transplanted kidney even when creatinine levels remain stable and donor-specific antibodies are undetectable. Despite its association with poorer graft outcomes, no treatments are currently approved specifically for this condition.
In an interview with HCPLive, Yasir Qazi, MD, a transplant nephrologist at Providence St. Joseph Hospital in Orange, California, associate professor of clinical medicine at the Keck School of Medicine of USC, and an investigator on the phase 2 TRANSPIRE trial of felzartamab, explained why this inflammation can go unrecognized until more substantial kidney injury has occurred.
“Creatinine, which is a reflection of how well the kidney is functioning, is a sum total of at least 1 million nephrons in the kidney, and if only 10, 15, 20, 30 nephrons are getting implicated with, let’s say, microvascular inflammation, the rest of the nephrons are doing a great job in fooling us to think that nothing’s going on in the kidney,” Qazi said.
One way this otherwise hidden injury has come into focus is through biomarkers. Qazi described how transplant centers began identifying patients with stable kidney function but abnormal biomarker findings, prompting biopsies that revealed MVI. Because a transplanted kidney carries DNA distinct from its recipient, donor-derived cell-free DNA can provide a signal of graft injury even before conventional measures of kidney function change.
The 2022 Banff classification recognized DSA-negative, C4d-negative MVI as a distinct phenotype,² and subsequent research associated this finding with approximately twice the risk of graft failure compared with patients without rejection.³ Together, these developments have drawn attention to inflammatory processes that may have previously gone undetected.
Qazi suggested that such injury could help explain why achieving decades of graft survival remains challenging, even as transplant medicine has advanced. He also noted that the Banff classification was undergoing further updates at the time of the interview, potentially refining how these inflammatory findings are characterized.
Testing Anti-CD38 Felzartamab in Isolated MVI
The Biogen-sponsored phase 2 TRANSPIRE trial is investigating whether felzartamab can resolve isolated MVI in kidney transplant recipients.¹ The investigational anti-CD38 monoclonal antibody targets CD38-expressing cells, including natural killer (NK) cells and plasma cells, which may contribute to inflammatory pathways involved in graft injury.
Qazi explained that targeting these cell populations could potentially interrupt a cycle in which inflammation activates additional damaging pathways, a process he described as “injury begets more injury.”
Adults with late isolated MVI are randomized to felzartamab or placebo for 24 weeks, followed by open-label felzartamab through week 52. The primary endpoint is biopsy-proven resolution of MVI, with results expected in 2028.
The study builds on felzartamab research in antibody-mediated rejection, including the phase 3 TRANSCEND trial, but extends investigation to patients whose MVI occurs without detectable donor-specific antibodies.
For Qazi, the significance of intervening at this stage extends beyond whether inflammation resolves on biopsy. The larger question is whether addressing injury before creatinine rises or protein appears in the urine could change the subsequent course of graft deterioration.
“We hope that this is going to protect that kidney from even having to go through a phase where you spill protein or you have a rise in the creatinine,” Qazi said.
Whether histologic resolution translates into longer graft survival remains to be established. Still, Qazi views earlier recognition and treatment of microvascular injury as a potential step toward a longstanding goal in transplant nephrology: one kidney for life.
Editors’ Note: Disclosures for Qazi include Natera, CareDx, and Eurofins. TRANSPIRE is sponsored by Biogen.
