Benefit of B7-1 staining and abatacept for treatment-resistant post-transplant focal segmental glomerulosclerosis in a predominantly pediatric cohort: time for a reappraisal

Abstract

Background Primary FSGS manifests with nephrotic syndrome and may recur following KT. Failure to respond to conventional therapy after recurrence results in poor outcomes. Evaluation of podocyte B7-1 expression and treatment with abatacept (a B7-1 antagonist) has shown promise but remains controversial. Methods From 2012 to 2020, twelve patients developed post-KT FSGS with nephrotic range proteinuria, failed conventional therapy, and were treated with abatacept. Nine/twelve (< 21 years old) experienced recurrent FSGS; three adults developed de novo FSGS, occurring from immediately, up to 8 years after KT. KT biopsies were stained for B7-1. Results Nine KTRs (75%) responded to abatacept. Seven of nine KTRs were B7-1 positive and responded with improvement/resolution of proteinuria. Two patients with rFSGS without biopsies resolved proteinuria after abatacept. Pre-treatment UPCR was 27.0 ± 20.4 (median 13, range 8–56); follow-up UPCR was 0.8 ± 1.3 (median 0.2, range 0.07–3.9, p < 0.004). Two patients who were B7-1 negative on multiple KT biopsies did not respond to abatacept and lost graft function. One patient developed proteinuria while receiving belatacept, stained B7-1 positive, but did not respond to abatacept. Conclusions Podocyte B7-1 staining in biopsies of KTRs with post-transplant FSGS identifies a subset of patients who may benefit from abatacept. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

The podocyte: glomerular sentinel at the crossroads of innate and adaptive immunity

“…Circulating factor(s) felt to be involved in the pathogenesis of FSGS may be Danger signal (DAMPs/PAMPs) mimetics (96,97). We have shown these changes in both specific (membrane biomarkers -SMPDL3b, and B7-1) and non-specific (foot process effacement by electron microscopy) fashion in our series of post-reperfusion kidney transplant biopsies (9,47,60,70). Studying the role of the podocyte in FSGS, specifically the innate immune response, with its expression of TLR's, inflammasome components, sphingolipids (SMPDL3b) and cGAS-STING and the adaptive immune response, including costimulatory molecules (B7-1/CD80, but not B7-2/CD86), may provide important insights into novel immune mechanisms.…”

“…While reducing the degree of proteinuria, belatacept did not result in resolution of proteinuria (78). It would be of interest to test whether abatacept may have been more effective in this setting of B7-1 positive podocyte staining in line with our most recent report (70). Secondly, in a rat model of adriamycinmediated proteinuric kidney disease, studied separately by two different groups: 1) rituximab was found to significantly reduce proteinuria via SMPDL3b-specific modulation (54), and 2) abatacept significantly reduced proteinuria, although B7-1 was not identified on podocytes, and the mechanism was felt to be related to an effect on peripheral blood Th17 lymphocytes (54).…”

“…Since the publication of this experience, a number of articles described difficulty in staining kidney transplant biopsies for B7-1 (61-65) and lack of efficacy of either abatacept or the secondgeneration anti-costimulatory agent, belatacept (63,(66)(67)(68)(69). Over the last decade we have followed 12 patients who experienced recurrent FSGS following KT despite receiving a peri-operative dose of rituximab (70) and found the following: 1) Nine/ten patients with recurrent proteinuria after KT responded to abatacept with improvement or resolution of proteinuria. Of these, two patients did not undergo a KT biopsy.…”

What is circulating factor disease and how is it currently explained?

“…Patients with positive B7-1 staining on kidney biopsies had higher odds of achieving remission with abatacept [29]. The most recent report was of 12 patients with posttransplant recurrence, with all 7 who were B7-1 positive on kidney biopsy demonstrating a response to abatacept, suggesting that selecting the subset correctly could lead to more effective targeted therapy [30].…”

The View of Pediatric Nephrotic Syndrome as a Podocytopathy

“…CD80 binds to CTLA-4, a protein receptor expressed on the T-cell surface, and an increase in podocyte B7-1 expression may cause consequent dysfunction or dysregulation of T lymphocytes [52]. Clinical trials tested CTLA-4 as a therapeutic agent, like abatacept [53] and belatacept [54], in FSGS, but results on efficacy are still conflicting.…”