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. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords: Abatacept; B7-1; Focal segmental glomerulosclerosis; Kidney transplantation; Nephrotic syndrome; Podocyte; Proteinuria.

Fig. 1

Flow diagram of twelve post-transplant FSGS patients showing age (pediatric or adult), recurrent FSGS vs. de novo FSGS, B7-1 KT biopsy staining results, and response to abatacept

Fig. 2

B7-1 positive cases of KT recipients with recurrent FSGS that responded to abatacept. Each graph shows post-transplant serum creatinine levels, tacrolimus levels, and urine protein/creatinine ratio. A–H Cases 1–7. Also shown: rituximab infusion time(s), plasmapheresis episodes, steroids, and abatacept treatment

Fig. 3

H&E, B7-1, and EM for B7-1 positive recurrence (case 6). A H&E (200 ×) demonstrated mesangial proliferative changes in glomeruli consistent with early segmental sclerosis. B Immunohistochemistry to B7-1 (200 ×) appears focally positive in podocytes (arrow) with 3 + intensity. C The overlying podocyte foot processes show moderate fusion (arrow) (EM, 3,500 ×). D Immunohistochemistry to B7-1 (200 ×) appears positive in lymph node

Fig. 4

Cases without KT biopsies that responded to abatacept. Each graph shows post-transplant serum creatinine levels, tacrolimus levels, and urine protein/creatinine ratio. A Case 8. B Case 9. Also shown: rituximab infusion time(s), plasmapheresis episodes, steroids, and abatacept treatment

Fig. 5

B7-1 negative cases of KT recipients with recurrent FSGS that did not respond to abatacept. A Case 10. B Case 11. Each graph shows post-transplant serum creatinine levels, tacrolimus levels (case 10 only), and urine protein/creatinine ratio. Also shown: biopsies, rituximab infusion time(s), plasmapheresis episodes, and abatacept treatment. Cyclosporine A and belatacept treatment are shown for case 11

Fig. 6

H&E, B7-1, and EM in B7-1 negative recurrence (case 11). A H&E (200 ×) demonstrated focal segmental glomerulosclerosis, with frequent non-collapsing segmental sclerosis, approximately 13 of 25 glomeruli. B Immunohistochemistry to B7-1 (200 ×) appears negative in podocytes. C The overlying podocyte foot processes show moderate fusion (arrow) (EM, 3740 ×)

Fig. 7

B7-1 positive case that did not respond to abatacept. The graph (case 12) shows post-transplant serum creatinine levels, tacrolimus levels, and urine protein/creatinine ratio. Also shown: rituximab infusion time(s), plasmapheresis episodes, steroids, belatacept, and abatacept treatment