suPAR (soluble plasminogen activator receptor)
Since the first report by Wei et al. of suPAR as a circulating permeability factor causing FSGS, there has been extensive research to elucidate its role in FSGS. Although administration of suPAR molecule to mice was initially thought to be sufficient to cause proteinuria mimicking FSGS, via activation of integrin beta 3 and derangement of actin cytoskeleton, the situation does not seem that straightforward. As Reiser et al. discussed, there are challenges to overcome: existence of different suPAR isoforms with different disease modifying effects; heterogeneity of FSGS itself, which make it complicated to interpret correlation between levels of suPAR and disease activity; involvement of suPAR in other disease process, including cardiovascular disease (KI 2014). However, suPAR remains an intriguing molecule and potential biomarker in FSGS disease process.
B7-1 (CD80)
A case series in the NEJM from Peter Mundel’s group in the end of 2013 brought us to an excitement for personalized treatment of a subgroup of B7-1 positive FSGS patients. They found strong B7-1 stain in primary FSGS as well as post-transplant recurrent FSGS. These patients were successfully treated with abatacept (CTLA4-Ig), resulting in complete remission of proteinuria. The hypothetical pathophysiological mechanism was via direct interaction of B7-1 and integrin beta 1 causing podocyte actin cytoskeleton changes. However, it was followed by comments and larger case series (AJKD 2014) questioning specificity of the immunostaining and treatment effect of abatacept. Exploration of this costimulatory molecule in FSGS was just started and further research is needed.
Micro RNA(s) as biomarkers for FSGS disease activity
A group from China suggested that certain micro RNAs are associated with disease activity (level of proteinuria) and progression (Zhang et al. CJASN and AJKD 2014). Potential candidates are miR-186 (involved in cell cycle control, AKT and insulin signaling etc.) and miR-125b (involved in NFkB signaling etc.). However, their contribution to pathogenesis is not clear so far.
Pre-transplant antibody panel (including anti-CD40) to predict post transplant recurrent FSGS
Expanding potential FSGS biomarkers is the publication by Delville et al. The authors did a beautiful translational work using human serum in protein arrays, validation of specific auto-antibodies and further experimentation using cell cultures and animals models. The authors elegantly showed that pre-transplant antibody panel, especially anti-CD40 antibody, can predict risk of post-transplant recurrent FSGS.
In more detail, they started by comparing pre-transplant sera of non-recurrent FSGS (nrFSGS) vs recurrent FSGS (rFSGS), identifying 789 autoantibodies upregulated only in rFSGS but not in nrFSGS. Then those antibodies were enriched for those Ab with antigen targets expressed in kidney (151 autoAbs) and more specifically in glomeruli (10 autoAbs). They validated the 7-antibody panel (CD40, CGB5 (chorionic gonadotropin b), PTPRO (protein tyrosine phosphatase receptor O), FAS (TNF receptor superfamily member 6), P2RY11 (P2Y purinoceptor 11), SNRPB2 (small nuclear retinoid X receptor a), and APOL2 (Apolipoprotein 2)) in rFSGS vs nrFSGS cohort, and obtained ROC AUC of 0.92. Surprisingly, anti-CD40 itself had a high ROC AUC (0.77). Then, the involvement of rFSGS-anti-CD40 IgG to enhance FSGS recurrence was confirmed in vitro—rFSGS-anti-CD40 IgG caused actin cytoskeleton derangement in podocyte cell culture—, as well as in vivo—co-injection of rFSGS-anti-CD40 IgG and suPAR molecule markedly enhanced proteinuria (in a suPAR-dependent manner), which was inhibited by CD40-blocking antibody or in CD40 knockout mice.
This suggests that by checking pre-transplant anti-CD40 antibody, we may be able to identify a high risk FSGS recurrence group. To manage these patients, current options are: peritransplant plasmaphresis or rituximab. Interesting to see if CD40 antagonist or blocking antibody can play a role in preventing/treating rFSGS in the clinic…
Naoka Murakami