Blog entry by Arif Khwaja

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by Arif Khwaja - Tuesday, 19 November 2013, 5:03 PM
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The management of FSGS particularly post -transplantation remains difficult with no clear evidence base on how to optimally manage recurrent disease. The search for a permeability factor continues and recent work suggested that serum-soluble urokinase-type plasminogen activator receptor (SuPAR) may have an important role in FSGS by modulating integrin signalling within podocytes promoting foot process effacement and proteinuria. As yet there is significant variablility in SuPAR levels (and no standardised assay) in differing FSGS cohorts so its utility as a biomarker is far from certain.

In last weeks NEJM there was some very elegant and preliminary translational work by  Yu and colleagues from Harvard looking at the role of costimulation blockade in FSGS. B7-1 is normally expressed on antigen presenting cells and provides a costimulatory signal necessary for T cell activation by interacting with 2 ligands on the T Cell - CD28 and Cytotoxic T Lymphocyte Antigen 4 (CTLA4). There are a number of costimulation blockers such as abatacept (licensed for rheumatoid arthritis) and belatacept (licensed in psoriasis and renal transplantation).
 
The group observed that B7-1 (CD80) is not expressed in normal kidney podocytes but was expressed in podocytes in biopsy specimens in a number of proteinuric kidney diseases (13 out of 21 biopsies from patients with proteinuric kidney disease were B7-1 positive). Furthermore the observation that B7-1 staining was seen in biopsies from patients with recurrent FSGS suggested that B7-1 expression had been induced during the disease process. The group go on to demonstrate in in vitro podocyte migration studies that overexpression of B7-1 leads to increased podocyte migration. Furthermore this migration is inhibited by abatacept suggesting that costimulation plays an important role in podocyte migration (which is taken as an in vitro 'surrogate' of podocyte effacement and proteinuria). B7-1 overexpression in podocytes caused a loss of beta1-integrin activation which again was reversed by abatacept. i.e. B7-1 promotes podocyte migration  (and therefore proteinuria) through inactivation of beta1-integrin signalling and this is blocked by abatacept. The putative mechanism of action of abatacept is that it binds to B7-1 thereby preventing B7-1 binding to and inactivating beta1-integrin.
 
The group then go on to present data on 5 patients with FSGS who had positive staining for B7-1 on renal biopsy and were refractory to treatment with immunosuppression including steroids and rituximab and plasmapharesis. 4 cases were post transplant and 1 was FSGS in a native kidney. In all cases there was an impressive reduction in proteinuria. In the methodology session the authors state that the treatment was in line with the 'institutional policies' of  Massachusetts General Hospital although its clear what this actually means in practice. The mechanism by which B7-1 becomes expressed in the podocyte is not clear.
 
So does this mean we should be using abatacept for patients with "B7-1 positive" FSGS? One certainly cant justify this on the basis of the a small case series and its important to note that significant numbers of proteinuric patients were B7-1 negative. However this is a promising avenue of future research and is perhaps an example of  'personalised' therapeutics that maybe increasingly seen in the future as the molecular mechanisms underlying glomerular diseases are more clearly delineated. Clearly an important next step is to see whether B7-1 positivity is seen in larger cohorts from different centres and define the mechanisms by which B7-1 expression can be induced.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]

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