Sunday, November 17, 2013

Abatacept for Glomerular Diseases: A New Era of Intelligent immunosuppression?

At ASN Kidney Week there was some interest in abatacept as a targeted therapy for glomerular diseases. T-cell activation requires 2 signals; (i) binding of the T-cell receptor to the antigen-MHC complex on the antigen-presenting cell and (ii) a co-stimulatory signal involving CTLA-4 on the T-cell and B7-1 on the antigen presenting cell. Abatacept is a fusion protein composed of the Fc region of IgG1 fused to the extracellular domain of CTLA-4 which inhibits the T-cell co-stimulatory pathway via B7-1 binding. 

The headlines must go to the small case series of abatacept in FSGS published in NEJM. The rationale for its use was the observation that B7-1 expression is not apparent in normal human podocytes but is found in certain diseased podocytes including a subset of FSGS patients. The series included 4 patients with recurrent FSGS post-transplantation (rituximab-resistant) and one with glucocorticoid-resistant primary FSGS. All patients achieved either partial or complete remission.
In vitro studies demonstrated that α3-Integrin knockout mice constitutively expressed B7-1 in podocytes and abatacept blocked B7-1 mediated podocyte migration in these cells. The molecular mechanism of B7-1-induced podocyte dysfunction was shown to be disruption of activation of the glomerular protein β1-integrin. The authors conclude that B7-1 immunostaining of biopsies may identify a subgroup of patients who would benefit from treatment with abatacept.

2       Lupus Nephritis
The late-breaking session included a randomized controlled trial of Euro-lupus regime cyclophosphamide (i.e. low dose IV) with or without abatacept for proliferative lupus nephritis [Access Trial]. Azathioprine was introduced at 3 months and stopped at 6 months in the abatacept group if they had achieved a remission. Overall, there was no difference in remission rate between the groups. Despite the neutral outcome, 2 points should be taken from the study: (i) The Euro-lupus regime appeared to work in a US cohort of patients where almost 80% were either Hispanic or African American. (ii) Abatacept patients who achieved remission maintained this at 1 year despite coming off immunosuppression at 6 months. However, with the growing confidence in Mycophenolate-based therapy for lupus nephritis and the lack of improved remission with Abatacept in this study, its place in the treatment of proliferative lupus nephritis remains uncertain.

      Diabetic Nephropathy
An oral presentation on abatacept in Diabetic Nephropathy [FR-OR010] reported increased B7-1 expression in both murine podocytes cultured in high-glucose and on human glomerular podocytes from biopsy specimens. The use of Abatacept in diabetic mice prevented an increase in albuminuria.

Bottom Line: The FSGS case series beautifully illustrates how targeted therapies may be applied to immune-mediated renal diseases. While this case series is very small, it demonstrates the potential for reclassifying disease based on pathogenesis (i.e. B7-1-mediated) rather than crude pathological patterns (focal segmental sclerosis). This is similar to the recent re-classification of MPGN into complement or immune complex-mediated forms. With new targeted therapies like abatacept (and eculizumab for complement mediated glomerulopathies), we may be entering an era of intelligent immunosuppression based on molecular pathogenic signals rather than crude histological patterns.

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