Role of TWEAK in lupus nephritis: a bench-to-bedside review

Abstract

There is significant unmet need in the treatment of lupus nephritis (LN) patients. In this review, we highlight the role of the TWEAK/Fn14 pathway in mediating key pathologic processes underlying LN involving both glomerular and tubular injury, and thus the potential for renal protection via blockade of this pathway. The specific pathological mechanisms of TWEAK - namely promoting inflammation, renal cell proliferation and apoptosis, vascular activation and fibrosis - are described, with supporting data from animal models and in vitro systems. Furthermore, we detail the translational relevance of these mechanisms to clinical readouts in human LN. We present the opportunity for an anti-TWEAK therapeutic as a renal protective agent to improve efficacy relative to current standard of care treatments hopefully without increased safety risk, and highlight a phase II trial with BIIB023, an anti-TWEAK neutralizing antibody, designed to assess efficacy in LN patients. Taken together, targeting the TWEAK/Fn14 axis represents a potential new therapeutic paradigm for achieving renal protection in LN patients.

Figure 1. Role of TWEAK/Fn14 pathway role in glomerular and tubular pathological processes involved in the development of kidney fibrosis and ESRD (modified from [76])

Italics indicate parameters that link glomerular and tubular injury/disease. Red text indicates cell types that express Fn14 in response to injury and thus where anti-TWEAK should protect kidney from pathological events occurring in glomeruli or tubules.