Dialogue: A blissful future for lupus nephritis: harnessing repeat kidney biopsies to identify meaningful biomarkers of disease

Correspondence to Dr Will Pendergraft; [email protected]. edu Kidney involvement in patients with systemic lupus erythematosus (SLE) portends a worse prognosis; thus, early and accurate detection of lupus nephritis is key. Unfortunately, current clinical markers, including creatinine clearance, autoantibodies, serum complement levels, urine sediment and proteinuria, do not always reliably identify patients with kidney disease. Moreover, these biomarkers do not help distinguish between various histopathological classes of lupus nephritis, which are often used as benchmarks to guide treatment. An intensely hot area of lupus research currently revolves around biased and unbiased approaches to identify biomarkers that can more reliably predict clinical and histopathological lupus-associated kidney activity and, perhaps even more importantly, durable response to treatment. Novel biomarkers of lupus nephritis currently under investigation include but are not limited to B Lymphocyte Stimulator (BLyS), A Proliferation-Inducing Ligand (APRIL), tumor necrosis factor (TNF)-like WEAK inducer of apoptosis (TWEAK), and Monocyte Chemoattractant Protein-1 (MCP-1). BLyS, also known as B cell Activating Factor belonging to the TNF Family (or BAFF), is a transmembrane protein that is cleaved by a furin protease into a biologically active soluble protein that is important for B cell activation and differentiation. Numerous studies have shown that serum BLyS levels are elevated in patients with SLE compared with controls, making it the target of the recently Food and Drug Administration (FDA)-approved lupus drug, belimumab. Currently, the Belimumab International Lupus Nephritis Study clinical trial is underway to determine the efficacy of belimumab in patients with lupus nephritis (http://www.clinicaltrials.gov, NCT01639339). Like BLyS, APRIL is a member of the TNF family, and is thought to have a regulatory role in B cell proliferation. APRIL levels have been shown to be elevated in patients with lupus compared with healthy controls, although one study has found that levels may be lower in patients with lupus nephritis compared with patients who have lupus without kidney involvement. 3 TWEAK, a soluble cytokine expressed primarily by infiltrating leucocytes, is upregulated locally on epithelial and mesenchymal cells in injured and diseased tissues. It binds to its receptor, Fn14, to mediate proinflammatory responses, vascular activation, angiogenesis, cell growth, cell death, fibrogenic responses and progenitor responses. Urinary TWEAK levels have been found to be elevated in patients with lupus nephritis compared with patients with lupus and no kidney disease, making this a promising biomarker. Furthermore, the Anti-Tweak in Lupus Nephritis Patients clinical trial examining the efficacy of an anti-TWEAK monoclonal antibody in lupus nephritis is also underway (http://www.clinicaltrials.gov, NCT01499355). MCP-1 is a monocyte chemoattractant protein that induces release of lysosomal enzymes and generation of superoxide anions from monocytes and macrophages. Studies have found that urinary levels of MCP-1 are elevated in patients with lupus nephritis and reportedly increase during active disease and decrease with treatment. 7 In this issue of Lupus Science and Medicine, Parodis and colleagues evaluate serum BLyS and APRIL levels in 64 patients with active lupus nephritis (52 proliferative, 12 membranous) in Sweden. Levels of these two biomarkers were measured and followed throughout treatment as potential predictors of treatment response. Baseline BLyS levels were higher in patients with lupus nephritis than in controls and they remained unchanged even after induction treatment. A