Vascular Biomarkers May Help Predict Lupus Nephritis Flares

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CHICAGO—Vascular biomarkers may forecast impending flare or flare outcome in patients with lupus nephritis (LN), according to researchers in New York.

Evaluation of markers that reflect endothelial activation and inflammatory cell recruitment appears to provide important adjunct information with regard to greater risk of relapse following induction therapy, according to lead investigator Robert Clancy, MD, Associate Professor of Medicine at New York University School of Medicine.

“People who are non-responders to standard of care need new medicines to keep them from going to end-stage renal disease,” Dr. Clancy said. “It is a huge problem and this research highlights some pathways that can be exploited for new therapies.”

The contribution of the vascular endothelium to the pathogenesis of LN is of central importance given the role of renal endothelial activation and recruitment of inflammatory cells, including monocytes, Dr. Clancy explained. Previous biomarker studies corroborating the involvement of the endothelium in LN have included the following cytokines/cofactors: adiponectin (ADPN), endothelial protein C receptor (EPCR), monocyte chemotactic protein-1 (MCP-1), interleukin-18 (IL-18), nitric oxide (NO), and neutrophil gelatinase-associated lipocalin (NGAL), he said. However, data regarding the utility of these biomarkers to predict stability and/or relapse in patients with LN achieving initial response to induction therapy is rather limited, he noted.

Dr. Clancy and his research team evaluated samples from the maintenance phase of the Aspreva Lupus Management Study to identify predictors of outcome following treatment with mycophenolate mofetil (MMF) or azathioprine (AZA). The study included 52 patients in whom LN was considered responsive following six months of induction therapy with either cyclophosphamide or MMF. At initiation of maintenance therapy, 27 and 25 patients were randomized to receive treatment with MMF and AZA, respectively.

For this investigation, Dr. Clancy's team defined treatment failure during maintenance phase as death, end-stage renal disease, sustained doubling of serum creatinine, and/or renal flare (proteinuric or nephritic). Treatment failure occurred in 12 patients (23%).

Dr. Clancy, who presented the study findings at the 2011 American College of Rheumatology annual meeting, said that at the start of the maintenance phase there were no statistical differences between patients who were treatment failures compared with responders with respect to mean baseline glomerular filtration rates (GFRs) and protein/creatinine ratios. However, patients who failed therapy had higher median levels of the following analytes compared with those who remained responders: u-ADPN (5.9 vs. 0.1 µg/mg), p-MCP1 (552 vs. 150 ng/mL), u-MCP-1 levels (64 vs. 26 ng/mg), and p-NO levels (23 vs. 16 uM).  

The investigators observed no significant differences in the levels of p-ADPN, u-NO, p/u-IL-18, or p/u-NGAL between failures or sustained responders. However, increased mEPCR expression in PTCs appeared to represent a novel marker for poor response to therapy for LN. The values of EPCR rose significantly by the last visit in those patients who failed therapy compared with subjects whose LN remained in remission (166% vs. 102%,). According to Dr. Clancy, u-ADPN also increased over time in patients whose LN flared compared with those who remained in remission (254 vs. 122). There was no association between response and change in levels of p/u-MCP-1 and p-NO.

“This is a formula that I hope can be adopted in the future. The lupus nephritis community can benefit from this,” Dr. Clancy told Renal & Urology News. “These findings support my hypothesis that vascular derived biomarkers would have clinical utility to segregate patients on the bases of response and non-response. So, I think we are headed in the right direction and that this can lead to new ways of treating lupus nephritis.”

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