Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Association of Adiponectin and Soluble Endothelial Protein C Receptor (sEPCR) with Longitudinal Assessments in the Induction Phase of a Randomized Multicenter Trial Comparing Mycophenalate Mofetil and Intravenous Cyclophosphamide
Clancy1, Robert M., Ginzler2, Ellen M., MMF/IVC Lupus Nephritis Induction Trial, , Kim4, Mimi
A major barrier to understanding and treating lupus nephritis (LN) is the paucity of sensitive and validated biomarkers. Recent evidence has suggested that two markers found on the endothelium of LN biopsies merit focus. Adiponectin is expressed on the endothelium of all vessels in biopsies from patients with LN but decreased in areas of fibrosis and/or inflammation. Adiponectin knockout mice suggest that adiponectin may be a key regulator of proteinuria. Increased expression of membrane EPCR in LN biopsies predicts a poor response to therapy. Based on these vascular clues, this study leveraged the LN induction trial comparing intravenous cyclophosphamide (IVC) and mycophenolate mofetil (MMF) to evaluate the relationship between clinical response of LN and levels of adiponectin and sEPCR as a proxy for vascular "protective" molecules.
The endothelial markers, adiponectin, sEPCR, e-selectin, and nitric oxide were measured in 109 plasma from 48 patients enrolled in the LN induction trial. Response was evaluated based on reaching a primary endpoint with a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. The span of the induction period was 24 weeks. Sample collection included visits 4 (4wks), 7 (15 wks) and 9 (24 wks).
There was a consistent trend toward increased levels of plasma adiponectin in responders vs nonresponders (19.2 ± 6.8 vs 16.4 ± 9.1 at visit 4; 13.0 ± 5.2 vs 11.7 ± 6.5 at visit 7; 13.7 ± 7.8 vs 10.9 ± 4.9 at visit 9). In patients with subnephrotic proteinuria (<3g/day urine protein; 63% of the total), plasma adiponectin was similarly increased in responders vs nonresponders at all visits. Moreover, when combining data across all visits nonreponders had significantly lower adiponectin (p=0.0032). There was a tendency of sEPCR to decrease in responders vs nonresponders (243 ± 164 vs 284 ± 167 at visit 4; 338± 271 vs 341 ± 197 at visit 7; 260 ± 104 vs 368 ± 216 at visit 9). In comparing MMF vs IVC, sEPCR, levels were significantly higher in the IVC group when data was combined over all visits (p=0.005). Consistent with evidence that therapy in the responder arm mobilizes vascular protective molecules, levels of nitric oxide changed in the predicted direction (62 ± 47 vs 68 ± 66 at visit 4; 39 ± 46 vs 52 ± 65 at visit 7; 27 ± 33 vs 92 ± 55 at visit 9; p=0.02). Combining data across all visits, nonresponders had significantly higher NO levels than responders (p=0.046). The differences in plasma NO were not accounted for by clearance as fractional excretion of NO did not differ between responders and nonresponders. Levels of sE selectin did not track with response.
These results demonstrate longitudinal associations between increased adiponectin and decreased sEPCR levels as a combined biomarker of renal response. Accordingly, vascular protection tracks with favorable outcomes.
To cite this abstract, please use the following information:
Clancy, Robert M., Ginzler, Ellen M., MMF/IVC Lupus Nephritis Induction Trial, , Kim, Mimi; Association of Adiponectin and Soluble Endothelial Protein C Receptor (sEPCR) with Longitudinal Assessments in the Induction Phase of a Randomized Multicenter Trial Comparing Mycophenalate Mofetil and Intravenous Cyclophosphamide [abstract]. Arthritis Rheum 2009;60 Suppl 10 :263