Urine proteomic insights from the belimumab in lupus nephritis trial

OBJECTIVE: Urine proteomic approaches have shown promise in identifying biological pathways in lupus nephritis (LN) which are not captured on renal histopathology or by measurement of proteinuria alone. We investigated how the urine proteome changes with treatment response and with belimumab therapy. METHODS: Urine samples from 54 Belimumab International Systemic Lupus Erythematosus–Lupus Nephritis trial participants (all with biopsy-proven LN) were collected at weeks 0, 24 and 52. At each time point, 1000 urinary proteins were quantified using antibody microarrays (Raybiotech Kiloplex), and their abundance was compared in responders (n=31) versus non-responders (n=22) and with belimumab treatment (n=28) versus standard of care therapy (n=26). Response was defined as proteinuria <500 mg/g(creatinine (cr)), serum creatinine ≤1.25 times the week 0 value and prednisone ≤10 mg/day at week 52. RESULTS: By week 52, CD163 was the urine protein with the most significant difference in abundance between complete responders (median 1.8 pg/mg(cr)) versus non-responders (median 8.2 pg/mg(cr), p=4e-7) regardless of treatment arm. At week 24, five urinary proteins were present at a significantly lower (CD23 and Siglec-5) or higher (AIF, CRELD2 and ROR2) level in the belimumab group. Belimumab therapy was particularly associated with reduction in CD23 between week 0 and week 24 (p=0.0001). CONCLUSIONS: Reduction in urinary CD163 was strongly associated with complete renal response, confirming the results of multiple prior studies. Treatment with belimumab can be detected in the urine proteome, and further study is needed to determine whether modulation of CD23-mediated immune enhancement pathways might be implicated in LN treatment response.