LO-006 Change in urinary biomarkers at three months predicts 1-year treatment response of lupus nephritis better than proteinuria
Year: 2023
Type: conference-abstract
Abstract: Background A decline of urine protein-to-creatinine ratio (UPCR) to < 0.5 is associated with better long-term preservation of kidney function in lupus nephritis (LN). UPCR < 0.5 defines complete response in guidelines and clinical trials when achieved after 1 or 2 years. Biomarkers of early response are needed to guide early treatment changes. We studied longitudinal urine proteomic profiles in LN to identify early predictors of proteinuric response. Methods We quantified 1200 biomarkers (Kiloplex, RayBiotech) in urine samples collected on the day of (73%) or within 3 weeks (27%) of kidney biopsy and week 12, 24, or 52 in LN patients (ISN class III, IV, V, or mixed) with proteinuria > 1 g/d. Response was defined at one year from renal biopsy: Complete = UPCR < 0.5, serum creatinine (sCr) < 125% of baseline, prednisone ≤ 10mg/d; Partial = UPCR < 50% from baseline but >0.5, sCr < 125% of baseline, but prednisone allowed to 15 mg/d; Non responder = not meeting previous definitions. Results A total of 127 patients were included: 48 (38%) with pure proliferative LN (class III or IV), 41 (32%) with mixed LN (III or IV +/- V), and 38% (30%) with pure membranous LN. Response was complete in 34 (27%), partial in 29 (23%), and none in 64 (50%). There were no urinary biomarkers at baseline that predicted response. We then analyzed the changes in urinary proteins at 3 months compared to baseline. Patients who responded at 1 year showed an early decline in 51 urinary proteins led by CD163, IL-16, and CD206 (macrophage mannose receptor) (figure 1A) which matched the proteomic signature associated with histological activity (figure 1B). No changes were observed in nonresponders. The decline of several urinary biomarkers at 3 months outperformed a decline in UPCR (clinical standard) in predicting the 1 year response. In particular, a decline of CD163 predicted 1 year response in ROC analysis with an area under the curve (AUC) of 83% compared to an AUC of 75% for UPCR decline. In proliferative LN, urinary biomarkers displayed superior performance with an AUC of 91%, 86%, and 78% for the decline of CD206, CD163, and UPCR, respectively (figure 1C-D). Pathway enrichment analysis identified leukocyte activation, neutrophil degranulation, and matrix degradation as the main pathways reduced at 3 months in responders. Conclusions An early decline in urinary biomarkers of histological activity is associated with proteinuric response at 1 year. These findings indicate that effective immunosuppression induces by three months an immunological response in the kidney that can be noninvasively monitored in the urine. Biomarkers of immunological response outperformed early decline of UPCR, the standard of care, in predicting 1-year proteinuric response, especially in proliferative LN. Because biomarkers of immunological response parallel intrarenal activity, they could detect early treatment response/failure and allow early treatment changes. They could serve as surrogate endpoints in clinical trials. Longitudinal studies are needed to confirm that this immunological response is a better predictor of long-term kidney function preservation than proteinuric responses.
Authors: Andrea Fava, Jill Buyon, Laurence Magder, Jeffrey Hodgin, Avi Rosenberg, Dawit Demeke, Deepak Rao, Arnon Arazi, Alessandra Ida Celia, Chaim Putterman, Jennifer Anolik, Jennifer Barnas, Maria Dall’Era, David Wofsy, Richard Furie, Diane Kamen, Kenneth Kalunian, Judith A James, Joel Guthridge, Mohamed G Atta, Jose Monroy-Trujillo, Derek Fine, Robert Clancy, H Michael Belmont, Peter Izmirly, William Apruzzese, Daniel Goldman, Celine Berthier, Paul Hoover, Nir Hacohen, Soumya Raychaudhuri, Anne Davidson, Betty Diamond, The Accelerating Medicines Partnership in ra/sle, Michelle Petri
Institutions: Johns Hopkins University, New York University, University of Michigan, Brigham and Women's Hospital, Harvard University, Feinstein Institute for Medical Research, Sapienza University of Rome, Albert Einstein College of Medicine, Bar-Ilan University, University of Rochester Medicine, University of Rochester, University of California, San Francisco, Medical University of South Carolina, University of California San Diego, Oklahoma Medical Research Foundation, University of Oklahoma, Broad Institute, University of Manchester
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4385631768