PT  - JOURNAL ARTICLE
AU  - Fava, Andrea
AU  - Buyon, Jill
AU  - Magder, Laurence
AU  - Hodgin, Jeffrey
AU  - Rosenberg, Avi
AU  - Demeke, Dawit
AU  - Rao, Deepak
AU  - Arazi, Arnon
AU  - Celia, Alessandra Ida
AU  - Putterman, Chaim
AU  - Anolik, Jennifer
AU  - Barnas, Jennifer
AU  - Dall’Era, Maria
AU  - Wofsy, David
AU  - Furie, Richard
AU  - Kamen, Diane
AU  - Kalunian, Kenneth
AU  - James, Judith A
AU  - Guthridge, Joel
AU  - Atta, Mohamed G
AU  - Monroy-Trujillo, Jose
AU  - Fine, Derek
AU  - Clancy, Robert
AU  - Michael Belmont, H
AU  - Izmirly, Peter
AU  - Apruzzese, William
AU  - Goldman, Daniel
AU  - Berthier, Celine
AU  - Hoover, Paul
AU  - Hacohen, Nir
AU  - Raychaudhuri, Soumya
AU  - Davidson, Anne
AU  - Diamond, Betty
AU - The Accelerating Medicines Partnership in ra/sle
AU  - Petri, Michelle
TI  - LO-006 Change in urinary biomarkers at three months predicts 1-year treatment response of lupus nephritis better than proteinuria
AID  - 10.1136/lupus-2023-KCR.6
DP  - 2023 Jul 01
TA  - Lupus Science & Medicine
PG  - A7--A8
VI  - 10
IP  - Suppl 1
4099  - http://lupus.bmj.com/content/10/Suppl_1/A7.short
4100  - http://lupus.bmj.com/content/10/Suppl_1/A7.full
SO  - Lupus Sci Med2023 Jul 01; 10
AB  - 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.Abstract LO-006 Figure 1 (A) Volcano plot of the changes of the urinary proteomic profile of treatment responders at 3 months after kidney biopsy compared to time of biopsy. (B) Correlation of urinary biomarkers at time of biopsy the NIH Activity Index. (C) Area under the curve (AUC) of the 1yr response prediction of the change of a biomarker at 3 months. (D) ROC curves comparing the performance of 3-months biomarker decline. FDR, false discovery rate. q, adjusted p value, UPCR, urine protein-to-creatinine ratio