Urine ALCAM, PF4 and VCAM-1 Surpass Conventional Metrics in Identifying Nephritis Disease Activity in Childhood-Onset Systemic Lupus Erythematosus Samar A. Soliman 1,2† , Anam Haque 2 , Kamala Vanarsa 2 , Ting Zhang 2 , Faten Ismail 1† , Kyung Hyun Lee 3 , Claudia Pedroza 3 , Larry A. Greenbaum 4† , Sherene Mason 5 , M. John Hicks 6† , Scott E. Wenderfer 6 * †‡ and Chandra Mohan 2 * †‡ 1 Rheumatology and Rehabilitation Department, Faculty of Medicine, Minia University, Minia, Egypt, 2 Department of Biomedical Engineering, University of Houston, Houston TX, United States, 3 Center for Clinical Research and Evidence- Based Medicine, University of Texas Health Science Center at Houston, Houston, TX, United States, 4 Pediatric Nephrology, Emory University, Atlanta, GA, United States, 5 Connecticut Children’s Medical Center, University of Connecticut School of Medicine, Hartford, CT, United States, 6 Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States Objectives: Serial kidney biopsy for repeat evaluation and monitoring of lupus nephritis (LN) in childhood-onset Systemic Lupus Erythematosus (cSLE) remains challenging, thus non-invasive biomarkers are needed. Here, we evaluate the performance of ten urine protein markers of diverse nature including cytokines, chemokines, and adhesion molecules in distinguishing disease activity in cSLE. Methods: Eighty-four pediatric patients meeting ≥4 ACR criteria for SLE were prospectively enrolled for urine assay of 10 protein markers normalized to urine creatinine, namely ALCAM, cystatin-C, hemopexin, KIM-1, MCP-1, NGAL, PF-4, Timp- 1, TWEAK, and VCAM-1 by ELISA. Samples from active renal (LN) and active non-renal SLE patients were obtained prior to onset/escalation of immunosuppression. SLE disease activity was evaluated using SLEDAI-2000. 59 patients had clinically-active SLE (SLEDAI score ≥4 or having a flare), of whom 29 patients (34.5%) were classified as active renal, and 30 patients (35.7%) were active non-renal. Twenty-five healthy subjects were recruited as controls. Results: Urine concentrations of ALCAM, KIM-1, PF4 and VCAM-1 were significantly increased in active LN patients versus active non-renal SLE, inactive SLE and healthy controls. Five urine proteins differed significantly between 2 (hemopexin, NGAL, MCP1) or 3 (Cystatin-C, TWEAK) groups only, with the highest levels detected in active LN patients. Urine ALCAM, VCAM-1, PF4 and hemopexin correlated best with total SLEDAI as well as renal-SLEDAI scores (p < 0.05). Urine ALCAM, VCAM-1 and hemopexin outperformed conventional laboratory measures (anti-dsDNA, complement C3 and C4) in identifying concurrent SLE disease activity among patients (AUCs 0.75, 0.81, 0.81 respectively), while urine ALCAM, VCAM-1 and PF4 were the best discriminators of renal disease activity in Frontiers in Immunology | www.frontiersin.org May 2022 | Volume 13 | Article 885307 1 Edited by: Andras Perl, Upstate Medical University, United States Reviewed by: Desmond Yat Hin Yap, University of Hong Kong, Hong Kong SAR, China Beatrice Goilav, Children’s Hospital at Montefiore, United States *Correspondence: Chandra Mohan cmohan@central.uh.edu Scott E. Wenderfer scott.wenderfer@cw.bc.ca † ORCID: Samar A. Soliman orcid.org/0000-0003-4638-2158 Larry A. Greenbaum orcid.org/0000-0002-2490-021X Faten Ismail orcid.org/0000-0002-7315-4524 Chandra Mohan orcid.org/0000-0001-7896-5740 Scott E. Wenderfer orcid.org/0000-0002-8991-8277 M. John Hicks orcid.org/0000-0002-1464-3803 ‡ These authors share senior authorship Specialty section: This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology Received: 27 February 2022 Accepted: 28 April 2022 Published: 26 May 2022 ORIGINAL RESEARCH published: 26 May 2022 doi: 10.3389/fimmu.2022.885307