Using Glycomic Signatures to Monitor Disease Progression and Predict Treatment Response in Lupus Nephritis

Abstract Systemic lupus erythematosus (SLE) is one of the most common autoimmune disorders, predominantly affecting women of childbearing age. Up to half of all lupus patients develop lupus nephritis (LN), a severe kidney disease characterized by persistent glomerular inflammation and associated with poor health outcomes. Although urinalysis tests for proteinuria or hematuria are utilized for patient monitoring, their lack of specificity often reveals significant and irreversible glomerular damage only after its onset. Additionally, conventional markers such as urinary protein/creatinine ratio (UPrUCr) fail to accurately reflect treatment response, prompting the need for repeated biopsies to monitor disease progression. Currently, kidney biopsies serve as the primary method for diagnosing LN and evaluating treatment effectiveness. The goal of this proposal is to identify more sensitive and less invasive clinical biomarkers for monitoring LN progression and assessing treatment response. The glycocalyx, comprised of glycoproteins and other molecules, plays a pivotal role in the glomerular filtration barrier within the glomeruli, which is damaged in LN. Utilizing mass spectrometry-based techniques, our laboratory can identify specific glycomic patterns in tissues and biofluids, offering a complementary approach to existing clinical tests for LN detection and monitoring. Given the severity of the pathology in LN the central hypothesis of this proposal is that glycosylation changes can be detected in urine earlier than conventional markers, and these unique glycomic signatures can differentiate LN from controls and serve as a noninvasive predictor of treatment response. In Aim 1, I will evaluate the precision of the distinct glycomic signatures in identifying LN compared to controls (Aim 1A) and ascertain the efficacy of these unique glycomic profiles in enhancing the differentiation between complete responders (CR) and non-responders (NR) (Aim 1B). In Aim 2, I will focus on determining the spatial localization of N-glycans within the kidney (Aim 2A) and identifying their protein carriers (Aim 2B) using an independent LN cohort with matched serum, urine, and kidney biopsy samples. Ultimately, this proposal seeks to deepen our understanding of LN pathophysiology, evaluate the predictive potential of glycomic signatures for disease severity and treatment response in patients, and introduce a less invasive urine-based approach that can complement current clinical methods to enhance patient care and outcomes.