Abstract Lupus nephritis (LN) is diagnosed by kidney biopsy in patients with proteinuria > 0.5g/24h, but the presence of proteinuria means that kidney damage has already occurred. It is estimated that 30% of nephrons are permanently lost with each flare of LN. The identification of LN before kidney damage using urine proteomic biomarkers could shift the management strategy of LN to prevention, potentially leading to earlier, more effective, and less toxic treatment. Three specific aims will be addressed in this R01 building on the work of the Hopkins Lupus Cohort (a 35 year, 2855 SLE longitudinal cohort in which patients are followed by protocol every 3 months) and in particular on the urine biomarker discoveries from the NIH RA/SLE Accelerated Medicines Partnership (AMP). Aim 1 - Develop a urine biomarker panel to identify new lupus nephritis BEFORE proteinuria. Previous AMP urine proteomic studies revealed that urinary IL-16, CD163, and neutrophil granule content indicate intrarenal LN activity. These biomarkers will be quantitated in urine samples collected within 3 months before the onset of proteinuria in lupus patients who ultimately were diagnosed with LN by renal biopsy to determine if the biomarkers are elevated compared to patients who do not develop LN. A full urine proteomic profile will also be assessed to discover additional biomarkers that could contribute to a robust panel for predicting onset of LN before proteinuria. Aim 2 - Develop a urine biomarker panel to guide tapering of immunosuppression in treated LN patients. Patients with a histological NIH activity index >2 on repeat biopsy developed a proteinuria flare and increased mortality upon tapering of immunosuppression in one study. Four urinary biomarkers associated with NIH activity index >2 in AMP (IL-16, CD163, Galectin-1, and PRTN3) will be quantitated ( with analysis of 1200 additional urine proteins) in urine samples from 12 LN patients in apparent clinical remission who flared upon tapering immunosuppression versus 12 LN patients who did not flare upon tapering. The most predictive biomarkers will be combined into a 10- plex panel to be validated in a prospective cohort of 60 patients tapering immunosuppression. Aim 3 - Develop a biomarker for detection of early chronic kidney disease (CKD) in LN. Urine proteomic studies on 187 patients enrolled in AMP identified TGF-β-mediated fibrosis and TNF signaling related proteins that may be superior to proteinuria alone in detecting early CKD. These AMP patients will be followed clinically for at least five years to determine the trajectory of their kidney disease and to find differences in urine proteomic (and other omic) profiles between those who maintain stable renal function versus those who do not.