ABSTRACT The NEPTUNE study has recruited and prospectively characterized 750 participants with primary glomerular diseases using a comprehensive renal biopsy tissue based analysis pipeline. The integration of this information in the NEPTUNE Knowledge Network (NKN) allowed significant progress by the glomerular disease community towards more precise diagnosis, prognosis and management of patients with nephrotic syndrome (NS). The goal of this renewal proposal is to identify subpopulations of the deeply phenotyped NEPTUNE participants with shared molecular mechanisms and link them to molecular targeted therapies currently in preclinical or clinical development for NS. For this goal, we propose to recruit 375 incident or prevalent NS patients undergoing a renal biopsy (Biopsy Cohort) with the histological diagnoses of Minimal Change Disease (MCD), Focal Segmental Glomerulosclerosis (FSGS) and Membranous Nephropathy (MN). Despite shared clinical symptoms, individual patients in the same disease category manifest marked variability in rates of disease progression and response to therapy. We will expand the focus from the past 9 years towards clinical trial readiness of our cohort participants and the field at large by leveraging the multiple datasets across the genotype-phenotype continuum. The combined NEPTUNE cohorts will enable us to accomplish the following goals: (a) to define NS patient subpopulations in functional terms using molecular information in combination with quantifiable histological parameters, environmental exposures and discrete clinical features; (b) to link these functionally defined subgroups with the prospectively ascertained clinical outcomes and define novel predictors of outcome from the multi-layered datasets; and (c) to identify in each individual participant the activation state of molecular pathways targeted in early stage clinical trials to implement, in real time, a precision medicine approach: the right treatment trial for the right patient at the right time. The NEPTUNE Biopsy Cohort study will serve as the comprehensive knowledge network to further develop the integrated biology approach on disease progression and treatment response prediction. The NS molecular board clinical research study (MNB, see study 3 of this application) will test these concepts in close collaboration with leading interventional trials in NS.