ABSTRACT Sickle cell disease (SCD) nephropathy or SCDN, as defined by the presence of proteinuria or low glomerular filtration rate (GFR), affects up to 30% of adult SCD patients. We have shown that GFR decline among SCD patients is nearly double that among African Americans without SCD. SCDN can progress to end-stage renal disease; both are potent risk factors for early mortality in SCD. This association may be partly attributable to the correlation of SCDN with other endotheliopathic conditions, especially pulmonary hypertension. SCDN therapeutic options are currently limited to those used for other renal diseases, such as diabetic nephropathy, and are not particularly efficacious. Thus, identifying at-risk patients early and developing effective therapeutics targeted specifically to the pathophysiology of SCDN is critical. Genetic factors, most notably APOL1, influence susceptibility to SCDN. However, APOL1 is insufficient to explain all SCDN risk, suggesting other clinical and genetic risk factors exist. NHLBI’s TOPMed program is an extraordinary opportunity to make significant discoveries in personalized medicine for SCD, including SCDN. Our cohort (OMG-SCD), together with other TOPMed SCD cohorts, total >4100 samples with whole genome sequence results and rich clinical data, including kidney-related phenotypes. Our OMG-SCD cohort has stored plasma samples, used previously to generate metabolomics and preliminary proteomics data and identify two metabolites associated with rapid GFR decline and eight proteins, including cystatin-C and complement factor D, with estimated GFR below 90 mL/min/1.73 m2. Generation of additional proteomic data would facilitate biomarker discovery and underlying biologic mechanisms of SCDN. Specifically, we propose to: (1) Identify novel clinical and genetic risk factors for SCDN; (2) Identify proteomic biomarkers for SCDN; and (3) Establish risk models to classify SCD patients with and without nephropathy. We will harness the large, well-characterized TOPMed SCD cohorts to uncover the molecular underpinnings of SCDN, one of the greatest clinical challenges in SCD, due to the profound risk for morbidity and mortality. Our work is poised to yield significant discoveries of SCDN risk factors (genetic loci, biomarkers), point toward causal biologic mechanisms, and thus facilitate risk-stratified clinical studies to further the development of precision medicine approaches in this patient population.