SUMMARY Living kidney donors continue to be a critical source of organs facilitating timely transplantation and excellent outcomes. Historically, living donors were healthy and free of baseline abnormalities. In response to the organ shortage, transplant centers now commonly approve donors classified as obese (body mass index (BMI) ≥ 30kg/m2), and currently, more than 25% of all living donors are considered obese at donation. Relaxation of selection criteria to include obese living donors has occurred despite a paucity of safety data. Determining candidacy for living donation among obese individuals remains challenging, as the appropriate BMI cutoff above which donation is no longer safe is unknown. Most centers have implemented a “one size fits all” approach to setting BMI limits (e.g. individuals with BMI > 35kg/m2 are excluded from donation) rather than a personalized approach that accounts for individual baseline differences. In the general population, obese individuals have a 3.57-fold higher risk for ESRD compared to individuals with normal weight (BMI 18.5-24.9 kg/m2). Donors are not drawn from the general population, but are very carefully screened, and the impact of obesity might be different in these healthier individuals. In a recent multi-cohort study of individuals healthy enough to be potential donors (healthy non-donors), the adjusted risk for ESRD associated with obesity was only 1.16-fold higher but varied significantly based on other baseline comorbidities. The true risk among obese living donors likely falls somewhere in between these estimates: obese living donors are otherwise healthy at baseline but lose half their nephron mass. Our preliminary findings suggest that risk for post-donation ESRD is significantly higher among obese compared with non-obese donors. However, it remains unclear if this risk is modified by other baseline comorbidities or obesity-related characteristics (e.g. BMI trajectory, metabolic syndrome), reflective of underlying differences between obese and non-obese persons, or directly attributable to donation itself. We hypothesize that the impact of obesity on post-donation ESRD risk varies significantly by obesity-related characteristics and other comorbidities, and an obese phenotype exists in whom living kidney donation is safe. To better understand the relationship between obesity and risk for post-donation kidney failure, we will leverage and build upon an existing NIH-funded retrospective cohort study of live donors to assemble the largest cohort of obese living donors and will: (1) explore the association of baseline health characteristics with risk for post-donation kidney failure among obese living kidney donors; (2) explore the association of obesity-specific risk factors with risk for post-donation kidney failure; (3) develop a tool for kidney failure risk among obese living donors; (4) estimate risk for post-donation kidney failure among obese living donors directly attributable to donation. ...