ABSTRACT The first phase of this grant aimed to generate evidence to promote appropriate, safe, and effective use of medications across the range of kidney function. We established a dedicated pharmacoepidemiology group and investigated medication use across the spectrum of glomerular filtration rate (GFR) in >5 million patients in 5 international health systems. We evaluated the risks and benefits of many common medications and medication classes: metformin, angiotensin converting enzyme (ACE)-inhibitors, angiotensin receptor blockers (ARBs), spironolactone, and rosuvastatin, among others. We identified large gaps in guideline-recommended monitoring and medical management, such as the pervasive undertesting of albuminuria among patients with diabetes and hypertension. In this renewal application, we expand the prior study population to include additional large health systems covering approximately 25 million patients with measures of kidney function. We incorporate current data to enable investigation of newer classes of medications, such as sodium glucose co-transporter-2 inhibitors (SGLT2-Is). We extend expertise of the investigative team to include leaders in implementation science and clinical decision support, allowing translation of findings back into local electronic health systems. The overall premise of the application is that, by using post-marketing real-world data, we can provide essential evidence to inform optimal care practices for patients with or at risk for chronic kidney disease (CKD). Using SGLT2-Is as the primary example, we propose first to identify gaps in care, quantifying the number of patients not receiving SGLT2-Is who are recommended to do so under clinical practice guidelines. Next, we identify subgroups of patients most likely to benefit from SGLT2-I therapy through a careful assessment of risks and benefits across individual patient characteristics. Finally, we develop and refine clinical decision support tools that identify high-risk patients in real time who are lacking SGLT2-I therapy. In summary, with the overall goal of simplifying provider decision-making and optimizing medical treatment for patients with or at risk for CKD, this renewal application proposes to identify gaps in care, refine target populations for beneficial medical therapies, and translate knowledge to the point of patient care. .