Targeting the Pathophysiology of Sickle Cell-Related Kidney Disease Using SGLT2 Inhibitors

Project Abstract Chronic kidney disease (CKD) is present in over 50% of adults with sickle cell disease (SCD) and is associated with increased morbidity and early mortality. However, the mechanisms underlying the development of SCD- related CKD are poorly understood and therapies to prevent and treat SCD-related CKD are urgently needed. Our group has reported that dysregulated tubuloglomerular feedback and proximal tubular stress may be implicated in the pathophysiology of SCD-related CKD. This proposal will leverage our robust preliminary data to target these mechanistic pathways using sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of drugs representing one of the largest advances in CKD treatment for the general population, although its impact on CKD in people with SCD has not yet been evaluated. SGLT2i have kidney-protective mechanisms that overlap with pathways implicated in SCD-related CKD, including reactivating tubuloglomerular feedback and ameliorating proximal tubular stress, making this class of therapy an ideal candidate for developing a targeted approach to treat SCD-related CKD. Our group has also demonstrated that kidney functional magnetic resonance imaging (fMRI)-derived perfusion, oxygenation, and fibrosis are able to differentiate patients with CKD from healthy volunteers. In the proposed study, we will leverage this noninvasive tool to gain valuable in vivo insights on the impact of SGLT2i in patients with SCD-related CKD. We will test our hypothesis that SGLT2i ameliorates critical pathophysiologic processes in SCD-related CKD via two specific aims. Specific Aim #1 will utilize a transgenic SCD mouse model to evaluate whether the SGLT2i, empagliflozin, improves biomarkers of kidney function and injury (subaim 1) as well as fMRI, histopathology, and gene expression patterns (subaim 2). Specific Aim #2 will investigate whether empagliflozin improves candidate biomarkers of tubuloglomerular feedback and proximal tubular stress (subaim 1) and kidney fMRI-derived perfusion, oxygenation, and fibrosis measures (subaim 2) in a pilot study of SCD patients with CKD treated for 48 weeks. Integrating biomarkers for candidate mechanistic pathways with fMRI will lead to a deeper understanding in the pathophysiology of kidney damage and guide therapeutic strategies for SCD-related CKD. This research team is exceptionally positioned to achieve the goals outlined in this proposal. In addition to our strong history of productivity in SCD-related CKD research and fMRI-related research, we have a robust institutional environment at the University of Illinois Chicago Comprehensive Sickle Cell Center that cares for over 800 SCD patients and has a long-standing tradition of successful implementation of research studies. Developing a better understanding of the pathways and effects of SGLT2i for treating SCD-related CKD has the potential to have a significant impact on this underserved, high-risk population.