Effect of Empagliflozin on Podocyte Specific Proteins (Injury Markers) in African American Veterans With Non-Diabetic Chronic Kidney Disease

Chronic kidney disease (CKD) is a complex medical condition imposing deleterious effects on multiple organ systems. Prevention of increased cardiovascular mortality and progression to end-stage kidney disease (ESKD) are two major unmet medical needs in patients with CKD, with or without diabetes mellitus especially in those with albuminuria [1].

In patients with Non-Diabetic Kidney Disease (NDKD), the cornerstone of management includes blood pressure control, maintenance of normal body weight, dietary adherence, and avoidance of nephrotoxic drugs [2,3].

The management of diabetic kidney disease (DKD) has undergone extensive changes with the advent of several foundational classes of guideline based medical therapies (GDMT) for DKD. These include SGLT2i, GLP1-RAs, and Finerenone, along with Renin-Angiotensin System-inhibitors (RASi). While the benefits of the SGLT2i such as Empagliflozin for cardio-kidney outcomes in NDKD are well recognized from the landmark EMPA-KIDNEY trial [12], there is less understood in terms of mechanisms of benefit, especially in high-risk phenotypes for progression to kidney failure, such as APOL1 +ve gene mutation.

African Americans suffer from CKD at significantly higher rates and account for more than 35% of all patients receiving dialysis in the United States [1]. While T2D is the number one cause of CKD overall, and Black adults are twice as likely to develop T2D compared to White adults [1], recently identified genetic variants in the APOL1 gene may explain a significant proportion of the rising burden of albuminuric NDKD in African Americans (4). APOL1 risk variants G1 and G2 are trypanolytic factors that protect against trypanosomiasis but have been shown to be associated with significantly higher risk for development of NDKD (4). Though NDKD is quite prevalent in African-American patients, the precise mechanism of APOL1 risk variants involved in the pathogenesis and progression of NDKD in this patient population is unknown and requires further investigation [5,6], given the disproportionate burden of CKD and kidney failure in this population.

Abnormalities in podocyte biology play a central role in the pathogenesis of CKD. In CKD podocyte injury is a key component in the pathophysiology of the progressive kidney disease, which is also accompanied by systemic inflammation [6-8]. The degree of podocyte injury is currently best assessed by kidney biopsy, which is an invasive procedure and not performed in the vast majority of patients with CKD. Often times proteinuria accompanies the clinical picture. However non albuminuric CKD is a growing clinical entity. The patterns, and extent of podocyte injury in non-albuminuric CKD is less well understood([7,8] and their management is often challenging.