Empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is a novel diabetic medication that reduces the risk of progression of chronic kidney disease (CKD) and heart failure and improves exercise tolerance regardless of the diabetes status. One of the important ways that empagliflozin improves health may be through its benefits on blood vessels. The effects of empagliflozin on blood vessels and physical function have not been examined in patients with chronic kidney disease, and it is less clear if empagliflozin may be beneficial in patients with chronic kidney disease without heavy urinary protein leakage. The investigators will examine if empagliflozin can improve blood vessel function and exercise tolerance in Veterans with chronic kidney disease without heavy urinary protein leakage.

Overall Strategy: The investigators propose a randomized, double-blind, placebo-controlled, phase-II study in 52 Veterans with non-diabetic CKD without heavy albuminuria (<300 mg/g) and eGFR 20-59 mL/min/1.73m2 to investigate if empagliflozin, a selective SGLT2i, can improve vascular function, functional capacity, and plasma biomarkers of inflammation, oxidative stress, and nitric oxide (NO). Veterans will be recruited from the Salt Lake City VA and randomized to 10 mg of empagliflozin or placebo at 1:1 ratio and treated for 16 weeks.

Overarching Hypothesis: SGLT2 inhibition improves endothelial function in both macro- and micro-vasculature, in part, by mitigating inflammation and oxidative stress and augmenting NO bioavailability in patients with CKD, even in the absence of heavy albuminuria. The improved vascular function contributes to increased functional capacity.

Specific Aim 1: Comprehensively evaluate the efficacy of empagliflozin to improve vascular health, as determined by conduit artery endothelium-dependent vasodilation (flow-mediated dilation, FMD), peripheral microvasculature reactivity (passive limb movement, PLM), and arterial stiffness (carotid-femoral pulse wave velocity, PWV), in non-diabetic Veterans with CKD and albuminuria <300 mg/g.

Specific Aim 2: Evaluate the efficacy of empagliflozin to improve functional capacity using (a) handgrip exercise and (b) mobility tests (Timed Up-and-Go test, gait speeds, and 6-minute walk).

Specific Aim 3 (Exploratory): Evaluate the efficacy of empagliflozin to (a) reduce plasma biomarkers of systemic inflammation (C-reactive protein, interleukin-6, tumor necrosis factor- ) and oxidative stress (free radical concentration assessed by electron paramagnetic resonance spectroscopy) and (b) increase plasma NO, as reflected by plasma nitrite and nitrosyl hemoglobin levels.

Inclusion Criteria:

• adults aged 18 years of age or older
• eGFR 20-59 mL/min
• albuminuria <300 mg/g

Exclusion Criteria:

• Type 1 or 2 diabetes mellitus
• expected to start dialysis or receive kidney transplantation or die within 4 months
• prior therapy with SGLT2i within the previous year
• unable to participate in the physical function tests (hand grip, walk)
• infections requiring intravenous antibiotic treatment
• malignancy requiring systemic therapy
• extremity skin ulceration requiring active therapy
• history of Fournier's gangrene
• severe hypoglycemia requiring external assistance within the past one year
• known allergy to empagliflozin
• pregnancy

Randomization to either the placebo or empagliflozin group will be performed using a secure web-based system and allocation of empagliflozin vs. placebo in 1:1 ratio. The allocation of the study group will remain blinded to both participants and all study staff and investigators until the completion of the study. Participants will receive encapsulated empagliflozin and matching placebo.