Role of Empagliflozin in Kidney Dysfunction and Podocyte Specific Injury in African American Veterans With Non-Diabetic Chronic Kidney Disease (CKD)

Study Overview
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Brief Summary
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Primary Objective: To study kidney dysfunction and podocyte-specific injury in African American Veterans with Non-diabetic kidney disease, following low dose of Empagliflozin therapy. Empagliflozin may be referred to as Empa hereafter. Correlate changes in exosome-based podocyte-specific proteins with standardized biomarkers of kidney injury including urine albumin/creatinine ratio (ACR) and estimated GFR. Secondary Objective: Correlate systemic inflammatory markers (focusing on vascular function and endothelium) that are already established such as interleukins and hs-CRP and arterial stiffness with urine exosome-based podocyte protein estimation To correlate urine podocyte-specific protein markers and serum inflammatory markers with APOL1 mRNA expression levels in blood mononuclear cells (MNC) (c-kit positive cells)

Detailed Description
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Nephropathy is a progressive complication of DKD and NDKD and substantially increases morbidity and mortality. Clinicians frequently measure proteinuria using urine protein /creatinine and urine albumin/creatinine ratios, which in several instances do not manifest substantial improvement, even after an intervention such as SGLT2i, particularly if the intervention period is short. There is therefore a clear need for validated markers of early podocyte injury. Based on published studies podocyte-specific injury proteins such as podocalyxin, nephrin and Wilms tumor 1 (WT1) can be candidate marker proteins of injury. Urinary exosome analysis is a non-invasive and potentially more sensitive assay. Performed standard-of-care assays, including urine microalbumin/creatinine ratio and plasma inflammatory markers which showed no difference over the 4-month time period. The current exploratory project proposal will allow to assess the degree of podocyte injury in NDKD subjects, which have not been a focus of SGLT2i treatment as compared to DKD subjects. Propose to assess apolipoprotein L1 (APOL1) gene expression. Rates of many types of progressive kidney disease are substantially higher in Black individuals than in other ethnic groups. In 2010, investigators discovered genetic variants in the APOL1 gene that explained a substantial fraction of this major health disparity. The Veterans Health Administration has been a prominent caregiver to the African American community across the United States. Over the past decade, investigators have established the basic population genetics and epidemiology of APOL1-associated kidney disease and are making progress in understanding disease mechanisms at the cellular and molecular levels. With therapeutic approaches for APOL1 kidney disease now being explored by many groups in pharma and academia, studies to assess the relationship of APOL1 gene expression levels with podocyte injury in CKD are of paramount importance and will better inform treatment in the near future. These studies may address one important cause of the significant racial disparity in CKD rates among African-Americans. As APOL-1 gene mutation is much more common in African Americans and approximately 80% of VA population is African Americans, it's important to enroll only from African American race in order to keep the population homogenous and achieve statistically significant results. Though the study will only include African Americans, the study will be quite relevant in USA as worsening CKD is a major health problem in this country and the African American patient population is at particularly high risk for progressive CKD. A largely under-recognized public health issue, CKD is the ninth leading cause of death in the U.S. today. Although African Americans constitute 13% of the population, they suffer more than triple the rate of kidney failure of Caucasians.

Official Title
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Role of Empagliflozin in Kidney Dysfunction and Podocyte Specific Injury in African American Veterans With Non-Diabetic Chronic Kidney Disease (CKD)

Conditions
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Chronic Kidney Diseases

Intervention / Treatment
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* Drug: Empagliflozin 10 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: African Americans age ≥ 20-90 eGFR ≥30-90 mL/min/1.73 m2 by the CKD-EPI equation Albuminuria of 30 mg/g or higher BMI=25-45 Blood pressure controlled to ≤140/90, while on a stable antihypertensive medication regimen Subjects without diabetes: HbA1C less than 6.5% Ability to provide informed consent before any trial related activities are conducted. Exclusion Criteria: Type 1 or Type 2 Diabetes Mellitus Beginning statin medications or change in statin dose in the past 1 month Biopsy proven diagnosis of glomerular disease/glomerulonephritis Active smokers, Active wounds (i.e., diabetic ulcers) or recent surgery within 1 month (due to possible aberrations in glycemic control and inability to match) Women who are pregnant or planning to become pregnant. Hypersensitivity to empagliflozin or any of the excipients in Jardiance, reactions such as angioedema Patients on dialysis eGFR < 20 mL/min/1.73 m2 by the CKD-EPI equation At the discretion of PI to ensure health, safety, and well-being of the veteran, participation in this study may be stopped (please see withdrawal criteria)

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo<br>Placebo 10 mg orally daily | Drug: Placebo<br>* Take Placebo 10 mg orally daily for 4 months<br>|
| Active Comparator: Empagliflozin<br>Empagliflozin 10 mg orally daily | Drug: Empagliflozin 10 MG<br>* Take Empagliflozin 10 mg orally daily for 4 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To study kidney dysfunction and podocyte specific injury | To study kidney dysfunction and podocyte specific injury in African American Veterans with Non-diabetic kidney disease, following low dose of Empagliflozin therapy. Empagliflozin may be referred to as Empa hereafter. Correlate changes in exosome-based podocyte specific proteins with standardized biomarkers of kidney injury including urine albumin/creatinine ratio (ACR) and estimated GFR. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic inflammatory markers | Correlate systemic inflammatory markers (focusing on vascular function and endothelium) that are already established such as interleukins and hs-CRP and arterial stiffness with urine exosome-based podocyte protein estimation To correlate urine podocyte-specific protein markers and serum inflammatory markers with APOL1 mRNA expression levels in blood mononuclear cells (MNC) (c-kit positive cells) | 3 years |