Effect of Empagliflozin on Podocyte Specific Proteins in African American Veterans With NDKD (EMPA CKD)

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

Primary Objective:

To study podocyte specific injury markers in African American Veterans with non-diabetic kidney disease (NDKD), on empagliflozin therapy.

Primary Endpoint: We will assess the effect of Empagliflozin on podocyte-specific proteins in exosomes isolated from subjects' urine, such as nephrin, podocalyxin and Wilms'Tumor (WT-1) protein.

Secondary Objectives:

1. Correlate changes in exosome-based podocyte specific proteins with standardized biomarkers of kidney injury including urine albumin/creatinine ratio (ACR) and estimated GFR.
2. Correlate systemic inflammatory markers (focusing on vascular and endothelial function) that are already established such as interleukins (IL1, IL6, IL-12) , hs-CRP and arterial stiffness measures with urine exosome-based podocyte protein estimation [11, 27-29].
3. Correlate urine podocyte-specific protein markers with APOL1 mRNA expression levels in blood mononuclear cells (MNC)

Study Overview

• Status: Recruiting
• Conditions: Chronic Kidney Diseases
• Intervention / Treatment: Drug: Placebo; Drug: Empagliflozin 10 MG

Detailed Description

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.

Several recent T2DM clinical trials have shown that SGLT2 inhibitors (SGLT2i) improve endothelial dysfunction. We and others [10,11] have shown decreased podocyte-specific urine protein injury markers production with SGLT2i in DKD [9-11]. Additionally, the literature suggests close cross-talk between the glomerular vascular endothelium and the podocyte [10]. The effect of SGLT2i on markers of podocyte injury, as well as markers of endothelial injury/inflammation deserve further elucidation. This maybe relevant in non albuminuric NDKD in lower eGFR stages (stages 3 and 4), albuminuric NDKD in stage 2, or more preserved eGFR states, in a population that may inherently be at high risk for progressive CKD and its subsequent rapid deterioration in kidney disease, such as APOL1 nephropathy.

In this pilot project, we plan to establish the degree to which podocyte inflammation or dysfunction in albuminuric or non-albuminuric NDKD, is modified by empagliflozin, an SGLT2i. Podocyte inflammation with increased excretion of podocyte-specific proteins such as Wilm's Tumor-1 has been noted in T2DM and other nephropathies [11,13-16]. We have studied and quantified the same biomarkers in diabetic nephropathy[11] and have also demonstrated amelioration and reduction of the same in DKD. However similar studies are lacking in NDKD, particularly in non albuminuric NDKD patients with low eGFR.

In this study, we focus on albuminuric or non-albuminuric NDKD where we would like to stratify two groups for inclusion: 1. Preserved eGFR such as 60 - 89 where we would like to see a concomitant UACR of at least 30 mg/g or 2. Less preserved eGFR between 20 - 59 with or without discernable albuminuria/UACR (see Inclusion criteria section of this protocol). This represents a wide range of baseline KDIGO risk using the KDIGO CKD heat map. The traditional method for assessing podocyte damage is by measuring urinary protein excretion. However other biomarkers may be more effective.

We and others have demonstrated that urinary exosomes are a defined entity in urine and estimation of podocyte specific proteins in urine exosomes may help identify and quantify podocyte inflammation [17-18].

Exosomes, are a class of extracellular vesicles, that are secreted from various tissues into the circulation or urine and they carry protein, nucleic acid and lipid cargoes and facilitate cell-to-cell communication. Exosomes have been proposed as potential biomarkers of specific physiological and pathological conditions. For example, exosomes have been implicated in the initiation and progression of diabetes mellitus and its complications [11,13]. However, the isolation of specific classes of exosomes in urine from CKD subjects to enable monitoring disease severity and level of inflammation has yet to be developed . Studying podocyte inflammation may also help to identify cross talk between podocyte , the glomerular endothelium, and systemic inflammation. [16-18] Moreover APOL1 mutation presence has been associated with progressive renal injury and even podocyte specific injury [19-24]. APOL1 mutation has been associated with systemic inflammation and podocytopathy, particularly in African Americans [24-26] Building on these preliminary data and literature review, the overall objective of this randomized, double-blinded, interventional, proof-of concept study is to understand the effect of empagliflozin 10 mg on markers of podocyte injury and systemic inflammation in patients with albuminuric or non-albuminuric NDKD. We plan to use singular 10mg dose (considered low dose) which has shown clinical efficacy in similar trials [12]. Please note our podocyte specific trial in diabetic CKD patients also used low dose SGLT2i, Canagliflozin 100mg [11] It will also explore the relationship between changes in markers of podocyte injury with the use of empagliflozin, in the backdrop of expression of APOL1 gene in individual patients. This will help elucidate mechanistic insights into the effects of SGLT2i on podocyte injury markers and markers of systemic inflammation in individuals with albuminuric or non-albuminuric NDKD, and further understand the effects in the backdrop of varying degrees of APOL1 expression.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Sabyasachi Sen, MD; Phone Number: 202-745-8000; Email: sabyasachi.sen@va.gov
• Study Contact Backup: Name: Shannen Ubalde, BS; Phone Number: 55835 202-745-8000; Email: shannen.ubalde@va.gov

Study Locations

• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20422
      • Recruiting
      • Washington DC Veterans Affairs Medical Center (688)
      • Contact: Sabyasachi Sen, MD; Phone Number: 202-745-8303; Email: sabyasachi.sen@va.gov
      • Contact: Ping Li, MD; Phone Number: 55910 202-745-8000; Email: ping.li2@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. African American veterans
2. Age > 18 years
3. eGFR ≥20-59 mL/min/1.73 m2 by the CKD-EPI equation, with or without any degree of albuminuria OR
4. eGFR 60-89, with UACR of ≥30mg/g
5. BMI = 18-39.9
6. Blood pressure controlled to ≤140/90
7. Subjects without diabetes: will be screened using routine glucose level test: of less than 126 fasting glucose or less than 200mg/dl of random or post glucose blood glucose level in standard of care laboratory workup.
8. Ability to provide informed consent before any trial related activities are conducted.

Exclusion Criteria:

1. Diagnosed with Type 1 or Type 2 Diabetes Mellitus
2. Any prescribed diabetes medication for patients, such as GLP1RA, SGLT2is, and sulphonylureas
3. If a patient is on statin, need to be on a stable dose for a month.
4. Biopsy proven diagnosis of glomerular disease/glomerulonephritis
5. Active smokers,
6. Active skin wounds undergoing treatment or recent surgery within 1 month (due to possible aberrations in glycemic control)
7. Women who are pregnant, planning to become pregnant, nursing mothers, women of childbearing potential not using birth control measure
8. Hypersensitivity to empagliflozin or any of the excipients in Jardiance, reactions such as angioedema
9. Patients on dialysis
10. eGFR less than 20 mL/min/1.73 m2 by the CKD-EPI equation
11. Planned surgery or planned hospital admission within 5 months of participation in the study
12. 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)
13. Patients with prior history of diagnosis of heart failure with documented EF of less than 50.
14. Proven diagnosis of Polycystic Kidney Disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Placebo; Placebo 10 mg orally daily	Drug: Placebo; Take Placebo 10 mg orally daily for 4 months
Active Comparator: Empagliflozin; Empagliflozin 10 mg orally daily	Drug: Empagliflozin 10 MG; Take Empagliflozin 10 mg orally daily for 4 months

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Washington D.C. Veterans Affairs Medical Center
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Sabyasachi Sen, MD, Washington VA Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: October 25, 2023
• First Submitted That Met QC Criteria: October 25, 2023
• First Posted (Actual): October 31, 2023

Study Record Updates

• Last Update Posted (Actual): August 21, 2026
• Last Update Submitted That Met QC Criteria: August 19, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Non-diabetic
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Renal Insufficiency; Pathological Conditions, Signs and Symptoms; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; empagliflozin
• Other Study ID Numbers: 1770617

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes