Cardiovascular and Renal Endpoints With Flozins - an Observational Prospective Study in CKD HFpEF Patients (CARE FOR CKD H)

The main aim of this study is to holistically assess the cardiovascular and renal outcomes in HFpEF CKD patients with and without SGLT2 inhibition, with focus on the endothelial disfunction, MACE and mortality using clinical evaluation, flow mediated dilatation, carotid-femoral pulse wave velocity, intima-media thickness, echocardiographic parameters, NMR metabolomics and a series of novel biomarkers.

Study Overview

• Status: Recruiting
• Conditions: Diabetes (DM); Heart Failure Preserved Ejection Fraction; CKD - Chronic Kidney Disease; SGLT2 Inhibitors
• Intervention / Treatment: Diagnostic test: Arterial stiffness; Diagnostic test: Echocardiography; Other: Biomarkers determination; Other: NMR metabolomics and uremic toxins mapping

Detailed Description

Chronic kidney disease (CKD) is considered to become the 5th cause of death worldwide by 2040. Aging populations, growing frequency of type 2 diabetes, hypertension, a low detection rate and therapeutic inertia in the early stages of CKD determined the increasing incidence and prevalence. CKD patients exhibit an elevated cardiovascular risk manifesting myocardial infarction and stroke, coronary artery disease, heart failure (HF), arrhythmias, and sudden cardiac death. The relationship between HF and CKD is bidirectional, with chronic HF promoting CKD development (cardio-renal syndrome type 1), and CKD promoting the development of HF (type 3). In the last decade, HF with preserved ejection fraction (HFpEF) represents the typical phenotype in patients with CKD, accounting for more than half of the cases of HF. Given the high burden of both HF and CKD, their complex interaction and challenging management, along with the prognostic implications regarding comorbidity and mortality, a comprehensive approach in the HFpEF population is mandatory, since HF diagnosis was evasive for years. The main aim of this study is to holistically assess the cardiovascular and renal outcomes in HFpEF CKD patients with and without SGLT2 inhibition, with focus on the endothelial disfunction, MACE and mortality using clinical evaluation, flow mediated dilatation, carotid-femoral pulse wave velocity, intima-media thickness, echocardiographic parameters, NMR metabolomics and a series of novel biomarkers.

The objectives of this prospective observational study are to determine:

• the feasibility of PWV measurement and ventricular strain in HFpEF CKD patients with and without SGLT2 inhibition;
• the cardiovascular outcomes, namely MACE, defined as time to first non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure or CV death and on all-cause mortality in HFpEF CKD patients with and without SGLT2 inhibition;
• the renal outcomes, such as rapid progression of renal disease - defined as sustained annual decline of at least 5mL/min/1,73m2 in eGFR or a sustained drop of 25% or more in eGFR within 12 months;
• the metabolomics profile related to uremic toxins panel determined by NMR spectroscopy and other biological markers as novel molecules with a higher potential accuracy of predicting further major cardiovascular events in HFpEF CKD patients with and without SGLT2 inhibition.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

Study Locations

• Romania
  • Iași, Romania
    • Recruiting
    • Dr. C.I. Parhon Hospital in Iasi
    • Contact: Adrian Covic C Head of Nephrology Clinic, MD, PhD; Phone Number: +40232211818; Email: adrian.covic@umfiasi.ro
    • Contact: Gianina Dodi Researcher, PhD; Phone Number: +40232211818; Email: gianina.dodi@umfiasi.ro
    • Principal Investigator: Adrian Covic, MD, PhD
    • Sub-Investigator: Anca Stefan, MD
    • Sub-Investigator: Alexandra Covic, MD
    • Principal Investigator: Gianina Dodi, PhD

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Patients with CKD stages 3 and 4 (eGFR calculated by CKD-EPI) with HFpEF

Description

Inclusion Criteria:

• age>18 years;
• ejection fraction > 40;
• patients with CKD stage 3-4 (eGFR between 15-60 mL/min/1.73m2), with iSGLT2 recommendation, diabetic and non-diabetic;
• age, sex and CKD stage 3 and 4 matched patients without iSGLT2 administration.

Exclusion Criteria:

• eGFR< 15 mL/min/1.73m2 or patients undergoing dialysis;
• presence of congenital heart disease, decompensated cirrhosis, pregnancy and active malignancies;
• coronary artery disease (including those with a history of acute coronary syndrome, angina pectoris, or prior coronary angiography or CT angiography demonstrating significant coronary artery lesions);
• cardiac medical devices, namely metallic joint prostheses, cardiac stent or pacemakers;
• active systemic infections (due to interference with biomarkers that can give false rise values).

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
iSGLT2 therapy; CKD and HFpEF with iSGLT2 therapy	Diagnostic test: Arterial stiffness; Arterial stiffness assessment will be performed by applanation tonometry with the patient being recumbent, 10 minutes before the measures were done. The carotid and femoral pulse will be acquired by applanation tonometry sequentially, allowing a single operator to acquire the measurement. The transit time from the R-wave of the simultaneously acquired electrocardiogram to the foot of the carotid and femoral pulse is measured. The difference acquired electrocardiogram to the foot of the carotid and femoral pulse is measured. The difference between these 2 transit times is divided by distances measured from the body surface to estimate the arterial path length in order to calculate carotid-femoral PWV.; Diagnostic test: Echocardiography; Echocardiography will be performed on each patient at baseline; the measurements will be carried out according to the recommendations of the American Society of Echocardiography. Echocardiographic evaluation will provide information about cardiac anatomy (e.g. volumes, geometry, mass) and function (e.g. left ventricular function and wall motion, valvular function, right ventricular function, pulmonary artery pressure, pericardium).; Other: Biomarkers determination; NT-pro BNP, Syndecan-1, VCAM-1, Endoglin, NO and ADMA will be determined by specific enzyme linked immunosorbent assay (ELISA) kits.; Other: NMR metabolomics and uremic toxins mapping; The aliquoted serum preserved at -80° C will be analysed by NMR using deuterated solvents (D2O, CDCl3, CD3OD, CD3CN), standards of metabolites and uremic toxins.
Control; CKD and HFpEF without iSGLT2 therapy	Diagnostic test: Arterial stiffness; Arterial stiffness assessment will be performed by applanation tonometry with the patient being recumbent, 10 minutes before the measures were done. The carotid and femoral pulse will be acquired by applanation tonometry sequentially, allowing a single operator to acquire the measurement. The transit time from the R-wave of the simultaneously acquired electrocardiogram to the foot of the carotid and femoral pulse is measured. The difference acquired electrocardiogram to the foot of the carotid and femoral pulse is measured. The difference between these 2 transit times is divided by distances measured from the body surface to estimate the arterial path length in order to calculate carotid-femoral PWV.; Diagnostic test: Echocardiography; Echocardiography will be performed on each patient at baseline; the measurements will be carried out according to the recommendations of the American Society of Echocardiography. Echocardiographic evaluation will provide information about cardiac anatomy (e.g. volumes, geometry, mass) and function (e.g. left ventricular function and wall motion, valvular function, right ventricular function, pulmonary artery pressure, pericardium).; Other: Biomarkers determination; NT-pro BNP, Syndecan-1, VCAM-1, Endoglin, NO and ADMA will be determined by specific enzyme linked immunosorbent assay (ELISA) kits.; Other: NMR metabolomics and uremic toxins mapping; The aliquoted serum preserved at -80° C will be analysed by NMR using deuterated solvents (D2O, CDCl3, CD3OD, CD3CN), standards of metabolites and uremic toxins.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MACE	Composite CV outcome: time to first non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure or CV death	20 months
All-cause mortality	All-cause mortality	10 and 20 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite renal outcome	Rapid progression of renal disease - defined as sustained annual decline of at least 5mL/min/1,73m2 in eGFR or a sustained drop of 25% or more in eGFR within 10 months	10 and 20 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in cardiac biomarkers	Blood levels of NT-pro BNP, Syndecan-1, VCAM-1, Endoglin, NO and ADMA will be measured at baseline and months 10 and 20. The outcome is defined as the change from baseline.	Baseline, 10 and 20 months
Changes in the NMR metabolomics and uremic toxins mapping	Blood levels of NMR metabolomics and uremic toxins will be measured at baseline and months 10 and 20. The outcome is defined as the change from baseline.	Baseline, 10 and 20 months

Collaborators and Investigators

• Sponsor: Grigore T. Popa University of Medicine and Pharmacy
• Collaborators: The Executive Agency for Higher Education, Research, Development and Innovation Funding; Dr. C.I. Parhon Hospital, Iasi

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2025
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: November 13, 2025
• First Submitted That Met QC Criteria: November 16, 2025
• First Posted (Actual): November 19, 2025

Study Record Updates

• Last Update Posted (Actual): November 19, 2025
• Last Update Submitted That Met QC Criteria: November 16, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: CKD; Biomarkers; HFpEF; PWV; SGTL2 inhibitors
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Cardiovascular Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Heart Diseases; Chronic Disease; Disease Attributes; Metabolic Diseases; Glucose Metabolism Disorders; Renal Insufficiency; Heart Failure; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Diabetes Mellitus; Renal Insufficiency, Chronic; Heart Failure, Diastolic; Diagnostic Techniques and Procedures; Diagnosis; Circulatory and Respiratory Physiological Phenomena; Diagnostic Imaging; Diagnostic Techniques, Cardiovascular; Heart Function Tests; Cardiac Imaging Techniques; Ultrasonography; Cardiovascular Physiological Phenomena; Echocardiography; Vascular Stiffness
• Other Study ID Numbers: CARE FOR CKD HFPEF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No