CKD - Chronic Kidney Disease, Heart Failure Preserved Ejection Fraction, SGLT2 Inhibitors, Diabetes (DM)
Conditions
Keywords
CKD, HFpEF, SGTL2 inhibitors, Biomarkers, PWV
Brief summary
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.
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.
Interventions
DIAGNOSTIC_TESTArterial 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_TESTEchocardiography
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).
NT-pro BNP, Syndecan-1, VCAM-1, Endoglin, NO and ADMA will be determined by specific enzyme linked immunosorbent assay (ELISA) kits.
OTHERNMR 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.
Sponsors
Dr. C.I. Parhon Hospital, Iasi
The Executive Agency for Higher Education, Research, Development and Innovation Funding
Grigore T. Popa University of Medicine and Pharmacy
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MACE | 20 months | Composite CV outcome: time to first non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure or CV death |
| All-cause mortality | 10 and 20 months | All-cause mortality |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite renal outcome | 10 and 20 months | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in cardiac biomarkers | Baseline, 10 and 20 months | 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. |
| Changes in the NMR metabolomics and uremic toxins mapping | Baseline, 10 and 20 months | 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. |
Countries
Romania
Outcome results
None listed