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.

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.

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).

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