[K23] Sodium Glucose Cotransporter-2 Inhibitors for the Amelioration of Acute Cardio-Renal Syndrome
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2030-04-30
Importo max: 192.258 EUR
Paese: US
Descrizione
PROJECT SUMMARY | Candidate: The candidate is an Instructor of Medicine (Nephrology) with 3 years of
ongoing training in clinical research in acute kidney injury (AKI) and clinical trial design and conduct under the
mentorship of the director of Yale’s Clinical and Translational Research Accelerator, a leading expert in clinical
trials and pharmaco-epidemiology in AKI. This award will also allow her to receive mentorship from renowned
experts in heart failure translational research, renal physiology and biostatistics to eventually become an
independent clinical researcher in cardiorenal syndromes.
Proposed Study: More than 1/3rd of patients hospitalized with acute heart failure (AHF) develop AKI, which is an
independent risk factor for cardiovascular and kidney disease progression and mortality. AKI in this setting, often
known as acute cardiorenal syndrome (CRS), is a cycle of venous congestion and overactive sodium
reabsorption mechanisms characterized by diuretic resistance leading to prolonged patient distress and
interruptions of essential HF therapy. The long-term goal of this study is to assess the efficacy of sodium-glucose
cotransporter-2 inhibitors (SGLT2i) for acute CRS. SGLT2i are oral anti-hyperglycemic drugs which target a key
sodium and glucose reabsorption mechanism in the kidney that have consistently slowed long-term kidney and
cardiovascular disease progression in randomized clinical trials, independent of patients’ diabetes status or heart
failure type. There is also pre-clinical evidence supporting their kidney tubular and endothelial protective and
reparative effects in AKI. However, the efficacy and safety of SGLT2i in humans with acute CRS is unknown and
AKI in this setting is a frequent reason for discontinuation. In a multicenter cohort study, we have shown that
SGLT2 inhibition during AHF-associated AKI is not associated with prolonged AKI. By inhibiting an energy-
demanding sodium reabsorption mechanism in the kidney’s proximal tubule, SGLT2i particularly when added to
standard loop diuretic therapy, could promote energy efficient diuresis by reducing O2 demand in the kidney’s
already O2-deprived environment, reduce oxidative stress and promote tubular integrity which may enhance
tubular secretion of loop diuretics and their efficient delivery to their downstream target. Based on these
assumptions, we hypothesize that SGLT2i improve diuretic response and promote quicker kidney recovery in
patients with acute CRS which we will test as follows. In Aim 1, we will assess the impact of SGLT2i on the
clinical improvement of individuals with acute CRS in a randomized placebo-controlled clinical trial of hospitalized
adults with AHF-associated AKI by comparing established symptomatic and biochemical metrics of diuretic
response. We will also examine safety and tolerability. In Aim 2, we will further assess the impact of SGLT2i on
early biomarkers of kidney tubular injury and health. This study has the potential to improve the
Istituzione: YALE UNIVERSITY
PI: Abinet M Aklilu
Progetto: 5K23DK142042-02
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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