This is a single-center, double blind, randomized, parallel-arms study designed to investigate the effects of a six-month treatment with the SGLT2i dapagliflozin on markers of kidney senescence, inflammation and tubulointerstitial damage compared to placebo. These mechanisms of renal damage will be investigated in proximal tubular epithelial cells (PTECs) isolated from urine from patients with CKD with or without T2DM and in renal biopsy specimens in a subgroup of patients with diabetic kidney disease.
In the run-in phase, clinical parameters will be optimized by the use of metformin/repaglinide and or RAAS-I on the basis of the presence/absence of a diagnosis of diabetes. Subsequently, patients will be randomly assigned to start with standard therapy and placebo or dapagliflozin at the dose of 10 mg and will continue the assigned treatment for 24 weeks in double-blind and with dapagliflozin at the dose of 10 mg for an additional 48 weeks in open-label/Extended treatment. Urine samples will be collected at T0, T1, T2, T3 and T4 and used as a source of PTECs in order to study the expression of mediators of senescence, fibrosis and inflammation in the kidney. 24-hour ambulatory blood pressure monitoring, Bio-impedancemetry will be evaluated at T0, and T2 and the assessment of tubular oxygen consumption by MRI with BOLD method will be performed at baseline (T0) and after 12 weeks of treatment (T1). This timeline seems to be more appropriate for investigating chances in functional parameters such as blood pressure behaviour, distribution of body water and tubular oxigen consumption. Based on health claims data published in scientific journals, the treatment extension with Dapaglifozin will be proposed to patients of both arms of the Study at the end of 24 Weeks of treatment (T2) for additional 48 Weeks (T3, T4).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
34
Dapagliflozin will be add on RAAS-i titrated with the aim to reach optimal blood pressure control as defined by European Society of Hypertension (i.e., 120-130/70-80 mmHg) in all subject. Prior to randomization all the patient with Type 2 Diabetes must have undergone at least 4 weeks of therapy with metformin and/or repaglinide
Placebo will be add on RAAS-i titrated with the aim to reach optimal blood pressure control as defined by European Society of Hypertension (i.e., 120-130/70-80 mmHg) in all subject. Prior to randomization all the patient with Type 2 Diabetes must have undergone at least 4 weeks of therapy with metformin and/or repaglinide
IRCCS Ospedale Policlinico San Martino
Genova, GE, Italy
Urinary proximal tubule cells changes in protein expression of inflammatory genes such as p16ink4a, TLR-4, phospho-p65, DKK3, Myostatin, TGFβ, SMAD 2,3 and MAPK pathways.
Time frame: baseline and every 3 months up to 18 month
Urinary proximal tubule cells changes in genes such as type IV collagen fibronectin, TGF-β, TNF receptor 1, EMF cadherin production, NF-kB, MCP-1 , DKK3, myostatin and Activin A
Time frame: baseline and every 3 months up to 18 month
Biopsy changes in the expression and location of senescence markers by immunohistochemistry
In the first six patients with T2DM, proteinuria \> 1 g/day and biopsy proven diabetic kidney disese allocated to the treatment with dapagliflozin, we will investigate the following changes in expression and location of p16inkA, SA-beta-galactosidase, TNF receptor 1, EMF cadherin NF-kB.
Time frame: Baseline and after 6 month
Changes in BOLD MRI
Changes in global and segmental renal oxygenation estimated by BOLD MRI (changes in R2\* value defined as 1/T2\*) at 12 and 24 weeks
Time frame: Baseline and after 3 month
Urinary markers of interstitial fibrosis
Changes in urinary markers of a proxy of interstitial fibrosis in patients with CKD (Mir 20)
Time frame: Baseline and every 3 months up to 18 month
Changes in urinary albumin excretion
Changes in urinary albumin excretion
Time frame: Baseline and every 3 months up to 18 month
Changes in eGFR
decrease of eGFR ml/min \> 30%
Time frame: Baseline and every 3 months up to 18 month
Outcomes of blood presssure control
changes in blood pressure values and in the need of antihypertensive drugs
Time frame: Baseline and every 6 months up to 18 month
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