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).

Inclusion Criteria:

• Albuminuria defined as urinary albumin:creatinine ratio ≥ 25 mg/g (or protein:creatinine ratio ≥ 30 mg/g) or albuminuria > 30 mg/24h
• eGFR > 25 and < 75 ml/minute 1.73m2
• BMI between 19 kg/m2 and 30 kg/m2
• Treatment with an ACE inhibitor and/or ARB at the maximum tolerated (for the individual subject) dose. The maximum tolerated dose for an individual subject may be less than the maximum labeled dose or may be zero if the medical reason is documented.
• Mean systolic and diastolic blood pressure (determined as the average of three replicates) must be < 180/90mmHg
• Pre-menopausal women of child-bearing potential 1 must have a negative pregnancy test performed before the inclusion in the study V e r s i o n 6 . 0 - P a g . 10 | 32
• Willingness to participate in the study (signed informed consent)

IN PARTICIPANTS WITH Type 2 Diabetes

• Clinical diagnosis of T2DM for at least 1 year
• Hemoglobin A1c (HbA1c) value of < 9.5%
• Patients treated only with metformin and/or repaglinide
• A diagnosis of Diabetic Nephropathy at renal biopsy made not more than 6 months before the screening visit (only for the subgroup of patients candidated to the second kidney biopsy)
• Proteinuria > 1g/24h (only for the subgroup of patients candidated to the second kidney biopsy)
• Hemoglobin A1c (HbA1c) value of > 6.5% (only for patients candidated to the second kidney biopsy) In PARTICIPANTS Without Type 2 Diabetes
• diagnosis of hypertension for at least 5 years

Exclusion Criteria:

• Type 1 Diabetes
• Hemoglobin A1c (HbA1c) value of > 9.5% during the Screening period (based on central laboratory measurement).
• The need for an adjunctive drugs on top on metformin and repaglinide
• Hemoglobin A1c (HbA1c) value of < 6.5% only for patients candidated to the second kidney biopsy
• Estimated glomerular filtration rate < 25 or > 75 ml/min/1.73m2 (according to the CKD-EPI) at screening
• Untreated urinary or genital infection at screening and follow-up
• Clear signs of volume depletion
• Symptomatic hypotension, or systolic blood pressure < 90 or non-controlled hypertension
• History of alcohol or drug abuse, anuria, dialysis, or acute kidney injury/acute renal failure in the 3 months prior to Screening Period
• Heart, liver or kidney transplant V e r s i o n 6 . 0 - P a g . 11 | 32
• Acute coronary syndrome, stroke, or transient ischemic attack within 3 months prior to informed consent
• Liver disease, defined by serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening
• Planned cardiac surgery or angioplasty within 3 months
• Cancer or medical history of cancer (except for basal cell carcinoma) within the last 5 years
• Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at time of screening leading to unstable body weight (e.g. surgery, aggressive diet regimen, etc.)
• SGLT2i treatment in the 10 weeks before the Screening Period
• Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent
• Any uncontrolled endocrine disorder except T2DM
• Women who are pregnant or breastfeeding
• Pre-menopausal women of child bearing potential who are not willing to employ effective contraception according to 2007 CTFG Recommendations related to contraception and pregnancy testing in clinical trials from screening for all the duration of the study
• Patients with a known hypersensitivity to Dapagliflozin or other SGLT2- inhibitors, including hypersensitivity to excipients (e.g. lactose)
• History of pancreatitis, or pancreatic surgery, diabetic ketoacidosis
• Prior lower extremity amputation or current threat of amputation (eg, lower extremity ulcer and peripheral artery disease)
• History of severe hypoglycaemia and hypoglycaemia unawareness.
• Contraindication to MRI

Once eligibility is verified, the Investigator will randomize the subject contacting by e-mail the Secretarial Office of the Nephrologic Clinic of the Ospedale Policlinico San Martino The assigned randomization number will communicated via e-mail and recorded by the Investigator in the CRF. Therefore both investigators and participants will be blind