Single-center, Randomized, Controlled Study to Evaluate the Effects of a Six-month Treatment with Renal Glucose Transport Inhibitor (SGLT2i) Drugs on Markers of Senescence, Inflammation and Tubulointerstitial Damage in the Kidney of Patients with Chronic Kidney Disease with or Without Type 2 Diabetes
Overview
- Phase
- Phase 2
- Intervention
- Dapagliflozin 10mg Tab
- Conditions
- Chronic Kidney Disease
- Sponsor
- IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
- Enrollment
- 34
- Locations
- 1
- Primary Endpoint
- 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
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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.
Detailed Description
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).
Investigators
Francesca Viazzi
Professor
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Eligibility Criteria
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%
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
Arms & Interventions
Type 2 Diabetes Dapagliflozin 10 mg
Patients with Type 2 Diabetes allocated to Dapagliflozin 10 mg
Intervention: Dapagliflozin 10mg Tab
Type 2 Diabetes Placebo
Patients with Type 2 Diabetes allocated to Placebo
Intervention: Placebo
Without Diabetes Dapagliflozin 10 mg
Patients without Type 2 Diabetes allocated to Dapagliflozin 10 mg
Intervention: Dapagliflozin 10mg Tab
Without Diabetes Placebo
Patients without Type 2 Diabetes allocated to Placebo
Intervention: Placebo
Outcomes
Primary Outcomes
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
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
Biopsy changes in the expression and location of senescence markers by immunohistochemistry
Time Frame: Baseline and after 6 month
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.
Secondary Outcomes
- Changes in BOLD MRI(Baseline and after 3 month)
- Urinary markers of interstitial fibrosis(Baseline and every 3 months up to 18 month)
- Changes in urinary albumin excretion(Baseline and every 3 months up to 18 month)
- Outcomes of blood presssure control(Baseline and every 6 months up to 18 month)
- Changes in eGFR(Baseline and every 3 months up to 18 month)