This is a phase 2b, prospective, randomized, cross-over, double-blind, placebo-controlled trial primarily aimed at assessing whether the SGLT2 inhibitor dapagliflozin ameliorates hyperfiltration and reduces proteinuria as compared to placebo in patients with non-diabetic CKD, with particular focus on those at highest risk of progression to end stage kidney disease (ESKD) because of severe renal insufficiency (Stage IV CKD) and proteinuria (\>0.5 g/24 hours). The study will also evaluate renal and systemic mechanisms mediating treatment effects on GFR and will explore biochemical factors possibly mediating these effects.
As chronic kidney disease (CKD) continues to increase worldwide, along with the demand for related life-saving therapies, the financial burden of CKD will place an increasing drain on health care systems. Experimental studies showed that glomerular capillary hypertension and impaired sieving function with consequent protein overload play a pathogenic role in the progression of CKD. Consistently, human studies show that proteinuria is an independent predictor of progression and that its reduction is renoprotective. At comparable BP control, inhibitors of the renin-angiotensin system (RAS), including angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), more effectively than non-RAS inhibitor therapy reduce proteinuria, slow progression to ESRD, and even improve the kidney function achieving disease regression in some cases. In participants with diabetes, RAS inhibitors delay the onset of microalbuminuria and its progression to macroalbuminuria, and ACE inhibitors may reduce the excess cardiovascular mortality associated with diabetic renal disease. In addition to RAS inhibitors, however, multimodal approaches including lifestyle modifications and multidrug therapy will be required in most cases to optimize control of the several risk factors for CKD and related cardiovascular morbidity. Novel medications, including proximal tubular sodium - glucose co-transporter -2 (SGLT2 inhibitors - that ameliorate glomerular hyperfiltration and proteinuria and slow renal disease progression in type 2 diabetes by mechanisms apparently independent of improved metabolic control - might help further improve the cost-effectiveness of renoprotective interventions even in non-diabetic CKD. This phase 2, prospective, randomized, cross over, placebo-controlled trial will primarily aim to assess whether the SGLT2 inhibitor dapagliflozin ameliorates hyperfiltration and reduces proteinuria as compared to placebo in patients with non-diabetic CKD, with particular focus on those at highest risk of progression to end stage kidney disease (ESKD) because of severe renal insufficiency (Stage IV CKD) and proteinuria (\>0.5 g/24 hours).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
32
Dapagliflozin 10 mg/die will be administered orally for six-weeks.
Placebo one tablet/die will be administered orally for six-weeks.
Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò"
Ranica, BG, Italy
Glomerular Filtration rate (GFR)
GFR measured by the Iohexol plasma clearance technique
Time frame: Changes from baseline and day 1, 8, 42,84, 92,126 and 140.
24-hour urinary protein excretion
24-hour urinary protein excretion will be measured as median of three measurements in three consecutive 24-hour urine collections
Time frame: Changes from start (day 0, day 84) and end (day 42, day 126) of each Treatment Period with dapagliflozin or placebo
Renal plasma flow (RPF)
RPF will be assessed by the Para Amino Hippuric (PAH) plasma clearance technique.
Time frame: Changes from baseline and day 1, 8, 42,84, 92,126 and 140.
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