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).
Phase:
Phase 2
Details
Lead Sponsor:
Mario Negri Institute for Pharmacological Research