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Publications

Journal Article Epublish

PubMed: 41141510 DOI: 10.1016/j.ekir.2025.07.020

Randomized Trial of Dapagliflozin in Patients With Nondiabetic Stage 4 CKD.

Kidney Int Rep 10(10):3340-3355

Authors: Matias Trillini, Alessandro Villa, Annalisa Perna, Tobia Peracchi, Diego Fidone, Nadia Rubis, Chiara Guarinoni, Davide Martinetti, Annamaria Chiappa, Tiziano Gamba, Elena Perticucci, Vincenzo Gambara, Stefano Rota, Nadia Stucchi, Fabiola Carrara, Giuseppe Remuzzi, Piero Ruggenenti

Affiliations

  • Department of renal Medicine, Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò," Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
  • Department of Medicine, Unit of Nephrology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
  • Department of Internal Medicine 2, San Giovanni Bianco Hospital, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.

Abstract

INTRODUCTION

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are nephroprotective in patients with chronic kidney disease (CKD) and mild-to-moderate renal insufficiency.

METHODS

This prospective, randomized, cross-over, placebo-controlled, double-blind study compared the effects of 6-week dapagliflozin (10 mg/d) with placebo treatment in 31 consenting nondiabetic Caucasian adults with stage 4 CKD and proteinuria > 0.5 g/24 h. Participants were identified at the Nephrology Unit of Papa Giovanni XXIII Hospital and treated at Mario Negri Institute (Bergamo, Italy) between December 2021 and December 2023. Normalized glomerular filtration rate (GFR) (using iohexol plasma clearance) and 24-hour proteinuria (median of 3 urinary measurements) were co-primary outcomes. Analyses were by modified intention-to-treat.

RESULTS

At 6 weeks, dapagliflozin significantly decreased GFR by 1.88 ± 5.00 ml/min per 1.73 m 2 (P = 0.022) and proteinuria by 0.50 (-0.10 to 0.80) g/24 h (P = 0.026) versus placebo. The dapagliflozin-induced GFR (P < 0.001) and proteinuria (P = 0.003) reduction was already significant at 1 week. At 6 weeks, dapagliflozin reduced absolute GFR (P = 0.026), the CKD-Epidemiology Collaboration (CKD-Epi) equation-based estimated GFR (eGFR) (P = 0.003), the Modification of Diet in Renal Disease (MDRD) equation-based eGFR (P = 0.002), 24-hour albuminuria (P = 0.001), total protein (P = 0.057) and albumin (P = 0.009) fractional clearances, and fasting blood glucose (P < 0.001); and increased serum albumin (P = 0.001), renin activity (P = 0.020), glucosuria (P < 0.001), and glucose fractional clearance (P < 0.001) versus placebo. All changes reversed completely after treatment withdrawal. GFR changes correlated inversely with changes in renal plasma flow (RPF) (P = 0.010) and positively with changes in postglomerular resistance (P < 0.001) but did not correlate with changes in preglomerular resistance. There were no serious adverse events.

CONCLUSION

Dapagliflozin safely ameliorates (compensatory) glomerular hyperfiltration and proteinuria and is glycosuric in nondiabetic patients with preterminal CKD. GFR reduction is likely because of postglomerular vasodilation rather than preglomerular vasoconstriction.

MeSH

Proteinuria, Therapeutics, Plasma