Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers

Claire C J Dekkers; Sergei Petrykiv; Gozewijn D Laverman; David Z Cherney; Ron T Gansevoort; Hiddo J L Heerspink

doi:10.1111/dom.13301

Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers

Diabetes Obes Metab. 2018 Aug;20(8):1988-1993. doi: 10.1111/dom.13301. Epub 2018 Apr 23.

Authors

Claire C J Dekkers¹, Sergei Petrykiv², Gozewijn D Laverman³, David Z Cherney^{4

5}, Ron T Gansevoort¹, Hiddo J L Heerspink¹

Affiliations

¹ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
² Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Department of Nephrology, Ziekenhuisgroep Twente, Almelo and Hengelo, The Netherlands.
⁴ Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Canada.
⁵ Department of Physiology and Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada.

Abstract

The mechanisms by which SGLT-2 inhibitors lower albuminuria are incompletely understood. We assessed in a post-hoc analysis of a cross-over trial the effects of the SGLT2 inhibitor dapagliflozin on glomerular markers (IgG to IgG4 and IgG to albumin), tubular markers (urinary KIM-1, NGAL and LFABP) and inflammatory markers (urinary MCP-1 and IL-6) to provide more insight into kidney protective effects. Dapagliflozin decreased albuminuria by 43.9% (95% CI, 30.3%-54.8%) and eGFR by 5.1 (2.0-8.1) mL/min/1.73m² compared to placebo. Dapagliflozin did not change glomerular charge or size selectivity index compared to placebo. Dapagliflozin decreased urinary KIM-1 excretion by 22.6% (0.3%-39.8%; P = .05) and IL-6 excretion by 23.5% (1.4%-40.6%; P = .04) compared to placebo, whereas no changes in NGAL, LFABP and MCP-1 were observed. During dapagliflozin treatment, changes in albuminuria correlated with changes in eGFR (r = 0.36; P = .05) and KIM-1 (r = 0.39; P = .05). In conclusion, the albuminuria-lowering effect of 6 weeks of dapagliflozin therapy may be the result of decreased intraglomerular pressure or reduced tubular cell injury.

Keywords: KIM-1; MCP-1; SGLT-2; acute kidney injury; dapagliflozin; type 2 diabetes.

Publication types

Clinical Trial
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury / complications
Acute Kidney Injury / immunology
Acute Kidney Injury / prevention & control*
Adult
Albuminuria / etiology
Albuminuria / prevention & control
Anti-Inflammatory Agents, Non-Steroidal / adverse effects
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Benzhydryl Compounds / adverse effects
Benzhydryl Compounds / therapeutic use*
Biomarkers / blood
Biomarkers / urine
Cross-Over Studies
Diabetes Mellitus, Type 2 / complications
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / physiopathology
Diabetic Nephropathies / immunology
Diabetic Nephropathies / prevention & control*
Double-Blind Method
Glomerular Filtration Rate / drug effects
Glucosides / adverse effects
Glucosides / therapeutic use*
Hepatitis A Virus Cellular Receptor 1 / metabolism
Humans
Inflammation Mediators / blood
Inflammation Mediators / urine
Interleukin-6 / urine
Kidney Glomerulus / drug effects*
Kidney Glomerulus / immunology
Kidney Glomerulus / physiopathology
Kidney Tubules / drug effects*
Kidney Tubules / immunology
Kidney Tubules / physiopathology
Netherlands
Renal Elimination / drug effects
Sodium-Glucose Transporter 2 Inhibitors / adverse effects
Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Benzhydryl Compounds
Biomarkers
Glucosides
HAVCR1 protein, human
Hepatitis A Virus Cellular Receptor 1
IL6 protein, human
Inflammation Mediators
Interleukin-6
Sodium-Glucose Transporter 2 Inhibitors
dapagliflozin