Dapagliflozin Mitigates Medullary Hypoxia in CKD Patients

KEY POINTS: Dapagliflozin significantly improves renal medullary oxygenation in CKD, constituting a potential mechanism of its nephroprotection. The enhancement of medullary oxygenation is more pronounced in nondiabetic patients, suggesting a distinct pathophysiologic response. Blood oxygenation level-dependent magnetic resonance imaging represents a promising noninvasive biomarker for assessing renal oxygenation. BACKGROUND: Renal hypoxia is believed to play a central role in the pathophysiology of both diabetic and nondiabetic CKD. Dapagliflozin has been shown to slow the progression of kidney disease by counteracting several pathogenic mechanisms. The advent of blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) has enabled the noninvasive assessment of renal oxygenation in humans. However, it remains uncertain whether dapagliflozin affects changes in renal oxygenation. The aim of the study was to assess whether dapagliflozin modifies kidney oxygenation measured by BOLD-MRI. METHODS: The GLUcose Transport and Renal PROtection in chronic kidney disease study is a randomized controlled clinical trial investigating the effect of dapagliflozin on kidney measures. Here, we investigate whether changes in global and segmental renal oxygenation estimated by BOLD-MRI (namely, changes in R2* parameter) can be measured, after randomization to dapagliflozin or placebo. We analyzed data from 720 pairs of regions of interest of 20 patients who underwent BOLD-MRI on a 3T magnetic resonance imaging scanner, comparing baseline measurements against the ones obtained after 3 months from the onset of treatment. RESULTS: After 12 weeks, dapagliflozin treatment significantly reduced the medullary R2* relaxation rate, indicating improved oxygenation ( P = 0.015), while cortical R2* remained unchanged ( P = 0.56). This effect was more pronounced in nondiabetic patients. Dapagliflozin was identified as the sole independent determinant of improved medullary renal oxygenation ( β , -14.4; 95% confidence interval, -23.9 to -4.89; P = 0.003) after accounting for other confounding factors such as age, presence of diabetes or macroalbuminuria, and BP levels. In addition, dapagliflozin appeared to alter the relationship between changes in renal oxygenation and the eGFR slope. CONCLUSIONS: These findings suggest that dapagliflozin may mitigate medullary hypoxia in patients with CKD. BOLD-MRI could serve as a valuable biomarker for assessing renal functional reserve and predicting CKD progression. Further studies are warranted to confirm these effects and explore underlying molecular mechanisms. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: EudraCT, 2020-004835-26 ; ClinicalTrials.gov, NCT05998837 .