Significance Statement: The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling.
Background: The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits.
Methods: This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide.
Results: Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT.
Conclusions: Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile.
Clinical Trial Registry Name And Registration Number: ClinicalTrials.gov ( NCT03027960 ).
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http://dx.doi.org/10.1681/ASN.0000000000000269 | DOI Listing |
Int J Mol Sci
January 2025
Department of Hypertension and Diabetology, Medical University of Gdańsk, 80-214 Gdańsk, Poland.
Aldosterone, the primary adrenal mineralocorticoid hormone, as an integral part of the renin-angiotensin-aldosterone system (RAAS), is crucial in blood pressure regulation and maintaining sodium and potassium levels. It interacts with the mineralocorticoid receptor (MR) expressed in the kidney and promotes sodium and water reabsorption, thereby increasing blood pressure. However, MRs are additionally expressed in other cells, such as cardiomyocytes, the endothelium, neurons, or brown adipose tissue cells.
View Article and Find Full Text PDFKidney Int
February 2025
Department of Pediatrics, The Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address:
Sodium reabsorption is tightly coupled to calcium reabsorption in the proximal tubule via the action of the Na/H exchanger isoform 3 (NHE3). Poulsen et al. provide evidence of reduced proximal calcium reabsorption in kidney tubule-specific NHE3-deficient mice that is compensated distally, unaltered phosphate homeostasis, and NHE3 involvement in the hypocalciuric effect of thiazides.
View Article and Find Full Text PDFInt Immunopharmacol
January 2025
School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China; Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China; Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China. Electronic address:
Background: Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear.
View Article and Find Full Text PDFMetabolism
January 2025
Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address:
Epithelial sodium channel (ENaC), located in the collecting duct principal cells of the kidney, is responsible for the reabsorption of sodium and plays a critical role in the regulation of extracellular fluid volume and consequently blood pressure. The G protein-coupled bile acid receptor (TGR5) is a membrane receptor mediating effects of bile acid and is implicated in kidney diseases. The current study aims to investigate whether TGR5 activation in the kidney regulated ENaC expression and potential mechanism.
View Article and Find Full Text PDFJ Chin Med Assoc
September 2024
Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.
Background: Many studies have reported the renal outcomes and metabolic consequences after augmentation cystoplasty (AC), however few studies have discussed changes in renal tubular function. The aim of this study was to determine the prevalence of metabolic disturbances, evaluate renal tubular function and 24-hour urine chemistry to evaluate the association between metabolic alterations and urolithiasis after AC.
Methods: We investigated serum biochemistry, blood gas, and 24-hour urinary metabolic profile of children who underwent AC between January 2000 and December 2020.
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