Intrarenal Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors on Tubuloglomerular Feedback and Natriuresis

Abstract

When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.

Results from a cross-specialty consensus on optimal management of patients with chronic kidney disease (CKD): from screening to complications

“…A steering group of experts (see author list) from 11 different countries convened in September 2022 to discuss current challenges in CKD management. The experts were defined as specialists in nephrology, endocrinology/diabetology, internal medicine and primary care medicine who had achieved an appropriate level of seniority within their field (eg, professors, clinical directors), or had published papers related to the management of CKD/HF/Diabetes, or had been involved in guidelines development 13–21. The steering group members were selected to provide representation across a range of development indicator levels external to Europe and North America (to avoid replication of previous published work22).…”

“…The experts were defined as specialists in nephrology, endocrinology/diabetology, internal medicine and primary care medicine who had achieved an appropriate level of seniority within their field (eg, professors, clinical directors), or had published papers related to the management of CKD/HF/Diabetes, or had been involved in guidelines development. [13][14][15][16][17][18][19][20][21] The steering group members were selected to provide representation across a range of development indicator levels external to Europe and North America (to avoid replication of previous published work 22 ). Steering group members were recruited to represent countries outside of North America and Europe.…”