Modeling the renoprotective effects of SGLT2 inhibition in nondiabetic chronic kidney disease

Abstract

Recently, SGLT2 inhibitors have been approved for chronic kidney disease (CKD) based on their ability to slow renal disease progression and reduce cardiovascular mortality independent of diabetes status. However, the exact mechanisms of their cardiovascular and renal protection in these patients remain unclear. While some believe hyperglycemia drives hyperfiltration through SGLT2-mediated proximal tubular sodium reabsorption and subsequent inhibition of tubuloglomerular feedback (TGF), recent experimental evidence suggest glucose-induced hyperfiltration in isolated nephrons occurs through SGLT1 activation at the macula densa. We hypothesize that, when nephron number is critically reduced, decreased sodium delivery to the macula densa from increased SGLT2 activation and increased glucose at the macula densa both inhibit TGF and exacerbate glomerular hyperfiltration in CKD, despite normoglycemia. To test this hypothesis, we used an established integrative mathematical model of human physiology (HumMod) that was derived from its precursor cardiovascular model created by Drs. Guyton and Coleman. Starting from baseline conditions, we simulated nondiabetic CKD in response to a high salt/high carbohydrate diet for 6 months. SGLT2 transporter effects were based on data from experimental literature describing the role of SGLT2 in proximal tubule sodium reabsorption and cardiac fibrosis as well as SGLT1 effects on modulating TGF based on local macula densa glucose concentrations. To our knowledge, this is the first physiological model that integrates the acute and chronic cardiovascular and renal responses to daily fluctuations in salt, glucose, and drug concentrations. Baseline CKD conditions were associated with hypertension, low renal function (60 mL/min), left ventricular hypertrophy, and peak post-prandial glucose levels around 200 mg/dL. This resulted in urinary glucose within the normal range (0.2 mmol/L) but a decrease in TGF and potentiation of pre-existing glomerular hypertension and nephron damage. Inhibition of SGLT2 (25 mg empagliflozin/day) for 6 months was associated with minor reductions in systolic blood pressure (-6 mmHg) and glomerular filtration rate (-2 mL/min) with no changes in plasma glucose or insulin as compared to the CKD control simulation. However, SGLT2 inhibition resulted in decreased proximal tubular sodium reabsorption and restoration of TGF as well as reductions in nephron damage, proteinuria, and cardiac fibrosis similar to findings in animal and human studies. Adding SGLT1 inhibitory effects further reduced proximal tubular sodium reabsorption, glomerular pressure, and nephron damage. This model supports the use of SGLT2 inhibitors to reduce hyperfiltration in CKD and mitigate renal disease progression, even in the absence of diabetes. These data suggest SGLT1/2 combination blockade (recently shown to improve outcomes in diabetic CKD but also increase ketoacidosis risk), may be especially beneficial in non-diabetic CKD. This work was supported by grants from the National Institute on Minority Health and Health Disparities (R00 MD014738), National Institute of General Medical Sciences (P20 GM104357), and the National Heart, Lung, and Blood Institute (T32 HL105324 and P01 HL051971). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.