Did you know how SGLT2 inhibitors protect the kidney?

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are anti-hyperglycemic agents that eliminate excess glucose by lowering proximal tubule glucose reabsorption and inducing a glucosuric effect. Besides its intended actions of glucose lowering and weight loss in people with type 2 diabetes mellitus (T2DM), SGLT2 inhibitors lower the risk of progression of kidney disease or death from cardiovascular causes among a wide range of diabetic and non-diabetic patients with chronic kidney disease (CKD) who were at risk for disease progression.1 How do they do that? SGLT2 inhibitors appear to protect the kidneys through pleiotropic effects.2 SGLT2 inhibitors preserve kidney function in part by reducing the physical stress on glomerular capillaries. This is accomplished via a three-pronged approach: by attenuating glomerular hyperfiltration, by increasing Bowman space pressure (PBow), and by decreasing glomerular capillary pressure (PGC). At the onset of diabetes, the proximal tubule hypertrophizes and reabsorbs more glucose and Na+ via SGLT2 and SGLT1, followed by Cl−, K+, and fluid. This hyper-reabsorption has several consequences. First, it lowers the delivery of NaCl to the macula densa, which activates tubuloglomerular feedback (TGF) and increases single nephron GFR (SNGFR). Hyper-reabsorption of fluid in the proximal tubule also reduces PBow, thereby further increasing filtration pressure and SNGFR.2 Because the above processes begin, in part, with hyper-reabsorption of glucose and Na+ via SGLT2, inhibition of SGLT2 can reverse some of these processes by lowering proximal tubule hyper-reabsorption in the diabetic kidney. As a result, tubular back pressure and PBow are restored, as is the delivery of Na+, Cl−, and K+ to the macula densa; and via TGF, glomerular hyperfiltration is attenuated.2 The initial GFR-lowering effect of SGLT2 inhibition was confirmed in people with type 1 diabetes mellitus (T1DM) and T2DM and is followed by long-term GFR preservation.3 SGLT2 inhibitors also protect the glomerular capillaries by reducing PGC. The TGF-induced ATP release promotes local formation of adenosine, which primarily constricts the afferent arteriole but can also dilate the efferent arteriole. Both effects are expected to lower PGC.4 Taken together, the hemodynamic impacts of SGLT2 inhibitors relieve physical stress on glomerular capillaries, thereby preserving glomerular and kidney function. Another pathway by which SGLT2 inhibitors protect the kidney is by preserving renal and particularly renal cortical oxygenation. Indeed, for patients with CKD, the preservation of renal cortical oxygenation seems crucial in preserving kidney function.5 Renal oxygen consumption depends on tubular transport work, a major determinant of which is the amount of filtered solutes and thus GFR. As such, SGLT2 inhibitors preserve renal oxygenation again with a three-pronged approach: by direct SGLT2 inhibition in the early proximal tubule, by lowering GFR, and via the functional coupling of SGLT2 to other transporters in the proximal tubule. Layton et al. built computational models of epithelial transport of electrolytes and fluid along the nephrons of the kidney of a diabetic rat.6, 7 Model simulations of the administration of a SGLT2 inhibitor predicted that, by lowering GFR, SGLT2 inhibition reduces oxygen consumption in the proximal convoluted tubule and renal cortex.6, 7 The predicted increase in cortical oxygenation has been observed in a diabetic rat model following the administration of the SGLT inhibitor phlorizin,8 as well as by an acute high dose of an SGLT2 inhibitor in albuminuric individuals with T1D, when assessed by magnetic resonance imaging despite unchanged renal blood/oxygen supply.9 SGLT2 inhibitors also lower cortical oxygen consumption through the functional coupling of SGLT2 to other transporters in the apical membrane of the early proximal tubule, such as the Na-H-exchanger NHE3, possibly involving the scaffolding protein MAP17, phosphorylation of NHE3, or insulin signaling.10 Hence, pharmacologic blockade of SGLT2 partially inhibits proximal tubule NHE3 activity.11 This co-inhibition further reduces proximal tubule transport work and oxygen consumption and is important for the acute natriuretic as well as the long-term effect of SGLT2 inhibition on volume homeostasis.11 Also, by shifting some of the glucose, NaCl, and fluid reabsorption to downstream segments, SGLT2 inhibitors enhance ATP consumption and simulate systemic hypoxia at the oxygen sensor in the deep cortex and outer medulla of the kidney, which may explain the observed increase in erythropoietin expression and plasma levels.12 Together with the diuretic effect, the resulting modest increase in hematocrit and hemoglobin in response to SGLT2 inhibition modestly increases the blood oxygen-carrying capacity and improve the oxygenation of renal outer medulla and cortex as well as other organs. Overall it appears that inhibiting early proximal tubule glucose uptake, tubular transport work and oxygen consumption can preserve the integrity of remaining nephrons and overall kidney function despite shifting a greater workload to downstream tubular segments.2 Do the above renoprotective mechanisms work in CKD, where the lower GFR in CKD yields a lesser blood glucose-lowering effect? The higher blood glucose in CKD results in a high glucose load on the single nephron level. Layton and Vallon built computational models of epithelial transport in rat kidneys with reduced nephron number (i.e., uninephrectomy or 5/6-nephrectomy) which partially approximate CKD.12 Model simulations predicted that the transport shift to the outer medulla and the natriuretic and diuretic effect of SGLT2 inhibition is in part preserved in CKD because of that high glucose load, which induces paracellular sodium secretion in the proximal tubule.12 This may contribute to the preserved protective effects of SGLT2 inhibitors in patients with CKD.1 The urinary loss of glucose also induces a fasting-like response with profound metabolic adaptions. These mechanisms have been refined extensively during evolution and are expected to be beneficial for organismal survival, including a shift to fatty acid and ketone body metabolism.2 On the other hand, hypoglycemia risk is low due to SGLT1 compensating in the late proximal tubule and an increase in hepatic and renal gluconeogenesis.2, 11 Finally, mediation analyses have associated beneficial kidney and heart outcomes in response to SGLT2 inhibitors with a lowering in blood urate levels, which has been linked to the glucosuric effect and functional inhibition of the proximal tubule urate transporter urat1, as shown in experimental13 and clinical studies.14 The above mechanisms are summarized in Figure 1. Many questions remain, however, including the role of off-target effects of SGLT2 inhibitors for kidney and, particularly, heart outcome,3 and whether we can translate insights from SGLT2 inhibitors to new molecular targets with similar characteristics, for example, as proposed for the early proximal tubule sodium-coupled amino acid transporter SLC6A19.15 None. No conflict of interest.

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