High-protein diet: A barrier to the nephroprotective effects of sodium-glucose co-transporter-2 inhibitors?

Glomerular hyperfiltration is a common finding in patients with diabetes and poor glycaemic control; whole-kidney hyperfiltration, with glomerular filtration rate (GFR) values above normal, should be differentiated from single nephron hyperfiltration, consequent to nephron loss and compensatory hyperfiltration of the remnant nephrons. This is the result of an imbalance between the vascular tone of the afferent and efferent arterioles. Hormonal influences and/or an impaired tubuloglomerular feedback (TGF) system, because of excessive sodium (Na⁺ ) and glucose reabsorption in the proximal tubule, contribute to determine hyperfiltration. Sodium-glucose co-transporter-2 inhibitors (SGLT2is), by decreasing Na⁺ reabsorption and increasing the delivery of Na⁺ to the macula densa, lead to normalization of TGF, and, consequently, decrease GFR (both whole and single nephron). High-protein diets are popular among patients with type 1 and type 2 diabetes; importantly, 80% of the amino acids are also reabsorbed in the proximal tubule of the nephron and are transported by symporters that use the electro-chemical gradient of Na⁺ . Indeed, an acute protein load is associated with increased Na⁺ reabsorption and an increase in GFR. Here, we hypothesize that high-protein diets, by increasing Na⁺ reabsorption and GFR, may offset the positive renal effects of SGLT2is.