Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease

Abstract

Purpose of review: This review offers a critical narrative evaluation of emerging evidence that sodium-glucose co-transporter-2 (SGLT2) inhibitors exert nephroprotective effects in people with type 2 diabetes.

Recent findings: The SGLT2 inhibitor class of glucose-lowering agents has recently shown beneficial effects to reduce the onset and progression of renal complications in people with and without diabetes. Randomised clinical trials and 'real world' observational studies, mostly involving type 2 diabetes patients, have noted that use of an SGLT2 inhibitor can slow the decline in glomerular filtration rate (GFR), reduce the onset of microalbuminuria and slow or reverse the progression of proteinuria. The nephroprotective effects of SGLT2 inhibitors are class effects observed with each of the approved agents in people with a normal or impaired GFR. These effects are also observed in non-diabetic, lean and normotensive individuals suggesting that the mechanisms extend beyond the glucose-lowering, weight-lowering and blood pressure-lowering effects that accompany their glucosuric action in diabetes patients. A key mechanism is tubuloglomerular feedback in which SGLT2 inhibitors cause more sodium to pass along the nephron: the sodium is sensed by macula cells which act via adenosine to constrict afferent glomerular arterioles, thereby protecting glomeruli by reducing intraglomerular pressure. Other effects of SGLT2 inhibitors improve tubular oxygenation and metabolism and reduce renal inflammation and fibrosis. SGLT2 inhibitors have not increased the risk of urinary tract infections or the risk of acute kidney injury. However, introduction of an SGLT2 inhibitor in patients with a very low GFR is not encouraged due to an initial dip in GFR, and it is prudent to discontinue therapy if there is an acute renal event, hypovolaemia or hypotension.

Keywords: Acute kidney disease; Albuminuria; Chronic kidney disease; Diabetic kidney disease; Sodium-glucose co-transporter-2 (SGLT2) inhibitors.

Fig. 1

Key sites of action of sodium-glucose co-transporter (SGLT) inhibitors. SGLT2 (encoded by the solute carrier gene slc5a2) is expressed almost entirely in the luminal membrane of epithelial cells lining the first and second segments of the proximal tubules. It is a high capacity co-transporter acting with a sodium-glucose stoichiometry of 1:1 to mediate the reabsorption of most of the filtered glucose. SGLT1 (encoded by slc5a1) is expressed in the luminal membrane of cells lining the third (straight) segment of the proximal tubules. It acts with a sodium-glucose stoichiometry of 2:1 and has a lower capacity but higher affinity than SGLT2 to retrieve low concentrations of glucose remaining in the tubule. SGLT1 is expressed widely and occurs most abundantly in the apical membranes of enterocytes in the small intestine where it mediates glucose uptake from the intestinal lumen. Both transporters are secondary active symporters that depend on the sodium gradient created by Na + -K + -ATPase pumps in the basolateral membranes which lower the intracellular sodium concentration. Glucose that is taken up by sodium-glucose co-transporters into proximal tubule cells and enterocytes is eliminated across the basolateral membranes and into the interstitium via facilitative glucose transporters (e.g. GLUT1 and GLUT2)

Fig. 2

Illustration to show the typical changes in estimated glomerular filtration rate (eGFR) following the introduction and long-term use of SGLT2 inhibitors in people with type 2 diabetes. The initial dip in eGFR is about 5 ml/min/1.73 m², reaches a nadir within 1–2 weeks and slowly returns towards pretreatment values over the next 3–9 months. Thereafter the rate of decline in eGFR is slower than in individuals who are not treated with an SGLT2 inhibitor. The illustration is loosely based on data from the EMPA-REG, CREDENCE and DAPA-CKD trials

Fig. 3

Schematic diagram to show the potential effects of SGLT2 inhibition on acute kidney injury (AKI). Use of an SGLT2 inhibitor is not a recognised risk for the occurrence of AKI, and available evidence indicates that SGLT2 inhibitors may be associated with a reduced occurrence of AKI. SGLT2 inhibitors may alter factors that ‘aggravate’ the severity of AKI. For example, SGLT2 inhibitors might improve the prognosis for people with AKI by decreasing the rate of decline of estimated glomerular filtration rate (eGFR) in people with chronic kidney disease (CKD) and by reducing the severity of heart failure. SGLT2 inhibitors might impair the prognosis for people with AKI if the SGLT2 inhibitor has been started recently and there is a drug-induced dip in eGFR and by dehydration or ketoacidosis