Sodium glucose co-transporter 2 inhibitors (SGLT2i) for pediatric kidney disease: the future is near

Abstract

The sodium glucose co-transporter 2 (SGLT2) functions in the proximal tubule to reabsorb the bulk of filtered glucose. SGLT2 inhibitors have been developed to promote renal glucose excretion to improve glycemic control in diabetes. Regulatory guidance mandated adequately powered studies to detect increased cardiovascular risk from emerging hypoglycemic medications. This led to recognition of remarkable improvement in cardiovascular and kidney outcomes with SGLT2 inhibition. Moreover, cardiovascular and kidney benefits extend beyond patients with diabetes. The dramatic kidney benefits of SGLT2 inhibitors documented in CKD in adult patients underscores the need for pediatric nephrologists to familiarize themselves with SGLT2 inhibitor therapies. This review explores the currently available body of knowledge regarding the kidney protective effects of SGLT2 inhibitors in adults and mechanisms thought to contribute to improved kidney outcomes. The limited data for SGLT2i treatment in pediatric kidney disease are reviewed and highlight the need for randomized controlled trials of this drug class in pediatric kidney patients as has been done for pediatric diabetes. Dosing patterns for SGLT2 inhibitors from other pediatric settings are reviewed as well as guidance for initiating SGLT2 inhibition in young adults remaining in pediatric nephrology care.

Keywords: IgA nephropathy; SGLT2 inhibitors; canagliflozin; chronic kidney disease; dapagliflozin; empagliflozin; pediatric chronic kidney disease; proteinuria.

Figure 1

Mechanism of action of sodium glucose co-transporter 2 inhibitors through enhanced tubular glomerular feedback. With permission from Ref. (, p. C664). A nephron is shown on the left with the glomerulus, juxtaglomerular apparatus, and early proximal tubule enlarged on the right. SGLT2 inhibitors (red text) block the reabsorption of Na+ and glucose in the proximal tubule leading to glucosuria and increased Na+ delivery to the distal tubule and macula densa. As a result, macula densa cells release ATP which is hydrolyzed locally to adenosine (red text). Adenosine acts on adjacent smooth muscle adenosine receptors to constrict the afferent arterioles. Decreased afferent arteriolar blood flow lowers intraglomerular pressure and decreases glomerular filtration, thus ameliorating proteinuria, podocyte derangement and loss, as well as downstream inflammation and renal fibrosis.

Figure 2

Change in estimated GFR (eGFR) from baseline in the DAPA-CKD trial. With permission from Ref. (29). The mean eGFR at baseline for the dapagliflozin group was 43.2 ml/min/1.73 m² and 43 ml/min/1.73 m² in the placebo group. Dapagliflozin treatment results in a prompt drop in eGFR but a slower decrease in eGFR over time, mitigating CKD progression.