Tubuloglomerular Feedback in Renal Glucosuria: Mimicking Long-term SGLT-2 Inhibitor Therapy

Abstract A patient with renal glucosuria due to a congenital knock-out of the sodium-glucose co-transporter (SGLT)-2 protein because of a compound heterozygous mutation in the SLC5A2 gene may provide a natural model mimicking the effects of long-term SGLT-2 inhibitor therapy, which has been shown to exert kidney protective effects beyond its anti-diabetic properties. One possible mechanism for the protective effects of SGLT-2 inhibitor therapy might be the activation of tubuloglomerular feedback by increased outflow of sodium, chloride and glucose to distal parts of the nephron including the macula densa. Subsequently, afferent arteriolar vasoconstriction is induced and blood flow, intra-glomerular filtration pressure and glomerular filtration rate (GFR) all decline. On the other hand, prolonged tubuloglomerular feedback activation could change the sensitivity of tubuloglomerular feedback and hence decrease the beneficial effects of SGLT-2 inhibition on kidney function. Tubuloglomerular feedback is mediated by the Na+/K+/2Cl- cotransporter. Hence, furosemide, which blocks this cotransporter, is a medical option to test tubuloglomerular feedback because GFR should increase after administration of this loop diuretic. In our patient with chronic activated tubuloglomerular feedback due to SGLT-2 mutations, we show that the sensitivity of tubuloglomerular feedback is maintained, demonstrated by an increase in GFR measured using iohexol clearance following furosemide administration. This observation supports the idea that long-term SGLT-2 inhibitor therapy is kidney protective via a functional tubuloglomerular feedback.