増田 貴博

The primary treatment goal of chronic kidney disease (CKD) is preserving renal function and preventing its progression to end-stage renal disease. Glomerular hypertension and tubular hypoxia are critical risk factors in CKD progression. However, the renal hemodynamics make it difficult to avoid both factors due to the existence of peritubular capillaries that supply oxygen to the renal tubules downstream from the glomerulus through the efferent arteriole. In the treatment strategies for balancing glomerular pressure and tubular oxygen supply, afferent and efferent arterioles of the glomerulus determine glomerular filtration rate and blood flow to the peritubular capillaries. Therefore, sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors as well as classical renin-angiotensin system inhibitors, which can change the diameter of afferent and/or efferent arterioles, are promising options for balancing this dual target and achieving renal protection. This review focuses on the clinical importance of glomerular pressure and tubular oxygen supply and proposes an effective treatment modality for this dual target.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase urine volume with glucosuria and natriuresis. We recently reported that osmotic diuresis by the SGLT2 inhibitor ipragliflozin induces fluid homeostatic action via the stimulation of fluid intake and vasopressin-induced water reabsorption in euvolemic rats. However, the effects of SGLT2 inhibitors on these parameters in hypervolemic animals remain unclear. In this study, Dahl salt-sensitive hypertensive rats, a hypervolemic rat model, were fed a low-salt (0.3%) or high-salt (8%) diet for 14 days, then divided into vehicle or ipragliflozin (0.01%) groups. During 7 days of treatment, the high-salt diet groups significantly increased fluid intake and urine volume. In the ipragliflozin groups, fluid intake and urine volume increased by 63% and 235%, respectively, in rats fed a normal-salt diet and by 46% and 72%, respectively, in rats fed a high-salt diet. Ipragliflozin increased urinary vasopressin by 200% and solute-free water reabsorption by 196% in the normal-salt group but by only 44% and 38%, respectively, in the high-salt group. A high-salt diet significantly increased fluid balance (fluid intake - urine volume) and Na+ balance (Na+ intake - urinary Na+), but ipragliflozin did not change fluid and Na+ balance in normal- or high-salt groups. A high-salt diet significantly increased systolic blood pressure, but ipragliflozin did not significantly change systolic blood pressure in normal- or high-salt groups. In conclusion, SGLT2 inhibitor ipragliflozin did not change fluid and Na+ balance regardless of basal fluid retention, suggesting the potential of SGLT2 inhibitors to maintain body water and Na+.