Invited commentary from Dr. Swapnil Hiremath

Glucose is one of the many important molecules that are freely filtered by the glomeruli, and almost completely reabsorbed by the tubules. Indeed, of the approximately 180 grams of glucose filtered by healthy kidneys daily, less than half a gram actually makes it into the urine. The sodium-dependent glucose co-transporters use the electronegative gradient created by the Na-K ATPase to reabsorb glucose along with sodium from the luminal surface.  Sodium glucose linked transporters (SGLT)-1 is located in the gut and the proximal tubule while SGLT-2 is found primarily in the proximal tubule. The discovery of these co-transporters in the gut by Robert K. Crane in 1960 lead to the formulation of oral rehydration therapy for diarrhea, and has been labeled “the most important medical advance of (the 20th) century.” However, inhibition of SGLT-2 in the treatment of hyperglycemia has only recently been possible with the development of SGLT-2 inhibitors. In their article published in AJKD, De Nicola and colleagues describe how studies of these novel agents have helped elucidate the “tubulocentric” pathway in the mechanism of diabetic nephropathy and review the data from the published clinical trials.

Early diabetic nephropathy is characterized by glomerular hyperfiltration and enlargement of the kidneys. The hemodynamic hypothesis of hyperfiltration considers increased plasma flow and intraglomerular pressure as its principal determinants. Activation of the renin-angiotensin system and release of pro-inflammatory cytokines and growth factors are then responsible for proximal tubular hypertrophy and enlargement of the kidneys. Now, some interesting data from diabetic rats show that SGLT-2 blockade, by increasing sodium along with glucose delivery distally, activates the tubuloglomerular feedback and ameliorates the glomerular hyperfiltration. As such, the effect on glomerular filtration rate is direct and not dependent on the blood glucose lowering effect of SGLT-2 inhibition. This was also noted in another mouse model of diabetes in Akita mice.  In these mice, SGLT-2 blockade also attenuated the increase in glomerular size and inflammatory markers that was dependent on its glucose-lowering effect. A recent short-term study in humans also confirms that SGLT-2 blockade attenuates hyperfiltration in type-1 diabetic individuals.

The clinical trials of SGLT-2 inhibitors also show some interesting results. There is a consistent weight loss and a modest blood pressure lowering effect with SGLT-2 inhibitors. In addition, the trials with longer follow up (52 to 104 weeks) show an immediate decline in kidney function followed by a long-term stabilization, similar to that seen with RAS inhibition in diabetic nephropathy. As expected, there is an increase rate of urogenital infections from the glycosuria. The only trial in patients with chronic kidney disease also suggested that the effect on blood pressure and weight loss was seen despite an attenuated response on euglycemia in these patients. Long term data on important clinical outcomes is still awaited, in addition to data on the effects of these agents in combination with RAS inhibition.

In summary, De Nicola and colleagues describe how SGLT-2 inhibition affects the pathophysiology of kidney injury in diabetes and may have a role in the treatment of diabetes and also perhaps, in the prevention of diabetic nephropathy.

Dr. Swapnil Hiremath
Ottawa Hospital Research Institute

To view the article abstract or full-text (subscription required), please visit AJKD.org.