As a #Flozinator, I have a confession to make: I've been intellectually bothered about the success of SGLT2i in non diabetic forms of CKD. I've had some time to think about this over the perpetual forced lockdowns due to COVID and I think I may have an explanation I can live with

It all goes back to the Brenner hypothesis regarding the distribution of single nephron GFR (SNGFR) that in aggregate make up the total kidney function (GFR). As you may recall Brenner's hypothesis is based on experimental observations about this distro
https://journals.physiology.org/doi/pdf/10.1152/ajprenal.1985.249.3.F324

This is Figure 2 from the Renal Adaptation paper. The distribution is narrow for normal rats but wide and with a fat tail in rats with kidney issues. The area under the curve is the total kidney function (GFR). While the GFR in rats with kidney disease is < normal ones ...

the distribution includes a large number of hyperfiltrating units. These make up a significant % of the GFR in rats with kidney issues; in fact at any level of GFR there are more of these units in the animals with abnormal kidney function compared to those without kidney issues.

Reabsorption of sugar filtered by the glomerulus is a rather important (and under-appreciated) kidney function and is preserved even as kidney function declines. In fact, with the exception of proximal tubular disorders, glucosuria does not develop during progression of CKD.

What are the implications of the preservation of sugar reabsorption? The total workload to be done is GFR * plasma glucose. While this workload will decline as the total GFR declines in Chronic Kidney Disease, the workload of many of the surviving nephrons will not not

To see why, enter Figure 3 of the Brenner paper again. It shows proximal fluid reabsorption as a function of the single nephron GFR: a rather linear relationship, showing the glomerulotubular balance at work. Now thing about what the large amount of reabsorbed fluid means ...

for the Tubulo Glomerular Feedback of the highly filtrating nephrons: a high TGF signal will be generated by the macula densa of these nephrons. But we know that such a signal will be detrimental to the nephron according to the tubular hypothesis
https://www.annualreviews.org/doi/abs/10.1146/annurev-physiol-020911-153333

In both diabetic and non-diabetic kidney disease, the proximal cause of bad things happening to good kidneys is triggered by the (maladaptive), yet evolutionary rational complete reabsorption of sugar in the proximal nephron, a process that has nothing to do with diabetes

Shutting down reabsorption of the sugar, is thus expected to eliminate the maladaptive TGF signals by increasing fluid deliver to the macula densa irrespective of the presence of diabetes. This a predestined outcome of the altered distribution of SNGFR in progressive CKD
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