Albuminuria is a clinical risk factor for both kidney and cardiovascular disease development and progression. The amount of albumin in the urine, or its excretion rate, is the algebraic sum of the filtration rate and the tubular reabsorption rate of albumin. The proximal tubule, especially the S1 segment, plays a major role in reabsorbing, catabolizing, and reclaiming albumin via transcytosis.1 Of the three proximal tubule segments, the S1 segment has by far the richest endowment of mitochondria and the largest capacity for ion, glucose, amino acid, and macromolecule transport. Sodium-glucose cotransporter 2 (SGLT2) is highly expressed on the brush border membrane of S1 tubules, and is normally responsible for the near-complete reabsorption of ~200 g/day of filtered glucose (and the ~25 g of sodium that are cotransported). The activities of SGLT2 and the albumin reabsorption pathways1 require a substantial fraction of the total kidney energy consumption.

Highly selective SGLT2 inhibitors reduce sodium-glucose reabsorption by 30–40%, thereby sparing the proximal tubule an equivalent percentage of energy consumption. SGLT2 inhibitors have also been consistently shown to reduce albuminuria. One question therefore is whether SGLT2-induced glycosuria bears any relation to concomitant albuminuria. We recently explored the role of glycosuria in SGLT2 inhibitor-induced cardiorenal protection by measuring urine glucose-to-creatinine ratio (UGCR) in proteinuric patients with type 2 diabetes (T2D) and high cardiovascular risk randomized to canagliflozin 100 mg or placebo (a subcohort of the CREDENCE trial2). At 1 year after randomization, UGCR rose from a baseline of 0.25 (1.09) to 15.8 (29.2) mg/mg (median (IQR)) in the canagliflozin arm versus 0.24 (1.09) to 0.24 (1.29) mg/mg in the placebo arm (p<0.0001 between arms). Over the same time period, the urine albumin-to-creatinine ratio (UACR) dropped from 920 (1,283) to 593 (1,311) mg/g with canagliflozin while numerically increasing (from 886 (1,266) to 1,016 (1,819) mg/g) with placebo (p<0.0001 between arms). As is typical of multicentric patient cohorts, the distributions of UACR and UGCR were both widely scattered. Notably, however, UACR was directly related to UGCR among participants on placebo but inversely related to UGCR among participants on canagliflozin (figure 1). Thus, from the equation, a subject with a UGCR of 15 mg/mg (corresponding to a glycosuria of 25–30 g/day) is predicted to have a UACR of 1,315 mg/g if on placebo and one of 546 mg/g if on canagliflozin. The interpretation of this relationship is straightforward, that is, without canagliflozin a large glycosuria marks worse glycemic control (and, presumably, greater renal damage), while with canagliflozin the same degree of glycosuria is associated with less albuminuria and lesser kidney damage. Importantly, at 1-year estimated glomerular filtration rate (eGFR): 49 (27) versus 50 (29) mL×min−1×1.73 m−2, canagliflozin versus placebo, p=n.s.—and plasma glucose concentrations: 8.0 (3.6) versus 8.3 (3.8) mmol/L, p<0.02—were little different between the arms. Also, the reduction of UACR with canagliflozin was detected at the earliest time tested after randomization—when glycosuria had been steadily ongoing—and stabilized thereafter.

Request permissionFigure 1

Relationship between albuminuria (as the urine albumin-to-creatinine ratio) and glycosuria (as the urine glucose-to-creatinine ratio) at 1 year following randomization. The full lines are the log–log fit and the dotted lines are 95% CIs. The p values in the legend are Spearman’s; the p value is for the interaction between the glucose–creatinine ratio and treatment. Median (IQR) values of the urine albumin-to-glucose ratio for the canagliflozin and placebo groups are 41 (185) and 2,587 (7,009) mg/mg, respectively (p<0.0001 by Wilcoxon test).

The congruence of site, that is, the proximal tubule, and timing, that is, relatively early after commencing SGLT2 inhibition, begs the question, what mechanisms may underlie the association between glycosuria and albuminuria? Lacking direct evidence, some circumstances suggest plausible explanations. First, the energy saved from glucose reabsorption may help reclaiming filtered albumin. Second, SGLT2 inhibitors have been shown to suppress the mTORC1 complex,3 which coordinates exocytic membrane traffic and albumin transcytosis with nutrient availability.1 Third, SGLT2 blockade may deliver more sodium to the macula densa, thereby activating a tubulo-glomerular feedback that reduces intraglomerular pressure and albumin leakage.4 It is also possible that the SGLT2 inhibition-induced rise in blood hemoglobin may contribute to the antiproteinuric effect.5 It should be noted, however, that in the current 1-year data the decrease in albuminuria (36%) was disproportionate to the decrease in eGFR (9%), and there was no correlation between either eGFR or hematocrit with glycosuria.

It must be emphasized that the present observation on the association between glycosuria and albuminuria was made in patients with T2D, chronic kidney disease and proteinuria, and may not extend to other patient phenotypes. More investigation on the subject nonetheless seems warranted.

Footnotes

Contributors: EF has analyzed the data and written the letter. AS and AN have commented, edited and approved the final manuscript. EF is the guarantor.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: No, there are no competing interests for any author.

Provenance and peer review: Not commissioned; externally peer reviewed.

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Back to topReferences Molitoris BA, Sandoval RM, Yadav SPS, et al. Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications. Physiol Rev 2022; 102:1625–67. doi:10.1152/physrev.00014.2021•Google Scholar Ferrannini E, Solini A, Baldi S, et al. Role of Glycosuria in SGLT2 Inhibitor-Induced Cardiorenal Protection: A Mechanistic Analysis of the CREDENCE Trial. Diabetes 2024; 73:250–9. doi:10.2337/db23-0448•Google Scholar Packer M. Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis. Circulation 2022; 146:1383–405. doi:10.1161/CIRCULATIONAHA.122.061732•Google Scholar van Bommel EJM, Muskiet MHA, van Baar MJB, et al. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial. Kidney Int 2020; 97:202–12. doi:10.1016/j.kint.2019.09.013•Google ScholarBack to top