SGLT2 Inhibitors May Reduce Tubular Protein Overload in CKD: Study
A new study published in the journal of Kidney Medicine found that among patients with chronic kidney disease (CKD), SGLT2 inhibitor (SGLT2i) therapy was associated with a significant increase in urinary α-1-microglobulin, particularly among those with normal to mildly increased albuminuria (UACR stage A1). As the tubular injury marker uDKK3 remained stable, the rise in urinary α-1-microglobulin may reflect reduced tubular protein reabsorption rather than tubular damage. This functional change could reduce intratubular protein overload and potentially represent an additional nephroprotective mechanism of SGLT2 inhibitors.
This research from Göttingen University Hospital in Germany followed 57 patients with CKD who were prescribed SGLT2i as part of routine clinical care. The study investigated how the therapy affected markers of tubular function and stress over a 6-month period by analyzing urine samples collected before treatment and at follow-up.
The participants had a mean age of 66.4 years, with women accounting for 42.1% of the cohort. At baseline, the average estimated glomerular filtration rate (eGFR) was 42.0 mL/min/1.73 m², which reflected moderate kidney impairment. As expected with SGLT2 inhibitor therapy, eGFR declined modestly by an average of 2.1 mL/min/1.73 m² during the study period, a well-recognized early effect of these drugs.
Significant rise in urinary α1-microglobulin (uα1-MG) was observed. Median uα1-MG levels increased by 9.7 mg/g creatinine over 6 months. The increase was most pronounced in patients with low (A1) and moderate (A2) albuminuria, while those with severe albuminuria (A3) showed only a numerical, non-significant increase. Also, two other important urinary markers, urinary albumin-to-creatinine ratio (UACR) and urinary Dickkopf-3 (uDKK3) did not change significantly.
The stable uDKK3 levels are particularly important because they suggest that the rise in uα1-MG does not indicate worsening tubular damage. Instead, researchers propose that SGLT2 inhibitors may reduce the kidney tubules' reabsorption of filtered proteins, thereby lowering protein overload within tubular cells. This functional adaptation could represent another mechanism through which these drugs protect kidney tissue beyond their established effects on reducing glomerular hyperfiltration.
The effect was especially obvious in patients with A1 albuminuria, a group in whom reductions in hyperfiltration are typically less pronounced, which highlighted a potentially distinct protective pathway. Overall, the findings provide fresh insight into the complex renal effects of SGLT2 inhibitors and suggest that changes in tubular protein handling may contribute to the drugs' well-documented kidney-protective benefits in patients with chronic kidney disease.
Source:
Schäfer, A.-K. C., Pieper, D., Bayram, B., Ajrab, J., Delistefani, F., Zeisberg, M., Koziolek, M. J., & Wallbach, M. (2026). Effects of SGLT2I therapy on tubular reabsorption and tubular epithelial stress injury in patients with CKD. Kidney Medicine, 8(8), 101416. https://doi.org/10.1016/j.xkme.2026.101416
