Expanding the Implications of Proximal Tubular Function Assessment.
Journal
Journal of the American Society of Nephrology : JASN
ISSN
1533-3450
Date Issued
2025-05-21
Author(s)
Abstract
In a recent JASN article, Madero et al. conducted an interesting pilot study to assess proximal tubular function by pharmacologically stimulating creatinine and furosemide tubular secretion, followed by analysis of the associations between the 1-hour maximal tubular secretion of creatinine (TScr) or tubular secretion of furosemide (TSfuro), GFR, and tubular markers.1 As the authors highlight, their approach may serve as a practical method for assessing proximal tubular function. I would like to propose several considerations that could further expand the implications of their insightful findings. Previous studies have demonstrated that biologic sex may regulate renal organic anion transporter (OAT) expression. Euteneuer et al. found that estrogen significantly upregulates human OAT1 expression through the activation of estrogen receptor alpha signaling.2 Sex differences in the renal abundance of OATs and organic cation transporters have clinical implications, influencing susceptibility to xenobiotics, drug metabolism, the incidence of treatment-related adverse events, and disease outcomes between sexes.3 Among the cohort of Madero et al., 14 of 31 individuals were female. It would be valuable to examine whether sex-specific differences exist in the correlation between TScr or TSfuro and tubular markers, as these results could help determine the necessity of assessing tubular function through a sex-specific lens. Furthermore, given that women are more prone to drug-related side effects and exhibit considerable heterogeneity in drug susceptibility, an additional important implication of the findings by Madero et al. is that TScr or TSfuro measurements might facilitate more precise drug dosage adjustments for patients receiving medications that are also OAT or organic cation transporter substrates. Another potential implication of TSfuro is its role in investigating the physiologic changes induced by sodium-glucose cotransporter-2 inhibitors (SGLT2is), as some candidates may receive these medications. Existing literature indicates that OAT3, which contributes to furosemide secretion, also aids in transporting the SGLT2i empagliflozin to the brush border of proximal tubules, where it exerts its glucosuric effect.4 This raises the hypothesis that individuals with a high TSfuro capacity may experience differential SGLT2i-induced acute glomerular hemodynamic changes, potentially influencing long-term nephroprotective effects. Further studies are required to affirm or refute this possibility. In conclusion, the study by Madero et al. provides an innovate strategy for assessing proximal tubular function. Investigating sex-related differences in TScr and TSfuro correlation, as well as the potential implications for drug metabolism and the physiologic response to SGLT2is, could further enhance our understanding of tubular function. Further research in these areas may help refine personalized treatment strategies, optimizing treatment efficacy while minimizing adverse effects in nephrology practice.
Subjects
creatinine
tubular physiology
SDGs
Type
journal article