In a Letter to the Editor,1 Dr. Chao raises the question of sex-specific differences in the response of tubular secretion of furosemide (TSfuro) and possible correlation with markers of tubular function. It is an important issue since mRNA and protein expression of organic anion transporter 1 (OTA1) and OAT3 are higher in male rodents,2 and human OAT1 is significantly activated by estradiol-induced estrogen receptor alpha signaling.3
The levels of 1-hour stimulated TSfuro (mg/min) were not different (P > 0.05) in women (0.38; 95% confidence interval [CI], 0.25 to 0.51) and men (0.30; 95% CI, 0.13 to 0.37) in our study. Similarly, the increment from baseline levels of TSfuro was not different in women (0.34; 95% CI, 0.20 to 0.37) and men (0.22; 95% CI, 0.10 to 0.34).
There were no significant differences in the urinary excretion (median, quartiles) found in women and men of EGF (ng/min; women=5.4, 1.8 and 18.6; men=5.3, 1.8 and 18.3), alpha 1 microglobulin (a1MG) (μg/min; women=3.5, 1.8 and 59.4; men=12.6, 1.6 and 53.5), ammonium (NH4) (mMol/min; women=16.5, 5.7 and 28.2; men=15.8, 9.5 and 25.8), uromodulin (μg/min; women=76, 42 and 161; men=76, 22 and 184), kidney injury molecule 1 (KIM-1) 1 (μg/min; women=1.6, 0.7 and 5.7; men=2.8, 1.2 and 4.9), and interleukin 18 (pg/min; women=170, 95 and 367; men=224, 152 and 561).
The correlations (Spearman, rs) between the increment of TSFuro and the urinary excretion of tubular function markers EGF, a1MG, NH4, uromodulin, and KIM1 were all significant in men (P < 0.05) but not in women: EGF (rs men=0.9, P = 0.002; rs women=0.23, P = 0.5), a1MG (rs men=−0.77, P = 0.011, rs women=−0.58, P = 0.11), NH4 (rs men=0.73, P = 0.009; rs women=0.37, P = 0.26), uromodulin (rs men=0.6, P = 0.043; rs women=0.55, P = 0.09), and KIM1 (rs men=−0.64, P = 0.03; rs women=−0.15, P = 0.65). Urinary excretion of IL-18 was not significantly correlated with the increment in TSfuro in either sex.
In relation to the tubular secretion of creatinine, that depends mainly on the activity of OCT2 and OCT3, and to a lesser extent OAT2,4 we found no significant differences between women and men in the parameters previously mentioned for TSfuro.
The lack of sexual differences in the stimulation of TSfuro and the absence of significant correlations in women (in contrast to men) between the increment in TSfuro and the urinary excretion of EGF, a1MG, NH4, uromodulin, and KIM1 is interesting, but our work5 in JASN included a limited number of patients and was not designed to identify differences between women and men. Therefore, additional studies are necessary to confirm these findings. The question of the potential role of OAT activity in the glomerular hemodynamic effects of sodium-glucose cotransporter 2 inhibitors, raised by Dr. Chao, is also of interest and deserves further investigation.
Acknowledgments
Because Dr. Magdalena Madero is an Associate Editor of JASN, she was not involved in the peer-review process for this manuscript. Another editor oversaw the peer-review and decision-making process for this manuscript.
Footnotes
See related letter to the editor, “Expanding the Implications of Proximal Tubular Function Assessment,” on pages 1887–1888, and original article, “Estimation of Proximal Tubular Function by Stimulation of Organic Anion and Cation Transporters,” on pages 1786–1797.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F194.
Author Contributions
Conceptualization: Magdalena Madero, Bernardo Rodriguez-Iturbe.
Formal analysis: Magdalena Madero, Bernardo Rodriguez-Iturbe.
Funding acquisition: Magdalena Madero.
Investigation: Ana Karen Fernández-Yepez, Magdalena Madero, Bernardo Rodriguez-Iturbe.
Methodology: Ana Karen Fernández-Yepez, Magdalena Madero, Bernardo Rodriguez-Iturbe.
Project administration: Ana Karen Fernández-Yepez, Magdalena Madero.
Resources: Ana Karen Fernández-Yepez.
Supervision: Ana Karen Fernández-Yepez, Bernardo Rodriguez-Iturbe.
Validation: Magdalena Madero, Bernardo Rodriguez-Iturbe.
Writing – original draft: Bernardo Rodriguez-Iturbe.
Writing – review & editing: Magdalena Madero.
Funding
This work was supported by Fundación Gonzalo Río Arronte (S55).
References
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