Urinary Follistatin-Like 3 Is Increased in Patients with AKI and Reflects Severity of Tubular Injury

Background: Follistatin is an essential physiological regulator of activin and other members of the TGFβ superfamily. In animal models of acute kidney injury (AKI), blockade of activin A by exogenous follistatin has been shown to attenuate renal injury and improve renal function. This suggests that endogenous activin A negatively modulates tubular repair following AKI. Follistatin serves as a local regulator of activin A in numerous tissues. In addition, urinary follistatin, which is undetectable in normal rats, was significantly increased in ischemic rats. Conversely, follistatin-like 3 (FSTL3) exhibits substantial structural and functional similarity to follistatin, albeit with some notable differences, including its prominent nuclear localization. Nonetheless, the precise role of FSTL3 remains unclear. Methods: To address this issue, we investigated the localization of FSTL3 in normal human kidneys and measured urinary FSTL3 in patients with AKI to evaluate its potential as a marker for AKI. A total of 127 patients with AKI and 19 healthy adults participated in this study. Serum and urinary FSTL3 levels were quantified using ELISA. We analyzed the correlations between urinary FSTL3 and other clinical parameters. Results: FSTL3 was localized in renal tubules of normal kidney. FSTL3-producing cells were positive for Na-Cl co-transporter and uromodulin but were negative for aquaporin 1, megalin and aquaporin 2. Urinary FSTL3, undetectable in healthy adults, was significantly increased in patients with AKI (0.00 ± 0.00 vs. 18.09 ± 17.66 ng/mL, p <0.0001). This increase was most pronounced in cases of sepsis (37.65 ± 17.56 ng/mL). In stages of the KDIGO classification, urinary FSTL3 was positively correlated with the severity of AKI (stage I, 7.34 ± 8.75 ng/mL, p<0.05; stage II 9.02 ± 7.60 ng/mL, p<0.01; stage III 25.62 ± 18.66 ng/mL, p<0.0001). There was a significant correlation of urinary FSTL3 with urinary protein, urinary NAG, urinary alpha1-microglobulin, urinary beta2-microglobulin, urinary NGAL, KIM-1 and serum FSTL3. Meanwhile, FSTL3 did not correlate with L-FABP and urinary serum creatinine. Conclusion: FSTL3 is localized in the distal tubules of normal kidneys. Urinary FSTL3 increases in AKI patients and serve as a valuable marker for monitoring the severity of acute tubular damage in AKI. Funding: Government Support – Non-U.S.