Background: The updated metabolic dysfunction-associated steatotic liver disease (MASLD) framework highlights the systemic impact of hepatic steatosis, including kidney dysfunction. We investigated both cross-sectional and 5-year longitudinal associations between Fatty Liver Index (FLI) and estimated glomerular filtration rate (eGFR), and between MASLD and Chronic kidney disease (CKD), using region-specific FLI cutoffs and the latest definitions and robust methodology.

Methods: We analyzed 9,911 adults from the Fasa Adults Cohort Study (FACS), including 2,906 with 5-year follow-up. FLI was calculated using sex-specific regionally validated cutoffs. eGFR was estimated using the 2021 CKD-EPI equation. Regression models assessed continuous FLI-eGFR and binary MASLD-CKD associations, with scatter plots to visualize patterns. Models were adjusted for extensive confounders. Subgroup analyses were stratified by sex, obesity, and physical activity, with formal interaction testing. Sensitivity analyses applied the commonly used European FLI ≥ 60 threshold.

Results: Cross-sectionally, MASLD was associated with 58% higher odds of CKD (OR = 1.58; 95% CI 1.35-1.85), and each ten-unit increase in FLI was associated with a 2.4 mL/min/1.73 m² lower eGFR (p < 0.001). A U-shaped FLI-eGFR association was detected, most prominent in men. Longitudinally, higher FLI predicted greater eGFR decline (β = -1.92; p = 0.005) and MASLD increased CKD risk (OR = 1.41; 95% CI 1.07-1.86), especially among males (OR = 2.27), non-obese (OR = 1.47) and physically active individuals (OR = 1.64). Subgroup differences by obesity and physical activity were descriptive only, as interaction terms were not significant (p > 0.05). Using FLI ≥ 60, cross-sectional results remained significant, whereas longitudinal associations attenuated, suggesting potential misclassification when non-population-specific cutoffs are applied.

Conclusions: Higher FLI and MASLD were associated with impaired kidney function cross-sectionally and prospectively. Region-specific FLI cutoffs resulted in more stable longitudinal associations than the European FLI ≥ 60 threshold, underscoring the relevance of population-calibrated indices. Although sex differences were evident, obesity- and activity-related variations were not statistically confirmed. FLI may offer a practical, scalable tool for early identification of CKD risk. Further studies should validate these findings across diverse populations and assess whether interventions targeting MASLD can mitigate kidney function decline.