Reevaluating Liver Enzyme Reference Ranges in Chronic Kidney Disease: A Population-Based Study

Background Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are essential liver biomarkers; however, consistently low values in chronic kidney disease (CKD) complicate their interpretation and diagnosis. Current reference ranges may contribute to the underdiagnosis of hepatic disorders. Objective To examine the relationship between aminotransferase levels and kidney function across CKD stages and evaluate the need for CKD-specific thresholds. Design, Setting, and Participants: Retrospective, population-based cohort study using the Clalit Health Services database (Israel). A total of 820,707 adults with normal body mass index and valid AST/ALT results were included. Patients were stratified by CKD stage and sex. Main Measures : ALT and AST distributions were analyzed by CKD stage and sex. Associations between enzyme levels and estimated glomerular filtration rate (eGFR) were assessed using descriptive statistics and regression models. Results ALT and AST levels declined progressively with the advancement of CKD, with steeper reductions observed in men. In males, the mean ALT decreased from 24.4 U/L in Stage I to 13.5 U/L in Stage V; in females, ALT declined from 16.0 U/L to 12.8 U/L. AST values also decreased, from 23.6 U/L to 15.6 U/L in males and 19.5 U/L to 16.5 U/L in females. A strong positive correlation was observed between aminotransferases and eGFR, particularly in younger males. Variability narrowed in advanced CKD. Conclusions The findings of this study underscore the urgent need for Specific thresholds for ALT and AST in CKD. These liver enzymes are suppressed in CKD, independent of overt liver disease. The use of standard reference ranges may lead to an underestimation of liver pathology in this population, potentially resulting in delayed or inadequate treatment and poorer patient outcomes. Therefore, the establishment of CKD-specific thresholds is not just a recommendation, but a necessity to improve the detection and management of liver diseases in CKD patients.