Liver fraction of circulating alkaline phosphatase is elevated in chronic kidney disease and associates with mortality in patients treated with hemodialysis

Abstract Background and Hypothesis Serum total alkaline phosphatase (ALP) is a robust predictor of all-cause mortality, both in the general population and in patients with chronic kidney disease (CKD). Individual ALP isozymes and isoforms exert specific physiological functions and may therefore inform separately on different disease processes and risks related to these. Serum ALP consists predominantly of bone and liver isoforms, with a smaller contribution from the intestinal isoenzyme. We aimed to characterize the impact of CKD on serum ALP fractions and to identify clinical and biochemical correlates. Methods Serum ALP liver, bone and intestinal fractions were analyzed by electrophoresis in 523 individuals across stages of CKD (stage G1-2: n = 90; G3: n = 100; G4-5: n = 139; G5D: n = 194) and in 21 kidney-healthy controls. Associations with demographics and parameters of mineral metabolism and inflammation were examined. In hemodialysis patients, we further explored the association between ALP isozymes and all-cause mortality. Results Total ALP levels increased significantly across stages of CKD, with liver, bone and intestinal fractions all contributing. In patients with CKD G5D, circulating levels of all three fractions were more than two-fold higher than in controls. Bone ALP associated with PTH while liver ALP associated with CRP, both independently of demographics and kidney function. Higher liver ALP levels associated with increased mortality risk, independently of traditional risk factors and inflammation. Conclusion In patients with CKD, elevations in liver, bone, and intestinal ALP fractions reflect distinct biological pathways and may differentially inform on risk related to different disease processes. While bone ALP reflects bone metabolism, liver ALP is linked with inflammation. The elevation in CKD and independent association of liver ALP fraction with mortality in patients treated with hemodialysis calls for additional clinical and mechanistic studies.