The Novel Bone Alkaline Phosphatase Isoform B1x Is Associated with Improved 5-Year Survival in Chronic Kidney Disease

Abstract

Circulating alkaline phosphatase (ALP) is an independent cardiovascular risk marker. Serum bone ALP (BALP) isoforms indicate bone turnover and comprise approximately 50% of total circulating ALP. In chronic kidney disease (CKD), mortality is highest in patients with increased ALP and BALP and low bone turnover. However, not all low bone turnover states are associated with increased mortality. Chronic inflammation and oxidative stress, features of protein energy wasting syndrome, induce cardiovascular BALP activity and fibro-calcification, while bone turnover is suppressed. Circulating BALP isoform B1x is associated with low ALP and low bone turnover and has been exclusively detected in CKD. We investigated the association of serum B1x with survival, abdominal aortic calcification (AAC) score, and aortic pulse wave velocity (PWV) in CKD. Serum ALP, BALP isoforms, parathyroid hormone (PTH), PWV, and AAC were measured repeatedly over 2 years in 68 prevalent dialysis patients. Mortality was assessed after 5 years. B1x was detected in 53 patients. A competing risk analysis revealed an association of B1x with improved 5-year survival; whereas, baseline PWV, but not AAC score, predicted mortality. However, PWV improved in 26 patients (53%), and B1x was associated with variation of PWV over time (p = 0.03). Patients with B1x had lower PTH and total ALP, suggesting an association with lower bone turnover. In conclusion, B1x is associated with time-varying PWV, lower circulating ALP, and improved survival in CKD, and thus may be an indicator of a reduced cardiovascular risk profile among patients with low bone turnover.

Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease

“…B1x is associated with low levels of ALP and the different BALP isoforms (B/I, B1, and B2), as well as low turnover in hemodialysis patients. Haarhaus et al [ 96 ], in a study of patients in hemodialysis, evaluated the association between B1x, PTH, abdominal aortic calcification, and vascular stiffness for 2 years. They demonstrated how B1x was associated at baseline with vascular stiffness and time-varying improvement in vascular stiffness during a 2-year follow-up, but not with baseline, or change in, aortic calcification.…”

“…They demonstrated how B1x was associated at baseline with vascular stiffness and time-varying improvement in vascular stiffness during a 2-year follow-up, but not with baseline, or change in, aortic calcification. Furthermore, B1x was associated with lower values of PTH and circulating ALP, but with better survival at 5 years, suggesting that B1x could be considered an indicator of low cardiovascular risk among patients with low bone turnover [ 96 ].…”

“…Another issue to speculate on is, whether the association of an increased activity of circulating ALP with mortality is mainly driven by systemic inflammation, a neutral or even positive bone balance, or direct effects of cardiovascular calcification on the circulating BALP isoforms. A possible modulatory role of ALP and BALP in fibrosis is an interesting new field of research, and the recent finding of an association of B1x with pulse wave velocity can point towards a possible clinical relevance [ 96 ]. To date, no studies have investigated the role of glycosylation differences among the BALP isoforms on the potential of ALP to modulate tissue fibrosis.…”