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

Mathias Haarhaus,Per Magnusson,Abdul Rashid Qureshi,Anders Fernström

doi:10.3390/nu13124402

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.

Highlights

Cardiovascular (CV) complications are the main reason for the high morbidity and mortality in patients with chronic kidney disease (CKD) on maintenance dialysis [1].Profound evidence has accumulated for an underlying, complex interaction between bone and the vasculature [2]
This is the first study to demonstrate a relationship of the novel bone alkaline phosphatase (BALP) isoform B1x with vascular stiffness and survival in CKD
The main findings were the association of serum B1x with baseline pulse wave velocity (PWV), PWV variation over time, and with improved long-term survival

Summary

Introduction

Cardiovascular (CV) complications are the main reason for the high morbidity and mortality in patients with chronic kidney disease (CKD) on maintenance dialysis [1].Profound evidence has accumulated for an underlying, complex interaction between bone and the vasculature [2]. Instead, underlying mechanisms, e.g., malnutrition and chronic inflammation, seem to determine the association of low bone turnover with negative outcomes in CKD [3]. Increased bone alkaline phosphatase (BALP) may even be a better predictor of short- and long-term mortality than total ALP, especially in combination with low parathyroid hormone (PTH); indicative of an extra-skeletal origin of ALP or BALP in the setting of low bone turnover [5,6]. Vascular stiffening and accelerated vascular calcification are common in CKD and are associated with increased serum total ALP activity and increased mortality [7,8]. Chronic inflammation and oxidative stress, which are features of protein energy wasting syndrome, induce vascular ALP and fibro-calcification in cardiovascular tissue [9], and clinical indicators of malnutrition are associated with increased circulating ALP [10]. The process of vascular calcification involves the transdifferentiation of vascular smooth muscle cells (VSMC)

Objectives

Methods

Results

Conclusion