Abstract
Cardiovascular disease is the main cause of early death in the settings of chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and ageing. Cardiovascular events can be caused by an imbalance between promoters and inhibitors of mineralization, which leads to vascular calcification. This process is akin to skeletal mineralization, which is carefully regulated and in which isozymes of alkaline phosphatase (ALP) have a crucial role. Four genes encode ALP isozymes in humans. Intestinal, placental and germ cell ALPs are tissue-specific, whereas the tissue-nonspecific isozyme of ALP (TNALP) is present in several tissues, including bone, liver and kidney. TNALP has a pivotal role in bone calcification. Experimental overexpression of TNALP in the vasculature is sufficient to induce vascular calcification, cardiac hypertrophy and premature death, mimicking the cardiovascular phenotype often found in CKD and T2DM. Intestinal ALP contributes to the gut mucosal defence and intestinal and liver ALPs might contribute to the acute inflammatory response to endogenous or pathogenic stimuli. Here we review novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases. We also discuss new drugs that target ALP, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization.
Highlights
Isoforms Variations of a protein that arise from single nucleotide polymorphisms, differential splicing of mRNA, or posttranslational modifications such as glycosylation
A meta-analysis showed that higher serum phosphate levels, but not serum calcium or Parathyroid hormone (PTH) levels, were associated with all-cause mortality and CVD76, whereas in some clinical studies low PTH levels combined with high bone-specific ALP (BALP) levels were more strongly associated with mortality[11] and CVD77 than high serum levels of PTH
In view of the robust evidence presented in this Review, we propose that alkaline phosphatase (ALP) is an evolving treatment target for cardiovascular disease (CVD) and metabolic syndrome
Summary
Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD. Mathias Haarhaus[1,2], Vincent Brandenburg[3], Kamyar Kalantar-Zadeh[4,5], Peter Stenvinkel[1] and Per Magnusson[2]. ALP is a well-recognized biomarker of renal osteodystrophy and a biomarker and risk factor for increased mortality in patients with CKD11 and in the general population[9] In this Review we discuss the clinical relevance of ALP, and in particular that of bone-specific ALP (BALP) and intestinal-type ALP (IALP), in CVD and mortality, including their roles as putative targets for the treatment and prevention of cardiovascular complications in patients with CKD. In this Review, we use the acronym ALP as a collective term for all isozymes and isoforms of ALP and when discussing studies that used unspecific methods for the determination of ALP.
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