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Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD

Nature Reviews Nephrology volume 13, pages 429–442 (2017)Cite this article

Subjects

Key Points

  • Circulating alkaline phosphatase (ALP) is a robust and independent predictor of all-cause mortality in the general population and in patients with chronic kidney disease (CKD)

  • Tissue-nonspecific ALP (TNALP) is the most abundant ALP isozyme in the body, comprising >90% of circulating ALP; functional differences between bone ALP (BALP) and liver TNALP are the result of post-translational glycosylation

  • BALP promotes tissue mineralization by inactivating calcification inhibitors and by supplying phosphate

  • Liver ALP and intestinal ALP (IALP) contribute to the immune response through dephosphorylation of circulating endotoxins

  • Modulation of ALP is a potential novel treatment strategy that might reduce vascular calcification and improve cardiovascular outcomes in patients with CKD or diabetes mellitus type 2

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.

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Figure 1: Role of bone-specific alkaline phosphatase (BALP) in tissue mineralization.
Figure 2: Pathological consequences of high alkaline phosphatase (ALP) levels.

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Authors and Affiliations

  1. Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital, Stockholm, SE-14186, Sweden

    Mathias Haarhaus & Peter Stenvinkel

  2. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, SE-58185, Sweden

    Mathias Haarhaus & Per Magnusson

  3. Department of Cardiology and Intensive Care Medicine, RWTH University Hospital Aachen, Pauwelsstraße 30, Aachen, D-52074, Germany

    Vincent Brandenburg

  4. Harold Simmons Center for Kidney Disease Research and Epidemiology and Division of Nephrology and Hypertension, University of California Irvine, School of Medicine, 101 The City Drive South, City Tower, Suite 400, Mail Code: 4088, Orange, 92868, California, USA

    Kamyar Kalantar-Zadeh

  5. Department of Epidemiology, UCLA Fielding School of Public Health, 1124 West Carson Street Suite C-1 Annex, Torrance, 90502, California, USA

    Kamyar Kalantar-Zadeh

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  1. Mathias Haarhaus
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Contributions

All authors researched data for the article. M.H. wrote the article. M.H., K.K.-Z. and P.M. provided the figures. M.H. and P.M. made substantial contributions to discussions of the content. All authors contributed to discussion of the content and reviewed and/or edited the manuscript before submission.

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Glossary

Isozymes

Proteins encoded by separate genes with similar catalytic specificity but different primary structure.

Isoforms

Variations of a protein that arise from single nucleotide polymorphisms, differential splicing of mRNA, or post-translational modifications such as glycosylation.

Syncytiotrophoblast

Epithelial layer that covers the highly vascular embryonic placental villi, which invades the wall of the uterus to establish nutrient circulation between the embryo and the mother.

Metabolic syndrome

Array of conditions — raised blood pressure, dyslipidaemia (raised triglycerides and lowered HDL cholesterol), raised fasting glucose, and increased waist circumference — that increase the risk of cardiovascular disease and type 2 diabetes mellitus.

Hypophosphatasia

Autosomal dominant or autosomal recessive rare metabolic disease with an extraordinary range of severity caused by loss-of-function mutations within ALPL, which encodes TNALP.

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Haarhaus, M., Brandenburg, V., Kalantar-Zadeh, K. et al. Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD. Nat Rev Nephrol 13, 429–442 (2017). https://doi.org/10.1038/nrneph.2017.60

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