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Soluble Klotho as Biomarker of Vascular Dysfunction in Chronic Kidney Disease

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General Methods in Biomarker Research and their Applications

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Abstract

Disturbed mineral metabolism in patients with chronic kidney disease (CKD), known as CKD-mineral and bone disorder (CKD-MBD), is associated with bone disease as well as a high risk of cardiovascular disease (CVD) and reduced patient survival due to the development of vascular calcification. Hyperphosphatemia is a risk factor for vascular calcification, CVD, and mortality. The fibroblast growth factor-23 (FGF-23)-Klotho system plays a key role in the regulation of mineral metabolism. Klotho was originally identified as an aging-suppressor gene and is predominantly expressed in the distal renal tubules. Klotho exists in two forms: membrane Klotho functions as an obligate coreceptor for FGF-23 in the kidneys and parathyroid gland, while secreted Klotho functions as a humoral factor with antiaging, renoprotective, and cardiovascular protective properties. The urinary and circulating Klotho levels have been found to be decreased in patients with acute kidney injury and CKD, and experimental studies have shown that Klotho has beneficial effects on the vascular system. Furthermore, Klotho exerts pleiotropic effects on the endothelium, including anti-inflammatory, antithrombotic, and vasodilatory effects, and increases the availability of nitric oxide, and Klotho deficiency is associated with the vascular calcification observed in CKD patients. Therefore, soluble Klotho has the potential to serve as a biomarker for diagnosing early CKD and predicting the progression of both CKD and CVD. The renoprotective and cardiovascular protective functions of Klotho have also led researchers to hope that this protein may be used as a therapeutic agent for improving the kidney function and CVD.

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Abbreviations

1,25D:

1,25-Dihydroxyvitamin D

ACI:

Aortic Calcification Index

ADAM:

A Disintegrin and Metalloproteinase Domain

ADPKD:

Autosomal Dominant Polycystic Kidney Disease

AKI:

Acute Kidney Injury

ARB:

Angiotensin II Receptor Blocker

BACE:

Beta-Site APP-Cleaving Enzyme

baPWV:

Brachial-Ankle Pulse Wave Velocity

CAD:

Coronary Artery Disease

CGN:

Chronic Glomerulonephritis

CKD:

Chronic Kidney Disease

CKD-MBD:

CKD-Mineral And Bone Disorder

CRP:

C-Reactive Protein

CVD:

Cardiovascular Disease

DCT:

Distal Convoluted Tubule

eGFR:

Estimated Glomerular Filtration Rate

ELISA:

Enzyme-Linked Immunosorbent Assay

ESKD:

End-Stage Kidney Disease

FePi:

Fractional Excretion of Phosphorus

FGF:

Fibroblast Growth Factor

FGFR:

Fibroblast Growth Factor Receptor

FMD:

Flow-Mediated Dilatation

HDL-C:

High-Density Lipoprotein Cholesterol

HMG-CoA:

3-Hydroxy-3-Methylglutaryl Coenzyme A

HUVEC:

Human Umbilical Vein Endothelial Cell

IgAN:

IgA Nephropathy

IMT:

Intima-Media Thickness

IS:

Indoxyl Sulfate

KIM-1:

Kidney Injury Molecule 1

LVH:

Left Ventricular Hypertrophy

MBP:

Mean Blood Pressure

MCD:

Minimal Change Disease

mRNA:

Messenger Ribonucleic Acid

NGAL:

N-Gelatinase-Associated Lipocalin

NO:

Nitric Oxide

Npt:

Sodium-Dependent Phosphate Cotransporters

PPAR:

Peroxisome Proliferator-Activated Receptor

PTH:

Parathyroid Hormone

ROMK:

Renal Outer Medullary Potassium Channel

SDS-PAGE:

Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis

TRPC6:

Transient Receptor Potential Channel 6

TRPV:

Transient Receptor Potential Vanilloid

VEGF:

Vascular Endothelial Growth Factor

VEGFR:

Vascular Endothelial Growth Factor Receptor

VSMC:

Vascular Smooth Muscle Cell

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Authors and Affiliations

  1. Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Masashi Kitagawa & Hirofumi Makino

  2. Department of Chronic Kidney Disease and Peritoneal Dialysis, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Hitoshi Sugiyama

  3. Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Kazufumi Nakamura & Hiroshi Ito

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  2. Hitoshi Sugiyama
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  3. Kazufumi Nakamura
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  4. Hiroshi Ito
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  5. Hirofumi Makino
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Corresponding author

Correspondence to Hitoshi Sugiyama .

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Editors and Affiliations

  1. Department of Nutrition and Dietetics, Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom

    Victor R. Preedy

  2. Faculty of Science & Technology, Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

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© 2015 Springer Science+Business Media Dordrecht

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Kitagawa, M., Sugiyama, H., Nakamura, K., Ito, H., Makino, H. (2015). Soluble Klotho as Biomarker of Vascular Dysfunction in Chronic Kidney Disease. In: Preedy, V., Patel, V. (eds) General Methods in Biomarker Research and their Applications. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7696-8_44

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