Background: Wnt signalling inhibitors (Dickkopf-1 and Sclerostin) signalling play a role in vascular development and may contribute to calcification. Aim: To investigate the association between Dickkopf-1 and sclerostin serum concentrations in children undergoing maintenance hemodialysis with intimal medial thickness and peak systolic velocity of the main arteries. Patients and Methods: A study was conducted on 40 children undergoing maintenance hemodialysis and controls of the same age and sex. The study measured the initial medial thickness (IMT) and peak systolic velocity (PSV) of the main vessels (carotid, ulnar, and femoral). Dickkopf-1 and sclerostin serum levels in both groups were assessed, and a routine investigation was performed. Results: The findings indicate that the levels of serum Dickkopf-1 and Sclerostin were significantly higher in the hemodialysis group 2540.65 (2215.4 - 2909.2 pg/ml) and 1.17 (0.85 - 2.03 ng/ml)respectively (P = 0.001), compared to their control group it was 1110.45 (885.45 - 1527.65 pg/ml) and 0.28 (0.25 - 0.32 ng/ml)) respectively P = 0.001. Additionally, there was a significant increase in intima-media thickness (IMT) with a decrease in peak systolic velocity (PSV) in the main blood vessels, including the carotid, ulnar, and femoral arteries. A significant correlation was also observed between Dickkopf-1 and sclerostin levels and IMT of the carotid, ulnar, and femoral arteries. Conclusion: Wnt signalling inhibitors (Dickkopf-1 and Sclerostin) exert effects beyond the bone and significantly contribute to early vascular calcification in pediatric patients undergoing maintenance hemodialysis.
References
[1]
Mitsnefes, M.M. (2012) Cardiovascular Disease in Children with Chronic Kidney Disease. Journal of the American Society of Nephrology, 23, 578-585. https://doi.org/10.1681/asn.2011111115
[2]
Georgianos, P.I., Sarafidis, P.A. and Lasaridis, A.N. (2015) Arterial Stiffness: A Novel Cardiovascular Risk Factor in Kidney Disease Patients. Current Vascular Pharmacology, 13, 229-238. https://doi.org/10.2174/15701611113119990147
[3]
Memmos, E., Sarafidis, P., Pateinakis, P., Tsiantoulas, A., Faitatzidou, D., Giamalis, P., et al. (2019) Soluble Klotho Is Associated with Mortality and Cardiovascular Events in Hemodialysis. BMC Nephrology, 20, Article No. 217. https://doi.org/10.1186/s12882-019-1391-1
[4]
Chavers, B.M., Molony, J.T., Solid, C.A., Rheault, M.N. and Collins, A.J. (2015) One-Year Mortality Rates in US Children with End-Stage Renal Disease. American Journal of Nephrology, 41, 121-128. https://doi.org/10.1159/000380828
[5]
Guérin, A.P., Pannier, B., Marchais, S.J. and London, G.M. (2008) Arterial Structure and Function in End-Stage Renal Disease. Current Hypertension Reports, 10, 107-111. https://doi.org/10.1007/s11906-008-0021-2
[6]
Shroff, R.C., Donald, A.E., Hiorns, M.P., Watson, A., Feather, S., Milford, D., et al. (2007) Mineral Metabolism and Vascular Damage in Children on Dialysis. Journal of the American Society of Nephrology, 18, 2996-3003. https://doi.org/10.1681/asn.2006121397
[7]
Litwin, M., Wu, E., Jourdan, C., Trelewicz, J., Niemirska, A., Fahr, K., et al. (2005) Altered Morphologic Properties of Large Arteries in Children with Chronic Renal Failure and after Renal Transplantation. Journal of the American Society of Nephrology, 16, 1494-1500. https://doi.org/10.1681/asn.2004110932
[8]
Schaefer, F., Doyon, A., Azukaitis, K., Bayazit, A., Canpolat, N., Duzova, A., et al. (2016) Cardiovascular Phenotypes in Children with CKD: The 4C Study. Clinical Journal of the American Society of Nephrology, 12, 19-28. https://doi.org/10.2215/cjn.01090216
[9]
Shroff, R.C., McNair, R., Figg, N., Skepper, J.N., Schurgers, L., Gupta, A., et al. (2008) Dialysis Accelerates Medial Vascular Calcification in Part by Triggering Smooth Muscle Cell Apoptosis. Circulation, 118, 1748-1757. https://doi.org/10.1161/circulationaha.108.783738
[10]
Shroff, R.C., McNair, R., Skepper, J.N., Figg, N., Schurgers, L.J., Deanfield, J., et al. (2010) Chronic Mineral Dysregulation Promotes Vascular Smooth Muscle Cell Adaptation and Extracellular Matrix Calcification. Journal of the American Society of Nephrology, 21, 103-112. https://doi.org/10.1681/asn.2009060640
[11]
Shroff, R., Long, D.A. and Shanahan, C. (2013) Mechanistic Insights into Vascular Calcification in CKD. Journal of the American Society of Nephrology, 24, 179-189. https://doi.org/10.1681/asn.2011121191
Baron, R. and Kneissel, M. (2013) WNT Signaling in Bone Homeostasis and Disease: From Human Mutations to Treatments. Nature Medicine, 19, 179-192. https://doi.org/10.1038/nm.3074
[14]
Monroe, D.G., McGee-Lawrence, M.E., Oursler, M.J. and Westendorf, J.J. (2012) Update on Wnt Signaling in Bone Cell Biology and Bone Disease. Gene, 492, 1-18. https://doi.org/10.1016/j.gene.2011.10.044
[15]
Evenepoel, P., D’Haese, P. and Brandenburg, V. (2015) Sclerostin and DKK1: New Players in Renal Bone and Vascular Disease. Kidney International, 88, 235-240. https://doi.org/10.1038/ki.2015.156
[16]
Cejka, D., Herberth, J., Branscum, A.J., Fardo, D.W., Monier-Faugere, M., Diarra, D., et al. (2011) Sclerostin and Dickkopf-1 in Renal Osteodystrophy. Clinical Journal of the American Society of Nephrology, 6, 877-882. https://doi.org/10.2215/cjn.06550810
[17]
Golledge, J. and Thanigaimani, S. (2022) Role of Sclerostin in Cardiovascular Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 42, e187-e202. https://doi.org/10.1161/atvbaha.122.317635
[18]
Krishna, S.M., Seto, S., Jose, R.J., Li, J., Morton, S.K., Biros, E., et al. (2017) Wnt Signaling Pathway Inhibitor Sclerostin Inhibits Angiotensin Ii-Induced Aortic Aneurysm and Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 37, 553-566. https://doi.org/10.1161/atvbaha.116.308723
[19]
Kidney Disease: Improving Global Outcomes (KDIGO) ANCA Vasculitis Work Group (2024) KDIGO 2024 Clinical Practice Guideline for the Management of Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. Kidney International, 105, S71-S116. https://doi.org/10.1016/j.kint.2023.10.008
[20]
Jayanthi, K.B., Rajasekaran, C., Madian, N. and Thyagarajah, K. (2017). Analysis on Various Segmentation Techniques—IMT Measurement of Common Carotid Artery. TENCON 2017-2017 IEEE Region 10 Conference, Penang, 5-8 November 2017, 2435-2440. https://doi.org/10.1109/tencon.2017.8228270
[21]
Claes, K.J., Viaene, L., Heye, S., Meijers, B., d’Haese, P. and Evenepoel, P. (2013) Sclerostin: Another Vascular Calcification Inhibitor? The Journal of Clinical Endocrinology & Metabolism, 98, 3221-3228. https://doi.org/10.1210/jc.2013-1521
[22]
Evenepoel, P., Goffin, E., Meijers, B., Kanaan, N., Bammens, B., Coche, E., et al. (2015) Sclerostin Serum Levels and Vascular Calcification Progression in Prevalent Renal Transplant Recipients. The Journal of Clinical Endocrinology & Metabolism, 100, 4669-4676. https://doi.org/10.1210/jc.2015-3056
[23]
Speer, M.Y., Yang, H., Brabb, T., Leaf, E., Look, A., Lin, W., et al. (2009) Smooth Muscle Cells Give Rise to Osteochondrogenic Precursors and Chondrocytes in Calcifying Arteries. Circulation Research, 104, 733-741. https://doi.org/10.1161/circresaha.108.183053
Herrington, W., Lacey, B., Sherliker, P., Armitage, J. and Lewington, S. (2016) Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease. Circulation Research, 118, 535-546. https://doi.org/10.1161/circresaha.115.307611
[26]
Clevers, H. (2006) Wnt/β-Catenin Signaling in Development and Disease. Cell, 127, 469-480. https://doi.org/10.1016/j.cell.2006.10.018
[27]
Catalano, A., Bellone, F., Morabito, N. and Corica, F. (2020) Sclerostin and Vascular Pathophysiology. International Journal of Molecular Sciences, 21, Article No. 4779. https://doi.org/10.3390/ijms21134779
[28]
Koos, R., Brandenburg, V., Mahnken, A.H., et al. (2013) Sclerostin as a Potential Novel Biomarker for Aortic Valve Calcification: An in-vivo and ex-vivo Study. The Journal of Heart Valve Disease, 22, 317-325.
[29]
Chae, W. and Bothwell, A.L.M. (2018) Canonical and Non-Canonical Wnt Signaling in Immune Cells. Trends in Immunology, 39, 830-847. https://doi.org/10.1016/j.it.2018.08.006
[30]
Foulquier, S., Daskalopoulos, E.P., Lluri, G., Hermans, K.C.M., Deb, A. and Blankesteijn, W.M. (2017) WNT Signaling in Cardiac and Vascular Disease. Pharmacological Reviews, 70, 68-141. https://doi.org/10.1124/pr.117.013896
[31]
Sage, A.P., Tintut, Y. and Demer, L.L. (2010) Regulatory Mechanisms in Vascular Calcification. Nature Reviews Cardiology, 7, 528-536. https://doi.org/10.1038/nrcardio.2010.115
[32]
Shao, J., Cai, J. and Towler, D.A. (2006) Molecular Mechanisms of Vascular Calcification. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 1423-1430. https://doi.org/10.1161/01.atv.0000220441.42041.20
[33]
Cai, T., Sun, D., Duan, Y., Wen, P., Dai, C., Yang, J., et al. (2016) WNT/β-Catenin Signaling Promotes VSMCs to Osteogenic Transdifferentiation and Calcification through Directly Modulating Runx2 Gene Expression. Experimental Cell Research, 345, 206-217. https://doi.org/10.1016/j.yexcr.2016.06.007
[34]
M. McArthur, K., M. Kay, A., A. Mosier, J., N. Grant, J., A. Stewart, J. and LaShan Simpson, C. (2017) Manipulating the Plasticity of Smooth Muscle Cells to Regulate Vascular Calcification. AIMS Cell and Tissue Engineering, 1, 165-179. https://doi.org/10.3934/celltissue.2017.3.165
[35]
Nguyen-Yamamoto, L., Tanaka, K., St-Arnaud, R. and Goltzman, D. (2019) Vitamin D-Regulated Osteocytic Sclerostin and BMP2 Modulate Uremic Extraskeletal Calcification. JCI Insight, 4, Article 126467. https://doi.org/10.1172/jci.insight.126467
[36]
Mori, H., Torii, S., Kutyna, M., Sakamoto, A., Finn, A.V. and Virmani, R. (2018) Coronary Artery Calcification and Its Progression. JACC: Cardiovascular Imaging, 11, 127-142. https://doi.org/10.1016/j.jcmg.2017.10.012
[37]
Li, M., Zhou, H., Yang, M. and Xing, C. (2018) Relationship between Serum Sclerostin, Vascular Sclerostin Expression and Vascular Calcification Assessed by Different Methods in ESRD Patients Eligible for Renal Transplantation: A Cross-Sectional Study. International Urology and Nephrology, 51, 311-323. https://doi.org/10.1007/s11255-018-2033-4
[38]
Qureshi, A.R., Olauson, H., Witasp, A., Haarhaus, M., Brandenburg, V., Wernerson, A., et al. (2015) Increased Circulating Sclerostin Levels in End-Stage Renal Disease Predict Biopsy-Verified Vascular Medial Calcification and Coronary Artery Calcification. Kidney International, 88, 1356-1364. https://doi.org/10.1038/ki.2015.194
[39]
Pelletier, S., Confavreux, C.B., Haesebaert, J., Guebre-Egziabher, F., Bacchetta, J., Carlier, M.-C., et al. (2015) Serum Sclerostin: The Missing Link in the Bone-Vessel Cross-Talk in Hemodialysis Patients? Osteoporosis International, 26, 2165-2174. https://doi.org/10.1007/s00198-015-3127-9
[40]
Paccou, J., Mentaverri, R., Renard, C., Liabeuf, S., Fardellone, P., Massy, Z.A., et al. (2014) The Relationships between Serum Sclerostin, Bone Mineral Density, and Vascular Calcification in Rheumatoid Arthritis. The Journal of Clinical Endocrinology & Metabolism, 99, 4740-4748. https://doi.org/10.1210/jc.2014-2327
[41]
Lee, Y., Ng, H., Chiu, T.T., Li, L., Pei, S., Kuo, W., et al. (2016) Association of Bone-Derived Biomarkers with Vascular Calcification in Chronic Hemodialysis Patients. Clinica Chimica Acta, 452, 38-43. https://doi.org/10.1016/j.cca.2015.10.031
[42]
Thambiah, S., Roplekar, R., Manghat, P., Fogelman, I., Fraser, W.D., Goldsmith, D., et al. (2012) Circulating Sclerostin and Dickkopf-1 (DKK1) in Predialysis Chronic Kidney Disease (CKD): Relationship with Bone Density and Arterial Stiffness. Calcified Tissue International, 90, 473-480. https://doi.org/10.1007/s00223-012-9595-4
[43]
Sarafidis, P.A., Loutradis, C., Karpetas, A., Tzanis, G., Piperidou, A., Koutroumpas, G., et al. (2017) Ambulatory Pulse Wave Velocity Is a Stronger Predictor of Cardiovascular Events and All-Cause Mortality than Office and Ambulatory Blood Pressure in Hemodialysis Patients. Hypertension, 70, 148-157. https://doi.org/10.1161/hypertensionaha.117.09023
[44]
Ueland, T., Otterdal, K., Lekva, T., Halvorsen, B., Gabrielsen, A., Sandberg, W.J., et al. (2009) Dickkopf-1 Enhances Inflammatory Interaction between Platelets and Endothelial Cells and Shows Increased Expression in Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 1228-1234. https://doi.org/10.1161/atvbaha.109.189761
[45]
Mikheev, A.M., Mikheeva, S.A., Maxwell, J., Rivo, J.V., Rostomily, R., Swisshelm, K., et al. (2007) Dickkopf-1 Mediated Tumor Suppression in Human Breast Carcinoma Cells. Breast Cancer Research and Treatment, 112, 263-273. https://doi.org/10.1007/s10549-007-9867-2
[46]
Urano, T., Shiraki, M., Ouchi, Y. and Inoue, S. (2012) Association of Circulating Sclerostin Levels with Fat Mass and Metabolic Disease—Related Markers in Japanese Postmenopausal Women. The Journal of Clinical Endocrinology & Metabolism, 97, E1473-E1477. https://doi.org/10.1210/jc.2012-1218
