Abstract
Background
Restless legs syndrome (RLS) is a neuromotor disorder, and dialysis patients are more likely to develop RLS. RLS often causes sleep disorders, anxiety and depression in patients. It will increase the risk of death and severely affect the life of patients. At present, RLS has not received enough recognition and attention, and the misdiagnosis rate can reach more than 10%.
Methods
The discovery set selected 30 peritoneal dialysis (PD) patients and 27 peritoneal dialysis patients with RLS (PD-RLS). A metabolomics method based on ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometric method (UPLC-Q-TOF/MS) was used to analyze the differential metabolites of the two groups. 51 PD patients and 51 PD-RLS patients were included in the validation set. The receiver operating characteristic (ROC) analysis was used to evaluate the early diagnostic biomarkers, and the correlation between the differential metabolites and laboratory test indexes was analyzed to explore the biological function of the differential metabolites.
Results
Through the integrated analysis, four metabolites can be used as markers for the diagnosis of PD-RLS, including Hippuric acid, Phenylacetylglutamine, N,N,N-Trimethyl-L-alanyl-L-proline betaine and Threonic acid. Through ROC analysis, it is found that they can be used as a metabolic biomarker panel, and the area under the curve of this combination is more than 0.9, indicating that the panel has good diagnostic and predictive ability.
Conclusion
Metabolomics based on UPLC-Q-TOF/MS technology can effectively identify the potential biomarkers, and provide a theoretical basis for the early diagnosis, prevention and treatment on PD-RLS.
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References
Abetz, L., Allen, R., Follet, A., Washburn, T., Earley, C., Kirsch, J., & Knight, H. (2004). Evaluating the quality of life of patients with restless legs syndrome. Clinical Therapeutics, 26(6), 925–935. https://doi.org/10.1016/s0149-2918(04)90136-1
Ahmed, S. M., Luo, L., Namani, A., Wang, X. J., & Tang, X. (2017). Nrf2 signaling pathway: Pivotal roles in inflammation. Biochimica et biophysica acta: Molecular Basis of Disease, 1863(2), 585–597. https://doi.org/10.1016/j.bbadis.2016.11.005
Allen, R. P., Picchietti, D. L., Garcia-Borreguero, D., Ondo, W. G., Walters, A. S., Winkelman, J. W., Zucconi, M., Ferri, R., Trenkwalder, C., Lee, H. B., International Restless Legs Syndrome Study Group. (2014). Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria–history, rationale, description, and significance. Sleep Medicine, 15(8), 860–873. https://doi.org/10.1016/j.sleep.2014.03.025
Allman, M. A., Truswell, A. S., Tiller, D. J., Stewart, P. M., Yau, D. F., Horvath, J. S., & Duggin, G. G. (1989). Vitamin supplementation of patients receiving haemodialysis. The Medical Journal of Australia, 150(3), 130–133. https://doi.org/10.5694/j.1326-5377.1989.tb136390.x
Araujo, S. M., de Bruin, V. M., Nepomuceno, L. A., Maximo, M. L., Daher, E., Correia Ferrer, D. P., & de Bruin, P. F. (2010). Restless legs syndrome in end-stage renal disease: Clinical characteristics and associated comorbidities. Sleep Medicine, 11(8), 785–790. https://doi.org/10.1016/j.sleep.2010.02.011
Bellei, E., Monari, E., Ozben, S., Koseoglu Bitnel, M., Topaloglu Tuac, S., Tomasi, A., & Bergamini, S. (2018). Discovery of restless legs syndrome plasmatic biomarkers by proteomic analysis. Brain and Behavior, 8(10), e01062. https://doi.org/10.1002/brb3.1062
Cannata-Andía, J. B., Martín-Carro, B., Martín-Vírgala, J., Rodríguez-Carrio, J., Bande-Fernández, J. J., Alonso-Montes, C., & Carrillo-López, N. (2021). Chronic kidney disease-mineral and bone disorders: Pathogenesis and management. Calcified Tissue International, 108(4), 410–422. https://doi.org/10.1007/s00223-020-00777-1
Carneiro, G., Radcenco, A. L., Evaristo, J., & Monnerat, G. (2019). Novel strategies for clinical investigation and biomarker discovery: A guide to applied metabolomics. Hormone Molecular Biology and Clinical Investigation. https://doi.org/10.1515/hmbci-2018-0045
de Menezes, A. F., Motta, D., de Carvalho, F. O., Santana-Santos, E., de Andrade Júnior, M. P., Figueirôa, M. F., Farias, M., & Bastos, K. A. (2018). Restless legs syndrome in dialysis patients: Does the dialysis modality influence its occurrence and severity? International Journal of Nephrology, 2018, 1414568. https://doi.org/10.1155/2018/1414568
Deltombe, O., Van Biesen, W., Glorieux, G., Massy, Z., Dhondt, A., & Eloot, S. (2015). Exploring protein binding of uremic toxins in patients with different stages of chronic kidney disease and during hemodialysis. Toxins, 7(10), 3933–3946. https://doi.org/10.3390/toxins7103933
Gonzalez-Covarrubias, V., Martínez-Martínez, E., & Del Bosque-Plata, L. (2022). The potential of metabolomics in biomedical applications. Metabolites, 12(2), 194. https://doi.org/10.3390/metabo12020194
Guleria, A., Bajpai, N. K., Rawat, A., Khetrapal, C. L., Prasad, N., & Kumar, D. (2014). Metabolite characterisation in peritoneal dialysis effluent using high-resolution (1) H and (1) H- (13) C NMR spectroscopy. Magnetic Resonance in Chemistry: MRC, 52(9), 475–479. https://doi.org/10.1002/mrc.4094
Ha, T. K., Sattar, N., Talwar, D., Cooney, J., Simpson, K., O’Reilly, D. S., & Lean, M. E. (1996). Abnormal antioxidant vitamin and carotenoid status in chronic renal failure. QJM: Monthly Journal of the Association of Physicians, 89(10), 765–769. https://doi.org/10.1093/qjmed/89.10.765
Hsu, C. Y., Chen, L. R., & Chen, K. H. (2020). Osteoporosis in patients with chronic kidney diseases: A systemic review. International Journal of Molecular Sciences, 21(18), 6846. https://doi.org/10.3390/ijms21186846
Huang, M., Wei, R., Wang, Y., Su, T., Li, P., & Chen, X. (2018). The uremic toxin hippurate promotes endothelial dysfunction via the activation of Drp1-mediated mitochondrial fission. Redox Biology, 16, 303–313. https://doi.org/10.1016/j.redox.2018.03.010
Jing, W., Jabbari, B., & Vaziri, N. D. (2018). Uremia induces upregulation of cerebral tissue oxidative/inflammatory cascade, down-regulation of Nrf2 pathway and disruption of blood brain barrier. American Journal of Translational Research, 10(7), 2137–2147.
Johnson, C. H., Ivanisevic, J., & Siuzdak, G. (2016). Metabolomics: Beyond biomarkers and towards mechanisms. Nature Reviews. Molecular Cell Biology, 17(7), 451–459. https://doi.org/10.1038/nrm.2016.25
Kikuchi, K., Itoh, Y., Tateoka, R., Ezawa, A., Murakami, K., & Niwa, T. (2010). Metabolomic analysis of uremic toxins by liquid chromatography/electrospray ionization-tandem mass spectrometry. Journal of chromatography B, Analytical Technologies in the Biomedical and Life Sciences, 878(20), 1662–1668. https://doi.org/10.1016/j.jchromb.2009.11.040
Kutner, N. G., Zhang, R., & Bliwise, D. L. (2013). Restless legs syndrome is underdiagnosed in the US Renal Data System. QJM: Monthly Journal of the Association of Physicians, 106(5), 487. https://doi.org/10.1093/qjmed/hct014
La Manna, G., Pizza, F., Persici, E., Baraldi, O., Comai, G., Cappuccilli, M. L., Centofanti, F., Carretta, E., Plazzi, G., Colì, L., Montagna, P., & Stefoni, S. (2011). Restless legs syndrome enhances cardiovascular risk and mortality in patients with end-stage kidney disease undergoing long-term haemodialysis treatment. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association, 26(6), 1976–1983. https://doi.org/10.1093/ndt/gfq681
Lee, T. H., Yen, T. T., Chiu, N. Y., Chang, C. C., Hsu, W. Y., Chang, Y. J., & Chang, T. G. (2019). Depression is differently associated with sleep measurement in obstructive sleep apnea, restless leg syndrome and periodic limb movement disorder. Psychiatry Research, 273, 37–41. https://doi.org/10.1016/j.psychres.2018.12.166
Levin, A., Stevens, P. E., Bilous, R. W., Coresh, J., & Winearls, C. G. (2013). Kidney disease: Improving global outcomes (kdigo) ckd work group: kdigo 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements, 3(1), 1–150. https://doi.org/10.1038/kisup.2012.73
Li, P. K., Chow, K. M., Van de Luijtgaarden, M. W., Johnson, D. W., Jager, K. J., Mehrotra, R., Naicker, S., Pecoits-Filho, R., Yu, X. Q., & Lameire, N. (2017). Changes in the worldwide epidemiology of peritoneal dialysis. Nature Reviews. Nephrology, 13(2), 90–103. https://doi.org/10.1038/nrneph.2016.181
Mondello, S., Kobeissy, F. H., Mechref, Y., Zhao, J., El Hayek, S., Zibara, K., Moresco, M., Plazzi, G., Cosentino, F., & Ferri, R. (2021). Searching for novel candidate biomarkers of RLS in blood by proteomic analysis. Nature and Science of Sleep, 13, 873–883. https://doi.org/10.2147/NSS.S311801
Moretti, M., Fraga, D. B., & Rodrigues, A. (2017). Ascorbic acid to manage psychiatric disorders. CNS Drugs, 31(7), 571–583. https://doi.org/10.1007/s40263-017-0446-8
Pignanelli, M., Bogiatzi, C., Gloor, G., Allen-Vercoe, E., Reid, G., Urquhart, B. L., Ruetz, K. N., Velenosi, T. J., & Spence, J. D. (2019). Moderate renal impairment and toxic metabolites produced by the intestinal microbiome: Dietary implications. Journal of Renal Nutrition: The Official Journal of the Council on Renal Nutrition of the National Kidney Foundation, 29(1), 55–64. https://doi.org/10.1053/j.jrn.2018.05.007
Poesen, R., Claes, K., Evenepoel, P., de Loor, H., Augustijns, P., Kuypers, D., & Meijers, B. (2016). Microbiota-derived phenylacetylglutamine associates with overall mortality and cardiovascular disease in patients with CKD. Journal of the American Society of Nephrology: JASN, 27(11), 3479–3487. https://doi.org/10.1681/ASN.2015121302
Prokopienko, A. J., West, R. E., 3rd., Stubbs, J. R., & Nolin, T. D. (2019). Development and validation of a UHPLC-MS/MS method for measurement of a gut-derived uremic toxin panel in human serum: An application in patients with kidney disease. Journal of Pharmaceutical and Biomedical Analysis, 174, 618–624. https://doi.org/10.1016/j.jpba.2019.06.033
Rizek, P., & Kumar, N. (2017). Restless legs syndrome. CMAJ: Canadian Medical Association Journal = journal de l’Association medicale canadienne, 189(6), E245. https://doi.org/10.1503/cmaj.160527
Sun, B., Wang, X., Liu, X., Wang, L., Ren, F., Wang, X., & Leng, X. (2020). Hippuric acid promotes renal fibrosis by disrupting redox homeostasis via facilitation of NRF2-KEAP1-CUL3 interactions in chronic kidney disease. Antioxidants (Basel, Switzerland), 9(9), 783. https://doi.org/10.3390/antiox9090783
Te Linde, E., van Roij, C., Meijers, B., De Loor, H., Kessels, R., & Wetzels, J. (2020). Cognitive function and uremic toxins after kidney transplantation: An exploratory study. Kidney360, 1(12), 1398–1406. https://doi.org/10.34067/KID.0000272020
Thomas, M., & Hughes, R. E. (1983). A relationship between ascorbic acid and threonic acid in guinea-pigs. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association, 21(4), 449–452. https://doi.org/10.1016/0278-6915(83)90101-1
Trenkwalder, C., & Paulus, W. (2010). Restless legs syndrome: Pathophysiology, clinical presentation and management: Nature reviews. Neurology, 6(6), 337–346. https://doi.org/10.1038/nrneurol.2010.55
Trezzi, J. P., Galozzi, S., Jaeger, C., Barkovits, K., Brockmann, K., Maetzler, W., Berg, D., Marcus, K., Betsou, F., Hiller, K., & Mollenhauer, B. (2017). Distinct metabolomic signature in cerebrospinal fluid in early Parkinson’s disease. Movement Disorders: Official Journal of the Movement Disorder Society, 32(10), 1401–1408. https://doi.org/10.1002/mds.27132
Velenosi, T. J., Thomson, B., Tonial, N. C., RaoPeters, A., Mio, M. A., Lajoie, G. A., Garg, A. X., House, A. A., & Urquhart, B. L. (2019). Untargeted metabolomics reveals N, N, N-trimethyl-L-alanyl-L-proline betaine (TMAP) as a novel biomarker of kidney function. Scientific Reports, 9(1), 6831. https://doi.org/10.1038/s41598-019-42992-3
Wang, Z., Jiang, H., Chen, X., Song, X., Xu, F., Chen, F., Mao, Z., Gao, S., & Chen, W. (2020). A rapid and sensitive method for simultaneous determination of eight protein-bound uremic toxins in human serum by UHPLC-MS/MS: Application in assessing peritoneal dialysis. Journal of Pharmaceutical and Biomedical Analysis, 186, 113312. https://doi.org/10.1016/j.jpba.2020.113312
Wiesenhofer, F. M., Herzog, R., Boehm, M., Wagner, A., Unterwurzacher, M., Kasper, D. C., Alper, S. L., Vychytil, A., Aufricht, C., & Kratochwill, K. (2019). Targeted metabolomic profiling of peritoneal dialysis effluents shows anti-oxidative capacity of alanyl-glutamine. Frontiers in Physiology, 9, 1961. https://doi.org/10.3389/fphys.2018.01961
Yang, K., Du, C., Wang, X., Li, F., Xu, Y., Wang, S., Chen, S., Chen, F., Shen, M., Chen, M., Hu, M., He, T., Su, Y., Wang, J., & Zhao, J. (2017). Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice. Blood, 129(19), 2667–2679. https://doi.org/10.1182/blood-2016-10-744060
Yang, Y., Da, J., Jiang, Y., Yuan, J., & Zha, Y. (2021). Low serum parathyroid hormone is a risk factor for peritonitis episodes in incident peritoneal dialysis patients: A retrospective study. BMC Nephrology, 22(1), 44. https://doi.org/10.1186/s12882-021-02241-0
Zhang, Q., Ford, L. A., Evans, A. M., & Toal, D. R. (2017). Structure elucidation of metabolite x17299 by interpretation of mass spectrometric data. Metabolomics: Official Journal of the Metabolomic Society, 13(8), 92. https://doi.org/10.1007/s11306-017-1231-x
Zhao, Y. Y., Lei, P., Chen, D. Q., Feng, Y. L., & Bai, X. (2013). Renal metabolic profiling of early renal injury and renoprotective effects of Poria cocos epidermis using UPLC Q-TOF/HSMS/MSE. Journal of Pharmaceutical and Biomedical Analysis, 81–82, 202–209. https://doi.org/10.1016/j.jpba.2013.03.028
Zhu, S., Zhang, F., Shen, A. W., Sun, B., Xia, T. Y., Chen, W. S., Tao, X., & Yu, S. Q. (2021). Metabolomics evaluation of patients with stage 5 chronic kidney disease before dialysis, maintenance hemodialysis, and peritoneal dialysis. Frontiers in Physiology, 11, 630646. https://doi.org/10.3389/fphys.2020.630646
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This work was supported by the National Natural Science Foundation of China (No. 81803961).
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All authors contributed specific text and/or figure content to the manuscript. All authors reviewed the manuscript. BY and HQY wrote the main manuscript text. LLS and HTY provided guidance, supervision and suggestions for this study.
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Yang, B., Yin, H., Wang, J. et al. A metabolic biomarker panel of restless legs syndrome in peritoneal dialysis patients. Metabolomics 18, 79 (2022). https://doi.org/10.1007/s11306-022-01938-z
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DOI: https://doi.org/10.1007/s11306-022-01938-z