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Relationship between serum uric acid level and vascular injury markers in hemodialysis patients

  • Nephrology - Original Paper
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Abstract

Purpose

It has been reported that hyperuricemia causes vascular endothelial injury. Most hemodialysis patients present with hyperuricemia and also with vascular injury, resulting in cardiovascular diseases (CVD). However, the association of serum uric acid (sUA) with vascular injury markers in hemodialysis patients remains unclear. This study aimed to investigate this and discuss the mechanism by which uric acid causes vascular injury.

Methods

We enrolled 48 Japanese maintenance hemodialysis patients without any history of CVD. The association between sUA level and three vascular injury markers (reactive hyperemia index [RHI], ankle–brachial index [ABI], and cardio ankle vascular index [CAVI]) was investigated by linear- and logistic regression analyses.

Results

The median natural logarithm RHI (LnRHI) was 0.36. Linear regression analysis revealed a significant positive correlation between sUA level and LnRHI (β = 0.42, p = 0.001) in all patients. Moreover, a significant, strongly positive correlation was observed between sUA and LnRHI in patients who were treated with xanthine oxidase inhibitors (XOIs) (β = 0.75, p = 0.001). Further, the linear analysis showed a significant negative correlation between sUA level and CAVI in patients who were treated with XOIs (β = − 0.52, p = 0.049). sUA level was not significantly associated with ABI abnormality.

Conclusions

It is possible that a high level of sUA is significantly associated with better vascular endothelial function and condition of vascular tone in hemodialysis patients who were treated with XOIs. The findings suggest a significant paradox between sUA level and vascular endothelial function in hemodialysis patients; however, the opposite has been reported in patients without hemodialysis.

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Availability of data and material

The data used in this study are available from the corresponding author on request.

References

  1. Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA (2010) Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 62:170–180. https://doi.org/10.1002/acr.20065

    Article  Google Scholar 

  2. Edwards NL (2008) The role of hyperuricemia and gout in kidney and cardiovascular disease. Cleve Clin J Med 75:S13–S16. https://doi.org/10.3949/ccjm.75.suppl_5.s13

    Article  PubMed  Google Scholar 

  3. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ (2005) Hyperuricemia induces endothelial dysfunction. Kidney Int 67:1739–1742. https://doi.org/10.1111/j.1523-1755.2005.00273.x

    Article  PubMed  Google Scholar 

  4. Parfrey PS, Foley RN (1999) The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 10:1606–1615

    CAS  PubMed  Google Scholar 

  5. Latif W, Karaboyas A, Tong L, Winchester JF, Arrington CJ, Pisoni RL, Marshall MR, Kleophas W, Levin NW, Sen A, Robinson BM, Saran R (2011) Uric acid levels and all-cause and cardiovascular mortality in the hemodialysis population. Clin J Am Soc Nephrol 6:2470–2477. https://doi.org/10.2215/CJN.00670111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Slinin Y, Foley RN, Collins AJ (2005) Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol 16:1788–1793. https://doi.org/10.1681/ASN.2004040275

    Article  CAS  PubMed  Google Scholar 

  7. Qureshi AR, Alvestrand A, Divino-Filho JC, Gutierrez A, Heimbürger O, Lindholm B, Bergström J (2002) Inflammation, malnutrition, and cardiac disease as predictors of mortality in hemodialysis patients. J Am Soc Nephrol 13:S28–S36

    PubMed  Google Scholar 

  8. Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A (2004) Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 44:2137–2141. https://doi.org/10.1016/j.jacc.2004.08.062

    Article  PubMed  Google Scholar 

  9. Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, Schnall RP, Holmes DR, Higano ST, Lerman A (2003) Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol 41:1761–1768. https://doi.org/10.1016/s0735-1097(03)00329-2

    Article  PubMed  Google Scholar 

  10. Aboyans V, Criqui MH, Abraham P, Allison MA, Creager MA, Diehm C, Fowkes FG, Hiatt WR, Jönsson B, Lacroix P, Marin B, McDermott MM, Norgren L, Pande RL, Preux PM, Stoffers HE, Treat-Jacobson D, American Heart Association Council on Peripheral Vascular Disease, Council on Epidemiology, and Prevention, Council on Clinical Cardiology, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology, and Intervention, Council on Cardiovascular Surgery, and Anesthesia (2012) Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association. Circulation 126:2890–2909. https://doi.org/10.1161/CIR.0b013e318276fbcb

    Article  PubMed  Google Scholar 

  11. Shirai K, Utino J, Otsuka K, Takata M (2006) A novel blood pressure-independent arterial wall stiffness parameter; cardio-ankle vascular index (CAVI). J Atheroscler Thromb 13:101–107. https://doi.org/10.5551/jat.13.101

    Article  PubMed  Google Scholar 

  12. Black MA, Cable NT, Thijssen DH, Green DJ (2008) Importance of measuring the time course of flow-mediated dilatation in humans. Hypertension 51:203–210. https://doi.org/10.1161/HYPERTENSIONAHA.107.101014

    Article  CAS  PubMed  Google Scholar 

  13. Pyke KE, Tschakovsky ME (2005) The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function. J Physiol 568:357–369. https://doi.org/10.1113/jphysiol.2005.089755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ (2011) Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol 300:H2–H12. https://doi.org/10.1152/ajpheart.00471.2010

    Article  CAS  PubMed  Google Scholar 

  15. Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48:452–458. https://doi.org/10.1038/bmt.2012.244

    Article  CAS  PubMed  Google Scholar 

  16. Matsuzawa Y, Sugiyama S, Sumida H, Sugamura K, Nozaki T, Ohba K, Matsubara J, Kurokawa H, Fujisue K, Konishi M, Akiyama E, Suzuki H, Nagayoshi Y, Yamamuro M, Sakamoto K, Iwashita S, Jinnouchi H, Taguri M, Morita S, Matsui K, Kimura K, Umemura S, Ogawa H (2013) Peripheral endothelial function and cardiovascular events in high-risk patients. J Am Heart Assoc 2(6):e000426. https://doi.org/10.1161/JAHA.113.000426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, Ohba K, Matsubara J, Maeda H, Horibata Y, Sakamoto K, Sugamura K, Yamamuro M, Sumida H, Kaikita K, Iwashita S, Matsui K, Kimura K, Umemura S, Ogawa H (2012) Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol 60:1778–1786. https://doi.org/10.1016/j.jacc.2012.07.036

    Article  PubMed  Google Scholar 

  18. Matsue Y, Yoshida K, Nagahori W, Ohno M, Suzuki M, Matsumura A, Hashimoto Y, Yoshida M (2014) Peripheral microvascular dysfunction predicts residual risk in coronary artery disease patients on statin therapy. Atherosclerosis 232:186–190. https://doi.org/10.1016/j.atherosclerosis.2013.11.038

    Article  CAS  PubMed  Google Scholar 

  19. Hirata Y, Sugiyama S, Yamamoto E, Matsuzawa Y, Akiyama E, Kusaka H, Fujisue K, Kurokawa H, Matsubara J, Sugamura K, Maeda H, Iwashita S, Jinnouchi H, Matsui K, Ogawa H (2014) Endothelial function and cardiovascular events in chronic kidney disease. Int J Cardiol 173:481–486. https://doi.org/10.1016/j.ijcard.2014.03.085

    Article  PubMed  Google Scholar 

  20. Liu W, Meng M, Chen J, Wang L, Sun Z, Li X, Zhou J, Gao C, Zhou J, Chu H, Fan W, Bai Y, Yang J (2017) Reactive hyperemia index in patients on maintenance hemodialysis: cross-sectional data from a cohort study. Sci Rep 7:45757. https://doi.org/10.1038/srep45757

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bombelli M, Ronchi I, Volpe M, Facchetti R, Carugo S, Dell'oro R, Cuspidi C, Grassi G, Mancia G (2014) Prognostic value of serum uric acid: new-onset in and out-of-office hypertension and long-term mortality. J Hypertens 32:1237–1244. https://doi.org/10.1097/HJH.0000000000000161

    Article  CAS  PubMed  Google Scholar 

  22. Liu WC, Hung CC, Chen SC, Yeh SM, Lin MY, Chiu YW, Kuo MC, Chang JM, Hwang SJ, Chen HC (2012) Association of hyperuricemia with renal outcomes, cardiovascular disease, and mortality. Clin J Am Soc Nephrol 7:541–548. https://doi.org/10.2215/CJN.09420911

    Article  CAS  PubMed  Google Scholar 

  23. Xia X, He F, Wu X, Peng F, Huang F, Yu X (2014) Relationship between serum uric acid and all-cause and cardiovascular mortality in patients treated with peritoneal dialysis. Am J Kidney Dis 64:257–264. https://doi.org/10.1053/j.ajkd.2013.08.027

    Article  CAS  PubMed  Google Scholar 

  24. Maruhashi T, Hisatome I, Kihara Y, Higashi Y (2018) Hyperuricemia and endothelial function: from molecular background to clinical perspectives. Atherosclerosis 278:226–231. https://doi.org/10.1016/j.atherosclerosis.2018.10.007

    Article  CAS  PubMed  Google Scholar 

  25. Beberashvili I, Sinuani I, Shapiro AAG, Feldman L, Stav K, Sandbank J, Averbukh Z (2015) Serum uric acid as a clinically useful nutritional marker and predictor of outcome in maintenance hemodialysis patients. Nutrition 31:138–147. https://doi.org/10.1016/j.nut.2014.06.012

    Article  CAS  PubMed  Google Scholar 

  26. McNally JS, Davis ME, Giddens DP, Saha A, Hwang J, Dikalov S, Jo H, Harrison DG (2003) Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol Heart Circ Physiol 285:H2290–2297. https://doi.org/10.1152/ajpheart.00515.2003

    Article  CAS  PubMed  Google Scholar 

  27. Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I (2018) Allopurinol protects human glomerular endothelial cells from high glucose-induced reactive oxygen species generation, p53 overexpression and endothelial dysfunction. Int Urol Nephrol 50:179–186. https://doi.org/10.1007/s11255-017-1733-5

    Article  CAS  PubMed  Google Scholar 

  28. Touyz RM (2000) Oxidative stress and vascular damage in hypertension. Curr Hypertens Rep 2:98–105. https://doi.org/10.1007/s11906-000-0066-3

    Article  CAS  PubMed  Google Scholar 

  29. Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P (2000) Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab 85:2970–2973. https://academic.oup.com/jcem/article/85/8/2970/2854373

  30. Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG (2000) Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 148:131–139. https://www.sciencedirect.com/science/article/pii/S0021915099002142

  31. Ames BN, Cathcart R, Schwiers E, Hochstein P (1981) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 78:6858–6862. https://www.pnas.org/content/78/11/6858

  32. Becker BF, Reinholz N, Leipert B, Raschke P, Permanetter B, Gerlach E (1991). Role of uric acid as an endogenous radical scavenger and antioxidant. Chest 100(3 Suppl):176S–181S. https://journal.chestnet.org/article/S0012-3692(16)32387-X

  33. Tsuruta Y, Kikuchi K, Tsuruta Y, Sasaki Y, Moriyama T, Itabashi M, Takei T, Uchida K, Akiba T, Tsuchiya K, Nitta K (2015) Febuxostat improves endothelial function in hemodialysis patients with hyperuricemia: a randomized controlled study. Hemodial Int 19:514–520. https://doi.org/10.1111/hdi.12313

    Article  PubMed  Google Scholar 

  34. Ishii T, Taguri M, Tamura K, Oyama K (2017) Evaluation of the effectiveness of xanthine oxidoreductase inhibitors on haemodialysis patients using a marginal structural model. Sci Rep 7:14004. https://doi.org/10.1038/s41598-017-13970-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Spiekermann S, Landmesser U, Dikalov S, Bredt M, Gamez G, Tatge H, Reepschläger N, Hornig B, Drexler H, Harrison DG (2003) Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 107:1383–1389. https://doi.org/10.1161/01.CIR.0000056762.69302.46

    Article  CAS  PubMed  Google Scholar 

  36. Butts B, Calhoun DA, Denney TS Jr, Lloyd SG, Gupta H, Gaddam KK, Aban I, Oparil S, Sanders PW, Patel R, Collawn JF, Dell'Italia LJ (2019) Plasma xanthine oxidase activity is related to increased sodium and left ventricular hypertrophy in resistant hypertension. Free Radic Biol Med 134:343–349. https://www.sciencedirect.com/science/article/pii/S0891584918314722

  37. Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P (2000) Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension 36:1072–1078. https://doi.org/10.1161/01.hyp.36.6.1072

    Article  CAS  PubMed  Google Scholar 

  38. De Leeuw PW, Thijs L, Birkenhäger WH, Voyaki SM, Efstratopoulos AD, Fagard RH, Leonetti G, Nachev C, Petrie JC, Rodicio JL, Rosenfeld JJ, Sarti C, Staessen JA, Systolic Hypertension in Europe (Syst-Eur) Trial Investigators (2002) Prognostic significance of renal function in elderly patients with isolated systolic hypertension: results from the Syst-Eur trial. J Am Soc Nephrol 13:2213–2222. https://doi.org/10.1097/01.asn.0000027871.86296.92

    Article  PubMed  Google Scholar 

  39. Sugihara S, Hisatome I, Kuwabara M, Niwa K, Maharani N, Kato M, Ogino K, Hamada T, Ninomiya H, Higashi Y, Ichida K, Yamamoto K (2015) Depletion of uric acid due to SLC22A12 (URAT1) loss-of-function mutation causes endothelial dysfunction in hypouricemia. Circ J 79:1125–1132. https://doi.org/10.1253/circj.CJ-14-1267

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the staff of the dialysis center of the Ueda kidney clinic for their support in this study.

Funding

No funding was received for this study.

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Author notes

  1. Makoto Harada and Kazuaki Fujii contributed equally to this study.

Authors and Affiliations

  1. Department of Nephrology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan

    Makoto Harada, Kazuaki Fujii, Yosuke Yamada, Koji Hashimoto & Yuji Kamijo

  2. Department of Nephrology and Urology, Jisyukai Ueda Kidney Clinic, 322 Sumiyoshi, Ueda, 386-0002, Japan

    Makoto Harada, Kazuaki Fujii, Yosuke Yamada, Wataru Tsukada & Manabu Tsukada

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  1. Makoto Harada
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  2. Kazuaki Fujii
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  3. Yosuke Yamada
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Contributions

MH, KF, YY, WT, MT, and KH designed this study; MH, KF, WT, and MT collected the data; MH, KF, WT, and MT drafted manuscript; and YY, KH, and YK revised the manuscript. MH and KF contributed equally to this study.

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Correspondence to Makoto Harada.

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The authors declare that they have no competing interests.

Ethics approval

This study was approved by the institutional review board of the ethical committee at Shinshu university school of medicine (approval number: 1996) and was conducted in accordance with the principles of the Declaration of Helsinki as revised in 2008.

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Written informed consents were obtained from all patients before starting the study.

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Harada, M., Fujii, K., Yamada, Y. et al. Relationship between serum uric acid level and vascular injury markers in hemodialysis patients. Int Urol Nephrol 52, 1581–1591 (2020). https://doi.org/10.1007/s11255-020-02531-w

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  • DOI: https://doi.org/10.1007/s11255-020-02531-w

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