Current Hypertension Reports

, Volume 15, Issue 4, pp 370–376 | Cite as

The Sympathetic Nervous System in Chronic Kidney Disease

  • Sebastian Ewen
  • Christian Ukena
  • Dominik Linz
  • Roland E. Schmieder
  • Michael Böhm
  • Felix Mahfoud
Secondary Hypertension: Adrenal and Nervous System Mechanisms (S Oparil, Section Editor)


Accumulating evidence has shown that the sympathetic nervous system plays an important role in the pathophysiology and progression of several chronic disorders, e.g., arterial hypertension, cardiac arrhythmias, heart failure, and in particular chronic kidney disease (CKD). Experimental and clinical studies provide evidence that sympathetic inhibition using either sympatholytic pharmacotherapy or catheter-based renal denervation has beneficial effects in patients with CKD. Randomized clinical trials are needed to characterize the underlying pathophysiological mechanisms, and systematically evaluate the therapeutic effects of sympathetic inhibition in this high-risk patient population. In this review current knowledge of the role of the sympathetic nervous system in the development and progression of CKD will be summarized, and novel treatment options targeting sympathetic nervous system activity will be discussed.


Hypertension Chronic renal failure CKD Sympathetic nervous system Sympathetic overdrive Renal injury Ischemia Nitric oxide NO Asymmetric dimethlyarginine (ADMA)-related mechanisms Oxidative stress Ang II Renalase Pharmacotherapy Renal denervation Dialysis Hypertension 

List of abbreviations


angiotensin-converting enzyme


asymmetric dimethlyarginine

Ang II

angiotensin II


angiotensin receptor blocker


blood pressure


chronic kidney disease


end-stage renal disease


glomerular filtration rate


muscle sympathetic nerve activity




nitric oxide


nitric oxide synthase


renin-angiotensin-aldosterone system


sympathetic nervous system.


Conflict of Interest

All authors participating have disclosed potential conflicts of interest that might cause a bias in the article. The institution has received scientific support from Medtronic/Ardian.

Michael Böhm, Roland E. Schmieder, and Felix Mahfoud were investigators in the Symplicity HTN-1 and HTN-2 trials. Christian Ukena, Michael Böhm, Roland E. Schmieder, and Felix Mahfoud have received speaker honoraria and consulting fees from Medtronic/Ardian. Christian Ukena, Michael Böhm, and Felix Mahfoud are supported by Deutsche Forschungsgemeinschaft (KFO 196). Sebastian Ewen and Felix Mahfoud are supported by Deutsche Hochdruckliga. Dominik Linz and Felix Mahfoud are supported by Deutsche Gesellschaft für Kardiologie.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Mahmoodi BK, Matsushita K, Woodward M, Blankestijn PJ, Cirillo M, Ohkubo T, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis. Lancet. 2012;380(9854):1649–61. doi: 10.1016/s0140-6736(12)61272-0. Important overwiev regarding the mortality of CK with and without hypertension.PubMedCrossRefGoogle Scholar
  2. 2.
    Borrelli S, De Nicola L, Stanzione G, Conte G, Minutolo R. Resistant hypertension in nondialysis chronic kidney disease. Int J Hypertens. 2013;2013:1–8. doi: 10.1155/2013/929183.CrossRefGoogle Scholar
  3. 3.
    Sarafidis PA, Li S, Chen SC, Collins AJ, Brown WW, Klag MJ, et al. Hypertension awareness, treatment, and control in chronic kidney disease. Am J Med. 2008;121(4):332–40. doi: 10.1016/j.amjmed.2007.11.025.PubMedCrossRefGoogle Scholar
  4. 4.
    Ligtenberg G, Blankestijn PJ, Oey PL, Klein IH, Dijkhorst-Oei LT, Boomsma F, et al. Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med. 1999;340(17):1321–8. doi: 10.1056/NEJM199904293401704.PubMedCrossRefGoogle Scholar
  5. 5.
    • Sobotka PA, Mahfoud F, Schlaich MP, Hoppe UC, Böhm M, Krum H. Sympatho-renal axis in chronic disease. Clin Res Cardiol. 2011;100(12):1049–57. doi: 10.1007/s00392-011-0335-y. Review article on the role of the sympathetic nervous system in different disease states and potential future indication of renal denervation.PubMedCrossRefGoogle Scholar
  6. 6.
    DiBona GF. Neural control of the kidney: past, present, and future. Hypertension. 2003;41(3 Pt 2):621–4. doi: 10.1161/01.HYP.0000047205.52509.8A.PubMedCrossRefGoogle Scholar
  7. 7.
    Buchner N, Vonend O, Rump LC. Pathophysiology of hypertension: what's new? Herz. 2006;31(4):294–302. doi: 10.1007/s00059-006-2821-y.PubMedCrossRefGoogle Scholar
  8. 8.
    DiBona GF. Physiology in perspective: The wisdom of the body. Neural control of the kidney. Am J Physiol Regul Integr Comp Physiol. 2005;289(3):R633–41. doi: 10.1152/ajpregu.00258.2005.PubMedCrossRefGoogle Scholar
  9. 9.
    Vonend O, Okonek A, Stegbauer J, Habbel S, Quack I, Rump LC. Renovascular effects of sympathetic cotransmitters ATP and NPY are age-dependent in spontaneously hypertensive rats. Cardiovasc Res. 2005;66(2):345–52. doi: 10.1016/j.cardiores.2004.12.005.PubMedCrossRefGoogle Scholar
  10. 10.
    Ishii M, Ikeda T, Takagi M, Sugimoto T, Atarashi K, Igari T, et al. Elevated plasma catecholamines in hypertensives with primary glomerular diseases. Hypertension. 1983;5(4):545–51.PubMedCrossRefGoogle Scholar
  11. 11.
    • Converse Jr RL, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992;327(27):1912–8. doi: 10.1056/NEJM199212313272704. Important work about the sympathetic overactivity in patients with CKD.PubMedCrossRefGoogle Scholar
  12. 12.
    Recordati G, Moss NG, Genovesi S, Rogenes P. Renal chemoreceptors. J Auton Nerv Syst. 1981;3(2–4):237–51.PubMedCrossRefGoogle Scholar
  13. 13.
    Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, Kisters K, et al. Sympathetic nerve activity in end-stage renal disease. Circulation. 2002;106(15):1974–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Grassi G, Quarti-Trevano F, Seravalle G, Arenare F, Volpe M, Furiani S, et al. Early sympathetic activation in the initial clinical stages of chronic renal failure. Hypertension. 2011;57(4):846–51. doi: 10.1161/HYPERTENSIONAHA.110.164780.PubMedCrossRefGoogle Scholar
  15. 15.
    • Penne EL, Neumann J, Klein IH, Oey PL, Bots ML, Blankestijn PJ. Sympathetic hyperactivity and clinical outcome in chronic kidney disease patients during standard treatment. J Nephrol. 2009;22(2):208–15. Important scientific statement regarding sympathetic hyperactivity in CKD.PubMedGoogle Scholar
  16. 16.
    Ditting T, Freisinger W, Siegel K, Fiedler C, Small L, Neuhuber W, et al. Tonic postganglionic sympathetic inhibition induced by afferent renal nerves? Hypertension. 2012;59(2):467–76. doi: 10.1161/HYPERTENSIONAHA.111.185538.PubMedCrossRefGoogle Scholar
  17. 17.
    Bigazzi R, Kogosov E, Campese VM. Altered norepinephrine turnover in the brain of rats with chronic renal failure. J Am Soc Nephrol. 1994;4(11):1901–7.PubMedGoogle Scholar
  18. 18.
    Campese VM. Neurogenic factors and hypertension in chronic renal failure. J Nephrol. 1997;10(4):184–7.PubMedGoogle Scholar
  19. 19.
    Campese VM, Kogosov E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension. 1995;25(4 Pt 2):878–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Campese VM, Kogosov E, Koss M. Renal afferent denervation prevents the progression of renal disease in the renal ablation model of chronic renal failure in the rat. Am J Kidney Dis. 1995;26(5):861–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Ye S, Ozgur B, Campese VM. Renal afferent impulses, the posterior hypothalamus, and hypertension in rats with chronic renal failure. Kidney Int. 1997;51(3):722–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Ye S, Zhong H, Yanamadala V, Campese VM. Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity. Am J Hypertens. 2002;15(8):717–24.PubMedCrossRefGoogle Scholar
  23. 23.
    Katholi RE, Whitlow PL, Hageman GR, Woods WT. Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog. J Hypertens. 1984;2(4):349–59.PubMedGoogle Scholar
  24. 24.
    Ye S, Gamburd M, Mozayeni P, Koss M, Campese VM. A limited renal injury may cause a permanent form of neurogenic hypertension. Am J Hypertens. 1998;11(6 Pt 1):723–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J Am Soc Nephrol. 2001;12(11):2427–33.PubMedGoogle Scholar
  26. 26.
    Bernhardt WM, Wiesener MS, Weidemann A, Schmitt R, Weichert W, Lechler P, et al. Involvement of hypoxia-inducible transcription factors in polycystic kidney disease. Am J Pathol. 2007;170(3):830–42. doi: 10.2353/ajpath.2007.060455.PubMedCrossRefGoogle Scholar
  27. 27.
    Schlaich MP, Socratous F, Hennebry S, Eikelis N, Lambert EA, Straznicky N, et al. Sympathetic activation in chronic renal failure. J Am Soc Nephrol. 2009;20(5):933–9. doi: 10.1681/ASN.2008040402.PubMedCrossRefGoogle Scholar
  28. 28.
    Lyson T, Ermel LD, Belshaw PJ, Alberg DG, Schreiber SL, Victor RG. Cyclosporine- and FK506-induced sympathetic activation correlates with calcineurin-mediated inhibition of T-cell signaling. Circ Res. 1993;73(3):596–602.PubMedCrossRefGoogle Scholar
  29. 29.
    Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol. 1992;262(6 Pt 1):E763–78.PubMedGoogle Scholar
  30. 30.
    Carlson SH, Wyss JM. Neurohormonal regulation of the sympathetic nervous system: new insights into central mechanisms of action. Curr Hypertens Rep. 2008;10(3):233–40.PubMedCrossRefGoogle Scholar
  31. 31.
    Hering D, Zdrojewski Z, Krol E, Kara T, Kucharska W, Somers VK, et al. Tonic chemoreflex activation contributes to the elevated muscle sympathetic nerve activity in patients with chronic renal failure. J Hypertens. 2007;25(1):157–61. doi: 10.1097/HJH.0b013e3280102d92.PubMedCrossRefGoogle Scholar
  32. 32.
    Mallamaci F, Tripepi G, Maas R, Malatino L, Boger R, Zoccali C. Analysis of the relationship between norepinephrine and asymmetric dimethyl arginine levels among patients with end-stage renal disease. J Am Soc Nephrol. 2004;15(2):435–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Grassi G, Seravalle G, Ghiadoni L, Tripepi G, Bruno RM, Mancia G, et al. Sympathetic nerve traffic and asymmetric dimethylarginine in chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(11):2620–7. doi: 10.2215/CJN.06970711.PubMedCrossRefGoogle Scholar
  34. 34.
    Bergamaschi CT, Campos RR, Lopes OU. Rostral ventrolateral medulla : A source of sympathetic activation in rats subjected to long-term treatment with L-NAME. Hypertension. 1999;34(4 Pt 2):744–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Hijmering ML, Stroes ES, Olijhoek J, Hutten BA, Blankestijn PJ, Rabelink TJ. Sympathetic activation markedly reduces endothelium-dependent, flow-mediated vasodilation. J Am Coll Cardiol. 2002;39(4):683–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Augustyniak RA, Victor RG, Morgan DA, Zhang W. L-NAME- and ADMA-induced sympathetic neural activation in conscious rats. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R726–32. doi: 10.1152/ajpregu.00768.2004.PubMedCrossRefGoogle Scholar
  37. 37.
    Zanzinger J. Role of nitric oxide in the neural control of cardiovascular function. Cardiovasc Res. 1999;43(3):639–49.PubMedCrossRefGoogle Scholar
  38. 38.
    Zanzinger J, Czachurski J, Seller H. Neuronal nitric oxide reduces sympathetic excitability by modulation of central glutamate effects in pigs. Circ Res. 1997;80(4):565–71.PubMedCrossRefGoogle Scholar
  39. 39.
    Sander M, Chavoshan B, Victor RG. A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension. 1999;33(4):937–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Sander D, Kukla C, Klingelhofer J, Winbeck K, Conrad B. Relationship between circadian blood pressure patterns and progression of early carotid atherosclerosis: A 3-year follow-up study. Circulation. 2000;102(13):1536–41.PubMedCrossRefGoogle Scholar
  41. 41.
    Kielstein JT, Zoccali C. Asymmetric dimethylarginine: a novel marker of risk and a potential target for therapy in chronic kidney disease. Curr Opin Nephrol Hypertens. 2008;17(6):609–15. doi: 10.1097/MNH.0b013e328314b6ca.PubMedCrossRefGoogle Scholar
  42. 42.
    Zoccali C, Mallamaci F, Maas R, Benedetto FA, Tripepi G, Malatino LS, et al. Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int. 2002;62(1):339–45. doi: 10.1046/j.1523-1755.2002.00437.x.PubMedCrossRefGoogle Scholar
  43. 43.
    Shi B, Ni Z, Zhou W, Yu Z, Gu L, Mou S, et al. Circulating levels of asymmetric dimethylarginine are an independent risk factor for left ventricular hypertrophy and predict cardiovascular events in pre-dialysis patients with chronic kidney disease. Eur J Intern Med. 2010;21(5):444–8. doi: 10.1016/j.ejim.2010.07.001.PubMedCrossRefGoogle Scholar
  44. 44.
    Campese VM, Ye S, Zhong H, Yanamadala V, Ye Z, Chiu J. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. Am J Physiol Heart Circ Physiol. 2004;287(2):H695–703. doi: 10.1152/ajpheart.00619.2003.PubMedCrossRefGoogle Scholar
  45. 45.
    Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007;116(1):85–97. doi: 10.1161/CIRCULATIONAHA.106.678342.PubMedCrossRefGoogle Scholar
  46. 46.
    Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure. J Am Soc Nephrol. 2003;14(2):425–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, et al. Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest. 2005;115(5):1275–80. doi: 10.1172/JCI24066.PubMedGoogle Scholar
  48. 48.
    Li G, Xu J, Wang P, Velazquez H, Li Y, Wu Y, et al. Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation. 2008;117(10):1277–82. doi: 10.1161/CIRCULATIONAHA.107.732032.PubMedCrossRefGoogle Scholar
  49. 49.
    Siddiqi L, Oey PL, Blankestijn PJ. Aliskiren reduces sympathetic nerve activity and blood pressure in chronic kidney disease patients. Nephrol Dial Transplant. 2011;26(9):2930–4. doi: 10.1093/ndt/gfq857.PubMedCrossRefGoogle Scholar
  50. 50.
    Cice G, Di Benedetto A, D'Isa S, D'Andrea A, Marcelli D, Gatti E, et al. Effects of telmisartan added to Angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure a double-blind, placebo-controlled trial. J Am Coll Cardiol. 2010;56(21):1701–8. doi: 10.1016/j.jacc.2010.03.105.PubMedCrossRefGoogle Scholar
  51. 51.
    Amann K, Koch A, Hofstetter J, Gross ML, Haas C, Orth SR, et al. Glomerulosclerosis and progression: effect of subantihypertensive doses of alpha and beta blockers. Kidney Int. 2001;60(4):1309–23. doi: 10.1046/j.1523-1755.2001.00936.x.PubMedCrossRefGoogle Scholar
  52. 52.
    Cice G, Ferrara L, D'Andrea A, D'Isa S, Di Benedetto A, Cittadini A, et al. Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J Am Coll Cardiol. 2003;41(9):1438–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Tangri N, Shastri S, Tighiouart H, Beck GJ, Cheung AK, Eknoyan G, et al. beta-Blockers for prevention of sudden cardiac death in patients on hemodialysis: a propensity score analysis of the HEMO Study. Am J Kidney Dis. 2011;58(6):939–45. doi: 10.1053/j.ajkd.2011.06.024.PubMedCrossRefGoogle Scholar
  54. 54.
    Bakris GL, Hart P, Ritz E. Beta blockers in the management of chronic kidney disease. Kidney Int. 2006;70(11):1905–13. doi: 10.1038/ Scholar
  55. 55.
    Vonend O, Marsalek P, Russ H, Wulkow R, Oberhauser V, Rump LC. Moxonidine treatment of hypertensive patients with advanced renal failure. J Hypertens. 2003;21(9):1709–17. doi: 10.1097/01.hjh.0000084733.53355.c3.PubMedCrossRefGoogle Scholar
  56. 56.
    Siddiqi L, Joles JA, Oey PL, Blankestijn PJ. Atorvastatin reduces sympathetic activity in patients with chronic kidney disease. J Hypertens. 2011;29(11):2176–80. doi: 10.1097/HJH.0b013e32834ae3c7.PubMedCrossRefGoogle Scholar
  57. 57.
    Mahfoud F. [Renal denervation in hypertension - pro]. Dtsch Med Wochenschr. 2012;137(14):720. doi: 10.1055/s-0032-1304839.PubMedCrossRefGoogle Scholar
  58. 58.
    • Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275–81. doi: 10.1016/S0140-6736(09)60566-3. First-in-man report of renal denervation in patients with resistant hypertension.PubMedCrossRefGoogle Scholar
  59. 59.
    • Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376(9756):1903–9. doi: 10.1016/S0140-6736(10)62039-9. Randomized controlled trial investigating the effect of renal denervation versus medical treatment alone in patients with resistant hypertension.PubMedCrossRefGoogle Scholar
  60. 60.
    Krum H, Barman N, Schlaich M, Sobotka P, Esler M, Mahfoud F, et al. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011;57(5):911–7. doi: 10.1161/HYPERTENSIONAHA.110.163014.CrossRefGoogle Scholar
  61. 61.
    • Mahfoud F, Cremers B, Janker J, Link B, Vonend O, Ukena C, et al. Renal Hemodynamics and Renal Function After Catheter-Based Renal Sympathetic Denervation in Patients With Resistant Hypertension. Hypertension. 2012. doi: 10.1161/HYPERTENSIONAHA.112.193870. Study showing that renal denervation reduces renal resistive indices and number of patients with micro- and macroalbuminuria, without impairing renal function.Google Scholar
  62. 62.
    Ott C, Janka R, Schmid A, Titze S, Ditting T, Sobotka PA, et al. Vascular and renal hemodynamic changes after renal denervation. Clin J Am Soc Nephrol. 2013. doi: 10.2215/CJN.08500812.PubMedGoogle Scholar
  63. 63.
    Ott C, Schmid A, Ditting T, Sobotka PA, Veelken R, Uder M, et al. Renal denervation in a hypertensive patient with end-stage renal disease and small arteries: a direction for future research. J Clin Hypertens. 2012;14(11):799–801. doi: 10.1111/jch.12017.CrossRefGoogle Scholar
  64. 64.
    • Schlaich MP, Bart B, Hering D, Walton A, Marusic P, Mahfoud F, et al. Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease. Int J Cardiol. 2013. doi: 10.1016/j.ijcard.2013.01.218. Important work about RDN in patients with ESRD.Google Scholar
  65. 65.
    Dörr O, Liebetrau C, Mollmann H, Achenbach S, Sedding D, Szardien S, et al. Renal sympathetic denervation does not aggravate functional or structural renal damage. J Am Coll Cardiol. 2012. doi: 10.1016/j.jacc.2012.09.051.PubMedGoogle Scholar
  66. 66.
    Zilch O, Vos PF, Oey PL, Cramer MJ, Ligtenberg G, Koomans HA, et al. Sympathetic hyperactivity in haemodialysis patients is reduced by short daily haemodialysis. J Hypertens. 2007;25(6):1285–9. doi: 10.1097/HJH.0b013e3280f9df85.PubMedCrossRefGoogle Scholar
  67. 67.
    Friedman O, Bradley TD, Chan CT, Parkes R, Logan AG. Relationship between overnight rostral fluid shift and obstructive sleep apnea in drug-resistant hypertension. Hypertension. 2010;56(6):1077–82. doi: 10.1161/HYPERTENSIONAHA.110.154427.PubMedCrossRefGoogle Scholar
  68. 68.
    Grassi G, Bertoli S, Seravalle G. Sympathetic nervous system: role in hypertension and in chronic kidney disease. Curr Opin Nephrol Hypertens. 2012;21(1):46–51. doi: 10.1097/MNH.0b013e32834db45d.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Sebastian Ewen
    • 1
  • Christian Ukena
    • 1
  • Dominik Linz
    • 1
  • Roland E. Schmieder
    • 2
  • Michael Böhm
    • 1
  • Felix Mahfoud
    • 1
  1. 1.Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische IntensivmedizinUniversitätsklinikum des SaarlandesHomburg/SaarGermany
  2. 2.Medizinische Klinik 4, Nephrologie und HypertensiologieUniversitätsklinikum ErlangenErlangenGermany

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