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  • Mini Review
  • Mini review series: Current topic in Hypertension
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Emerging topics on renal denervation in hypertension: anatomical and functional aspects of renal nerves

Hypertension Research volume 46, pages 1462–1470 (2023)Cite this article

Abstract

Inappropriate sympathetic activation is closely associated with the development and progression of hypertension. Renal denervation (RDN) is a neuromodulation therapy performed using an intraarterial catheter in patients with hypertension. Recent randomized sham-operated controlled trials have shown that RDN has significant antihypertensive effects that last for at least 3 years. Based on this evidence, RDN is nearly ready for general clinical application. On the other hand, there are remaining issues to be addressed, including elucidation of the precise antihypertensive mechanisms of RDN, the appropriate endpoint of RDN during the procedure, and the association between reinnervation after RDN and the long-term effects of RDN. This mini review focuses on studies implicating anatomy of the renal nerves, which consist of afferent or efferent and sympathetic or parasympathetic nerves, the response of blood pressure to renal nerve stimulation, and reinnervation of renal nerves after RDN. A comprehensive understanding of the anatomical and functional aspects of the renal nerves and the antihypertensive mechanisms of RDN, including its long-term effects, will enhance our ability to incorporate RDN into strategies to treat hypertension in clinical practice.

This mini review focuses on studies implicating anatomy of the renal nerves, which consist of afferent or efferent and sympathetic or parasympathetic nerves, the response of blood pressure to renal nerve stimulation, and reinnervation of renal nerves after renal denervation. Whether the ablation site is sympathetic dominant or parasympathetic dominant, and afferent dominant or efferent dominant, would in turn determine the final output of renal denervation. BP: blood pressure.

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References

  1. Schlaich MP, Lambert E, Kaye DM, Krozowski Z, Campbell DJ, Lambert G, et al. Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and Angiotensin neuromodulation. Hypertension. 2004;43:169–75.

    Article  CAS  PubMed  Google Scholar 

  2. Katsurada K, Shinohara K, Aoki J, Nanto S, Kario K. Renal denervation: basic and clinical evidence. Hypertens Res. 2022;45:198–209.

    Article  PubMed  Google Scholar 

  3. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N. Engl J Med. 2014;370:1393–401.

    Article  CAS  PubMed  Google Scholar 

  4. Weber MA, Mahfoud F, Schmieder RE, Kandzari DE, Tsioufis KP, Townsend RR, et al. Renal denervation for treating hypertension: current scientific and clinical evidence. JACC Cardiovasc Inter. 2019;12:1095–105.

    Article  Google Scholar 

  5. Kandzari DE, Mahfoud F, Bhatt DL, Bohm M, Weber MA, Townsend RR, et al. Confounding factors in renal denervation trials: revisiting old and identifying new challenges in trial design of device therapies for hypertension. Hypertension. 2020;76:1410–7.

    Article  CAS  PubMed  Google Scholar 

  6. Kario K, Kim BK, Aoki J, Wong AY, Lee YH, Wongpraparut N, et al. Renal Denervation in Asia: consensus statement of the Asia Renal Denervation Consortium. Hypertension. 2020;75:590–602.

    Article  CAS  PubMed  Google Scholar 

  7. Mogi M, Maruhashi T, Higashi Y, Masuda T, Nagata D, Nagai M, et al. Update on hypertension research in 2021. Hypertens Res. 2022;45:1276–97.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bohm M, Kario K, Kandzari DE, Mahfoud F, Weber MA, Schmieder RE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet. 2020;395:1444–51.

    Article  PubMed  Google Scholar 

  9. Kandzari DE, Bohm M, Mahfoud F, Townsend RR, Weber MA, Pocock S, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet. 2018;391:2346–55.

    Article  PubMed  Google Scholar 

  10. Azizi M, Schmieder RE, Mahfoud F, Weber MA, Daemen J, Davies J, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet. 2018;391:2335–45.

    Article  PubMed  Google Scholar 

  11. Azizi M, Sanghvi K, Saxena M, Gosse P, Reilly JP, Levy T, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial. Lancet. 2021;397:2476–86.

    Article  CAS  PubMed  Google Scholar 

  12. Ogoyama Y, Tada K, Abe M, Nanto S, Shibata H, Mukoyama M, et al. Effects of renal denervation on blood pressures in patients with hypertension: a systematic review and meta-analysis of randomized sham-controlled trials. Hypertens Res. 2022;45:210–20.

    Article  PubMed  Google Scholar 

  13. Bhatt DL, Vaduganathan M, Kandzari DE, Leon MB, Rocha-Singh K, Townsend RR, et al. Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 Trial. Lancet. 2022;400:1405–16.

    Article  PubMed  Google Scholar 

  14. Mahfoud F, Kandzari DE, Kario K, Townsend RR, Weber MA, Schmieder RE, et al. Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial. Lancet. 2022;399:1401–10.

    Article  CAS  PubMed  Google Scholar 

  15. Osborn JW, Foss JD. Renal Nerves and Long-Term Control of Arterial Pressure. Compr Physiol. 2017;7:263–320.

    Article  PubMed  Google Scholar 

  16. Kopp UC. Role of renal sensory nerves in physiological and pathophysiological conditions. Am J Physiol Regul Integr Comp Physiol. 2015;308:R79–95.

    Article  CAS  PubMed  Google Scholar 

  17. Kopp UC, Cicha MZ, Smith LA, Hokfelt T. Nitric oxide modulates renal sensory nerve fibers by mechanisms related to substance P receptor activation. Am J Physiol Regul Integr Comp Physiol. 2001;281:R279–290.

    Article  CAS  PubMed  Google Scholar 

  18. Ferguson M, Bell C. Ultrastructural localization and characterization of sensory nerves in the rat kidney. J Comp Neurol. 1988;274:9–16.

    Article  CAS  PubMed  Google Scholar 

  19. Marfurt CF, Echtenkamp SF. Sensory innervation of the rat kidney and ureter as revealed by the anterograde transport of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) from dorsal root ganglia. J Comp Neurol. 1991;311:389–404.

    Article  CAS  PubMed  Google Scholar 

  20. Osborn JW, Tyshynsky R, Vulchanova L. Function of Renal Nerves in Kidney Physiology and Pathophysiology. Annu Rev Physiol. 2021;83:429–50.

    Article  CAS  PubMed  Google Scholar 

  21. Okusa MD, Rosin DL, Tracey KJ. Targeting neural reflex circuits in immunity to treat kidney disease. Nat Rev Nephrol. 2017;13:669–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Norvell JE, Anderson JM. Assessment of possible parasympathetic innervation of the kidney. J Auton Nerv Syst. 1983;8:291–4.

    Article  CAS  PubMed  Google Scholar 

  23. Gattone VH 2nd, Marfurt CF, Dallie S. Extrinsic innervation of the rat kidney: a retrograde tracing study. Am J Physiol. 1986;250:F189–196.

    PubMed  Google Scholar 

  24. Ong J, Kinsman BJ, Sved AF, Rush BM, Tan RJ, Carattino MD, et al. Renal sensory nerves increase sympathetic nerve activity and blood pressure in 2-kidney 1-clip hypertensive mice. J Neurophysiol. 2019;122:358–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cheng X, Zhang Y, Chen R, Qian S, Lv H, Liu X, et al. Anatomical evidence for parasympathetic innervation of the renal vasculature and pelvis. J Am Soc Nephrol. 2022;33:2194–210.

    Article  CAS  PubMed  Google Scholar 

  26. Rossi J, Balthasar N, Olson D, Scott M, Berglund E, Lee CE, et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 2011;13:195–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2010;13:133–40.

    Article  CAS  PubMed  Google Scholar 

  28. Wu D, Hersh LB. Choline acetyltransferase: celebrating its fiftieth year. J Neurochem. 1994;62:1653–63.

    Article  CAS  PubMed  Google Scholar 

  29. Schafer MK, Eiden LE, Weihe E. Cholinergic neurons and terminal fields revealed by immunohistochemistry for the vesicular acetylcholine transporter. II. The peripheral nervous system. Neuroscience. 1998;84:361–76.

    Article  CAS  PubMed  Google Scholar 

  30. Zhou H, Li Y, Xu Y, Liu H, Lai Y, Tan K, et al. Mapping renal innervations by renal nerve stimulation and characterizations of blood pressure response patterns. J Cardiovasc Transl Res. 2022;15:29–37.

    Article  PubMed  Google Scholar 

  31. Liu H, Chen W, Lai Y, Du H, Wang Z, Xu Y, et al. Selective renal denervation guided by renal nerve stimulation in canine. Hypertension. 2019;74:536–45.

    Article  CAS  PubMed  Google Scholar 

  32. Lai Y, Zhou H, Chen W, Liu H, Liu G, Xu Y, et al. The intrarenal blood pressure modulation system is differentially altered after renal denervation guided by different intensities of blood pressure responses. Hypertens Res. 2023;46:456–67.

  33. Huang HC, Cheng HM, Chia YC, Li Y, Van Minh H, Siddique S, et al. The role of renal nerve stimulation in percutaneous renal denervation for hypertension: A mini-review. J Clin Hypertens. 2022;24:1187–93.

    Article  Google Scholar 

  34. Hoogerwaard AF, Adiyaman A, de Jong MR, Smit JJ, Heeg JE, van Hasselt B, et al. Renal nerve stimulation: complete versus incomplete renal sympathetic denervation. Blood Press. 2021;30:376–85.

    Article  CAS  PubMed  Google Scholar 

  35. Kario K, Mahfoud F, Kandzari DE, Townsend RR, Weber MA, Schmieder RE, et al. Long-term reduction in morning and nighttime blood pressure after renal denervation: 36-month results from SPYRAL HTN-ON MED trial. Hypertens Res. 2023;46:280–8.

    Article  CAS  PubMed  Google Scholar 

  36. Mulder J, Hokfelt T, Knuepfer MM, Kopp UC. Renal sensory and sympathetic nerves reinnervate the kidney in a similar time-dependent fashion after renal denervation in rats. Am J Physiol Regul Integr Comp Physiol. 2013;304:R675–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rodionova K, Fiedler C, Guenther F, Grouzmann E, Neuhuber W, Fischer MJ, et al. Complex reinnervation pattern after unilateral renal denervation in rats. Am J Physiol Regul Integr Comp Physiol. 2016;310:R806–818.

    Article  PubMed  Google Scholar 

  38. Li S, Hildreth CM, Rahman AA, Barton SA, Wyse BF, Lim CK, et al. Renal denervation does not affect hypertension or the renin-angiotensin system in a rodent model of juvenile-onset polycystic kidney disease: clinical implications. Sci Rep. 2021;11:14286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kline RL, Stuart PJ, Mercer PF. Effect of renal denervation on arterial pressure and renal norepinephrine concentration in Wistar-Kyoto and spontaneously hypertensive rats. Can J Physiol Pharm. 1980;58:1384–8.

    Article  CAS  Google Scholar 

  40. Booth LC, Nishi EE, Yao ST, Ramchandra R, Lambert GW, Schlaich MP, et al. Reinnervation of renal afferent and efferent nerves at 5.5 and 11 months after catheter-based radiofrequency renal denervation in sheep. Hypertension. 2015;65:393–400.

    Article  CAS  PubMed  Google Scholar 

  41. Singh RR, McArdle ZM, Iudica M, Easton LK, Booth LC, May CN, et al. Sustained decrease in blood pressure and reduced anatomical and functional reinnervation of renal nerves in hypertensive sheep 30 months after catheter-based renal denervation. Hypertension. 2019;73:718–27.

    Article  CAS  PubMed  Google Scholar 

  42. Sakakura K, Tunev S, Yahagi K, O’Brien AJ, Ladich E, Kolodgie FD, et al. Comparison of histopathologic analysis following renal sympathetic denervation over multiple time points. Circ Cardiovasc Inter. 2015;8:e001813.

    Article  Google Scholar 

  43. Rousselle SD, Brants IK, Sakaoka A, Hubbard B, Jackson ND, Wicks JR, et al. Neuromatous regeneration as a nerve response after catheter-based renal denervation therapy in a large animal model: immunohistochemical study. Circ Cardiovasc Inter. 2015;8:e002293.

    Article  Google Scholar 

  44. Sakaoka A, Rousselle SD, Hagiwara H, Tellez A, Hubbard B, Sakakura K. Safety of catheter-based radiofrequency renal denervation on branch renal arteries in a porcine model. Catheter Cardiovasc Inter. 2019;93:494–502.

    Article  Google Scholar 

  45. Sharp ASP, Tunev S, Schlaich M, Lee DP, Finn AV, Trudel J, et al. Histological evidence supporting the durability of successful radiofrequency renal denervation in a normotensive porcine model. J Hypertens. 2022;40:2068–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Biffi A, Dell’Oro R, Quarti-Trevano F, Cuspidi C, Corrao G, Mancia G, et al. Effects of renal denervation on sympathetic nerve traffic and correlates in drug-resistant and uncontrolled hypertension: a systematic review and meta-analysis. Hypertension. 2023;80:659–67.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported in part by JSPS KAKENHI Grant Number JP21K16094, MSD Life Science Foundation, Public Interest Incorporated Foundation and Jichi Medical University Young Investigator Award (to K. Katsurada).

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan

    Kenichi Katsurada & Kazuomi Kario

  2. Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan

    Kenichi Katsurada

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Correspondence to Kenichi Katsurada.

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K. Kario MD, PhD. received speaker fees and works as a consultant to JIMRO Co., Ltd., Medtronic Co. Inc. and Terumo Co. Inc. The other authors declare that they have no conflict of interest.

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Katsurada, K., Kario, K. Emerging topics on renal denervation in hypertension: anatomical and functional aspects of renal nerves. Hypertens Res 46, 1462–1470 (2023). https://doi.org/10.1038/s41440-023-01266-2

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