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Renal nerves in physiology, pathophysiology and interoception

Nature Reviews Nephrology volume 21, pages 57–69 (2025)Cite this article

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Abstract

Sympathetic efferent renal nerves have key roles in the regulation of kidney function and blood pressure. Increased renal sympathetic nerve activity is thought to contribute to hypertension by promoting renal sodium retention, renin release and renal vasoconstriction. This hypothesis led to the development of catheter-based renal denervation (RDN) for the treatment of hypertension. Two RDN devices that ablate both efferent and afferent renal nerves received FDA approval for this indication in 2023. However, in animal models, selective ablation of afferent renal nerves resulted in comparable anti-hypertensive effects to ablation of efferent and afferent renal nerves and was associated with a reduction in sympathetic nerve activity. Selective afferent RDN also improved kidney function in a chronic kidney disease model. Notably, the beneficial effects of RDN extend beyond hypertension and chronic kidney disease to other clinical conditions that are associated with elevated sympathetic nerve activity, including heart failure and arrhythmia. These findings suggest that the kidney is an interoceptive organ, as increased renal sensory nerve activity modulates sympathetic activity to other organs. Future studies are needed to translate this knowledge into novel therapies for the treatment of hypertension and other cardiorenal diseases.

Key points

  • Activation of sympathetic efferent renal nerves, which relay information from the brain to the kidney, promotes renal sodium retention, renin release and renal vasoconstriction, which are thought to contribute to the development of hypertension.

  • Sensory afferent renal nerves respond to physical and chemical changes in the kidney and relay information to the brain; whether specific nociceptive afferent renal nerves exist has not yet been determined.

  • Catheter-based renal denervation (RDN), which ablates both afferent and efferent renal nerves, has been approved by the FDA as a treatment for hypertension.

  • Preclinical and clinical studies have shown beneficial effects of RDN beyond blood pressure control in chronic kidney disease and other conditions that are associated with increased sympathetic activity, including heart failure and arrhythmias.

  • In preclinical studies, selective afferent RDN reduced sympathetic drive to the kidney and other organs and had beneficial effects in models of hypertension, chronic kidney disease and chronic heart failure.

  • Interruption of afferent renal sensory pathways that modulate the activity of the sympathetic nervous system are likely to underlie some of the beneficial effects of RDN, suggesting that the kidney is an interoceptive organ.

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Fig. 1: Efferent renal nerves.
Fig. 2: Afferent renal nerves.

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References

  1. Osborn, J. W. & Foss, J. D. Renal nerves and long-term control of arterial pressure. Compr. Physiol. 7, 263–320 (2017).

    PubMed  Google Scholar 

  2. Osborn, J. W., Tyshynsky, R. & Vulchanova, L. Function of renal nerves in kidney physiology and pathophysiology. Annu. Rev. Physiol. 83, 429–450 (2021).

    CAS  PubMed  Google Scholar 

  3. Johns, E. J., Kopp, U. C. & DiBona, G. F. Neural control of renal function. Compr. Physiol. 1, 731–767 (2011).

    PubMed  Google Scholar 

  4. Foss, J. D., Wainford, R. D., Engeland, W. C., Fink, G. D. & Osborn, J. W. A novel method of selective ablation of afferent renal nerves by periaxonal application of capsaicin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308, R112–R122 (2015).

    CAS  PubMed  Google Scholar 

  5. Ong, J. et al. Renal sensory nerves increase sympathetic nerve activity and blood pressure in 2-kidney 1-clip hypertensive mice. J. Neurophysiol. 122, 358–367 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Zheng, H., Katsurada, K., Liu, X., Knuepfer, M. M. & Patel, K. P. Specific afferent renal denervation prevents reduction in neuronal nitric oxide synthase within the paraventricular nucleus in rats with chronic heart failure. Hypertension 72, 667–675 (2018).

    CAS  PubMed  Google Scholar 

  7. Frame, A. A., Carmichael, C. Y., Kuwabara, J. T., Cunningham, J. T. & Wainford, R. D. Role of the afferent renal nerves in sodium homeostasis and blood pressure regulation in rats. Exp. Physiol. 104, 1306–1323 (2019).

    CAS  PubMed  Google Scholar 

  8. Schlaich, M. P. et al. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension 54, 1195–1201 (2009).

    CAS  PubMed  Google Scholar 

  9. Rey-Garcia, J. & Townsend, R. R. Renal denervation: a review. Am. J. Kidney Dis. 80, 527–535 (2022).

    PubMed  Google Scholar 

  10. Mountfort, K. et al. Catheter-based renal sympathetic denervation — long-term Symplicity™ renal denervation clinical evidence, new data and future perspectives. Interv. Cardiol. 8, 118–123 (2013).

    PubMed  PubMed Central  Google Scholar 

  11. Kandzari, D. E. et al. The SPYRAL HTN Global Clinical Trial Program: rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. Am. Heart J. 171, 82–91 (2016).

    PubMed  Google Scholar 

  12. Azizi, M. et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet 391, 2335–2345 (2018).

    PubMed  Google Scholar 

  13. FDA. Premarket Approval (PMA) Symplicity Spyral® Renal Denervation System. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P220026 (2023).

  14. FDA. Premarket Approval (PMA) Paradise® Ultrasound Renal Denervation System. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P220023 (2023).

  15. Mancia, G. et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J. Hypertension 41, 1874–2071 (2023).

    CAS  Google Scholar 

  16. Barbato, E. et al. Renal denervation in the management of hypertension in adults. A clinical consensus statement of the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur. Heart J. 44, 1313–1330 (2023).

    CAS  PubMed  Google Scholar 

  17. Barbato, E. et al. Renal denervation in the management of hypertension in adults. A clinical consensus statement of the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). EuroIntervention 18, 1227–1243 (2023).

    PubMed  PubMed Central  Google Scholar 

  18. Schlaich, M. P., Sobotka, P. A., Krum, H., Lambert, E. & Esler, M. D. Renal sympathetic-nerve ablation for uncontrolled hypertension. N. Engl. J. Med. 361, 932–934 (2009).

    CAS  PubMed  Google Scholar 

  19. Kassab, K., Soni, R., Kassier, A. & Fischell, T. A. The potential role of renal denervation in the management of heart failure. J. Clin. Med. 11, 4147 (2022).

    PubMed  PubMed Central  Google Scholar 

  20. Lauar, M. R. et al. Renal and hypothalamic inflammation in renovascular hypertension: role of afferent renal nerves. Am. J. Physiol. Regul. Integr. Comp. Physiol. 325, R411–R422 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Veiga, A. C. et al. Selective afferent renal denervation mitigates renal and splanchnic sympathetic nerve overactivity and renal function in chronic kidney disease-induced hypertension. J. Hypertens. 38, 765–773 (2020).

    CAS  PubMed  Google Scholar 

  22. Banek, C. T. et al. Resting afferent renal nerve discharge and renal inflammation: elucidating the role of afferent and efferent renal nerves in deoxycorticosterone acetate salt hypertension. Hypertension 68, 1415–1423 (2016).

    CAS  PubMed  Google Scholar 

  23. Nishi, E. E., Bergamaschi, C. T. & Campos, R. R. The crosstalk between the kidney and the central nervous system: the role of renal nerves in blood pressure regulation. Exp. Physiol. 100, 479–484 (2015).

    PubMed  Google Scholar 

  24. Diaz-Morales, N., Baranda-Alonso, E. M., Martinez-Salgado, C. & Lopez-Hernandez, F. J. Renal sympathetic activity: a key modulator of pressure natriuresis in hypertension. Biochem. Pharmacol. 208, 115386 (2023).

    CAS  PubMed  Google Scholar 

  25. Kopp, U. C. Neural Control of Renal Function Integrated Systems Physiology: from Molecule to Function to Disease (Morgan & Claypool, 2011).

  26. DiBona, G. F. & Kopp, U. C. Neural control of renal function. Physiol. Rev. 77, 75–197 (1997).

    CAS  PubMed  Google Scholar 

  27. DiBona, G. F. & Sawin, L. L. Effect of renal nerve stimulation on NaCl and H2O transport in Henle’s loop of the rat. Am. J. Physiol. 243, F576–F580 (1982).

    CAS  PubMed  Google Scholar 

  28. Frame, A. A. et al. Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats. Am. J. Physiol. Renal Physiol. 317, F1623–F1636 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Pontes, R. B. et al. Renal nerve stimulation leads to the activation of the Na+/H+ exchanger isoform 3 via angiotensin II type I receptor. Am. J. Physiol. Renal Physiol. 308, F848–F856 (2015).

    CAS  PubMed  Google Scholar 

  30. Mansley, M. K., Neuhuber, W., Korbmacher, C. & Bertog, M. Norepinephrine stimulates the epithelial Na+ channel in cortical collecting duct cells via α2-adrenoceptors. Am. J. Physiol. Renal Physiol. 308, F450–F458 (2015).

    CAS  PubMed  Google Scholar 

  31. Ferguson, M. & Bell, C. Ultrastructural localization and characterization of sensory nerves in the rat kidney. J. Comp. Neurol. 274, 9–16 (1988).

    CAS  PubMed  Google Scholar 

  32. Marfurt, C. F. & Echtenkamp, S. F. 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. 311, 389–404 (1991).

    CAS  PubMed  Google Scholar 

  33. Ditting, T. et al. Do distinct populations of dorsal root ganglion neurons account for the sensory peptidergic innervation of the kidney? Am. J. Physiol. Renal Physiol. 297, F1427–F1434 (2009).

    CAS  PubMed  Google Scholar 

  34. Tyshynsky, R. et al. Periglomerular afferent innervation of the mouse renal cortex. Front. Neurosci. 17, 974197 (2023).

    PubMed  PubMed Central  Google Scholar 

  35. Struthoff, H. et al. Histological examination of renal nerve distribution, density, and function in humans. EuroIntervention 19, 612–620 (2023).

    PubMed  PubMed Central  Google Scholar 

  36. Garcia-Touchard, A., Maranillo, E., Mompeo, B. & Sanudo, J. R. Microdissection of the human renal nervous system: implications for performing renal denervation procedures. Hypertension 76, 1240–1246 (2020).

    CAS  PubMed  Google Scholar 

  37. Hackenthal, E., Paul, M., Ganten, D. & Taugner, R. Morphology, physiology, and molecular biology of renin secretion. Physiol. Rev. 70, 1067–1116 (1990).

    CAS  PubMed  Google Scholar 

  38. Johns, E. J. An investigation into the type of β-adrenoceptor mediating sympathetically activated renin release in the cat. Br. J. Pharmacol. 73, 749–754 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Persson, P. B. Renin: origin, secretion and synthesis. J. Physiol. 552, 667–671 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Mahfoud, F. et al. Changes in plasma renin activity after renal artery sympathetic denervation. J. Am. Coll. Cardiol. 77, 2909–2919 (2021).

    CAS  PubMed  Google Scholar 

  41. Cheng, X. et al. Anatomical evidence for parasympathetic innervation of the renal vasculature and pelvis. J. Am. Soc. Nephrol. 33, 2194–2210 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Niijima, A. Observation on the localization of mechanoreceptors in the kidney and afferent nerve fibres in the renal nerves in the rabbit. J. Physiol. 245, 81–90 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Knuepfer, M. M., Akeyson, E. W. & Schramm, L. P. Spinal projections of renal afferent nerves in the rat. Brain Res. 446, 17–25 (1988).

    CAS  PubMed  Google Scholar 

  44. Knuepfer, M. M. & Schramm, L. P. The conduction velocities and spinal projections of single renal afferent fibers in the rat. Brain Res. 435, 167–173 (1987).

    CAS  PubMed  Google Scholar 

  45. Ma, M. C., Huang, H. S., Wu, M. S., Chien, C. T. & Chen, C. F. Impaired renal sensory responses after renal ischemia in the rat. J. Am. Soc. Nephrol. 13, 1872–1883 (2002).

    PubMed  Google Scholar 

  46. Ammons, W. S. Spinoreticular cell responses to renal venous and ureteral occlusion. Am. J. Physiol. 254, R268–R276 (1988).

    CAS  PubMed  Google Scholar 

  47. Genovesi, S. et al. Renal afferents signaling diuretic activity in the cat. Circ. Res. 73, 906–913 (1993).

    CAS  PubMed  Google Scholar 

  48. Kopp, U. C., Smith, L. A. & Pence, A. L. Na+-K+-ATPase inhibition sensitizes renal mechanoreceptors activated by increases in renal pelvic pressure. Am. J. Physiol. 267, R1109–R1117 (1994).

    CAS  PubMed  Google Scholar 

  49. Moss, N. G. Electrophysiology of afferent renal nerves. Fed. Proc. 44, 2828–2833 (1985).

    CAS  PubMed  Google Scholar 

  50. Katholi, R. E., Whitlow, P. L., Hageman, G. R. & Woods, W. T. Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog. J. Hypertens. 2, 349–359 (1984).

    CAS  PubMed  Google Scholar 

  51. Smits, J. F. & Brody, M. J. Activation of afferent renal nerves by intrarenal bradykinin in conscious rats. Am. J. Physiol. 247, R1003–R1008 (1984).

    CAS  PubMed  Google Scholar 

  52. Kopp, U. C. et al. Activation of EP4 receptors contributes to prostaglandin E2-mediated stimulation of renal sensory nerves. Am. J. Physiol. Renal Physiol. 287, F1269–F1282 (2004).

    CAS  PubMed  Google Scholar 

  53. Zhu, Y., Xie, C. & Wang, D. H. TRPV1-mediated diuresis and natriuresis induced by hypertonic saline perfusion of the renal pelvis. Am. J. Nephrol. 27, 530–537 (2007).

    CAS  PubMed  Google Scholar 

  54. Goodwill, V. S., Terrill, C., Hopewood, I., Loewy, A. D. & Knuepfer, M. M. CNS sites activated by renal pelvic epithelial sodium channels (ENaCs) in response to hypertonic saline in awake rats. Auton. Neurosci. 204, 35–47 (2017).

    CAS  PubMed  Google Scholar 

  55. Ma, G. & Ho, S. Y. [Observation on the afferent nerve activity induced by stimulation of renal receptors in the rabbits]. Sheng Li Xue Bao 42, 269–276 (1990).

    CAS  PubMed  Google Scholar 

  56. Gabow, P. A. Autosomal dominant polycystic kidney disease–more than a renal disease. Am. J. Kidney Dis. 16, 403–413 (1990).

    CAS  PubMed  Google Scholar 

  57. Lugo-Gavidia, L. M. et al. Interventional approaches for loin pain hematuria syndrome and kidney-related pain syndromes. Curr. Hypertens. Rep. 22, 103 (2020).

    PubMed  Google Scholar 

  58. Prasad, B., Giebel, S., Garcia, F., Goyal, K. & St Onge, J. R. Renal denervation in patients with loin pain hematuria syndrome. Am. J. Kidney Dis. 69, 156–159 (2017).

    PubMed  Google Scholar 

  59. de Jager, R. L. et al. Catheter-based renal denervation as therapy for chronic severe kidney-related pain. Nephrol. Dial. Transpl. 33, 614–619 (2018).

    Google Scholar 

  60. Casteleijn, N. F., de Jager, R. L., Neeleman, M. P., Blankestijn, P. J. & Gansevoort, R. T. Chronic kidney pain in autosomal dominant polycystic kidney disease: a case report of successful treatment by catheter-based renal denervation. Am. J. Kidney Dis. 63, 1019–1021 (2014).

    PubMed  Google Scholar 

  61. Reed, A., Cho, D., Gillcrist, N. & Allam, C. Laparoscopic renal denervation for chronic renal colic in a previous stone forming patient. Urol. Case Rep. 19, 13–15 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. Rossi, N. F., Pajewski, R., Chen, H., Littrup, P. J. & Maliszewska-Scislo, M. Hemodynamic and neural responses to renal denervation of the nerve to the clipped kidney by cryoablation in two-kidney, one-clip hypertensive rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310, R197–R208 (2016).

    PubMed  Google Scholar 

  63. Biffi, A. 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 80, 659–667 (2023).

    CAS  PubMed  Google Scholar 

  64. Scalise, F. et al. Renal denervation in patients with end-stage renal disease and resistant hypertension on long-term haemodialysis. J. Hypertens. 38, 936–942 (2020).

    CAS  PubMed  Google Scholar 

  65. Kiuchi, M. G. et al. Sympathetic activation in hypertensive chronic kidney disease-a stimulus for cardiac arrhythmias and sudden cardiac death? Front. Physiol. 10, 1546 (2019).

    PubMed  Google Scholar 

  66. Yaxley, J. P. & Thambar, S. V. Resistant hypertension: an approach to management in primary care. J. Fam. Med. Prim. Care 4, 193–199 (2015).

    Google Scholar 

  67. Berra, E. et al. Evaluation of adherence should become an integral part of assessment of patients with apparently treatment-resistant hypertension. Hypertension 68, 297–306 (2016).

    CAS  PubMed  Google Scholar 

  68. Kottke, F. J., Kubicek, W. G. & Visscher, M. B. The production of arterial hypertension by chronic renal artery-nerve stimulation. Am. J. Physiol. 145, 38–47 (1945).

    CAS  PubMed  Google Scholar 

  69. Asirvatham-Jeyaraj, N. et al. Renal denervation and celiac ganglionectomy decrease mean arterial pressure similarly in genetically hypertensive schlager (BPH/2J) mice. Hypertension 77, 519–528 (2021).

    CAS  PubMed  Google Scholar 

  70. Jacob, F., Clark, L. A., Guzman, P. A. & Osborn, J. W. Role of renal nerves in development of hypertension in DOCA-salt model in rats: a telemetric approach. Am. J. Physiol. Heart Circ. Physiol. 289, H1519–H1529 (2005).

    CAS  PubMed  Google Scholar 

  71. Singh, R. R. 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 73, 718–727 (2019).

    CAS  PubMed  Google Scholar 

  72. Xiao, L. et al. Renal denervation prevents immune cell activation and renal inflammation in angiotensin II-induced hypertension. Circ. Res. 117, 547–557 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Banek, C. T., Gauthier, M. M., Van Helden, D. A., Fink, G. D. & Osborn, J. W. Renal inflammation in DOCA-salt hypertension. Hypertension 73, 1079–1086 (2019).

    CAS  PubMed  Google Scholar 

  74. Katsurada, K., Ogoyama, Y., Imai, Y., Patel, K. P. & Kario, K. Renal denervation based on experimental rationale. Hypertens. Res. 44, 1385–1394 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Calzavacca, P. et al. Effects of selective beta1-adrenoceptor blockade on cardiovascular and renal function and circulating cytokines in ovine hyperdynamic sepsis. Crit. Care 18, 610 (2014).

    PubMed  PubMed Central  Google Scholar 

  76. Banek, C. T. et al. Targeted afferent renal denervation reduces arterial pressure but not renal inflammation in established DOCA-salt hypertension in the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 314, R883–R891 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Foss, J. D., Fink, G. D. & Osborn, J. W. Differential role of afferent and efferent renal nerves in the maintenance of early- and late-phase Dahl S hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310, R262–R267 (2016).

    PubMed  Google Scholar 

  78. Ikeda, S. et al. Contribution of afferent renal nerve signals to acute and chronic blood pressure regulation in stroke-prone spontaneously hypertensive rats. Hypertens. Res. 46, 268–279 (2023).

    CAS  PubMed  Google Scholar 

  79. Saxena, M. et al. Predictors of blood pressure response to ultrasound renal denervation in the RADIANCE-HTN SOLO study. J. Hum. Hypertens. 36, 629–639 (2022).

    PubMed  Google Scholar 

  80. Townsend, R. R. & Sobotka, P. A. Catheter-based renal denervation for hypertension. Curr. Hypertens. Rep. 20, 93 (2018).

    PubMed  Google Scholar 

  81. Ukena, C., Cremers, B., Ewen, S., Bohm, M. & Mahfoud, F. Response and non-response to renal denervation: who is the ideal candidate? EuroIntervention 9, Suppl. R, R54–R57 (2013).

    PubMed  Google Scholar 

  82. Burlacu, A. et al. Predicting renal denervation response in resistant high blood pressure by arterial stiffness assessment: a systematic review. J. Clin. Med. 11, 4837 (2022).

    PubMed  PubMed Central  Google Scholar 

  83. Alsheikh, A. J. et al. CCL2 mediates early renal leukocyte infiltration during salt-sensitive hypertension. Am. J. Physiol. Renal Physiol. 318, F982–F993 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Baumann, D., Van Helden, D., Evans, L. & Osborn, J. IL-1R mediated renal sensory nerve activity drives hypertension in the DOCA-Salt mouse. Physiology 38, 1811–1821 (2023).

    Google Scholar 

  85. Drawz, P., Baumann, D. & Dayton, A. Renal denervation: recent developments in clinical and preclinical research. Curr. Opin. Nephrol. Hypertens. 32, 404–411 (2023).

    PubMed  Google Scholar 

  86. Ahmad, Y., Francis, D. P., Bhatt, D. L. & Howard, J. P. Renal denervation for hypertension: a systematic review and meta-analysis of randomized, blinded, placebo-controlled trials. JACC Cardiovasc. Interv. 14, 2614–2624 (2021).

    PubMed  Google Scholar 

  87. Azizi, M. 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 397, 2476–2486 (2021).

    CAS  PubMed  Google Scholar 

  88. Azizi, M. et al. Endovascular ultrasound renal denervation to treat hypertension: the radiance ii randomized clinical trial. JAMA 329, 651–661 (2023).

    PubMed  PubMed Central  Google Scholar 

  89. Bohm, M. 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 395, 1444–1451 (2020).

    PubMed  Google Scholar 

  90. Kandzari, D. E. et al. Safety and efficacy of renal denervation in patients taking antihypertensive medications. J. Am. Coll. Cardiol. 82, 1809–1823 (2023).

    CAS  PubMed  Google Scholar 

  91. Townsend, R. R. et al. Impact of antihypertensive medication changes after renal denervation among different patient groups: SPYRAL HTN-ON MED. Hypertension 81, 1095–1105 (2024).

    CAS  PubMed  Google Scholar 

  92. Ogoyama, Y. 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. 45, 210–220 (2022).

    PubMed  Google Scholar 

  93. Bohm, M. et al. Ambulatory heart rate reduction after catheter-based renal denervation in hypertensive patients not receiving anti-hypertensive medications: data from SPYRAL HTN-OFF MED, a randomized, sham-controlled, proof-of-concept trial. Eur. Heart J. 40, 743–751 (2019).

    PubMed  Google Scholar 

  94. Sata, Y. et al. Ambulatory arterial stiffness index as a predictor of blood pressure response to renal denervation. J. Hypertens. 36, 1414–1422 (2018).

    CAS  PubMed  Google Scholar 

  95. Fengler, K. et al. Assessment of arterial stiffness to predict blood pressure response to renal sympathetic denervation. EuroIntervention 18, e686–e694 (2022).

    PubMed  PubMed Central  Google Scholar 

  96. Protogerou, A., Blacher, J., Stergiou, G. S., Achimastos, A. & Safar, M. E. Blood pressure response under chronic antihypertensive drug therapy: the role of aortic stiffness in the REASON (Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind) study. J. Am. Coll. Cardiol. 53, 445–451 (2009).

    CAS  PubMed  Google Scholar 

  97. Rea, F., Morabito, G., Savare, L., Corrao, G. & Mancia, G. The impact of renal denervation procedure on use of antihypertensive drugs in the real-life setting. Blood Press. 31, 245–253 (2022).

    CAS  PubMed  Google Scholar 

  98. Sesa-Ashton, G. et al. Catheter-based renal denervation: 9-year follow-up data on safety and blood pressure reduction in patients with resistant hypertension. Hypertension 80, 811–819 (2023).

    CAS  PubMed  Google Scholar 

  99. Warchol-Celinska, E. et al. Renal denervation in resistant hypertension and obstructive sleep apnea: randomized proof-of-concept phase II trial. Hypertension 72, 381–390 (2018).

    CAS  PubMed  Google Scholar 

  100. Witkowski, A. et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 58, 559–565 (2011).

    CAS  PubMed  Google Scholar 

  101. Zhao, M. M., Tan, X. X., Ding, N. & Zhang, X. L. [Comparison of efficacy between continuous positive airway pressure and renal artery sympathetic denervation by radiofrequency ablation in obstructive sleep apnea syndrome patients with hypertension]. Zhonghua Yi Xue Za Zhi 93, 1234–1237 (2013).

    PubMed  Google Scholar 

  102. Venkataraman, S., Vungarala, S., Covassin, N. & Somers, V. K. Sleep apnea, hypertension and the sympathetic nervous system in the adult population. J. Clin. Med. 9, 591 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Thomas, G. et al. Prevalence and prognostic significance of apparent treatment resistant hypertension in chronic kidney disease: report from the chronic renal insufficiency cohort study. Hypertension 67, 387–396 (2016).

    CAS  PubMed  Google Scholar 

  104. Kaur, J., Young, B. E. & Fadel, P. J. Sympathetic overactivity in chronic kidney disease: consequences and mechanisms. Int. J. Mol. Sci. 18, 1682 (2017).

    PubMed  PubMed Central  Google Scholar 

  105. Grassi, G. et al. Early sympathetic activation in the initial clinical stages of chronic renal failure. Hypertension 57, 846–851 (2011).

    CAS  PubMed  Google Scholar 

  106. Converse, R. L. Jr et al. Sympathetic overactivity in patients with chronic renal failure. N. Engl. J. Med. 327, 1912–1918 (1992).

    PubMed  Google Scholar 

  107. Hausberg, M. et al. Sympathetic nerve activity in end-stage renal disease. Circulation 106, 1974–1979 (2002).

    PubMed  Google Scholar 

  108. Koomans, H. A., Geers, A. B., Boer, P. & Dorhout Mees, E. J. Plasma volumes, noradrenaline levels and renin activity during posture changes in end-stage renal failure. Clin. Physiol. 4, 103–115 (1984).

    CAS  PubMed  Google Scholar 

  109. Mauriello, A. et al. Increased sympathetic renal innervation in hemodialysis patients is the anatomical substrate of sympathetic hyperactivity in end-stage renal disease. J. Am. Heart Assoc. 4, e002426 (2015).

    PubMed  PubMed Central  Google Scholar 

  110. Singh, R. R. et al. Increase in bioavailability of nitric oxide after renal denervation improves kidney function in sheep with hypertensive kidney disease. Hypertension 77, 1299–1310 (2021).

    CAS  PubMed  Google Scholar 

  111. Singh, R. R. et al. Catheter-based renal denervation exacerbates blood pressure fall during hemorrhage. J. Am. Coll. Cardiol. 69, 951–964 (2017).

    PubMed  Google Scholar 

  112. Reddy, Y. S. et al. Nitric oxide status in patients with chronic kidney disease. Indian J. Nephrol. 25, 287–291 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Schmidt, R. J. et al. Indices of activity of the nitric oxide system in hemodialysis patients. Am. J. Kidney Dis. 34, 228–234 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Ott, C. et al. Renal denervation in patients with versus without chronic kidney disease: results from the Global SYMPLICITY Registry with follow-up data of 3 years. Nephrol. Dial. Transpl. 37, 304–310 (2022).

    Google Scholar 

  115. Hering, D. et al. Effect of renal denervation on kidney function in patients with chronic kidney disease. Int. J. Cardiol. 232, 93–97 (2017).

    PubMed  Google Scholar 

  116. Heerspink, H. J., Kropelin, T. F., Hoekman, J. & de Zeeuw, D. Drug-induced reduction in albuminuria is associated with subsequent renoprotection: a meta-analysis. J. Am. Soc. Nephrol. 26, 2055–2064 (2015).

    CAS  PubMed  Google Scholar 

  117. Ott, C. et al. Improvement of albuminuria after renal denervation. Int. J. Cardiol. 173, 311–315 (2014).

    PubMed  Google Scholar 

  118. Kiuchi, M. G. et al. Long-term effects of renal sympathetic denervation on hypertensive patients with mild to moderate chronic kidney disease. J. Clin. Hypertens. 18, 190–196 (2016).

    Google Scholar 

  119. Schmieder, R. E. Renal denervation in patients with chronic kidney disease: current evidence and future perspectives. Nephrol. Dial. Transpl. 38, 1089–1096 (2023).

    CAS  Google Scholar 

  120. Di Daniele, N., De Francesco, M., Violo, L., Spinelli, A. & Simonetti, G. Renal sympathetic nerve ablation for the treatment of difficult-to-control or refractory hypertension in a haemodialysis patient. Nephrol. Dial. Transpl. 27, 1689–1690 (2012).

    Google Scholar 

  121. Hering, D. et al. Renal denervation in moderate to severe CKD. J. Am. Soc. Nephrol. 23, 1250–1257 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04264403 (2023).

  123. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05198674 (2024).

  124. Borovac, J. A., D’Amario, D., Bozic, J. & Glavas, D. Sympathetic nervous system activation and heart failure: current state of evidence and the pathophysiology in the light of novel biomarkers. World J. Cardiol. 12, 373–408 (2020).

    PubMed  PubMed Central  Google Scholar 

  125. Sica, D. A. Sodium and water retention in heart failure and diuretic therapy: basic mechanisms. Cleve. Clin. J. Med. 73, S2–S7 (2006). discussion S30–S33.

    PubMed  Google Scholar 

  126. Ghionzoli, N. et al. Current and emerging drug targets in heart failure treatment. Heart Fail. Rev. 27, 1119–1136 (2022).

    PubMed  Google Scholar 

  127. Gronda, E. et al. Sympathetic activation in heart failure(). Eur. Heart J. Suppl. 24, E4–E11 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Farzam, K. & Jan, A. Beta blockers. StatPearls (2024).

  129. Goyal, A., Cusick, A. S. & Thielemier, B. ACE inhhibitors. StatPearls (2024).

  130. Zheng, H., Liu, X., Sharma, N. M. & Patel, K. P. Renal denervation improves cardiac function in rats with chronic heart failure: effects on expression of beta-adrenoceptors. Am. J. Physiol. Heart Circ. Physiol. 311, H337–H346 (2016).

    PubMed  PubMed Central  Google Scholar 

  131. Polhemus, D. J. et al. Radiofrequency renal denervation protects the ischemic heart via inhibition of GRK2 and increased nitric oxide signaling. Circ. Res. 119, 470–480 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sharp, T. E. 3rd et al. Renal denervation prevents heart failure progression via inhibition of the renin-angiotensin system. J. Am. Coll. Cardiol. 72, 2609–2621 (2018).

    PubMed  Google Scholar 

  133. Wang, L. et al. Renal denervation improves cardiac function by attenuating myocardiocyte apoptosis in dogs after myocardial infarction. BMC Cardiovasc. Disord. 18, 86 (2018).

    PubMed  PubMed Central  Google Scholar 

  134. Polhemus, D. J. et al. Renal sympathetic denervation protects the failing heart via inhibition of neprilysin activity in the kidney. J. Am. Coll. Cardiol. 70, 2139–2153 (2017).

    PubMed  Google Scholar 

  135. DiBona, G. F., Herman, P. J. & Sawin, L. L. Neural control of renal function in edema-forming states. Am. J. Physiol. 254, R1017–R1024 (1988).

    CAS  PubMed  Google Scholar 

  136. DiBona, G. F. & Sawin, L. L. Role of renal nerves in sodium retention of cirrhosis and congestive heart failure. Am. J. Physiol. 260, R298–R305 (1991).

    CAS  PubMed  Google Scholar 

  137. Roh, J., Hill, J. A., Singh, A., Valero-Munoz, M. & Sam, F. Heart failure with preserved ejection fraction: heterogeneous syndrome, diverse preclinical models. Circ. Res. 130, 1906–1925 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Noll, N. A., Lal, H. & Merryman, W. D. Mouse models of heart failure with preserved or reduced ejection fraction. Am. J. Pathol. 190, 1596–1608 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Valero-Munoz, M., Backman, W. & Sam, F. Murine models of heart failure with preserved ejection fraction: a “Fishing Expedition”. JACC Basic Transl. Sci. 2, 770–789 (2017).

    PubMed  PubMed Central  Google Scholar 

  140. Weber, M. A. et al. Renal denervation for treating hypertension: current scientific and clinical evidence. JACC Cardiovasc. Interv. 12, 1095–1105 (2019).

    PubMed  Google Scholar 

  141. Nawar, K., Mohammad, A., Johns, E. J. & Abdulla, M. H. Renal denervation for atrial fibrillation: a comprehensive updated systematic review and meta-analysis. J. Hum. Hypertens. 36, 887–897 (2022).

    PubMed  PubMed Central  Google Scholar 

  142. Henegar, J. R. et al. Catheter-based radiorefrequency renal denervation lowers blood pressure in obese hypertensive dogs. Am. J. Hypertens. 27, 1285–1292 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Pan, T., Guo, J. H. & Teng, G. J. Renal denervation: a potential novel treatment for type 2 diabetes mellitus. Medicine 94, e1932 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Davies, J. E. et al. First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int. J. Cardiol. 162, 189–192 (2013).

    PubMed  Google Scholar 

  145. Chen, W. et al. Preliminary effects of renal denervation with saline irrigated catheter on cardiac systolic function in patients with heart failure: a prospective, randomized, controlled, pilot study. Catheter Cardiovasc. Interv. 89, E153–E161 (2017).

    PubMed  Google Scholar 

  146. Li, M. et al. Renal denervation in management of heart failure with reduced ejection fraction: a systematic review and meta-analysis. J. Cardiol. 81, 513–521 (2023).

    PubMed  Google Scholar 

  147. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04947670 (2022).

  148. Brandt, M. C. et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J. Am. Coll. Cardiol. 59, 901–909 (2012).

    PubMed  Google Scholar 

  149. Mahfoud, F. et al. Effect of renal denervation on left ventricular mass and function in patients with resistant hypertension: data from a multi-centre cardiovascular magnetic resonance imaging trial. Eur. Heart J. 35, 2224–2231b (2014).

    PubMed  Google Scholar 

  150. Kresoja, K. P. et al. Renal sympathetic denervation in patients with heart failure with preserved ejection fraction. Circ. Heart Fail. 14, e007421 (2021).

    CAS  PubMed  Google Scholar 

  151. Bazoukis, G. et al. Impact of renal sympathetic denervation on cardiac magnetic resonance-derived cardiac indices in hypertensive patients — a meta-analysis. J. Cardiol. 78, 314–321 (2021).

    PubMed  Google Scholar 

  152. Shiraki, T. et al. Cardiac sympathetic nerve activity trends after renal denervation in heart failure with preserved ejection fraction. ESC Heart Fail. 11, 2426–2431 (2024).

    PubMed  PubMed Central  Google Scholar 

  153. Patel, H. C. et al. Renal denervation in heart failure with preserved ejection fraction (RDT-PEF): a randomized controlled trial. Eur. J. Heart Fail. 18, 703–712 (2016).

    CAS  PubMed  Google Scholar 

  154. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05030987 (2024).

  155. Khan, A. A., Lip, G. Y. H. & Shantsila, A. Heart rate variability in atrial fibrillation: the balance between sympathetic and parasympathetic nervous system. Eur. J. Clin. Invest. 49, e13174 (2019).

    PubMed  Google Scholar 

  156. Shen, M. J. & Zipes, D. P. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ. Res. 114, 1004–1021 (2014).

    CAS  PubMed  Google Scholar 

  157. Tsai, W. C. et al. Autonomic modulation of atrial fibrillation. JACC Basic Transl. Sci. 8, 1398–1410 (2023).

    PubMed  PubMed Central  Google Scholar 

  158. Fazio, G. et al. Sympathetic tone and ventricular tachycardia. J. Cardiovasc. Med. 9, 963–966 (2008).

    Google Scholar 

  159. Carnagarin, R., Kiuchi, M. G., Ho, J. K., Matthews, V. B. & Schlaich, M. P. Sympathetic nervous system activation and its modulation: role in atrial fibrillation. Front. Neurosci. 12, 1058 (2018).

    PubMed  Google Scholar 

  160. Tsai, W. C. et al. Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs. Heart Rhythm 14, 255–262 (2017).

    PubMed  Google Scholar 

  161. Kwon, S. et al. Novel laparoscopic renal denervation immediately reduces atrial fibrillation inducibility: a swine model study. Sci. Rep. 13, 19679 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Zhang, W. H. et al. Renal denervation reduced ventricular arrhythmia after myocardial infarction by inhibiting sympathetic activity and remodeling. J. Am. Heart Assoc. 7, e009938 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Steinberg, J. S. et al. Effect of renal denervation and catheter ablation vs catheter ablation alone on atrial fibrillation recurrence among patients with paroxysmal atrial fibrillation and hypertension: the ERADICATE-AF randomized clinical trial. JAMA 323, 248–255 (2020).

    PubMed  PubMed Central  Google Scholar 

  164. Dzeshka, M. S., Shantsila, A., Shantsila, E. & Lip, G. Y. H. Atrial fibrillation and hypertension. Hypertension 70, 854–861 (2017).

    CAS  PubMed  Google Scholar 

  165. Parkash, R. et al. Effect of aggressive blood pressure control on the recurrence of atrial fibrillation after catheter ablation: a randomized, open-label clinical trial (SMAC-AF [Substrate Modification With Aggressive Blood Pressure Control]). Circulation 135, 1788–1798 (2017).

    CAS  PubMed  Google Scholar 

  166. Kiuchi, M. G., Chen, S., Paz, L. M. R. & Purerfellner, H. Renal sympathetic denervation guided by renal nerve stimulation to treat ventricular arrhythmia in CKD patients with ICD. Oncotarget 8, 37296–37307 (2017).

    PubMed  PubMed Central  Google Scholar 

  167. Evranos, B. et al. Role of adjuvant renal sympathetic denervation in the treatment of ventricular arrhythmias. Am. J. Cardiol. 118, 1207–1210 (2016).

    PubMed  Google Scholar 

  168. Simon, O. R. & Schramm, L. P. The spinal course and medullary termination of myelinated renal afferents in the rat. Brain Res. 290, 239–247 (1984).

    CAS  PubMed  Google Scholar 

  169. Kopp, U. C., Cicha, M. Z., Smith, L. A., Mulder, J. & Hokfelt, T. Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2-dependent activation of α1- and α2-adrenoceptors on renal sensory nerve fibers. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1561–R1572 (2007).

    CAS  PubMed  Google Scholar 

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Acknowledgements

L.C.E.’s work is funded by grant R01HL152166. A.D.’s work is funded by grant T32HL144472. J.W.O.’s work is funded by grant U54AT012307.

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  1. These authors contributed equally: Louise C. Evans, Alex Dayton.

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  1. Department of Surgery, University of Minnesota, Minneapolis, MN, USA

    Louise C. Evans & John W. Osborn

  2. Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN, USA

    Alex Dayton

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J.W.O. is a consultant for ReCor Medical, which developed the Paradise ultrasound renal denervation system. The other authors declare no competing interests.

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Evans, L.C., Dayton, A. & Osborn, J.W. Renal nerves in physiology, pathophysiology and interoception. Nat Rev Nephrol 21, 57–69 (2025). https://doi.org/10.1038/s41581-024-00893-3

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