Preclinical Model and Histopathology Translational Medicine and Renal Denervation

  • Kenichi Sakakura
  • Elena Ladich
  • Fumiyuki Otsuka
  • Kazuyuki Yahagi
  • Frank D. Kolodgie
  • Michael Joner
  • Renu Virmani


The prevalence of resistant hypertension, which is defined as failure to achieve control of blood pressure (BP) (<140/90) despite treatment with optimal doses of three or more antihypertensive medications (including diuretics), is as high as 12–15 % of all hypertensive patients. Renal sympathetic denervation is a new treatment option for resistant hypertension. Catheter-radiofrequency renal denervation has demonstrated its efficacy and safety in the SYMPLICITY I, SYMPLICITY II and EnligHTN trials. However, there are still many unanswered questions in this field, and preclinical studies using animal models may help researchers and clinicians to find answers to those questions. Generally, larger animals such as pig, dog, or sheep are needed for the preclinical study. The swine model is frequently used for the preclinical study, since the anatomy of renovascular system is similar to that of humans. A semi-quantitative ordinal grading system is useful, when the changes of nerves, renal artery, and peri-arterial soft tissue induced by renal denervation are evaluated.


Renal Artery Resistant Hypertension Renal Denervation Renal Nerve Nerve Fascicle 


  1. 1.
    Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–23.PubMedCrossRefGoogle Scholar
  2. 2.
    Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–72.PubMedCrossRefGoogle Scholar
  3. 3.
    Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–13.PubMedCrossRefGoogle Scholar
  4. 4.
    Gu Q, Burt VL, Dillon CF, Yoon S. Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: the National Health and Nutrition Examination Survey, 2001 to 2010. Circulation. 2012;126:2105–14.PubMedCrossRefGoogle Scholar
  5. 5.
    James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–20.PubMedCrossRefGoogle Scholar
  6. 6.
    Grassi G, Mancia G. New therapeutic approaches for resistant hypertension. J Nephrol. 2012;25:276–81.PubMedCrossRefGoogle Scholar
  7. 7.
    Sarafidis PA. Epidemiology of resistant hypertension. J Clin Hypertens (Greenwich). 2011;13:523–8.CrossRefGoogle Scholar
  8. 8.
    Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51:1403–19.PubMedCrossRefGoogle Scholar
  9. 9.
    Worthley SG, Tsioufis CP, Worthley MI, et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J. 2013;34:2132–40.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Krum H, Schlaich MP, Bohm M, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet. 2014;383:622–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Ahmed H, Neuzil P, Skoda J, et al. Renal sympathetic denervation using an irrigated radiofrequency ablation catheter for the management of drug-resistant hypertension. JACC Cardiovasc Interv. 2012;5:758–65.PubMedCrossRefGoogle Scholar
  14. 14.
    Wang Q, Guo R, Rong S, et al. Noninvasive renal sympathetic denervation by extracorporeal high-intensity focused ultrasound in a preclinical canine model. J Am Coll Cardiol. 2013;61:2185–92.PubMedCrossRefGoogle Scholar
  15. 15.
    Fischell TA, Vega F, Raju N, et al. Ethanol-mediated perivascular renal sympathetic denervation: preclinical validation of safety and efficacy in a porcine model. EuroIntervention. 2013;9:140–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Rocha-singh K. Renal artery denervation: a brave new frontier. Endovasc Today. 2012; p. 45–53.Google Scholar
  17. 17.
    Medtronic. Renal denervation. Minneapolis: RDN Press Release; 2014.Google Scholar
  18. 18.
    Kandzari DE, Bhatt DL, Sobotka PA, et al. Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol. 2012;35:528–35.PubMedCrossRefGoogle Scholar
  19. 19.
    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:R675–82.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Nagasu H, Satoh M, Kuwabara A, et al. Renal denervation reduces glomerular injury by suppressing NAD(P)H oxidase activity in Dahl salt-sensitive rats. Nephrol Dial Transplant. 2010;25:2889–98.PubMedCrossRefGoogle Scholar
  21. 21.
    Girchev R, Markova P, Vuchidolova V. Influence of renal denervation on renal effects of acute nitric oxide and ETA/ETB receptor inhibition in conscious normotensive rats. J Physiol Pharmacol. 2006;57:17–27.PubMedGoogle Scholar
  22. 22.
    Rippy MK, Zarins D, Barman NC, Wu A, Duncan KL, Zarins CK. Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol. 2011;100:1095–101.PubMedCrossRefGoogle Scholar
  23. 23.
    Lerman LO, Schwartz RS, Grande JP, Sheedy PF, Romero JC. Noninvasive evaluation of a novel swine model of renal artery stenosis. J Am Soc Nephrol. 1999;10:1455–65.PubMedGoogle Scholar
  24. 24.
    Tellez A, Rousselle S, Palmieri T, et al. Renal artery nerve distribution and density in the porcine model: biologic implications for the development of radiofrequency ablation therapies. Transl Res. 2013;162:381–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Atherton DS, Deep NL, Mendelsohn FO. Micro-anatomy of the renal sympathetic nervous system: a human postmortem histologic study. Clin Anat. 2012;25:628–33.PubMedCrossRefGoogle Scholar
  26. 26.
    Sakakura K, Ladich E, Edelman ER et al. Methodological standardization for the preclinical evaluation of renal sympathetic denervation. JACC Cardiovasc Interv. 2014. doi: 10.1016/j.jcin.2014.04.024.
  27. 27.
    Whitney KM, Schwartz Sterman AJ, O’Connor J, Foley GL, Garman RH. Light microscopic sciatic nerve changes in control beagle dogs from toxicity studies. Toxicol Pathol. 2011;39:835–40.PubMedCrossRefGoogle Scholar
  28. 28.
    Biberthaler P, Mussack T, Wiedemann E, et al. Evaluation of S-100b as a specific marker for neuronal damage due to minor head trauma. World J Surg. 2001;25:93–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Pace V, Perentes E, Germann PG. Pheochromocytomas and ganglioneuromas in the aging rats: morphological and immunohistochemical characterization. Toxicol Pathol. 2002;30:492–500.PubMedCrossRefGoogle Scholar
  30. 30.
    Burgi K, Cavalleri MT, Alves AS, Britto LR, Antunes VR, Michelini LC. Tyrosine hydroxylase immunoreactivity as indicator of sympathetic activity: simultaneous evaluation in different tissues of hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2011;300:R264–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Ammar S, Ladich E, Steigerwald K, Deisenhofer I, Joner M. Pathophysiology of renal denervation procedures: from renal nerve anatomy to procedural parameters. EuroIntervention. 2013;9(Suppl R):R89–95.PubMedCrossRefGoogle Scholar
  32. 32.
    Wittkampf FH, Nakagawa H, Yamanashi WS, Imai S, Jackman WM. Thermal latency in radiofrequency ablation. Circulation. 1996;93:1083–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Steigerwald K, Titova A, Malle C, et al. Morphological assessment of renal arteries after radiofrequency catheter-based sympathetic denervation in a porcine model. J Hypertens. 2012;30:2230–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Skanes AC, Dubuc M, Klein GJ, et al. Cryothermal ablation of the slow pathway for the elimination of atrioventricular nodal reentrant tachycardia. Circulation. 2000;102:2856–60.PubMedCrossRefGoogle Scholar
  35. 35.
    Deisenhofer I, Zrenner B, Yin YH, et al. Cryoablation versus radiofrequency energy for the ablation of atrioventricular nodal reentrant tachycardia (the CYRANO Study): results from a large multicenter prospective randomized trial. Circulation. 2010;122:2239–45.PubMedCrossRefGoogle Scholar
  36. 36.
    Skanes AC, Klein G, Krahn A, Yee R. Cryoablation: potentials and pitfalls. J Cardiovasc Electrophysiol. 2004;15:S28–34.PubMedCrossRefGoogle Scholar
  37. 37.
    Prochnau D, Figulla HR, Romeike BF, et al. Percutaneous catheter-based cryoablation of the renal artery is effective for sympathetic denervation in a sheep model. Int J Cardiol. 2011;152:268–70.PubMedCrossRefGoogle Scholar
  38. 38.
    Mabin T, Sapoval M, Cabane V, Stemmett J, Iyer M. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention. 2012;8:57–61.PubMedCrossRefGoogle Scholar
  39. 39.
    Ng KK, Poon RT, Chan SC, et al. High-intensity focused ultrasound for hepatocellular carcinoma: a single-center experience. Ann Surg. 2011;253:981–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Kennedy JE. High-intensity focused ultrasound in the treatment of solid tumours. Nat Rev Cancer. 2005;5:321–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Illing RO, Kennedy JE, Wu F, et al. The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population. Br J Cancer. 2005;93:890–5.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Marsac L, Chauvet D, Larrat B, et al. MR-guided adaptive focusing of therapeutic ultrasound beams in the human head. Med Phys. 2012;39:1141–9.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Aptel F, Charrel T, Lafon C, et al. Miniaturized high-intensity focused ultrasound device in patients with glaucoma: a clinical pilot study. Invest Ophthalmol Vis Sci. 2011;52:8747–53.PubMedCrossRefGoogle Scholar
  44. 44.
    Waksman R, Barbash IM, Chan R, Randolph P, Makuria AT, Virmani R. Beta radiation for renal nerve denervation: initial feasibility and safety. EuroIntervention. 2013;9:738–44.PubMedCrossRefGoogle Scholar
  45. 45.
    Streitparth F, Walter A, Stolzenburg N, et al. MR-guided periarterial ethanol injection for renal sympathetic denervation: a feasibility study in pigs. Cardiovasc Intervent Radiol. 2013;36:791–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2015

Authors and Affiliations

  • Kenichi Sakakura
    • 1
  • Elena Ladich
    • 1
  • Fumiyuki Otsuka
    • 1
  • Kazuyuki Yahagi
    • 1
  • Frank D. Kolodgie
    • 1
  • Michael Joner
    • 1
  • Renu Virmani
    • 1
  1. 1.CVPath Institute, Inc.GaithersburgUSA

Personalised recommendations