BACKGROUND: Renal denervation (RDN) is a promising therapeutic method in cardiology. Its currently most investigated indication is resistant hypertension. Other potential indications are atrial fibrillation, type 2 diabetes mellitus and chronic renal insufficiency among others. Previous trials showed conflicting but promising results, but the real benefits of RDN are still under investigation. Patients with renal insufficiency and resistant hypertension are proposed to be a good target for this therapy due to excessive activation of renal sympathetic drive. However, only limited number of studies showed benefits for these patients. We hypothesize that in our experimental model of chronic kidney disease (CKD) due to ischemia with increased activity of the renin-angiotensin-aldosterone system (RAAS), renal denervation can have protective effects by slowing or blocking the progression of renal injury. METHODS: An experimental biomodel of chronic renal insufficiency induced by ischemia was developed using selective renal artery embolization (remnant kidney porcine model). 27 biomodels were assessed. Renal denervation was performed in 19 biomodels (denervated group), and the remaining were used as controls (n = 8). The extent of renal injury and reparative process between the two groups were compared and assessed using biochemical parameters and histological findings. RESULTS: Viable remnant kidney biomodels were achieved and maintained in 27 swine. There were no significant differences in biochemical parameters between the two groups at baseline. Histological assessment proved successful RDN procedure in all biomodels in the denervated group. Over the 7-week period, there were significant increases in serum urea, creatinine, and aldosterone concentration in both groups. The difference in urea and creatinine levels were not statistically significant between the two groups. However, the level of aldosterone in the denervated was significantly lower in comparison to the controls. Histological assessment of renal arteries showed that RDN tends to produce more damage to the arterial wall in comparison to vessels in subjects that only underwent RAE. In addition, the morphological damage of kidneys, which was expressed as a ratio of damaged surface (or scar) to the overall surface of kidney, also did not show significant difference between groups. CONCLUSIONS: In this study, we were not able to show significant protective effect of RDN alone on ischemic renal parenchymal damage by either laboratory or histological assessments. However, the change in aldosterone level shows some effect of renal denervation on the RAAS system. We hypothesize that a combined blockade of the RAAS and the sympathetic system could provide more protective effects against acute ischemia. This has to be further investigated in future studies.

2nd Department of Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague U Nemocnice 2 128 00 Prague 2 Czech Republic

Department of Cardiology Na Homolce Hospital Roentgenova 2 37 150 30 Prague 5 Czech Republic

Institute of Physiology 1st Faculty of Medicine Charles University Prague Albertov 5 128 00 Prague 2 Czech Republic

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Members Task Force. Mancia G, Fagard R, Narkiewicz K, et al. ESH/ESC guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) J Hypertens. 2013;2013(31):1281–1357. PubMed

Sarganas G, Neuhauser HK. Untreated, Uncontrolled, and apparent resistant hypertension: results of the German health examination survey 2008–2011. J Clin Hypertens. 2016;18:1146–1154. doi: 10.1111/jch.12886. PubMed DOI PMC

Doumas M, Faselis C, Papademetriou V. Renal sympathetic denervation and systemic hypertension. Am J Cardiol. 2010;105(4):570–576. doi: 10.1016/j.amjcard.2009.10.027. PubMed DOI

Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275–1281. doi: 10.1016/S0140-6736(09)60566-3. PubMed DOI

Symplicity HTN-2 Investigators. 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):1903–1909. doi: 10.1016/S0140-6736(10)62039-9. PubMed DOI

Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125:1635–1642. doi: 10.1161/CIRCULATIONAHA.111.068064. PubMed DOI PMC

Persu A, Jin Y, Azizi M, et al. Blood pressure changes after renal denervation at 10 European expert centers. J Hum Hypertens. 2014;28:150–156. doi: 10.1038/jhh.2013.88. PubMed DOI PMC

Bhatt DL, Kandzari DE, O’Neill WW, et al. SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393–1401. doi: 10.1056/NEJMoa1402670. PubMed DOI

Mathiassen ON, Vase H, Bech JN, et al. Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial. J Hypertens. 2016;34:1639–1647. doi: 10.1097/HJH.0000000000000977. PubMed DOI PMC

Desch S, Okon T, Heinemann D, et al. Randomized SHAM-controlled trial of renal sympathetic denervation in mild resistant hypertension novelty and significance. Hypertension. 2015;65:1202–1208. doi: 10.1161/HYPERTENSIONAHA.115.05283. PubMed DOI

Martinez-Maldonado M. Role of hypertension in the progression of chronic renal disease. Nephrol Dial Transpl. 2001;16(Suppl 1):63–66. doi: 10.1093/ndt/16.suppl_1.63. PubMed DOI

Misra S, Gordon JD, Fu AA, Glockner JF, Chade AR, Mandrekar J, Lerman L, Mukhopadhyay D. The porcine remnant kidney model of chronic renal insufficiency. J Surg Res. 2006;135(2):370–379. doi: 10.1016/j.jss.2006.04.001. PubMed DOI

McGlone JJ, Swanson J. Update on the guide for the care and use of agricultural animals in research and teaching. J Dairy Sci. 2010;93:12–12. doi: 10.3168/jds.2009-2244. PubMed DOI

Lubanda JC, Kudlicka J, Mlcek M, Chochola M, Neuzil P, Linhart A, Kittnar O. Renal denervation decreases effective refractory period but not inducibility of ventricular fibrillation in a healthy porcine biomodel: a case control study. J Transl Med. 2015;16(13):4. doi: 10.1186/s12967-014-0367-y. PubMed DOI PMC

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(12):1095–1101. doi: 10.1007/s00392-011-0346-8. PubMed DOI

Hering D, Mahfoud F, Walton AS, Krum H, Lambert GW, Lambert EA, et al. Renal denervation in moderate to severe CKD. J Am Soc Nephrol. 2012;23:1250–1257. doi: 10.1681/ASN.2011111062. PubMed DOI PMC

Sanders MF, Blankestijn PJ. Chronic kidney disease as a potential indication for renal denervation. Front Physiol. 2016;8(7):220. PubMed PMC

Converse RL, Jr, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F, Victor RG. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992;327:1912–1918. doi: 10.1056/NEJM199212313272704. PubMed DOI

Klein IE, 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;12:2427–2433. PubMed

Zoccali C, Mallamaci F, Parlongo S, Cutrupi S, Benedetto FA, Tripepi G, et al. Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation. 2002;105:1354–1359. doi: 10.1161/hc1102.105261. PubMed DOI

Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Parlongo S, Cutrupi S, et al. Prospective study of neuropeptide y as an adverse cardiovascular risk factor in end-stage renal disease. J Am Soc Nephrol. 2003;14:2611–2617. doi: 10.1097/01.ASN.0000089026.28617.33. PubMed DOI

Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, Kisters K, Dietl KH, Rahn KH. Sympathetic nerve activity in end-stage renal disease. Circulation. 2002;106:1974–1999. doi: 10.1161/01.CIR.0000034043.16664.96. PubMed DOI

Neumann J, Ligtenberg G, Klein IE, Boer P, Oey PL, Koomans HA, Blankestijn PJ. Sympathetic hyperactivity in hypertensive chronic kidney disease patients is reduced during standard treatment. Hypertension. 2007;49:506–510. doi: 10.1161/01.HYP.0000256530.39695.a3. PubMed DOI

Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol. 2010;56:1254–1258. doi: 10.1016/j.jacc.2010.03.089. PubMed DOI

Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol. 2011;58:765–773. doi: 10.1016/j.jacc.2011.06.008. PubMed DOI

Hoppe UC, Brandt M-C, Wachter R, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial. J Am Soc Hypertens. 2012;6:270–276. doi: 10.1016/j.jash.2012.04.004. PubMed DOI

Wallbach M, Lehnig L-Y, Schroer C, et al. Effects of baroreflex activation therapy on ambulatory blood pressure in patients with resistant hypertension novelty and significance. Hypertension. 2016;67:701–709. doi: 10.1161/HYPERTENSIONAHA.115.06717. PubMed DOI

Lobo MD, Sobotka PA, Stanton A, et al. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial. Lancet. 2015;385:1634–1641. doi: 10.1016/S0140-6736(14)62053-5. PubMed DOI

Veelken R, Schmieder RE. Renal denervation-implications for chronic kidney disease. Nat Rev Nephrol. 2014;10(6):305–313. doi: 10.1038/nrneph.2014.59. PubMed DOI