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. 2023 Feb 6;18(13):e1120-e1128.
doi: 10.4244/EIJ-D-22-00369.

Translational value of preclinical models for renal denervation: a histological comparison of human versus porcine renal nerve anatomy

Yu Sato  1 , Andrew S P Sharp  2 , Felix Mahfoud  3 , Stefan Tunev  4 , Ashley Forster  1 , Matthew Ellis  1 , Ana Gomez  1 , Roma Dhingra  1 , Jeremy Ullman  1 , Markus Schlaich  5 , David Lee  6 , Julie Trudel  4 , Douglas A Hettrick  4 , David E Kandzari  7 , Renu Virmani  1 , Aloke V Finn  1   8
Affiliations

Translational value of preclinical models for renal denervation: a histological comparison of human versus porcine renal nerve anatomy

Yu Sato et al. EuroIntervention. .

Abstract

Background: Preclinical models have provided key insights into the response of local tissues to radiofrequency (RF) renal denervation (RDN) that is unobtainable from human studies. However, the anatomic translatability of these models to the procedure in humans is incompletely understood. Aims: We aimed to compare the renal arterial anatomy in normotensive pigs treated with RF-RDN to that of human cadavers to evaluate the suitability of normotensive pigs for determining the safety of RF-RDN.

Methods: Histopathologic analyses were performed on RF-treated renal arteries in a porcine model and untreated control renal arteries. Similar analyses were performed on untreated renal arteries from human cadavers. Results: In both human and porcine renal arteries, the median number of nerves was lower in the more distal sections (the numbers in the proximal, middle, distal, 1st bifurcation, and 2nd bifurcation sections were 65, 58, 47, 22.5, and 14.7 in humans, respectively, and 39, 26, 29, 16.5, and 9.3 in the porcine models, respectively). Renal nerves were common in the regions between arteries and adjacent veins, but only 3% and 13% of the renal nerves in humans and pigs, respectively, were located behind the renal vein. The semiquantitative score of RF-induced renal arterial nerve necrosis was significantly greater at 7 days than 28 days (0.98 vs 0.75; p=0.01), and injury to surrounding organs was rarely observed.

Conclusions: The distribution of nerve tissue and the relative distribution of extravascular anatomic structures along the renal artery was similar between humans and pigs, which validates the translational value of the normotensive porcine model for RDN.

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Conflict of interest statement

A. Sharp receives consulting fees/honoraria from Medtronic, Philips and ReCor Medical. F. Mahfoud is supported by Deutsche Gesellschaft für Kardiologie and Deutsche Forschungsgemeinschaft (SFB 219); and has received scientific support and/or speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic, Merck, and ReCor Medical. S. Tunev is a full-time employee of Medtronic. J. Trudel is a full-time employee of Medtronic. D.A. Hettrick is a full-time employee of Medtronic. M. Schlaich is supported by an NHMRC Senior Research Fellowship; and has received consulting fees and/or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer, and Boehringer Ingelheim. D. Lee reports grants from and serves on the advisory board for Medtronic; and research support from Ablative Solutions. D.E. Kandzari reports institutional research/grant support from Medtronic CardioVascular and Ablative Solutions and personal consulting honoraria from Medtronic CardioVascular and Ablative Solutions. A.V. Finn reports consulting honoraria from Amgen, Abbott Vascular, Biosensors, Boston Scientific, CeloNova, Cook Medical, CSI, Lutonix Bard, Medtronic, and Terumo. R. Virmani reports institutional grant/research support from NIH-HL141425, Leducq Foundation Grant, 4C Medical, 4Tech, Abbott Vascular, Ablative Solutions, Absorption Systems, Advanced NanoTherapies, AerWave Medical, Alivas, Amgen, Asahi Medical, Aurios Medical, Avantec Vascular, BD, Biosensors, Biotronik, Biotyx Medical, Bolt Medical, Boston Scientific, Canon USA, Cardiac Implants, Cardiawave, CardioMech, Cardionomic, CeloNova, Cerus EndoVascular, Chansu Vascular Technologies, Childrens National Medical Center, Concept Medical, Cook Medical, Cooper Health, Cormaze Technologies GmbH, CRL/AccelLab, Croivalve, CSI, Dexcom, Edwards Lifesciences, Elucid Bioimaging, eLum Technologies, Emboline, Endotronix, Envision, Filterlex, Imperative Care, Innovalve, Innovative Cardiovascular Solutions, Intact Vascular, Interface Biologics, InterShunt Technologies, InVatin Technologies, Lahav CRO, LimFlow, L&J Biosciences, Lutonix, Lyra Therapeutics, Mayo Clinic, Maywell, MD Start, MedAlliance, Medanex, Medtronic, Mercator, Microport, Microvention, Neovasc, Nephronyx, Nova Vascular, Nyra Medical, Occultech, Olympus, Ohio Health, OrbusNeich, Ossio, Phenox, Pi-Cardia, Polares Medical, Polyvascular, PulseTherapeutics, Profusa, ProKidney, Protembis, Pulse Biosciences, Qool Therapeutics, Recombinetics, ReCor Medical, Regencor, Renata Medical, Restore Medical, Ripple Therapeutics, Rush University, Sanofi, Shockwave, Sahajanand Medical Technologies, SoundPipe, Spartan Micro, SpectraWAVE, Surmodics, Terumo, the Jacobs Institute, Transmural Systems, Transverse Medical, TruLeaf Medical, UCSF, UPMC, Vascudyne, Vesper, Vetex Medical, Whiteswell, W.L. Gore, and Xeltis; has received consulting honoraria from Abbott Vascular, Boston Scientific, CeloNova, OrbusNeich, Terumo, W.L. Gore, Edwards Lifesciences, Cook Medical, CSI, ReCor Medical, SinoMedical Sciences Technology, Surmodics, and Bard BD; and is a scientific advisory board member of Medtronic and Xeltis. The other authors have no conflicts of interest to declare.

Figures

Central illustration
Central illustration. Representative images of untreated human and treated porcine renal arteries and their surrounding tissues in various locations.
Human (A) and porcine (E) proximal renal artery segments. Peri-arterial structures, such as lymph nodes (LN) and neuroganglia (NG), are frequently observed around the renal artery (RA). Peri-arterial nerves are seen near and far from the renal arteries (red crosses in human and red circles in porcine sections) but are not found "behind" the renal vein (RV). In the porcine RA section, the areas where treatment changes are seen are surrounded by a black line. Human (B) and porcine (F) distal renal artery segments. Peri-arterial structures (i.e., LN and NG) are not seen. Peri-arterial nerves are located closer to the renal artery than the proximal segments, and not seen “behind” the RV. Human (C) and porcine (G) post-1st bifurcation segments. Two branched renal arteries are observed. In the porcine section, the ureter and kidney are visible. Human (D) and porcine (H) post-2nd bifurcation segments. The kidney and ureter are seen in the histologic sections. Peri-arterial nerves are located close to the renal arteries. All sections are stained with haematoxylin and eosin.
Figure 1
Figure 1. The number of peri-arterial nerves in human and porcine renal arteries in proximal, middle, distal, post-1st bifurcation, and post-2nd bifurcation segments.
The numbers were corrected for the number of renal arteries seen in sections. Values are shown as median and interquartile ranges.
Figure 2
Figure 2. Prevalence of organs surrounding human and porcine renal arteries in proximal, middle, distal, post-1st bifurcation, and post-2nd bifurcation segments.
The presence of surrounding non-target organs was relatively minimal in the post-1st bifurcation sections for both the human and porcine samples. Number of sections analysed at each location in human: proximal 36, middle 31, distal 24, post-1st bifurcation 43, and post-2nd bifurcation 45; in porcine: proximal 46, middle 37, distal 30, post-1st bifurcation 41, and post-2nd bifurcation 23.
Figure 3
Figure 3. Mean semiquantitative scoring of histological tissue samples from porcine model.
Despite nerve necrosis at the site of RF ablation and downstream axonal loss (nerve atrophy), minimal cell disruption was observed to adjacent tissues including the ureter, kidney, lymph, skeletal muscle, and adrenal glands at 7 days following RF ablation. Non-target organ scores decreased even further at 28 days. However, substantial axonal loss persisted at 28 days. Scoring: 0=no changes; 1=minimal changes; 2=notable changes not effacing pre-existing tissue elements or limited to a small tissue area; 3=overwhelming feature involving large tissue areas. Values are shown as mean with error bar (standard deviation). P-values determined via unpaired t-test.
See this image and copyright information in PMC

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