Neuromatous regeneration as a nerve response after catheter-based renal denervation therapy in a large animal model: immunohistochemical study.
BACKGROUND
Renal denervation (RDN) emerged as a therapeutic option for resistant hypertension. Nerve regrowth after RDN has been questioned. We aimed to characterize the nerve response after RDN.


RESULTS
Swine underwent bilateral RDN and were followed up for 7, 30, and 90 days and evaluated with S100 (Schwann cell), tyrosine hydroxylase (TH; efferent nerves), and growth-associated protein 43 (neurite regeneration) markers. At 7 days, nerve changes consisted of necrosis associated with perineurial fibrosis and distal atrophy with inflammation. At 30 days changes were substituted by healing changes (ie, fibrosis). This response progressed through 90 days resulting in prominent neuroma formation. Immunohistochemistry at 7 days: TH staining was strongly decreased in treated nerves. Early regenerative attempts were observed with strongly TH and growth-associated protein 43 positive and weak S100 disorganized nerve sprouts within the thickened perineurium. Distal atrophic nerves show weak staining for all 3 markers. At 30 days, affected nerves show a weak TH and S100 staining. Evident growth-associated protein 43+ disorganized neuromatous tangles in the thickened perineurium of severed nerves were observed. At 90 days, some TH expression was observed together with prominent S100+ and growth-associated protein 43+ neuromatous tangles with disorganized architecture. The potential for regenerative activity is unlikely based on the disrupted architecture of these neuromatous tangles at the radiofrequency lesion sites.


CONCLUSIONS
This study is the first documentation that a progressive regenerative response occurs as early as 7 days after RDN, resulting in a poorly organized neuromatous regeneration. This finding is of paramount importance to further establish the potential functional significance of a regeneration after RDN.
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
Serge D
SD
Rousselle
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
Irena K
IK
Brants
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
Atsushi
A
Sakaoka
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
Brad
B
Hubbard
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
Nicolette D
ND
Jackson
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
Joan R
JR
Wicks
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
Krista N
KN
Dillon
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
L A
LA
Naiche
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
Randy
R
Hart
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.).
Javier A
JA
Garza
From the Alizée Pathology, LLC, Thurmont, MD (S.D.R., N.D.J., J.R.W., K.N.D., L.A.N., R.H., J.A.G., A.T.); Translational Testing and Training (T3) Laboratories, Atlanta, GA (I.K.B., B.H.); and Terumo Corporation, Kanagawa, Japan (A.S.). atellez@alizeepathology.com.
Armando
A
Tellez
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D017115:Catheter Ablation / Q000379:methods*; D003714:Denervation; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D007668:Kidney / Q000294:innervation*; D023421:Models, Animal; D009416:Nerve Regeneration / Q000502:physiology*; D009418:S100 Proteins / Q000378:metabolism; D034421:Sus scrofa; D013564:Sympathetic Nervous System / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015415:Biomarkers; D019922:GAP-43 Protein; D009418:S100 Proteins; D014446:Tyrosine 3-Monooxygenase
models, animal; nerve regeneration; renal denervation