Transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of pediatric nephrotic syndrome: a pilot study

Kumail Merchant, Stavros Zanos, Timir Datta-Chaudhuri, Clifford S Deutschman, Christine B Sethna, Kumail Merchant, Stavros Zanos, Timir Datta-Chaudhuri, Clifford S Deutschman, Christine B Sethna

Abstract

Background: Children with frequently relapsing nephrotic syndrome (FRNS) and steroid resistant nephrotic syndrome (SRNS) are exposed to immunosuppressant medications with adverse side effects and variable efficacy. Transcutaneous auricular vagus nerve stimulation (taVNS) modulates the immune system via the inflammatory reflex and has become a therapy of interest for treating immune-mediated illnesses.

Methods: An open-label, pilot study of tavNS for five minutes daily for 26 weeks via a TENS 7000 unit was conducted.

Results: Three FRNS participants and 4 SRNS participants had a mean age of 9.5±4.2 years (range 4 to 17). Those with FRNS remained relapse-free during the study period; two participants continued treatment and remained in remission for 15 and 21 months, respectively. Three SRNS participants experienced a reduction in first morning UPC (mean of 42%, range 25-76%). Although UPC decreased (13.7%) in one SRNS participant with congenital nephrotic syndrome, UPC remained in nephrotic range. All but one participant (non-compliant with treatment) experienced a reduction in TNF (7.33pg/mL vs. 5.46pg/mL, p=0.03). No adverse events or side effects were reported.

Conclusions: taVNS was associated with clinical remission in FRNS and moderately reduced proteinuria in non-congenital SRNS. Further study of taVNS as a treatment for nephrotic syndrome in children is warranted. ClinicalTrials.gov Identifier: NCT04169776, Registered November 20, 2019, https://ichgcp.net/clinical-trials-registry/NCT04169776 .

Keywords: Children; Focal segmental glomerular sclerosis; Minimal change disease; Nephrotic syndrome; Vagus nerve stimulation; taVNS.

Conflict of interest statement

Dr. Datta-Chaudhuri received grant funding from General Electric and United Therapeutics. Dr. Zanos received grant funding from General Electric and BARDA.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Ear-clip at the left cymba concha
Fig. 2
Fig. 2
Urine protein:creatinine change in steroid resistant nephrotic syndrome participants during the study and follow-up periods
Fig. 3
Fig. 3
Change in TNF levels from baseline to 26 weeks while on transcutaneous vagus nerve stimulation therapy

References

    1. Chapter 3 Steroid-sensitive nephrotic syndrome in children. Kidney Int Suppl (2011) 2012;2(2):163–71.
    1. Zhang H, Wang Z, Dong LQ, Guo YN. Children with Steroid-resistant Nephrotic Syndrome: Long-term Outcomes of Sequential Steroid Therapy. Biomed Environ Sci. 2016;29(9):650–5.
    1. Alfakeekh K, Azar M, Sowailmi BA, et al. Immunosuppressive burden and risk factors of infection in primary childhood nephrotic syndrome. J Infect Public Health. 2019;12(1):90–4.
    1. Youssef DM, Elbehidy RM, El-Shal AS, Sherief LM. T helper 1 and T helper 2 cytokines in atopic children with steroid-sensitive nephrotic syndrome. Iran J Kidney Dis. 2015;9(4):298–305.
    1. Gomez-Chiarri M, Ortiz A, Gonzalez-Cuadrado S, et al. Interferon-inducible protein-10 is highly expressed in rats with experimental nephrosis. Am J Pathol. 1996;148(1):301–11.
    1. Petrovic-Djergovic D, Popovic M, Chittiprol S, Cortado H, Ransom RF, Partida-Sanchez S. CXCL10 induces the recruitment of monocyte-derived macrophages into kidney, which aggravate puromycin aminonucleoside nephrosis. Clin Exp Immunol. 2015;180(2):305–15.
    1. Kaneko K, Tsuji S, Kimata T, Kitao T, Yamanouchi S, Kato S. Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes. World J Pediatr. 2015;11(1):21–8.
    1. Lai KW, Wei CL, Tan LK, et al. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol. 2007;18(5):1476–85.
    1. Kanai T, Shiraishi H, Yamagata T, et al. Th2 cells predominate in idiopathic steroid-sensitive nephrotic syndrome. Clin Exp Nephrol. 2010;14(6):578–83.
    1. Araya CE, Wasserfall CH, Brusko TM, et al. A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol. 2006;21(5):603–10.
    1. Kaneko K, Tuchiya K, Fujinaga S, et al. Th1/Th2 balance in childhood idiopathic nephrotic syndrome. Clin Nephrol. 2002;58(6):393–7.
    1. Bagga A, Sinha A, Moudgil A. Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med. 2007;356(26):2751–2.
    1. Dotsch J, Muller-Wiefel DE, Kemper MJ. Rituximab: is replacement of cyclophosphamide and calcineurin inhibitors in steroid-dependent nephrotic syndrome possible? Pediatr Nephrol. 2008;23(1):3–7.
    1. Kimata T, Hasui M, Kino J, et al. Novel use of rituximab for steroid-dependent nephrotic syndrome in children. Am J Nephrol. 2013;38(6):483–8.
    1. Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. J Exp Med. 2012;209(6):1057–68.
    1. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853–9.
    1. Inoue T, Abe C, Sung SS, et al. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through alpha7nAChR+ splenocytes. J Clin Invest. 2016;126(5):1939–52.
    1. Gigliotti JC, Huang L, Bajwa A, et al. Ultrasound Modulates the Splenic Neuroimmune Axis in Attenuating AKI. J Am Soc Nephrol. 2015;26(10):2470–81.
    1. Gigliotti JC, Huang L, Ye H, et al. Ultrasound prevents renal ischemia-reperfusion injury by stimulating the splenic cholinergic anti-inflammatory pathway. J Am Soc Nephrol. 2013;24(9):1451–60.
    1. Tanaka S, Abe C, Abbott SBG, et al. Vagus nerve stimulation activates two distinct neuroimmune circuits converging in the spleen to protect mice from kidney injury. Proc Natl Acad Sci U S A. 2021;118(12).
    1. Butt MF, Albusoda A, Farmer AD, Aziz Q. The anatomical basis for transcutaneous auricular vagus nerve stimulation. J Anat. 2020;236(4):588–611.
    1. Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat. 2002;15(1):35–7.
    1. al. FAe. Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation. Frontiers Human Neuroscience. 2021;March 23(14:568051).
    1. Aranow C, Atish-Fregoso Y, Lesser M, et al. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Ann Rheum Dis. 2020.
    1. Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113(29):8284–9.
    1. D’Haens GCZ, Eberhardson M, Danese S, Levine Y, Zitnik R. A clinical trial of the effects of Vagus nerve stimulation in biologic-refractory Crohn’s disease. United European gastroenterology week (UEGW) Vienna Dent Abstr;P. 2016;1420:52.
    1. Bonaz B. Is-there a place for vagus nerve stimulation in inflammatory bowel diseases? Bioelectron Med. 2018;4:4.
    1. Bonaz B, Sinniger V, Hoffmann D, et al. Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol Motil. 2016;28(6):948–53.
    1. Addorisio ME, Imperato GH, de Vos AF, et al. Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear. Bioelectron Med. 2019;5:4.
    1. Meregnani J, Clarencon D, Vivier M, et al. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci. 2011;160(1-2):82–9.
    1. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458–62.
    1. Huston JM, Gallowitsch-Puerta M, Ochani M, et al. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis *. Critical Care Medicine. 2007;35(12):2762–8.
    1. Guarini S, Altavilla D, Cainazzo MM, et al. Efferent vagal fibre stimulation blunts nuclear factor-kappaB activation and protects against hypovolemic hemorrhagic shock. Circulation. 2003;107(8):1189–94.
    1. Levy G, Fishman JE, Xu D-z, et al. Vagal nerve stimulation modulates gut injury and lung permeability in trauma-hemorrhagic shock. Journal of Trauma Acute Care Surgery. 2012;73(2):338–42.
    1. Levine YA, Koopman FA, Faltys M, et al. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PLoS One. 2014;9(8):e104530.
    1. Costes LM, van der Vliet J, van Bree SH, Boeckxstaens GE, Cailotto C. Endogenous vagal activation dampens intestinal inflammation independently of splenic innervation in postoperative ileus. Auton Neurosci. 2014;185:76–82.
    1. van Westerloo DJ, Giebelen IA, Meijers JC, et al. Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats. J Thromb Haemost. 2006;4(9):1997–2002.
    1. Ma J, Qiao P, Li Q, et al. Vagus nerve stimulation as a promising adjunctive treatment for ischemic stroke. Neurochemistry International. 2019;131:104539.
    1. Mueller MH, Karpitschka M, Gao Z, et al. Vagal Innervation and Early Postoperative Ileus in Mice. Journal of Gastrointestinal Surgery. 2011;15(6):891–901.
    1. . Accessed.
    1. KDIGO. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney International Supplements. 2012;2.
    1. KDIGO. Draft Clinical Practice Guidelines for Glomerular Disease. 2020.
    1. Mekahli D, Liutkus A, Ranchin B, et al. Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study. Pediatric nephrology. 2009;24(8):1525–32.
    1. Paik KH, Lee BH, Cho HY, et al. Primary focal segmental glomerular sclerosis in children: clinical course and prognosis. Pediatr Nephrol. 2007;22(3):389–95.
    1. Badran BW, Yu AB, Adair D, et al. Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. J Vis Exp. 2019(143).
    1. Redgrave J, Day D, Leung H, et al. Safety and tolerability of Transcutaneous Vagus Nerve stimulation in humans; a systematic review. Brain Stimul. 2018;11(6):1225–38.
    1. Aranow C, Atish-Fregoso Y, Lesser M, et al. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Ann Rheum Dis. 2021;80(2):203–8.
    1. Wang CS, Travers C, McCracken C, et al. Adrenocorticotropic Hormone for Childhood Nephrotic Syndrome: The ATLANTIS Randomized Trial. Clin J Am Soc Nephrol. 2018;13(12):1859–65.
    1. Duff JP, Topjian AA, Berg MD, et al. 2019 American Heart Association Focused Update on Pediatric Advanced Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2019;140(24):e904–14.
    1. Marsal SCH, dr Augustin J, Perez-Garcia C, et al. Non-invasive Vagus Nerve Stimulation for Rheumtoid Arthritis: A Proof-of-Concept Study. Lancet Rheumatology. 2021.
    1. Drewes AM, Brock C, Rasmussen SE, et al. Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study. Scand J Rheumatol. 2021;50(1):20–7.
    1. Weisbach A, GBea Serum tumor necrosis factor-alpha levels in children with nephrotic syndrome: a pilot study. Israel Medical Association Journal. 2017;19:30–3.
    1. Mariani LESea. Multidimensional data integation identifies tumor necorsis factor activation in nephrotic syndrome: a model for precision nephrology. medrxiv.
    1. Xiao MBSea. Correlation of TNF alpha and IL-10 gene polymorphisms with primary nephrotic syndrome. Exp Ther Med. 2020;20(5):87.

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