Contactin-1 Antibodies Link Autoimmune Neuropathies to Nephrotic Syndrome

Background: There is an established association between acquired inflammatory demyelinating neuropathies and nephrotic syndrome, but a common immunopathological mechanism has yet to be determined. Antibodies to known glomerular podocyte antigens occur in up to 90% of patients with nephrotic syndrome due to idiopathic membranous glomerulonephritis (MGN), the majority targeting the phospholipase A2 receptor (PLA2R). In patients with immune-mediated neuropathies, antibodies targeting molecules of the node of Ranvier, such as contactin-1 (CNTN1), are increasingly recognised. Methods: In this study, sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, were tested for CNTN1 antibodies. Topographical binding patterns were determined using teased nerve fibres and live myelinated nerve co-cultures. CNTN1 expression in human kidney was characterised by immunohistochemistry, western blotting and PCR. Findings: A total of 16 patients with an immune-mediated neuropathy and MGN were seropositive for IgG4 anti-CNTN1 antibodies. The onset and resolution of both disorders had a close temporal relationship. The majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Four further patients with isolated MGN were also positive for the same antibodies at lower titres. CNTN1 protein was detected within glomerular deposits in biopsies from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. Interpretation: These data provide evidence that CNTN1 antibodies precipitate both autoimmune neuropathy and MGN. The temporal correlation of these disorders, as well as the presence of CNTN1 protein and antibodies in both peripheral nerve and diseased glomeruli, supports a common antibody-mediated pathological process, and defines a new antigenic target in MGN. CNTN1 antibodies have diagnostic and therapeutic relevance, and may additionally serve as a means of monitoring disease activity in both conditions. Funding Statement: Medical Research Council (MRC), GBS/CIDP Foundation International, MRC and Kidney Research UK. Declaration of Interests: SR runs a not-for-profit diagnostic testing service for nodal/paranodal antibodies. He has received a speaker’s honorarium and/or travel expenses from Fresenius Medical Care, Excemed, Alnylam and argenx. AR has received honoraria from Sarepta, Roche and Sanofi Aventis, is a member of MND Association Clinical Advisory Board, and was a member of NICE MND Guideline Development Group. ASC receives funding from NIHR University College London Hospitals Biomedical research centre. AM is a clinical fellow with grant reference number MR/P001777/1. SPi is was funded by a grant from the Karolinska Institutet during the course of the study. All other authors have nothing to declare. Ethics Approval Statement: Research Ethics Committee approval number 14/SC/0280