Contactin-1 Membranous Nephropathy Without Neuropathy and Serum Antibodies

Introduction

Contactin-1 (CNTN1)–associated membranous nephropathy (MN) without neurological symptoms or serum CNTN1 antibodies is rare. Key teaching points of this case are presented in Table 1.

Table 1.

Teaching points

•Contactin-1 (CNTN1) is a cell membrane protein essential for axoglial junctions; though it is typically associated with chronic inflammatory demyelinating polyneuropathy, it is a recognized target antigen in membranous nephropathy (MN).

•Although CNTN1-associated MN usually presents with severe neurological deficits, it can manifest as a renal-limited phenotype without clinical neuropathy or detectable serum anti-CNTN1 antibodies.

•In cases of MN negative for common antigens such as phospholipase A2 receptor, thrombospondin type 1 domain containing 7A, and neural epidermal growth factor–like protein 1, using laser microdissection and mass spectrometry is critical for identifying rare or novel target antigens.

•Distinguishing antigen-specific subtypes of MN is vital for clinical management, becauseCNTN1-associated disease may precede neurological symptoms by years, necessitating long-term surveillance for potential neuromuscular progression.

•Immunofluorescence showing IgG4 subclass predominance is a common feature of CNTN1-associated MN, suggesting a specific autoimmune pathway.

Case Presentation

We present the case of a 50-year-old man with no relevant past medical history who presented in June 2025 with migratory joint pain, urticarial rash, cervical lymphadenopathy, and peripheral eosinophilia. He also complained of numbness in his left shoulder, tongue, lips, and right thigh. This prompted an extensive evaluation, including a whole-body fluorine-18 fluorodeoxyglucose positron emission tomography–computed tomography scan with no evidence of malignancy, autoimmune disease, or infection (Supplementary Table S1). In August 2025, he was evaluated in Rheumatology and placed on prednisone 40 mg and hydroxychloroquine for a presumed diagnosis of an undifferentiated autoimmune disease. At that time, proteinuria (1.8 g/24 h) was detected and the patient was referred to Nephrology. A kidney biopsy was performed, which was diagnostic of an MN (Figure 1). Immunofluorescence microscopy was negative for phospholipase A2 receptor, thrombospondin type 1 domain containing 7A, and neural epidermal growth factor–like protein 1. To further evaluate the putative antigen, laser microdissection and mass spectrometry of the kidney biopsy was performed and showed high total spectral counts (Figure 1), while negative for all other known antigens. Ig subclass analysis showed IgG4 subclass predominance.

Figure 1.

Kidney biopsy showing membranous nephropathy with (a) no significant thickened glomerular basement membranes on light microscopy (periodic acid–Schiff stain, ×40), (b) granular IgG staining along the glomerular capillary walls on immunofluorescence microscopy, and (c) negative staining for PLA2R. (d) Electron microscopy showing moderate foot process effacement, few mesangial deposits but no subepithelial deposits, and (e) mass spectrometry showing high spectral counts for Contactin 1.

Neurological examination was normal and extensive neuromuscular evaluation showed no evidence for any inflammatory or autoimmune neuropathy. Electromyography and nerve conduction studies indicated very mild, nonspecific, length-dependent, sensory-predominant axonal neuropathy without small or large-fiber deficits seen on physical exam. These findings are not consistent with the typical demyelinating polyradiculoneuropathy seen in CNTN1 autoimmunity. Both the sweat test and autonomic reflex screen were normal, as were the magnetic resonance imaging results of the lumbar spine and plexus. The cerebrospinal fluid profile was normal, except for a mild elevation in protein concentration compatible with age; serum anti–CNTN1 and antineurofascin 155 antibodies were negative (Supplementary Table S1).

Following treatment with prednisone, the symptoms improved rapidly, proteinuria decreased to 200 mg/24 h, kidney function remained preserved, with prednisone tapered and discontinued by October 2025. At the last follow-up in in April 2026 there was no evidence of neurological progression or recurrence of proteinuria.

Discussion

MN is a pattern of injury caused by autoantibodies binding to specific target antigens in the glomerular basement membranes. Over the past 2 decades, there have been substantial and transformative advancements in our understanding of MN, particularly through the identification of target antigens and their corresponding autoantibodies.¹ CNTN1 has been described as a target antigen in MN associated with a rare form of a chronic inflammatory demyelinating polyneuropathy, characterized by a rapidly progressive motor-predominant neuropathy with early axonal loss, and symmetric weakness of proximal and distal muscles.² Pain, ataxia, tremor, cranial nerve palsies, and autonomically dysfunction can occur. Although the relationship between chronic demyelinating neuropathy and MN dates back to the 1970s,³ it has not been until recently that antibodies targeting paranodal CNTN1, as well as neurofascin 155, and neurofascin 186, were found to be present in patients with inflammatory neuropathies and nephrotic syndrome owing to MN²; suggesting a shared autoimmune mechanism involving both the kidney and peripheral nervous system. Additional studies have documented the association between the 2 entities, typically manifesting either concurrently or with a temporal gap ranging from months to years, with neurological symptoms generally preceding the onset of nephrotic syndrome.^2,4, 5, 6, 7 There has been only 1 previous report of 4 patients with isolated MN, positive anti-CNTN1 antibodies, but no neurological involvement.⁸ Therefore, to the best of our knowledge, this is the first report of CNTN1-associated MN occurring in the absence of both neurological symptoms and negative anti-CNTN1 antibodies in the serum. Although immunosuppressive treatment can reduce the level of these antibodies, seropositive patients are frequently resistant to standard immunosuppressive therapy.⁸ The patient received a limited dosage of steroids, suggesting that this is unlikely to be the reason for the absence of detection. Higher titers of anti-CNTN1 antibodies were reported in cases on chronic inflammatory demyelinating polyneuropathy combined with MN than with chronic inflammatory demyelinating polyneuropathy alone.² An alternative explanation is that some patients may have a more gradual onset of these diseases,^4,7 and we may be observing an early stage of the disease process. Therefore, extended follow-up will be necessary to document if neurological symptoms or anti-CNTN1 antibodies will develop.

The pathophysiology process is not yet completely understood. CNTN1 is a glycosylphosphatidylinositol-anchored cell membrane protein expressed on the extracellular side that provides a critical signal for axon-glia communication in central nervous system myelin and is essential for myelin sheath formation and establishment of paranodal axoglial junctions that enable rapid nerve impulse conduction of myelinated nerves. Antibodies against CNTN1 induce the disorganization of the septate-like junctions at the paranodes causing nodo-paranodopathy.³ Similar to phospholipase A2 receptor, CNTN1 is present in human glomeruli as a native integral membrane protein of podocytes and anti-CNTN1 antibodies target both glomeruli and neural CNTN1.^3,9 However, as with other MN antigens, CNTN1 is expressed at low levels at the podocyte under normal conditions,² requiring unmasking of the antigen. However, the unmasking mechanism that initiates the immune-complex formation and damage cascade has not been elucidated. It is possible to hypothesize that damage to the glomerular basement membrane and podocytes may lead to increased expression of concealed glomerular antigens, which in turn could initiate an immune reaction against these antigens.⁹ Why some patients with anti-CNTN1 antibodies develop a predominant neurological or renal phenotype is unknown.

This case underscores the importance of classifying MN based on antigens using laser microdissection and mass spectrometry, because this method enables precise and specific diagnosis of MN.¹ This case also expands the phenotypic spectrum of CNTN1-associated MN and adds to the paucity of cases of renal-limited CNTN1-associated MN.

Disclosure

All the authors declared no competing interests.

Patient Consent

The authors declare that they have obtained consent from the patients discussed in the report.

Supplementary Material

Supplementary File (PDF)

Supplementary Methods. Table S1. Analytical, serological and neurological analysis.