De Novo Contactin-1-Associated Membranous Nephropathy in Kidney Allograft

Introduction

Membranous nephropathy (MN) results from the accumulation of antigen–antibody immune complexes along the glomerular basement membrane. MN is further classified into primary, in cases with no underlying disease association, and secondary MN, in cases with known disease association.¹ Approximately 70% to 80% of primary MN cases are associated with antibodies to phospholipase A2 receptor. Over the past decade, significant advances have been made with the discovery of novel antigens both for remaining primary MN and more importantly secondary MN. These include exostosin-1 and/or exostosin-2 (EXT1/EXT2) that is associated with autoimmune diseases, neural epidermal growth factor-like 1 with malignancies and certain drugs, neural cell adhesion molecule 1 with autoimmune diseases, contactin-1 (CNTN1) with polyneuropathies, FAT protocadherin with hematopoietic stem cell transplant, neuron-derived neurotrophic factor with syphilis, and proprotein convertase subtilisin and/or kexin type 6 with nonsteroidal anti-inflammatory drugs.² CNTN1 is a novel antigen that is detected in the setting of chronic inflammatory demyelinating polyneuropathy (CIDP), an autoimmune disease of the peripheral nervous system, where CNTN1 is a shared antigen between the MN and polyneuropathy.³

Laser microdissection and mass spectrometry (LMD/MS) is a sensitive and specific methodology that is used to detect the MN antigens.⁴ LMD/MS is particularly useful for detection of uncommon antigens for which immunohistochemical staining methodology is typically not available.

In this report, we present an unusual case of CNTN1-associated MN in allograft kidney that was detected by LMD/MS. Furthermore, on review of the medical history we learnt the patient was diagnosed with CIDP 15 years before development of MN. The case is unique and provides useful teaching points (Table 1). Also, to the best of our knowledge, CNTN1-associated MN has not been described in the allograft kidney.

Table 1.

Teaching points

CNTN1-associated MN is a rare type of MN associated with chronic inflammatory demyelinating polyneuropathy.

CNTN1-associated MN can occur in the allograft many years after the transplant.

Clinical and laboratory evaluation in such cases will reveal a chronic inflammatory demyelinating polyneuropathy, although the disease may be clinically quiescent.

Laser microdissection and mass spectrometry are useful methodology for detection of MN antigens.

Case Presentation

The patient is a 53-year-old male with end-stage liver disease secondary to hemochromatosis and alcohol use, complicated by the development of dialysis-dependent acute kidney injury in the setting of Escherichia coli sepsis in December 2017. He subsequently underwent combined liver–kidney transplantation in August 2018. His post-transplant course was notable for transient cytomegalovirus viremia without complications, with otherwise stable renal function and no proteinuria (baseline creatinine ∼1.0 mg/dl; most recent 1.1 mg/dl).

However, in early 2026 the patient presented with urine albumin-to-creatinine ratio of 4 gm/gm. Donor specific antibodies were negative, serum anti-phospholipase A2 receptor antibodies were also negative. Physical examination revealed minimal pedal edema. The proteinuria prompted a kidney biopsy.

Biopsy Findings

The allograft kidney biopsy findings showed no evidence of acute cellular or antibody-mediated rejection. The glomeruli appeared unremarkable with no capillary wall abnormalities suggestive of MN. There was only mild tubular atrophy and interstitial fibrosis (10%) present. Arteries showed mild intimal sclerosis. However, immunofluorescence studies demonstrated granular staining along the glomerular capillary walls for IgG (3+), C3 (1+), C4d (3+), kappa (3+), and lambda (3+). IgG subclass staining revealed predominance of IgG1 (3+), IgG3 (2+), and IgG4 (3+), with negative staining for IgG2 (Figure 1A). C4d staining was negative in the peritubular capillaries. Phospholipase A2 receptor immunofluorescence was equivocal. No glomeruli were present in tissue submitted for electron microscopy; therefore, ultrastructural evaluation was performed using frozen tissue, which demonstrated scattered subepithelial deposits with minimal to early glomerular basement membrane reaction, consistent with stage I MN.

Figure 1.

Kidney biopsy findings. Figure 1a. (i) Light microscopy showing a normal-appearing glomerulus, (ii–iv) immunofluorescence microscopy showing granular (ii) IgG 3+, (iii) C3 trace-1+ and (iv) IgG4 3+ along the capillary walls, (v–vi) electron microscopy showing scattered subepithelial deposits, stage I membranous nephropathy. (b) Laser microdissection and mass spectrometry showing moderate total spectral counts for Contactin-1. Samples were done in duplicate. Also shown are IgG subclass detection and actin and alpha contactin 4, which serve as loading and adequacy controls.

Laser Microdissection and Mass Spectrometry

LMD/MS showed moderate total spectral counts for CNTN1 (Figure 1b), confirming the diagnosis of CNTN1-associated MN. The counts detected in duplicate samples were 13 and 35 , with an average total spectral count of 24 (SD, ± 15.5). LMD/MS did not detect any other known MN antigen.

Follow-Up

Upon diagnosis of CNTN1-associated MN on the allograft biopsy, a detailed review of the patient’s medical history revealed a previous history of severe CIDP, diagnosed in 2012. The disease was refractory to i.v. Ig and prednisone but ultimately responded to plasma exchange and cyclophosphamide in 2013, with marked clinical improvement. The patient has remained off treatment since that time.

After the diagnosis of MN, the patient was started on anti-CD20 treatment (Rituximab) therapy, with stable renal function (1.13 mg/dl), with improvement of proteinuria from urine albumin-to-creatinine ratio 4.4 g/g in early January 2026 to 868 mg/g in April 2026.

Discussion

MN is the most common cause of nephrotic syndrome in adults, and since the discovery of phospholipase A2 receptor in 2009 and more recently novel antigens such as EXT1 and/or EXT2, neural epidermal growth factor-like 1, neural cell adhesion molecule 1, FAT protocadherin, neuron-derived neurotrophic factor and CNTN1, among others has dramatically changed the understanding of MN.¹ Among the recently identified MN antigens, CNTN1 has been associated with CIDP, an autoimmune disorder of the peripheral nervous system characterized by progressive, motor-predominant neuropathy with early axonal loss and symmetric proximal and distal weakness.^5,6 Other autoantibodies against nodal and paranodal proteins such as neurofascin (NF)155, NF186, contactin-associated protein 1 have been described in patients with CIDP as well.^3,5 The predominant IgG subclass of the autoantibodies is IgG4.These IgG4-associated forms tend to exhibit more severe disease and a heterogeneous response to therapy, with reduced responsiveness to i.v. Ig.^3,5,6 A recent case of CNTN1-associated MN in the absence of polyneuropathy has also been described.⁷

Our patient had a complex clinical history with end-stage liver disease secondary to hemochromatosis and alcohol use, complicated by the development of dialysis-dependent acute kidney injury in the setting of sepsis, needing both a liver and kidney transplant. Kidney biopsy before transplant was not done, and since the patient did not have proteinuria, it is presumed that the patient did not have MN in the native kidney biopsy. 8 years post-transplant, the patient presented with nephrotic range proteinuria without any significant neurological symptoms. Kidney biopsy done to explain the nephrotic range proteinuria revealed a MN, and LMD/MS identified the target antigen as CNTN1. These findings prompted a detailed review of the patient’s history, which revealed a previous diagnosis of CIDP, providing a plausible unifying mechanism. It is puzzling that the MN developed 8 years following the transplant, and with no clinical neurological disease. However, serologic evaluation was performed during the follow up appointment after the diagnosis of MN and was positive for IgG- and IgM (NF186), and IgM (NF155).Taken together, the likely absence of MN in the native kidney (explained by no proteinuria and renal failure following sepsis), and the late onset of MN in the allograft in the setting of quiescent CIDP suggest a de novo CNTN1-associated MN rather than a recurrent CNTN1-associated MN.

CNTN1 is expressed at low levels in podocytes under physiologic conditions, and the mechanism by which it becomes antigenically exposed or “unmasked” remains incompletely understood.³ Although circulating CNTN1 antibodies are often detected in patients with MN and CIDP, they were absent in our case. However, it should be pointed out that the patient received anti-CD20 treatment before blood work for anti-CNTN1 antibodies which may explain the negative findings. The patient demonstrated antibodies against NF155 and NF186 indicating serologies that are positive for CIDP. Lastly, it has been proposed that CNTN1 antibodies may be produced by short-lived plasma cells requiring ongoing B-cell replenishment, which could explain their disappearance following effective therapy.⁸

This case highlights the critical role LMD/MS in establishing a precise etiologic diagnosis of MN, as well, the importance of detailed clinical history identifying systemic associations that may influence prognosis and management. Finally, this report expands the spectrum of CNTN1-associated MN and shows that CNTN1-associated MN can occur many year post transplant in the allograft even in the setting of clinically quiescent CIDP (Table 1).

Disclosure

All authors declared no competing interests.

Patient Consent

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