NELL1-Associated Membranous Nephropathy in a Patient with Papillary Thyroid Carcinoma: A Case Report and Literature Review

Abstract

Introduction

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults. NELL1 accounts for approximately 10% of MN cases and is emerging as a distinct subtype often linked to secondary conditions, such as malignancies and drugs. Here, we describe a case of MN in a patient with metastatic papillary thyroid carcinoma.

Case Presentation

A 78-year-old man with metastatic papillary thyroid carcinoma and a distant history of treated syphilis presented with nephrotic syndrome. A renal biopsy revealed segmental MN with positive NELL1 staining, while the thyroid carcinoma tissue also demonstrated NELL1 staining at weak to moderate intensity. The patient was managed conservatively without immunosuppression due to the lack of oncologic treatment options and syphilis was treated with doxycycline due to positive serologies, though active infection was not suspected. Follow-up showed stabilization of renal function and marked reduction in proteinuria.

Conclusion

NELL1-positive MN is increasingly recognized for its association with malignancy. The patient achieved partial remission with supportive, non-immunosuppressive therapy. Clinicians should maintain a high index of suspicion for secondary conditions when NELL1-positive MN is encountered. This case report reviews secondary NELL1 associations and underscores the diagnostic challenges in MN when multiple potential secondary causes exist.

Introduction

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults [1]. Data from the UK Biobank show an incidence of 1.29 per 100,000 person-years and a baseline prevalence of 72 cases per million [2]. Presenting symptoms include edema, weight gain, and frothy urine. The gold standard for diagnosing MN is kidney biopsy, which typically shows thickening of the glomerular basement membrane, subepithelial immune deposits, and podocyte foot-process effacement [3]. Approximately 75–80% of MN cases are idiopathic, while 20–25% are secondary to systemic processes such as malignancy, toxins/medications, infections, or systemic autoimmune conditions [3–5].

Neutral endopeptidase (NEP) was the first described culprit antigen in primary MN [6]. In 2009, M-type phospholipase A2 receptor (PLA2R) was identified as the target antigen in approximately 70% of primary MN cases [7]. Subsequently, other antigens including thrombospondin type-1 domain-containing 7A (THSD7A) [8] and neural epidermal growth factor-like 1 protein (NELL1) [9] have been identified. NELL1 accounts for approximately 10% of MN cases and has been associated with both malignancy and exposure to drugs such as lipoic acid and traditional indigenous medications [10–12], but not with syphilis [13]. Here, we describe a unique case of NELL1-positive membranous nephropathy in a patient with both metastatic papillary thyroid carcinoma and positive syphilis serologies. We review the literature on malignancy, MN, and the NELL1 target antigen.

Case Report

A 78-year-old man presented to the nephrology clinic for evaluation of lower extremity edema and proteinuria. His medical history included hypertension, benign prostatic hyperplasia, atopic dermatitis, syphilis treated in 1964, metastatic papillary thyroid cancer (status post-total thyroidectomy and radioactive iodine), former tobacco use, and heavy alcohol consumption. Medications included losartan, hydrochlorothiazide, omeprazole, and tamsulosin. He was not taking any supplements. Treatment with tralokinumab for atopic dermatitis started after the patient noted edema, and it was discontinued after the discovery of nephrotic range proteinuria by his medical provider.

Physical examination was notable for blood pressure of 158/83 mm Hg and 1+ peripheral edema. Laboratory findings revealed serum creatinine of 1.4 mg/dL (baseline 1.0 mg/dL), serum albumin of 3.1 g/dL (previously 3.5 g/dL), and a spot albumin-to-creatinine ratio >4,745 mg/g. Additional workup including ANA, RF, HIV, hepatitis B/C serologies, anti-PLA2R antibody, and complement levels were unremarkable. Syphilis non-treponemal test (Rapid Plasma Reagin) was positive at a low titer of 1:2, and the treponemal enzyme immunoassay (Trep-Sure EIA) was also reactive. No clinical symptoms of syphilis were present and the medical team deemed active syphilis unlikely. However, because of his presentation with nephrotic syndrome, he was treated with a 4-week course of doxycycline (allergic to penicillin). He subsequently underwent a kidney biopsy.

Kidney Pathology

Light microscopy revealed segmental MN with focal global glomerulosclerosis and positive staining for NELL1 (shown in Fig. 1).

Fig. 1.

NELL1 MN with rigid appearing capillary loops but no visible spikes on Jones silver stain (a; ×200), and segmental granular capillary wall staining for NELL1 (b; ×200). Papillary thyroid carcinoma (c; ×200) with granular cytoplasmic staining for NELL1 at weak to moderate intensity (d; ×200).

Final Diagnosis

NELL1-positive segmental MN.

Thyroid Pathology

Staining of archival papillary thyroid carcinoma tissue demonstrated punctate cytoplasmic positivity for NELL1 at weak to moderate intensity, consistent with previous reports in malignancy-associated MN [11].

Follow-Up

The patient was started on oral empagliflozin 12.5 mg daily (10 mg was not on formulary), later increased to 25 mg daily, and maintained on oral losartan 100 mg daily. Hematology-oncology elected surveillance due to a lack of effective oncologic options for metastatic thyroid cancer. At the 6-month follow-up, the patient reported adherence to and good tolerance of the prescribed medications. At this time, his creatinine remained stable (1.4 mg/dL), albumin improved to 4 g/dL, and the albumin-to-creatinine ratio decreased to 1,127 mg/g. At 1-year follow-up, the proteinuria further improved to 790 mg/g, with a creatinine of 1.6 mg/dL (shown in Fig. 2).

Fig. 2.

Evolution of proteinuria and serum creatinine in relation to clinical events over time. FNA, fine needle aspiration of thyroid nodule; PTC, papillary thyroid carcinoma; I-131, radioactive iodine-131 therapy.

Discussion

This patient developed MN in the background of positive syphilis serologies and metastatic papillary thyroid cancer, both of which have been associated with MN. The kidney biopsy stained positively for NELL1, and subsequent staining of the thyroid tumor also demonstrated NELL1 expression. This aligns with previously reported cases where NELL1-positive MN was associated with malignancy and the corresponding tumor tissue stained for NELL1 [11]; however, this alone does not establish a causal link between the malignancy and MN.

This case underscores a frequent clinical conundrum in MN when multiple potential secondary causes exist. Establishing the most plausible pathogenic trigger becomes essential to guiding management.

Malignancy is associated with approximately 5–11% of MN cases [14–16], most commonly solid tumors such as lung and prostate cancers, followed by hematological malignancies [16]. The pathogenesis of malignancy-associated MN is multifactorial. Genetic predispositions may play a role in immune dysregulation [17]. Tumor-associated antigens may provoke an immune response, resulting in circulating immune complexes (CICs) or direct antibodies targeting podocyte antigens. These circulating immune complexes may deposit in the subepithelial space of the glomeruli, activating the complement system, leading to podocyte injury and proteinuria [18].

NELL1 and its closely related protein NELL2 have emerged as important players in tumor biology. Maeda et al. demonstrated that NELL1 and NELL2 are expressed in neuronal and neuroblast-derived tumors, suggesting a role in neural differentiation [19]. Shah et al. found upregulation of NELL2 in benign prostatic hyperplasia and prostate cancer [20], whereas Osman et al. [21] reported downregulation of NELL2 in bladder cancer. Similarly, loss of NELL1 expression has been linked to the molecular pathogenesis of Hodgkin lymphoma, possibly through disrupted growth regulation in Hodgkin/Reed-Sternberg cells [22]. In renal cell carcinoma, in vitro studies suggest that NELL1 and NELL2 may function as tumor suppressors, and their downregulation is attributed to promoter hypermethylation [23]. These highlight NELL proteins’ complex interaction in tumor biology, suggesting that their differential expression and regulation could serve as a novel biomarker or therapeutic target in oncology. The documented expression of NELL1 in various malignancies provides a potential mechanistic link to the observed association of NELL1-positive MN with the underlying malignancies.

Initial descriptions of NELL1-associated MN reported no significant malignancy association [9]. However, subsequent studies have shown a wide variability in the reported prevalence of malignancy, ranging from 2% to 33% in NELL1-positive cases [11, 12, 24, 25], compared to 4–5% in PLA2R and 11% in THSD7A-associated MN [11, 24]. The majority of malignancy-associated NELL1MN cases involve solid tumors, particularly lung (10–60%), prostate (19–20%), and breast cancers (6–17%) [10, 11].

Given the well-documented association between malignancy and MN, comprehensive cancer screening is crucial in patients with newly diagnosed MN, especially in older individuals and those with high-risk features such as prior malignancy, heavy smoking, alcohol use, or systemic symptoms like weight loss or night sweats [26, 27]. Malignancy is most frequently detected within the first year of MN diagnosis, but the elevated cancer risk may persist for at least 5 years [28, 29]. The KDIGO 2021 Clinical Practice Guidelines recommend screening for malignancy in all patients with MN, though specific recommendations on who and how to screen are not yet standardized [30].

Management of secondary MN, particularly when associated with active malignancy, often prioritizes treatment of the underlying cancer. In many instances, effective oncologic therapy alone may induce remission of MN, making additional immunosuppression unnecessary. Caza et al. [11] reported that 9 out of 12 patients with NELL1-positive MN with underlying malignancy, achieved remission of proteinuria with cancer therapy alone. Our case highlights the effectiveness of supportive care in patients with NELL1, even those with active, untreated malignancy.

Segmental MN, which our patient had, is characterized by involvement of <50% of glomerular tuft by the disease process and is frequently associated with NELL1MN and malignancies [11]. Two retrospective reviews of segmental MN revealed that isolated segmental MN had favorable prognosis with 60%–71% having complete or partial remission of proteinuria, although in these populations, 48%–84% had early stage MN and only 32%–48% of the cases had nephrotic syndrome [25, 31].

In contrast to malignancy-associated MN, NELL1 has not been identified as a target antigen in syphilis-associated MN. In a retrospective study of 17 patients with MN with syphilis infection, neuron-derived neurotrophic factor (NDNF) was the predominant antigen, being positive in nearly half of syphilis-MN cases. PLA₂R was positive in most of the remaining cases, and the lone PLA₂R/NDNF-negative biopsy was also NELL1 negative. [13]. The patient’s non-treponemal test (RPR) was positive at a low titer of 1:2, and the treponemal test (Trep-Sure EIA) was also reactive. Records from his initial infection in 1964 were unavailable. Treponemal tests generally remain positive for life, while non-treponemal tests usually revert to negative after adequate treatment; however, they may persist at low titers in some individuals (serofast state) [32]. As the patient had no clinical features suggestive of syphilis, he likely did not have active syphilis, and syphilis is unlikely to have been the cause of his MN.

Cases of drug-induced MN have been reported in association with monoclonal antibody therapy [33–35]. In our patient, however, tralokinumab was initiated several months after the onset of leg edema. The medication was administered for less than 2 months and was discontinued once proteinuria was confirmed to be in the nephrotic range. Since the clinical signs of MN preceded tralokinumab initiation, the drug was not considered the causative agent.

In the present case, due to lack of effective therapy for metastatic thyroid carcinoma, immunosuppression was avoided, and conservative management with RAAS blockade and SGLT2 inhibition was initiated. The decline in proteinuria occurred gradually following the initiation of antiproteinuric therapy, overlapping with the period of doxycycline therapy for positive syphilis serologies. Given the low likelihood of active syphilis and the established antiproteinuric effects of RAAS blockade and SGLT2 inhibition, the improvement in proteinuria is more plausibly attributed to renoprotective therapy rather than antibiotic treatment.

This case has several limitations. Serum NELL1 antibody testing was not available, and a repeat renal biopsy was not performed to document histologic evolution after treatment. The absence of prior RPR titers made it difficult to determine whether the serologic findings represented active syphilis or a serofast state. In addition, the overlap of RAAS blockade and SGLT2 inhibitor therapy initiation with antibiotic treatment for syphilis made it difficult to disentangle their antiproteinuric therapy effects from the impact of treating potential secondary causes.

This case highlights the diagnostic and therapeutic complexity of MN when more than one potential associated condition is present. A comprehensive and systematic evaluation remains vital, even when a seemingly definitive cause is identified. This approach ensures that no contributing factors are overlooked and facilitates the most appropriate management strategy for each individual patient.

This case report has been prepared in accordance with the CARE guidelines, and the completed CARE checklist is provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000549351).

Statement of Ethics

This study was performed in accordance with the Declaration of Helsinki. Ethical approval was not received for this human study because, according to the Oregon Health and Science University Institutional Review Board, a case report involving 3 subjects or fewer does not require ethical approval. Ethical approval is not required for this study in accordance with local or national guidelines. The adult participant provided written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

Rupali S. Avasare was a member of the journal’s Editorial Board at the time of submission. The remaining authors have no conflicts of interest to declare.

Funding Sources

R.S.A. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number K23DK135855. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author Contributions

Basheer Ahamad Kummangal: data curation, writing – original draft, review and editing. Oliver Padgett: supervision, resources, writing – review and editing. Lisa Kumasaka: writing – original draft. Nicole Andeen: resources and writing – review and editing. Rupali S. Avasare: conceptualization, supervision, and writing – review and editing.

Funding Statement

R.S.A. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number K23DK135855. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data Availability Statement

The data supporting the findings of this case report are available within the article itself; further data are protected health information. Further enquiries can be directed to the corresponding author.