Sustained remission of NELL-1-positive membranous nephropathy after lung adenocarcinoma resection and during subsequent atezolizumab therapy in a 68-year-old man: a case report

Introduction

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults. The identification of neural epidermal growth factor-like 1 (NELL-1) as a target antigen in a subset of MN expanded the antigen-based classification of the disease (1). NELL-1-positive MN represents a clinically distinct entity, frequently characterized by predominant immunoglobulin G (IgG) 1 subclass deposition along the glomerular basement membrane (GBM) (1,2). A critical clinical aspect of NELL-1-positive MN is its reported association with underlying solid malignancies, particularly lung and gastrointestinal carcinomas, with reported malignancy rates varying across cohorts (ranging from 10% to 33%) and potentially influenced by differences in patient age, referral patterns, and screening intensity (1,2). Consequently, the identification of NELL-1-positive MN warrants careful evaluation for secondary causes, including age-appropriate cancer screening (3).

When an associated malignancy is identified in a patient with NELL-1-positive MN, substantial therapeutic uncertainties arise regarding the management of both the renal disease and the underlying cancer. Although treatment of an underlying malignancy may influence the course of malignancy-associated MN, clinical data regarding the long-term renal course following oncological interventions remain limited (4,5). This therapeutic complexity is further heightened in the setting of cancer recurrence requiring immune checkpoint inhibitors (ICIs). ICIs can induce renal immune-related adverse events (irAEs); while acute tubulointerstitial nephritis is the most common ICI-associated renal irAE, glomerular diseases—including new-onset or recurrent MN—have also been documented (6,7). Thus, whether ICI therapy can be administered without triggering nephrotic relapse in patients with resolved paraneoplastic NELL-1-positive MN remains poorly defined. Here, we present a clinically informative case of NELL-1-positive MN in a 68-year-old man associated with a NELL-1-negative stage IIIA lung adenocarcinoma. The patient’s nephrotic syndrome progressively improved following surgical tumor resection without renal-directed pharmacological therapy and subsequently entered clinical remission. Upon subsequent systemic recurrence, he received atezolizumab-based chemoimmunotherapy and has maintained renal remission without nephrotic relapse during more than 1 year of ongoing atezolizumab therapy to date. This clinical course provides insight into the behavior of NELL-1-positive MN during cancer recurrence and subsequent ICI therapy. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0756/rc).

Case presentation

A 68-year-old man presented with bilateral lower extremity edema. Physical examination confirmed marked pitting edema of the lower extremities, whereas other systemic findings were unremarkable. Initial laboratory investigations revealed severe nephrotic syndrome characterized by profound hypoalbuminemia (serum albumin: 1.3 g/dL) and massive proteinuria [urine protein-to-creatinine ratio (UPCR): 8.0 g/gCr]. Renal function remained relatively preserved at presentation [serum creatinine: 1.12 mg/dL, estimated glomerular filtration rate (eGFR) 51.3 mL/min/1.73 m²] (Table 1). The patient had no significant past medical history. He was a former smoker with a 33-pack-year history and had previous occupational exposure to concrete dust. To investigate secondary etiologies of nephrotic syndrome, extensive diagnostic work-up was performed. Serological testing for autoimmune diseases was negative or within normal limits [antinuclear antibody (ANA): 1:40, proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA): <1.0 U/mL, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA): <1.0 U/mL, anti-dsDNA: 1 U/mL, anti-CCP: <0.4 U/mL, anti-RNP: 3.7 U/mL, anti-Jo-1: 0.6 U/mL]. Viral hepatitis markers [hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody] were negative. Serum free light-chain testing showed no evidence of monoclonal gammopathy, and no medications known to be associated with secondary MN were identified. Tumor markers revealed CYFRA at 2.4 ng/mL and sialyl Lewis X antigen (SLX) at 52.2 U/mL (Table 1).

To determine the etiology of the nephrotic syndrome, a percutaneous renal biopsy was performed. Light microscopy revealed diffuse thickening of the GBM with characteristic holes on periodic acid-methenamine-silver staining, consistent with Ehrenreich-Churg stage II MN (Figure 1A). Electron microscopy confirmed numerous subepithelial electron-dense deposits with associated podocyte foot process effacement (>80%) (Figure 1B,1C). Immunofluorescence microscopy demonstrated granular global deposition of IgG and C3 along the glomerular capillary walls. Subclass analysis revealed relative IgG1 predominance (+), with weaker staining for IgG2 (+/−), IgG3 (+/−), and IgG4 (+/−) (Figure 2). Furthermore, immunohistochemical staining for NELL-1 showed strong positivity (+) along the GBM (Figure 3), whereas staining for PLA2R and THSD7A was equivocal (+/−) (data not shown). Based on these findings, a diagnosis of NELL-1-positive MN was established. Given the known association between NELL-1-positive MN and malignancy, extensive systemic screening was initiated. Chest radiography showed a pulmonary nodule in the left upper lung field (Figure 4A), and chest computed tomography (CT) revealed a 15-mm irregular spiculated nodule in the left pulmonary apex, with suspected enlargement of the left hilar lymph node (Figure 4B,4C). Thus, the onset of edema and nephrotic-range proteinuria clearly preceded the diagnosis of lung cancer. He subsequently underwent a left upper lobectomy with systematic lymph node dissection. Histopathological evaluation of the resected specimen revealed lung adenocarcinoma, and the pathological stage was determined to be pT1bN2M0, stage IIIA. Molecular profiling using the Oncomine Dx Target Test identified no actionable genetic mutations, and immunohistochemical staining for programmed death-ligand 1 was negative. No postoperative adjuvant systemic therapy was administered because renal function remained somewhat unstable and the subsequent course of the recently diagnosed nephrotic syndrome after tumor resection was still uncertain. Following surgical resection of the lung tumor, nephrotic parameters gradually improved without any renal-directed pharmacological treatment. A clear decline in proteinuria became evident approximately 4 months after surgery, accompanied by a progressive increase in serum albumin. At approximately 4 months after surgery, serum albumin had increased from 1.3 to 2.4 g/dL and UPCR had decreased from 8.0 to 2.3 g/gCr. Renal function remained stable, with serum creatinine remaining approximately 1.1 mg/dL. Thereafter, proteinuria continued to decline and serum albumin progressively recovered. Importantly, no medications were administered for the renal disease during the perioperative or follow-up periods—including renin–angiotensin system inhibitors, diuretics, anticoagulants, corticosteroids, or other systemic immunosuppressive therapies. The temporal improvement in nephrotic syndrome following tumor resection in the absence of renal-directed pharmacological treatment was considered consistent with a possible paraneoplastic relationship, although causality could not be established.

Figure 1 Renal biopsy findings. (A) Light microscopy (PAM staining) showing diffuse thickening of the GBM with holes corresponding to subepithelial deposits (arrow). The boxed area is shown at higher magnification in the inset, where holes indicating subepithelial deposits are highlighted (blue arrow). (B) Electron microscopy (low magnification) demonstrating numerous subepithelial electron-dense deposits along the GBM. (C) Electron microscopy (high magnification) showing subepithelial electron-dense deposits (red arrows) accompanied by extensive podocyte foot-process effacement. GBM, glomerular basement membrane; PAM, periodic acid-methenamine-silver.

Figure 2 Immunofluorescence microscopy for IgG subclasses. Granular staining along the glomerular capillary walls shows relative IgG1 predominance, whereas IgG2, IgG3, and IgG4 show weaker staining (original magnification, ×200). IgG, immunoglobulin G.

Figure 3 NELL-1 staining in the kidney. Immunohistochemical staining for NELL-1 shows strong granular positivity along the glomerular basement membrane (original magnification, ×400). NELL-1, neural epidermal growth factor-like 1.

Figure 4 Chest imaging findings. (A) Chest radiograph showing a pulmonary nodule in the left upper lung field (red arrow). (B) Chest CT (lung window) demonstrating a 15-mm irregular spiculated nodule in the apex of the left upper lobe (red arrow). (C) Chest CT (mediastinal window) showing enlargement of the left hilar lymph node (red arrow). CT, computed tomography.

However, 8 months after surgery, surveillance CT revealed multiple pulmonary nodules, signifying pulmonary recurrence of adenocarcinoma. On repeated assessments immediately before systemic therapy, serum albumin was 3.6–3.8 g/dL, serum creatinine was approximately 1.1 mg/dL, eGFR was approximately 51 mL/min/1.73 m², and urinalysis was negative for protein. At the time of recurrence, several therapeutic options were considered, including cytotoxic chemotherapy alone because of concerns regarding MN relapse. After discussion of the potential benefits of chemoimmunotherapy and the risks of nephrotic relapse and other irAEs, a combination of chemotherapy and an ICI was selected. In June 2025, he initiated first-line chemoimmunotherapy comprising carboplatin, nab-paclitaxel, and atezolizumab. He received 4 cycles of the three-drug combination, followed by maintenance atezolizumab administered every 3 weeks. During atezolizumab-based therapy, he achieved a sustained partial response. Serum chemistry and urinalysis were assessed at every 3-week treatment visit. Urinary protein remained negative throughout treatment, serum creatinine remained stable at approximately 1.1–1.3 mg/dL, and eGFR was generally maintained at approximately 48–55 mL/min/1.73 m², without recurrence of hypoalbuminemia or nephrotic syndrome. Surveillance CT was performed approximately every 3–4 months. As of July 2026, he remained on maintenance atezolizumab after 14 maintenance cycles, with ongoing tumor control and sustained renal remission. No irAEs, including renal irAEs, had occurred. Immunohistochemical staining for NELL-1 was performed on the resected primary lung tumor, which showed no NELL-1 expression (Figure 5). All procedures performed in this case were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 5 NELL-1 staining in the lung tumor. (A) Hematoxylin and eosin staining shows glandular structures with relatively large tumor cells containing abundant cytoplasm and large nuclei in the lung tumor. (B) Immunohistochemical staining demonstrates no NELL-1 expression in the lung tumor cells. (Original magnification, ×200). NELL-1, neural epidermal growth factor-like 1.

Discussion

This case highlights two important clinical observations: the improvement of NELL-1-positive MN following tumor resection of lung adenocarcinoma, without renal-directed pharmacological therapy, suggesting a possible paraneoplastic association, and the sustained renal remission during subsequent atezolizumab therapy for recurrent malignancy. In this patient, nephrotic syndrome progressively improved following resection of the primary lung tumor and remained in remission despite subsequent recurrence requiring ICI treatment. Although this temporal relationship is clinically suggestive, it does not establish causality. Spontaneous remission of MN remains a plausible alternative explanation (4). Nevertheless, the progressive reduction in proteinuria and recovery of serum albumin after tumor resection occurred without renin–angiotensin system blockade, diuretics, corticosteroids, or other immunosuppressive therapy. Thus, the clinical course favors, but does not prove, a possible paraneoplastic association between the lung adenocarcinoma and NELL-1-positive MN.

NELL-1-positive MN has emerged as a distinct clinicopathological subtype with a reported association with malignancy, although the frequency of malignancy varies among cohorts (1,2). In contrast to PLA2R-associated primary MN, patients with NELL-1-positive MN are typically older and more frequently harbor solid tumors, particularly lung and gastrointestinal malignancies (1,2). These findings underscore the clinical importance of careful evaluation for secondary causes, including age-appropriate malignancy screening, in this setting (3). However, the coexistence of malignancy should not itself be considered evidence of a causal relationship, and its clinical significance should be interpreted in the context of the pathological findings and subsequent clinical course.

In our case, renal biopsy showed strong NELL-1 positivity, and immunohistochemical staining of the resected lung tumor was negative for NELL-1. This discordance represents an important uncertainty in interpreting the relationship between the tumor and MN and weakens a simple model in which direct expression of NELL-1 by the tumor serves as the antigenic stimulus for the renal immune response. Although some studies have demonstrated NELL-1 expression within tumor tissues (2,8), its absence in the primary tumor in our case requires consideration of alternative explanations. Several possibilities may be hypothesized. First, intratumoral heterogeneity could result in focal NELL-1 expression that was not captured in the examined sections, or expression could have been present in unsampled tumor or metastatic tissue (2,8). Second, the tumor may have indirectly promoted immune dysregulation, tissue injury, or loss of tolerance to endogenous NELL-1 derived from non-neoplastic tissue (4,8). Finally, low-level NELL-1 expression below the detection threshold of immunohistochemistry cannot be excluded. Epigenetic regulation could theoretically contribute to reduced antigen expression (9), although this was not investigated in this patient and evidence from other tumor types cannot establish such a mechanism in this case. More broadly, the pathogenesis of malignancy-associated MN may involve mechanisms beyond direct expression of the target antigen by tumor cells (8,10). These explanations remain speculative, and none was directly demonstrated in this patient. Accordingly, the absence of detectable NELL-1 expression in the lung tumor neither confirms nor excludes a possible paraneoplastic association. The resolution of nephrotic syndrome after tumor resection provides additional clinical support for such an association but cannot establish the underlying mechanism or causality.

The stable renal remission observed during ICI therapy for tumor recurrence represents another clinically relevant aspect of this case. ICIs induce various renal irAEs, most commonly acute tubulointerstitial nephritis, while glomerular diseases, including new-onset or recurrent MN, have also been reported (6,7). However, reports of ICI-associated MN do not necessarily indicate that ICI treatment will trigger relapse in a patient whose MN is already in remission. In the present case, renal remission had been established before atezolizumab initiation, and repeated monitoring during treatment showed persistently negative urinary protein and stable renal function without recurrent hypoalbuminemia. Importantly, no renal or other irAEs were observed during treatment.

The absence of nephrotic relapse despite cancer recurrence and prolonged atezolizumab exposure is noteworthy, but the mechanism underlying this clinical course remains unknown. In particular, the present case does not provide sufficient evidence to determine whether changes in tumor antigen expression, the immune response after tumor resection, or subsequent tumor control contributed to the sustained renal remission. We therefore consider it more appropriate to report this observation without assigning a specific immunological mechanism. This case suggests that ICI therapy may be feasible in selected patients with previously resolved paraneoplastic MN, but a single case cannot establish its safety. Individualized assessment of the potential oncological benefit and renal risk is required, together with close monitoring of urinary protein, serum albumin, and renal function during treatment. Overall, this case supports three cautious clinical considerations. First, NELL-1-positive MN should prompt careful evaluation for secondary causes, including malignancy. Second, when a paraneoplastic relationship is suspected, treatment of the underlying malignancy may influence the renal course, although temporal improvement alone does not establish causality. Third, the use of ICIs in patients with a history of paraneoplastic MN should be individualized and accompanied by close renal monitoring.

Conclusions

This case highlights the importance of careful malignancy screening in patients with NELL-1-positive MN. The improvement in nephrotic syndrome after lung cancer resection suggests a possible paraneoplastic association, although causality cannot be established from a single case. The sustained renal remission during subsequent atezolizumab therapy indicates that ICI treatment was feasible in this patient, but individualized risk assessment and close renal monitoring remain essential.

Acknowledgments

We sincerely thank the patient who provided consent for the publication of this case report.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0756/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0756/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0756/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this case were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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