The association between glomerular diseases and malignancies was first recognized as early as the 1920s by Galloway in patients with Hodgkin’s disease (1). Subsequent studies have reported that renal involvement may occur in over 7% of cancer patients. (2, 3). A recent Brazilian retrospective cohort analysis found that 1.97% of patients had concurrent glomerulopathy and neoplasms, with hematologic malignancies being the most common (35.8%), followed by colon and gynecologic tumors (4).

In this study, we present a case series of paraneoplastic nephrotic syndrome (PNS) in association with three solid tumors: ovarian cancer, pancreatic neuroendocrine tumor (NET), and bladder cancer. The occurrence of PNS in conjunction with these malignancies is rarely documented. Notably, all patients achieved complete or partial remission without corticosteroid or immunosuppressive therapy. These observations accentuate the critical role of malignancy in the pathogenesis of glomerulopathy and underscore the therapeutic primacy of oncological control in these patients.

Paraneoplastic glomerular diseases refer to glomerular lesions that are indirectly caused by the presence of malignancy through tumor-related mechanisms and which tend to improve following effective treatment of the underlying cancer (5). The clinical diagnosis is often supported by the following characteristics (6, 7): (1) Clinical manifestations of renal injury have a time correlation with tumor (5, 8), especially within 2 years (9); (2) effective treatment of tumor, either surgical or chemical, is the premise for clinical and histologic remission of renal injury (10); (3) deterioration of renal function attributed to tumor relapse (5, 11); and (4) a pathophysiological connection between glomerular lesion and tumorigenesis, namely tumor antigens or antibody components detected by pathological examination (6). Among these, MN represents the most frequently reported histologic pattern, although other pathological alterations may occur (5, 12, 13). Importantly, there are currently no established consensus guidelines for the management of both cancer and paraneoplastic glomerulopathy (14, 15). In this context, we present three rare instances of solid malignancy-associated NS, including ovarian cancer, pancreatic NET, and bladder carcinoma, which are highly suggestive of a paraneoplastic etiology. A paramount and unifying observation across all cases is the achievement of complete or partial NS remission solely through antitumor and supportive therapies, without the use of corticosteroids or immunosuppressive agents. This finding accentuates a critical role of underlying malignancy in the pathogenesis of glomerulopathy in these patients and underscores the therapeutic primacy of oncological control. Clinical characteristics, management, and outcomes of three presenting cases are summarized in Table 1.

Ovarian cancer, one of the most common gynecologic malignancies, frequently presents with non-specific symptoms in its early stages (16, 17). Its association with paraneoplastic glomerulopathy remains rare, with only 20 documented cases to date (including 5 benign teratomas) (Table 2) (18–33). Notably, 70% (14/20) of these patients achieved renal remission during follow-up, despite approximately half receiving steroids or immunosuppressive therapy, suggesting a favorable renal prognosis in ovarian cancer-associated PNS, although oncologic outcomes were frequently unreported. Recent studies have also indicated associations between gynecological neoplasms and glomerular lesions, although the histological characteristics remain undefined (4). In our first case, the temporal dynamics between tumor activity and renal response were particularly revealing. Although a definitive histological diagnosis is lacking, complete and sustained NS remission was induced following cytoreductive surgery and chemotherapy, providing strong clinical evidence for a paraneoplastic etiology. Although the patient had been on long-term irbesartan therapy prior to the onset of NS, and spontaneous remission could not be entirely ruled out, the immediate response to tumor debulking remains the most plausible explanation and underscores the value of steroid-sparing approaches in such scenarios. Another important point is the potential nephrotoxicity of oncological therapies, such as bevacizumab, used in this case. Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF-A) and is known to be associated with proteinuria and other glomerular lesions, such as glomerular microangiopathy (34, 35). Critically, the temporal sequence of events in this patient, which showed significant renal improvement after tumor-directed therapy but persisted despite the administration of bevacizumab, supports the primacy of a paraneoplastic mechanism–rather than drug-induced nephrotoxicity—is the primary cause. Notably, the renal remission in this case proved remarkably resilient, persisting even upon subsequent oncologic progression, a phenomenon rarely documented in prior ovarian cancer-associated PNS cases. This suggests that initial reduction in tumor burden might disrupt paraneoplastic pathways sufficiently to induce prolonged stabilization of glomerular permeability, independent of later tumor progression, which is consistent with previous findings that glomerular lesions may be indirectly related to tumor burden, invasion, or metastasis (5, 6).

In this case, the initial parallel decline of both CA125 and HE4 with NS remission, followed by their subsequent dissociation (isolated HE4 elevation during cancer progression without NS relapse), revealed a fascinating nuance not previously emphasized in the literature. This dissociation may be clinically significant, since HE4 has been shown to possess higher specificity for ovarian malignancy than CA125 (36, 37), and its elevation has been observed in chronic kidney disease (CKD) independent of renal function (38, 39). Therefore, the isolated HE4 increase likely reflected genuine tumor progression, whereas the sustained NS remission suggested a decoupling of the paraneoplastic mechanism. This observation suggests complex biomarker interactions in PNS that merit further investigation.

Neuroendocrine neoplasms (NENs) represent a diverse group of tumors predominantly originating from gastroenteropancreatic (GEP) tissues (40, 41). The majority are indolent neuroendocrine tumors (NETs), while approximately 10–20% are neuroendocrine carcinomas (NECs) with rapid disease progression (41, 42). To date, only two cases of NEN-associated PNS have been reported worldwide, one including a case of pancreatic NEC (43), and another a pancreatic NET (Table 3) (44). Our study presents the third global case and the first Asian case of pancreatic NEN-related PNS. Of particular interest is the temporal pattern of the paraneoplastic glomerulopathy, occurring before the administration of sunitinib and remitting during postoperative surufatinib therapy, and recurring with tumor progression. This pattern strongly suggests that tumor burden, rather than drug toxicity (45, 46), serves as the primary driver of renal injury, similar to our first case. More notably, subsequent tumor progression under everolimus therapy was paradoxically associated with partial NS remission, indicating a complex and non-linear relationship between tumor burden and paraneoplastic glomerulopathy. This observation also suggests a potential nephroprotective role for everolimus through mTORC1 inhibition, as demonstrated in previous studies (36, 37), adding a novel therapeutic dimension to the management of such complex cases that has not been adequately described in the existing literature.

In the literature, only eight cases of bladder tumor-related paraneoplastic NS have been reported (47–54), with four cases demonstrating partial or complete NS remission after surgical treatment. Corticosteroid therapy failed to improve proteinuria in two of these cases (49, 50), contrasting with the more favorable renal outcomes observed in ovarian cancer-associated PNS. Our third case of bladder cancer-associated MN provides critical new insights into its diagnostic and therapeutic challenges. Although the pathological pattern itself may not be unusual, the clinical presentation and course were highly instructive, expanding upon the eight previously reported cases of bladder tumor-related PNS (47–54). Different from prior cases (Table 3), in our patient, the manifestation of NS preceded bladder malignancy detection by several months. Significantly, partial remission was achieved with losartan monotherapy even before tumor detection, and this remission was further accelerated following surgical resection. This might be attributed to diagnostic limitations, since initial urological screening with ultrasonography revealed no masses at the time of NS diagnosis, while sensitive methods, including CT urography or contrast-enhanced ultrasound, are not routinely applied for scanning NS patients in the clinical setting, even in the elderly. Furthermore, while malignancy-associated MN is associated with other antigens such as THSD7A (13, 55), these biomarker assays are not yet widely integrated into routine clinical practice in our institution, due to cost constraints. Importantly, the observed treatment response in the third case indicates a dual potential mechanism: first, the reduction in tumor burden removes the antigenic stimulus; second, angiotensin receptor blockers (ARBs) may exert nephroprotective and potential antitumor effects by inhibiting the renin–angiotensin–aldosterone system (RAAS), which has been implicated in tumorigenesis via signaling pathways including Ras/RAF/MAPK/ERK, PI3K/AKT/mTOR, and Wnt/β-catenin (56–61). Therefore, this case highlights the importance of maintaining a high index of suspicion for occult malignancy in patients with NS, even after an initially negative urological evaluation, and the importance of scheduled monitoring, even after treatment initiation.

Current understanding of paraneoplastic glomerulopathy pathogenesis remains incomplete despite several proposed molecular mechanisms (62–66). Our cases contribute to this understanding by demonstrating that: (1) the relationship between tumor burden and glomerulopathy is not always linear and may exhibit complex temporal dynamics; (2) different cancer types may use distinct pathophysiological pathways to induce glomerular injury, which may be reflected in variations of specific biomarkers; (3) non-immunosuppressive treatments, including both RAAS inhibition and targeted antitumor agents, can be effective while potentially minimizing side effects; and (4) certain antineoplastic agents may possess underrecognized nephroprotective effects in PNS. Future research should prioritize the identification of novel biomarkers through the analysis of renal biopsy specimens from cancer patients with glomerular involvement, combined with functional validation in reliable in vitro and in vivo models. Large-scale cohort studies are needed to identify epidemiological characteristics, including the influence of race, ethnicity, age, and gender, as well as temporal relationships between tumor diagnosis and renal manifestations. Such investigations would advance our understanding of disease mechanisms and contribute to the establishment of more precise diagnostic criteria and prognostic indicators for this complex paraneoplastic phenomenon.