Concomitant Nephrotic Syndrome and Cryoglobulinemia in a Case of Malignant Mesothelioma

Malignant pleural mesothelioma is rarely associated with nephrotic syndrome. Cryoglobulinemia is found in various pathological statuses, such as hepatitis C virus infection but rarely in malignant neoplasms. We recently encountered a patient with malignant mesothelioma coincident with nephrotic syndrome and cryoglobulinemia in the course of chemotherapy. A 60-year-old man employed as a building painter was diagnosed with malignant mesothelioma by lung biopsy two years earlier and was started on chemotherapy. Nivolumab seemed effective in controlling mesothelioma, but skin immune-related adverse events occurred during the course of treatment. After discontinuation of nivolumab and administration of gemcitabine as an alternative therapy, the patient was referred to a nephrologist because of the subsequent development of edema, renal injury, and proteinuria. Following the investigation, he was diagnosed with nephrotic syndrome and cryoglobulinemia with C4-dominant cold activation. However, a percutaneous renal biopsy could not be performed due to persistent severe cough induced by pleural involvement. The patient died a little over three years after the pathological diagnosis of pleural mesothelioma. Our case had three key features nephrotic syndrome was possibly associated with malignant mesothelioma; cryoglobulinemia occurred in malignant mesothelioma; and concomitant nephrotic syndrome and cryoglobulinemia occurred after chemotherapy. Unfortunately, our rare case lacks a basis in renal pathology or evidence of links between the pathogenesis of malignant mesothelioma, cryoglobulinemia, and nephrotic syndrome. This case does not provide a causal mechanism, but may be worth adding to the case list as one of the rare renal involvement in a patient with malignant mesothelioma.

Cryoglobulinemia is found in various pathologic statuses. Before the appearance of specific antiviral treatments, the main etiology was chronic hepatitis C virus (HCV) infection, and currently, cryoglobulinemia is mainly associated with systemic autoimmune diseases, malignant neoplasms, and cases without an identified etiology (i.e., essential cryoglobulinemia) [17,18]. Malignant mesothelioma with the development of cryoglobulinemia is very rare but has been reported in some cases [19].
In addition to such rare cases, we recently encountered a patient with malignant mesothelioma with concomitant nephrotic syndrome and cryoglobulinemia during the course of chemotherapy.

Case Presentation
A 60-year-old man visited a nephrologist due to edema, renal injury, and proteinuria. e man was a building painter and had developed massive lateral pleural effusions three years earlier. He was finally diagnosed with malignant mesothelioma from a thoracoscopic lung biopsy 2 years earlier and was started on chemotherapy ( Figure 1). Cisplatin plus pemetrexed (CDDP + PEM) was administered as first-line therapy, followed by carboplatin plus pemetrexed (CBDCA + PEM) as second-line treatment.
is regimen proved ineffective and the disease progressed, so the patient was switched to nivolumab. Nivolumab seemed effective in controlling mesothelioma, but skin immune-related adverse events (irAEs) occurred during the course of treatment. Prednisolone (20 mg/day) was given to alleviate irAEs and was gradually tapered. After discontinuation of nivolumab and administration of gemcitabine (GEM) as fourth-line therapy, drug-induced lung injury occurred and GEM was also discontinued. e patient was referred to a nephrologist after edema, renal injury and proteinuria developed.
At the first visit, as shown in Table 1, laboratory data showed massive proteinuria (4.3 g/day) and hypoalbuminemia (2.4 g/day), suggesting nephrotic syndrome. Notable findings were newly developed polyclonal gammopathy (IgG 2,288 mg/dL, IgA 455 mg/dL, and IgM 94 mg/dL) and characteristic low complementemia (C3 170 mg/dL, C4 17 mg/dL, and CH50 57 U/mL), suggesting C4-dominant cold activation. Cryoglobulins were qualitatively found to be positive. Other causes of secondary cryoglobulinemia, such as hepatitis B virus and HCV chronic infections were serologically excluded. Since cryoglobulin might occur with antigens from malignant disease, the patient was administered another line of chemotherapy for nephrotic syndrome with cryoglobulinemia due to the progression of malignant mesothelioma after careful consideration and informed consent. Nephrotic syndrome gradually improved along with the administration of vinorelbine (VNR) as the fifth-line treatment ( Figure 1). Low serum C4, cryoglobulinemia, and nephrotic range of   Figure 1: e clinical course of the patient. Two years earlier, the patient had been diagnosed with malignant mesothelioma by lung biopsy and treated with chemotherapy. Cisplatin plus pemetrexed (CDDP + PEM) and carboplatin plus pemetrexed (CBDCA + PEM) were determined to result in an insufficient response, and nivolumab was considered to have induced immune-related adverse events and was discontinued. After starting the administration of gemcitabine (GEM), drug-induced lung injury occurred. He was also referred to a nephrologist because of the subsequent development of edema, renal injury, and proteinuria. After investigations and careful consideration, vinorelbine (VNR) was administered to treat the nephrotic syndrome with cryoglobulinemia due to the progression of malignant mesothelioma. Response of chemotherapy to malignant mesothelioma is presented as partial response (PR), stable disease (SD), and progressive disease (PD). Palliative care was subsequently provided, along with radiation therapy for metastatic bone lesions and antibiotics against bacterial pneumonia. e patient died a little over 3 years after the pathological diagnosis of mesothelioma without recurrence of nephrotic syndrome in the end-stage of cancer.
proteinuria had disappeared after VNR therapy. Percutaneous renal biopsy could not be performed due to persistent severe cough induced by pleural involvement. e clinical diagnosis was thought to be nephrotic syndrome with cryoglobulinemia due to the progression of malignant mesothelioma. ereafter, palliative care was provided, along with radiotherapy for metastatic bone lesions and antibiotics against bacterial pneumonia. e patient died a little over three years after pathological diagnosis of mesothelioma without recurrence of nephrotic syndrome in the end-stage of cancer.

Discussion
e present case showed three features newly developed nephrotic syndrome was possibly associated with malignant mesothelioma; cryoglobulinemia occurred in malignant mesothelioma; and concomitant transient nephrotic syndrome and cryoglobulinemia occurred after the use of nivolumab or GEM, but not VNR. Unfortunately, this case lacked a basis in renal pathology or evidence of links between the pathogenesis of malignant mesothelioma, cryoglobulinemia, and nephrotic syndrome. However, we discuss here the causal relationship between the three events based on the literature as much as possible. We reviewed 15 publications presenting cases of nephrotic syndrome with malignant mesothelioma at various sites [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Seven cases included information on complement levels, all of which were within the normal range. A description of cryoglobulins was absent in all previous cases ( Table 2). Most of the renal pathology involved minimalchange disease in patients with malignant mesothelioma and nephrotic syndrome [12], accounting for 9 of the 15 cases (60%) in Table 2. ree cases of membranous nephropathy were identified, followed by one case each of focal segmental glomerulosclerosis and mesangial proliferative nephritis, but no reports of membranous proliferative glomerulonephritis, which may occur in cryoglobulinemia. Meanwhile, definitively assessing the pathological characteristics of this case is difficult because renal biopsy could not be performed at the moment of nephrotic syndrome due to the condition of the patient. Nevertheless, the result of the high selectivity of proteinuria (index, 0.09; Table 1) suggests the possibility of minimal-change disease, consistent with previous cases.  Cryoglobulinemia-associated glomerulonephritis is most commonly seen in the context of hepatitis C infection and occasionally seen in relation to lymphoma and malignant neoplasm [18,[20][21][22]. In contrast with renal disease associated with HCV, renal involvement in patients with cryoglobulinemia not associated with HCV has only been poorly described, and few cases have been reported [23]. In an analyzed series of 20 cases without HCV-associated cryoglobulinemia, renal involvement was characterized by nephrotic range proteinuria in 75% of patients and renal failure in 85% of patients (mean glomerular filtration rate, 46 mL/min/1.73 m 2 ) [23]. Membranoproliferative glomerulonephritis with subendothelial deposits was observed in all kidney specimens [23]. Generally, therapeutic options for the disease include removal of circulating cryoglobulin by plasmapheresis, immunosuppression, and pharmacological treatment to address the underlying cause of protein production. After excluding the possibility of any infectious diseases, including viral hepatitis, and careful consideration, we tried suppression of cancer progression by next-line chemotherapy with VNR after the diagnosis of nephrotic syndrome. In this case, cryoglobulin disappeared without apheresis or immunosuppressive drugs, suggesting that one of the relevant mechanisms was anticancer therapy reducing the tumor burden as an antigen against cryoglobulin.
Another possibility for the pathogenesis was that the concomitant nephrotic syndrome and cryoglobulinemia were driven by chemotherapy. In terms of the time course, in this case, the suspect drug was nivolumab or GEM, but not VNR. Only one study suggested that anti-PD-1-related cryoglobulinemia during nivolumab treatment in a patient with lung cancer [24]. He was treated with prednisone and cryoprecipitates disappeared after 26 days of steroid therapy. e patient continued to receive nivolumab for a total of eight cycles with no recurrence of cryoglobulinemia [24]. Nivolumab is also known as a rare cause of nephrotic syndrome during cancer therapy, represented by minimal-change disease [25], membranous nephropathy [26], membranoproliferative glomerulonephritis [27], and renal vasculitis [28]. A hemolytic uremic syndrome is the most perilous adverse effect of gemcitabine, with an incidence of approximately 0.15% based on reported cases [29]. GEM-induced secondary thrombotic microangiopathy may be diagnosed as a nephrotic syndrome [30]. Membranous nephropathy as a cause of nephrotic syndrome was also found in a case treated using GEM [31]. Collectively, both nivolumab and GEM could cause nephrotic syndrome, while no previous reports have shown any association between GEM and cryoglobulinemia.
erefore, if we consider nephrotic syndrome and cryoglobulinemia to represent linked complications rather than coincidences, the suspect drug is most likely nivolumab, not GEM.
To the best of our knowledge, this represents the first description of concomitant nephrotic syndrome and cryoglobulinemia in a case of malignant mesothelioma. Although no causal mechanisms or pathological findings were identified, this case may be worth adding to the case list as a rare coincidence in a patient with malignant mesothelioma.