**3. Diagnosis and mechanism of paraneoplastic glomerulopathy associated with renal cell carcinoma**

Recent development or worsening of diabetes mellitus, increased platelet or C-reactive pro‐ tein (CRP), and hypercalcemia also suggests the existence of paraneoplastic syndrome. Glo‐ merulonephritis is considered when urinalysis shows dysmorphic red blood cells and red blood cell casts, as hematuria caused by renal cell carcinoma usually shows isomorphic red blood cells. When proteinuria exceeds 1g per day, it is also better to speculate overlapping glomerulonephritis and examine serological tests including immunoglobulins (IgG, IgA, IgM), complements (CH50, C3, C4), anti-nuclear antibody, and anti-dsDNA antibody. A fi‐ nal diagnosis of glomerulonephritis can only be given by a renal biopsy. Renal cysts or masses identified by renal ultrasonography at the time of renal biopsy should be further in‐ vestigated with CT and MRI. Renal cancer will progress rapidly after steroid therapy for glomerulonephritis.

The diagnosis of paraneoplastic glomerulopathy will be suggested following the criteria; 1) existence of a time relationship between the diagnosis of the glomerulopathy and cancer, 2) no obvious etiology for glomerular diseases, 3) clinical or histological remission of glomerul‐ opathy after complete remission by surgical removal of carcinoma, 4) recurrence of the carci‐ noma associated with deterioration of glomerular diseases [3,23].

As mentioned above, inactivation of the *VHL* gene by frame-shift mutation is observed in about 60% of sporadic RCC [5]. Activated HIF-1α without VHL protein stimulates hypoxiarelated proteins such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which lead to tumor growth and trigger angiogenesis (Figure 1) [8,10]. The increased VEGF accelerates glomerular permeability and causes proteinuria, and PDGF and IL-6 stimulates mesangial cell proliferation, and TGF-β increases the mesangial matrix, contributing to the development of glomerulonephritis.

[32], thus, the elevated IL-6 in renal cell carcinoma may increase circulating IgA, which de‐

Paraneoplastic Glomerulopathy Associated with Renal Cell Carcinoma

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**Figure 3.** Clear cell renal cell carcinoma in association with IgA nephropathy. (A) PAS staining of clear cell carcinoma with a capsule. (B) immunostaining for IL-6 showing positive immunoreactivity in the infiltrating lymphocytes and plasma cells around the clear cell carcinoma and capsule. (C) IgA immunoreactivity positive in the plasma cells around renal cell carcinoma. (D) Renal biopsy sample showing segmental mesangial cell proliferation. (E) Immunofluores‐

The most frequent paraneoplastic glomerulopathy associated with solid tumors is membra‐ nous nephropathy and it is easy to detect because most of the cases manifest the nephrotic syndrome (paraneoplastic nephrotic syndrome) [3,23,33]. Since membranous nephropathy associated with malignancy has been attributed to tumor antigen-antibody immune com‐ plex formation, the cancer related antigens have been identified in immune complex in some cases including PSA in prostate cancer, CEA in gastrointestinal cancer [34]. Renal cell carci‐ noma has been reported to be associated with membranous nephropathy [35-43], but its prevalence is lower compared with gastrointestinal cancer and lung cancer (Table 3). As an‐ tibodies against phospholipase A2 receptor antibody have been identified in 70 % of pa‐ tients with primary membranous nephropathy [44], a diagnosis of secondary membranous nephropathy should be considered when it is negative. IgG subclass immunofluorescence is useful to distinguish the primary membranous nephropathy in which IgG4 is stained pre‐ dominately. In a case of secondary membranous nephropathy associated with renal cell car‐ cinoma, showed predominantly IgG1 and IgG3 staining compared to IgG4 (Figure 4). The renal tubular epithelial antigen (RTE) has been identified in one case of renal cell carcinoma [45], but in most cases the tumor antigen-antibody complex were not identified in the serum

cence showed positive staining of IgA in the mesangial area, and weak staining of C3 (F).

**4.2. Membranous nephropathy and renal cell carcinoma**

posits in the mesangial area causing IgA nephropathy.

It is interesting that IgA nephropathy showed a higher prevalence than membranous nephr‐ opathy in renal cell carcinoma, whereas about 50% of glomerulopathies associated with gas‐ trointestinal neoplasias and lung cancers were membranous nephropathy (Table 3). The mechanisms of paraneoplastic nephropathy may be different in renal cell carcinoma com‐ pared with gastrointestinal neoplasias and lung cancers. The paraneoplastic nephropathy of renal cell carcinoma may depend more upon overproduction of cytokines rather than crossreaction with tumor antigen and production of autoantibodies.


**Table 3.** Type of glomerulopathy in renal cell carcinoma compared with gastrointestinal neoplasia and lung cancer. Modified from [3].
