**4. Types of paraneoplastic nephropathy**

### **4.1. IgA nephropathy and renal cell carcinoma**

Although IgA nephropathy is more common in younger patients, when it occurs in patients older than 60 years, a high prevalence of malignancy (23%) is observed [24]. Solid tumors that invade mucosal tissue like the respiratory tract, the buccal cavity, and the nasopharynx increase circulating IgA levels and show deposition of IgA in the mesangium [24]. Several cases of IgA nephropathy associated with renal cell carcinoma have been reported previous‐ ly [21,25-28]. In Figure 3, a 66 year-old male diagnosed IgA nephropathy with mesangial IgA deposition but weak C3 staining showed a rapid increase in renal cyst during steroid treatment, and a clear cell renal cell carcinoma was found in the resected kidney (Figure 3). The infiltrating plasma cells around the renal cell carcinoma produced IL-6 and IgA (Figure 3). Elevated levels of IL-6 have been reported in 18 (25%) of 71 patients with renal cell carci‐ noma [29], and IL-6 increased in more than 50% of patients with metastatic renal cell carci‐ noma, playing a role as a prognostic marker [19,20,30,31]. IL-6 stimulates IgA production [32], thus, the elevated IL-6 in renal cell carcinoma may increase circulating IgA, which de‐ posits in the mesangial area causing IgA nephropathy.

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

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

PDGF and IL-6 stimulates mesangial cell proliferation, and TGF-β increases the mesangial

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 cross-

**N=48**

**Gastrointestinal neoplasia**

3 (6%) 2 (4%) 5 (12%)

**Lung cancer N=41**

matrix, contributing to the development of glomerulonephritis.

reaction with tumor antigen and production of autoantibodies.

**4. Types of paraneoplastic nephropathy**

**4.1. IgA nephropathy and renal cell carcinoma**

Membranoproliferative glomerulonephritis

114 Renal Tumor

Modified from [3].

**Renal cell carcinoma N=49**

Membranous nephropathy 10 (20%) 26 (54%) 20 (49%) IgA nephropathy 15 (31%) 1 (2%) 2 (5%) Minimal change disease 6 (12%) 9 (19%) 9 (22%) Focal segmental glomerulonephritis 5 (10%) 2 (4%) 1 (2%)

Crescentic glomerulonephritis 10 (20%) 8 (17%) 4 (10%)

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

Although IgA nephropathy is more common in younger patients, when it occurs in patients older than 60 years, a high prevalence of malignancy (23%) is observed [24]. Solid tumors that invade mucosal tissue like the respiratory tract, the buccal cavity, and the nasopharynx increase circulating IgA levels and show deposition of IgA in the mesangium [24]. Several cases of IgA nephropathy associated with renal cell carcinoma have been reported previous‐ ly [21,25-28]. In Figure 3, a 66 year-old male diagnosed IgA nephropathy with mesangial IgA deposition but weak C3 staining showed a rapid increase in renal cyst during steroid treatment, and a clear cell renal cell carcinoma was found in the resected kidney (Figure 3). The infiltrating plasma cells around the renal cell carcinoma produced IL-6 and IgA (Figure 3). Elevated levels of IL-6 have been reported in 18 (25%) of 71 patients with renal cell carci‐ noma [29], and IL-6 increased in more than 50% of patients with metastatic renal cell carci‐ noma, playing a role as a prognostic marker [19,20,30,31]. IL-6 stimulates IgA production

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 and elutes of glomeruli in patients with membranous nephropathy associated with renal cell carcinoma [35,40].

chondria, also show the paraneoplastic minimal change nephrotic syndrome [51]. The pathogenesis of minimal change nephrotic syndrome in not clear, but T cell-mediated im‐ mune response has been postulated. The increased secretion of VEGF from renal cell carci‐ noma may alter glomerular permeability and induce minimal change nephrotic syndrome.

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Magyarlaki et al [21] reported 5 cases (8%) of focal segmental glomerulosclerosis in 60 au‐ topsy cases of renal cell carcinoma, however, there are only a few reports of focal segmental glomerulosclerosis with renal cell carcinoma [52] and Wilms' tumor [53]. Glomerulosclerotic lesions are often observed in the renal parenchyma adjacent to a tumor, so parenchymal compression and urinary outflow obstruction by renal tumor may be involved in the devel‐

**4.4. Crescentic rapidly progressive glomerulonephritis and vasculitis with renal cell**

gression to end-stage renal failure with need of hemodialysis has been reported [54].

**Figure 5.** ANCA-related crescentic nephritis associated with renal cell carcinoma. A) The clear cell renal cell carcinoma was surrounded by many infiltrating inflammatory cells including lymphocytes, plasma cells and some neutrophils. B) Some glomeruli around the renal cell carcinoma demonstrated crescents, and the MPO-ANCA level was decreased

Crescentic glomerulonephritis with rapid progressive renal failure in conjunction with renal cell carcinoma has been reported previously [54-57]. The prevalence of renal cell carcinoma is significantly higher in patients with ANCA-positive Wegener's granulomatosis (7 in 477 patients) than in those with rheumatoid arthritis (1 in 479 patients) with an odds-ratio for development of renal cell carcinoma of 8.73 (p=0.0464, 95% CI 1.04-73.69) [58]. In most of the 7 cases, Wegener's granulomatosis was developed shortly after or simultaneously with the diagnosis of renal cell carcinoma [58]. There are many infiltrating cells around the clear cell renal cell carcinoma (Figure 5), and the chronic inflammation observed in renal cell carcino‐ ma may induce anti-neutrophil cytoplasmic antibodies (ANCA) or the renal cancer cells may serve as an antigen source [59]. The renal prognosis in crescentic glomerulonephritis with renal cell carcinoma becomes poor when an anti-GBM antibody exists, and a rapid pro‐

opment of focal segmental glomerulosclerosis.

from 217 EU to 99 EU after nephrectomy.

**carcinoma**

Even though tumor antigen-antibodies have not been identified yet, renal tumors may have some contribution to the pathogenesis of membranous nephropathy because nephrotic syn‐ drome is transiently ameliorated after tumor excision [40-43].

**Figure 4.** Secondary membranous nephropathy associated with clear cell renal cell carcinoma.

Light microscopy of PAM staining demonstrated thickening of the glomerular basement membrane, and electron microscopy revealed subepithelial electron dense deposits with spike formation. IgG1 and IgG3 were more strongly stained along the capillary wall than IgG4, suggesting secondary membranous nephropathy.

### **4.3. Minimal change disease and focal segmental glomerulosclerosis with renal cell carcinoma**

In contrast to Hodgkin's disease, renal cell carcinoma associated with minimal change neph‐ rotic syndrome is rare [46,47]. The onset of nephrotic syndrome is simultaneous [48,49] or precedes the diagnosis of renal tumor by 3-4 weeks [47,50], and there was a case in which complete remission was achieved after nephrectomy without steroids [49]. These lines of evidence suggest that occurrence of minimal change nephrotic syndrome may be a paraneo‐ plastic syndrome associated with renal cell carcinoma. Renal oncocytoma, characterized by increased cytoplasmic volume containing abundant fine eosinophilic granules and mito‐ chondria, also show the paraneoplastic minimal change nephrotic syndrome [51]. The pathogenesis of minimal change nephrotic syndrome in not clear, but T cell-mediated im‐ mune response has been postulated. The increased secretion of VEGF from renal cell carci‐ noma may alter glomerular permeability and induce minimal change nephrotic syndrome.

and elutes of glomeruli in patients with membranous nephropathy associated with renal cell

Even though tumor antigen-antibodies have not been identified yet, renal tumors may have some contribution to the pathogenesis of membranous nephropathy because nephrotic syn‐

drome is transiently ameliorated after tumor excision [40-43].

**Figure 4.** Secondary membranous nephropathy associated with clear cell renal cell carcinoma.

IgG4, suggesting secondary membranous nephropathy.

**carcinoma**

Light microscopy of PAM staining demonstrated thickening of the glomerular basement membrane, and electron microscopy revealed subepithelial electron dense deposits with spike formation. IgG1 and IgG3 were more strongly stained along the capillary wall than

In contrast to Hodgkin's disease, renal cell carcinoma associated with minimal change neph‐ rotic syndrome is rare [46,47]. The onset of nephrotic syndrome is simultaneous [48,49] or precedes the diagnosis of renal tumor by 3-4 weeks [47,50], and there was a case in which complete remission was achieved after nephrectomy without steroids [49]. These lines of evidence suggest that occurrence of minimal change nephrotic syndrome may be a paraneo‐ plastic syndrome associated with renal cell carcinoma. Renal oncocytoma, characterized by increased cytoplasmic volume containing abundant fine eosinophilic granules and mito‐

**4.3. Minimal change disease and focal segmental glomerulosclerosis with renal cell**

carcinoma [35,40].

116 Renal Tumor

Magyarlaki et al [21] reported 5 cases (8%) of focal segmental glomerulosclerosis in 60 au‐ topsy cases of renal cell carcinoma, however, there are only a few reports of focal segmental glomerulosclerosis with renal cell carcinoma [52] and Wilms' tumor [53]. Glomerulosclerotic lesions are often observed in the renal parenchyma adjacent to a tumor, so parenchymal compression and urinary outflow obstruction by renal tumor may be involved in the devel‐ opment of focal segmental glomerulosclerosis.

### **4.4. Crescentic rapidly progressive glomerulonephritis and vasculitis with renal cell carcinoma**

Crescentic glomerulonephritis with rapid progressive renal failure in conjunction with renal cell carcinoma has been reported previously [54-57]. The prevalence of renal cell carcinoma is significantly higher in patients with ANCA-positive Wegener's granulomatosis (7 in 477 patients) than in those with rheumatoid arthritis (1 in 479 patients) with an odds-ratio for development of renal cell carcinoma of 8.73 (p=0.0464, 95% CI 1.04-73.69) [58]. In most of the 7 cases, Wegener's granulomatosis was developed shortly after or simultaneously with the diagnosis of renal cell carcinoma [58]. There are many infiltrating cells around the clear cell renal cell carcinoma (Figure 5), and the chronic inflammation observed in renal cell carcino‐ ma may induce anti-neutrophil cytoplasmic antibodies (ANCA) or the renal cancer cells may serve as an antigen source [59]. The renal prognosis in crescentic glomerulonephritis with renal cell carcinoma becomes poor when an anti-GBM antibody exists, and a rapid pro‐ gression to end-stage renal failure with need of hemodialysis has been reported [54].

**Figure 5.** ANCA-related crescentic nephritis associated with renal cell carcinoma. A) The clear cell renal cell carcinoma was surrounded by many infiltrating inflammatory cells including lymphocytes, plasma cells and some neutrophils. B) Some glomeruli around the renal cell carcinoma demonstrated crescents, and the MPO-ANCA level was decreased from 217 EU to 99 EU after nephrectomy.

Membranoproliferative glomerulonephritis with crescents has been reported in patients with renal cell carcinoma, and elective nephrectomy improved both proteinuria and renal function after seven months [60]. Henoch-Schönlein purpura with leukocytoclastic vasculitis was also observed in a 25-year-old man with a small size (0.9x0.8cm) clear cell renal cell car‐ cinoma [61]. Vasculitis associated with cancer is common in lymphoma and leukemia, but only 37 cases associated with solid tumor malignancies have been reported [62], including lung cancer, prostate cancer, colon cancer, renal cell carcinoma, breast cancer and squamous cell carcinoma [63]. Cytokine production by malignant cells, like renal cell carcinoma, may contribute to the development of vasculitis.

**4.6. Amyloidosis associated with renal cell carcinoma**

nephrectomy [65,67,68].

**carcinoma**

**4.7. Tubulointerstitial nephritis**

About 3% of patients with renal cell carcinoma develop systemic amyloidosis [64], and the amyloid is composed of AA protein [65,66]. The renal cell carcinoma may be involved in the stimulation of hepatic production of acute phase reaction proteins including serum amyloid A protein, and the modification of amyloidogenic proteins by the monocyte-macrophage system in the chronic inflammatory lesion of renal cell carcinoma, causing the secondary amyloidosis. Remission of amyloidosis and nephrotic syndrome has been reported after

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119

Tubulointerstitial nephritis is often difficult to identify because it does not show obvious ab‐ normalities in urine. However, 27% of patients with renal cell carcinoma showed tubuloin‐ terstitial nephritis in resected kidney (Table 2) [21]. Recently, as a mechanism of tubulointerstitial nephritis, the antibody against carbonic anhydrase II (CAII) was identified in Sjögren syndrome with renal tubular acidosis [69] and IgG4 related tubulointerstitial nephritis [70]. Carbonic anhydrase is a zinc metalloenzyme that catalyzes the hydration of carbon dioxide and the dehydration of bicarbonate in the proximal tubules and the distal nephron including the intercalated cells of the collecting duct. CA has 15 isoforms and CAII accounts for more than 95 % of CA activity in the kidney and exists in the cytosol, and the remaining 5% renal CA is membrane associated CAIV and CAXII [71]. CAIX is not ex‐ pressed in the normal kidney, however, in renal cell carcinoma CAIX is induced by hypoxia as a tumor-associated antigen [72,73]. Inactivation of the VHL gene complex leads to the sta‐ bilization of hypoxia inducible factor-1α which activates CAIX gene expression [74]. CAIX may promote tumor growth and survival in hypoxic and acidic environments [73]. Serum levels of CAIX are higher in clear cell renal cell carcinoma than non-clear cell renal cell carci‐ noma and it is a useful marker for the differential diagnosis of renal cell carcinoma and also as a maker of tumor size [75]. It could be possible that an autoantibody against CAIX could

be induced and cause tubulointerstitial nephritis in renal cell carcinoma.

**5. Treatment of paraneoplastic glomerulopathy associated with renal cell**

The primary treatment for renal cell carcinoma is surgical excision including radical neph‐ rectomy, nephron-sparing partial nephrectomy, laparoscopic nephrectomy and percutane‐ ous ablation by radiofrequency heat or cryoablation [5]. Most cases of nephrotic syndrome associated with renal cell carcinoma showed remission or transient reduction of proteinuria just after nephrectomy as summarized in Table 4. It is interesting that only nephrectomy can achieve remission of nephropathy with amyloidosis [65,67,68], which is usually refractory to treatment. Some cases of IgA nephropathy, membranous nephropathy, crescentic glomeru‐ lonephritis and focal segmental nephrosclerosis associated with renal cell carcinoma pro‐ gressed to end stage renal failure. In addition to nephrectomy, treatment with prednisolone

### **4.5. Scleroderma and lupus erythematosus with renal cell carcinoma**

Renal cell carcinoma has an immunogenic feature. An interesting case was reported recently where clinical manifestations of scleroderma and proteinuria associated with renal cell carci‐ noma and membranous nephropathy in a 55-year-old man improved after heminephrecto‐ my of the renal cell carcinoma [43]. Similarly, lupus nephritis developed in a 64 year-old male with clear cell renal carcinoma with para-aortic lymph node metastasis. After one year of partial nephrectomy, the renal cell carcinoma recurred with nephrotic syndrome and per‐ icarditis, and laboratory examination showed an increase in IgG (3449 mg/dL), IgA (371 mg/ dL), IgM (715 mg/dL), anti-nuclear antibody (x320) and anti-double strand DNA antibody (41 IU/mL) with low complement levels (CH50 10 U/mL, C3 60, C4 10 mg/dL). Immunohis‐ tochemical examination of the resected kidney and para-aortic lymph nodes revealed in‐ creased infiltration of plasma cells producing IgG, IgM and IgA around the tumor (Figure 6), suggesting that renal cell carcinoma may have some role in the development of lupus er‐ ythematosus.

**Figure 6.** Immunohistochemistry for IgG, IgM, and IgA in the resected kidney of renal cell carcinoma and its para-aort‐ ic lymph node metastasis. The patient developed lupus erythematosus and nephrotic syndrome when renal cell carci‐ noma recurred and progressed.

### **4.6. Amyloidosis associated with renal cell carcinoma**

About 3% of patients with renal cell carcinoma develop systemic amyloidosis [64], and the amyloid is composed of AA protein [65,66]. The renal cell carcinoma may be involved in the stimulation of hepatic production of acute phase reaction proteins including serum amyloid A protein, and the modification of amyloidogenic proteins by the monocyte-macrophage system in the chronic inflammatory lesion of renal cell carcinoma, causing the secondary amyloidosis. Remission of amyloidosis and nephrotic syndrome has been reported after nephrectomy [65,67,68].

### **4.7. Tubulointerstitial nephritis**

Membranoproliferative glomerulonephritis with crescents has been reported in patients with renal cell carcinoma, and elective nephrectomy improved both proteinuria and renal function after seven months [60]. Henoch-Schönlein purpura with leukocytoclastic vasculitis was also observed in a 25-year-old man with a small size (0.9x0.8cm) clear cell renal cell car‐ cinoma [61]. Vasculitis associated with cancer is common in lymphoma and leukemia, but only 37 cases associated with solid tumor malignancies have been reported [62], including lung cancer, prostate cancer, colon cancer, renal cell carcinoma, breast cancer and squamous cell carcinoma [63]. Cytokine production by malignant cells, like renal cell carcinoma, may

Renal cell carcinoma has an immunogenic feature. An interesting case was reported recently where clinical manifestations of scleroderma and proteinuria associated with renal cell carci‐ noma and membranous nephropathy in a 55-year-old man improved after heminephrecto‐ my of the renal cell carcinoma [43]. Similarly, lupus nephritis developed in a 64 year-old male with clear cell renal carcinoma with para-aortic lymph node metastasis. After one year of partial nephrectomy, the renal cell carcinoma recurred with nephrotic syndrome and per‐ icarditis, and laboratory examination showed an increase in IgG (3449 mg/dL), IgA (371 mg/ dL), IgM (715 mg/dL), anti-nuclear antibody (x320) and anti-double strand DNA antibody (41 IU/mL) with low complement levels (CH50 10 U/mL, C3 60, C4 10 mg/dL). Immunohis‐ tochemical examination of the resected kidney and para-aortic lymph nodes revealed in‐ creased infiltration of plasma cells producing IgG, IgM and IgA around the tumor (Figure 6), suggesting that renal cell carcinoma may have some role in the development of lupus er‐

**Figure 6.** Immunohistochemistry for IgG, IgM, and IgA in the resected kidney of renal cell carcinoma and its para-aort‐ ic lymph node metastasis. The patient developed lupus erythematosus and nephrotic syndrome when renal cell carci‐

contribute to the development of vasculitis.

ythematosus.

118 Renal Tumor

noma recurred and progressed.

**4.5. Scleroderma and lupus erythematosus with renal cell carcinoma**

Tubulointerstitial nephritis is often difficult to identify because it does not show obvious ab‐ normalities in urine. However, 27% of patients with renal cell carcinoma showed tubuloin‐ terstitial nephritis in resected kidney (Table 2) [21]. Recently, as a mechanism of tubulointerstitial nephritis, the antibody against carbonic anhydrase II (CAII) was identified in Sjögren syndrome with renal tubular acidosis [69] and IgG4 related tubulointerstitial nephritis [70]. Carbonic anhydrase is a zinc metalloenzyme that catalyzes the hydration of carbon dioxide and the dehydration of bicarbonate in the proximal tubules and the distal nephron including the intercalated cells of the collecting duct. CA has 15 isoforms and CAII accounts for more than 95 % of CA activity in the kidney and exists in the cytosol, and the remaining 5% renal CA is membrane associated CAIV and CAXII [71]. CAIX is not ex‐ pressed in the normal kidney, however, in renal cell carcinoma CAIX is induced by hypoxia as a tumor-associated antigen [72,73]. Inactivation of the VHL gene complex leads to the sta‐ bilization of hypoxia inducible factor-1α which activates CAIX gene expression [74]. CAIX may promote tumor growth and survival in hypoxic and acidic environments [73]. Serum levels of CAIX are higher in clear cell renal cell carcinoma than non-clear cell renal cell carci‐ noma and it is a useful marker for the differential diagnosis of renal cell carcinoma and also as a maker of tumor size [75]. It could be possible that an autoantibody against CAIX could be induced and cause tubulointerstitial nephritis in renal cell carcinoma.
