**1. Introduction**

Renal cell carcinoma is often associated with paraneoplastic syndromes caused by the secretion of tumor cell products such as hormones, cytokines, growth factors and tu‐ mor antigens, which show manifestations including impaired glucose metabolism, hy‐ percalcemia, hypertension, Cushing syndrome, polycythemia, thrombosis, eosinophilia, leukemoid reactions and amyloidosis [1]. It has been reported that 10-40% of patients with renal cell carcinoma present paraneoplastic symptoms [1]. However, paraneoplas‐ tic glomerulonephritis associated with renal cell carcinoma has often been overlooked, for the urinary abnormalities including proteinuria and hematuria are often interpreted as clinical manifestations of the tumor itself, especially when the proteinuria is nonnephrotic.

The term of paraneoplastic glomerulopathy was first described by Galloway in 1922 in a case of nephrotic syndrome associated with Hodgkin's disease [2]. Hodgkin's lym‐ phoma is associated with minimal change nephrotic syndrome, while solid carcinomas including lung cancer and carcinomas of the gastrointestinal tract frequently develop membranous nephropathy, which is the most common paraneoplastic glomerulopathy [3,4]. Although renal cell carcinoma is not a frequent cause of paraneoplastic glomerul‐ opathy, recent advances in the study of the molecular mechanism of renal cell carcino‐ ma as a cytokine producing tumor have promoted a better understanding of the mechanism of paraneoplastic nephropathy associated with renal cell carcinoma. In this chapter, I will discuss the mechanisms of paraneoplastic nephropathies associated with renal cell carcinoma.

© 2013 Tojo; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Tojo; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1.1. Pathological types of renal cell carcinoma and molecular mechanisms of paraneoplastic syndrome**

The von Hippel-Lindau protein (pVHL) binds with hypoxia inducible factor 1α (HIF-1α) transcription factor and promotes the ubiqutination of HIF-1α, resulting in degradation by the proteasome under normoxic conditions. In renal cell carcinoma, the absence of wild type pVHL stimulates the accumulation of HIF-1α and activates transcription at hypoxia-re‐ sponse elements (HREs) in genes including vascular endothelial growth factor (VEGF), pla‐ telet-derived growth factor (PDGF), transforming growth factor α (TGF-α) and TGF-β,

Paraneoplastic Glomerulopathy Associated with Renal Cell Carcinoma

http://dx.doi.org/10.5772/53534

111

MMP: matrix metalloproteinase; Ang-2: angiopoietin-2; Aglike-4: angiopoietin-like 4; COX-2: cyclooxygenase-2; BNIP3: BCL2/adenovirus E1B 19 kD interacting protein 3; PAX2:

The serum levels of VEGF and IL-6 are increased according to the stage of renal cell carcino‐ ma, whereas TNF-α and IL-1β showed a slight increase as they are probably produced by infiltrating monocytes or macrophages (Figure 2) [18,19]. This indicates that clear cell renal cell carcinoma is a cytokine-producing tumor, whose functions are linked to the develop‐

**Figure 2.** Serum vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and

**2. Incidence of paraneoplastic syndrome and glomerulopathy in renal**

The most frequent features of the paraneoplastic syndrome in renal cell carcinoma are hy‐ percalcemia, hypertension and polycythemia. Their prevalence and their causative hor‐

interleukin-1β (IL-1β) in various stages of renal cell carcinoma. Adapted from [18] and [19].

glucose transporter (GLUT-1) and carbonic anhydrase IX (CA IX).

ment of the various features of the paraneoplastic syndrome [9,20].

paired box gene 2.

**cell carcinoma**

mones and cytokines are listed in Table1 [1].

Renal cell carcinoma accounts for 85 % of renal neoplasms, and 25% of patients with renal cell carcinoma show advanced disease with local invasion or metastasis at the time of diag‐ nosis [5]. Renal cell carcinoma is classified pathologically into five types: clear cell (75%), papillary (12%), chromophobe (4%), oncocytoma (4%), collecting duct carcinoma (<1%), and unclassified (3-5%) [5]. The most common type, clear cell renal cell carcinoma, shows hyper‐ vascularity. About 60% of sporadic clear cell renal cell carcinoma have mutations in the von Hippel-Lindau tumor suppressor gene (*VHL*) [6], which is a causative gene for von Hippel-Lindau disease, an autosomal dominant familial cancer syndrome consisting retinal angio‐ ma, hemangioblastoma of the central nervous system, pheochromocytomas, and clear cell renal cell carcinoma. VHL protein normally suppresses hypoxia-inducible genes by inhibit‐ ing HIF-1α [7] (Figure 1). However, when VHL protein is lost in clear cell renal cell carcino‐ ma, various cytokines and growth factors induced by HIF-1α are enhanced; vascular endothelial growth factor (VEGF) which stimulates angiogenesis of carcinoma, platelet-de‐ rived growth factor (PDGF) and transforming growth factor alpha (TGF- α), which lead to tumor growth, glucose transporter (GLUT-1) and carbonic anhydrase IX (CA IX), which leads to tumor cell survival in an acidic environment [8-10]. NF-kB activity is also regulated by VHL protein, and cytokine-inducible transcription factors including NF-kB and STAT3 are activated in renal cell carcinoma [11-15]. Renal cell carcinoma tissue and cell lines of the tumor express mRNA of IL-6 and IL-6 receptor [16, 17], which may play a role in cancer cell growth in an autocrine or paracrine manner.

**Figure 1.** Molecular mechanisms of renal cell carcinoma as a cytokine-producing tumor.

The von Hippel-Lindau protein (pVHL) binds with hypoxia inducible factor 1α (HIF-1α) transcription factor and promotes the ubiqutination of HIF-1α, resulting in degradation by the proteasome under normoxic conditions. In renal cell carcinoma, the absence of wild type pVHL stimulates the accumulation of HIF-1α and activates transcription at hypoxia-re‐ sponse elements (HREs) in genes including vascular endothelial growth factor (VEGF), pla‐ telet-derived growth factor (PDGF), transforming growth factor α (TGF-α) and TGF-β, glucose transporter (GLUT-1) and carbonic anhydrase IX (CA IX).

**1.1. Pathological types of renal cell carcinoma and molecular mechanisms of**

Renal cell carcinoma accounts for 85 % of renal neoplasms, and 25% of patients with renal cell carcinoma show advanced disease with local invasion or metastasis at the time of diag‐ nosis [5]. Renal cell carcinoma is classified pathologically into five types: clear cell (75%), papillary (12%), chromophobe (4%), oncocytoma (4%), collecting duct carcinoma (<1%), and unclassified (3-5%) [5]. The most common type, clear cell renal cell carcinoma, shows hyper‐ vascularity. About 60% of sporadic clear cell renal cell carcinoma have mutations in the von Hippel-Lindau tumor suppressor gene (*VHL*) [6], which is a causative gene for von Hippel-Lindau disease, an autosomal dominant familial cancer syndrome consisting retinal angio‐ ma, hemangioblastoma of the central nervous system, pheochromocytomas, and clear cell renal cell carcinoma. VHL protein normally suppresses hypoxia-inducible genes by inhibit‐ ing HIF-1α [7] (Figure 1). However, when VHL protein is lost in clear cell renal cell carcino‐ ma, various cytokines and growth factors induced by HIF-1α are enhanced; vascular endothelial growth factor (VEGF) which stimulates angiogenesis of carcinoma, platelet-de‐ rived growth factor (PDGF) and transforming growth factor alpha (TGF- α), which lead to tumor growth, glucose transporter (GLUT-1) and carbonic anhydrase IX (CA IX), which leads to tumor cell survival in an acidic environment [8-10]. NF-kB activity is also regulated by VHL protein, and cytokine-inducible transcription factors including NF-kB and STAT3 are activated in renal cell carcinoma [11-15]. Renal cell carcinoma tissue and cell lines of the tumor express mRNA of IL-6 and IL-6 receptor [16, 17], which may play a role in cancer cell

**paraneoplastic syndrome**

110 Renal Tumor

growth in an autocrine or paracrine manner.

**Figure 1.** Molecular mechanisms of renal cell carcinoma as a cytokine-producing tumor.

MMP: matrix metalloproteinase; Ang-2: angiopoietin-2; Aglike-4: angiopoietin-like 4; COX-2: cyclooxygenase-2; BNIP3: BCL2/adenovirus E1B 19 kD interacting protein 3; PAX2: paired box gene 2.

The serum levels of VEGF and IL-6 are increased according to the stage of renal cell carcino‐ ma, whereas TNF-α and IL-1β showed a slight increase as they are probably produced by infiltrating monocytes or macrophages (Figure 2) [18,19]. This indicates that clear cell renal cell carcinoma is a cytokine-producing tumor, whose functions are linked to the develop‐ ment of the various features of the paraneoplastic syndrome [9,20].

**Figure 2.** Serum vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) in various stages of renal cell carcinoma. Adapted from [18] and [19].
