**6. Molecular-target therapy related nephropathy in renal cell carcinoma**

was attempted in some cases, especially in minimal change nephrotic syndrome, and showed reduction of proteinuria. However, it is noteworthy to recognize that the cyst at the time of biopsy rapidly enlarged after treatment with prednisolone for IgA nephropathy, and a diagnosis of renal cell carcinoma was made later [28]. Thus, the first line of treatment of paraneoplastic glomerulopathy associated with renal cell carcinoma is nephrectomy, and

the use of steroids should be limited only to cases of controlled renal cell carcinoma.

**Glomerulopathy Age, sex Treatment Outcomes References** IgAN 61 M nephrectomy Remission Tanaka [26] IgAN 8 cases nephrectomy Remission (6/8) Magyarlaki [21]

> Steroid, nephrectomy Steroid 30mg, nephrectomy nephrectomy

MN 76 F nephrectomy Died (33 days) Stein [37] MN 69 M steroid 50mg Died (6 months) Nishihara [38] MN 62 M Partial nephrectomy PR Fujita [39] MN 57 M nephrectomy TR/relapse Togawa [40] MN 72M nephrectomy TR/ESRD Kapolas [41] MN 77 F nephrectomy remission Kuroda [42] MN 55 M nephrectomy remission Nunez [43] MCNS 49 M Nephrectomy, steroid PR Forland [51] MCNS 70 M nephrectomy Remission after biopsy Lee [49]

CPM150mg

60mg

1mg/kg

amyloidosis 66 F diuretics NS, Died (respiratory

splenectomy

amyloidosis 54 F nephrectomy Remission (5years) died of

**Table 4.** Treatment and outcomes of glomerulopathy with renal cell carcinoma

amyloidosis 62 M nephrectomy Remission (3years) Karsenty [67]

IgAN: IgA nephropathy, MN: membranous nephropathy, MCNS: minimal change nephrotic syndrome, FSGS: focal seg‐ mental glomerulosclerosis, cresGN: crescentic glomerulonephritis, MPGN: Membranoproliferative glomerulonephritis, PR: partial remission, ESRD: end-stage renal disease, TR transient remission, CPM cyclophosphamide, HD: hemodialysis,

FSGS 48 M nephrectomy Worsened sCr Ejaz [52] CresGN /GBM-Ab 74 M nephrectomy ESRD Hatakeyama [54] CresGN/MPO-ANCA 68 F nephrectomy, steroid Remission Karim [56] CresGN 35 F HD ESRD died on HD Jain [ 57] MPGN 26 F nephrectomy remission Tydings [76] MPGN 65 M nephrectomy remission Ahmed [60]

failure)

relapse

Remission ESRD Remission Mimura [28]

Died of infection Abouchacra [48]

PR Woodrow [50]

Complete remission Auguet [47]

Remission (7months) Vanatta [65]

Pras [66]

Tang [68]

IgAN 58 M 66 M

120 Renal Tumor

59 M

MCNS 69 M Steroid 80mg,

amyloidosis 58 F Nephrectomy,

NS: nephrotic syndrome.

MCNS 64 F Nephrectomy, steroid

MCNS 78 M nephrectomy, steroid

About 30% patients will have distant metastasis at the time of diagnosis, and medical therapies including interleukin-2, interferons, and molecular-target therapy are generally offered for advanced renal cancer as listed in Table 5. Interleukin-2 showed transient proteinuria and renal dysfunction, but these changes are reversible and did not cause long-term intrinsic renal damage [77-79]. Interferons are well known to show proteinuria in 15-20% of patients [80]. The nephrotic syndrome and acute renal failure induced by interferon therapy are histologically due to minimal change disease and acute tubuloin‐ terstitial nephritis [80-82].

Bevacizumab, a humanized monoclonal anti-vascular endothelial growth factor antibody, is used for the treatment of metastatic renal cell carcinoma, but adverse effects such as hypertension, anorexia and proteinuria are increased with combination therapy of bevaci‐ zumab and interferon α compared with interferon α monotherapy [83,84]. High-dose bevacizumab therapy showed proteinuria of more than 1+ in 64% of patients with renal cell carcinoma and nephrotic range proteinuria of more than 3.5 g/day in 7.7% patients [85]. Renal biopsy revealed thrombotic microangiopathy in two patients treated with Bevacizumab and interferon-α [86]. As VEGF is expressed in the podocyte and its recep‐ tors are found in glomerular endothelial cells, blocking VEGF may disturb the function of VEGF to maintain the glomerular capillary permeability barrier, causing thrombotic microangiopathy [87,88].

Treatment of renal cell carcinoma with sunitinib or sorafenib, which inhibit the VEGF re‐ ceptor and multi-tyrosine kinases, induced severe nephrotic syndrome with acute renal failure, and renal biopsy revealed minimal change disease and thrombotic microangiop‐ athy with acute tubular necrosis [89,90]. Sunitinib also develops other pathological forms of renal diseases including acute interstitial nephritis [91], acute nephritic syndrome with subendothelial C3 deposition [92], FSGS [93], and sorafenib is also associated with IgA nephropathy [94], and interstitial nephritis [95]. Withdrawal of sunitinib or sorafenib with or without use of steroids ameliorated increased serum creatinine and proteinuria as well as hypertension and edema [91,93-95], but in some advanced cases hemodialysis was needed [89, 92] or proteinuria persisted [90]. Thus, early detection of renal adverse effects of these drugs is necessary.

Temsirolimus is a highly specific inhibitor of the mammalian target of rapamycin, which is a central regulator of intracellular signaling pathways and an inhibitor of angiogenesis. Tem‐ sirolimus has prolonged overall survival in patients with advanced renal cell carcinoma compared to interferon-α [96]. However, temsirolimus reduced synaptopodin and nephrin expression in podocytes and induced nephrotic syndrome caused by focal segmental glo‐ merulosclerosis [97]. The amount of proteinuria decreased after withdrawal of temsirolimus, so it is necessary to notice the nephrotic adverse effects of this drug.


**Acknowledgements**

**Author details**

Akihiro Tojo

**References**

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Paraneoplastic Glomerulopathy Associated with Renal Cell Carcinoma

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

123

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Address all correspondence to: akitojo-tky@umin.ac.jp

MCNS: minimal change nephrotic syndrome, IN: interstitial nephritis, ARF: acute renal failure, TMA: thrombotic micro‐ angiopathy, iATN: ischemic acute tubular necrosis, AGN:acute glomerulonephritis.

**Table 5.** Interleukin, interferon and molecular-target drugs related nephropathy in the renal cell carcinoma

### **7. Summary**

Recent advances in the molecular understanding of renal cell carcinoma have shed light on the mechanism of paraneoplastic glomerulopathy. Clear cell renal cell carcinoma with a VHL gene mutation stimulates HIF-1α transcription, and produces various cytokines and growth factors including VEGF, PDGF, TGF−α/β, IL-6, CAIX and EPO. Renal cell carcinoma has a feature of cytokine disease or immunogenic disease, and enhanced cytokines and growth factors stimulate lymphocytes and plasma cells, and the latter works as a causative factor for various forms of paraneoplastic glomerulopathies. The precise mechanism of glo‐ merulonephritis has not been completely elucidated, and further investigation of renal cell carcinoma related glomerulopathies will open a new perspective in the understanding of glomerular diseases.
