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

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 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.

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

Paraneoplastic Glomerulopathy Associated with Renal Cell Carcinoma

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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‐

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

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

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.

terstitial nephritis [80-82].

microangiopathy [87,88].

effects of these drugs is necessary.


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, NS: nephrotic syndrome.

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