Mei-Chin Wen

A reduction of unilateral ureteral obstruction-induced renal fibrosis by a therapy combining valsartan with aliskiren

The protective effect of combination therapy with valsartan and aliskiren against renal fibrosis remains to be defined. This study was undertaken to examine the protective effects of the combination of valsartan and aliskiren against renal fibrosis induced by unilateral ureteral obstruction (UUO). Combination therapy with valsartan (15 mg·kg(-1)·day(-1)) and aliskiren (10 mg·kg(-1)·day(-1)), valsartan monotherapy (30 mg·kg(-1)·day(-1)), and aliskiren monotherapy (20 mg·kg(-1)·day(-1)) all significantly ameliorated the increase in blood urea nitrogen and the degree of hydronephrosis determined by the increase in weight and length of the obstructed kidney. The dose titration study and blood pressure measurement confirmed that the combination therapy provided a greater benefit independent of the vasodilatory effect. There were no significant changes in serum levels of creatinine, sodium, and potassium in UUO rats and any treatment groups. Combination therapy also attenuated UUO-related increases in the scores of tubular dilatation, interstitial volume, interstitial collagen deposition, α-smooth muscle actin, the activation of ERK 1/2, the infiltration of monocytes/macrophages, the mRNA expression of snail-1, and transforming growth factor-β1 to a greater extent compared with aliskiren or valsartan used alone. The mRNA expression of renin and the (pro)renin receptor significantly increased after UUO. Combination therapy and monotherapy of valsartan and aliskiren had a comparable enhancing effect on the mRNA expression of renin, whereas all these treatments did not affect the expression of the (pro)renin receptor. In conclusion, a direct renin inhibitor in conjunction with an angiotensin II receptor blocker exerts increased renal protection against renal fibrosis and inflammation during obstruction over either agent alone.

Cilostazol Ameliorates Nephropathy in Type 1 Diabetic Rats Involving Improvement in Oxidative Stress and Regulation of TGF-β and NF-κB

Diabetic nephropathy is characterized as the progressive development of renal insufficiency in a setting of hyperglycemia. Previous studies indicate that reactive oxygen species (ROS) play an important role in high glucose-induced renal injury. Cilostazol was reported to lower the production of superoxide significantly in situ. We hypothesized that cilostazol administration in streptozotocin-induced diabetic rats exerts effects via improving oxidative stress. Male Sprague–Dawley rats were fed with cilostazol (5 mg/kg or 25 mg/kg) for 12 weeks after streptozotocin-induced diabetes mellitus. The results showed that cilostazol decreased reactive oxygen species activity significantly in the kidneys of diabetic rats and improved the urine albumin/creatinine ratio. Cilostazol can also improve the levels of serum cholesterol, triglyceride, and LDL-cholesterol. Additionally, diabetes-caused increased glomerular size, TGF-β, and NF-κB decreased under treatment with cilostazol in diabetic rats. Our results indicate that cilostazol has beneficial effects in early diabetic nephropathy.

High Incidence of Malignancy in Polyomavirus-Associated Nephropathy in Renal Transplant Recipients

Human polyomaviruses (PV), including JC and BK virus, have been reported to cause polyomavirus-associated nephropathy (PVAN), in renal transplant patients. PV infection has been demonstrated to be associated with malignancies in animals; however, the association between malignancy and viral infections in humans is not clear. We retrospectively reviewed our 864 (M:F=502:362) kidney transplant patients over the past 25 years. We identified PVAN in 6 patients (0.69%), including BK nephropathy (n=5) and JC nephropathy (n=1). Three patients (50%) improved after reducing the immunosuppression, but 3 (50%) progressed to graft loss despite this reduction. Malignancy occurred in 5 out of the 6 patients (83%; P<.0001 compared with patients without PVAN), including transitional cell carcinoma (n=2), renal cell carcinoma (n=1), squamous cell carcinoma of skin (n=1) and Kaposi sarcoma (n=1). We concluded that kidney transplant patients with PVAN are at a significantly greater risk to develop malignancy. Whether this is due to a direct effect of PV infection or the result of overimmunosuppression remains to be determined in a future study.

Combined Primary Neuroendocrine Carcinoma and Hepatocellular Carcinoma of the Liver

We report a unique case of combined primary neuroendocrine carcinoma (NEC) and hepatocellular carcinoma (HCC) of the liver in a 65-year-old male patient. The patient underwent segmental resection of the liver and regional lymph node dissection for a tumor mass that measured 7.5 cm in diameter in the right lobe, with regional lymphadenopathy. Histologically, the hepatic tumor was composed of predominantly small-cell NEC, but admixed with a small island of moderately differentiated HCC. We speculate that the NEC originated from a poorly differentiated tumor clone of an HCC that underwent neuroendocrine differentiation, and that this tumor was now at the end stage of the transitional period from HCC to NEC, based on the small amount of disappearing HCC. Ki-67 and p53 expression were higher in the NEC than in the HCC, and the lymph nodes showed only metastatic NEC. Therefore, this kind of tumor had a more aggressive clinical course in accordance with being an NEC rather than a conventional HCC. Three months after operation, the patient had multiple recurrent tumor nodules within the liver, spreading the metastasis to the adrenal glands and para-aortic lymph nodes. The patient died 1 year after operation.

Rictor-dependent AKT activation and inhibition of urothelial carcinoma by rapamycin

OBJECTIVE We previously reported a very high cumulative incidence of urothelial carcinoma in Taiwanese kidney transplant recipients. Rapamycin, the inhibitor of mTOR Complex 1, provides alternative immunosuppressive therapy after kidney transplantation with less neoplastic potential. We examined the in vivo and in vitro effects of rapamycin on urothelial carcinoma. MATERIALS AND METHODS The rat model of urothelial carcinoma was induced by 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in Fischer F344 rats. The anti-tumor effect of rapamycin was assessed grossly, microscopically, and by Western blot analysis. The mechanism of rapamycins attenuation of urothelial carcinoma was also evaluated by T24 cells. RESULTS Rapamycin significantly reduced urinary bladder tumor growth in the rat model of 0.05% BBN-induced urothelial carcinoma (P < 0.001). The blood trough levels of rapamycin were correlated with the occurrence of urothelial carcinoma. In vitro, rapamycin also inhibited the cell proliferation, migration, and invasion, as well as the protein expression of vascular endothelial growth factor-A of T24 urothelial carcinoma cells, whereas rapamycin did not induce significant apoptosis in T24 cells. Rapamycin decreased the expression of phospho-mTOR, phospho-S6K, cyclin D1, and VEGF-A. Rapamycin also activated AKT in T24 cells in the rat model of urothelial carcinoma. The rapamycin-associated activation of AKT was inhibited by rictor siRNA, but not raptor siRNA. CONCLUSIONS This study provides in vitro and in vivo evidence that rapamycin may inhibit the development of urothelial carcinoma. The present findings also suggest rictor-dependent AKT activation as a consequence of mTORC1 inhibition.

Prediction of chronic allograft damage index of renal allografts using serum level of plasminogen activator inhibitor‐1

Abstract: Background:  Plasminogen activator inhibitor‐1 (PAI‐1) plays an important role in renal fibrosis. We conducted this study to examine whether serum PAI‐1 has a role in predicting chronic allograft nephropathy (CAN).

The predominant monophasic variant of spindle epithelial tumour with thymus-like differentiation (SETTLE) of neck soft tissue with late pulmonary metastasis.

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A syndrome resembling Bartter's syndrome in sarcoidosis

Acquired Bartter-like syndrome, albeit rare, has not been reported to be associated with sarcoidosis. We describe the case of a 32-year-old male patient who presented with progressive muscular weakness of both lower extremities. Profound hypokalaemia associated with renal (K(+)) wasting, bilateral nephrocalcinosis and high plasma renin activity resembled Bartters syndrome (BS). Both mediastinal lymph node and renal biopsy demonstrated sarcoidosis with non-caseating granuloma. Genetic testing responsible for hereditary BS or Gitelmans syndrome (GS) was negative. Hypokalaemia was well controlled with the administration of spironolactone with oral steroids and KCl. Early recognition and prompt treatment of sarcoidosis-associated Bartter-like syndrome avoids unnecessary complications.

Langerhans Cell Sarcoma in a Chronic Myelogenous Leukemia Patient Undergoing Imatinib Mesylate Therapy A Case Study and Review of the Literature

Langerhans cell sarcoma (LCS) is a rare malignancy requiring differential diagnosis from other high-grade nonhematologic and hematologic tumors. The pathogenesis of LCS remains unknown. Notably, LCS and its benign counterpart, Langerhans cell histiocytosis (LCH), are frequently associated with other malignancies. To the best of our knowledge, we describe the first case of LCS in a chronic myelogenous leukemia (CML) patient undergoing imatinib mesylate therapy. We performed molecular cytogenetic analyses for investigating the association between LCS and CML. In our case, molecular cytogenetic analysis did not reveal BCR-ABL1 fusion and BRAF V600E mutation, suggesting that LCS may be coincident in this patient. However, recurrent BRAF V600E mutation has been found in LCH. Published reports have revealed the clonal relationship between LCH/LCS and other hematologic malignancies, especially lymphoid neoplasms. However, there are only 2 reports demonstrating the clonal relationship between LCH and myeloid neoplasms. The association of LCH/LCS with myeloid neoplasms and the role of BRAF V600E mutation in LCS are discussed.

Polyomavirus nephropathy in renal allograft: Prevalence and correlation of histology with graft failure

Background:  While polyomavirus nephropathy (PVN) is recognized as an emerging cause of graft loss in renal transplants, the prevalence rate of PVN in renal grafts is unclear in Taiwan.