Katsuya Nonomura

Direct targeting of fibroblast growth factor-inducible 14 protein protects against renal ischemia reperfusion injury

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to have pivotal roles in various inflammatory processes. The TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), has various unique functions under physiological and pathological conditions; however, the therapeutic potential of its direct targeting remains unknown. Here, we found that Fn14 expression was highly upregulated in ischemic renal tissues and tubular epithelial cells of patient biopsies and experimental animal models of renal injury. To clarify the function of Fn14 in ischemia reperfusion injury, we coincubated renal tubular cells with ITEM-2, an anti-Fn14 blocking monoclonal antibody, and found that it inhibited the production of proinflammatory cytokines and chemokines after injury. Furthermore, Fn14 blockade downregulated the local expression of several proinflammatory mediators, reduced accumulation of neutrophils and macrophages in ischemic tissues, and inhibited tubular cell apoptosis. Importantly, Fn14 blockade attenuated the development of chronic fibrosis after ischemia reperfusion injury and significantly prolonged the survival of lethally injured mice. Thus, we conclude that Fn14 is a critical mediator in the pathogenesis of ischemia reperfusion injury.

Prognostic significance of CD45RO+ memory T cells in renal cell carcinoma

Background:Memory T cells are well known to have a critical role for host defense in humans. However, their role in actual human cancer remains largely unknown. In this study, we tried to reveal the clinical importance of tumour-infiltrating CD45RO+ memory T cells in renal cell carcinoma (RCC).Methods:We analysed 105 patients with RCC, who received radical or partial nephrectomy. Those were 65 in TNM stage I, 7 in stage II, 15 in stage III, and 18 in stage IV, respectively. CD45RO expression was evaluated by immunohistochemistry. CD4 and CD8 expressions were also systematically assessed in the same manner.Results:Patients with higher TNM stage or high nuclear grade were found to have higher densities of CD45RO. Furthermore, CD45RO status was positively correlated with preoperative C-reactive protein level. In prognostic analysis, CD45RO+lo patients had a significantly better prognosis than CD45RO+hi patients. There was also a significant difference between CD4+lo and CD4+hi groups, whereas no significant difference was observed in CD8 T-cell status. Finally, multivariate analysis revealed that CD45RO+ status was the independent prognostic factor for patient overall survival.Conclusion:CD45RO+ memory T-cell status has a significant independent prognostic value, indicating that the adaptive immune response is functionally critical in human RCC.

Impact of Diagnostic Ureteroscopy on Intravesical Recurrence and Survival in Patients With Urothelial Carcinoma of the Upper Urinary Tract

PURPOSEnWe determined whether diagnostic ureteroscopy for upper urinary tract cancer affects intravesical recurrence and cancer specific mortality.nnnMATERIALS AND METHODSnIn a retrospective, multi-institutional study we evaluated 208 patients undergoing nephroureterectomy for upper urinary tract cancer who had no perioperative systemic chemotherapy, history of invasive bladder cancer, distant metastasis or incomplete followup data. Of these 208 patients 55 who composed the study group underwent diagnostic ureteroscopy before nephroureterectomy while 153 serving as controls did not. We analyzed intravesical recurrence and cancer specific survival using the Kaplan-Meier method with the log rank test used to assess significance.nnnRESULTSnThere was no significant difference between the 2 groups in patient characteristics or upper urinary tract cancer stage and grade while followup, and the proportion of multiple tumors and lymphovascular invasion positive tumors were significantly greater in controls. The 2-year bladder recurrence-free survival rate was 60.0% in the study group and 58.7% in controls. There was no significant difference in the intravesical recurrence rate between the 2 groups (log rank test p = 0.972). Estimated Kaplan-Meier cancer specific survival was 88.3% and 78.1% at 5 years in the study and control groups, respectively (log rank test p = 0.0687).nnnCONCLUSIONSnDiagnostic ureteroscopy did not affect intravesical recurrence or cancer specific survival in patients with upper urinary tract cancer undergoing nephroureterectomy.

Rapid estimation of split renal function in kidney donors using software developed for computed tomographic renal volumetry

PURPOSEnTo evaluate the speed and precision of split renal volume (SRV) measurement, which is the ratio of unilateral renal volume to bilateral renal volume, using a newly developed software for computed tomographic (CT) volumetry and to investigate the usefulness of SRV for the estimation of split renal function (SRF) in kidney donors.nnnMETHODnBoth dynamic CT and renal scintigraphy in 28 adult potential living renal donors were the subjects of this study. We calculated SRV using the newly developed volumetric software built into a PACS viewer (n-SRV), and compared it with SRV calculated using a conventional workstation, ZIOSOFT (z-SRV). The correlation with split renal function (SRF) using (99m)Tc-DMSA scintigraphy was also investigated.nnnRESULTSnThe time required for volumetry of bilateral kidneys with the newly developed software (16.7±3.9s) was significantly shorter than that of the workstation (102.6±38.9s, p<0.0001). The results of n-SRV (49.7±4.0%) were highly consistent with those of z-SRV (49.9±3.6%), with a mean discrepancy of 0.12±0.84%. The SRF also agreed well with the n-SRV, with a mean discrepancy of 0.25±1.65%. The dominant side determined by SRF and n-SRV showed agreement in 26 of 28 cases (92.9%).nnnCONCLUSIONnThe newly developed software for CT volumetry was more rapid than the conventional workstation volumetry and just as accurate, and was suggested to be useful for the estimation of SRF and thus the dominant side in kidney donors.

Immunomodulatory effects of eicosapentaenoic acid through induction of regulatory T cells

Dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) has been found to affect inflammation and metabolism, and many researchers have shown that omega-3 PUFAs provide benefits in immunologic and metabolic disorders. These effects were assumed to result mainly from a modification in the production of inflammatory mediators and the suppression of inflammatory leukocytes. Among PUFAs, eicosapentaenoic acid (EPA), a component of fish oil, apparently has the most potent effect. Recently, much research has focused on regulatory T cells (Tregs) as controllers of immune responses not only to self-antigens but also to non-self-antigens, including donor alloantigens. Therefore, induction of antigen-specific Tregs may be an attractive strategy for managing autoimmune diseases and transplant rejection. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear receptor that regulates lipid and glucose metabolism, can be activated by thiazolidinediones, fatty acids, and eicosanoids, including EPA. PPARγ was recently found to have immunoregulatory effects, and a PPARγ agonist inhibited immune responses in a rat model of autoimmune disease. Furthermore, in a murine model, one high dose of purified EPA given the day of transplantation induced marked prolongation of cardiac allograft survival in a dose-dependent manner. These findings suggest that EPA induced Tregs by means of a PPARγ-dependent mechanism. This review describes the immunomodulatory effects of PUFAs, especially EPA, and summarizes recent research that may have implications for the development of therapies for autoimmune diseases and transplant rejection that are based on induction of Tregs.

Mamld1 Knockdown Reduces Testosterone Production and Cyp17a1 Expression in Mouse Leydig Tumor Cells

Background MAMLD1 is known to be a causative gene for hypospadias. Although previous studies have indicated that MAMLD1 mutations result in hypospadias primarily because of compromised testosterone production around the critical period for fetal sex development, the underlying mechanism(s) remains to be clarified. Furthermore, although functional studies have indicated a transactivation function of MAMLD1 for the non-canonical Notch target Hes3, its relevance to testosterone production remains unknown. To examine these matters, we performed Mamld1 knockdown experiments. Methodology/Principal Findings Mamld1 knockdown was performed with two siRNAs, using mouse Leydig tumor cells (MLTCs). Mamld1 knockdown did not influence the concentrations of pregnenolone and progesterone but significantly reduced those of 17-OH pregnenolone, 17-OH progesterone, dehydroepiandrosterone, androstenedione, and testosterone in the culture media. Furthermore, Mamld1 knockdown significantly decreased Cyp17a1 expression, but did not affect expressions of other genes involved in testosterone biosynthesis as well as in insulin-like 3 production. Hes3 expression was not significantly altered. In addition, while 47 genes were significantly up-regulated (fold change >2.0×) and 38 genes were significantly down-regulated (fold change <0.5×), none of them was known to be involved in testosterone production. Cell proliferation analysis revealed no evidence for compromised proliferation of siRNA-transfected MLTCs. Conclusions/Significance The results, in conjunction with the previous data, imply that Mamld1 enhances Cyp17a1 expression primarily in Leydig cells and permit to produce a sufficient amount of testosterone for male sex development, independently of the Hes3-related non-canonical Notch signaling.

Is Memorial Sloan-Kettering Cancer Center risk classification appropriate for Japanese patients with metastatic renal cell carcinoma in the cytokine era?

OBJECTIVESnWe investigated the prognosis of Japanese patients with metastatic renal cell carcinoma (RCC), and analyzed the validity of Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification.nnnMATERIALS AND METHODSnThe endpoint of the present study was overall survival. Relationships between overall survival and potential prognostic factors were assessed using the Cox proportional hazard model with a step-wise procedure. Prognostic assessment was also performed according to the MSKCC risk classification. The predictive accuracy of the MSKCC risk classification was measured employing the concordance index.nnnRESULTSnThe median survival for all patients was 22 months (95% CI, 19-28 months). The eight factors were identified as independent prognostic factor; time from initial diagnosis to metastasis, low hemoglobin (Hb), lactate dehydrogenase (LDH), corrected serum calcium (cCa), C-reactive protein (CRP), and the presence or absence of liver metastasis, bone metastasis, and lymph node metastasis. When the MSKCC risk classification was applied to patients, the median overall survival was not reached and 26 and 10 months in the patients classified as favorable, intermediate, and poor risk, respectively. The c-index was 0.73.nnnCONCLUSIONSnThe prognosis of Japanese metastatic renal cell carcinoma patients may be better than that of previous studies from North America or Europe. Although there are some differences in the rate of patients in the risk groups and survival time by risk group between these patients, the MSKCC risk classification may be applicable for Japanese patients with metastatic renal cell carcinoma.

Renal Hypothermia with Ice Slush in Laparoscopic Partial Nephrectomy: The Outcome of Renal Function

PURPOSEnTo investigate changes in renal function after retroperitoneal laparoscopic partial nephrectomy (LPN) with renal hypothermia induced by ice-slush cooling.nnnPATIENTS AND METHODSnSeventy-one patients undergoing retroperitoneal LPN with renal hypothermia were included. Perioperative outcomes were reviewed retrospectively. The total renal function was evaluated by an estimated glomerular filtration rate (eGFR) preoperatively and 6 months postoperatively in 69 patients. Split renal function (SRF) was also evaluated by 99mTc-mercaptoacetyltriglycine scintigraphy preoperatively and 6 months postoperatively in 61 patients.nnnRESULTSnThe median operative time was 246 minutes (range, 155-424). The median cold ischemic time, including the initial 15 minutes of hypothermia, was 57 minutes (range, 34-112). In the 21 patients whose renal temperature was monitored, median lowest renal temperature was 20.7°C (range, 12.1-27.6). The median baseline eGFR and 6-month postoperative eGFR were 77.2 mL/min/1.73 m(2) (range, 36.1-121.3) and 68.3 mL/min/1.73 m(2) (range, 33.2-103.4), and the median baseline SRF and 6-month postoperative SRF of the affected kidney were 49.3% (range, 40.3-57.6) and 40.7% (range, 13.8-54.5). Using multivariate analysis, the baseline eGFR (p<0.0001) and the ischemic time (p=0.0073) were associated with the 6-month postoperative eGFR, and the 6-month postoperative SRF was only associated with a baseline SRF (p=0.0185).nnnCONCLUSIONSnIce-slush cooling could provide renal hypothermia also under LPN. The decrease in renal function was small, whereas our ischemic time was longer than experts warm ischemic series. These observations suggested the protective effect of our cooling methods against ischemic injury.

Influence of baseline renal function and dose reduction of nephrotoxic chemotherapeutic agents on the outcome of metastatic urothelial carcinoma: A retrospective study

Objectives:u2003 To investigate the influence of baseline renal function and dose reduction of chemotherapeutic agents on the outcome of metastatic urothelial carcinoma patients with renal impairment.

A new prognostic classification for overall survival in Asian patients with previously untreated metastatic renal cell carcinoma

The aims of the present study were to: (i) develop a clinically useful prognostic classification in Asian patients with metastatic renal cell carcinoma (RCC) by combining metastatic features with several pretreatment parameters; and (ii) evaluate the validity of this prognostic classification. Baseline characteristics and outcomes were collected for 361 patients who underwent interferon‐α‐based therapy between 1995 and 2005. Relationships between overall survival (OS) and potential prognostic factors were assessed using Coxs proportional hazard model. The predictive performance of the model was evaluated using bootstrap resampling procedures and by using an independent dataset obtained from randomly selected institutions. The predictive accuracy was measured using the concordance index (c‐index). Four factors were identified as independent prognostic factors: time from initial diagnosis to treatment, anemia, elevated lactate dehydrogenase (LDH), and poor prognostic metastatic group (liver only, bone only, or multiple organ metastases). Each patient was assigned to one of three risk groups: favorable risk (none or one factor; n = 120), in which median OS was 51 months; intermediate risk (two factors; n = 101), in which median OS was 21 months; and poor risk (three or four factors; n = 102), in which median OS was 10 months. The c‐index was 0.72 in the original dataset and 0.72 in 500 random bootstrap samples. In the independent dataset for external validation, the c‐index was 0.73. Thus, the new prognostic classification is easily applicable for Asian patients with previously untreated metastatic RCC and should be incorporated into patient care, as well as clinical trials performed in Asia.