Yasuo Kohjimoto

Intravesical instillation therapy with bacillus Calmette-Guérin for superficial bladder cancer : Study of the mechanism of bacillus Calmette-Guérin immunotherapy

Aim:  In order to clarify the initial step of the mechanism by which bacillus Calmette‐Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured.

Association of Metabolic Syndrome Traits and Severity of Kidney Stones: Results From a Nationwide Survey on Urolithiasis in Japan

BACKGROUND Although metabolic syndrome and its individual components have been associated with kidney stone disease, whether the clustering of metabolic syndrome traits increases the severity of kidney stone disease has not been examined in a large-scale study. STUDY DESIGN Cross-sectional analysis. SETTING & PARTICIPANTS Data were obtained from 30,448 patients enrolled in the 6th Nationwide Survey on Urolithiasis in Japan conducted in 2005. Patients with lower urinary tract stones, struvite stones, cystine stones, or hyperparathyroidism and those younger than 15 years were excluded. PREDICTOR Number of metabolic syndrome traits (obesity [body mass index ≥25 kg/m(2)], diabetes, hypertension, and dyslipidemia). OUTCOMES Severe form of kidney stone disease, defined as recurrent and/or multiple stones, and abnormalities in urine constituents (hypercalciuria, hyperuricosuria, hyperoxaluria, and hypocitraturia). RESULTS 11,555 patients were included in the final analyses. Proportions of patients with recurrent and/or multiple stones were 57.7%, 61.7%, 65.2%, 69.3%, and 73.3% with 0, 1, 2, 3, and 4 metabolic syndrome traits, respectively (P < 0.001). There was a significant and stepwise increase in the odds of recurrent and/or multiple stones after adjustment for age and sex. In patients with 4 metabolic syndrome traits, the odds was 1.8-fold greater compared with patients with 0 traits (OR, 1.78; 95% CI, 1.22-2.66). In addition, the presence of metabolic syndrome traits was associated with significantly increased odds of having hypercalciuria, hyperuricosuria, hyperoxaluria, and hypocitraturia after adjustment for age and sex. LIMITATIONS Cross-sectional design, absence of dietary data, ill-defined diagnostic criteria for metabolic syndrome traits, and missing data for the majority of participants. CONCLUSIONS Metabolic syndrome trait clustering is associated with greater severity of kidney stone disease; increased urinary calcium, uric acid, and oxalate excretion; and decreased urinary citrate excretion. These results suggest that kidney stone disease should be regarded as a systemic disorder linked to metabolic syndrome.

The cytotoxic effects of fleroxacin and ciprofloxacin on transitional cell carcinoma in Vitro

There have been few reports concerning the cytotoxic effects of fluoroquinolone antibiotics on transitional cell carcinoma. This investigation was designed to study the cytotoxic effects of fleroxacin and ciprofloxacin on transitional cell carcinoma quantitatively in vitro.

Oxalate toxicity in renal cells

Exposure to oxalate, a constituent of the most common form of kidney stones, generates toxic responses in renal epithelial cells, including altered membrane surface properties and cellular lipids, changes in gene expression, disruption of mitochondrial function, formation of reactive oxygen species and decreased cell viability. Oxalate exposure activates phospholipase A2 (PLA2), which increases two lipid signaling molecules, arachidonic acid and lysophosphatidylcholine (Lyso-PC). PLA2 inhibition blocks, whereas exogenous Lyso-PC or arachidonic acid reproduce many of the effects of oxalate on mitochondrial function, gene expression and cell viability, suggesting that PLA2 activation plays a role in mediating oxalate toxicity. Oxalate exposure also elicits potentially adaptive or protective changes that increase expression of proteins that may prevent crystal formation or attachment. Additional adaptive responses may facilitate removal and replacement of dead or damaged cells. The presence of different inflammatory cells and molecules in the kidneys of rats with hyperoxaluria and in stone patients suggests that inflammatory responses play roles in stone disease. Renal epithelial cells can synthesize a variety of cytokines, chemoattractants and other molecules with the potential to interface with inflammatory cells; moreover, oxalate exposure increases the synthesis of these molecules. The present studies demonstrate that oxalate exposure upregulates cyclooxygenase-2, which catalyzes the rate-limiting step in the synthesis of prostanoids, compounds derived from arachidonic acid that can modify crystal binding and may also influence inflammation. In addition, renal cell oxalate exposure promotes rapid degradation of IκBα, an endogenous inhibitor of the NF-κB transcription factor. A similar response is observed following renal cell exposure to lipopolysaccharide (LPS), a bacterial cell wall component that activates toll-like receptor 4 (TLR4). While TLRs are primarily associated with immune cells, they are also found on many other cell types, including renal epithelial cells, suggesting that TLR signaling could directly impact renal function. Prior exposure of renal epithelial cells to oxalate in vitro produces endotoxin tolerance, i.e. a loss of responsiveness to LPS and conversely, prior exposure to LPS elicits a similar heterologous desensitization to oxalate. Renal cell desensitization to oxalate stimulation may have profound effects on the outcome of renal stone disease by impairing protective responses.

Interactions between calcium oxalate monohydrate crystals and Madin-Darby canine kidney cells: endocytosis and cell proliferation

The present investigation was designed to study the biological responses in cultures of Madin-Darby canine kidney (MDCK) cells exposed to calcium oxalate monohydrate (COM) crystals, the most common type of urinary crystals. The addition of COM crystals significantly accelerated the multiplication of MDCK cells and significantly activated the cell viability. After exposure of MDCK cells to COM crystals, scanning electron microscopy revealed that some crystals adhered to the plasma membrane and others were endocytosed by the cell. This cellular uptake of crystals was time dependent from 1 to 8 h and showed a specificity according to crystal type. However, the endocytosis of aggregated COM crystals was less marked than that of non-aggregated crystals. Pre-treatment with each of the glycosaminoglycans (sodium pentosan polysulphate, heparin, and chondroitin sulphate C) produced a significant reduction of the cellular uptake of COM crystals, suggesting that these glycosaminoglycans may play some critical roles in preventing the cellular uptake of crystals. Although investigation in further detail is necessary, we speculate that these crystal-cell interactions, that is, the cellular uptake of crystals and cell proliferation, may be among the earliest processes in the formation of kidney stones.

The prognostic significance of human equilibrative nucleoside transporter 1 expression in patients with metastatic bladder cancer treated with gemcitabine-cisplatin-based combination chemotherapy

What’s known on the subject? and What does the study add?

Insulin resistance increases the risk of urinary stone formation in a rat model of metabolic syndrome

To investigate the association between metabolic syndrome and urinary stone disease, and whether insulin resistance associated with adiposity affects the risk of urinary stone formation, using a rat model of metabolic syndrome.

Adhesion of calcium oxalate crystals to Madin-Darby canine kidney cells and some effects of glycosaminoglycans or cell injuries.

The present investigation studied the quantitative adhesion of calcium oxalate monohydrate (COM) crystals to the surface of Madin-Darby canine kidney cells, which exhibit many characteristics of renal cortical collecting tubule cells. COM crystals adhered to the cell surface, and the attachment showed a time and concentration dependency with plateau. The results suggested that the attachment of microcrystals to the cortical tubular cell might be one of the earliest processes in the formation of kidney stones. Pretreatment with glycosaminoglycans significantly reduced the adherent crystals. Injuries to the Madin-Darby cells induced by 0.1 M HCl and gentamicin resulted in significant decreases of COM crystal adhesion to the cell surface. It was suggested that urinary glycosaminoglycans might play some critical role in preventing crystal adhesion to these cellular membranes and that cell injuries might not be essential for the attachment of microcrystals to the tubular cells.

Histological observations of the adhesion and endocytosis of calcium oxalate crystals in MDCK cells and in rat and human kidney

Adhesion and/or endocytosis of calcium oxalate crystals to the three kinds of tubular cells (Madin-Darby canine kidney (MDCK) cells, rat and human kidney) were demonstrated morphologically to presume the initial formation of kidney stone. After removal of the nonadhesion crystals, the cells were subsequently recultured in the vertical position. At various times thereafter, the interactions between COM crystals and MDCK cells were evaluated morphologically by SEM. COM crystals adhered to the surface of MDCK cells immediately, and the crystals were then endocytosed. The microvilli of the cells appeared to play an important role in these processes. At later times, some complexes that consist of aggregated calcium oxalate crystals and cell debris were observed sporadically. Kidney tissues were obtained from male Sprague-Dawley rats which were injected with sodium oxalate intraperitoneally. Experimentally induced calcium oxalate crystals were evaluated histologically using polarized light microscopy. Some crystals in the cortical portion were attached to the tubular epithelium or internalized into the luminal membrane. Whereas in the papilla, the aggregated crystals were observed lying free from the degenerated tubular lumen along with the cell debris. Human kidney tissues were obtained from 38 patients with calcium oxalate nephrolithiasis who underwent nephrolithotomy or partial nephrectomy before the era of ESWL. The specimens were examined for calcium crystals within the tubular lumen, attached to the tubular walls or internalized into the tubular cells, by polarized light microscopy. Approximately 50% of the specimens observed crystals attached to the tubular cell epithelium and some of them were seen inside the tubular cells. In conclusion, crystal-cell interaction resulted in movement of crystals from the lumen into the cells by an action of microvilli from the results of MDCK cells. However, it was not clear from the results in rats or human kidney tissue that crystal adhesion and/or endocytosis might be vital in the crystal growth in the kidney.

Calcium oxalate crystal deposition in metabolic syndrome model rat kidneys.

Objective:  Although an epidemiological link between the metabolic syndrome and kidney stone formation has been reported, the mechanism by which metabolic syndrome promotes kidney stone formation has yet to be elucidated. We investigated calcium oxalate (CaOx) kidney stone formation in a rat metabolic syndrome model.