Hiroshi Kameoka

Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus

Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patients prognosis. In study 1, the effects of immunosuppressants, cyclosporine (CsA) and tacrolimus on serum lipids were compared in-patients undergoing renal transplantation. The study included 32 cases of renal transplantation recipients who randomized to the CsA treatment group (15 patients) and the tacrolimus group (17 patients). Before and 1 month after the transplantation, we assessed the serum lipid levels, apolipoprotein levels, the concentrations of cholesterol in the respective lipoprotein fractions and the enzyme activities related to lipid-metabolism. The serum lipid levels in both groups were significantly increased at 1 month after renal transplantation. In the CsA group, there were significant increases in cholesterol contents in very-low-density lipoprotein (VLDL), LDL2 and HDL2 fractions, whereas, in the tacrolimus group, cholesterol content was increased in VLDL and HDL2 fractions. In study 2, 1 month after renal transplantation, 19 patients with hypercholesterolemia (total cholesterol (TC) >200 mg/dl) and hypertriglyceridemia (triglyceride (TG) >150 mg/dl) were treated with simvastatin 5-10 mg/day for 6 months. Simvastatin treatment significantly decreased serum TC (240+/-29-200+/-22 mg/dl, P<0.001), low-density lipoprotein cholesterol (LDL-C; 114+/-20-99+/-17 mg/dl, P<0.05) and TG levels (217+/-103-130+/-38 mg/dl, P<0.01). In addition, there were significant decreases in very-low-density lipoprotein cholesterol (VLDL-C; 53+/-20-34+/-15 mg/dl, P<0.001). The Cmax and AUC of simvastatin were increased about eight-fold, when simvastatin was given in combination with CsA. In contrast, no significant changes in simvastatin levels were observed when combination with tacrolimus. Although simvastatin levels were increased with CsA, there were no abnormal changes in renal and liver functions, creatinine phosphokinase (CPK) levels or in incidence of adverse effects.

FK506-induced kidney tubular cell injury

Some renal changes associated with cyclosporine, such as tubular vacuolization and glomerular thrombosis, have also been reported with FK506. Furthermore, FK506 therapy is associated with a decrease in glomerular filtration rate and renal plasma flow and an increase in renal vascular resistance. We studied the in vitro tubular cell sensitivity to FK506 in comparison with CsA, the ultrastructural changes induced by FK506 and CsA, and the effect of both drugs on tubular cell growth in vitro. We also investigated whether FK506 and CsA induced endothelin-1 (ET-1) secretion of cultured tubular cells and whether this stimulatory effect coincided with a change in the endothelin systemic synthesis. Exposure of tubular cells to high concentrations of FK506 or CsA (10, 50, 100 μM) induced a time- and dose-dependent cell injury in vitro. The damage induced by FK506 and CsA was characterized by a direct cytotoxic effect on tubular cells, as expressed by release of 3H thymidine from prelabeled cells, N-acetyl-β-D-glu-cosaminidase release, and cell detachment. Ultrastructural changes (vacuolizations, swelling, and mitochondrial enlargement) and inhibition of the growth of cultured tubular cells were also observed at high concentrations of FK506 and CsA. Low concentrations of FK506 and CsA (1, 0.1, 0.01, 0.001 %mUM) were not cytotoxic and induced only a minimal inhibitory effect on the growth of tubular cells in vitro. We demonstrated that FK506 (1, 0.1, 0.01 μM) time-dependently stimulated the secretion of endothelin by cultured tubular cells. CsA 10, 1, 0.1, 0.01 also exerted an enhancing effect on ET-1 secretion in cultured tubular cells. We observed that the concentration of CsA that induced the most important enhancing effect was 10 or 100 times higher than that required for FK506 to observe the same effect. The concentrations of FK506 or CsA that induced ET-1 secretion were not cytolytic for tubular cells in vitro. FK506− or CsA-treated rats showed an increase in serum level of ET-1 in comparison with the control. Through the stimulatory effect on endothelin secretion by tubular cells, FK506 and CsA may induce a perturbation of renal hemodynamics. Concentrations of FK506 and CsA, higher than established serum levels but close to those reached in tissues, are cytotoxic for tubular cells and induced ultrastructural changes and a significant delayed regeneration.

Early efficacy of silodosin in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia

Objectives:  To evaluate the early efficacy of the α1A‐adrenoceptor selective drug, silodosin, for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

Interferon‐Gamma Stimulates Neopterin Release from Cultured Kidney Epithelial Cells

The ability of cultured kidney epithelial cells (KEC) to secrete neopterin, which is a marker of the activation of immune system was studied. In this study inlerferon gamma (IFN‐γ) was shown to induce neopterin release from KEC in a dose‐ and time‐dependent manner. Many other cytokines and mitogens (IL‐1β, IL‐2, IL‐6, LPS and phorbol ester) were tested for their ability to induce neopterin in KEC but all failed to induce a significant release of neopterin from KEC. By itself TNF‐ á induced a release of small amounts of neopterin but strongly potentiated the effect of IFN‐γ in a synergistic manner to induce neopterin secretion. These data indicate that not only monocytes and macrophages which it is well known secrete neopterin, but KEC are responsible also for the high serum or urine level of neopterin observed in patients with kidney allograft rejection or infections episodes. As the amount of neopterin released by KEC is smaller than that secreted by activated macrophages, the contribution of KEC to the overall production of neopterin during certain diseases may be small.

Serum and urinary neopterin as markers in renal transplant patients.

For monitoring neopterin levels, serial serum and urinary samples were obtained from 21 renal transplant patients. In renal transplant patients, serum neopterin levels were significantly higher than in healthy volunteers, even though in a clinically stable state urinary neopterin levels were also higher than in healthy volunteers, but statistically not significantly. In cases with rejection, both serum and urinary neopterin levels were significantly more elevated than in the stable state. In contrast, serum and urinary neopterin levels were not clevated in nephrotoxicity events. These results suggest that serum and urinary neopterin levels might be valuable indicators of acute rejection. Moreover, they could be useful for differentiating acute rejection from nephrotoxicity episode.

In vitro FK506 kidney tubular cell toxicity

Nephrotoxicity is the most prominent side effect of the new immunosuppressive drug FK506. Some of the histopathological changes associated with cyclosporine (CyA) nephrotoxicity such as tubular vacuolization and glomerular thrombosis have also been reported with FK506 therapy. In this study we used kidney tubular cells in culture to address the issue of FK506- and CyA-induced tubular damage. Exposure of tubular cells to high concentrations of FK506 or CyA (10, 50 and 100 microM) induced a time- and dose-dependent cell injury in vitro characterized by a direct cytotoxic effect on tubular cells as expressed by release of 3H-thymidine from prelabelled cells, N-acetyl-beta-D-glucosaminidase (NAG) release and cell detachment. Ultrastructural changes (vacuolization, swelling and mitochondrial enlargement) and inhibition of the growth (DNA and RNA synthesis) of cultured tubular cells were also observed at high concentrations of FK506 and CyA. These concentrations are higher than those reached in clinical situations, but close to the concentrations that may be reached by FK506 or CyA in tissues. Low concentrations of FK506 and CyA (1, 0.1 and 0.01 microM) were not cytotoxic and induced only a minimal inhibitory effect on the growth of tubular cells in vitro. At the same concentration CyA induced more cell detachment, more NAG release and a stronger inhibitory effect on cell growth than FK506 (P < 0.01). Since an evident cytotoxic effect was observed only at high concentrations, we can speculate that tubular toxicity is due to the accumulation of drug in the cells inducing cell disruption and death.

Interferon α therapy for chronic active hepatitis type C after renal transplantation and allograft rejection

An acute type rejection episode occurred in one of two patients treated with Interferon α (IFN α) for type C hepatitis (CHC).Histopathological examination of the graft kidney revealed focal cellular infiltration and chronic transplant glomerulopathy which showed acute or chronic type rejection.In spite of bolus administration of methyl-prednisolone, the elevation of serum creatinine level continued. After administration of anti-human lymphocyte globulin (AHLG), renal function improved, but urinary protein was still positive.Another patient had no episode of rejection during or after IFN α therapy.

FK506 mechanism of nephrotoxicity: stimulatory effect on endothelin secretion by cultured kidney cells

The administration of FK506 or cyclosporin A (CyA) to animals and humans induces a decrease in glomerular filtration rate and renal plasma flow and an increase in renal vascular resistance. Endothelins (ET-1), very powerful renal vasoconstrictors, are involved in CyA-related alteration in renal haemodynamics. In this study we sought to determine whether FK506 and CyA had a stimulatory effect on endothelin secretion by cultured kidney cells (tubular and mesangial cells) and whether this stimulatory effect coincided with an increase in ET-1 serum level in FK506- and CyA-treated rats. FK506 concentrations of 1, 0.1, 0.01 and 0.001 microM significantly stimulated ET-1 secretion by cultured tubular and mesangial cells. CyA at 10, 1, 0.1 and 0.01 microM also exerted an enhancing effect on ET-1 secretion in cultured tubular cells whereas CyA only at 10 and 1 microM had a stimulatory effect on ET-1 secretion by human mesangial cells. We observed that the concentrations of CyA that induced the most substantial enhancing effect were 10 or 100 times higher than those required for FK506 to produce the same effect. The concentrations of FK506 or CyA which induced ET-1 secretion by tubular cells and kidney cells were not cytolytic as assessed by N-acetyl-beta-D-glucosaminidase (NAG) release and lactic dehydrogenase (LDH) release. FK506 or CyA treatment at toxic doses induced an increase in serum level of ET-1 in treated rats. We conclude that FK506 and CyA induced an increase in the synthesis of endothelin in the kidney which may explain the increase in circulating ET-1. This stimulatory effect may contribute to the genesis of haemodynamic preturbations associated with FK506 and CyA.

Splenic Gonadal Fusion with Persistent Müllerian Duct Syndrome

Splenic gonadal fusion is a rare anomaly that is frequently associated with skeletal abnormalities or occasionally with cryptorchism. But the case of this anomaly accompanied by male pseudohermaphroditism here represents, to our knowledge, the first report of splenic gonadal fusion with persistent müllerian duct syndrome.

Mucinous Adenocarcinoma of the Male Urethra

We report a case of primary mucinous adenocarcinoma arising in the bulbomembranous urethra. The patient underwent radical cystectomy and total penectomy, followed by systemic chemotherapy. Metastases in lungs, skin, and lymph nodes (inguinal, iliac, para-aortic, and tracheobronchial) were found within 2 months after operation. We reviewed 37 cases of primary adenocarcinomas of the male urethra.