Takao Sonoda

Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas.

Interleukin‐6 (IL‐6) was found to be a growth factor of renal cell carcinomas. Furthermore, renal cell carcinomas freshly isolated from the patients expressed mRNA of IL‐6 and secreted biologically active IL‐6 under the culture conditions where the tumor cells could grow, but they did not produce IL‐6 nor proliferate in the absence of fetal calf serum. The production of IL‐6 by the tumor cells was also demonstrated by immunostaining of the IL‐6‐producing cells utilizing anti‐IL‐6 antiserum. Moreover, anti‐IL‐6 antiserum specifically inhibited the in vitro tumor growth. All data indicated that IL‐6 functions as an in vitro autocrine growth factor of renal cell carcinomas.

Human Herpesvirus 6 Infection In Renal Transplantation

The relationship between renal transplantation and human herpesvirus 6 (HHV-6) infection was studied. All 21 kidney donors examined had antibody to HHV-6 at the time of transplantation. The 21 kidney recipients also had detectable antibody to HHV-6 before transplantation--and, of these, 8 patients showed a significant increase of serum antibody titer against HHV-6 after transplantation. All these 8 recipients suffered severe kidney rejection. Furthermore, virus isolation from peripheral blood lymphocytes of 2 recipients who suffered rejection was attempted, and in both cases HHV-6 was isolated. Biopsy specimens of rejected kidneys of 9 other patients were examined for the presence of HHV-6 antigens, and in 5 of these specimens antigens were detected in the tubular epithelium, as well as in infiltrating histiocytes and lymphocytes. These results suggest that HHV-6 can infect renal tissues and that the infection may be correlated with rejection or with immunosuppressive therapy.

Surgical repair of varicocele at puberty: preventive treatment for fertility improvement.

In 40 pubertal boys with a varicocele a comparative followup study was performed to evaluate the efficacy of surgical correction of the varicocele in this age group in regard to improvement of fertility after completion of sexual maturation. The varicocele was corrected surgically in 24 patients and it was left uncorrected in 16. Testicular atrophy was noted in all cases at the initial visit and after followup. Of the 24 corrected patients 16 had atrophy of at least 1 testis before surgical treatment, whereas only 7 demonstrated atrophy after followup. Of the 16 uncorrected patients testicular atrophy was noted in 8 at the initial visit but 12 had atrophy after followup. Semen examination of 23 patients who had completed sexual maturation demonstrated a higher quality of routine seminal parameters, for example sperm density, sperm motility and percentage of morphologically normal spermatozoa, in the corrected group than in the uncorrected group.

Current status of renal replacement therapy in Japan

The study of the current status of renal replacement therapy in Japan is based on the analysis of data from the registry reports for regular dialysis therapy and kidney transplantation. The total number of patients receiving regular dialysis therapy was 123,926 at the end of 1992: 117,809 (95.1%) on hemodialysis and 6,117 (4.9%) on peritoneal dialysis. The primary diseases of newly accepted patients were chronic glomerulonephritis (42.2%), diabetic nephropathy (28.4%), nephrosclerosis (5.9%), polycystic kidney disease (2.7%), chronic pyelonephritis (1.6%), and others. The number of kidney transplant patients in Japan was 8,384 at the end of 1991: 6,154 (73.4%) received a living donor transplantation and 2,230 (26.9%) received a cadaver donor transplantation. Overall 5-year survival rates of dialysis patients were 60.4%: 69.7% for chronic glomerulonephritis, 41.7% for diabetic nephropathy, 39.6% for nephrosclerosis, 73.6% for diffuse polycystic kidney disease, and 66.6% for chronic pyelonephritis. The causes of death of dialysis patients were heart failure (31.1%), cerebrovascular accident (13.6%), infectious diseases (11.3%), malignancies (7.1%), cachexia/uremia (6.7%), myocardial infarction (5.8%), and others. The gross mortality rate of dialysis patients was increased in cases of less than 4 hours of the average length of each dialysis session, less than 4% and more than 9% of the average weight loss during each dialysis session, less than 1.0 of Kt/V, and less than 0.9 and more than 1.7 g/kg/d of protein catabolic rate. Overall 5-year patient and graft survival rates of kidney transplant patients since 1964 were 82.7% and 60.3%: 84.4% and 65.0% in living donor cases, and 77.4% and 46.2% in cadaver donor case, respectively. Those since 1983 were 90.1% and 68.2%: 91.3% and 72.6% in living donor cases, and 87.8% and 59.3%, respectively. Graft survival rates were superior in cases treated with combined steroid, cyclosporine and azathioprine or mizoribine, to those treated with other immuno-suppressive regimens, and they decreased as the number of HLA-A, -B and -DR increased.

A novel rescue drug, 15-deoxyspergualin: first clinical trials for recurrent graft rejection in renal recipients

The present multicentral clinical study performed in 6 institutes demonstrated that the novel immunosuppressive agent, 15-deoxyspergualin (DSG), is very effective on rejection. In 34 cases of rejection, 30 were treated with DSG at 40 mg/m2 (1 case), 80 mg/m2 (7 cases), 120 mg/m2 (9 cases), 180 mg/m2 (9 cases), and 220 mg/m2 (8 cases). The overall remission rate was 79% in 34 cases of rejection including accelerated, acute, and chronic rejection in different periods after transplantation. Analyzing the remission rates of early phase acute rejection occurring within 3 months after transplantation according to treatment pattern, the remission rate was 100% in 3 cases treated with DSG alone (using DSG 1 week or longer after other agents), 88% in 8 cases treated by rescue use of DSG (using DSG within 1 week after other agents), and 86% in 7 cases treated by combined use of DSG with other agents. Adverse reactions included reductions in WBC and platelets, anemia, perioral numbness, gastrointestinal troubles, and others. However all these symptoms were so mild that DSG treatment was not discontinued. Further studies are necessary on the effect of DSG, especially in acute rejection under conditions that reduce the many influences of other agents as much as possible.

Surgical Management of Undescended Testis: Retrospective Study of Potential Fertility in 274 Cases

To determine the fertility potential of men with an undescended testis a retrospective study was performed on 274 patients by evaluating sperm density and sperm motility, as well as histopathological findings of the seminiferous tubules. The patients, who had been treated surgically when they were 2 to 5 or 9 to 12 years old and who were examined when they were 18 to 39 years old, were divided into 4 groups: group 1 (61 patients) underwent bilateral orchiopexy, group 2 (149) underwent unilateral orchiopexy, group 3 (26) underwent unilateral orchiectomy and group 4 (38) received no surgical treatment for a unilateral undescended testis. Significant differences in the sperm density and motility were detected between group 1 (normal range 0 to 7 per cent) and group 2 or 3 (normal range 72 to 79 per cent), and between group 2 or 3 and group 4 (normal range 42 to 58 per cent). Histopathological differences were significant between group 1 or 2 (Johnsens score count 6.06 to 6.11) and group 4 (4.72) for the affected side, and between group 2 or 3 (9.09 to 9.20) and group 4 (8.60) for the unaffected side. The results suggest that surgical treatment may not significantly ameliorate the fertility potential of patients with bilateral undescended testes. On the other hand, in patients with unilateral undescended testis an operation not later than at early puberty is advisable to maintain the spermatogenic function in the unaffected testis. It is suggested that some unknown factors relating to the highly impaired unilateral undescended testis may in some way inhibit function of the contralateral unaffected testis.

Distribution of calcitonin gene-related peptide-containing fibers in the urinary bladder of the rat and their origin

SummaryBy use of indirect immunofluorescence, this study demonstrated the presence of calcitonin gene-related peptide-like immunoreactive (CGRPI) fibers in the bladder of the rat. These fibers were abundant in the muscle layer, in which they ran parallel to the muscles, submucosa, and epithelium. No immunoreactive cells were detected. We also examined the origins of these fibers, using a method that combined biotinized retrograde tracer (biotin-wheat germ agglutinin) (B-WGA) and immunocytochemistry. Injection of the tracer into the bladder resulted in the demonstration of small to medium-sized labeled cells that contain CGRPI structures in single dorsal root ganglion cells mostly at the level of L6 and S1, but also a few at L2.Double-staining for CGRPI and immunoreactive P-like substance (SPI) indicated that there are cells in the dorsal root ganglia at the level of L6 and S1 that react to both, but that there are many CGRPI-positive cells that contain no demonstrable SPI; most of the latter are large.

Analysis of the Arterial Blood Flow Patterns of Normal and Allografted Kidneys by the Directional Ultrasonic Doppler Technique

AbstractThe arterial blood flow of the allotransplanted kidney was examined 52 times in 40 recipients and that of the normal kidney 6 times in 6 donors by means of the directional ultrasonic Doppler technique.The blood flow patterns showed a rapid forward phase in systole and a slow forward phase in diastole but nothing indicative of a reverse flow was found. A significant correlation was observed between the acceleration time of flow component and graft function, while there were no correlations among diastole/systole ratio, appearance time and graft function. The arterial blood flow patterns of the grafts were classified into 3 groups based on acceleration time: I—excellent, II—intermediate and III—poor graft functions.Additionally, in pursuit of possible relationships between the ultrasonic Doppler flow patterns of the grafts and their morphological features, histopathology and angiography were done for 20 and 15 recipients, respectively. As a result the histologic vascular changes with interstitial da...

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.

Interleukin-6 Activity in Urine and Serum in Patients with Bladder Carcinoma

To investigate the correlation between interleukin-6 and urothelial neoplasms, interleukin-6 activities in blood and urine samples of patients with bladder carcinoma were measured with a proliferation assay using an interleukin-6 dependent murine hybridoma clone, MH60.BSF2. A total of 43 patients and 15 normal volunteers were entered into this study. All of the patients were examined preoperatively and 26 were reexamined more than 6 days postoperatively to eliminate the effect of surgical injury on interleukin-6 secretion. The interleukin-6 titers in urine and serum increased in accordance with the progression of the tumor stage, and tumor removal induced a remarkable decrease in the titer of urinary interleukin-6. Although the interleukin-6-producing site has not been elucidated yet, our study suggests that interleukin-6 activity in bladder carcinoma patients may reflect the immunoreaction against the tumor in local urothelium.