Norio Yoshimura

Expression of cyclooxygenase-2 in prostate carcinoma

Nonsteroidal antiinflammatory drugs inhibiting cyclooxygenase (COX) enzyme activity in both its constitutive (COX‐1) and inducible (COX‐2) isoforms were shown also to inhibit the development of colon carcinoma in animal models. COX‐2 is an inducer of angiogenesis of new blood vessels. The expression of COX‐1 and COX‐2 in prostate tissues from patients with prostate carcinoma was investigated using reverse transcriptase‐polymerase chain reaction (RT‐PCR) and immunohistochemistry.

Excellent Long‐term Outcome of ABO‐Incompatible Living Donor Kidney Transplantation in Japan

Owing to the severe shortage of cadaveric grafts in Japan, we have performed ABO‐incompatible living donor kidney transplantation since 1989. This study assessed short‐ and long‐term outcomes in 441 patients who received ABO‐incompatible living donor kidney transplants between January 1989 and December 2001. We compared our results with historical data from 1055 recipients of living kidney transplantation. Overall patient survival rates 1, 3, 5, 7, and 9 years after ABO‐incompatible transplantation were 93%, 89%, 87%, 85%, and 84%, respectively. Corresponding overall graft survival rates were 84%, 80%, 71%, 65%, and 59%. After ABO‐incompatible transplantation, graft survival rates were significantly higher in patients 29 years or younger than in those 30 years or older and in patients who received anticoagulation therapy than in those who did not receive such therapy. There were no significant differences between A‐incompatible and B‐incompatible recipients with respect to clinical outcomes. The graft survival rate at 1 year in the historical controls was slightly but not significantly higher than that in our recipients of ABO‐incompatible transplants. We conclude that long‐term outcome in recipients of ABO‐incompatible living kidneys is excellent. Transplantation of ABO‐incompatible kidneys from living donors is a radical, but effective treatment for end‐stage renal disease.

Initial MRI findings of non-traumatic osteonecrosis of the femoral head in renal allograft recipients

Fifty-one renal allograft recipients (15-62 years old, mean: 37 years) were monitored for 2.5-6.5 years (average: 4.3 years) after surgery by using magnetic resonance imaging (MRI) to find (i) initial signs of osteonecrosis of the femoral head (ONF), (ii) the presence of bone marrow edema as an initial sign of ONF, (iii) any changes of MRI patterns, and (iv) the relationship between these MRI findings and prognosis. MRI was performed preoperatively (baseline), and whenever possible during the 6-9th week, 12-16th week, 12th month, and yearly thereafter. T1- and T2-weighted images were obtained by using a spin echo technique. Abnormalities were first detected on MRI of 23 femoral heads in 13 patients between 6 weeks and 12 months. All lesions first showed a low intensity band on T1-weighted images and a high intensity band on T2-weighted images. No symptoms or diffuse patterns, such as bone marrow edema, preceded the appearance of the band pattern. After the 12th month, no new abnormal findings on MRI were detected. The lesions were classified into Type A, B, or C, according to the location. 12 of the 16 Type C femoral head lesions, which extend beyond the medial two thirds of the weight-bearing portion of the acetabulum, became symptomatic 7-14 months after transplantation and then progressed to collapse. Bone marrow edema appeared with radiological collapse and symptoms. With the exception of five lesions in three patients who failed to be MR imaged until 12 months postoperatively, all lesions were first detected on MRI within 16 weeks after transplantation. We therefore postulate that the ischemic event that causes ONF will have occurred within 12 weeks after transplantation, considering the time lag of reparative reaction to the dead bone.

Effect of a new immunosuppressive agent, FK506, on human lymphocyte responses in vitro. II. Inhibition of the production of IL-2 and gamma-IFN, but not B cell-stimulating factor 2.

The mechanism whereby FK506 inhibits immune responses was assessed in in vitro human studies. FK506 inhibited in a dose-dependent manner both interleukin 2 and gamma-interferon secretion of PBMC stimulated with PHA. Complete inhibition was obtained at the concentration of 0.25 nM of FK506 for IL-2 and 1 nM of FK506 for gamma-IFN production. Inhibition of 50% (IC50) was detected with 0.06 nM for IL-2 and 0.25 nM for gamma-IFN production. On the other hand, FK506 could not inhibit the B cell-stimulating factor 2 (BSF-2) production of PBMC, indicating the possibility that FK506 might spare the B cell function. Cloned T cells and cloned B cells, once activated, were scarcely affected by the agent; neither IL-2-driven proliferation of cloned T cells nor BSF-2-driven proliferation of cloned B cells was inhibited by FK506 at any concentration.

Short- and long-term donor outcomes after kidney donation: analysis of 601 cases over a 35-year period at Japanese single center.

Background. The lack of deceased donors in Japan means that living-donor kidney transplantation is necessary in as many as 80% of cases. However, there are few data on perioperative complications and long-term outcome for live kidney donors. Methods. To determine associated perioperative morbidity and long-term mortality among live kidney donors, we reviewed 601 donor nephrectomies performed at our institution between 1970 and 2006 and attempted to contact all of the donors (or their families) to ascertain their present physical status. The survival rate and causes of death were compared with an age- and gender-matched cohort from the general population. Results. Although three donors (0.5%) experienced major perioperative complications, that is, femoral nerve compression, pulmonary thrombosis, and acute renal failure, all of the donors recovered and left hospital without complications. Among 481 donors (80%) for whom details were available at the time of inspection, 426 (88.5%) were still surviving. Donor survival rates at 5, 10, 20, and 30 years were 98.3%, 94.7%, 86.4%, and 66.2%, respectively. The mean interval between kidney donation and death was 183±102 (7–375) months, and the mean age at death was 70±11 years. The survival rate of kidney donors was better than the age- and gender-matched cohort from the general population, and the patterns and causes of death were similar. Conclusions. Our data suggest that continuation of living-donor kidney transplantation programs is justified in short- and long-term donor safety.

The effects of pravastatin on hyperlipidemia in renal transplant recipients.

Hyperlipidemia may be one of the risk factors in the development of atherosclerotic disease in renal transplant recipients. In the present study, 24 kidney recipients with hyperlipidemia were treated with an HMG-CoA reductase inhibitor, pravastatin (10 mg/day). All recipients had been treated with cyclosporine (CsA), azathioprine (Az), and prednisolone (Pred). The mean total cholesterol (T-chol) level decreased from 323±7.4 to 261±7.9 mg/dl at one month after starting treatment (P<0.01) and this level did not change during treatment for further 6 months. The mean LDL cholesterol level was also decreased from 205.9±11.2 to 118.7±8.1 mg/ dl at 3 months after starting treatment (P<0.01). On the other hand, pravastatin did not affect the levels of HDL-cholesterol and triglycerides. Pravastatin did not show any effects on the white blood cell, monocyte, and lymphocyte counts, or the hemoglobin concentration (NS). One patient displayed a slight elevation of aspar-tate aminotransferase and alanine aminotransferase levels, but this was not sufficient to cease treatment. Pravastatin did not adversely affect the renal function or creatinine phosphokinase (CPK) levels. Two recipients developed nausea and vomiting and their treatment was stopped. Pravastatin appears to be a safe and efficacious method of treating hyperlipidemia in renal transplant recipients.

Effect of Cyclosporine on the Endocrine and Exocrine Pancreas in Kidney Transplant Recipients

In order to assess whether cyclosporine (CsA) affects the endocrine and exocrine pancreas, 105 patient courses comprised of 87 living related donor (LRD) and 18 cadaver donor (CAD) transplants treated with cyclosporine and prednisolone (Pred) were compared with the results of historical controls of 170 LRD and 10 CAD transplants treated with azathioprine (Az) and Pred. All of the recipients were followed for over 6 months after transplantation. There were no differences in age, sex, Broca index, family history, and preoperative evaluation on diabetic dispositions between the two treatment groups. The incidence of diabetes mellitus (DM) requiring insulin therapy was higher in CsA-treated recipients (18/105, 17.1%) than in Az-treated recipients (23/180, 12.8%; P less than 0.05), although both the daily Pred and cumulative doses of methylprednisolone (MP) at the onset of DM were significantly smaller in the CsA group than in the Az group (26.1 +/- 2.2 mg v 41.4 +/- 3.4 mg, P less than 0.01 and 3,086 +/- 626 mg v 7,133 +/- 1,129 mg, P less than 0.01, respectively). Diabetic patients with CsA showed higher levels of blood glucose (401 +/- 46 mg/dL), but lower amounts of urinary glucose (40 +/- 4.3 g/d) compared with patients treated with Az (239 +/- 31 mg/dL, and 61.4 +/- 4.6 g/d, respectively, P less than 0.05). In the CsA group, the onset of DM was related to high CsA plasma trough levels (greater than 350 ng/mL) in 23% of patients. Insulin could be withdrawn within 3 months in six of eight patients who had been converted from CsA to Az.(ABSTRACT TRUNCATED AT 250 WORDS)

FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study.

Background. FTY720 is a novel immunomodulator that was developed to produce optimal graft protection with improved safety and tolerability. Phase II studies have demonstrated the efficacy of FTY720 up to the doses of 2.5 mg with full-dose cyclosporine (FDC). Methods. This multicenter, double-blind, Phase IIb, randomized study evaluated the safety and efficacy of 5 mg FTY720 (n=87; Group 1) vs. 2.5 mg FTY720 (n=90; Group 2) vs. mycophenolate mofetil (MMF; n=94; Group 3) in de novo renal transplant patients receiving FDC and prednisone. Results. The primary efficacy endpoint was the occurrence of treated biopsy-proven acute rejection, graft loss, death, or premature study discontinuation (composite endpoint) within 6 months. The primary endpoint was superior in Group 1 (24%) and statistically noninferior in Group 2 compared to Group 3 (24.1% vs. 29.2% vs. 39.4%; P=0.025 and 0.0039, respectively). FTY720 plus FDC was generally well tolerated, with a similar incidence of adverse events across all groups. FTY720 was associated with higher incidence of bradycardia (Group 1: 26.4%, P=0.0002 and Group 2: 15.6%, P=0.046, vs. Group 3: 6.4%), respiratory disorders (Group 1: 40.2%, not significant [P=NS] and Group 2: 34.4%, P=NS vs. Group 3: 28.7%). One macular edema occurred in Group 2. Lower creatinine clearances were observed with FTY720 versus MMF (Group 1: 52.4 ml/min, P=NS and Group 2: 51.7 ml/min, P=0.039 vs. Group 3: 62.5 ml/min). Conclusions. Although FTY720 with FDC provided adequate protection from acute rejection the safety profile was less favorable for adverse events than current standard immunosuppression in de novo renal transplant patients.

The Effects Of Perioperative Portal Venous Inoculation With Donor Lymphocytes On Renal Allograft Survival In The Rat: I. Specific Prolongation Of Donor Grafts And Suppressor Factor In The Serum

In order to investigate the in vivo functional role of the liver in the immune responses in organ transplantation, effects of perioperative portal venous p.v. administration of donor lymphocytes on renal allograft survival were tested in the rat kidney transplant model. Donor lymphocytes were prepared from BN (BN, RT-1n) or third-party DA (RT1a) rat spleens and lymph nodes and injected p.v. or intravenously to Lewis (LEW, RT-1l) hosts on the day of transplantation (day 0). Untreated LEW hosts rejected BN renal grafts at 7.8 +/- 0.6 days (n = 10). Intravenous administration of 1 x 10(8) BN cells to LEW hosts on day 0 caused a slight, but not significant, prolongation of renal allograft survival (MST = 9.5 +/- 3.0 days, n = 13, NS), whereas portal venous inoculation of 1 x 10(8) BN cells on day 0 remarkably prolonged renal graft survival to 22.2 +/- 5.3 (n = 10, P less than 0.01). The prolongation of graft survival was antigen-specific; the administration of 1 x 10(8) DA cells p.v. to LEW hosts did not prolong the survival of BN renal grafts (MST = 7.4 +/- 0.8, n = 5). Spleen cells from p.v. treated LEW hosts 10 days after transplantation had no suppressor effect on the one-way MLC reaction of normal LEW responder cells toward donor BN or third-party DA stimulators. On the other hand, when serum from p.v.-treated LEW hosts was added to MLC at a concentration of 3 per cent of total volume, it suppressed the MLC reaction toward donor BN cells by 71.6 per cent, but not toward third-party DA stimulators (-8.5 per cent suppression, NS). Histological examination of p.v.-treated LEW hosts at 10 days after transplantation revealed that the liver had normal lobular architecture without expansion of portal tracts and infiltration of inflammatory cells. On the other hand, the transplanted kidney demonstrated a moderate mononuclear cell infiltration around the artery without an interstitial hemorrhage. Moreover, adoptive transfer of the serum from p.v.-treated LEW rats into the virgin secondary LEW hosts significantly prolonged the graft survival of BN kidneys from 7.8 days to 18.9 +/- 5.5 days (P less than 0.01), but not third-party DA graft survivals (MST = 7.5 +/- 0.6 days), indicating that an antigen-specific tolerogenic factor was released into the circulation through the process of allogeneic cells in the liver.

Effect of a new immunosuppressive agent, FK506, on human lymphocyte responses in vitro. I. Inhibition of expression of alloantigen-activated suppressor cells, as well as induction of alloreactivity.

The effect of FK506 on in vitro human lymphocyte responses was assessed in comparison with cyclosporine. FK506 suppressed, in a dose-dependent fashion, the lymphocyte response to stimulation with PHA and with alloantigens in primary mixed lymphocyte reactions at a 70-100-fold lower concentration than CsA--namely, 50% inhibition (IC50) was obtained with 8.6 nM FK506 and with 750 nM CsA in the PHA response, and with 0.21 nM FK506 and with 20 nM CsA in MLR. Allocytolytic T lymphocyte induction was also inhibited by FK506, whereas the ability of CTL to lyse targets was not affected by the agent, indicating that FK506 did not affect the recognition and binding of alloantigen by CTL. FK506 inhibited, in a dose-dependent fashion, both IL-2 receptor and transferrin receptor expression on the alloactivated lymphocytes--whereas this agent inhibited only incompletely both expression of both receptors on lymphocytes stimulated with PHA. Lymphocytes from primary MLR cultured in the presence of FK506 were tested for suppressor cell activity on day 8 of culture. FK506 did not allow for the expression of alloantigen-activated suppressor cells when used in a dose sufficient to inhibit CTL generation.