Satoshi Teraoka

Intimal hyperplasia and hemodynamic factors in arterial bypass and arteriovenous grafts: a review.

Stenosis at the graft–vein junction caused by intimal hyperplasia (IH) is the major cause of failure of vascular access grafts used for hemodialysis. There is a strong relationship between hemodynamic factors and formation of IH. The hemodynamic pattern and the location of IH are different in arterial bypass grafts (ABGs) compared with arteriovenous grafts (AVGs). In an ABG, end-to-side anastomosis of the expanded polytetrafluoroethylene graft and artery produces hemodynamic changes around the junction. IH develops at the arterial floor and the toe and heel of the distal anastomosis. Low shear stress and oscillating shear forces at the arterial floor and the heel plus a high wall sheer stress (WSS) gradient at the toe probably promote IH development. Compliance mismatch between the graft and artery causes turbulence that may contribute to IH formation. The blood flow rate in AVGs is 5–10 times greater than that in ABGs. High flow causes turbulence that injures endothelial cells and eventually results in IH. The peak WSS in AVGs is about 6 N/m2, much higher than that in ABGs. Excessively high WSS may effect IH formation in AVGs. Several venous cuff or patch anastomotic designs have been used in attempts to regulate hemodynamic factors in grafts. In ABGs, these designs appear to help decrease IH formation. In AVGs, however, they generally have not improved patency rates. In a high-flow system such as an AVG, more drastic changes in anastomotic design may be required.

Preventive effect of pirfenidone against experimental sclerosing peritonitis in rats

We investigated the preventive effect of pirfenidone (PFD), a newly developed anti-fibrotic agent, on experimental sclerosing peritonitis (sp) which we had established in rats. Male Wistar rats (150-250 g) were divided into the following two groups; 7 rats were treated with daily intraperitoneal (i.p.) injection of 0.1% chlorhexidine gluconate (CH) and 15% ethanol solved in 2 ml of saline for 26 days as a control of SP model (CH group) and 6 rats were treated daily with peroral (p.o.) administration of 350 mg/kg of PFD in addition to the daily i.p. injection of aforementioned CH-ethanol-saline solution for 26 days (CH + PFD group). Macroscopic intraperitoneal changes and histological fibrotic changes were graded by scoring in a blind manner. Actual subserosal thickness was measured by observation under light microscope. Body weight gain was significantly greater in CH + PFD group than in CH group (P < 0.05). Macroscopic intraperitoneal adhesion changes in CH + PFD group were significantly fewer than in CH group (P < 0.05). Fibrotic changes were fewer and subserosal thickness in liver and intestine were smaller in CH + PFD group with statistical significance (p < 0.1). We concluded that PFD markedly inhibited or prevented fibrotic changes in the experimental sclerosing peritonitis induced by CH.

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.

Anti-AB titer changes in patients with ABO incompatibility after living related kidney transplantations: survey of 101 cases to determine whether splenectomies are necessary for successful transplantation.

Background. A shortage of organ donors for transplantation has become a serious problem throughout the world. To overcome this problem, transplantations across ABO blood barriers have been performed with some success. In general, however, the graft survival rate for transplantation with ABO incompatibility is lower than that of transplantation with ABO compatibility. Unfortunately, the mechanism by which isohemagglutinins might injure an ABO-incompatible graft remains uncertain. Here, the pre- and posttransplantation anti-AB titers in patients who received transplants from ABO-incompatible living donors are reviewed and the pathological findings are compared. Methods One hundred and one patients underwent ABO-incompatible living related kidney transplantation (i-LKT) between January 1989 and October 1999 at our hospital. Plasmapheresis and immunoadsorption were performed in all of the i-LKT patients before the transplantation to remove anti-AB antibodies. A splenectomy was also performed during the operation, followed by the local irradiation of the graft with a dose of 150 rad. The anti-AB titers and pathological findings for 93 i-LKT patients, excluding 8 patients who died, were then examined. Results Immediately after the i-LKT, the anti-AB titer dropped rapidly to below 1:4 in all 93 cases. Seventy of patients (70/93, 75%) showed no elevation in their anti-AB titer during their follow-up. However, the remaining 23 patients (23/93, 25%) showed a significant elevation of their anti-AB titer to over 1:16. Sixteen of these patients (16/93, 17%) exhibited an anti-AB titer of over 1:32. Out of these 16 patients, 11 patients (11/16, 69%) lost their grafts. The anti-AB titer in the remaining five patients (5/16, 31%) spontaneously decreased without any special treatment. Seven patients (7/93, 8%) exhibited an elevated titer of 1:16. Out of these patients, only one patient (1/7, 14%) lost his graft. The elevated titers in the remaining six patients (6/7, 86%) eventually decreased. The graft function improved in patients whose elevated anti-AB titers eventually decreased. Control patients (ABO-compatible kidney transplant patients) showed a normal elevation of their titer values compared with preoperative titers. Pathological findings showed severe humoral rejections in all cases with high anti-AB titers that lost grafts. Humoral rejection was also detected in most of the patients whose anti-AB titer was elevated to over 1:16 after the transplantation, but excellent renal function was resumed once the titers decreased to below 1:4. Conclusions In 23 out of 93 i-LKT patients (25%), the anti-AB titers were significantly elevated after the splenectomy. In view of other reports of i-LKT without splenectomy, we feel that a splenectomy in i-LKT patients might be unnecessary. Pathological evidence suggests that the decrease in the anti-AB titer after transplantation might be the net result of plasmapheresis before the operation and the adsorption of antibodies to the endothelium of the transplanted organ after the operation, neither of which is influenced by a splenectomy.

The 5-year outcome of ABO-incompatible kidney transplantation with rituximab induction.

Background. In 2002, we introduced the anti-CD20 chimeric antibody, rituximab, for ABO-incompatible kidney transplantation (ABO-IKT). Here, we report the 5-year outcome obtained using rituximab as part of the preoperative regimen for ABO-IKT. Methods. Between January 2002 and December 2008, 408 patients underwent living-related kidney transplantation at our department. The patients were divided into three groups: group A (n=280), ABO-compatible kidney transplantation (ABO-CKT); group B (n=63), ABO-IKT without rituximab induction; and group C (n=50), ABO-IKT with rituximab induction. Basic immunosuppression was the same in all three groups except for the use of rituximab, which was administered at 100 mg (n=6), 200 mg (n=26), and 500 to 1000 mg (n=18). Results. The graft survival rates in groups A, B, and C were 99.2%, 96.8%, and 100% at 1 year, 93.8%, 94.9%, and 100% at 3 years, and 88.4%, 90.3%, and 100% at 5 years after transplantation, respectively. Serum creatinine levels in the three groups were not different at 1, 3, and 5 years after transplantation. The numbers of episodes of acute antibody-mediated rejection in groups A, B, and C were 7 (2.5%), 10 (15.9%), and 2 (4.0%), respectively (P=0.651), and acute cellular rejection was observed in 40 (14.3%), 6 (9.5%), and 2 (4.0%) patients, respectively (P=0.0957). There was no increased risk of cytomegalovirus infection in group C. Conclusions. In the long term, inclusion of rituximab in the preoperative regimen yielded an even better outcome than that of ABO-CKT and rituximab-untreated ABO-IKT, without any increase in the risk of infection.

Preconditioning regimen consisting of anti-CD20 monoclonal antibody infusions, splenectomy and DFPP-enabled non-responders to undergo ABO-incompatible kidney transplantation

Abstract:  Patients undergoing ABO‐incompatible kidney transplantation must have their anti‐donor blood‐type antibody titer (ADBT) reduced to below 1:16 by using either plasma‐exchange (PEX) or double filtration plasma exchange (DFPP) before they can safely undergo a transplantation. The ADBT can be reduced to under 1:16 in most cases; however, some cases (non‐responders) do not respond to PEX or DFPP treatment. To enable kidney transplantations to be performed in non‐responders, we developed a new preconditioning regimen consisting of anti‐CD20 monoclonal antibody (rituximab) infusions, a splenectomy, and DFPP. Four non‐responders were infused with rituximab at a dose of 375 mg/m2 weekly for 3–4 wk and splenectomized 1 or 2 wk before transplantation. Four to five DFPP‐sessions were then performed after the splenectomy. Using this preconditioning regimen, the ADBT was reduced to below 1:16, enabling kidney transplantations to be successfully performed in all patients. After the kidney transplantation, no episodes of humoral rejection were observed, and only one episode of cellular rejection was encountered. The cellular rejection was associated with a reduction in immunosuppressant administration because of CMV infection that occurred 80 d after the kidney transplantation. The renal allografts were functioning well in all patients after a mean follow‐up period of 390 d. No serious complications or side effects were encountered. We have developed a new preconditioning regimen that enables PEX and DFPP non‐responders to undergo ABO‐incompatible kidney transplantations.

Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates

Anergic T cells generated ex vivo are reported to have immunosuppressive effects in vitro and in vivo. Here, we tested this concept in nonhuman primates. Alloreactive T cells were rendered anergic ex vivo by coculture with donor alloantigen in the presence of anti-CD80/CD86 mAbs before adoptive transfer via renal allograft to rhesus monkey recipients. The recipients were briefly treated with cyclophosphamide and cyclosporine A during the preparation of the anergic cells. Thirteen days after renal transplantation, the anergic T cells were transferred to the recipient, after which no further immunosuppressive agents were administered. Rejection-free survival was prolonged in all treated recipients, and 3 of 6 animals survived long term (410-880 days at studys end). In the long-surviving recipients, proliferative responses against alloantigen were inhibited in a donor-specific manner, and donor-type, but not third-party, skin allografts were also accepted, which demonstrated that antigen-specific tolerance had been induced. We conclude that anergic T cells generated ex vivo by blocking CD28/B7 costimulation can suppress renal allograft rejection after adoptive transfer in nonhuman primates. This strategy may be applicable to the design of safe clinical trials in humans.

Lobular damage caused by cellular and humoral immunity in liver allograft rejection.

Abstract:  Backgrounds:  Diagnosis of acute liver allograft rejection (ALAR) is usually performed by the estimation of changes in portal areas. In this study, changes in the hepatic lobules were investigated retrospectively by immunohistochemistry, and compared with changes in the portal areas. Humoral immunity in ALAR was also studied by C4d‐staining.

The ACE inhibitor, quinapril, ameliorates peritoneal fibrosis in an encapsulating peritoneal sclerosis model in mice.

Encapsulating peritoneal sclerosis (EPS) is a serious complication of patients on continuous ambulatory peritoneal dialysis. In the present study, the inhibitory effect of angiotensin-converting enzyme inhibitor, quinapril, on the peritoneal fibrosis was examined in an experimental EPS model in mice. C57BL/6 mice were divided into three groups. Group 1 (n=20) mice received daily intraperitoneal injection of 0.3 ml of SH solution which consists of 0.1% chlorhexidine gluconate and 15% ethanol dissolved in saline. Group 2 (n=20) and group 3 (n=20) mice received SH solution by the same manner of group 1 mice, and were given orally 1 or 3 mg kg(-1) of quinapril, respectively, on daily basis. Five mice from each group were sacrificed on day 3, 7, 21, and 56, and evaluated macroscopically and histologically. Macroscopic examination revealed that fibrotic change in parietal peritoneum in group 1 was more severe than in group 2 and 3, accompanied with statistical significance. Histological examination demonstrated that peritoneal thickening in group 2 and 3 were markedly ameliorated than in group 1. Semi-quantitative analysis showed that histological fibrotic score was significantly higher in group 1 than in group 2 and 3. These results suggest that quinapril ameliorate the fibrotic change in parietal peritoneum in experimental EPS model in mice, and may have a clinical utility for the prevention of EPS.

Effective oral administration of tacrolimus in renal transplant recipients.

Background: Tacrolimus is usually administered orally based on mg/kg or the trough concentration (Cmin) in whole blood. However, it is not easy to determine the optimal oral dose because of considerable variation of tacrolimus bioavailability between patients. In this study, pharmacokinetics of tacrolimus in various conditioning kidney transplant recipients was investigated. 
Methods: 1) Thirty‐three patients were randomly assigned to participate in two groups. In 17 patients, tacrolimus was administered orally after an overnight fast with breakfast given 1 h later, and in the other 16 patients it was administered orally 1 h after breakfast. 2) In 4 patients, the same dose tacrolimus was given after an overnight fast and 0.5 h after breakfast on two consecutive days. 3) Five patients who underwent continuous ambulatory peritoneal dialysis (CAPD) before transplantation were studied. All patients were investigated in daily profile of tacrolimus blood levels. 
Results: There was a strong correlation between area under the curve (AUC) and the trough concentration in both preprandial and postprandial oral administration, with correlation coefficients of 0.838 and 0.860, respectively. Significant increases in the peak concentration (Cmax) and AUC were observed in the preprandial oral administration subjects. Absorption of CAPD patients was obviously insufficient. 
Conclusions: Since tacrolimus absorption was better under fasted condition than under the presence of food, it is thought that the highest medicine effect with the least dosage is provided by preprandial oral administration. Furthermore, preprandial oral administration is recommended from a respect of economic burden reduction and side effect reduction.