Effects of cyclosporin A on the blood flow of the native and transplanted rat pancreas and duodenum

The aim of the present study was to evaluate the effects of cyclosporin A (CyA) on the blood perfusion of the transplanted pancreas. For this purpose syngeneic pancreaticoduodenal transplantations were performed in Wistar-Furth rats. After nephrectomy the graft was anastomosed using a nonsuturing cuff technique to the left renal vessels. Beginning 7 days after transplantation and then continuing for 2 weeks, CyA (15 mg/kg body weight) or vehicle was given p.o. once daily, 6 days a week. The serum CyA concentrations were greater than 600 ng/ml at all points in time tested. Intraperitoneal glucose tolerance tests were normal in CyA-treated animals after 12 days, but the pancreatic insulin concentration was decreased to the same extent in the native and transplanted pancreas. A microsphere technique was used to measure the blood perfusion of the pancreaticoduodenal graft, the native pancreas and duodenum, and remaining kidney 14 days after starting the CyA treatment. The renal blood flow was markedly decreased by CyA when compared with the control animals. In rats given vehicle alone, pancreatic, islet, and duodenal blood flows were higher in the graft than in the corresponding native organs. However, in rats given CyA, hyperperfusion of the graft was not observed. We conclude that the administration of CyA prevents the transplantation-induced blood flow increase seen in pancreaticoduodenal grafts of vehicle-treated rats. These observations may reflect graft denervation.     

The beneficial effects of oral nifedipine on cyclosporin-treated renal transplant recipients — a randomised prospective study

The aim of this study was to test the hypothesis that nifedipine will improve graft survival in cyclosporin A (CyA)-treated renal transplant recipients. One hundred and forty-seven patients were randomised to one of three regimens. Group A received CyA, 7 mg/kg per day, and prednisolone; group B followed the same regimen as group A plus oral nifedipine and group C received CyA, 4 mg/kg per day, prednisolone and azathioprine. Calcium channel blockers were avoided in groups A and C. The crude 2-year (P=0.0223) and 4-year (P=0.0181) graft survival was significantly better in group B (86% and 81%, respectively) than in group A (75% and 63%, respectively). Delayed initial function was seen least frequently in group B (10.2%) compared to groups A (31%) and C (28%; P<0.01). Group B also experienced fewer rejection episodes than groups A and C (P<0.05). We conclude that the combination of oral nifedipine and CyA significantly improves initial graft function, rejection frequency and long term graft survival.     

The effect of cyclosporine on mortality and renal function in living related pediatric kidney transplant recipients

The outcome, incidence of acute rejection episodes, complications and cyclosporine (CyA) induced nephrotoxicity were studied in 10 pediatric kidney transplant recipients who were grafted from one-haplotype indentical parent with immunosuppression of CyA and prednisolone (Pred). Excellent patient and graft survival could be achieved in this population with low incidences of acute rejection or serious complications as when compared with the results of azathioprine (AZ) treated pediatric patients. With a mean follow-up of 12.9 months (range 1 to 50 months), the patient survival rate was 100 per cent and the graft survival rate was 100, 84, 84 and 84 per cent at 1, 2, 3 and 4 years post transplantation, respectively. Serum creatinine levels in the group were 0.97, 1.17, 1.14 and 1.2 mg/dl at 3, 6, 12 and 24 months post transplantation, respectively. The incidence of treated acute rejection episodes was 20 per cent (2 out of 10) in the CyA-treated children, whereas it was 53 per cent (9 of 17) in the Az-treated children. Five children who had undergone transplant surgery before they were 11 years old displayed linear growth in height after their transplantation. There have been no opportunistic infections, aseptic necrosis or peptic ulcers in this group and cyclosporine nephrotoxicity has not been a serious problem in the pediatric recipients. Only 10 per cent (1 out of 10) of the recipients displayed acute nephrotoxicity and only one recipient has converted from CyA+Pred to CyA+AZ+Pred (Three drug therapy) due to persistent nephrotoxicity. Cyclosporine and prednisolone have therefore constituted a relatively safe, effective immunosuppressive regimen for pediatric renal allograft recipients. This paper was presented at the 7th international congress of pediatric nephrology.     

Hypertension two years after renal transplantation: causes and consequences

The incidence of hypertension 2 years after renal transplantation and the possible causes of hypertension were studied retrospectively. A group of 93 patients treated with cyclosporin (CyA), azathioprine (Aza), and/or prednisolone (Pred) were compared to a group of 31 patients treated with Aza and Pred. There were more patients with hypertension in the CyA group (73%) than in the Aza group (58%). Hypertension before transplantation predisposed to hypertension after transplantation. After transplantation, hypertension was most common among patients with polycystic kidney disease (46%), chronic glomerulonephritis (67%), and diabetes (71%). The accumulated immunosuppressive medication (CyA/Pred) did not affect the occurrence of hypertension. Hypertensive patients had significantly poorer graft function than did normotensive patients (serum creatinine level 229 mol/l vs 162 mol/l, P<0.01). The 10-year graft survival was markedly impaired in the group with hypertension (42% vs 65% for normotensives, P<0.05). The 10-year patient survival was 59% vs 79% (P=NS). The study further confirms the frequent finding that hypertension has a negative effect on graft and patient survival rates.     

The Use of an Approved Biodegradable Polymer Scaffold as a Solid Support System for Improvement of Islet Engraftment

The aim of this study was to investigate whether the use of a medically approved biodegradable scaffold as a solid support system would enhance graft survival following transplantation into the omental pouch in a preclinical large animal model. Six beagle dogs underwent total pancreatectomy followed by islet autotransplantation into the omental pouch. Four dogs received islets seeded in a biodegradable polymer scaffold and two received free islets without a scaffold. All four animals that received islets in the scaffold became normoglycemic without exogeneous insulin injection. One dog, transplanted with the largest number of islets, maintained a normal metabolic state until the graft was removed at 5 months posttransplant. In two out of the three that received a marginal islet mass, insulin independence was sustained up to 2 months. In contrast, two dogs transplanted with a similar marginal mass without the scaffold never became normoglycemic. Histological examination of the grafts in the scaffold showed numerous well‐granulated, insulin‐containing cells as well as glucagon‐positive cells. These results indicate that biodegradable scaffolds may enhance survival and function of islet grafts. Manipulation of the microenvironment of transplanted islets may constitute the basis for new approaches to enhance islet engraftment.     

Does regressed posttransplantation Kaposi's sarcoma recur following reintroduction of immunosuppression?

We report a patient who developed generalized Kaposi's sarcoma (extensive skin and stomach lesions) 24 months after renal transplantation whilst on cyclosporin (CyA) and prednisolone. Kaposi's sarcoma disappeared completely upon withdrawal of CyA. The patient remained with a well-functioning graft and free of Kaposi's sarcoma for 36 months on prednisolone alone. CyA was reintroduced following an episode of acute rejection. Within 8 weeks, Kaposi's sarcoma reappeared on the skin at the same sites as the previously healed lesions. They completely disappeared again upon withdrawal of CyA. Azathioprine was then introduced and Kaposi's sarcoma lesions reappeared 6 months later.     

Effects of donor pretreatment with antilymphocyte serum and cyclosporin on rejection and graft-versus-host disease after small bowel transplantation in immunosuppressed and nonimmunosuppressed rats

After fully allogeneic small bowel transplantation, both graft-versus-host disease (GVHD) and rejection may occur. Donor pretreatment may prevent GVHD, but this sometimes leads to accelerated graft rejection. To study a possible balance between GVHD and rejection, fully allogeneic total orthotopic small bowel transplantation was performed in rats using the WAG-to-BN donorhost combination. Untreated control grafts were rejected in 16.6±2.7 days (mean ±SEM), and 35% of the animals had mild, transient GVHD. Pretreatment of the donor with antilymphocyte serum on days-2 and-1 before grafting, either intravenously or intraperitoneally, completely eliminated the occurrence of clinical GVHD but led to significantly shortened survival times (12.3±0.8 and 10.3±0.9 days, respectively). Donor pretreatment with 50 mg/kg cyclosporin (CyA) on days-2 and-1 prolonged graft survival significantly to 22.1 days but had no significant effect on the incidence of GVHD. Administration of 25 mg/kg CyA on days 0, 1, 2, 4, and 6 after grafting prolonged survival to 38.3 days with no evidence of GVHD. Pretreatment of the donor with antilymphocyte serum (ALS), combined with the same postoperative, short-term CyA regimen, increased survival to more than 50 days, again with no evidence of GVHD. When CyA was used as both donor pretreatment and postoperative therapy, there was no survival advantage compared to the use of postoperative CyA alone. These results show that an in vivo balance between GVHD and rejection exists and that abrogation of GVHD leads to accelerated rejection. Immunosuppression of the recipient may overrule this accelerated rejection while preserving the beneficial effect of donor pretreatment: elimination of clinical GVHD.     

Moderate effect of preoperative blood transfusions on pancreas allograft survival in rats and dogs

Treatment of type I diabetes by early pancreas transplantation requires the availability of a safe and effective transplantation technique. With the currently available immunosuppressive drugs it is difficult to obtain long-term pancreatic allograft survival. In this respect pancreas grafts compare unfavorably with heart or kidney grafts. Using a relatively simple and safe subcutaneous transplantation technique we investigated the effect of blood transfusions combined with low-dose immunosuppressive drugs in rats and dogs in order to attain an immunosuppressive schedule of low toxicity. Subcutaneous pancreas transplantation appeared to be a feasible technique, with long-term graft survival in syngeneically transplanted rats and autotransplanted dogs. Only a moderate prolongation of pancreatic allograft survival by blood transfusions was demonstrated in both models. In rats one or three preoperative donor-specific blood transfusions significantly prolonged pancreas graft survival to 23 +/- 15 and 29 +/- 15 days, respectively, compared with 12 +/- 2 days in untreated controls. Low-dose cyclosporine (15 mg/kg on the day of operation) led to improved graft survival in nontransfused recipients (17 +/- 4 days), however, this treatment could not further prolong graft survival in transfused animals (34 +/- 20 days). In dogs, treated postoperatively with azathioprine and prednisolone, three preoperative third-party blood transfusions led to 29 +/- 19 days of pancreas graft survival, which was not significantly different from nontransfused controls (17 +/- 5 days). These results indicate that, in rats as well in dogs, pancreatic allografts are less sensitive to the immunomodulating effect of blood transfusions than heart and kidney grafts.     

The induction of operational tolerance is not prevented by simultaneous administration of cyclosporin A1

In this study, the effect of combining anti-CD4 monoclonal antibody (mAb) and cyclosporin (CyA) therapy at the time of transplantation was examined. A mouse cardiac allograft model was used. Anti-CD4 mAb administered perioperatively induces long-term survival. The addition of a short course of CyA given subcutaneously in a regimen of either a high-dose treatment or a standard dose treatment to the anti-CD4 mAb treatment protocol did not have a detrimental effect on graft survival. Despite having no significant effect on graft survival, the addition of CyA to the treatment protocol did result in a significant decrease in the level of IL-2 present in the hearts 7 days after transplantation. The decrease in IL-2 production was directly related to the presence of CyA in vivo. When CyA treatment was continued throughout the period during which unresponsiveness to the graft is induced by anti-CD4 mAb therapy, 50 % of the grafted hearts were rejected once the CyA was discontinued. In conclusion, the combined use of anti-CD4 mAb therapy and CyA did not have a negative effect on graft survival in this model when the two agents were used concurrently at the time of transplantation. Received: 2 October 1996 Received after revision: 31 January 1997 Accepted: 5 February 1997     

Cyclosporin A in pediatric kidney transplantation and its effect on posttransplantation growth

Results of cyclosporin A (CyA) treatment following kidney transplantation in 28 children were compared with those of conventional immunosuppression with azathioprine (Aza) in 34 children. CyA was given in combination with low-dose prednisolone. Under CyA the 2-year survival rate of patients and grafts was 96%, under Aza the 2-year survival rate of patients was 94% and of grafts 68% (p less than 0.01). Graft function was slightly lower in the CyA than in the Aza group. Growth after kidney transplantation was evaluated in those patients with a first graft and a function of longer than 1 year. Annual growth velocity for bone age was normal or even accelerated in all children treated with CyA and significantly better than in the children treated with Aza. It is concluded that CyA treatment combined with low-dose prednisolone yields excellent results and allows normal growth rates after kidney transplantation.     

肝肾联合移植术中肝脏对肾脏的保护作用

目的：探讨肝肾联合移植术中肝脏对肾脏的保护作用。方法：给1例肾移植术后移植肾失功并肝炎后肝硬化患者先行丧失功能移植肾切除术，术后第5天始每天口服环磷酰胺50mg，连服3个半月。经两次血浆置换，群体反应抗体(PRA)由66％降至22．5％，施行一期肝肾联合移植。供肝血流开放前及开放后每间隔半小时动态检测PRA，共7次，术后1个月、3个月、9个月复查PRA。术后免疫抑制治疗采用FK506、霉酚酸酯(MMF)和激素联合应用。结果：术后供肝、肾立即发挥功能，肝动静脉血流开放后，PRA由22．5％降至5％，并维持在7．5％(见图1)，术后未发生排斥反应现象。随访9个月，移植肝、肾功能正常，术后1个月、3个月、9个月复查PRA分别为7．5％、8．33％和7．5％。结论：肝肾联合移植术中肝脏对肾脏有一定的保护作用。     

Factors contributing to long graft survival in non-heart-beating cadaveric renal transplantation in Japan: a single-center study at Kitasato University

A total of 107 cadaveric kidneys from non-heart-beating donors (NHBDs) have been transplanted between 1974 and 2000 at Kitasato University Hospital, Sagamihara, Japan. The patient survival of the 107 recipients of cadaveric renal transplants at 1, 5 and 10 yr was 0.857, 0.770 and 0.746, respectively. The 50% graft survival was 3.8 yr. The 5 and 10-yr graft survival was 0.457 and 0.337, respectively. Twenty of the 107 recipients of non-heart-beating cadaveric renal transplantation had graft survival longer than 10 yr. Of these 20 patients, 14 survivors still maintain functioning renal grafts and two died with functioning graft, although the remaining four reverted to dialysis because of chronic rejection and nephropathy. The average graft survival of these 20 patients at the time of study was 13.3 yr and the longest was 21.4 yr. The average serum creatinine level at 10 yr after transplantation was 1.63 mg/dL, almost identical to that at 5 yr post-transplant. The donors aged on average 40.2 yr; 13 were male and seven were female. The youngest donor was 9-yr-old and the oldest was 66. The graft survival was significantly better in the group with donor age younger than 55 yr (Log-rank: p=0.007). The average weight of the renal graft was not different between the long and shorter graft survival groups. The average warm ischemic time and total ischemic time were 9.7 and 539.7 min, respectively. The duration of post-transplant acute tubular necrosis averaged 9.2 days. These parameters tended to be shorter than those in recipients with graft survival >10 yr, but with no statistical significance. The mean numbers of acute rejection (AR) episode within 3 months after transplantation were 0.25 +/- 0.66 and 0.92 +/- 0.90 (p=0.020) in long survival and shorter survival groups, respectively. Long survivors had a significantly lower incidence of AR. Two of 20 cases received conventional immunosuppression with prednisolone, azathioprine and mizoribin, and 18 had prednisolone and calcineurin inhibitor (CNI). Kaplan-Meier analysis showed a significant contribution of CNI to graft survival (p=0.036). However, the graft survival reduction rate after 1 yr post-transplant did not differ between conventional and CNI immunosuppression. These data suggest that renal grafts retrieved with proper organ procurement procedures from NHBDs may survive long-term and help to overcome donor shortage.     

Prognostic factors of long-term allograft survival in 632 CyA-treated recipients of a primary renal transplant

A total of 632 cyclosporin (CyA)-treated primary renal allograft recipients with a functioning graft at 6 months were retrospectively evaluated for risk factors correlated with long-term allograft function. Mean follow-up after the 6th month was 68.4 ± 40.6 months. One hundred twenty-one of these patients (19 %) were lost: 29 died (23/29 with a functioning graft), 77 of the remaining 92 (83 %) lost their graft because of chronic allograft dysfunction, 9 due to recurrence of glomerulonephritis, 5 due to renal artery thrombosis, and 1 due to chronic CyA toxicity. At univariate analysis, factors correlated with a better renal (R) and pure renal (PR) allograft survival were: dialysis duration of less than 5 years, fewer than 2 rejections within the 6th post-Tx month, immediate graft function recovery, plasma creatinine below 1.5 mg/dl at the 6th month, age at Tx above 15 years, and receiving a living donor graft. Cox's regression analysis was also performed to obtain relative risks for the same parameters. Long-term dialysis patients had more frequent late recoveries (P = 0.002) and reductions in therapy (P = 0.01) in order to reduce the side effects of steroids. In young patients receiving an initial oral CyA dose of 17 mg/kg per day, steroids were stopped at the 6th month in order to achieve catch-up growth: only one such patient lost his graft. In contrast, 72 % of the young patients who lost their grafts received an initial oral CyA dosage of 13 mg/kg per day. Thus, young patients did worse not because of steroid withdrawal, but because of inadequate initial CyA dosage. These results suggest that although we cannot exclude alloantigen-independent mechanisms as factors that stimulate progression of chronic allograft dysfunction, it would appear that the initial lesions are induced by events mostly mediated by immunological mechanisms. Received: 28 January 1997 Received after revision: 4 April 1997 Accepted: 8 April 1997     

Discontinuation of steroids in ABO‐incompatible renal transplantation

A steroid‐free protocol for ABO‐compatible renal transplantation has been used at our center since 1983. To minimize the adverse effects of steroids, we also developed a steroid sparing protocol for ABO‐incompatible renal transplantation in 2008. The present study is a report of our results. A retrospective review of the first 50 ABO‐incompatible renal transplantations performed at a single university center. If no immunological events occurred in the post‐transplant period, prednisolone tapering was initiated approximately 3 months after transplantation. Forty‐three patients completed prednisolone tapering after 289 ± 58 days. Three patients died during follow‐up, and four patients lost graft function. None of these adverse events were rejection related. Eleven patients experienced rejections; seven were on prednisolone and four were after weaning from prednisolone. All patients responded well to antirejection treatment. Overall, 1‐year rejection rate was 19%. One‐ and 3‐year graft survival was 94% and 91%, respectively. One‐year post‐transplant median serum creatinine was 123 μmol/L. We found acceptable rejection rates, graft survival, and creatinine levels in patients undergoing ABO‐incompatible renal transplantations with a steroid sparing protocol. However, a longer follow‐up of a lager cohort is needed before firm conclusions can be made.     

Elective withdrawal of mycophenolate mofetil in renal transplant recipients treated with mycophenolate mofetil, cyclosporine, and prednisone

In a retrospective study we investigated the risk of acute rejection after the withdrawal of mycophenolate mofetil (MMF) in 39 adult patients treated with cyclosporine (CyA), prednisone, and MMF for at least 6 months following renal transplantation. After reaching a stable renal graft function, MMF was withdrawn and CyA and prednisone were continued. Preceding the withdrawal of MMF, four patients experienced an acute rejection. During a median follow-up of 38 months after discontinuing MMF, no acute rejection occurred. The mean serum creatinine level did not change during the first 6 months after withdrawal of MMF. We conclude that elective withdrawal of MMF in stable renal transplant recipients at 6 months after transplantation bears no important risk of an occurrence of acute rejection. Received: 24 November 1999 Revised: 11 May 2000 Accepted: 18 December 2000     

Prior renal transplantation does not facilitate subsequent canine islet allograft survival

Successful islet allografts can be established in rats bearing long surviving renal allografts, without additional immunosuppression, when kidney and islet donor animals are of the same strain. The applicability of such a scheme to clinical practice has been investigated in a large animal model of diabetes: the pancreatectomized dog. Eight dogs with previously established renal allografts and immunosuppressed with cyclosporin A received islet allografts from their respective original kidney donors. The median islet graft functional survival was only 10.5 days, significantly less than for six similarly immunosuppressed dogs receiving islet allografts alone (48.5 days, P less than 0.05). Three of the sequentially transplanted dogs had had no renal graft rejection episodes before islet transplantation, yet their islet grafts were all rejected within 19 days. In the pancreatectomized dog, prior donor specific renal transplantation has an adverse effect upon subsequent islet graft survival.     

Steroid withdrawal 3 months after liver transplantation - does FK 506 confer any advantage over cyclosporin?

Abstract Eighty-one liver recipients were randomised to FK 506 Or cyclosporin (CyA) and azathioprine (AzA), both in combination with steroids. Twenty-even FK 506 and 29 CyA/AzA patients continued in the trial 3 months after transplantation. Steroids were ceased in 23 (85%) FK 506 patients and in 27 (93%) CyA patients. After steroid withdrawal, 2 FK 506 and 4 CyA patients were excluded from the study, all for reasons other than rejection. The median follow-up was 16 months for the FK 506, and 19 months for CyA group. There were no acute rejection episodes or graft losses in the FK 506 group. None of the CyA patients lost their graft but three (13%) had episodes of acute rejection requiring steroids to be recommenced in two cases. There was no evidence of chronic rejection in any of the annual review biopsies in either group. Our results suggested no advantage of FK 506 over CyA in its steroid-paring effect.     

A randomized multicenter trial of cyclosporin and prednisolone versus cyclosporin,azathioprine, and prednisolone following primary living donor renal transplantation

A total of 195 consecutive recipients of primary living donor renal transplants were randomized to receive either cyclosporin (CyA) and prednisolone (double therapy) or CyA, prednisolone, and azathioprine (triple therapy). There was no significant difference in patient or graft survival, incidence of acute rejection episodes, or major complications between the groups. The graft survival at 5 years was 71.5% in patients receiving double therapy and 71.6% in patients receiving triple therapy. In a Cox regression analysis, recipient age and occurrence of acute rejection were the only independently significant variables affecting graft survival, whereas treatment schedule did not. Renal function was stable throughout the observation period and did not differ between the double and triple therapy groups. A linear regression analysis showed that recipient age, donor age, gender, and occurrence of acute rejection significantly influenced the serum creatinine level. This and previous similar prospective studies in cadaveric renal transplantation indicate that there is no advantage of routinely adding azathioprine to a double drug regimen.     

Canine whole pancreatic transplantation with exocrine drainage into the bladder

A canine model of whole pancreas transplantation with pancreaticocystostomy was studied for reproducibility and long-term graft function with oral cyclosporine. The feasibility of the operative technique was established in three dogs and the graft histology at 5 days was studied. Seven pancreatectomized dogs were transplanted without immunosuppression; acute rejection was evident at a median of 10 days (range: 7-12 days). Another 14 non-pancreatectomized dogs were given oral cyclosporine (25 mg/kg per day) resulting in prolonged graft survival (P less than 0.01) with a median (actuarial) survival of 91 days (range: 8-159 days); five dogs had vascular thrombosis or graft rejection and eight dogs died with functioning grafts. Early technical loss in two dogs (8.3%) was due to arterial thrombosis. It is concluded that the model of whole pancreas transplantation was reproducible in dogs, that long-term graft function can be achieved on oral cyclosporine, and that duct patency can be maintained. Graft infarction, either primary or due to rejection, continues to complicate this model of pancreas transplantation.     

Local cyclosporine immunotherapy of heart transplants in rats enhances survival

High-dose systemic cyclosporine (CyA) administration frequently results in severe side effects. To evaluate a means of limiting the adverse effects of CyA, we implanted CyA-collagen matrices (0.2 or 1 mg/kg/day released) around the cardiac homografts at the time of rat heterotopic (neck) heart transplantation. Control animals received empty collagen (nondrug) matrix implants. A fourth group received CyA matrix (1 mg/kg/day released), implanted in a distal subdermal leg pouch at the time of heart transplantation. Rejection was determined by the absence of contraction in the transplanted heart. No animal received any other immunosuppression. Parallel groups of animals had whole blood, heart, and kidney CyA levels measured on the sixth posttransplant day. Local immunosuppression with high-dose CyA in a controlled-release matrix resulted in a significant survival advantage (mean survival time, 17.1 days; control, 6.9 days; p less than 0.001). The lower dose of CyA also demonstrated significant survival benefits (10.1 days), with clinically negligible blood CyA levels and very low kidney CyA levels. Both doses of epicardial local release CyA were well absorbed locally, resulting in very high CyA levels in cardiac tissue. Local immunotherapy of transplanted hearts with CyA was shown to be an effective means of preventing rejection. If this technology can be developed, this approach may prove advantageous clinically, both in extending transplantation and in minimizing systemic side effects of immunosuppression.