FTY720 for treatment of ischemia-reperfusion injury following complete renal ischemia in C57/BL6 mice

BACKGROUND: Organ dysfunction followed by single-organ or even multiorgan failure due to ischemia-reperfusion injury (I/RI) is a common problem in liver and heart transplantation. Various approaches had been attempted to prevent this I/RI. One is the administration of FTY720, a synthetic structural analogue of sphingosine, which induces T-lymphocyte homing with consecutive lymphopenia. The purpose of this study was to evaluate the effect of intraoperative FTY720 administration following controlled bilateral kidney ischemia in comparison to steroid or placebo application. METHODS: Male c57BL6/J mice (n = 115; body weight 25 to 30 g) received either FTY720 (1 mg/kg body weight) or steroids or saline solution. Ischemia was applied for 30 or 60 minutes with subsequent follow-up for 48 hours. At termination all surviving animals were sacrificed. RESULTS: Following 30 minutes of ischemia, FTY720, but neither steroid nor vehicle treatment showed significant protective effects on long-term survival after controlled bilateral warm kidney ischemia. Fluorescein-activated cell sorting (FACS) analysis showed a significant T-lymphocyte depletion in peripheral blood after FTY720 treatment, which was not observed after steroid or vehicle treatment. CONCLUSION: The improved long-term survival shown in this study might be due to a protective effect of FTY720 to prevent I/RI, which may be mediated by the lymphocyte depletion shown in the FACS analysis.     

FTY720 prevents renal T-cell infiltration after ischemia/reperfusion injury

Ischemia/reperfusion (I/R) injury, a common early feature in renal transplantation, results from both free radical species generation and local inflammatory responses that attract different types of cells. The interaction with infiltrating leukocytes could promote damage and death of resident renal cells contributing to worsening of renal function. It has been shown that depletion of host T cells protects against kidney damage after I/R injury, although the mechanism is not fully understood. FTY720, a synthetic analog of a natural product extracted from Isaria sincclairii has shown modulatory properties in experimental models of autoimmune disease, transplantation, and I/R injury. FTY720 alters lymphocyte responses to chemokine homing signals, thereby decreasing the number of lymphocytes in inflammatory sites. We evaluated renal function in mice at 3, 5, and 7 days after I/R injury in the presence or absence of FTY720 treatment. FTY720 treatment promoted earlier recovery of renal function associated with a lower number of renal-infiltrating lymphocytes. These findings confirm previous results showing a protective effect of FTY720 in I/R injury models.     

FTY720 application following isolated warm liver ischemia improves long-term survival and organ protection in a mouse model

BACKGROUND: Ischemia-reperfusion-Injury (I/RI) is a common complication in transplant-, liver-, and heart surgery. The I/RI is mediated and aggravated by different types of leukocytes such as lymphocytes, monocytes, and neutrophil granulocytes, with consecutive enlargement of the expression of adhesion molecules. This study shows an organ-protective effect of an intraoperative FTY720 administration following warm liver ischemia (Pringle's maneuver). METHODS: Male c57BL6/J mice (n = 46, body weight [BW] 25 to 30 g) were used. Either FTY720 (1 mg/kg BW), steroids (5 mg/kg BW), or physiological saline solution was administered intraperitoneally. Liver-ischemia was applied for 30 minutes with subsequent follow-up for 48 hours. At termination, all surviving animals were sacrificed. The impact of the drugs administered on long-term survival, time of death, and development of blood T-lymphocyte concentration was determined. Follow-up of T-lymphocyte concentration in peripheral blood was examined throughout FACS-analysis. RESULTS: Following 30 minutes of ischemia, FTY720, but not steroid or vehicle treatment, showed a significant protective effect on long-term survival. FACS-analysis showed significant T-lymphocyte depletion in peripheral blood following FTY720 but not steroids or vehicle treatment. CONCLUSION: The improved long-term survival following FTY720 application shown in this study might be due to a protective effect of FTY720 in prevention of I/RI. This might be mediated by the T-lymphocyte depletion shown in the FACS-analysis.     

Use of FTY 720 and ICAM-1 antisense oligonucleotides for attenuating chronic renal damage secondary to ischemia-reperfusion injury

INTRODUCTION: Chronic allograft nephropathy is the main cause of graft loss. Although many factors are involved in its development, ischemia-reperfusion injury has received increasing attention as a risk determinant. In a previous study of syngeneic renal transplantation and ischemia, we demonstrated a protective effect of acute damage by FTY 720 and antisense oligonucleotides of ICAM-1 (Oligos). The purpose of the current study was to evaluate the impact of these agents on the development of chronic graft damage in the same model. METHODS: Lewis rat were used as donors and recipients. The harvested left kidney was kept in Collins solution for 2 hours. Recipient animals received treatment with FTY 720 or Oligos or saline. At 12 and 36 weeks after transplantation, creatinine clearance, GFR, proteinuria, and arterial blood pressure were recorded. Tissue from some animals were submitted for histological studies and quantification of mRNA TGF-beta1. RESULTS: All groups showed decreased levels of GFR and creatinine clearence, but only the untreated animals showed significant deterioration compared to the pretransplant values (0.53 +/- 0.24 versus 0.21 +/- 0.24 at 36 weeks respectively; P < .05). Proteinuria was also significant in control animals at 36 weeks. Blood pressure showed a moderate increase in all groups. Histological analysis showed that treated animals had fewer signs of chronic damage according to the Banff score. All groups displayed slight increases in TGF-beta1 without differences among them. CONCLUSIONS: In this model the use of FTY or antisense oligonucleotides of ICAM-1 were associated with less functional and morphological evidence of chronic graft damage secondary to an ischemia-reperfusion injury.     

Skin allograft survival and analysis of renal parameters after FTY720 + tacrolimus treatment in mice

Calcineurin inhibitors such as cyclosporine (CsA) and tacrolimus (FK506) show similar efficacy to prevent rejection within the first year after organ transplantation. However, their use is limited by side effects, such as kidney damage, hypertension, new-onset diabetes, and hyperlipidemia. The consensus opinion suggests that compared with CsA, FK506 has fewer negative effects on blood pressure, serum lipids, and renal function. Nevertheless, FK506 use is associated with a higher incidence of posttransplantation diabetes mellitus. FTY720 is a new compound that has shown beneficial effects in animal models of rejection in transplantation, ischemia/reperfusion injury, autoimmune diseases, and tumor development. Our aim was to investigate whether FTY720 + tacrolimus association could provide additional immunosuppression without causing renal toxicity. FTY720 as a monotherapy or in association with FK506 was administered to C57BL/6 mice for 21 days to prevent skin graft rejection and to evaluate renal function and structure. Increased skin allograft survival in the FTY720 + FK506 group was associated with decreased cell numbers in the spleen, blood, and axillary lymph nodes. Changes in major histocompatibility complex (MHC) class II and intercellular adhesion molecule-1 (ICAM-1) expressions in splenocytes were also found in this group. The major effects already described for FK506 (diabetes) or FTY720 (lymphopenia) were observed after 21 days administration even when the drugs were associated. FTY720 associated with FK506 caused fewer changes in kidney structure, and blood glucose levels were lower than in FK506 monotherapy.     

Prevention of renal ischemic reperfusion injury using FTY 720 and ICAM-1 antisense oligonucleotides

BACKGROUND: Renal damage secondary to ischemia-reperfusion injuries (I-R) is frequent in organ transplantation and adversely affects the graft survival. An important component of this damage is caused by initial adhesion of neutrophils and lymphocytes to endothelial cells. FTY 720, which induces lymphopenia, has previously been shown to display protective effects in models of I-R. The purpose of the present study was to evaluate the combination of FTY 720 and intracellular adhesion molecule and ICAM-1 antisense oligonucleotides (AS-oligos), an agent designed to block the adhesion process. METHODS: Sprague-Dawley rats underwent syngenic kidney transplantation after donor kidneys had been preserved in cold solution for 2 hours. The treatment groups included: (1) FTY 720 (1 mg/kg) before reperfusion, (2) AS-oligos (2 mg/kg) during kidney perfusion, and (3) the combination of FTY 720 and AS-oligos. All animals were followed daily after transplantation; some were sacrificed on the second day for histologic analysis. RESULTS: All treated groups showed a maximal serum creatinine that was significantly less than the control (group 1: 2.76 +/- 1.4, group 2: 2.44 +/- 2.05, group 3: 1.51 +/- 0.42, and control: 4.04 +/- 0.5; P <.01) and returned to the basal value earlier. Also, treated animals showed less histologic stigmata of acute tubular damage. FTY 720 and AS-oligos used in combination showed a mild additive effect. CONCLUSIONS: The use of FTY 720 and/or AS-oligos significantly prevents functional renal damage secondary to I-R, displaying a mild additive effect in this model. Both agents offer the advantage of use during the donor and the graft operations.     

Effect of a novel immunosuppressant, FTY720, on allograft survival after renal transplant in rats

FTY720 was developed by chemical modification of ISP-1 which was purified from culture filtrates of an ascomycete, Isaria sinclairii. We evaluated the effect of FTY720 on allograft survival using a rat renal transplantation model in which Wistar King Aptekman Hokkaido rats (WKAH, RT1(K)) served as the organ donor and Lewis rats (LEW, RT1(l)) as the recipient. WKAH renal allografts were acutely rejected by the untreated LEW recipients at a mean graft survival +/- SD of 7.2 +/- 0.4 days (n = 5). Consecutive oral administration of FTY720 following transplantation significantly prolonged allograft survival in a dose-dependent manner over the range of 0. 05-3 mg/kg/day. The mean allograft survival of the recipients treated with FTY720 at a doses of 0.05, 0.1, 0.5, 1, and 3 mg/kg/day was 12.2 +/- 3.3 (n = 5, p < 0.05, vs. untreated host), 11.2 +/- 2.4 (n = 5, p < 0.05, vs. untreated host), 13.6 +/- 0.9 (n = 5, p < 0.01, vs. untreated host), 14.6 +/- 1.7 (n = 5, p < 0.01, vs. untreated host) and 20.2 +/- 0.8 days (n = 5, p < 0.01, vs. untreated host). In the recipients treated with FTY720 (3 mg/kg/day), the number of peripheral blood lymphocytes significantly decreased. From the results of the flow cytometric study, FTY720 significantly diminished the percentage of interleukin-2 receptor (IL-2R)-positive cells in the allografts (6.34 +/- 0.81% in the untreated recipients vs. 3.10 +/- 0.86% in the recipients treated with FTY720, p < 0.05). As to the CD4/CD8 ratio of splenic cells and graft infiltrate, there was no significant difference between the untreated hosts and the recipients treated with FTY720. In conclusion, FTY720 significantly extended rat renal allograft survival and the immunosuppressive effects of FTY720 may be due to a reduction in not only the number of peripheral lymphocytes but also the percentage of IL-2R-positive cells in the allografts.     

The impact of FTY720 (fingolimod) on vasodilatory function and arterial elasticity in renal transplant patients.

BACKGROUND: FTY720 has recently demonstrated a similar efficacy in prevention of acute graft rejection compared with mycophenolate mofetil (MMF) in a large phase III trial of de novo renal transplant recipients. Creatinine clearance, however, was significantly lower in FTY720-treated patients. In the present study, we examined the impact of FTY720 on vascular function in a subgroup of patients of this trial. METHODS: Eighteen patients (12 FTY720, 6 MMF) agreed to be enrolled for an analysis of vascular function. Vascular measurements were performed 1.5 years post-transplant and were repeated 3 months after conversion of the patients from FTY720 to MMF. Arterial stiffness was assessed as augmentation index (AI(75)); endothelium-dependent and -independent vasodilation were measured sonographically as flow-mediated dilation (FMD) and as vasodilation after application of glyceroltrinitrate (GTN). RESULTS: Conversion from 2.5 mg FTY720 to MMF led to a significant improvement of FMD (5.40 +/- 1.84 vs 7.77 +/- 3.36%, P 0.02). AI(75) and GTN tended to be higher after conversion without reaching significance (83 +/- 20.43 vs 78.69 +/- 15.39%, P 0.06; 13.76 +/- 4.52 vs 17.39 +/- 3.76%, P 0.07). In the MMF group, AI(75), FMD and GTN did not significantly change during the observation period. CONCLUSION: The present study constitutes the first analysis of the impact of FTY720 on vascular function in humans and reveals an improvement of arterial vasodilatory function after discontinuation of FTY720 in de novo renal transplant recipients on cyclosporine.     

热缺血时间对小鼠肾脏缺血再灌注损伤后肾功能的影响

目的 探讨热缺血时间对小鼠肾脏缺血再灌注损伤(IRI)后肾功能的影响及与肾脏损伤分子1(KIM-1)的关系.方法 选取雄性C57BL/6小鼠36只,异氟烷吸入麻醉下阻断双侧肾蒂血管,建立双侧肾脏IRI模型.根据肾缺血时间将小鼠分为四组,即假手术组(Sham组)、阻断28 min组(28 Min组)、30 min组(30...     

Long-term effect of FTY720 on lymphocyte count and islet allograft survival in mice

This study was performed to observe the long-term effect of FTY720 on lymphocyte count change and islet allograft survival. Diabetic C57BL/6 mice were given FTY720 (group 1, 0.5 mg/kg/day; group 2, 1.0 mg/kg/day) or its vehicle (group 3, controls) after transplantation. Median graft survival time was prolonged in a dose-dependent manner (group 1, 84.5 days; group 2, >100 days, and group 3, 10 days, P < 0.01). Peripheral blood lymphocytes in groups 1 and 2 decreased to 23.81% and 12.59% compared with control group after FTY720 treatment. Lymphocytes from mesenteric lymph nodes and axillary nodes in groups 1 and 2 significantly increased on day 5, but decreased on day 14. Lymphocyte infiltration to the graft site was attenuated in groups 1 and 2. In conclusion, continuous FTY720 administration can induce and maintain lymphopenia, and inhibit lymphocytes from infiltrating the graft site so as to prolong islet allograft survival in mice.     

Effects of immunosuppressant FTY720 on renal and hepatic hemodynamics in the rat

BACKGROUND: FTY720 is a novel immunomodulator that may provide an opportunity for a reduction in calcineurin inhibitor dosage in transplant recipients with renal/hepatic side effects. However, the effects of FTY720 on renal or hepatic hemodynamics are unknown. The aim of this study was to establish the hemodynamic and renal actions of FTY720 at therapeutically relevant dosages. METHODS: The effects of acute and repeat oral administration of FTY720 on systemic, renal, and hepatic hemodynamics were investigated in the anesthetized male Lewis rat. Renal function and renal tubular parameters were examined in animals that received repeat high dosage of FTY720. RESULTS: Seven-day oral administration of FTY720 did not cause any significant changes in markers of hepatocyte injury, nor did it cause any reduction in renal function (elevated urea and creatinine). Histological examination of liver and kidney from animals treated with repeat FTY720 for 1 or 3 weeks did not reveal any sclerosis, tubular changes, infiltrates, or fibrosis. Hepatocyte, vascular, and biliary structures were normal. Compared with the vehicle (saline), oral administration of FTY720 at dosages up to 5 mg/kg/day for 1 week did not have any significant effects on systemic, hepatic, or renal hemodynamics. Five min after intravenous FTY720 administration (1 mg/kg), mean arterial pressure (MAP) rose to 114+/-3.3% of baseline (P <0.01) before returning to the normal range within 30-45 min. Lower doses of FTY720 (0.3 and 0.5 mg/kg, i.v.) did not affect MAP. Renal cortical perfusion, renal artery blood flow, and renal vascular resistance were not altered by FTY720 at i.v. doses up to 1 mg/kg. Animals that received FTY720 (5 mg/kg/day) for 3 weeks showed a significant reduction in body weight (-4.8+/-1% of baseline at 3 weeks, P <0.001); however, weight-adjusted creatinine clearance, 24 h urine production, and urine osmolality were not different from those in control animals (0.71+/-0.1 vs. 0.74+/-0.1 ml/min/100 g, 2.63+/-0.2 vs. 3.12+/-0.2 ml/100 g, and 2003+/-33 vs. 1966+/-56 mOsm/kg, respectively). FTY720 at the same repeat oral dosage was, nevertheless, associated with a significantly lower 24 h sodium excretion and a significantly lower fractional excretion of sodium compared with those in control animals (223.4+/-35 vs. 304.5+/-50 micromol/100 g and 1.75+/-0.3 vs. 2.23+/-0.3%, respectively; P <0.05). CONCLUSIONS: Our data indicate that, at least in the short term, oral FTY720 does not cause any significant adverse effects on renal or hepatic hemodynamics, nor does it cause any reduction in glomerular perfusion and thus may provide reasonable rescue/add-on therapy in calcineurin-inhibitor treated transplant recipients. At high repeat oral dosages, however, FTY720 may alter renal handling of sodium.     

Impact of long-term therapy with FTY720 or mycophenolate mofetil on cardiac conduction and rhythm in stable adult renal transplant patients

The novel immunomodulator FTY720 has been associated with a mild reduction in heart rate (HR) in clinical trials. A total of 421 patients (FTY720, n=94; mycophenolate mofetil [MMF], n=327) underwent 2-day electrocardiogram and 24-h Holter monitoring. Patients had been maintained on cyclosporine plus MMF or FTY720 (2.5 mg and 5.0 mg) for > or =12 months. No significant differences in mean hourly heart rate (HR) over 24 hrs were noted between groups. Bradycardia (HR 35-50 bpm) and sustained bradycardia (HR <50 bpm for >1 min) were more common with MMF than FTY720 (53% vs. 37% and 34% vs. 21%, respectively). Electrocardiogram parameters did not differ significantly between FTY720 and MMF groups, or between FTY720 groups, supporting the absence of a dose-dependent effect. The absence of any clinically significant effect of FTY720 on cardiac rhythm demonstrates that the reduction in HR seen after the first dose does not persist in the maintenance phase.     

转化生长因子-β1转基因联合FTY720对大鼠心脏移植物缺血-再灌注损伤的影响

目的 探讨经冠脉灌注转化生长因子(TGF)-β1基因联合FTY720对移植心脏缺血-再灌注损伤(IRI)的影响及其机制.方法 实验分为空白对照组、空载体组、FTY720组、转基因组和转基因+FTY720组.心脏移植8 h后切取移植心脏,免疫组织化学检测mTGF-β1、ICAM-1、核转录因子(NF)-κB表达;逆转录-聚合酶链反应(RT-PCR)检测mTGF-β1 mRNA转录强度;测定超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量、髓过氧化物酶(MPO)活性.结果 mTGF-β1成功转到心肌细胞,转基因组和转基因+FIY720组mTGF-β1的表达强度分别是(1.08±0.24)和(1.16±0.22),明显高于其他3组(P<0.01);而两组ICAM-1的表达积分分别是(2.43±0.46)和(1.90±0.20),NF-κB的表达积分分别是(9.80±1.85)和(10.10±2.27),较其他3组显著下调(P<0.01);FRY720组、转基因组和转基因+FTY720组心肌细胞凋亡指数分别是(9.20±1.12)、(5.90±1.09)和(5.40±0.77),显著减少(P<0.01);FTY720组、转基因组和转基因+FTY720组SOD活性分别是(51.03±5.54)、(55.91±6.66)和(73.42±6.42)U/mg,明显升高(P<0.01),MDA含量(10.90±1.93)、(11.02±2.45)和(9.28±1.64)U/g,明显下降(P<0.01);而MPO活性分别是(4.38±1.43)、(4.63±1.04)和(3.16±0.64)U/g,亦明显下降(P<0.01);转基因和FTY720两因素对减轻心肌细胞凋亡以及对SOD、MDA和MPO的影响存在交互作用(P<0.05).结论 TGF-β1和FTY720均具有减轻移植心脏缺血-再灌注损伤的作用,机制可能与抑制心肌细胞凋亡、下调ICAM-1、NF-κB表达、增高SOD活性等因素有关;两者联合应用在减轻缺血-再灌注损伤方面有协同作用.     

Cold ischemia and the reduced long-term survival of cadaveric renal allografts

BACKGROUND: Prolonged cold ischemia time (CIT) is accompanied by delayed cadaveric renal allograft function and early allograft loss, but the effect of CIT on long-term allograft survival is less certain and has not been studied in detail. METHODS: Using data from the United Network for Organ Sharing, we identified 6465 patients who received a kidney-only transplant of cadaveric origin for the first time in 1995. We examined the effect of CIT on the 6-year survival of these kidneys using Cox proportional hazard analysis. RESULTS: The mean CIT of the kidney was 21 +/- 7 hours (mean +/- SD) and correlated with the serum creatinine on discharge (R= 0.20, P < 0.001) and the distance traveled by the kidneys (R= 0.30, P < 0.001). CIT had a significant effect on the 6-year allograft survival (a 10-hour increase in CIT was associated with a hazard risk ratio (RR) of 1.20 for graft failure (P < 0.001) that persisted (RR = 1.40, P= 0.021) after adjusting for donor age, recipient age and race, human leukocyte antigen (HLA) mismatch, panel reactive antibodies, and first 6 months' rejection treatments. Similarly, compared to CIT category of 0 to 10 hours, the 6-year graft survival was progressively worse for 11 to 20 hours (RR = 1.03), 21 to 30 hours (RR = 1.12), and, significantly so, for >30 hours (RR = 1.32; P= 0.011). The gain in HLA match with increasing CIT was not uniform; for instance, HLA match in >30 hours was lower than for 21 to 30 hours (2.4 +/- 1.5 vs. 2.7 +/- 1.6; P < 0.001). CONCLUSION: (1) Cadaveric kidneys continue to undergo prolonged periods of cold ischemia; (2) prolonged cold storage is associated with longer distance traveled by the kidneys, but is not associated with any significant gain in tissue matching; and (3) prolonged cold ischemia is a significant predictor of long-term graft loss. Reducing prolonged cold ischemia by regional distribution of organs and less stringent tissue matching may reduce the persistent high rate of long-term loss of cadaveric renal allografts.     

The impact of renal failure on survival following cardiac transplantation

OBJECTIVE: Renal failure after cardiac transplantation is a common and serious complication. In this study we investigated the incidence and effects of renal failure on survival among patients who underwent cardiac transplantation. PATIENTS: Eight patients underwent cardiac and one patient combined cardiac and renal transplantation. The mean age of the patients was 33 +/- 11.6 years (range, 17 to 51). On preoperative echocardiographic evaluation, the mean ejection fraction was calculated as 19 +/- 3.11% (range, 16% to 24%). One patient had compensated renal failure and one patient, dialysis-dependent renal failure. Hemofiltration was routinely used during the operations. Corticosteroids, cyclosporine, and mycophenolate mofetil were used for immunosuppression. Early renal replacement therapy was performed in patients with acute renal failure. RESULTS: The incidence of acute renal failure was 55.5% (5 patients). In the early postoperative and follow-up periods, the mean ejection fraction was 55 +/- 9.9% and 57 +/- 4.5%, respectively. The mean follow-up period was 21.3 +/- 8.8 (range, 6 to 33) months. In the early initiation period, the mean peak value of cyclosporine blood level was 479 +/- 201.8 ng/mL during the first month, 250 +/- 95.3 and after the third month, 195 +/- 43.7 ng/mL. The mean creatinine level at last follow-up was 1.27 +/- 0.4. One patient experienced a grade III-A rejection episode. One patient died due to coronary artery occlusive disease at 31 months after transplantation. COMMENT: In our study we have observed that renal failure had no negative effect on patient survival. This can be explained by improved cardiac performance, keeping cyclosporine levels low finding and utilizing early renal replacement treatment.     

Transplant renal artery stenosis: potential role of ischemia/reperfusion injury and long-term outcome following angioplasty

PURPOSE: We assess long-term arterial pressure, renal function, and patient and graft survival in recipients of cadaveric kidney transplant with or without transplant renal artery stenosis. We also evaluate the risk factors for transplant renal artery stenosis. MATERIALS AND METHODS: We reviewed and analyzed baseline clinical, immunological and outcome data for 26 patients with transplant renal artery stenosis before and after angioplasty, and 72 without stenosis on angiography. We also analyzed graft and patient survival in 304 cases in which angiography was not performed. RESULTS: The incidence of transplant renal artery stenosis was 6.6% (26 of 402 patients). Acute rejection episodes (42 versus 22%, p <0.05) and delayed graft function (50 versus 32%, p <0.10) were more frequent, and mean cold ischemia time plus or minus standard error (29.2+/-1.7 versus 24.8+/-1.3 hours, p <0.01) was longer in patients with than without transplant renal artery stenosis. The technical success of angioplasty was 92.3%. Restenosis was documented in 6 of 26 patients (23.1%). Revascularization resulted in a decrease in arterial pressure and better renal function. The 8-year patient (100, 98.6 and 95.7%, respectively) and graft (88.1, 88.9 and 89.3%, respectively) actuarial survival rates were similar among patients with or without transplant renal artery stenosis, and those who did not undergo angiography. CONCLUSIONS: Transplant renal artery stenosis had no detectable influence on long-term arterial pressure control, renal function, and patient and graft survival rates, which were similar to those in patients without stenosis. Long cold ischemia time may have a role in the development of transplant renal artery stenosis through ischemia/reperfusion injury.     

丙泊酚对大鼠肾缺血-再灌注期血清白细胞介素-8的影响

目的观察丙泊酚对大鼠肾缺血-再灌注期血清白细胞介素-8(IL-8)的合成和释放的影响,并探讨其肾保护机制。方法选用12~14周雄性大鼠75只,随机分为三组,每组25只,以无创动脉夹夹闭双侧肾蒂60min制备急性肾缺血-再灌注模型。A组为肾缺血-再灌注组,B组为丙泊酚处理组,C组为假手术组。各组设立五个时间观察点:缺血前10min(T0),缺血60min(T1),再灌注1h(T2)、3h(T3)、6h(T4),每个时间点5只大鼠。C组:肾脏缺血60min,缺血前5min从股静脉注射丙泊酚20mg/kg,继之经微量泵持续输入丙泊酚(0·5mg/ml)50mg·kg-1·h-1,持续60min;A、B组以等容生理盐水取代丙泊酚,但A组不夹闭双侧肾蒂,术中保持大鼠呼吸、循环稳定。各组大鼠存活至预定时间后再次麻醉取标本,测定血浆丙二醛(MDA)、超氧化物歧化酶(SOD)、血清IL-8,同时用光学显微镜观察肾组织形态学改变及肾小管损伤情况。结果血浆MDA在C组T1~T4时无明显变化,同A组相似,较B组相应时点显著降低,而B组T1~T4时较T0时及A组各时点显著升高;SOD则呈相反变化;C组T1~T3时血清IL-8无明显变化,仅在T4时较T0时和A组有显著升高,而B组在T1~T4时分别增加1·73、2·50、2·76、2·89倍,同C组和A组相比有显著性差异;光镜下观察发现B组肾小管上皮细胞变性、坏死,细胞脱落,肾小管管腔变窄,肾间质水肿、充血伴炎性细胞浸润明显;而C组以肾小管肿涨为主,个别呈坏死样改变,肾间质水肿、充血、炎性细胞浸润不明显。结论丙泊酚除了有抗氧作用外,还能有效地抑制血清IL-8合成和释放,这可能是丙泊酚减轻肾缺血-再灌注损伤的机制之一。