A randomized trial of cyclosporine and prednisolone versus cyclosporine, azathioprine, and prednisolone in primary cadaveric renal transplantation.

A randomized trial was performed with the aim to compare two immunosuppressive treatment schedules in adult recipients of first cadaveric renal transplants. A total of 229 patients were randomized to double therapy with cyclosporine and prednisolone and 234 patients were randomized to triple therapy with cyclosporine, azathioprine, and prednisolone. Minimum follow-up was 4 years. The actuarial 5-year patient survival was 79.8% in the double therapy group and 82.3% in the triple therapy group (n.s.). The corresponding graft survival figures were 54.4% and 59.6% in the two groups, respectively (n.s.). There were no differences between the groups regarding cause of death or cause of graft loss. Renal function as determined by serum creatinine did not differ between the groups and was stable throughout the observation period. Azathioprine was instituted in a total of 51 patients randomized to double therapy. This subgroup of patients had a patient and graft survival not different from the remaining patients randomized to double therapy or from the patients randomized to triple therapy. There were no differences between the double and triple therapy groups regarding incidence and timing of acute rejection or infections. The incidence of other medical diseases and adverse events such as nephrotoxicity or malignancy did not differ between the groups. Azathioprine-induced leukopenia was uncommon (19 episodes in the triple therapy group). In a multivariate analysis of the whole series the only covariates that significantly influenced graft survival were age of recipient and occurrence of acute rejection, while among other factors treatment schedule did not. Thus this prospective study, in accordance with previous such studies, failed to find support for the use of triple therapy as first choice immunosuppression in first cadaveric renal transplantation. However, the study could not rule out the possibility that some patients at risk for the development of irreversible rejection or nephrotoxicity of CsA might benefit from the addition of azathioprine to the treatment schedule.     

Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation

Recent reports have intimated that the use of antilymphocyte globulin in combination with azathioprine and steroids has ameliorated the beneficial affects of cyclosporine. We believe that even in the absence of significant statistical differences between patient survival rates and graft survival rates of cyclosporine-treated renal transplant patients compared with conventionally treated renal transplant patients, there are distinct advantages to cyclosporine use in renal transplantation. Twenty-three consecutive cadaveric renal transplant patients who received azathioprine, prednisone, and antilymphoblast globulin were compared with 23 cadaveric renal transplant patients who received cyclosporine and prednisone. Fewer statistically significant rejection episodes, multiple rejection episodes, and cytomegalovirus infections were demonstrated in those who received cyclosporine. Most notably, cyclosporine decreased the initial hospital stay, was associated with fewer readmissions, and therefore markedly reduced the initial cost of transplantation.     

Experience with cyclosporine and steroids in clinical renal transplantation.

We have reviewed the results of patient survival and transplant function of the last 100 recipients of renal allografts treated with cyclosporine (CyA) plus low-dose steroids since November 1981; the follow-up varies between 3 months and 2 years. A group of 56 individuals transplanted between January 1980 and October 1982 and immunosuppressed with azathioprine (Aza) and steroids were used as comparison. There were five deaths among 100 patients treated with CyA and two among 56 treated with Aza. There were, however, marked differences in allograft function. Using actuarial curves, 2-year allograft survival from 24 living, related, one haplotype matched donors was 83%, as compared to an unsatisfactory 60% graft function among 24 nonrandomized, comparable, Aza-treated recipients. The 2-year actuarial survival of 76 allografts from cadaver donors was 76%; that of 36 grafts in patients treated with Aza, 48%. Interestingly, function of first cadaver allografts was 84% at 2 years, far better (p less than 0.002) than cadaver graft function (58%) in patients who had been previously transplanted; these latter results are comparable to Aza-treated cadaver recipients. Side effects and complications of this difficult drug, as well as its benefits, have been stressed in this article.     

环孢素新剂型Neoral在肾移植中的应用

对10例肾移植患者作山地明转换Neoral试验进行药效动力学对比研究，30例新移植患者应用Neoral进行临床观察。结果表明，Neoral最高血浓度（Cmax）较山地明高282±84ng／ml，达峰时间（Tmax）短0．79±0．29h，CSA暴露（AUC）大1533±169ng／（h·ml）（P＜0．05）。提示Neoral有较好地抗排斥反应作用，但由于吸收迅速，血药浓度易超过治疗窗水平而引起毒副反应。本组肝中毒达20％。认为Neoral与山地明转换比例应为1：0．8～1：0．9，以避免毒副作用发生；Neoral服药量可较山地明常规剂量减少25％。     

Antilymphoblast globulin, cyclosporine, and steroids in cadaveric renal transplantation

In order to avoid cyclosporine (CsA) nephrotoxicity and rejection, especially during the early posttransplant periods, different immunosuppression regimens have been adopted. A prospective trial was conducted to evaluate the benefits of initially low CsA doses associated with antilymphoblast globulin and steroids in the first days after transplant, in comparison with higher doses of CsA and steroids. Between 1/86 and 1/88, two groups of first-cadaver renal transplant recipients were documented based on the immunosuppression regimen used. In group A (n = 50), oral CsA was started at 8 mg/kg/day and subsequent doses adjusted to maintain CsA whole-blood levels between 300 and 600 ng/ml. Horse ALG at 10 mg/kg was given the day after transplant and on alternate days to a maximum of 6 doses. After 3 doses, ALG was stopped if CsA blood levels were equal to or greater than 400 ng/ml. ALG dosage modifications were made in order to maintain peripheral CD3+ cells between 10 and 20%. Prednisone was given at 0.25 mg/kg/day. In group B (n = 50), oral CsA was started at 15 mg/kg/day. The CsA whole-blood levels were maintained between 300 and 800 ng/ml. Prednisone was administered at 0.5 mg/kg/day. The incidence of postransplant renal failure was the same in both groups (16%), but the duration of oliguria was lower in group A than in group B (3.3 +/- 2 vs. 16.2 +/- 10.7 days, P less than 0.05), as well as the incidence of acute rejection during the first 3 months (18% vs. 40%, P = 0.01. The cumulative doses of CsA and steroids were significantly lower in group A than in group B. Mean serum creatinine at 6 and 12 months remained similar in both groups. There was no difference between the 2 groups in the incidence of infection. There was no mortality in either group. The actuarial graft survival was significantly higher in group A than in group B at one (100% vs. 94%), two (97% vs. 87%), and three years (89% vs. 73%), respectively (P = 0.041). In summary, the triple regimen using simultaneously low-dose CsA, ALG, and steroids minimizes early graft dysfunction, provides efficient immunosuppression without severe infections, and gives good long-term patient and graft survival.     

Results of conversion from cyclosporine to azathioprine in cadaveric renal transplantation

Between December 1983 and August 1985, 110 cadaver transplants were performed at our institution. All were started on cyclosporine (CsA) and prednisone (P) for immunosuppressive therapy. Of the 110 patients, 46 were converted from CsA to azathioprine (AZA) for a variety of reasons (cost, toxicity, patient preference, prolonged dysfunction posttransplant, or nonresponsive rejection). The course and outcome of these patients are described. The only group of patients who had consistent benefit and stable course following the CsA-to-AZA switch were primary cadaver transplants with stable renal function (serum creatinine less than 2 mg/dl) who were converted an average of 7.97 months posttransplant. All other groups of patients had severe problems or graft loss postconversion.     

A randomized prospective trial comparing cyclosporine monotherapy with triple-drug therapy in renal transplantation

In a prospective trial 151 recipients of renal transplants were randomly assigned to treatment with CsA alone (74 patients) and to low dose of AZA, prednisolone, and CsA (77 patients). At two years, graft survival was 84% for the monotherapy and 90% for the triple therapy. This difference was not statistically significant. The number of rejection episodes was similar in the two groups, but the severity of rejection was significantly worse among the patients on monotherapy. More kidneys were lost because of rejection (6 versus 3), and a higher number of methylprednisolone pulses was used for treating rejection (5.2 +/- 2.3 versus 4.3 +/- 2.9; P = 0.0077). CsA nephrotoxicity episodes were more frequent among patients on monotherapy (23 versus 7; P less than 0.02). Infectious episodes were equally distributed between the two groups. Creatinine clearance was poorer in the monotherapy-treated patients at the third month (42 +/- 16 ml/min versus 48 +/- 15 ml/min; P = 0.02), but no differences were observed between the two groups since the sixth month after transplantation. Many patients on monotherapy required changes in maintenance therapy. In fact, one patient was switched to conventional immunosuppression because of Cremophor-induced anaphylaxis. Another patient who developed Kaposi's sarcoma 4 months after surgery was switched to steroids alone. Excluding 5 patients who lost their grafts a few days after transplantation, only 30 of 74 patients (40%) could be kept without steroids. We conclude that both the therapeutic protocols can give good results in renal allotransplantation; however, monotherapy could create some problems in keeping the balance between drug toxicity and significant immunosuppression. On the contrary, triple therapy is easier to handle, especially in the early posttransplant period when the differential diagnosis between acute rejection and CsA-related nephrotoxicity can be difficult even for a skilled clinician.     

Impact of cyclosporine on cadaveric renal transplantation: a summary statement

CsA has now been used in this country for about four years and has been widely available for a little more than one year. Both the experience of those centers that have been using it longest, and total US national experience, suggest that CsA is now, with the sole exception of recipients matched for both HLA-DR antigens, the immunosuppressive of choice for all cadaveric renal allografts, conferring approximately a 10% advantage in graft survival. The advantages of CsA seem particularly apparent in the management of high-risk patients such as those over 50 years old and those with diabetes. CsA appears to reduce the frequency of rejection episodes and to permit reduction of steroid dosage. These factors, together with the improved graft survival rate, may contribute to a substantially higher rate of patient rehabilitation. The role of transfusion and HLA matching in association with CsA remains somewhat controversial. While large multicenter studies show the continued importance of both transfusion and optimal HLA matching, it has been argued that avoidance of pretransplant transfusions has avoided presentation of potential recipients, and that simplification of matching requirements has saved money and has permitted speedier transplantation of patients, favoring improved rehabilitation. Careful monitoring of the experience with this major new immunosuppressive agent over the next several years may answer these remaining questions.     

Sequential use of Minnesota antilymphoblast globulin and cyclosporine in cadaveric renal transplantation

The use of Cyclosporine (CsA) immediately after renal transplantation may be associated with an increased incidence and duration of acute tubular necrosis (ATN) and permanent primary graft nonfunction. To avoid this potential interaction we treated recipients of primary cadaveric grafts initially with azathioprine (AZA), methylprednisolone (MP), and 5 daily doses of Minnesota antilymphoblast globulin (MAG) (postoperative days 3-7). AZA was discontinued and CsA started on day 6 if the graft was functioning by then. If ATN persisted beyond day 6, AZA and MAG (maximum 12 doses) were continued and CsA withheld until graft function was established (group 1-33 patients). This protocol is compared to our previous regimen of MAG (14 doses over the first 3 weeks), AZA and MP (group 2-68 primary cadaveric graft recipients). Improved one-year graft survival (81% vs. 60%, P less than 0.05) and patient survival (93% vs. 81%, P less than 0.05) were seen in group 1. The incidence and duration of ATN did not differ in the two groups. During the first year after transplantation more patients in group 1 were completely free of rejection episodes (40% vs. 20%, P less than 0.05) and the number of rejection episodes per patient was also lower in this group (1.0 +/- 15 vs. 1.6 +/- 49, P less than 0.05). The incidence of infections was not different in the two groups. No tumors have developed in either group. We conclude that in primary cadaveric renal transplantation the initial administration of a short course of MAG followed by CsA therapy results in excellent graft and patient survival while avoiding the potential adverse effect of CsA on an allograft already subjected to preservation injury.     

他克莫司与环孢素A在尸肾移植中应用的长期疗效和安全性比较

目的　比较他克莫司 (FK5 0 6 )和环孢素A(CsA)在尸肾移植中应用的长期疗效和安全性。方法　 2 10例尸肾移植患者分为FK5 0 6组和CsA组 ,随访 12～ 32个月 ,观察两个组血药浓度变化、急性排斥和慢性排斥反应发生率、人 /肾 1年存活率、血肌酐、肝功能、血糖及血脂水平、药物不良反应、感染发生率以及FK5 0 6逆转顽固性急性排斥反应的效果。结果　血中FK5 0 6和CsA浓度谷值的变化趋势基本相同。FK5 0 6组与CsA组相比 ,急、慢性排斥反应发生率明显降低 (P <0 .0 5 ) ;肝功能异常发生率、高脂血症和牙龈增生发生率以及术后 3个月血肌酐水平均明显降低 (P <0 .0 5 ) ;高血糖和震颤发生率明显升高 (P <0 .0 5 ) ;感染发生率及人 /肾 1年存活率的差异无显著性。结论　与CsA相比 ,FK5 0 6是一种更高效的免疫抑制剂 ,长期使用可以有效降低肾移植后急、慢性排斥反应的发生率 ,有利于移植肾功能的恢复。     

A randomized long-term trial of tacrolimus/sirolimus versus tacrolimums/mycophenolate versus cyclosporine/sirolimus in renal transplantation: three-year analysis

BACKGROUND: We report three-year (interim) effects of combining sirolimus (Siro) vs. mycophenolate mofetil (MMF) as adjunctive therapy with calcineurin inhibitors (CI) in renal transplantation in the three different CI-based regimens. METHODS: Between May 2000 and December 2001, 150 recipients of deceased donor (DD) and living donor (LD) kidney transplants were randomized into three groups (n=50/group): Group A (Tacro/Siro), Group B (Tacro/MMF) and Group C (CsA/Siro). This report details drug dosing and monitoring, protocol discontinuance, biopsy-proven rejection, graft failure, other adverse events, and death at 36 months postoperatively. RESULTS: Actual patient and graft survival respectively in Group A was 90% and 82%, in Group B was 92% and 88%, and in Group C was 96% and 88% (not significant). Biopsy-confirmed acute rejection incidents showed a trend in favor of Group B (10%) vs. Group A (26%) and Group C (20%) combined (P=0.07). The geometric mean */SE serum creatinine concentration and arithmetic mean +/- SE Cockroft-Gault creatinine clearance calculations, respectively, were 1.39*/1.1 and 72.8+/-4.3 for Group A, 1.36*/1.1 and 72.1+/-4.1 for Group B, and 1.60*/1.1 and 61.8+/-3.8 for Group C, a statistically favorable difference for Group B over Group C (P=0.04). There was also less de novo development of posttransplant diabetes mellitus and lipid disorders in Group B vs. A and C (P<0.04). CONCLUSIONS: This three-year (interim) analysis has indicated a trend towards better graft function, fewer endocrine disorders, and fewer acute rejection episodes comparing adjunctive MMF and Tacro vs. Siro and Tacro or Siro and CsA, in the dosages used.     

The clinical status of cadaveric renal transplant patients treated for 10 year with cyclosporine therapy

In this paper we assessed the clinical status of 150 cadaveric renal transplant patients who received cyclosporine without interruption for 10 yr. The mean creatinine clearance was 59.2 +/- 15.71 at 1 yr and 55.6 +/- 24.91 mL/min at 10 yr (p = 0.039). Patients were subdivided into four quartiles according to the mean creatinine clearance at 1 yr. The 14 patients with the lowest quartile showed a significant decrease of creatinine clearance from the 1st to 10th year (from 31.5 +/- 5.83 to 24.8 +/- 14.00 mL/min; p = 0.038) while no difference between the mean creatinine clearance at 1 and at 10 yr was found in the other three quartiles. At 10 yr, 84.6% patients needed antihypertensive therapy, a rate similar to that seen at 1 yr (81.4%). The mean plasma cholesterol (253 +/- 57.8 mg/dL) and triglyceride (197 +/- 113.1 mg/dL) at 10 yr were similar to those found at +/- yr (243 +/- 48.2 and 201 +/- 143.0 mg/dL, respectively). Most patients have a high degree of rehabilitation 10 yr after uninterrupted cyclosporine therapy and all patients but 3 were able to work.     

Elective conversion from cyclosporine to azathioprine in sensitized patients following cadaveric renal transplantation

The safety of conversion from cyclosporine to azathioprine following renal transplantation in patients generally considered to be at immunologic risk for allograft loss has not been established. We examined a group of 59 patients who underwent cadaveric renal transplantation and elective conversion from cyclosporine to azathioprine 8.3 +/- 3.8 months following transplantation. Forty-three of these patients received a first transplant and had panel-reactive antibodies (PRA) less than 40% (unsensitized). Sixteen patients received at least their second allograft or had PRA of 40% or more (sensitized). Average follow-up was 17.9 +/- 8.2 months. Nine patients (15%) failed conversion as manifested by the need to restart cyclosporine 1 to 10 months following conversion. All were in the unsensitized group. Of those successfully converted, there were six allograft failures, two from patient death, one from acute rejection, one from recurrent diabetic nephropathy, and two from patient noncompliance. All were in the unsensitized group, although the difference from the sensitized group was not statistically significant (P = 0.051). There were three rejection episodes, all successfully reversed, in the sensitized group and six rejection episodes in the unsensitized group, five of which were reversed. Overall renal function improved in both groups as shown by a significant decrease in serum creatinine. Neither group required increased doses of steroid to compensate for lack of cyclosporine. From these data we can recommend conversion from cyclosporine to azathioprine in patients with cytotoxic antibodies or those undergoing retransplantation.     

Randomised open clinical trial of conversion from mycophenolate mofetil to azathioprine in cadaveric renal transplantation

Abstract Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The search for a less expensive immunosuppressive protocol has led to an open randomised clinical trial of conversion from MMF to azathioprine (Aza). A total of 28 renal allograft recipients treated with prednisone, cyclosporine, and MMF was randomised into two groups: converted (early conversion) and control (late conversion). Conversion from MMF to Aza was conducted at the end of the 4th post‐transplant month in the converted group and after the 12th month in the control. During the 20‐month observation period, biopsy‐proven acute rejection occurred more frequently in the converted than in the control group, although the difference was not statistically significant. Early conversion from MMF to Aza increased the risk of subsequent rejection in those patients who underwent at least one episode of acute rejection prior to conversion.