Evidence that addition of azathioprine improves renal function in cyclosporine-treated patients with allograft dysfunction

Several approaches have been attempted to manage renal allograft dysfunction in cyclosporine-prednisone (CsA-Pred)-treated patients. Conversion to conventional therapy and perioperative triple drug have been associated with high rates of acute rejection episodes, infections, or neoplasms. We report our experience in delayed addition of azathioprine (1-2 mg/kg/day) to CsA/Pred protocol in three groups of patients. Group I (n = 9) had chronic renal function deterioration due to chronic rejection; group II (n = 10) had repeated or severe acute rejection episodes despite adequate CsA levels; and group III (n = 8) had CsA toxicity despite drug tapering. In group I, serum creatinine (SCr) had risen from 2.2 +/- 0.9 to 2.9 +/- 0.7 mg/dl over the 6 months prior to Aza addition (P less than 0.05), renal function declining at a rate of -0.14 +/- 0.12 Cr-1/year. In the 6-month post-Aza, renal function improved at a rate of 0.06 +/- 0.06 Cr-1/year and during the entire follow-up at a rate of 0.04 +/- 0.12 Cr-1/year (P less than 0.05) with stable CsA levels (288 +/- 167 vs. 251 +/- 172 ng/dl, NS). In group II response was worse, though the rate of declining renal function prior to Aza (-0.10 +/- 0.10 Cr-1/year) was almost stopped after Aza. In group III there was very good response to Aza addition, as 7 out of 8 patients improved graft function (baseline SCr 2.5 +/- 0.7 mg/dl vs. 1.9 +/- 0.6 mg/dl at last follow-up, P less than 0.05), with significantly decreased CsA levels (480 +/- 97 vs. 268 +/- 120, P less than 0.05). One patient from group II died from pneumonia, and 6 patients (1 from group I and 5 from group II) lost their grafts. Fifteen patients improved graft function, and 9 worsened after addition of Aza. The bad-responders had significantly higher SCr at baseline compared with the good-responders (3.8 +/- 1.8 vs. 2.7 +/- 0.6 mg/dl, P less than 0.01). Amelioration of chronic graft dysfunction can be achieved by delayed addition of Aza to CsA-Pred in patients with chronic rejection or CsA toxicity. This is accompanied by low rate of acute rejection, good patient and graft survival, and low rate of infections. A worse outcome can be seen in patients with high-baseline SCr levels, suggesting the need for addition of Aza in the initial chronic graft dysfunction.     

Randomized study comparing cyclosporine with azathioprine one year after renal transplantation-15-year outcome data

BACKGROUND: The introduction of cyclosporine (CsA) improved 1-year graft survival and reduced the incidence of acute rejection episodes after renal transplantation compared to azathioprine (Aza). However, CsA has many side effects and reducing exposure of this drug after the first year may benefit long-term patient and graft survival. METHODS: We report 15-year outcome data from a single center, randomized controlled study comparing CsA withdrawal and conversion to Aza with continuation of CsA 1-year posttransplant. RESULTS: Two hundred sixteen patients who showed a serum creatinine less than 300 mumol/L with no acute rejection episodes in the preceding 6 months were enrolled (CsA 114, Aza 102). There was no difference in patient survival at 15 years: 62.4% in the CsA group and 64.4% in the Aza group (P=0.6). Fifteen-year transplant survival was 41.9% for the CsA group and 48.8% for the Aza group (P=0.8). Fifteen-year graft survival censoring for death with a functioning graft was 58% in the CsA group and 72% in the Aza group (P=0.5). Predictors of patient survival were younger recipient age (P<0.001) and lower systolic blood pressure at randomization (P=0.01). Predictors of graft survival were older recipient age (P<0.001) and better renal function at randomization (P=0.01). Assigned drug showed no effect on graft or patient survival. Patients assigned to CsA showed significantly worse renal function up to 10 years posttransplantation and required more anti-hypertensive treatment throughout the study period. CONCLUSION: In a selected group of patients, either Aza or low-dose CsA is safe and effective. Despite lower estimated glomerular filtration rate (eGFR) up to 10 years posttransplantation and increased use of anti-hypertensive agents, low-dose CsA was not associated with a worse patient or graft survival.     

Expression of HLA-DR antigens on peripheral blood T lymphocytes and renal graft tubular epithelial cells in association with rejection

Since the expression of HLA-DR antigens on peripheral blood T lymphocytes and renal graft tubular epithelial cells may be associated with immunological stimulation, we investigated the expression of these antigens on blood T lymphocytes and graft tubular epithelium in 84 renal transplant patients. Peripheral blood T lymphocytes were monitored by flow cytometry during the first 3 months after transplantation. Since the DR+ lymphocytes were selected by a double-labeling technique used for the Leu2a phenotype, the majority of the DR+ lymphocytes were also Leu2a+ with a small percentage of unidentified Leu2a- lymphocytes. Forty-one patients were treated with cyclosporine (CsA) and 43 with azathioprine (Aza), while both groups received low-dose steroids. Frozen sections of 57 renal biopsies from 43 patients (21 on CsA and 22 on Aza) were stained for HLA-DR antigens. In the Aza group, clinical rejection episodes correlated with an increased percentage of DR+ peripheral lymphocytes (P = 0.0005), and the expression of DR antigens on graft epithelial cells (P less than 0.001). In the CsA group, no relation between the expression of DR antigens on blood lymphocytes and clinical rejection episodes was evident, and the correlation between tubular DR staining and clinical rejection episodes was weaker than in the Aza group (P = 0.03). In both the Aza and CsA group, an increase in DR+ peripheral lymphocytes correlated with positive staining of the renal tubular cells for HLA-DR antigens (P less than 0.001).     

Individualization of immediate posttransplant immunosuppression. The value of antilymphocyte globulin in patients with delayed graft function

In patients with delayed graft function (DGF), the use of cyclosporine (CsA) has been reported to prolong DGF, increase the number of required dialyses, increase the duration of hospitalization, and be associated with decreased graft survival. Routine postoperative antilymphocyte globulin (ALG) use has been advocated, but ALG is associated with increased viral infection. We studied outcome of individualization of immunosuppression. Between 11/84 and 8/86, first-cadaver transplant recipients whose serum creatinine (Cr) fell greater than or equal to 30% in the first 24 hr (immediate function) were started on CsA and prednisone (P) (group 1, n = 26). The remainder were randomized to P and azathioprine (group 2, n = 32) or P and ALG (group 3, n = 26), and switched to CsA when serum Cr fell greater than 30% (minimum 5 days ALG for the ALG group). P taper was the same in all groups. Patients with DGF (groups 2 and 3) had longer preservation time and higher peak PRA (P less than .05) than group 1. Groups were otherwise equivalent. One and 2-year patient survival was 96% (3 cardiovascular deaths; all with functioning grafts). One-year graft survival was 87% for group 1, 87% for group 2, and 82% for group 3(NS). In patients requiring dialysis, mean day off dialysis was 12 +/- 3 in both groups 2 and 3. Mean hospital stay was 12.5 +/- 1.3 days for group 1, 21.6 +/- 2.1 days for group 2 (P less than .05 vs. 1 & 3), and 14.5 +/- 1.2 days for group 3 (NS vs. 1). The increased hospital stay for group 2 patients was mainly due to increased in-hospital rejections: 75% for group 2, (P less than .05 vs. group 1 [35%], and group 3 [11.5%]). In addition, more group 2 in-hospital 1st rejections were steroid resistant as compared to group 1; 46% group 1 patients have remained rejection free as compared to 0% group 2 (P less than .05 vs. 1 and 3) and 35% of group 3 (P less than .05 vs. 1 and 2). Mean serum creatinine at 6-12 months remained higher in patients with DGF (group 1 P less than .05 vs. 2 and 3). Rejection was the major cause of graft loss in all groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

Results of the Minnesota randomized prospective trial of cyclosporine versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients

Between September 26, 1980 and June 8, 1984, 246 splenectomized, transfused renal allograft recipients were randomized to treatment with either cyclosporine (CsA)-prednisone (n = 131) or azathioprine (Aza)-prednisone-antilymphocyte globulin (n = 115). On December 31, 1984, actuarial patient survival rates at three years were 89% in the CsA group and 90% in the Aza group, and the corresponding graft survival rates were 82% and 79% (statistically insignificant differences). The results were also compared separately in diabetic and nondiabetic patients and in recipients of related and cadaver donor grafts; only in the subgroup of diabetic recipients of cadaver kidneys were the differences in graft survival rates significantly different between CsA- and Aza-treated patients. The incidence of posttransplant acute tubular necrosis was similar in CsA- and Aza-treated patients (33% v 27%), but the duration was significantly longer in CsA- than in Aza-treated recipients (15.7 +/- 18.4 v 7.7 +/- 3.0 days). Rejection episodes and infections (particularly CMV) occurred significantly less frequently in CsA- than in Aza-treated patients. Mean serum creatinine levels were significantly higher in CsA- than in Aza-treated recipients (2.0 +/- 0.6 v 1.5 +/- 0.5 mg/dl). Treatment of hypertension and hyperkalemia was required significantly more frequently in the CsA-treated patients than in the Aza-treated patients. Initial mean hospitalization time was significantly shorter in the CsA group than in the Aza group (15.6 +/- 9.5 v 19.8 +/- 10.7 days). In the CsA group, 19% of the patients were switched to Aza and 35% had Aza added to their regimen with a concomitant lowering of the CsA dose because of nephrotoxicity. The results of our randomized trial are at variance with those of others in that the graft survival rates in our trial were not different between CsA and Aza-treated patients, primarily because our conventionally-treated patients had a higher graft survival rate than in the other trials. The advantages of CsA (fewer rejection episodes, fewer infections, shorter hospitalization) outweigh the disadvantages (higher serum creatinine, more hypertension), and thus we believe it should be used in most renal allograft recipients, perhaps in combination with Aza so that a lower dose of CsA can be used and the side effects minimized--a regimen that we are currently evaluating.     

The Milan clinical trial with cyclosporine in cadaveric renal transplantation. A three-year follow-up

Between February and November 1983, 108 recipients of cadaveric renal transplants entered a randomized multicenter trial and were treated either with cyclosporine (CsA) and prednisone (n = 55) or with conventional treatment based on azathioprine (Aza) and glucocorticoids (n = 53). The graft survival probability at 3 years was 76% for CsA patients and 48% for Aza patients (P less than 0.001). The cumulative number of acute rejections was significantly lower in the CsA group (32 vs. 104, P less than 0.001). Incidence of early posttransplant anuria was similar in both groups and did not affect renal function after three years. Nephrotoxicity in CsA patients, when present, was handled by reducing the dose of CsA, but in 12/55 patients a change to conventional therapy was thought to be necessary. However, in this group of 12, one patient lost the allograft because of irreversible rejection and one patient died 14 months later because of an infection. Mean creatinine clearance after three years was significantly lower in the CsA patients (54.7 +/- 2.6 ml/min) than in Aza patients, (67.2 +/- 4.9 ml/min, P less than 0.05). Considering only patients with grafts functioning after three years and still on the original randomized therapy, the mean creatinine clearance was similarly and significantly decreased from 1 to 3 years in both groups. There were no significant differences in occurrence of severe infections. Side effects such as hypertension, hypertrichosis, tremor and gum hyperplasia were more frequent in CsA patients.     

Cyclosporine toxicity: the effect of combined therapy using cyclosporine, azathioprine, and prednisone

Forty-nine patients among 360 who received renal transplants under cyclosporine (CsA)/prednisone (Pred) immunosuppression required alteration of the immunosuppressive regimen because of intractable nephrotoxicity. Twenty-five patients, converted totally to azathioprine (Aza)/Pred, suffered intractable nephrotoxicity with no associated evidence suggesting ongoing rejection. The results with Aza/Pred conversion were disappointing because of an unacceptably high incidence of rejection and allograft loss. Twenty-four patients with intractable CsA nephrotoxicity were, therefore, treated using an alternative approach combining Aza with aggressive CsA dose reduction, and continued Pred therapy. All patients tolerated initiation of Aza without complication; allograft rejection was not common. Renal function improved for 23 of the 24 (96%) CsA/Aza/Pred patients with mean serum creatinine levels falling from 3.5 +/- 0.5 mg/dL to 2.2 +/- 0.4 mg/dL after a mean follow-up of 14 months (P less than .001). Among 18 patients observed at least 12 months, seven (39%) enjoyed serum creatinine values less than or equal to 2 mg/dL. Nine CsA/Aza/Pred-treated patients (37.5%) required hospitalization because of infectious complications, all of which resolved with temporary reduction of immunosuppression and specific antimicrobial therapy when indicated. One patient sustained acute allograft rejection as a result of patient noncompliance, and one patient on a seemingly appropriate CsA/Aza/Pred dose responded initially to steroid pulse antirejection therapy; however, renal function again worsened. Two patients developed progressive renal dysfunction due to chronic rejection, and returned to dialysis 13 and 17 months, respectively, following initiation of CsA/Aza/Pred. Overall, the actuarial graft survival for CsA/Aza/Pred-treated patients was 100% at 1 year, and 84% at 2 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

Amelioration of chronic renal allograft dysfunction in cyclosporine-treated patients by addition of azathioprine

Management of chronic renal allograft dysfunction in cyclosporine-prednisone treated renal allograft recipients remains problematic. We therefore initiated a protocol of azathioprine addition (1.0-1.5 mg/kg/day) to ongoing CsA/Pred therapy. Three groups were treated. Group A (n = 21) had chronic progressive renal dysfunction (serum creatinine greater than or equal to 2.5 mg/dl or more than 15% above baseline) four or more months after transplantation. Group B (n = 8) had frequent or severe rejection episodes occurring despite adequate CsA levels. Group C (n = 7) had constitutional side effects of CsA with or without renal dysfunction persisting despite drug taper or financial difficulty in affording CsA. Aza was initiated 17.8 +/- 2.8 months after transplantation in group A, the mean serum creatinine having risen from 2.55 +/- 27 mg/dl to 3.04 +/- .20 mg/dl (P = .07) over the six months preceding Aza initiation, despite stable and low therapeutic range HPLC whole-blood CsA levels (118 +/- 10 ng/ml vs. 133 +/- 11 ng/ml, P = NS). Renal function declined at a rate of -0.20 +/- .06 Cr1/year in the six-month period before addition of Aza, and then improved at a rate of 0.09 +/- .04 Cr-1/year after addition of Aza (P = .002). These changes in renal function occurred without a decrease in CsA levels (118 +/- 10 six months before Aza vs. 126 +/- 26 six months after Aza, P = NS). In group B Aza was initiated at 58 +/- 8 days after transplantation when mean sCr was 3.56 +/- .29 mg/dl and mean CsA level was 222 +/- 17 ng/ml. At least follow-up 12.7 +/- 2.0 months after addition of Aza, all group B grafts were functioning, mean sCr was 2.69 +/- .31 mg/dl (P = .09 compared with baseline), and mean CsA level was 128 +/- 34 ng/ml (P = .07 compared with baseline). Group C patients had addition of Aza at 43 +/- 19 months after transplantation when mean sCr was 2.97 +/- .60 and mean CsA level was 125 +/- 30 ng/ml; addition of Aza had no influence on the rate of decline in renal function in this group. Of these 36 patients, 6 received therapy for acute rejection over the entire follow-up period of 12.3 +/- 1.4 months after addition of Aza; 4 of these retain graft function. Infectious complications consisted of 2 urinary tract infections, 1 bacterial pneumonia, and one case of otitis media.(ABSTRACT TRUNCATED AT 400 WORDS)     

Treatment of renal transplant rejection episodes in patients receiving prednisone and azathioprine. A cost-effective approach

Antilymphocyte globulin (ALG) has been advocated for the treatment of renal transplant rejection episodes in patients maintained on prednisone and azathioprine. Treatment with steroids (outpatient) is considerably less expensive than with ALG (inpatient), so we studied whether routine ALG was necessary. Between 3/82 and 11/83, 54 cadaver transplant recipients maintained on prednisone and azathioprine who developed a first rejection episode were randomized to receive--for treatment of their first, and if necessary second, rejection--methylprednisolone (MP) plus ALG (n = 24), or MP alone, with ALG added if treatment failed (n = 30). Treatment failure was defined as continuing deterioration on T131 iodohippuran scan, rising serum creatinine level, or lack of improvement within 7 days. There was no significant difference in patient survival, graft survival, mean number of rejections, and infection rate between the two groups: 60% (18/30) of first and 50% (10/10) of second rejection episodes responded to MP alone. We conclude that patients are not penalized by initial rejection treatment with MP. Many rejection episodes respond to steroids alone; elimination of routine ALG use will save hospitalization time and expense.     

An increased incidence of late acute rejection episodes in cadaver renal allograft recipients given azathioprine, cyclosporine, and prednisone

We studied the incidence of biopsy-proven, acute rejection episodes occurring after 1 year posttransplant in cadaver renal allograft recipients. The 328 patients evaluated were given three immunosuppressive drug protocols. Group I (transplanted 9/80-6/84) (n = 75) received azathioprine, prednisone (P), and antilymphoblast globulin; group II (transplanted 9/80-6/84) (n = 83) received cyclosporine and P; group III (transplanted 7/84-12/86) (n = 170) received ALG, AZA, CsA, and P (sequential therapy). The incidence of first acute rejection episodes occurring up to 1 year posttransplant was 55% in group I and 35% in groups II and III. The incidence of late (greater than 1 year) acute rejection episodes was 6.5% in group I, 2.5% in group II, and 9.5% in group III (group II vs. III, P = 0.02). In group III, 50% of the late rejections were first, 44% second, and 6% third. The primary etiologies of this increased incidence of late acute rejection may have included subtherapeutic CsA levels and lower P doses. Sequential immunosuppressive therapy has been shown to be advantageous in the first posttransplant year. However, unless adequate immunosuppression is maintained, this approach can be associated with a significantly increased incidence of late acute rejection.     

Sequential discontinuation of azathioprine and prednisone in renal transplantation

We report the time course of rejections in 110 patients of first cadaver kidney grafts entered into a randomized controlled trial of induction ALG vs continuous IV CyA, with both groups receiving Aza for 30 days and Pred for 3 months. There was no difference in 1-year graft or patient survival in the two induction regimens. Despite a slight delay in time to first rejection, the number, severity, and outcome of rejections were the same in both. Fifty percent of patients never had a rejection, and 80% of these were on CyA monotherapy at 1 year vs only 22% in patients with rejections. Thirty-five percent had a rejection in the first month, and one fourth of these had a repeat in the second month. The risk of graft loss was 10% with a first, 38% with a second, and 50% with a third rejection. First rejections occurring after 30 days rarely caused graft loss and rejection after 90 days proved to be unusual.     

肾移植后免疫抑制用药方案与移植肾长期存活的关系

目的 分析肾移植后不同的免疫抑制用药方案对移植肾长期存活的影响。方法 根据不同用药组合将患者分为环孢素Ａ（ＣｓＡ）、硫唑嘌呤（Ａｚａ）和泼尼松（Ｐｒｅｄ）三联治疗组、ＣｓＡ和Ｐｒｅｄ二联治疗组、Ａｚａ和Ｐｒｅｄ传统二联治疗组。统计分析免疫抑制用药、排斥反应发生及人、肾存活情况;对发生排斥反应的患者追踪其发生排斥前１２个月内的药物更动情况。结果 采用三联治疗的患者人／肾５年存活率（８８％／７８％）显     

Conversion from mycophenolate mofetil to azathioprine in renal allograft [corrected] patients within the first month posttransplantation

This retrospective study evaluated the safety of conversion from mycophenolate mofetil (MMF) to azathioprine (Aza) within the first month posttransplantation in 117 renal allograft patients concomittantly treated with cyclosporine (CsA) and prednisone. In 52 Conversion from MMF to Aza was conducted at 2 to 4 weeks posttransplantation in 52 patients (conversion group). Thirty-six patients received MMF (MMF group) and 29 patients were treated with Aza (Aza group). Patients were monitored for allograft function, acute rejection episodes, and CsA levels. The demographics were comparable between groups with respect to age, as well as warm and cold ischemic times of allografts. The cumulative allograft survival rates at 1, 2, 3, and 5 years were 98% +/- 2%, 96% +/- 3%, 90% +/- 4%, 90% +/- 4% in the conversion (n = 52) group versus 79% +/- 7%, 79% +/- 7%, 79% +/- 7%, and 75% +/- 8% in the MMF group (n = 36) versus 93% +/- 5%, 93% +/- 5%, 82% +/- 7%, and 78% +/- 8% in the Aza group (n = 29). The CsA trough levels at 1 year posttransplantation were 208.39 +/- 93.79 ng/mL in the conversion group; 159.30 +/- 52.99 ng/mL in the MMF group; and 241.82 +/- 112.76 ng/mL in the Aza group. The acute rejection rates during a 5-year follow-up were 28.85% in the conversion group; 27.78% in the MMF group; and 24.14% in the Aza group. The rejection-free allograft survival between the conversion group and the MMF group was identical (P < .921). However, allograft survival in the conversion group with acute rejection was significantly higher than the MMF group (P < .024). In conclusion, early conversion from MMF to Aza among renal allograft patients was safe without increased acute allograft rejection during a 5-year follow-up. The overall allograft survival in the conversion group was comparable to patients treated with MMF or Aza therapies.     

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.     

Low-dose maintenance prednisone and antilymphoblast globulin for the treatment of acute rejection. A steroid-sparing approach to immunosuppressive therapy

The purpose of this prospective randomized trial was to evaluate an immunosuppressive protocol involving reduced maintenance and antirejection steroid dosages in cadaver renal transplantation. The study comprises 23 first cadaver graft recipients who experienced an acute rejection episode. All patients received an initial 14-day course of antilymphocyte globulin (ALG) and azathioprine 1.5 to 2.0 mg/kg/day. In 11 patients (group 1), a low maintenance dose of prednisone (30 mg/day) was administered and first rejection episodes were treated with a second 10-day course of ALG. The remaining 12 patients (group 2) received high maintenance doses of prednisone (2 mg/kg/day with tapering) and intravenous methylprednisolone (IVMP) for first rejection episodes. Subsequent rejections in both groups were treated with high doses of steroids. In group 1, all first rejection episodes were reversed with ALG alone, 6 patients experienced no subsequent rejection, and 10 patients currently have a functioning graft. In Group 2, the first rejection episode was reversed with IMVP alone in 10 patients; in two patients in whom IVMP therapy was unsuccessful, ALG was then administered, and subsequent rejection reversal was effected. In group 2, 4 patients experienced no subsequent rejection, and 9 patients currently have a functioning graft. Patients in group 1 received significantly lower (P less than .01) cumulative steroid doses in the first six months following transplantation, which resulted in a reduced number of major infections, as compared with patients in group 2. We conclude that the steroid-sparing regimen of low maintenance prednisone and ALG for first rejection is as effective immunologically as the established high steroid protocol.     

Beneficial effect of concomitant induction with antilymphoblast globulin, cyclosporine, and steroids on long-term renal allograft outcome

BACKGROUND: The addition of induction therapy with antilymphocytic antibodies to cyclosporine (CsA) based immunosuppression, has reduced acute rejection incidence and improved short-term survivals, but has not had well-established effects on long-term renal transplant survival. PATIENTS: We analyzed the long-term allograft outcome of patients included in a prospective randomized clinical study conducted in our center 15 years ago by comparing two strategies: (A) horse antilymphoblast globulin (ALG) given at 10 mg/kg on alternate days to a maximum of 6 doses with low-dose CsA started at 8 mg/kg per day and prednisone at 0.25 mg/kg per day, versus (B) CsA started at 15 mg/kg per day and prednisone at 0.5 mg/kg per day. Diabetic and highly sensitized patients (PRA > 70%) were excluded from the study. RESULTS: The characteristics of the 50 patients enrolled in each group were not different. Although patient survival was not different (88% in group A vs 77% in group B), recipients treated with ALG showed a lower incidence of acute rejection episodes (20% vs 44%, P = .01) and better death-censored renal allograft survival (57% vs 41%, P = .03). Among rejection-free patients, graft survival was 15% higher in group A (60% vs 45%, P = .12). Multivariate Cox regression analysis showed that an acute rejection episode (relative risk [RR]: 2.44, 95% confidence interval [CI] 1.36-4.39; P = .0029) rather than ALG immunosuppression (RR 0.74, 95% CI 0.41-1.33; P = NS) was an independent predictor of death-censored graft survival. CONCLUSIONS: In summary, we confirmed that concomitant induction therapy with ALG, CsA, and steroids improves long-term renal allograft survival.     

Experimental and clinical experience with urine amylase monitoring for early diagnosis of rejection in pancreas transplantation

Pancreas allograft rejection in dogs with pancreaticocystostomy can be predicted in advance of hyperglycemia by monitoring the urinary amylase (UA) concentration (U/L): In initial experiments, UA values declined to less than 1000 1.3 +/- 0.2 days before hyperglycemia in nonimmunosuppressed dogs, 3.3 +/- 1.0 days in dogs treated with cyclosporine (CsA), and 9.3 +/- 0.7 days in dogs treated with CsA, azathioprine (Aza), and prednisone (triple therapy). Autotransplanted control dogs maintained high urine amylase concentrations indefinitely (mean 125,544 +/- 36,931). In a subsequent experiment, in 19 dogs with bladder-drained pancreas allografts on CsA only for prophylactic immunosuppression, a five-day course of antirejection treatment with Aza (5.0 mg/kg) and antilymphocyte globulin ALG (1 mg/kg) was started in group A (n = 10) when a raise in serum glucose was detected, and in group B (n = 9) when a drop of UA below 1000 was observed. The functional allograft survival rate was 9.2 +/- 0.5 days in group A (treatment started after hyperglycemia) and 29.0 +/- 5.7 days in group B (treatment started after drop in UA) (P = .002). The UA dropped in all dogs before hyperglycemia, at a mean of 2.7 days in group A and 20.8 days in group B. Clinically, 8 patients received a whole cadaver pancreas transplant with urinary drainage of the exocrine secretions. All were followed with UA monitoring. Three recipients lost the grafts for technical reasons. Three recipients lost the grafts for technical reasons. One had a primary non-function and UA was below 1000 U/24 hr; two developed abscesses and the grafts were removed while functioning with high UA values. Five grafts are currently functioning; 3 recipients had no rejection episodes and their UA values ranged from 30,000 to 100,000 U/24 hr during their entire postoperative course. The other two had rejection episodes. In both cases UA decreased to baseline levels 1 and 4 days in advance of the hyperglycemia. After antirejection treatment UA rose again to high values and plasma glucose levels declined. Both patients are currently insulin-independent, with UA values ranging from 10,000 to 200,000 U/24 hr. Both experimentally and clinically UA is an early predictor of pancreas allograft rejection. The institution of early treatment of rejection episodes in dogs, based on UA, significantly improved allograft survival. Urine amylase monitoring in pancreas transplant recipients could lead to an early treatment of rejection and improve graft survival.     

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.     

The adverse impact of cyclosporine on serum lipids in renal transplant recipients

The extent to which cyclosporine (CsA) directly, or indirectly, influences serum lipid levels in renal transplant patients treated with multiple-drug immunosuppression protocols is unclear. Indeed, patients treated with CsA have reduced corticosteroid requirements, fewer acute rejection episodes, and other differences from patients receiving conventional immunosuppression that may reduce serum lipid levels. We studied patients treated with low-dose CsA, corticosteroids, azathioprine, and Minnesota antilymphocyte globulin ([ALG] n = 205) versus conventional (three-drug) immunosuppression (n = 368) and evaluated the impact of CsA, acute rejection episodes, and other clinical parameters on serum lipids. Fasting serum lipid levels from stable patients transplanted between 1976 to 1989 were studied at 3 (n = 573), 12 (n = 565), 26 (n = 55), and 52 (n = 521) weeks posttransplant using multivariate, linear regression analysis. The incidence of acute rejection episodes was reduced by CsA, but patients with fewer acute rejection episodes in the early posttransplant period had higher serum total cholesterol (increased by .33 +/- .12 mmol/L [13 +/- 5 mg/dL] and .27 +/- .12 mmol/L [10 +/- 5 mg/dL], P less than 0.05, at 3 and 12 weeks, respectively) and low-density lipoprotein (LDL) (increased by .23 +/- .11 mmol/L [9 +/- 4 mg/dL] and .23 +/- .11 mmol/L [9 +/- 4 mg/dL], P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The long-term effects of prophylactic OKT3 monoclonal antibody in cadaver kidney transplantation--a single-center, prospective, randomized study.

We conducted a randomized, prospective study to determine the long-term effects of prophylactic OKT3 in cadaveric renal transplantation. In the first group of patients (n = 56) OKT3 (5 mg/day) was administered for the first 14 postoperative days in association with azathioprine (AZA) and low-dose steroids, cyclosporine (CsA) being introduced on day 11. The other group of patients (n = 52) received CsA from the first POD, together with AZA and steroids. Both protocols were identical from POD 14 on. The total number of infections was higher in OKT3 patients (124/1455 patient-months [P-M] vs. 68/1320 in CsA patients, P less than 0.001) without impact on patient survival (94.5% in OKT3 vs. 93% in CsA patients). OKT3 patients experienced a lower number of rejection episodes (61 per 1455 P-M of risk exposure vs. 81/1320 in CsA patients, P less than 0.05). In addition, the frequency of corticoresistant rejection episodes was lower in OKT3 patients (9 out of 61 vs. 24 out of 81 in CsA patients, P less than 0.05). This resulted in a trend toward improved overall graft survival (83% vs. 75%, P = 0.12) and in a significant increase in immunological graft survival (92% vs. 79%, P = 0.02) in OKT3 patients at 3 years. Taken together, these data suggest that prophylactic OKT3 therapy might have long-term beneficial effects in cadaveric renal transplantation.