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.     

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.     

Improved results using OKT3 as induction immunosuppression in renal allograft recipients with delayed graft function

Delayed graft function remains a major problem in cadaveric renal allograft transplantation. We have used 2 different immunosuppressive induction regimens in patients with delayed graft function. The first regimen, used in 40 patients from January 1985 to December 1986, consisted of CsA (8 mg/kg/day, orally within 48 hr of cadaveric renal transplantation regardless of graft function), azathioprine (1.5-2.5 mg/kg/day), and steroids (methylprednisolone 375 mg on day 0, then prednisone tapered to 30 mg/day by day 10 with slow tapering to 7.5-10 mg/day over the first 6 months after transplantation). A second regimen, used from January 1987 to March 1989, employed the same doses of azathioprine and steroids; however, OKT3 (5 mg i.v./day for 7-21 days) was administered in the 34 patients who had delayed graft function. CsA was withheld until ATN resolved. The use of OKT3 as induction immunosuppression in patients with ATN led to a significant increase in 1-year graft survival (80% vs. 55%) while markedly decreasing the incidence of rejection episodes (44% vs. 82%) and the duration of nonfunction (9.4 vs. 14.9 days). There were 5 CMV infections in patients treated with OKT3. Antibodies to OKT3 developed in only 1 of 34 patients treated with OKT3. Five of 7 patients who received a second course of OKT3 successfully reversed the rejection episode. Patient survival (89%) was the same in the 2 groups. The benefit of OKT3 on long-term graft survival appears to stem from elimination of early rejection episodes that may be difficult to diagnose in a poorly functioning allograft. We conclude that OKT3 induction provides superior results over CsA induction at doses given in renal allograft recipients with delayed graft function without a significant increase in morbidity or mortality and permits the reuse of OKT3 for treatment of rejection in most cases.     

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.     

Renal transplants from HLA-haploidentical living-related donors. The influence of donor-specific transfusions and different immunosuppressive regimens

A total of 151 potential recipients of kidney grafts from one-HLA-haplotype-mismatched MLC-positive (RR greater than 20%) donors treated during 1980-1984 was investigated. The recipients were divided retrospectively into four groups: (A) 42 patients who received pretransplant donor-specific transfusions (DST) and posttransplant azathioprine/prednisolone (DST-only); (B) 10 patients who received DST with azathioprine before and azathioprine/prednisolone after grafting (DST-aza); (C) 42 patients who received no pretreatment and azathiprione/prednisolone posttransplant (aza group) and (D) 57 patients who also received no pretreatment but cyclosporine/prednisolone posttransplant (CsA group). DST-only led to persistently positive crossmatch in nine (21%) and transient positive crossmatch in two patients, while no sensitization occurred in the DST-aza group. Posttransplant, early acute rejection episodes were frequent in the DST-only group, but no graft was lost to acute rejection during first year; one-year graft survival (GS) = 94%. Similar GS (93%) was obtained in the CsA group, while in the aza group poorer results were obtained; GS = 69%. In the DST-aza group clinical problems including serious infections were observed. As CsA treatment without DST gave as high graft survival as in the DST groups, but avoided the sensitization risk by DST alone and the bone marrow complications of DST-aza, such treatment has become our preferred therapy for haploidentical renal transplants.     

Follow-up of cyclosporine-treated pediatric renal allograft recipients after cessation of prednisone

We attempted cessation of prednisone therapy in 16 pediatric renal allograft recipients who were between the ages of 3 1/2 and 16 years at the time of transplantation. Fourteen had primary grafts and 2 had second grafts. Nine had cadaver and 7 had living-related donor grafts. At the time of cessation of prednisone, cyclosporine was the only other immunosuppressive therapy for 15 of the patients and 1 patient was receiving CsA and azathioprine. All the patients had stable serum creatinines at the time prednisone was stopped, between 7 months and 5 years posttransplantation. Seven patients have had no episodes of rejection, continuing to receive CsA as their only immunosuppressive therapy and have stable renal function between 16 months and 3 1/2 years (mean: 2 years) after stopping prednisone. Stopping the small maintenance dose of prednisone resulted in improved growth in patients whose epiphyses were not fused. They improved their weight:height ratios and lost their cushingoid appearance. Serum cholesterol levels declined significantly. Patients who required antihypertensive drugs to control their blood pressure while receiving prednisone required fewer or no drugs when off prednisone. Nine patients had acute rejection episodes and were put back on maintenance prednisone following a 3-day steroid pulse. All these patients had a prompt improvement in renal function following the steroid pulse. However, only 3 stabilized function at preprotocol baseline Scr. Four currently have functioning grafts with Scr greater than the preprotocol Scr. Two patients have returned to dialysis. Although stopping steroids is a worthy goal in pediatric renal allograft recipients, we cannot recommend this strategy as routine management because of the 56% rate of acute rejection episodes in the patients who had prednisone withdrawn.     

Acute rejection episodes after renal transplantation in children under cyclosporin A treatment

Thirty-two pediatric renal transplant patients receiving cyclosporin and 34 receiving azathioprine treatment (historical controls) were investigated for the occurrence of rejection episodes; their clinical symptoms and findings, time of onset, influence of donorship, relation to cyclosporin blood levels and graft function outcome were also studied. In the cyclosporin group, four grafts were lost in the 2nd year, while in the azathioprine group five grafts were lost within the first 5 weeks after transplantation due to acute irreversible rejection. Clinical signs of rejection episodes under cyclosporin were mild and usually presented a silent increase of serum creatinine. First rejection episodes occurred later in patients treated with cyclosporin than in azathioprine-treated patients (50% probability after 7 weeks as opposed to 2 weeks). The percentage of patients receiving cyclosporin who had experienced no rejection episodes was 18,8% as opposed to 11,8% of patients receiving azathioprine. The lowest incidence of rejection episodes was observed in patients with living related grafts receiving cyclosporin treatment, 75% of whom were free of rejection episodes after 2 years. Cyclosporin blood levels below 400 ng/ml were observed in 74% of rejection episodes. Biopsies were often used to differentiate between cyclosporin nephrotoxicity and rejection when the cyclosporin levels were above 400 ng/ml. Both treatment groups exhibited a parallel decline in graft function, which correlated with the number of rejection episodes.     

Renal transplantation despite a positive antiglobulin crossmatch with and without prophylactic OKT3

The antiglobulin crossmatch (AGXM) is a sensitive technique employed by many transplant centers to enhance detection of preformed antibody to donor antigens that may cause hyperacute rejection. However, positive AGXM may detect irrelevant or very low titers of anti-HLA antibody precluding transplantation in suitable recipients. To investigate the significance of a positive AGXM, cadaveric renal transplantation was carried out despite a weakly positive AGXM (defined as cell killing above background but not greater than 20%) in 48 recipients. In an initial group (n = 10), maintained on triple therapy (cyclosporine, azathioprine, and prednisone), accelerated acute rejection occurred in 4 recipients and 3 grafts were lost. A subsequent group (n = 38) was treated with a prophylactic course of OKT3 then triple therapy. There were no episodes of accelerated acute rejection (P less than 0.01) although clinical hyperacute rejection claimed one graft and the incidence of delayed graft function was high (75%). The prophylactic OKT3 group had a reduced incidence of acute rejection (0.5 versus 1.0) per recipient and the onset of first episodes was delayed (mean onset: 13 versus 35 days after transplantation). One year actuarial primary graft survival was 88% in the prophylactic OKT3 group as compared with only 50% in the initial group. The outcome in the positive AGXM group was similar to a concurrent group (n = 32) with a negative AGXM and immediate graft function. On the other hand, the subset of positive AGXM regraft recipients treated with prophylactic OKT3 fared poorly, with a 36% (4/11) incidence of primary nonfunction. In summary, a positive AGXM, as defined in this report, is not a contraindication to primary renal transplantation--in fact, the use of the AGXM will identify recipients that would benefit from prophylactic OKT3.     

Risk of steroid withdrawal in pediatric renal transplant patients with suspected steroid toxicity.

BACKGROUND: Glucocorticoids are still a cornerstone in immunosuppressive regimens in pediatric patients after renal transplantation (Tx). Due to the side effects, steroid withdrawal may significantly improve the appearance and growth of children with renal grafts, but bears a substantial risk for late rejections. AIM OF THE STUDY: To investigate whether exclusion of subclinical acute rejection by renal histology in combination with a prolonged steroid withdrawal period is predictive of a successful outcome. PATIENTS AND METHODS: Ten children (5 females) with a median age of 12.3 (range 7.9-20.9) years and 1.8 (0.7-7.5) years after Tx with a stable graft function and a median calculated creatinine clearance (C(Cr)) of 71 (60.5-99.7) ml/min/1.73 m2 were included. All patients showed steroid toxicity signs. Immunosuppressive regimen included low-dose steroids (median 2.72 mg/m2) in all patients, in addition to cyclosporin A (CsA) and azathioprine in 8, CsA on its own and CsA combined with mycophenolate mofetil in one patient each. A graft biopsy was performed in 8 patients prior to the start of steroid withdrawal, which was done over a median period of 6 months. Renal function was calculated as creatinine clearance using the Schwartz formula. RESULTS: None of the biopsied grafts showed histologic signs of rejection. Cyclosporin A dosage and trough levels were not significantly different before and after steroid withdrawal. While steroid side effects improved in most of the patients after withdrawal, C(Cr) decreased significantly within a median observation time of 42 (11.4-49.3) months. This decrease was due to loss of renal function in 4 patients who had biopsy-proven rejection episodes at 21.6 (8.1-29.9) months after the start of steroid withdrawal. CONCLUSION: Slow steroid withdrawal in pediatric Tx patients using conventional immunosuppression reduces side effects, but bears a high risk of late rejection. A pre-withdrawal renal biopsy was not useful for the prediction of successful steroid withdrawal.     

Early function as the principal correlate of graft survival. A multivariate analysis of 200 cadaveric renal transplants treated with a protocol incorporating antilymphocyte globulin and cyclosporine

We examined the factors determining graft survival in 200 consecutive cadaveric renal transplants managed on a quadruple-therapy protocol: Minnesota antilymphoblast globulin, cyclosporine, azathioprine, and low-dose prednisone. Perioperative central venous pressure monitoring and volume expansion were emphasized. To avoid CsA nephrotoxicity in the early posttransplant period, patients were treated with ALG until renal function was established (a mean of 7 days). Therapeutic CsA levels were achieved before ALG was discontinued. Azathioprine was used to supplement CsA in patients with nephrotoxicity or rejection. Twelve-month graft survival was 85% (first transplants 86%, retransplants 79%), with patient survival of 95%. ALG was not associated with excessive clinical cytomegalovirus infections, which occurred in 5% of patients, or with malignancy. When 3 technical failures were excluded, an analysis of numerous factors in the pretransplant and peritransplant period revealed that the strongest correlate of one-year graft survival was early renal function. Grafts with delayed function (DF) had 75% survival, compared with 91% for grafts with good early function (EF). A multivariate analysis confirmed this association: the relative risk of graft loss was increased 2.86 times for DF compared with EF. The mechanism of the deleterious effect of DF was apparently multifactorial: the DF group, by definition, contained all the kidneys that never functioned, but some risk also persisted in kidneys that achieved function. One reason for this may be that DF kidneys that achieved function had higher mean serum creatinine values at 1 month: elevated serum creatinine values at 1 month were strongly associated with increased risk of graft loss regardless of initial function. There was also a higher number of rejection episodes diagnosed in the DF group. These observations suggest that early renal function is a major determinant of graft outcome and should be a target for efforts to further improve renal graft survival.     

Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients

INTRODUCTION: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus. METHODS: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured. RESULTS: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often. DISCUSSION: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.     

Prospective randomized study of azathioprine vs cyclosporine based therapy in primary haplo-identical living-donor kidney transplantation: 20-year experience

Background The achievements in short-term graft survival since the introduction of cyclosporine (CsA) have not been matched by improvements in long-term graft function. Chronic allograft nephropathy (CAN) remains the second most common cause of graft attrition over time, after patient mortality. We aimed to evaluate the long-term results of azathioprine vs CsA in live-donor kidney transplantation in a prospective randomized study. Methods We studied 475 renal transplant recipients who had had transplantations performed at the Urology and Nephrology Center, Mansoura University, before 1988 and who had received a primary immunosuppressive protocol consisting of either steroid and azathioprine (steroid/Aza; group 1, 300 patients) or steroid and CsA (steroid/CsA; group 2, 175 patients). Only adult primary renal transplant recipients aged between 18 and 60 years and with one haplotype HLA mismatch were included. All patients received kidneys from living-related donors, with previous donor nonspecific blood transfusions. The study was based on the long-term follow-up data of these renal transplant recipients. Comparative analyses included patient and graft survival rates, condition at last follow up, rejection (acute and chronic), and graft function (serum creatinine and creatinine clearance). Results The overall frequency of acute rejection episodes was not significantly different between the two groups. Graft survival rates were: group 1 vs group 2, 69% vs 58% at 5 years, and 52% vs 36% at 10 years, but at 20 years, graft survival rates had declined to 26% and 24%. No significant differences were encountered between the two groups regarding post-transplant malignancies, diabetes mellitus, hepatic impairment, or serious bacterial infections. Conclusions From this study we can conclude that the long-term result of historical conventional therapy (steroid/Aza) without induction therapy is effective for living-donor kidney transplants. In spite of the comparable graft function for the two groups, the steroid/CsA group experienced more hypertension, as well as many adverse reactions to CsA. Nowadays, since the introduction of induction therapy and the utilization of newer maintenance immunosuppressive agents – such as mycophenolate mofetil (MMF) and rapamycin – it is possible to achieve an excellent calcineurin inhibitors (CNI)-free regimen.     

A randomized prospective trial of anti-Tac monoclonal antibody in human renal transplantation.

Patient entry is now complete in a prospective trial of anti-Tac, a murine IgG2a monoclonal antibody directed against the p55 chain of the human IL-2 receptor, for the prevention of renal allograft rejection. Recipients of primary cadaver allografts were randomized to receive either anti-Tac (20 mg q.d. x 10 days beginning POD 1) plus low-dose CsA (4 mg/kg/day), azathioprine (2 mg/kg/day), and prednisone (30 mg q.d.), or conventional triple therapy with CsA (8 mg/kg/day), azathioprine, and prednisone. Forty patients were entered in each group, with current followup from 6 to 26 months. The results show a significant reduction in early rejection episodes in the anti-Tac-treated patients. During the 10-day treatment, 5 of 40 anti-Tac patients had rejection episodes, compared with 21 of 40 control patients (P less than 0.001). Anti-Tac significantly delayed the time to the first rejection (12.5 +/- 6.3 vs. 7.6 +/- 6.7 days) (P less than 0.05). Despite these effects, there were no differences in either actual or actuarial graft or patient survival between the two groups. Pneumonia, primarily CMV, developed in 5 treated and 4 control patients. In patients with functioning grafts mean serum creatinine at 3 months was 1.8 +/- 0.7 in the anti-Tac group and 2.0 +/- 0.8 in the control group (P = NS); at 12 months the values were 2.3 +/- 1.5 and 1.8 +/- 0.5, respectively (P = NS). The peak expression of IL-2 receptors on circulating T-cells was significantly lower in anti-Tac patients (15.1 +/- 3.6%) than in controls (21.9 +/- 4.5%) (P less than 0.05). Seven of 10 patients tested to date developed antimouse immunoglobulin antibodies, with antiidiotype shown in 6. These antibodies do not preclude subsequent treatment with OKT3. Five patients in this and previous anti-Tac protocols have received OKT3 for acute rejection despite known pretreatment antimouse antibodies, with resolution of rejection in all cases.     

WOFIE synergizes with calcineurin-inhibitor treatment and early steroid withdrawal in kidney transplantation

BACKGROUND: According to the window of opportunity for immunologic engagement (WOFIE) concept, as designed by R. Calne, the authors prospectively analyzed the effect of a 72-hr immunosuppressive window on graft function in renal transplant recipients. METHODS: Immunosuppressive therapy comprised tacrolimus (trough levels, 5-8 ng/mL after day 8 posttransplantation), daclizumab (1 mg/kg body weight at day 0 and 2, 4, 6, and 8 weeks posttransplantation), mycophenolate mofetil (MMF) (1-2 g/day), and prednisolone. All patients received an induction therapy including daclizumab, prednisolone, and MMF. WOFIE patients were stopped from immunosuppression for 72 hr posttransplant. Steroids were withdrawn in both groups 12 to 16 weeks after transplantation and dual therapy with MMF and low-dose tacrolimus ensued. RESULTS: Thirty renal transplant recipients (16 in the WOFIE group and 14 in the control group) have been enrolled since May 2000. Patient and graft survival were 93.8% and 87.5%, respectively, in the WOFIE group and 100.0% and 92.9% in the control group, respectively. One patient in the WOFIE group died of cytomegalovirus infection with stable graft function. There were no grafts lost because of acute rejection or primary nonfunction in either group. Patients treated according to the WOFIE protocol revealed less acute rejection episodes during the time of observation (first biopsy-confirmed acute rejection rate 12.5% in the WOFIE group vs. 42.9% in the control cohort). Whereas 92.1% of the WOFIE patients were successfully discontinued from steroids, permanent steroid withdrawal was achieved in only 60% of the control cohort. CONCLUSIONS: Initial interruption of immunosuppression was associated with a decrease of acute graft rejections. Subsequently, the authors postulate a synergistic effect on the immunosuppressive efficiency of calcineurin inhibitors when combined with an initial drug-free window.     

Influence of low-dose cyclosporine on the outcome of treatment with OKT3 for acute renal allograft rejection

The outcomes of 51 consecutive patients who received OKT3 for acute renal allograft rejection were analyzed. Thirty patients (group 1), previously maintained on cyclosporine, continued to receive 50% of their maintenance dose of CsA during OKT3; 21 patients (group 2) either never received CsA or temporarily discontinued CsA during OKT3. All patients received low doses of azathioprine and prednisone during OKT3. Rejection was reversed by OKT3 in 90% of patients in group 1 and in 62% of patients in group 2. Continuation of CsA during OKT3 did not increase the incidence of serious infections following OKT3. Serum creatinine concentrations in groups 1 and 2 were comparable before, during, and after therapy with OKT3 suggesting that low doses of CsA do not induce graft dysfunction during therapy with the monoclonal antibody. In a subset of 22 prospectively studied patients, anti-OKT3 antibodies developed in 2 of 13 patients (15%) who continued low-dose CsA during OKT3 and in 6 of 9 patients (67%) in whom CsA was temporarily discontinued during OKT3. We conclude that administration of low doses of CsA during therapy with OKT3 may reduce the formation of anti-OKT3 antibodies without compromising reversal of rejection by the monoclonal antibody and without increasing the short-term risk of infection or graft dysfunction.     

Cyclosporin A withdrawal in live related renal transplantation: long-term results

Cyclosporin A (CsA) withdrawal after 1 yr of stable graft function has been shown to be beneficial in cadaveric renal transplantation. This strategy could be even more suitable for 'immunologically advantaged' grafts as in live related renal transplantation. We report the long-term outcome of patients in a live related transplantation programme undergoing early (between 1989 and 1992) and late (1993 onwards) CsA withdrawal as compared with those on long-term low dose CsA (1993 onwards). Two-hundred and fifty-two patients were divided into three groups based on the following immunosuppressive protocol: group ECyW (n=99), early CsA withdrawal (9 months after transplantation); group LCyW (n=44), late CsA withdrawal (median 16 months, range 13--22 months after transplantation); and group LDCy (n=109), long-term low dose CsA. The median period of follow-up was 66 months after transplantation (range 43--84 months). There was no difference in the actuarial 6-yr patient or graft survival among the three groups. Acute rejection episodes were more frequent in ECyW (54.4%) than in LDCy (31.8%) and LCyW (23.8%) (p=0.001). The risk of developing late (> or =9 months) acute rejection was highest in ECyW 32/99 (32.3%) as compared with LCyW 8/44 (18.4%; p=0.08) and LDCy 8/109 (7.3%; p=0.0001). Of the 32 ECyW patients who developed acute rejection episodes after CsA withdrawal, 13 (40.6%) lost their grafts either due to uncontrolled acute rejection or to chronic rejection. Chronic rejection was higher in ECyW (24%) than in LCyW (11%; p=0.04) and LDCy (17%; p=0.17). Antihypertensive requirement was highest in patients maintained on low dose CsA. Graft function, as measured by serum creatinine levels, was significantly better in LCyW (1.24+/-0.4 mg%) as compared with ECyW (1.49+/-0.5 mg%) and LDCy (1.48+/-0.6 mg%). Early CsA withdrawal after live related renal transplantation is associated with a significant risk of acute rejection and subsequent chronic rejection. Slow withdrawal after 1 yr is safe and more economical than the long-term administration of low dose CsA.     

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.     

Misoprostol in renal transplant recipients: a prospective, randomized, controlled study on the prevention of acute rejection episodes and cyclosporin A nephrotoxicity

The aim of this prospective and randomized study was to determinewhether misoprostol, an analogue of PGE1, could decrease theincidence and the number of rejection episodes and could improvethe renal function over a 12-month follow-up, when given at400 µg/day for 12 months in renal transplant patients.Given the known side-effects and the additive cost of misoprostol,a benefit of the therapy should be a decrease of at least 50%in the incidence of rejection episodes in the treated group.Therefore, 60 consecutive renal transplant patients were randomizedto receive misoprostol or to receive aluminium and magnesiumhydroxide. Patients received steroids, azathioprine, antithymocyteglobulins, and cyclosporin A (CsA). CsA was randomly startedon day 0 or on day 8. At 12 months, no difference in the incidenceof rejection episodes was observed: 63.3% in the 30 patientsof the misoprostol + group versus 70.0% in the misoprostol-group(P=0.558 Mantel-Cox). The renal function, assessed by plasmacreatinine, inulin, and para-aminohippuric acid clearances,was not significantly different between misoprostol + and misoprostol-groups.No episode of CsA nephrotoxicity was observed in any patientof group one or group two. At 12 months, the mean dosage ofCsA was 4.9±0.28 mg/kg/day in the misoprostol+group versus4.52 ± 0.23 mg/kg/day in the misoprostol - group andthe trough level was not significantly different between thetwo groups. The graft survival rate at 12 months was 86.7% inthe Misoprostol+ group and 83.33% in the misoprostol- group.The trial failed to demonstrate a significant beneficial effectof misoprostol on the decrease of acute rejection episodes,on the prevention of CsA nephrotoxicity, or on the improvementof renal function over a 12-month period.     

An open randomized study comparing immunosuppression therapy initiated before or after kidney transplantation in haploidentical living recipients

BACKGROUND: Acute rejection is the most important risk factor for graft survival. Although many centers start immunosuppressive therapy days before the surgery in living donors, there is no systematic study concerning the possible advantages of this procedure. In this open randomized study, we compared the efficacy and safety of administration of cyclosporine (CSA; Neoral) and azathioprine before renal transplantation with the administration of the same schema after transplantation, in HLA haploidentical grafts. METHODS: Sixty renal transplant recipients of an HLA haploidentical allograft from living donors were randomized in two groups: (A) patients that started immunosuppression 3 d before transplantation (n = 30) and (B) those who started the drug schema on the first day after surgery (n = 30). We analyzed the incidence and severity of acute rejection, graft function and infection during the first 3 months after transplantation. RESULTS: The group of patients who started immunosuppression before had a mean trough level of CSA (299.70 +/- 154.03 ng/mL) in the expected range for an efficacious prevention of acute rejection at the surgery day. Thirteen patients (43.3%) in each group had acute rejection during the follow up (p = 1.00). Two grafts losses (3.3%) occurred, one in each group. Both groups had similar 3-month rejection-free graft survival (56.7 and 56.3%). The incidence of infection was also statistical comparable between groups A and B (56.7 vs. 46.7, p = 0.430). Graft function was similar in patients from both groups. CONCLUSIONS: Pre-transplant administration of immunosuppression did not reduce the incidence or severity of acute rejection episodes during the first 3 months of transplantation. Immunosuppressive drugs administered before engraftment did not increase the incidence of graft dysfunction or infection.     

肾移植后应用雷帕霉素口服液的两年临床观察

目的观察肾移植后应用雷帕霉素(Rap)进行免疫抑制治疗的有效性和安全性。方法将接受首次尸体肾移植的患者50例随机分为两组,研究组30例,术后采用Rap、环孢素A(CsA)和泼尼松(Pred)预防急性排斥反应;对照组20例,术后采用硫唑嘌呤、CsA及Pred预防急性排斥反应。两个组CsA和Pred的用法和用量相同。密切观察和详细记录手术后发生的不良事件,并定期对实验室各项指标进行分析。结果研究组如期完成观察的例数为26例,对照组为18例。在观察的104周内,两组的人、肾存活率为100%;研究组和对照组急性排斥反应的发生率分别为3.7%(1/27)和25.0%(5/20),经激素冲击治疗后逆转;研究组在维持血CsA浓度与对照组相当的情况下,其CsA的用量低于对照组;研究组血胆固醇总量和甘油三酯的水平明显高于对照组。结论Rap用于预防肾移植后急性排斥反应是安全有效的,其与CsA合用可减少CsA的用量,Rap的副作用主要是导致血脂升高。