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.     

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).     

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.     

Impact of the variability of cyclosporin A trough levels on long-term renal allograft function.

BACKGROUND: Among renal allograft recipients, there is a considerable variability in cyclosporin A (CsA) trough levels. Some of the CsA metabolites are pharmacologically active. The variability of polyclonal CsA trough levels may contribute to the fact that long-term renal allograft survival is still not satisfactory. In a retrospective, single-centre study, we investigated the influence of the variability of polyclonal CsA trough levels on long-term renal allograft function. METHODS: Patients (n=381) received double immunosuppression consisting of CsA and methylprednisolone (MP). For each patient the CsA coefficient of variation (CCV) and the mean CsA trough level during the observation period (5 years) were calculated. Based on receiver operating characteristic (ROC) analysis, patients were divided into two groups: group I, CCV <28.05%, n=231; group II, CCV >28.05%, n=150. Additionally, patients were divided into three groups according to their mean CsA trough level: group A, <270 ng/ml, n=50; group B, 270-370 ng/ml, n=282; group C: >370 ng/ml, n=49. RESULTS: Compared to group I, patients in group II experienced a higher incidence of acute rejection episodes (40.7% vs 29.4%, P=0.02), reduced 5-year graft survival (81.1% vs 93.3%, P=0.002), and higher serum creatinine levels (1.7+/-1.2 mg/dl vs 1.4+/-0.5 mg/dl, P=0.03). In patients with low mean CsA trough levels, the incidence of acute rejection episodes was elevated (group A vs B, 50.0% vs 30.9%, P=0.008) and 5-year graft survival was reduced (group A vs B, 79.8% vs 89.5%, P=0.005). Multiple logistic regression analysis confirmed that the risk of graft failure within 5 years after transplantation was markedly elevated in group II (RR: 6.2, P=0.013) and in group A (RR: 8.9, P=0.008). Whereas the effect of CCV on 5-year graft survival was still evident in patients with normal or high mean CsA trough levels (>270 ng/ml, 81.9% vs 94.8%, P=0.0005), graft survival was independent from CCV in patients with low mean CsA trough levels (<270 ng/ml, 77.0% vs 81.7%, P=NS). CONCLUSIONS: Both, the intra-individual variability and the mean of polyclonal CsA trough levels influence long-term renal allograft survival. Targeting at sufficiently high mean CsA levels with a low intra-individual variability may help to further improve long-term renal allograft survival.     

Tacrolimus plus low-dose mycophenolate mofetil in renal transplant recipients: better 2-year graft and patient survival than with a higher mycophenolate mofetil dose

OBJECTIVES: Mycophenolate mofetil (MMF) has become more widely prescribed in recent years, but its adverse effects on the gastrointestinal system and bone marrow restrict its use in certain settings. The aim of this study was to compare the demographic features and clinical data for 173 renal transplant recipients who received tacrolimus (TAC) plus 1 g/d MMF (group I, n = 112) versus TAC plus 2 g/d MMF (group II, n = 61 patients) over a 2-year period. Each patient received similar TAC doses. METHODS: We compared demographic data and clinical data for each case: acute rejection (AR) episodes, chronic rejection (CR) episodes, death, graft loss, development of posttransplantation diabetes mellitus (PTDM), and posttransplantation hypertension rates. RESULTS: Demographic features were similar. There were also no significant differences between groups I and II with respect to number of AR episodes (17/112 vs 12/61, respectively), number of CR episodes (4/112 vs 1/61, respectively), PTDM, and hypertension rate (P > .05). Kaplan-Meier survival analysis revealed 2-year graft survival rates of 94% in group I versus 83% in group II. The corresponding 2-year patient survival rates were 100% in group I versus 91% in group II. The graft survival and patient survival rates in group I were significantly higher than those in group II (log-rank 0.005 and 0.001, respectively). CONCLUSIONS: The 2-year graft and patient survival rates for the renal transplant recipients in this study suggest that the combination of a full TAC dose with 1 g/d MMF is a better choice than 2 g/d MMF.     

sCD30 and neopterin as risk factors of chronic renal transplant rejection: impact of cyclosporine A, tacrolimus, and mycophenolate mofetil

High pretransplantation sCD30 levels have been shown to be associated with lower 5-year kidney graft survival in mainly Cyclosporine A (CsA)-treated recipients (Collaborative Transplant Study database). To analyze the effect of different immunosupressive regimens (CsA/Azathioprine [Aza], CsA/Mycophenolate Mofetil [MMF], Tacrolimus [Tacr]/Aza) on sCD30, we assessed serum sCD30 and neopterin together with in vitro cytokine responses in a prospective randomized study of 84 renal transplant recipients before, 4 months, and 1 year after transplantation. Panel-reactive antibody (PRA) formation, HLA matching, ATG induction therapy, and acute rejections had no impact on sCD30 levels, whereas cytomegalovirus (CMV) infections induced an up-regulation of sCD30 4 months posttransplantation (P = .003). Whereas MMF showed no effect on sCD30 compared with Aza therapy, we found a significant impact of Tacr versus CsA treatment (1-year sCD30 ≥60 U/mL: 14/42 (33%), CsA; 1/38 (3%), Tacr; P < .0005). Chronic rejection 2 years posttransplantation was associated with elevated 1-year sCD30 (P = .001) and neopterin levels (P = .006). Our data indicate that the Th2 activation marker sCD30 provides a risk factor for chronic rejection independent of classical immunological risk factors and may be down-regulated using Tacr treatment.     

Predictive factors of acute rejection after early cyclosporine withdrawal in renal transplant recipients who receive mycophenolate mofetil: results from a prospective, randomized trial

The aim of this randomized, open-labeled trial was to compare the incidence of acute rejection after an early (3 mo posttransplantation) withdrawal of cyclosporine (CsA) or mycophenolate mofetil (MMF) in renal transplantation. Among 218 eligible recipients, 108 nonsensitized, rejection-free patients who were under a triple drug regimen (CsA-MMF-prednisone) and had received a first kidney from a deceased donor were enrolled. At 3 mo after graft, they were gradually withdrawn from CsA (MMF group, n = 54) or MMF (CsA group, n = 54). A graft biopsy and a pharmacokinetic study of CsA and mycophenolic acid were systematically performed before the randomization. At 1 yr, graft and patient survival rates were 100% in each group. Renal function was improved in the MMF group compared with the CsA group (Cockcroft calculated clearance 64.7 +/- 18.7 versus 56.5 +/- 18.0 ml/min; P = 0.023). However, the probability of acute rejection was higher in the MMF group (18.5 versus 5.6%; P = 0.045). The 10 patients who developed acute rejection after CsA withdrawal had a significantly higher incidence of borderline changes on the randomization biopsy than the 44 rejection-free patients (five of 10 versus eight of 44; P = 0.034), and they displayed a lower area under the curve of mycophenolic acid (43 +/- 9 versus 58 +/- 22 mg/h per L; P = 0.045). Multivariate analysis confirmed that borderline changes and area under the curve of mycophenolic acid were significant risk factors of acute rejection after CsA discontinuation. It is concluded that a systematic graft biopsy and a pharmacokinetic study of mycophenolic acid are needed to reduce the risk for acute rejection after CsA withdrawal.     

Optimization of the immunosuppressive protocol after lung transplantation.

BACKGROUND: The successful use of tacrolimus (Tac)-based immunosuppressive therapy in organ transplantation and our own positive experience in heart transplantation led us to investigate regimens including this agent at our center for lung transplantation. METHODS: From 1991 to 1998, 86 patients underwent lung transplants at our center and 78 of them were included in this analysis. The first 34 patients were treated with cyclosporin (CsA), azathioprine (Aza), and rabbit antilymphocyte globulin; the subsequent 30 patients received Tac with Aza, and the most recent 12 patients Tac with mycophenolate mofetil (MMF). In addition, all patients received prednisone. RESULTS: The number of acute rejection episodes per 100 patient days was 1.5, 0.6, and 0.3 for three treatment groups, respectively. Similarly, the incidence of refractory acute rejection per 100 patient days was lower in both Tac groups (0.20, 0.03, and 0, respectively). Freedom from acute rejection was highest in the Tac-MMF group (P=0.0037 vs. Tac/Aza, P=0.0007 vs. CsA/Aza). Freedom from recurrent acute rejection was significantly higher in both Tac groups (P=0.027 Tac/ Aza vs. CsA/Aza and P=0.025 Tac/MMF vs. CsA/Aza). The incidence of infections per 100 patient days was similar (0.8, 0.5, and 0.8) in all three treatment groups, with a similar distribution of fungal, bacterial, and viral infections. Freedom from infection also showed no difference. The survival rate was significantly higher for the Tac population, with actuarial 1- and 3-year survival rates of 93% and 71%, compared with the CsA group (71% and 51%, respectively, P=0.04). Prevalence of renal dysfunction (creatinine >2.0 mg/ dL) was 18%, 13%, and 0% in the 3 treatment groups, respectively. The development of glucose metabolism disorders was lower in the CsA group than in the Tac-Aza group (15% vs. 27%, P<0.05). CONCLUSIONS: Tac-based immunosuppressive therapy results in a lower rate of acute rejection after pulmonary transplantation, with similar infection rates and a slightly higher incidence of new onset diabetes mellitus compared with CsA-based therapy.     

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.     

Long-term, low-dose cyclosporine treatment of renal allograft recipients. A randomized trial

Ninety-two adult renal allograft recipients, receiving baseline immunosuppression with CsA and prednisone, were assigned randomly to one of the following regimens. CsA was discontinued (D/C group) in 47 recipients who were then maintained on Aza and prednisone; or Aza was added to continued low-dose CsA and prednisone (triple drug [TD] group) in 45 patients. Entry into the study required an absence of rejection and a stable creatinine for at least four months prior to randomization. The mean month of randomization was 8.34 +/- 2.9 for the D/C group, and 7.2 +/- 3.2 for the TD group. Following randomization, a significantly greater rate of rejection (P less than .01) was observed in the D/C group (40%) than in the TD group (13%). With a mean follow-up of 30 months, 41/47 of D/C allografts (87.2%) and 39/45 TD allografts (86.6%) were functioning. Nevertheless, rejection had a persistent adverse effect on allograft function, in both the D/C and TD groups, up to 36 months following randomization. Parameters such as donor-type and rejection prior to randomization did not identify recipients at risk for rejection following randomization. Therefore, although the CsA withdrawal regimen might be ideal, the opportunity to select appropriate candidates remained elusive. In contrast, the safety of the TD regimen became apparent. Neither significant nephrotoxicity nor hypertension was observed, and the opportunity for less daily prednisone was evident. Despite its additional cost, the TD regimen utilizing indefinite low-dose CsA, is preferred.     

Antilymphocyte globulin versus OKT3 induction therapy in cadaveric kidney transplantation: a prospective randomized study.

Different induction therapies have been used in renal transplantation to avoid cyclosporine (CsA) nephrotoxicity and early acute graft rejection. This study compares the efficacy of a short course of prophylactic OKT3 to that of antilymphocyte globulin (ALG) in preventing acute renal allograft rejection when administered concomitantly with CsA and steroids. Between March 1988 and December 1990, 140 first-cadaver renal transplant recipients were randomly allocated to two immunosuppression groups--ALG group (n = 68): ALG 15 mg/kg just before transplant surgery, ALG 12 mg/kg the first day after transplant, followed by four doses of 10 mg/kg on alternate days; and OKT3 group (n = 72): OKT3 5 mg just before transplant, followed by four doses of 5 mg/d. Both groups included low-dose CsA and steroids. The incidence of rejection during the first 3 months after transplantation was 15% in the ALG group and 19% in the OKT3 group (NS). Kaplan-Meier estimates of patients free of rejection at 2 years was 85% in the ALG group and 77% in the OKT3 group (NS). The 3-year actuarial graft survival was 82% and 85% (NS), and 3-year patient survival was 97% and 98% (NS), in the ALG and OKT3 groups, respectively. These results indicate that the concomitant association of CsA and ALG or OKT3 constitutes a safe and effective therapeutic strategy that provides a low incidence of rejection and gives good results for patient and graft survival.     

The incidence and impact of early rejection episodes on graft outcome in recipients of first cadaver kidney transplants.

The objective of this study was to define the incidence and significance of acute rejection occurring in the first year following transplantation. The influence of contemporary induction immunosuppression on rejection, as well as the effect of rejection on graft and patient loss, renal function, and maintenance immunosuppression during the first year in 110 recipients of first cadaver renal transplants were analyzed. All patients received CsA, Aza, and prednisone for 30 days with withdrawal of Aza at 30 days and then prednisone at 105 days; 57 patients were prospectively randomized to receive ALG (Merieux) until serum creatinine was less than 300 mumol/L. Short-term ALG administration did not influence the incidence, severity, nature, or outcome of rejection episodes. Fifty-five (50%) patients had at least 1 rejection in the first 90 days. All patients with delayed graft function and 7/8 (88%) sensitized patients (current PRA greater than 50%) had at least 1 rejection episode; 71% (n = 35) of all rejection episodes occurred in the first 30 days posttransplant. Patients rejection free at 90 days remained rejection free the entire first year. Graft loss was 18% for rejections in the first month, 13% for rejections occurring later (P = NS); 20% (n = 11) of patients had a second rejection and 1% (n = 2) had a third rejection. The risk of graft loss was 9% with a first rejection, 38% with a second rejection, and 50% with a third rejection. Of 12 (22%) rejections that were steroid resistant, 10 (83%) were reversed with OKT3. One-year graft survival for patients without rejection, with steroid-sensitive rejection, and with steroid-resistant rejection was 96%, 88% (P = ns), and 58% (P less than 0.001), respectively; 1 year SCr was 168 +/- 93, 196 +/- 77 (P = ns), and 268 +/- 96 microMol/L (P less than 0.05), respectively. Patients free of rejection and with stable renal function continued to do well on maintenance CsA monotherapy, and they were more likely to be on CsA monotherapy than those with rejection episodes (P less than 0.01).     

Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination

BACKGROUND: Sirolimus (Rapamune; SRL) in combination with cyclosporine (CsA) reduces the incidence of acute rejection episodes in renal allograft recipients. This study evaluated whether renal function could be improved by elimination of CsA from an SRL-based regimen. METHODS: This phase 2, open-label, controlled, randomized study was conducted at 17 centers in the United States and Europe. Two hundred forty-six first cadaveric renal allograft recipients were enrolled, and 197 were randomized to full-dose CsA (microemulsion) plus fixed-dose SRL (2 mg/day; group A, n=97) or reduced-dose CsA plus concentration-controlled SRL (troughs 10-20 ng/mL; group B, n=100). Most patients with acute tubular necrosis-delayed graft function that resolved later than posttransplantation day 7 were not randomized but were assigned to a third group (nonrandomized, n=49) and received up to 5 mg per day of SRL as part of their individualized treatment regimen. All patients received standard doses of corticosteroids. At the end of posttransplantation month 2, eligible patients (those not treated for rejection within 3 weeks) in group B had CsA tapered and eliminated over the subsequent 4 to 6 weeks. RESULTS: At 12 months after transplantation, renal function was significantly better in the CsA-elimination arm. In patients who were on therapy and who had not experienced an acute rejection episode before month 6, serum creatinine level was significantly lower (1.38 mg/dL vs. 1.82 mg/dL, P < 0.001) and calculated glomerular filtration rate (Nankivell method) was significantly higher (73.5 mL/min vs. 57.1 mL/min, P < 0.001) in group B than in group A. In the intention-to-treat population, rates of biopsy-confirmed acute rejection at 12 months were similar between groups A and B (18.6% vs. 22.0%, respectively; P = 0.598). In addition, graft survival (92.8% and 95.0%) and patient survival (96.9% and 96.0%) rates at 12 months were not significantly different between groups A and B, respectively. Furthermore, there were no significant differences between black and nonblack recipients within treatment groups in terms of rejection rates and graft survival at 12 months. Black recipients in group B had better serum creatinine levels at 12 months compared with black recipients in group A (1.55 mg/dL vs. 2.69 mg/dL, respectively, P = 0.011), as did nonblack recipients in group B compared with nonblack recipients in group A (1.53 mg/dL vs. 1.75 mg/dL, respectively, P = 0.055). Black patients in group A had higher mean serum creatinine levels (2.69 mg/dL) than nonblack patients in group A (1.75 mg/dL, P = 0.028). Hypertension, edema, hypomagnesemia, and dyspnea were reported significantly less frequently in patients randomly assigned to undergo CsA elimination compared with patients in group A (P < 0.05); group B patients had a significantly greater (P < 0.05) incidence of abnormal liver function tests, diarrhea, hypokalemia, and thrombocytopenia. CONCLUSION: Concentration-controlled SRL with early elimination of CsA is safe and results in improved renal function. Reduced exposure to CsA does not result in a clinically significant increase in the incidence of acute rejection episodes. This is true for both black and nonblack recipients. SRL may be used to reduce the exposure of renal allograft recipients to the nephrotoxic effects of CsA.     

骁悉、环孢素A和泼尼松在肾移植受者联合应用中最适剂量探讨

目的探讨国人肾移植后骁悉(MMF)、环孢素A(CsA)和泼尼松(Pred)联合应用的最适剂量。方法比较常规剂量组(104例)和低剂量组(96例)患者肾移植术后免疫抑制剂用量和急性排斥反应、肺部感染发生率和人/移植肾生存率。结果MMF和CsA用量在术后3个月、Pred用量在术后6个月内常规剂量组明显高于低剂量组。常规剂量组在6个月内包括活检证实、临床推断和亚临床排斥,其总的急性排斥发生率为17.3%,而低剂量组为19.8%,两组间差异无显著性意义(P=0.55)。两组患者在6个月内肺部感染发生率分别为40.4%和11.5%(P<0.0001),尤其是重症肺部感染发生率常规剂量组明显要高(26.9%比5.2%,P<0.0001)。两组患者人/肾1年生存率分别为87.4%/85.5%和97.9%/96.9%(P均<0.01)。排除感染所致的带功死亡后两组患者人/肾1年生存率差异无显著性意义。结论低剂量MMF、CsA和Pred联合应用并不增加急性排斥率、亚临床排斥发生率、排斥治疗逆转率和排斥反应的严重程度,但明显降低肺部感染发生率和病死率。     

Causes of graft loss beyond two years in the cyclosporine era

While CsA has improved renal-allograft survival rates in the first 2 years compared with Aza, Terasaki's multicenter study (1) failed to show any difference in long-term graft survival in CsA-Pred versus Aza-Pred-treated recipients. The present study examines the long-term graft-survival rates at a single center using CsA immunosuppression and seeks to discern the causes of 58 graft losses among 343 patients with functioning grafts beyond 2 years posttransplantation. The 6-year primary and cadaveric actuarial graft survival at this institution is 59% with a graft half-life of 10 years, which is better than the 40% and 7.7 years, respectively, reported by Terasaki (1) for primary cadaveric recipients on Aza-Pred. It is also better than the 41%, 6-year survival and 5.5-year half-life for primary cadaveric recipients treated with CsA-Pred as reported in the multicenter study. (1) Less experience with the use of CsA may explain the latter comparison. Primary LRD grafts at this institution (2/3 haploidentical) have a 6-year actuarial survival of 77% and a half-life very closely approximating that of HLA-identical LRD grafts under Aza (23.4 years). These results demonstrate that CsA mitigates the effects of HLA incompatibility to reduce graft survival. The most common cause of graft loss beyond 2 years was chronic rejection (36.2%) followed by noncompliance (27.6%). Patient deaths resulted in 13 of the 58 graft losses; most of the deaths were related to cardiovascular diseases. Only 3 patients died from causes that could be attributed to CsA immunosuppression; 2 from sepsis and 1 from viral hepatitis. Acute rejection caused 8.6% of the graft losses on continuous CsA therapy. When immunologic risk factors were analyzed, the entire graft-loss group had a significantly higher proportion of retransplant patients than the graft-survival group (P less than 0.005), suggesting that prior transplantation imposes a higher risk for graft loss not only acutely but long term as well. However, retransplanted patients were significantly less likely to lose their grafts because of noncompliance (P less than 0.005). Male patients were found to be significantly more noncompliant.     

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.     

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.     

Outcome of cadaveric renal transplant patients treated for 10 years with cyclosporine: is chronic allograft nephropathy the major cause of late graft loss?

BACKGROUND: The introduction of cyclosporine (CsA) has improved the short-term outcome of renal transplantation, but its effect on the long-term survival is not well known. METHODS: We analyzed 128 cadaveric first renal transplant recipients with CsA and prednisone as basal immunosuppression followed for at least 10 years, and we have compared them with a group of 185 historical patients treated with azathioprine (Aza) and prednisone. RESULTS: The 1-year graft survival was 83% in the CsA-treated patients and 68% in the Aza-treated patients (P<0.025), and the differences were significant for 3 years. Acute rejection accounted for the 10.9% of losses in CsA-treated patients and for 23.8% of losses in Aza-treated patients (P=0.046). Chronic allograft nephropathy was the cause of graft losses in 40.6% and 16.8% of cases (P=0.008). Patient survival at 5 years was 88% in CsA-treated patients and 79% in the Aza-treated patients (P<0.025). When analyzing the data of the 64 CsA-treated patients and the 84 Aza-treated patients with one functioning graft at 10 years, mean serum creatinine values were significantly higher in the CsA-treated patients at all time points but the increases were not significantly different. At 10 years, mean blood pressure was higher (P=0.002), and hypercholesterolemia (P=0.011) and hyperuricemia (P=0.000) were more prevalent in the CsA-treated patients. CONCLUSIONS: CsA resulted in a better short-time patient and graft survival that was not maintained in the long-term outcome. Chronic allograft nephropathy was the leading cause of graft loss in CsA-treated patients. Graft function was poorer in the CsA-treated patients, but its decline was similar in the two groups.     

The long-term outcomes of transplantation of kidneys with multiple renal arteries

Kidneys with multiple renal arteries are increasingly procured for transplantation. To compare the outcomes of kidney transplantation using allografts with multiple arteries, we studied long-term graft function and survival according to their number of arterial anastomoses during an 18-year period from July 1, 1990, through December 31, 2008, in which only the recipient's external iliac artery or internal iliac artery was used for anastomosis (n = 1186). The recipients were divided into four groups: group I, single renal artery with single anastomosis (n = 890, 75.0%); group Il, multiple renal arteries, single anastomosis (n = 26, 2.2%); group Ill, multiple renal arteries, multiple anastomoses (n = 236, 19.9%); and group IV, polar artery ligation (n = 34, 2.9%). We compared the following variables patient and graft survivals; mean creatinine levels at 1 and 6 months, as well as 1-, 3-, and 5-years posttransplant; the number of acute rejection episodes, and the rates of vascular and urologic complications. The creatinine values and incidences of acute rejection episodes did not differ significantly (P = 0.399 and P = 0.990, respectively). There were no significant differences among the four groups in graft survival (P = 0.951), patient survival (P = 0.751), incidence of vascular (P = 0.999) or urologic complications (P = 0.371). The four groups were subdivided according to the recipient arterial anastomosis to the main graft renal artery. The subdivided groups showed no significant differences in graft or patient survival, or complications rates. The results indicated that multiplicity of renal arteries in kidney transplantation did not adversely affect allograft or patient survival compared with single renal artery transplantation. Moreover, the type of the arterial anastomosis (main renal artery end-to-end anastomosed to internal iliac artery or end-to-side anastomosed to external iliac artery appeared to not affect graft or patient survival or the incidence of vascular or urologic complications.