Mycophenolate mofetil vs azathioprine in a large population of elderly renal transplant patients.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to decrease acute rejection episodes after kidney transplantation, and has been associated with better graft and patient survival vs azathioprine (AZA). Previous studies reported a higher risk of death due to infection in elderly recipients treated with MMF-based immunosuppression. METHODS: We analysed 5069 elderly ( > 65 years of age) primary renal allograft recipients treated with either MMF or AZA reported to the Scientific Registry of Transplant Recipients between 1988 and 2000, and compared rates of acute rejection, late acute rejection, graft survival, death-censored graft survival, patient survival and death with a functioning graft. RESULTS: In Cox proportional hazard models, MMF was associated with lower rates of late acute rejection with 12 (RR = 0.72, P = 0.11) and 24 months (RR = 0.50, P = 0.028) of continuous therapy. In univariate analysis (Kaplan-Meier), MMF was associated with improved patient (P = 0.0003) and graft (P<0.0001) survival vs AZA, and trends toward improved patient and graft survival in multivariate analyses. CONCLUSIONS: These findings demonstrate the efficacy of MMF-based immunosuppression in elderly transplant recipients and do not suggest an increased risk of death compared to treatment with AZA.     

Triple immunosuppression with tacrolimus in pediatric renal transplantation: single-center experience

AIM: In this single-center cohort, we retrospectively analyzed the efficacy and safety of tacrolimus in pediatric renal transplantation. METHODS: We examined the medical records of 22 consecutive renal transplantation recipients (12 boys, 10 girls) receiving tacrolimus, to evaluate occurrence of acute rejection (AR) episodes, glomerular filtration rates (GFR), and side effects. RESULTS: The mean recipient age was 15.07 +/- 3.96 years. Seven grafts came from cadaveric, and 15 from living related donors. The patients were placed on immunosuppression with prednisolone and tacrolimus plus azathioprine (n = 8) or mycophenolate mofetil (MMF) (n = 12) or enteric-coated mycophenolate sodium (n = 2). Eighteen patients received basiliximab on days 0 and 4. There were three AR episodes at 5, 9, and 12 months. Mean GFR at the end of 1 and 2 years were 97.1 +/- 24.0 mL/min/1.73 m(2) and 116.9 +/- 42.2 mL/min/1.73 m(2), respectively. There was no graft loss. Hypertension, hyperlipidemia, and hyperglycemia were present in 14 (63.6%), 3 (13.6%), and 3 (13.6%) patients, respectively, without gingival hyperplasia, tremor, or hypertrichosis. Supraventricular tachycardia was noticed in five patients (22.7%), three of whom needed antiarrhythmic drugs (13.6%). CONCLUSION: Our single-center experience with tacrolimus, steroid plus azathioprine or MMF or enteric-coated mycophenolate sodium regimen in pediatric kidney recipients showed a low rate of AR with excellent graft survival and function at 1 and 2 year posttransplantation. The increased rate of supraventricular tachycardia in this regimen had not been previously reported; this association merits further studies.     

Effective immunoprophylaxis with basiliximab plus triple therapy in renal transplantation: five-year single-center experience

We studied prospectively the efficacy and safety of basiliximab combined with triple immunosuppression in adult recipients of > or = 1 HLA-mismatched deceased donor renal grafts. All studied patients received equal immunosuppressive drugs: 20 mg infusion of basiliximab on day 0 and on day 4, cyclosporine microemulsion (Neoral), mycophenolate mofetil, and methylprednisolone. An analysis of 1-year data assessed the incidence of acute rejection episodes, safety of this therapy, renal graft function, and patient and graft survivals. One hundred seventy-two patients were studied. The HLA-antigen mismatches were 2.9 +/- 0.9 (mean +/- SD), and the cold ischemia time was 22.0 +/- 7.5 hours. Fifty-three (31.5%) patients experienced delayed graft function. At 12 months, 5 (3.0%) patients experienced acute rejection. Six renal grafts were lost, but not from rejection. Two patients died. Sixty-six infections required treatment in the hospital. One carcinoma of cervix (in situ) and two basal cell carcinomas of skin were detected. Hypersensitivity reactions and cytokine-release syndrome were not observed. At 12 months, serum creatinine was significantly higher (119 +/- 46 micromol/L; P < .001) in patients with delayed graft function than in patients with immediate graft function (99 +/- 26 micromol/L). Patient and graft survivals were 98.8% and 97.1%, respectively. Basiliximab combined with this triple therapy was an efficient and safe immunosuppression strategy, demonstrated with very low incidence of acute rejections, an acceptable adverse event profile, excellent graft function, and high short-term survival rates in adult recipients of deceased donor renal transplant.     

Mycophenolate mofetil: ten years' experience of a renal transplant unit

Mycophenolate mofetil (MMF) use in renal transplantation has allowed a significant decrease in early acute rejection rates. We retrospectively evaluated the incidence of acute rejection episodes, renal function at the first year posttransplant, patient and graft survivals, cytomegalovirus (CMV) infection rate, influence of the degree of sensitization, and number of MHC antigen mismatches on graft survival in two groups of patients receiving either MMF or azathioprine. Group 1 included 149 patients receiving cyclosporine, MMF, and prednisolone; group 2 included 191 patients receiving cyclosporine, azathioprine, and prednisolone. The two groups did not differ in terms of age, sex, degree of sensitization (expressed as percentage of antibodies reactive to panel), MHC mismatch number, cold ischemia time, donor age, or anti-thymocyte globulin induction. In group 1 (MMF) there was a significant decrease in early acute rejection rate (19% vs 57%, P < .0001), longer graft survival at 10 years (92% vs 75%, P = .006), and higher rate of CMV infection (22% vs 12%, P = .004). Renal function at the first year posttransplant and patient survival during follow-up did not differ between the groups. The degree of sensitization influenced graft survival in group 2. The number of MHC mismatches did not influence graft survival in either group. With MMF, there was a significant reduction in early acute rejection rate, a significant increase in graft survival at 10-year follow-up, and diminished impact of the degree of sensitization on graft survival.     

Mycophenolate mofetil tolerability and dose changes in tacrolimus-treated renal allograft recipients

Mycophenolate mofetil (MMF) reduces acute rejection episodes (AREs) and may be associated with better renal graft survival than azathioprine. However, MMF-related adverse events are frequent; dose reduction or even withdrawal are quite common. Between 1999 and 2003, 115 renal transplantation patients were treated with tacrolimus, MMF, and steroids. An observational study was undertaken until graft loss (n = 7), death with a functioning graft (n = 2), or October 31, 2005 (mean follow-up-50 months). We assessed MMF dose reductions due to adverse events with the possible consequences on AREs and graft function. Treated acute ARE occurred in 11.3% of recipients, all of which were steroid-responsive. The median MMF initial daily dose was 1000 mg. In 44 patients (38.3%), the MMF dose was not changed; in 48 (41.7%) it was reduced; and in 23 (20%), withdrawn. The causes for dose modification were diarrhea (n = 33, 28.7% of all patients), leukopenia (n = 22, 19.1%), both of these (n = 7, 6.1%), or other events (n = 9, 7.8%). No AREs were attributed to MMF dose changes. Tacrolimus blood levels were higher at 3 years and serum creatinine values at 4 years among patients with dose changes (8.43 +/- 2.42 vs 7.37 +/- 2.23 ng/mL; P = .051 and 1.75 +/- 0.71 vs 1.48 +/- 0.38 mg/dL; P = .038, respectively). The need for MMF dose reduction or withdrawal was frequent in our patients with diarrhea or leukopenia during treatment with tacrolimus, MMF, and steroids. These adverse event-related changes were not associated with AREs, but produced deleterious effects on long-term graft function.     

Mycophenolate mofetil in pediatric renal transplantation

INTRODUCTION: Since kidney transplantation is the therapy of choice for children with end-stage renal disease (ESRD), we investigated the effects of mycophenolate mofetil (MMF) in pediatric renal transplantation. METHODS AND SUBJECTS: Two hundred sixteen children received renal transplants between 1985 and 2003: 100 patients received MMF with cyclosporine and prednisolone (cases), and 116 patients, azathioprine with cyclosporine and prednisolone (controls). RESULTS: The MMF group (100 patients) showed better graft survival and function than the AZA group (116 patients). Patients who received MMF immediately after transplantation experienced less graft loss and acute rejection episodes in the first 3 months after transplantation (P < .05). Patients who received MMF at the time of diagnosis of chronic rejection had stable renal function and remarkably better graft survival than those with chronic rejection who received AZA instead of MMF (P < .05). CONCLUSION: This study suggests that MMF may stop persistent graft dysfunction in chronic rejection, improving graft survival in the short and long terms posttransplantation.     

Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection

BACKGROUND: Mycophenolate Mofetil (MMF) has been shown to significantly decrease the number of acute rejection episodes in renal transplant recipients during the 1st year. A beneficial effect of MMF on long-term graft survival has been more difficult to demonstrate. This beneficial effect has not been detected, despite the impact of acute rejection on the development of chronic allograft nephropathy and experimental evidence that MMF may have a salutary effect on chronic allograft nephropathy independent of that of rejection. METHODS: Data on 66,774 renal transplant recipients from the U.S. renal transplant scientific registry were analyzed. Patients who received a solitary renal transplant between October 1, 1988 and June 30, 1997 were studied. The Cox proportional hazard regression was used to estimate relevant risk factors. Kaplan-Meier analysis was performed for censored graft survival. RESULTS: MMF decreased the relative risk for development of chronic allograft failure (CAF) by 27% (risk ratio [RR] 0.73, P<0.001). This effect was independent of its outcome on acute rejection. Censored graft survival using MMF versus azathioprine was significantly improved by Kaplan-Meier analysis at 4 years (85.61% v. 81.9%). The effect of an acute rejection episode on the risk of developing CAF seems to be increasing over time (RR=1.9, 1988-91; RR=2.9, 1992-94; RR=3.7, 1995-97). CONCLUSION: MMF therapy decreases the risk of developing CAF. This improvement is only partly caused by the decrease in the incidence of acute rejection observed with MMF; but, is also caused by an effect independent of acute rejection.     

Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years

BACKGROUND: Mycophenolate mofetil (MMF)-based immunosuppression has reduced the acute rejection rate in adults and in children in the early posttransplantation period. Three-year posttransplantation results have been reported for adults but not for children thus far. In the present open-labeled study, patients 18 years old and younger were evaluated prospectively for up to 3 years after renal transplantation (RTX). METHODS: Eighty-six patients receiving MMF in combination with cyclosporine and prednisone without induction were evaluated for patient survival, transplant survival, renal function, arterial blood pressure, adverse events, and opportunistic infections. These patients were compared with a historic control group (n=54) receiving azathioprine (AZA) instead of MMF. RESULTS: Patient survival after 3 years was 98.8% in the MMF group and 94.4% in the AZA group (NS). Intent-to-treat analysis of graft survival demonstrated superiority for MMF (98% vs. 80%; P<0.001). Cumulative acute rejection episodes occurred in 47% of patients in the MMF group versus 61% in the AZA group (P<0.05). Renal function was not significantly different, neither after 3 years nor in the long-term calculation. Antihypertensive medication was administered to 73% to 84% of patients, similar in both groups. Opportunistic infections were recorded only for MMF. Infection rates were comparable to those reported in adults. CONCLUSIONS: These results suggest that MMF is safe and beneficial as a longer term maintenance immunosuppressive drug in children and adolescents.     

Clear benefit of mycophenolate mofetil-based triple therapy in reducing the incidence of acute rejection after living donor renal transplantations.

BACKGROUND: According to a pooled analysis of three randomized clinical studies concerning the prevention of acute rejection in cadaveric renal transplantation, mycophenolate mofetil (MMF) proved superior to azathioprine or placebo in conjunction with cyclosporine (CsA) and steroids. MMF-treated patients showed reduced incidence and severity of acute rejection, similar graft survival, and better graft function over 12 months. However, the multicenter trials did not include the Asian recipients of living donor kidneys. METHODS: To assess the efficacy of MMF as the third component of a triple therapy in addition to CsA-Neoral and steroids in living donor renal transplantation recipients in Asians, a total of 100 recipients were randomized to receive CsA-Neoral and steroids (control group, n=50), or MMF-based triple therapy (1.0 g of MMF twice daily from postoperative day 2, MMF group, n=50). The dosing plan for Neoral and steroids was essentially same between groups. During 12 months of follow-up, we compared the incidence of acute rejection, adverse events such as infections, and 12-month actual graft and patient survival. RESULTS: The graft and patient survival at 1 year was excellent in both groups: 96/98% in the control group and 98/100% in the MMF group, respectively. MMF significantly reduced the proportion of patients with at least one episode of acute rejection (34% in the control group vs. 14% in the MMF group), cumulative incidence of acute rejection episodes (46% vs. 16%), and requirement of antilymphocyte antibody (21.7% vs. 12.5%). In the MMF group, viral infection such as herpes zoster or chicken pox was more prevalent than in the control group. CONCLUSIONS: Like cadaveric renal transplantation, this open clinical trial showed MMF to be effective in reducing the incidence and severity of acute rejection if used in conjunction with Neoral and steroids after living donor renal transplantation in Asian ethnicity.     

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.     

Evolution of suboptimal renal transplantations: experience of a single Spanish center

The increase in patients on dialysis awaiting transplantation has led to the use of grafts from suboptimal donors. The aim of this study was to analyze the function of suboptimal grafts. The secondary objectives were to study vascular and urological complications, as well as delayed renal function and acute rejection episodes. The study included 135 transplantations performed over 4 years with 27% of grafts being from suboptimal donors. Early graft loss was 12%, of which 69% were due to vascular thrombosis. These thromboses were more frequent among grafts from suboptimal donors (30% vs 4%, P < .001). There were no significant differences between the groups in the incidence of acute rejection episodes (17% vs 13%) or delayed graft function (14% vs 13%). A greater incidence of urologic complications was observed among recipients of grafts from older donors. The 1-year creatinine clearance was significantly lower among recipients of grafts from older donors (73 +/- 19 vs 51 +/- 14 mL/min, P < .0001). Sequential immunosuppressive therapy resulted in a lack of significant differences in creatinine clearance at 6 months, 1 year, or 2 years after transplantation between suboptimal grafts with cold ischemia greater or less than 20 hours or in warm ischemia greater or less than 60 minutes. Logistic regression analysis showed that the best determinant of graft loss was donor age older than 60 years. Accordingly, grafts from suboptimal donors were more likely to be lost during the first month after transplantation, particularly because of thrombosis, which was not due to a higher degree of technical complexity of the transplant operation.     

Long-term graft outcome with mycophenolate mofetil and azathioprine: A paired kidney analysis

BACKGROUND: Randomized controlled trials and U.S. Registry data have demonstrated that mycophenolate mofetil (MMF) reduces acute rejection rates and improves graft survival. We undertook the first paired kidney analysis comparing the effects of MMF and azathioprine on graft outcome in the United Kingdom. METHODS: In all, 238 deceased donors from 1999 to 2002 who donated one kidney to a patient treated with MMF and the other kidney to a patient treated with azathioprine were identified from the national transplant database held by U.K. Transplant. Graft function and rates of change of graft function were compared using multiple linear regression analyses adjusting for covariates on an intention-to-treat basis. Incidence of acute rejection and delayed graft function were studied using logistic regression. Patient and graft survival censored for death were evaluated with Cox regression analyses. RESULTS: The MMF-treated patients exhibited a nonsignificant trend towards improved graft function but with increased rejection rates (44% versus 31%, P < 0.01). Treatment with MMF did not reduce delayed graft function rates. Univariate analysis showed that graft survival was inferior in MMF-treated patients (90% versus 95%, log-rank, P = 0.02) but in multivariate Cox regression models, MMF treatment was not a significant factor. Surprisingly, in the first year 32% of patients achieved daily doses of less than 2 g of MMF compared to 18% of patients who received less than 100 mg of azathioprine (P < 0.01). CONCLUSION: In this real-life study, there was no difference in patient or graft outcome between MMF and azathioprine treated groups despite increased rejection rates in patients receiving MMF therapy.     

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.     

Randomized trial of conversion from mycophenolate mofetil to azathioprine 6 months after renal allograft transplantation.

BACKGROUND: In the first year after renal allograft transplantation, triple therapy immunosuppression with cyclosporin (CsA), prednisone (P), and mycophenolate mofetil (MMF) is superior to a triple therapy treatment that includes azathioprine (AZA) instead of MMF. Whether long-term treatment with CsA-P-MMF is better than treatment with CsA-P-AZA is a matter of debate, as 3-year graft survival is similar in MMF- and AZA-treated patients. The purpose of the present study was to examine the short-term effect of changing MMF to AZA in low-risk renal allograft recipients 6 months after transplantation. METHOD: This was a randomized, open-label single-centre study, recruiting 48 low risk renal allograft recipients on CsA-P-MMF therapy 6 months after transplantation, comparing the outcome with continued MMF treatment (2 g b.i.d.) (group A, n=22) or switching MMF to AZA (1 mg/kg) treatment (group B, n=26). RESULTS: The outcome after a 6-months follow-up of patients in group A and group B was similar. Treatment failure rates (defined as clinically diagnosed acute rejection episodes) were 4.5% in group A and 3.8% in group B. There were no patient deaths and no graft failures during the 6-months observation period. Graft function was excellent and similar in both groups. CONCLUSION: Replacing MMF with AZA 6 months after transplantation in low-risk renal allograft recipients is safe and is not associated with altered graft function in the short term.     

Comparison of 2-drug and 3-drug immunosuppression for cadaveric renal transplantation

We compare the results in recipients of cadaveric renal allografts immunosuppressed with cyclosporine and prednisone to those who received immunosuppression with cyclosporine, azathioprine and prednisone. The 2 groups were compared relative to HLA-ABDR matching, plasma reactive antibodies, cold ischemia time, diabetes as a cause of renal failure and recipient age greater than 50 years. The incidences of clinical allograft rejection and grafts lost to rejection were not significantly different in these 2 groups evaluated at 1 year. In the 2-drug immunosuppressed group the actual 3, 6 and 12-month graft function was 87, 86 and 85%, respectively, compared to 79, 78 and 74%, respectively, in the 3-drug immunosuppressed group. A difference in graft survival was due to graft loss secondary to vascular thrombosis and patient death, and not to immunological events. No advantage was demonstrated for the use of 3-drug immunosuppression for kidney allografts over a 2-drug protocol of cyclosporine and prednisone.     

Basiliximab and mycophenolate mofetil in combination with low-dose cyclosporine and methylprednisolone effectively prevent acute rejection in kidney transplant recipients

The aim of the study was to analyze whether immunosuppressive treatment with basiliximab and mycophenolate mofetil (MMF), allowed a reduction in methylprednisolone and cyclosporine dosages without increasing the incidence of acute rejection episodes, reducing 1-year graft and patient survivals, or increasing the rates of infections and malignancy in the first year. The two groups were group A (n = 72), treated with methylprednisolone and cyclosporine and in the first 2 weeks with azathioprine; group B (n = 72), treated with basiliximab, MMF, and low-dose cyclosporine and methylprednisolone. The patients were followed for 1 year. The incidence of acute rejection episodes in the first year was significantly lower in group B (2.8%) than group A (12.5%; P < .05). The cumulative methylprednisolone dose, the daily dose, and the average cyclosporine trough blood level were significantly lower in group B (P < .001). One-year serum creatinine was significantly lower in group B (112 +/- 45 micromol/L) than group A (138 +/- 51 micromol/L; P < .01). One-year graft survival was 91.7% in group A and 98.6% in group B. One-year patient survival was 98.6% in group A and 100% in group B. The groups did not differ significantly in the incidence of bacterial, viral, or fungal infections. Immunosuppression with basiliximab and MMF allowed a reduction in cyclosporine and methylprednisolone dosages and was associated with significantly lower incidences of acute rejections episodes with better graft function in the first year as opposed to immunosuppression with higher doses of cyclosporine and methylprednisolone alone. Both immunosuppressive regimens showed the same infection rates and did not differ significantly in the occurrence of malignant diseases within the first year.     

Role of cold ischemia in acute rejection: characterization of a humoral-like acute rejection in experimental renal transplantation

The aim of the study was to characterize the role of cold ischemia in the process of acute rejection using an experimental renal transplant model. Syngeneic renal transplants were performed between Wistar Agouti rats and allogeneic grafts using Wistar-Agouti rats as recipients of Brown-Norway kidneys. For cold ischemia (CI), kidneys were preserved in Euro-Collins (4 degrees C/ 2.5 hours). Rats were bilaterally nephrectomized at the moment of renal transplant and did not receive any immunosuppressant. The groups were NoAR (n = 6): immediate syngeneic transplant; CI-NoAR (n = 6): syngeneic transplant with CI; AR (n = 13): immediate allogeneic graft; CI-AR (n = 6): allogeneic graft with CI. Allogeneic rats were followed for the survival study. Syngeneic rats, with mean survival time beyond 6 months, were sacrificed on the day 7 to compare grafts with those in the allogeneic groups. H&E- and PAS-stained grafts were evaluated using the Banff criteria. Tissue INF-gamma and TNF-alpha were quantified by RT-real time-PCR on the kidney grafts. Renal insufficiency did not appear in the NoAR group, but it did from the posttransplant day 5 in both acute rejection groups. While NoAR kidneys showed well-conserved renal architecture, then AR group displayed variable degrees of tubular necrosis with scarce cellular infiltration, interstitial hemorrhage, vascular damage with fibrinoid necrosis, perivascular edema, and nuclear disruption. Cold ischemia in rejecting animals increased the mortality rate due to renal insufficiency and accelerated acute rejection. Independently of CI, the proinflammatory cytokines TNF-alpha and INF-gamma were increased in both rejection groups. In conclusion, addition of CI overactivates the acute rejection process via a humoral component.     

Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen: results of a five-year, prospective, randomized study

Maintenance immunosuppression with cyclosporine (CsA) is associated with nephrotoxicity, hyperlipidemia, and hypertension. This long-term study (core study + 4 yr of follow-up) investigated the long-term efficacy and safety of CsA withdrawal from a mycophenolate mofetil (MMF)-based regimen. Seventy-seven patients were maintained on CsA, MMF, and steroids (CsA-MMF group), and 74 were given a CsA-free regimen of MMF and steroids (MMF group). Serum creatinine and creatinine clearance were measured at 6-month intervals. Patient and graft survival, acute rejection episodes, malignancies, BP, and lipid profile were also recorded. At 5 yr, patient and graft survival was 93 and 88%, respectively, for the MMF group and 95 and 92%, respectively, for the CsA-MMF group. During follow-up, seven MMF patients experienced acute rejection episodes compared with one CsA-MMF patient (P = 0.0283). Nine grafts were lost to chronic rejection in the MMF group versus three in the CsA-MMF group. No demographic or immunologic characteristics were associated with acute or chronic rejection in the MMF group, but the doses of both MMF and steroids decreased significantly between 1 and 5 yr. The MMF group showed a trend toward improved creatinine clearance (67.4 versus 61.7 ml/min; P = 0.0500). Withdrawal of CsA from an MMF-containing immunosuppressive regimen resulted in an increased risk for acute rejection episodes and graft loss as a result of rejection throughout the 5-yr study period. The creatinine clearance-confirmed improvement in renal function observed at year 1 was maintained at 5 yr BP and cholesterol levels were well controlled in both groups.     

Portal enteric-drained solitary pancreas transplantation without surveillance biopsy: is it safe?

BACKGROUND: Most solitary pancreas transplants (SPTx) fail due to unrecognized rejection episodes. Consequently, SPTx are monitored by drainage into the bladder or by surveillance biopsies. METHODS: Between April 2001 and June 2003, a consecutive series of 48 SPTx were performed using portal enteric drainage (PED). Rejection episodes were diagnosed empirically, based on the elevated pancreatic enzymes without a surveillance biopsy. Immunosuppression consisted of basiliximab (n = 42) or ATG (n = 6), low-dose steroids, MMF, and tacrolimus. Donors (mean age 28.9 year; range 9 to 54 year) were selected according to standard criteria irrespective of HLA match, although the best HLA matching was considered at the time of graft allocation. RESULTS: After a mean cold ischemia time of 676 minutes (range 475 to 900 minutes), all but two pancreata (95.8%) functioned immediately. Relaparotomy was required in seven cases (14.6%). Three grafts were lost in the early posttransplant period due to hyperacute rejection. Two additional grafts were lost later due to arterial thrombosis or to chronic rejection. After a median follow-up period of 12.2 months (range 0.2 to 27 months) three further recipients were diagnosed with rejection episodes that were reversed with steroid boluses. Actuarial 1-year patient and graft survival rates were 100% and 93.1% and 2-year figures 100% and 88.7%, respectively. At the longest follow-up no recipient was diagnosed with a malignancy. CONCLUSIONS: With current immunosuppression protocols SPTx achieves high rates of insulin independence even without surveillance biopsy or routine use of T-cell-depleting therapies.     

Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients

BACKGROUND: Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation. METHOD: In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction. RESULTS: By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133+/-45 vs. 155+/-46 micromol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74+/-32 mL/min vs. AZA 62+/-24 mL/min, P=0.004). CONCLUSION: Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.