Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation

BACKGROUND: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.     

Is acute rejection the key predictor for long-term outcomes after renal transplantation when comparing calcineurin inhibitors?

In the context of modern immunosuppressive regimens, the overall incidence of acute rejection may no longer be the most accurate surrogate marker for long-term kidney graft survival. The type, severity, timing, and clinical course of acute rejection each influence the impact of a rejection episode, and if renal function recovers fully, there appears to be no survival disadvantage. Randomized clinical trials in renal transplant patients have generally shown that there are fewer acute rejection episodes with tacrolimus compared with cyclosporine, although with contemporary regimens, including mycophenolate acid, this difference is less marked than previously. In randomized trials, kidney graft survival rates with cyclosporine and tacrolimus have proven similar. Large-scale registry analyses have consistently shown no graft survival benefit with tacrolimus vs cyclosporine, and indeed, 2 such analyses have reported significantly higher graft survival with cyclosporine-based immunosuppression compared with tacrolimus in living-donor kidney transplant patients receiving mycophenolate mofetil. There are no reports of improved patient survival with either calcineurin inhibitor after kidney transplantation. In conclusion, the perception of better efficacy with tacrolimus vs cyclosporine based on the incidence of acute rejection is not supported by a difference in graft or patient survival after kidney transplantation.     

Anti-CD25 monoclonal antibody sequential immunosuppressive induction therapy in renal transplants with high risk of delayed graft function

There is little experience on the use of monoclonal antibodies that block the high-affinity interleukin-2 receptor (basiliximab and daclizumab) in sequential therapy in renal transplants with risk of delayed graft function. This study sougth to test the efficacy and safety of the substitution of anticalcineurins with two doses of basiliximab or daclizumab in the immediate posttransplant period for recipients at risk of delayed renal graft function. Immunosuppression consisted of steroids, mycophenolate mofetil, and two doses of basiliximab (20 mg/day) on days 0 and 4 posttransplant or daclizumab (1 mg/kg per day) on days 0 and 15 posttransplant. Anticalcineurins were not administered until the beginning of graft function. Among 49 recipients (mean age 63.5 +/- 10.5 years), 40 received a kidney from a donor over 60 years of age, three from a non-heart-beating donor, and six from donors with an acute elevation of serum creatinine to 2.4 +/- 0.86 (1.7-3.7). At a mean follow-up of 14.2 +/- 8.4 months, five patients experienced acute rejection episodes. Only 15 patients needed posttransplant dialysis (2.7 +/- 1.6). In 11 patients, cyclosporine (CsA) was introduced at 6 +/- 2.9 days posttransplant and in 37, tacrolimus on 8.6 +/- 3.6 days posttransplant. The incidence of kidney graft loss was 16.3%. Patient survival was 96%. Thirty-nine recipients are alive with functioning grafts, with mean serum creatinine of 1.4 mg/dL. In conclusion, substitution for anticalcineurins with interleukin-2-receptor blockade in the immediate posttransplant period for patients at risk of delayed graft function minimizes nephrotoxicity and reduces tubular necrosis, without increasing the risk of an acute rejection episode.     

Simultaneous pancreas-kidney transplantation: analysis of rejection

The 3-year data concerning the occurrence of rejection episodes (RE) are reported herein. PATIENTS AND METHODS: Two hundred five simultaneous pancreas-kidney (SPK) transplantations were performed from May 1998 to September 2000, including 103 patients randomly assigned to tacrolimus (Tac) and 102 to cyclosporine microemulsion (CsA-ME). All patients received concomitant rATG induction therapy, mycophenolate mofetil (MMF), and short-term corticosteroids. RESULTS: After a follow-up of 3 years, acute rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving CsA ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93% and 90%, respectively) and in most cases were treated with corticosteroids (88% and 90%). Actuarial rejection-free graft survival was not significantly different between the two groups (54% and 44% at 3 years posttransplant). In a multivariate analysis, HLA compatibility (P = .003) and graft vessel extension (P = .0005) had a significant influence on rejection-free survival. Rejection influenced pancreatic graft survival (P = .01) and pancreatic graft loss owing to rejection influenced patient survival (P = .02). In the intent-to-treat analysis of early rejection, first moderate-to-severe episodes (1 of 40 versus 12 of 47; P = .004) and refractory episodes (2 of 40 versus 10 of 47; P = .03) were significantly lower with tacrolimus than with CsA ME. Pancreatic graft survival was worse among late rejectors (53%) than nonrejectors (86%; P = .002). In addition, serum creatinine was highest in late rejectors. In conclusion, Tac-based immunosuppressive therapy shows advantages over CsA ME in terms of the severity of acute rejection episodes among patients undergoing SPK transplantation.     

Results of 3-year phase III clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation

BACKGROUND: Daclizumab (Zenapax, Roche Pharmaceuticals), a humanized monoclonal antibody directed against the alpha chain of the interleukin 2 receptor, has been shown to reduce the incidence of acute rejection at 6 months after renal transplantation in two phase III clinical trials. This report presents the combined 1- and 3-year outcomes of kidney transplant recipients who participated in these two phase III clinical trials. METHODS: Data from two multicenter, randomized, placebo-controlled trials were evaluated with regard to graft survival, patient survival, incidence of malignancies (including lymphoma), renal function (serum creatinine and glomerular filtration rate [GFR]), and current maintenance immunosuppressive regimen. In addition, the impact of acute rejection and acute rejection requiring treatment with antilymphocyte therapy upon 3-year graft survival was evaluated. Daclizumab was compared to placebo on a background of cyclosporine (CsA), azathioprine, and corticosteroids (triple therapy, TT) or CsA and corticosteroids (double therapy, DT). RESULTS: Treatment with daclizumab in the pooled analysis demonstrated a significant reduction in the incidence of biopsy-proven acute rejection episodes at 12 months posttransplant (43% vs. 28%, P<0.001). The 3-year graft survival was not significantly different between placebo and daclizumab-treated patients in the TT trial (83% vs. 84%) or in the DT trial (78% vs. 82%). Pooled patient survival was excellent in both placebo- (91%) and daclizumab- (93%) treated patients. The incidence of malignancies or posttransplant lymphoproliferative disorder (PTLD) in placebo- versus daclizumab-treated groups was comparable in both clinical trials. Renal function was similar between placebo- and daclizumab-treated groups in both the TT and DT trials. The occurrence of delayed graft function, acute rejection requiring antilymphocyte therapy at 6 months, and acute rejection at 12 months posttransplant were associated with decreased graft survival rates at 3 years posttransplant. CONCLUSIONS: The beneficial effect of daclizumab prophylaxis upon the incidence of acute rejection after renal transplant with TT or with DT was not associated with adverse clinical sequelae, including the development of PTLD, at 3 years posttransplant. There was no beneficial effect of daclizumab on graft survival at 3 years, but the trial was inadequately powered to detect this. Both studies showed excellent graft and patient survival at 3 years.     

Tacrolimus and cyclosporine efficacy in high-risk kidney transplantation on behalf of the European Multicentre Tacrolimus (FK506) Renal Study Group

Abstract The efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens were compared in a prospectively defined subgroup of kidney transplant recipients from the European, open, multicentre, 2:1 randomised, parallel group study. Patients were stratified as high risk for immunological events if they had a panel-reactive antibodies grade greater than 80% and/or a previous transplant functional for less than 1 year. The primary efficacy variables evaluated were the incidence of acute rejection, steroid usage and patient and graft survival. Safety was assessed based on adverse events and laboratory evaluations. At 1 year, the tacrolimus group ( n = 22) had a lower incidence of biopsy-proven acute rejection (31.8%) and a higher graft survival (86.0%) than the 11 patients in the cyclosporine group (54.5 % and 72.0 %, respectively). The frequencies of adverse events were similar between the two groups. The tacrolimus regimen appears more beneficial for high risk patients than cyclosporine.     

A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years

BACKGROUND: The 1-year results of the Phase III U.S. Multicenter Trial comparing tacrolimus (FK506)- and cyclosporine (CsA)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. The present report at 5 years of follow-up focuses on the long-term impact of tacrolimus treatment on kidney allograft outcome. METHODS: The study protocol permitted crossover of patients to the alternate treatment arm under stringent conditions. The effect of crossover on graft survival was analyzed. Cardiovascular risk factors and serious adverse events were also monitored over 5 years. RESULTS: Intent-to-treat analysis revealed equivalent patient and graft survival between treatment arms at 5 years of follow-up (79.1% vs. 81.4%; P=0.472 and 64.3% vs. 61.6%; P=0.558 among tacrolimus and CsA-treated patients, respectively). However, the rate of crossover was significantly higher among patients randomized to receive CsA-based therapy (27.5% vs. 9.3%; P<0.001). The incidence of treatment failure (43.8% vs. 56.3%; P=0.008) was significantly lower among tacrolimus-treated patients. Graft survival was significantly improved in the tacrolimus treatment arm when crossover due to rejection was counted as graft failure (63.8% vs. 53.8%; P=0.014). Tacrolimus therapy was also associated with a significantly reduced requirement for medications to control hypertension and hyperlipidemia. There was a substantial rate of reversal of tacrolimus-associated insulin dependence. CONCLUSION: Tacrolimus-based therapy resulted in significantly reduced risk of graft failure, without an increase in the incidence of adverse events associated with long-term immunosuppression.     

Decreased incidence of acute rejection in adolescent kidney transplant recipients using antithymocyte induction and triple immunosuppression

BACKGROUND: Acute rejection is a frequent event in pediatric renal transplantation; it can diminish allograft function and affect long-term outcome. Recent data from the North American Pediatric Renal Transplant Cooperative Study indicates that the rate of acute rejection remains high despite current immunosuppressive regimens. METHODS: In this retrospective series, we examined 37 pediatric renal transplant recipients who received induction doses of antithymocyte globulin combined with maintenance immunotherapy using tacrolimus, mycophenolate mofetil, and prednisone. The postoperative course was reviewed for initial and total hospital stay, number of rehospitalizations, evidence of posttransplant complications, graft fibrosis, and overall patient and graft survival. RESULTS: Three episodes of acute rejection (8.1%) were recorded in the first year posttransplant. The median initial hospital stay for patients receiving a kidney transplant was 8 days. Patient and graft survival were 100% and 91.9% at 1 year, respectively. The incidence of viral infection (cytomegalovirus, BK virus, and Epstein-Barr virus) and posttransplant lymphoproliferative disease remained low. Urinary tract infection and fluid and electrolyte complications were the main causes of posttransplant hospitalization. CONCLUSIONS: We conclude that induction with antithymocyte globulin and maintenance immunosuppression with tacrolimus, mycophenolate, and prednisone should be considered a valuable tool in the management of children undergoing renal transplantation.     

The utility of cyclosporine weaning in renal transplantation.

Abrupt conversion of cyclosporine immunosuppression to conventional treatment with azathioprine and prednisone avoids long-term cyclosporine nephrotoxicity, albeit at the cost of a 20% to 40% rejection rate. The authors investigated the benefits and risks of a cyclosporine weaning protocol in 24 cadaveric and 9 live donor kidney recipients treated with a sequential quadruple immunosuppressive protocol. In cadaver kidney recipients, slow tapering of cyclosporine resulted in a 19% (p less than 0.001) improvement in the glomerular filtration rate, as estimated by the inverse ratio of the plasma creatinine concentration. Cadaver kidney recipients were stratified according to graft function (GFR ratio greater than 0.76, less than 0.76) at the of cyclosporine discontinuation. In 12 patients with well-functioning grafts, a 24% improvement was observed, whereas in 12 patients with poor graft function, the gain was limited to 13%. Patients with limited graft function tended to have more acute rejection episodes before cyclosporine weaning (0.92 +/- 0.64 versus 0.42 +/- 0.64, not significant). When the 24 cadaver kidney recipients were stratified according to onset of graft function after transplantation (days to plasma creatinine of 250 mumol/L), need for dialysis, panel reactive antibodies (PRA), and duration of cyclosporine treatment, no significant differences in graft function were observed at the onset or end of cyclosporine weaning. Acute graft rejection before cyclosporine weaning was the only variable associated with a significantly lower estimated glomerular filtration rate ratio at the end of cyclosporine treatment (0.83 +/- 0.11 versus 0.67 +/- 0.16, p less than 0.01). Weaning of cyclosporine was associated with a minimal risk of acute graft rejection. A single patient with stable graft function at the onset of the weaning process experienced an acute but reversible rejection episode 2 months after cyclosporine was discontinued. In summary, gradual weaning of cyclosporine improves graft function, and eliminates the excessive risk of acute graft rejection without the need for additional corticosteroid treatment.     

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.     

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

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

Calcineurin nephrotoxicity

Calcineurin inhibitors, cyclosporine and tacrolimus, have improved allograft survival in solid organ transplantation. Indeed, they have reduced the incidence of acute rejection episodes of cadaveric allograft recipients. Although marked progression has been made in initial survival rates, long-term kidney graft survival has yet to show such encouraging results. Chronic allograft dysfunction is the major hindrance to long-term graft survival and many components contribute to this entity, both immunologic and nonimmunologic. Chronic calcineurin nephrotoxicity is a major factor in chronic allograft dysfunction. This review will highlight the current understanding and management of calcineurin nephrotoxicity in kidney transplantation.     

Calcineurin Inhibitor Minimization in the Symphony Study: Observational Results 3 Years after Transplantation

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: −0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 ± 23.8 ml/min vs. 65.9 ± 26.2 ml/min in the standard-dose cyclosporine, 64.0 ± 23.1 ml/min in the low-dose cyclosporine and 65.3 ± 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.     

The effect of cyclosporine on mortality and renal function in living related pediatric kidney transplant recipients

The outcome, incidence of acute rejection episodes, complications and cyclosporine (CyA) induced nephrotoxicity were studied in 10 pediatric kidney transplant recipients who were grafted from one-haplotype indentical parent with immunosuppression of CyA and prednisolone (Pred). Excellent patient and graft survival could be achieved in this population with low incidences of acute rejection or serious complications as when compared with the results of azathioprine (AZ) treated pediatric patients. With a mean follow-up of 12.9 months (range 1 to 50 months), the patient survival rate was 100 per cent and the graft survival rate was 100, 84, 84 and 84 per cent at 1, 2, 3 and 4 years post transplantation, respectively. Serum creatinine levels in the group were 0.97, 1.17, 1.14 and 1.2 mg/dl at 3, 6, 12 and 24 months post transplantation, respectively. The incidence of treated acute rejection episodes was 20 per cent (2 out of 10) in the CyA-treated children, whereas it was 53 per cent (9 of 17) in the Az-treated children. Five children who had undergone transplant surgery before they were 11 years old displayed linear growth in height after their transplantation. There have been no opportunistic infections, aseptic necrosis or peptic ulcers in this group and cyclosporine nephrotoxicity has not been a serious problem in the pediatric recipients. Only 10 per cent (1 out of 10) of the recipients displayed acute nephrotoxicity and only one recipient has converted from CyA+Pred to CyA+AZ+Pred (Three drug therapy) due to persistent nephrotoxicity. Cyclosporine and prednisolone have therefore constituted a relatively safe, effective immunosuppressive regimen for pediatric renal allograft recipients. This paper was presented at the 7th international congress of pediatric nephrology.     

Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant Study Group

BACKGROUND: Tacrolimus (FK506) is a safe and effective treatment for the prevention of rejection of renal allografts. Mycophenolate mofetil (MMF) has been used as adjunct immunosuppressive therapy with cyclosporine and corticosteroids for the same purpose. The objective of this study was to investigate the safety and efficacy of FK506 and MMF in renal transplant recipients. METHODS: After cadaveric renal transplant, patients were randomized to receive tacrolimus in combination with either azathioprine (AZA, n=59), MMF 1 g/day (n=59), or MMF 2 g/day group (n=58). Patients were followed for 1 yr posttransplant for the incidence of biopsy-confirmed acute rejection, patient and graft survival, and adverse events. RESULTS: Tacrolimus doses and trough concentrations were similar between treatment groups at all time points; 80% of patients were maintained within a range of 5.0-13.9 ng/ml at 12 months posttransplant. The mean dose of MMF decreased in the 2 g/day group to 1.5 g/day by 6 months posttransplant, primarily due to gastrointestinal GI-related disorders. The incidence of biopsy-confirmed acute rejection at 1 year was 32.2%, 32.2%, and 8.6% in the AZA, MMF 1 g/day, and MMF 2 g/day groups, respectively (P<0.01). The use of antilymphocyte antibodies for the treatment of rejection was comparable across treatment groups. The incidence of most adverse events was similar across treatment groups and comparable with previous reports. The overall incidence of posttransplant diabetes mellitus was 11.9%, with the lowest rate observed in the MMF 2 g/day group (4.7%), and was reversible in 40% of patients. The incidence of malignancies and opportunistic infections was low and not different across treatment groups. CONCLUSION: Tacrolimus in combination with an initial dose of MMF 2 g/day is a very effective and safe regimen in cadaveric kidney transplant recipients.     

Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity

Tacrolimus (or FK506), a calcineurin inhibitor (CNI) introduced in field of transplantation in the 1990s, is the cornerstone of most immunosuppressive regimens in solid organ transplantation. Its use has revolutionized the future of kidney transplantation (KT) and has been associated with better graft survival, a lower incidence of rejection, and improved drug tolerance with fewer side effects compared to cyclosporine. However, its monitoring remains complicated and underexposure increases the risk of rejection, whereas overexposure increases the risk of adverse effects, primarily nephrotoxicity, neurotoxicity, infections, malignancies, diabetes, and gastrointestinal complaints. Tacrolimus nephrotoxicity can be nonreversible and can lead to kidney graft loss, and its diagnosis is therefore best made with reference to the clinical context and after exclusion of other causes of graft dysfunction. Many factors contribute to its development including: systemic levels of tacrolimus; local renal exposure to tacrolimus; exposure to metabolites of tacrolimus; local susceptibility factors for CNI nephrotoxicity independent of systemic or local tacrolimus levels, such as the age of a kidney; local renal P-glycoprotein, local intestinal and hepatic cytochrome P450A3, and renin angiotensin system activation. The aim of this review is to describe the pharmacokinetics, pharmacodynamics, and mechanisms of acute and chronic tacrolimus nephrotoxicity in adult KT.     

Long-term results of mycophenolate mofetil as part of immunosuppressive induction therapy after liver transplantation

BACKGROUND: The addition of mycophenolate mofetil (MMF) to the induction protocol resulted in a lower incidence of rejection episodes. However, the question whether MMF should be administered in combination with tacrolimus or cyclosporine has not been answered yet. In our study, we report on the long-term results of triple induction therapy after orthotopic liver transplantation (OLT), consisting of MMF and low-dose corticosteroids, in combination with either tacrolimus or cyclosporine. METHODS: Between March 1996 and April 1997, 120 consecutive patients, who underwent OLT at our institution, were enrolled in this study. Of these patients, 80 received triple induction therapy consisting of cyclosporine and MMF (40) or tacrolimus and MMF (40), in combination with low-dose corticosteroids, whereas the remaining 40 patients served as 'MMF-free' control group receiving dual induction therapy with tacrolimus and corticosteroids. Besides the eight-yr follow-up of patient and graft survival, clinical data were also reviewed for episodes of rejection and infection. Additionally, the early post-operative pharmacokinetics of mycophenolic acid (MPA, immunological active metabolite of MMF) were evaluated. RESULTS: Long-term results provided higher patient and graft survival after tacrolimus/MMF-based induction therapy than after cyclosporine/MMF-based induction therapy. However, the tacrolimus-based control protocol yielded similar results and, therefore, no significantly superior effect was observed when MMF was added. The same observation was made for incidence of rejection and infection episodes. AUC and C(max) of MPA increased in combination with tacrolimus compared with cyclosporine. CONCLUSIONS: Although pharmacological synergy between tacrolimus and MMF was observed, MMF showed no significant beneficial effects in the immunosuppressive induction protocol, neither in combination with tacrolimus nor with cyclosporine.     

Evaluation of Immunosuppressive Regimens in ABO-Incompatible Living Kidney Transplantation—Single Center Analysis

Several protocols allow the successful ABO incompatible living-related kidney transplantation (ABO-ILKT), yet no single method has emerged as the best. We have made several substantial changes to our ABO-ILKT protocol over the past decade and a half and have attempted to determine whether the changes in immunosuppressive agents have resulted in a better outcome. We used methylprednisolone (MP), cyclosporine (CsA), azathioprine (AZ), antilymphocyte globulin (ALG) and deoxyspergualine (DSG) in the 105 cases of ABO-ILKT (group 1) between 1989 and 1999, and MP, tacrolimus (FK506), mycophenolate mofetil (MMF) in the 117 cases of ABO-ILKT (group 2) between 2000 and 2004. We compared the patient and graft survival rates as well as the incidence rate of acute rejection in these two eras, when different regimens were used. There were significant differences in the 1- and 5-year graft survival rates between groups 1 and 2 (1-year: 78% in group 1 vs. 94% in group 2; 5-year: 73% in group 1 vs. 90% in group 2, p = 0.008). Also, a higher incidence rate of acute rejection was significantly observed in group 1 (50/105, 48%) than in group 2 (18/117, 15%) (p < 0.001). We conclude that the FK/MMF combination regimen provides excellent graft survival results in ABO-ILKT.     

One year results of preoperative single bolus ATG-Fresenius induction therapy in sensitized renal transplant recipients

Sensitization in kidney transplantation is associated with more acute rejections, inferior graft survival, and an increase in delayed graft function. This study was designed to evaluate the efficacy and safety of preoperative single bolus antithymocyte globulin (ATG) induction therapy in sensitized renal transplant recipients. METHODS: Fifty-six cadaveric donor kidney transplant recipients were divided into two groups: Group I (nonsensitized group, n = 30) and group II (sensitized group, PRA>10%, n = 26). ATG was given as a single preoperative bolus induction therapy to group II (ATG IV; 9 mg/kg). The group I patients were treated with mycophenolate mofetil preoperatively as induction therapy. The basic immunosuppressive regimen included tacrolimus (FK-506) or cyclosporine, mycophenolate mofetil, and prednisolone. After hospital discharge, patients were followed on a routine outpatient basis for 12 months. RESULTS: Acute rejection episodes (ARE) occurred in 20% (6/30) of group I and 15.38% (4/26) of group II patients (P = NS). Infections occurred in eight patients (26.7%) as 11 episodes (36.7%), averaging 1.4 episodes per infected patient in group 1, and 6 patients (23.1%) for a total of 10 episodes (38.5%), averaging 1.7 episodes per infected patient, in group II (P = NS). Occurrence of side effects and hospital stay were almost comparable in the two groups. No delayed graft function was observed in either group. The 12-month actuarial patient and graft survival were 100% in Group I and II. CONCLUSION: A preoperative single bolus ATG induction therapy was an effective and safe therapeutic measure, yielding an acceptable acute rejection rate in presensitized renal transplant recipients.     

Alemtuzumab induction with tacrolimus monotherapy in de novo renal transplantation

OBJECTIVES: Alemtuzumab is increasingly being used as induction therapy for kidney transplantation, allowing immunosuppression minimization. This study examined the efficacy of alemtuzumab induction followed by low-dose tacrolimus monotherapy in standard risk primary kidney transplant patients. METHODS: This retrospective cohort of primary standard risk renal transplant recipients were given alemtuzumab induction and low-dose tacrolimus maintenance immunosuppression (target trough 7 to 10 ng/mL for the first 6 months and 5 to 7 ng/mL thereafter). Serum creatinine values, acute rejection episodes, and graft survival were noted at week 1 as well as months 3, 6, 12, and 18. RESULTS: At the time of analysis, 47 patients were at 6 months, 28 at 12 months, and 6 patients at 18 months from transplant. Mean follow-up was 12.53 months (range, 6 to 23). Mean serum creatinine was 1.47 +/- 0.65 mg/dL at 3 months, 1.56 +/- 0.84 at 6 months, 1.45 +/- 0.37 at 12 months, and 1.74 +/- 0.35 at 18 months. The 1-year clinical acute rejection rate was 21% (6/28), occurring at 0 to 3 months in 2 (33%), 4 to 6 months in 1 (17%), and >6 months in 3 patients (50%). Biopsy-proven acute rejection was 14% (4/28). The episodes were classified as borderline in one, Banff 2A in two, and Banff 3 in one patients. One patient had both acute cellular and acute humoral rejection; half responded to steroid pulse therapy. The 1-year patient survival rate was 90%. The 1-year death-censored graft survival rate was 98%. CONCLUSION: Alemtuzumab induction with tacrolimus monotherapy is an acceptable option in standard risk patients. BPAR was 14%, but renal function remained satisfactory at 18 months posttransplant.