Avoidance of cyclosporine in renal transplantation: effects of daclizumab, mycophenolate mofetil, and steroids

Cyclosporine (CsA) has been implicated in both acute and chronic graft dysfunction. The addition of humanized IL-2 receptor antibody daclizumab (DZB) to CsA-based immunosuppression decreases the rate of acute renal transplant rejection. Therefore, 45 patients were evaluated in an immunosuppressive protocol that included DZB, mycophenolate mofetil (MMF), and steroids without CsA. This was a prospective, nonrandomized, open-label trial of the efficacy and safety of the treatment. DZB was given intravenously at 2 mg/kg before transplantation and then at 1 mg/kg every 2 wk for four doses, MMF was given orally at 3 g/d, and methylprednisolone/prednisone was given at 7 mg/kg per day and tapered to 15 mg/d at 6 mo. CsA was added to the regimen when patients developed acute rejection episodes or adverse effects to steroids or MMF; 49% of patients were spared CsA maintenance. Patients without CsA had lower serum creatinine at 6 mo and needed fewer medications to control BP. Incidence of biopsyproven rejections was 31% and occurred early (median, 10 d). These rejection episodes occurred earlier in cadaver transplants (median, 7 d) and later in living donor transplants (median, 62 days). Acute rejections occurred at a higher frequency (46% versus 34%) and earlier (6.5 versus 15 d) in patients with delayed graft function compared with patients without delayed graft function. Most of the rejections were moderate and easily reversible. The actuarial 1-yr graft survival was 95% with 100% patient survival.     

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 At 3 mo after graft, they were gradually withdrawn from CsA (MMF group, n = 54) or MMF (CsA group, n = 54).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.     

Renal transplantation: can we reduce calcineurin inhibitor/stop steroids? Evidence based on protocol biopsy findings

How to combine antirejection drugs and which is the optimal dose of steroids and calcineurin inhibitors beyond the first year after kidney transplantation to maintain adequate immunosuppression without major side effects are far from clear. Kidney transplant patients on steroid, cyclosporine (CsA), and azathioprine were randomized to per-protocol biopsy (n = 30) or no-biopsy (n = 29) 1 to 2 yr posttransplant. Steroid or CsA were discontinued or reduced on the basis of biopsy to establish effects on drug-related complications, acute rejection, and graft function over 3 yr of follow-up. Serum creatinine, GFR (plasma clearance of iohexol), RPF (renal clearance of p-aminohippurate), CsA pharmacokinetics, and adverse events were monitored yearly. At the end, patients underwent a second biopsy. Per-protocol biopsy histology revealed no lesions (n = 5, steroid withdrawal), CsA nephropathy (n = 13, CsA discontinuation/reduction), or chronic rejection (n = 12, standard therapy). Reducing the drug regimen led to overall fewer side effects related to immunosuppression as compared with standard therapy or no-biopsy. Steroids were safely stopped with no acute rejection or graft loss. Complete CsA discontinuation was associated with acute rejection in the first four patients. Lowering CsA to low target CsA trough (30 to 70 ng/ml) never led to acute rejection or major renal function deterioration. Biopsy patients on conventional regimen had no acute rejection, one graft loss, no significant change in GFR, and significant RPF decline. No-biopsy controls: no acute rejection, one graft loss, significant decline of GFR and RPF. By serial biopsy analysis, severe lesions did not develop in patients with steroid discontinuation in contrast to patients on standard therapy over follow-up. CsA reduction did not adversely affect histology. Per-protocol biopsy more than 1 yr after kidney transplantation is a safe procedure to guide change of drug regimen and to lower the risk of major side effects.     

The use of an anti-CD25 monoclonal antibody and mycophenolate mofetil enables the use of a low-dose tacrolimus and early withdrawal of steroids in renal transplant recipients

BACKGROUND: Reducing calcineurin-inhibitor-induced nephrotoxicity and simultaneously avoiding long-term steroid related side-effects is a desirable goal in renal transplantation. We examined the hypothesis that using anti-CD25 monoclonal antibody induction and mycophenolate mofetil (MMF) would allow the lowering of target pre-dose blood concentrations of tacrolimus immediately after transplantation and subsequently stopping steroids at 5 months. METHODS: Eighty-two kidney recipients were enrolled in a single-center study comparing two tacrolimus-based protocols. Group I (n = 41) patients received a standard-dose tacrolimus (blood concentration 10-15 ng/mL) with MMF and a standard dose corticosteroid. Group II (n = 41) patients were treated with a low-dose tacrolimus (blood concentration 5-10 ng/mL) and MMF, a low-dose corticosteroid (stopped after 5 months) and induction with daclizumab. RESULTS: Patient (95.1 versus 100%) and graft survival (92.6 versus 97.5%) at 1 yr were not different between groups. Patients of group II experienced significantly less acute rejections than group I (17.1 versus 41.4% p = 0.03). Delayed graft function occurred less often in group II (5 versus 12% p = 0.43). Graft function at 1 yr was significantly better in group II (serum creatinine 1.49 versus 1.69 mg/dL and creatinine clearance 59.6 versus 49 mL/min; p < 0.05). Corticosteroids could be stopped after 5 months in 82.9% of group II patients. CONCLUSION: A regimen consisting of anti-CD25 monoclonal antibody induction and MMF allows the safe and efficient use of low-target pre-dose trough concentrations of tacrolimus and enables the early discontinuation of steroids. Preliminary results indicate a better 1-yr graft function compared to a normal-dose tacrolimus regimen.     

A phase III prospective,randomized study to evaluate concentration-controlled sirolimus (rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients

BACKGROUND: This study evaluated the safety and efficacy of sirolimus plus steroids as a maintenance regimen with or without small-dose cyclosporine (CsA) adjunctive therapy in renal transplant recipients. METHODS: A total of 133 recipients of kidney allograft transplantations recruited in the United Kingdom and Ireland were enrolled into the study and are presented in this interim analysis. In the first 3 months, all patients received CsA plus sirolimus and small-dose steroids after transplantation. At 3 months, patients were randomized 1:1 to CsA elimination (e)CsA or CsA dose minimization (m)CsA. Dosing of agents was concentration-controlled and open label. RESULTS: Patient and graft survival were 97.7% and 95.5%, respectively (n = 133), whereas the biopsy-proven acute rejection rate in the first 6 months was 19.5% (26 episodes in 133 patients); incidents of acute rejection rates comprised 22 episodes (16.5%) during the first 3 months of the study and four episodes (3%) after randomization. Eighty-seven patients were randomized to receive eCsA or mCsA. At 6 months, creatinine clearance was significantly higher in the eCsA group versus mCsA group, respectively (65 mL/min vs. 57 mL/min; P = 0.027). There was no significant difference in serum cholesterol, triglycerides, low-density lipoprotein, or high-density lipoprotein levels between the groups. CONCLUSION: These data demonstrate that withdrawal of CsA from a small-dose sirolimus maintenance regimen is safe and is associated with an improvement in renal function. The study also suggests that the addition of small-dose CsA to a sirolimus maintenance regimen does not increase immunosuppressive efficacy.     

Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen in stable kidney transplant recipients: a randomized,controlled study

BACKGROUND: Long-term maintenance immunosuppression with cyclosporine (CsA) is associated with chronic transplant nephropathy and adverse effects on blood pressure and lipid profile. Several nonrandomized studies suggest that CsA might safely be withdrawn from immunosuppressive regimens containing mycophenolate mofetil (MMF; CellCept). METHODS: A randomized, controlled study with 187 patients enrolled from 21 centers was conducted to compare CsA withdrawal with ongoing CsA therapy in stable renal transplant recipients receiving a triple-drug immunosuppressive regimen of MMF (2 g/day), CsA (Neoral), and corticosteroids. The primary endpoint was creatinine clearance at 6 months after complete withdrawal. RESULTS: In the intent-to-treat population, CsA withdrawal was associated with lower total cholesterol and low-density lipoprotein cholesterol (-0.3 mmol/L, P=0.02; -0.4 mmol/L, P=0.015). There was a trend toward improved creatinine clearance (4.5 mL/min, P=0.16) and serum creatinine (-1 vs. +4 micromol/L, P=0.34). In the per-protocol population, which excluded patients with acute rejections, the improvements in creatinine clearance and serum creatinine were statistically significant (7.5 mL/min, P=0.02; -11 vs. +4 micromol/L, P=0.0003). Reversible acute rejections, the majority of which were mild, occurred in nine CsA withdrawal versus two CsA continuation patients (10.6% vs. 2.4% of each group, P=0.03), with no graft loss. CONCLUSION: Withdrawal of CsA from an MMF-containing triple-drug immunosuppressive regimen improves renal function and lipid profile at the cost of a modest increase in acute rejections, without graft loss.     

CMV infections after two doses of daclizumab versus thymoglobulin in renal transplant patients receiving mycophenolate mofetil, steroids and delayed cyclosporine A.

BACKGROUND: Cytomegalovirus (CMV) infection is a major complication after renal transplantation and is involved in graft rejection. The anti-interleukin-2-receptor antibody daclizumab reduces the incidence of acute rejection without increasing the incidence of CMV infection. METHODS: This multicentre, randomized trial compared safety and efficacy, at 1 year, of two doses of daclizumab (54 patients, group D) with thymoglobulin (55 patients, group T) plus delayed cyclosporine (CsA), MMF (mycophenolate mofetil) and steroids in first cadaver kidney transplant patients. Primary criterion was CMV infection/syndrome/disease. D+/R- patients received oral ganciclovir prophylaxis for 90 days. RESULTS: Status for CMV was identical in the both groups. The incidence of CMV infection/syndrome/disease was 39% in group D versus 51% in group T (NS). Time to onset of CMV replication was delayed in group D (P = 0.015) and mean number of pp65-positive cells was lower at 4 and 6 months (P < 0.001). Incidence of symptomatic CMV episodes was not reduced in whole group D (5.6% versus 16.4%, NS), but lower in D+/R+ and D-/R+ patients without chemoprophylaxis, compared to group T (2.8% versus 21.6%, P = 0.028). Patient and graft survivals and incidence of biopsy-proven acute rejection were identical. CONCLUSIONS: Limited dosing regimen of daclizumab with MMF, steroids and delayed CsA introduction was safe and effective. The incidence of CMV infection was not significantly different, but without chemoprophylaxis, clinical manifestations and viral replication were reduced with this regimen.     

Three-year observational follow-up of a multicenter, randomized trial on tacrolimus-based therapy with withdrawal of steroids or mycophenolate mofetil after renal transplant

BACKGROUND: The challenge in renal transplantation is to improve long-term patient and graft survival without increasing early acute rejection by minimizing immunosuppression. METHODS: This multicenter, observational study investigated the effects of withdrawal of steroids or mycophenolate mofetil (MMF) from a tacrolimus-based triple regimen (tac/MMF/steroids) 3 months posttransplant at 3 years; no additional interventions or assessments were undertaken. Adult patients, included in the intent-to-treat population of the THOMAS study, participated. Patient and graft survival, adverse events, rejection episodes, and immunosuppressive and concomitant medications were assessed. RESULTS: Data at Year 3 was available for 718 patients (triple therapy, n=237; steroid stop, n=235; MMF stop, n=246). The original randomized regimen was maintained in 45.6% of patients in the triple, 62.6% in the steroid stop, and 53.9% in the MMF stop groups. Graft survival rates were 88.1% (triple), 86.4% (steroid stop), and 85.8% (MMF stop); patient survival was 96.1%, 95.9%, and 95.7%, respectively. The incidence of biopsy-proven acute rejection was similar in all groups between Month 7 and Year 3: 1.2% (triple), 2.0% (steroid stop) and 2.0% (MMF stop). Patients in the steroid stop group had less hypertension and significantly lower mean total cholesterol and LDL-cholesterol at Year 3 compared with Month 3 (P=0.02). Median serum creatinine levels remained stable throughout the follow-up and were comparable between groups. CONCLUSION: Immunosuppression minimization initiated at Month 3 was maintained at Year 3 in over half of the patients. Steroid withdrawal was advantageous in reducing the cardiovascular risk factors hyperlipidemia, hypertension and diabetes mellitus. Renal function was stable in all groups.     

Short-term combination of mycophenolate mofetil with cyclosporine as a therapeutic option for renal transplant recipients: A prospective,multicenter, randomized study

BACKGROUND: Mycophenolate mofetil (MMF), compared to azathioprine (AZA), reduces acute rejection and treatment failure in cyclosporine (CsA) and steroid regimens, but its effect on graft survival is unproven from prospective studies and prolonged use is costly. This study evaluated the efficacy and tolerability of replacing MMF by AZA after 3 months. METHODS: This 28 center, prospective, 12-month, parallel group, open-label study, randomized patients to three groups with microemulsion formulation of CsA (ME-CsA) and steroids as baseline therapy. Group 1 (n=158) received MMF for 3 months, replaced by AZA for 9 months; group 2 (n=162) received MMF for 12 months; and group 3 (n=157) received AZA for 12 months. RESULTS: Treatment failure and the cumulative rate of acute rejection were significantly lower in the MMF groups compared with the AZA group (P=0.007 and P=0.03, respectively). Graft loss, death, and safety profiles of all three treatments were similar over 12 months, as were mean serum creatinine levels. Switching from MMF to AZA did not affect treatment failure. No patient in group 1 experienced a recurrent rejection after month 3, one patient died, and nine patients experienced first rejection episodes. Most rejections (6/9) were steroid-sensitive and histologically mild. CONCLUSIONS: Replacement of MMF by AZA after 3 months of therapy with ME-CsA and steroids provides comparable efficacy and safety profiles to continuous MMF over 12 months. Although apparently a cost-effective option, long-term studies are required to assess the benefit/risk ratio of this therapy switch in different patient subpopulations.     

Efficacy on Renal Function of Early Conversion from Cyclosporine to Sirolimus 3 Months After Renal Transplantation: Concept Study

Sirolimus (SRL) allows to minimize the use of cyclosporine (CsA), but de novo administration after transplantation is associated with various complications. We report a prospective, open-label, multicenter randomized study to evaluate conversion from a CsA-based regimen to a SRL-based regimen 3 months after transplantation. One hundred ninety-two of a total of 237 patients were eligible at 3 months to be converted to SRL (n = 95) or to continue CsA (n = 97). All patients were also given mycophenolate mofetil (MMF) and oral steroids, planned to be discontinued at month 8. The primary endpoint, the clearance estimated according to Cockcroft and Gault at week 52, was significantly better in the SRL group (68.9 vs. 64.4 mL/min, p = 0.017). Patient and graft survival were not statistically different. The incidence of acute rejection episodes, mainly occurring after withdrawal of steroids, was numerically but not statistically higher in the SRL group (17% vs. 8%, p = 0.071). Sixteen patients discontinued SRL, mainly for adverse events (n = 11), and seven patients discontinued CsA for renal failure or acute rejection. Significantly, more patients in the SRL group reported aphthous, diarrhea, acne and high triglyceride levels. Conversion CsA to SRL 3 months after transplantation combined with MMF is associated with improvement in renal function.     

Mycophenolate mofetil, an alternative to cyclosporine A for long-term immunosuppression in kidney transplantation?

BACKGROUND: Mycophenolate-mofetil (MMF) is a nonnephrotoxic immunosuppressant most often used in combination with cyclosporine A (CsA) and prednisone (Pred). This study reports the outcome of 17 adult renal recipients whose immunosuppressive regimen was changed from CsA-Pred to MMF-Pred because of CsA nephrotoxicity. METHODS: CsA nephrotoxicity was diagnosed in all patients based on suggestive histopathological lesions on a renal biopsy. Sixteen patients had deteriorating graft function and 1 had isolated persistent proteinuria. Immunosuppressive therapy was changed 57+/-32 months posttransplant. RESULTS: After replacement of CsA by MMF, a reduction in serum creatinine was observed in all patients (mean 26+/-17%). This reduction was maintained 20+/-8 months after the change in therapy without any episodes of acute rejection. Serum lipids and blood pressure also decreased significantly. CONCLUSION: This study demonstrates that MMF-Pred can be an effective long-term immunosuppressive treatment alternative for renal transplant patients experiencing CsA nephrotoxicity. Such treatment may result in improved graft function, and better control of hypertension and hyperlipidemia.     

Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?

BACKGROUND: The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage. METHODS: Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded. RESULTS: Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08). CONCLUSIONS: At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.     

Sirolimus rescue therapy for refractory rejection in renal transplantation.

BACKGROUND: Acute renal allograft rejection episodes refractory to antilymphocyte preparations almost inevitably progress to transplantation loss. To reverse ongoing rejection processes, we administered sirolimus (RAPA) after failure of conventional immunosuppressive regimens including full courses of antilymphocyte sera. METHODS: All 36 renal transplantation recipients reported herein displayed either Grade IIB or Grade III biopsy-proven (Banff 1993 criteria) ongoing rejection episodes despite prior treatment with pulse and/or oral recycling of steroids and at least one 14- to 21-day course of murine (OKT3) or equine (ATGAM) antilymphocyte treatment. We compared the actual 12-month outcomes of two demographically similar cohorts of patients treated for refractory rejection with RAPA (Group I; n=24) or mycophenolate mofetil (MMF; Group II; n=12) added to a baseline regimen of cyclosporine (CsA)/prednisone (Pred). RESULTS: Rescue therapy reversed the renal dysfunction in 96% of patients in the RAPA group versus 67% in the MMF group (P=0.03) despite the fact that a greater fraction of patients in the RAPA (17 of 24) than the MMF group (6 of 12) had experienced two or more episodes of acute rejection before study entry and the fact that the recurrent bouts of acute rejection occurred within the first 6 months posttransplant in 94% of patients in the RAPA group compared with 50% (P=0.005) in the MMF group. Among the patients who were reversed successfully, the rates of rebound acute rejection were similar (4% vs. 8%). The mean serum creatinine values were slightly, although not significantly, lower among RAPA than MMF patients at 1, 3, 6, and 12 months: namely, 2.6 vs. 2.8, 2.8 vs. 3.2, 3.0 vs. 3.3, and 2.8 vs. 3.2 mg/dL, respectively. The 1-year patient and graft survival rates were similar: namely, 88% vs. 92% and 83% vs. 67% for the RAPA versus MMF groups. CONCLUSION: RAPA is a potent immunosuppressive agent for the treatment of refractory renal allograft rejection.     

Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: the "creeping creatinine" study

BACKGROUND: This study determined whether cyclosporine A (CsA)-treated renal allograft recipients with deteriorating renal function ("creeping creatinine") secondary to chronic allograft nephropathy (CAN) benefit from the addition of mycophenolate mofetil (MMF) to their immunosuppressive regimen, followed by withdrawal of CsA. METHODS: In a controlled, open, multicenter study, CsA-treated renal allograft recipients with progressively deteriorating renal function were randomized to have their CsA discontinued with the concomitant addition of MMF to their regimen (group A) or to continue treatment with CsA (group B). The primary endpoint was the response rate over the 6-month period after withdrawal of CsA in group A or the equivalent time in group B. Response was defined as a stabilization or reduction of serum creatinine (SCr), as evidenced by a flattening or positive slope of the 1/SCr plot and no graft loss. Secondary endpoints included the incidence of acute rejection, graft and patient survival, and changes in selected metabolic parameters. RESULTS: The response rate in the primary intent-to-treat population (n=122) was 58% (36/62) in group A versus 32% (19/60) in group B (P=0.0060). The corresponding percentages of responders in the per-protocol population (n=107) were 60% (36/60) and 26% (12/47), respectively (P=0.0008). There were no acute rejections in group A during the study period. Patients in this group also experienced a significant decrease in total cholesterol. CONCLUSIONS: In patients with progressively deteriorating renal function secondary to CAN, addition of MMF followed by withdrawal of CsA results in a significant improvement in transplant function without the risk of acute rejection.     

Reduced kidney transplant rejection rate and pharmacoeconomic advantage of mycophenolate mofetil.

BACKGROUND: Several multinational controlled clinical trials have shown that triple therapy immunosuppressive regimens which include mycophenolate mofetil (MMF), cyclosporin A (CSA) and steroids (S) are superior compared with conventional regimens which include azathioprine (AZA), CSA and S, mainly because MMF reduces the rate of acute rejection episodes in the first 6 months after kidney transplantation. Post-marketing studies are useful to evaluate the general applicability and costs of MMF-based immunosuppressive regimens. METHODS: Based on the excellent results of the published controlled clinical trials, we have changed the standard triple therapy immunosuppressive protocol (AZA+CSA+S) to an MMF-based regimen (MMF+CSA+S) at our centre. To analyse the impact of this change in regimen, we have monitored 6-month patient and graft survival, rejection rate, serum creatinine and CSA levels, as well as the costs of the immunosuppressive and anti-rejection treatments, in 40 consecutive renal transplant recipients (MMF group) and have compared the data with 40 consecutive patients transplanted immediately prior to the change in regimen (AZA group). RESULTS: Recipient and donor characteristics were similar in the AZA and MMF groups. Patient survival (37/40; 92.5% in the AZA group vs 38/40; 95% in the MMF group), graft survival (36/40 vs 36/40; both 90%) and serum creatinine (137+/-56 vs 139+/-44 micromol/l) after 6 months were not significantly different. However, the rate of acute rejection episodes (defined as a rise in creatinine without other obvious cause and treated at least with pulse steroids) was significantly reduced with MMF from 60 to 20% (P=0.0005). The resulting cost for rejection treatment was lowered 8-fold (from sFr. 2113 to 259 averaged per patient) and the number of transplant biopsies was lowered > 3-fold in the MMF group. The cost for the immunosuppressive therapy was increased 1.5-fold with MMF (from sFr. 5906 to 9231 per patient for the first 6 months). CONCLUSIONS: The change from AZA to MMF resulted in a significant reduction in early rejection episodes, resulting in fewer diagnostic procedures and rehospitalizations. The optimal long-term regimen in terms of patient and pharmacoeconomic benefits remains to be defined.     

Renal function after liver transplantation: calcineurin inhibitor nephrotoxicity

Renal failure, mainly due to calcineurin inhibitor (CNI) nephrotoxicity, is the most common complication following orthotopic liver transplantation (ltx). The aim of this study was to evaluate the incidence and course of renal failure in adult ltx patients. Severe acute renal failure in early postoperative period due to impaired hemodynamics and CNI nephrotoxicity, occurred in 14 patients, 3 of whom required dialysis. The creatinine clearance after ltx showed a tendency to decrease, but there was no statistically significant difference (P >.05) in the change in serum creatinine clearance levels between patients treated with tacrolimus (TAC) versus Cyclosporine (CsA) during the first 2 years of follow-up. Fourteen patients required conversion of their regimen because of CNI nephrotoxicity namely, dose reduction (n = 7) or discontinuation of CNI therapy with the replacement by mycophenolate mofetil (MMF) (n = 5) or SRL (n = 5). Dose reduction or CNI withdrawal significantly improved the creatinine clearance (P <.05) without affecting lives graft function. No episode of acute rejection was observed after conversion. Neither conversion of CsA to TAC nor the reverse maneuver significantly influenced the serum creatinine level (P >.05). Reduction of the CNI dose or CNI discontinuation or replacement with MMF or SRL in patients with stable liver but impaired renal function is safe, resulting in a significant improvement in renal function.     

Observations on quadruple immunosuppression maintenance therapy using rapamycin, low-dose cyclosporine, mycophenolate mofetil, and prednisone following ATG induction

INTRODUCTION: We prospectively evaluated an immunosuppressive regimen consisting of rapamycin (Rapa), low-dose cyclosporine (CsA), low-dose mycophenolate mofetil (MMF), and prednisone (group 1) versus a regimen of CsA, MMF, and prednisone (group 2) in mismatched living related donor (LRD) and living unrelated donor (LUD) kidney transplantation. METHODS: Group 1 included 24 transplant recipients of eight mismatched LRD and 16 LUD, treated with Rapa, low-dose MMF, CsA, and prednisone. Group 2 included 53 transplant recipients (25 LRD, 27 LUD, and one cadaveric donor), treated with MMF, CsA, and prednisone. All patients in group 1 received a single bolus of rabbit-anti-human T-lymphocyte immune serum (ATG-Fresenius 4 to 6 mg/kg). In group 2, patients received either a single ATG or an extended ATG course (3 to 5 days postoperatively). RESULTS: Acute rejection occurred in one patient in group 1 (4.2%) and in five patients (9.4%) in group 2, all of which resulted in graft loss. Serum creatinine was not significantly different between the two groups. CONCLUSION: The immunosuppressive protocol of Rapa, CsA, MMF, and prednisone with single-bolus induction ATG achieves excellent immunosuppression and graft survival with no apparent risks in the short and intermediate term.     

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

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

Steroid withdrawal in living donor renal transplant recipients using tacrolimus and cyclosporine: a randomized prospective study.

Steroids have been a mainstay of immunosuppressive regimens in renal transplantation despite their adverse effects. The introduction of new immunosuppressant has improved the survival rates and prompted trials of steroid withdrawal. We conducted a randomized prospective study to compare steroid withdrawal at 6 months post-transplant between tacrolimus + mycophenolate mofetil (MMF) (FK group) versus cyclosporine A + MMF (CsA group). Steroid was withdrawn at 6 months post-transplant under the condition of no rejection episode proven by biopsy and maintenance of serum creatinine level <2.0 mg/dl. Fourteen recipients were excluded because of acute rejection within 6 months or protocol violation. Steroid could be tapered off in 62 in FK group and 55 in CsA. Three cases in FK group and five in CsA had acute rejection within another 6 months after steroid withdrawal (P > 0.05). At 12 months, the incidence of post-transplant diabetes was 18.6% vs. 8.0% in FK and CsA group. And hypercholesterolemia was presented in 8.5% vs. 2.0%, hypertension in 47.5% vs. 56.0%, and serum creatinine level 1.18 +/- 0.24 mg/dl vs. 1.18 +/- 0.20 mg/dl, respectively (P > 0.05). Steroid withdrawal may be carried out successfully using both FK and CsA with MMF, but long-term follow-up is necessary.     

Results of a 6-month, multicenter, open-label, prospective study concerning efficacy and safety of mycophenolate sodium in de novo kidney transplant recipients

BACKGROUND: Mycophenolate sodium (MPS) was designed to reduce the gastrointestinal side effects of mycophenolic acid. The aim of our study was to determine the safety and efficacy of MPS in de novo renal transplant recipients. PATIENTS AND METHODS: This 6-month, multicenter, open-label, single-arm, prospective study was carried out in three centers in Poland. Thirty patients were recruited. Immunosuppressive regimen contained of MPS and cyclosporine (CsA) with or without steroids. RESULTS: The 6-month graft and patient survival was 100%. The incidence of suspected acute rejection episodes (ARE) was 5/30 (16.7%), including biopsy-proven ARE in 2 (6.7%) cases. ARE reversed after therapy. At month 6, the mean serum creatinine level was 1.4 mg/dL, and the mean creatinine clearance (according to the Cockroft-Gault formula) was >70 mL/min. The most frequent adverse effects included diarrhea, delayed graft function, anemia, and lymphocele. Among infections, most common were infections of urinary tract, cytomegalovirus infections, and infections of respiratory tract. Only three patients (10.0%) terminated the study prematurely, including two who discontinuated because of an adverse event, and one because of noncompliance. CONCLUSIONS: An immunosuppressive regimen, including MPS and CsA, with or without steroids, provided effective antirejecton prophylaxis and was well tolerated.