Tacrolimus with Mycophenolate Mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in Cardiac Transplant Patients: 1-Year Report

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.     

Long‐term follow‐up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin

Cholongitas E, Shusang V, Germani G, Tsochatzis E, Raimondo ML, Marelli L, Senzolo M, Davidson BR, Patch D, Rolles K, Burroughs AK. Long‐term follow‐up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin.
Clin Transplant 2011: 25: 614–624. © 2010 John Wiley & Sons A/S. Abstract: Background: Early withdrawal of steroids after liver transplantation has benefits, but rarely is total avoidance of steroids used. We evaluated long‐term results of patients with ab initio monotherapy with cyclosporin (CYA) vs. tacrolimus (TAC), in randomized and cohort studies. Methods: We evaluated long‐term outcomes in 66 adults randomized to TAC or CYA and 94 subsequent patients who received TAC. Protocol liver biopsies were performed. Rejection was treated with three 1 g/d methylprednisolone. Further rejection after two courses of methylprednisolone was defined as monotherapy failure. Results: Actuarial five‐yr survival was 68% in TAC and 70% CYA. Monotherapy failed in 8% TAC and 13% CYA patients; no rejection in 24% TAC and 19% CYA patients; 42% TAC and 33% CYA patients were not exposed to any steroids. Rejection episodes were less with TAC, compared to CYA: mean 1.8 vs. 2.5, p = 0.042. Chronic rejection occurred in only 4 (11%) CYA patients. During follow‐up of median 97 months (range: 0.06–145), there were 16 (44%) deaths in CYA and 48 (39%) in TAC patients (p > 0.05). Conclusions: TAC monotherapy ab initio is a viable immunosuppressive strategy in liver transplantation and was associated with lower rejection rates and renal complications, compared to CYA.     

Evolution of cardiovascular risk after liver transplantation: A comparison of cyclosporine A and tacrolimus (FK506)

The development of atherosclerotic cardiovascular complications is a common and serious problem for the long-term survivors of organ transplantation. Cyclosporine A plus steroid-based immunosuppression regimens in these patients are associated with the development of hypertension, hyperlipidemia, obesity, and diabetes mellitus. Whether the new immunosuppressive agent tacrolimus (FK506) confers any advantage in terms of these cardiovascular risk factors has been less well studied. We compared serial changes in blood pressure, lipids, body weight, and glucose levels during the first 12 months after liver transplantation in patients using either cyclosporine A (n = 39) or tacrolimus (n = 24)-based immunosuppression. By 12 months, the prevalence of hypertension, hypercholesterolemia, and obesity was increased in the cyclosporine A group compared to tacrolimus: 82% versus 33%, 33% versus 0%, and 46% versus 29%, respectively (all p < .05). Triglyceride and total cholesterol levels were 196 +/- 23 versus 125 +/- 13 mg/dL and 225 +/- 9 versus 159 +/- 7 mg/dL for the cyclosporine A versus tacrolimus groups, respectively (p < .05). Cumulative posttransplant steroid dose was not related to the observed lipid changes in either group, although the increase in triglycerides was positively correlated to weight gain and diuretic use in the cyclosporine A group. The incidence of diabetes mellitus was not increased from baseline in either group. These results indicate that tacrolimus, compared to cyclosporine A, is associated with a less adverse cardiovascular risk profile in the first year after liver transplantation. Whether these differences persist and become clinically relevant to a liver transplant recipient population that is increasingly older and has more preexisting cardiovascular disease remains to be determined. (Liver Transpl Surg 1997 Jan;3(1):1-9)     

Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months

BACKGROUND: This is the first report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Results at 6 months of follow-up are presented. METHODS: Before transplantation, patients were randomized to receive tacrolimus plus corticosteroids with sirolimus (n=185) or MMF (n=176). The primary endpoint of the study was the incidence of biopsy-confirmed acute rejection. Patient and graft survival, renal function, and composite endpoints also were evaluated. Safety was assessed by monitoring laboratory parameters and adverse events. RESULTS: By 6 months of follow-up, the incidence of biopsy-confirmed acute rejection was similar in both treatment groups (13.0% tacrolimus+sirolimus vs. 11.4% tacrolimus+MMF; P=0.64 log-rank). Patient survival (97.3% tacrolimus+sirolimus vs. 97.7% tacrolimus+MMF) and graft survival (93.0% tacrolimus+sirolimus vs. 95.5% tacrolimus+MMF) were equivalent (P=0.53, overall survival log-rank). There was a significantly higher incidence of study drug discontinuation in patients receiving sirolimus (21.1% vs. 10.8%; P=0.008). Renal function was significantly better in the MMF-treatment group (serum creatinine 1.44+/-0.45 mg/dL vs. 1.77+/-1.42 mg/dL; P=0.018). Hyperlipidemia was significantly more prevalent in the sirolimus-treatment group. Diastolic blood pressure was significantly higher in sirolimus-treated patients. There were significantly more leukopenia and gastrointestinal adverse events in the MMF-treatment group. The incidence of posttransplant diabetes mellitus was 7.6% in the sirolimus group and 7.7% in the MMF group. CONCLUSION: Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.     

Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results.

BACKGROUND: Comparison studies of calcineurin inhibitors as cornerstone immunosuppressants in renal transplantation have demonstrated that tacrolimus consistently reduces acute rejection rates and, in some studies, also improves long-term renal outcome in comparison to cyclosporin A (CsA). The aim of the present 2 year follow-up of the European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was to investigate long-term clinical outcome in terms of rate of acute rejection, graft and patient survival and graft function. METHODS: The European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was a randomized, comparative 6 month trial of the calcineurin inhibitors tacrolimus and CsA in combination with both azathioprine and steroids. The intent-to-treat population (ITT) consisted of 286 patients in the tacrolimus arm and 271 in the CsA microemulsion (CsA-ME) arm. Whereas whole blood level targets were 10-20 and 5-15 ng/ml for tacrolimus and 100-400 and 100-200 ng/ml for CsA during months 0-3 and 4-6, respectively, during the investigator-driven follow-up after termination of the main study (months 7-24) no specific calcineurin inhibitor target levels were required. Follow-up data were collected at 2 years post-transplantation from 237 (82.9% of the ITT population) patients who received tacrolimus and 222 (81.9% of the ITT population) patients who received CsA-ME. RESULTS: Calculated on ITT populations, mortality (2.0% vs 3.3%; P<0.05 in Kaplan-Meier analysis) was lower, but rate of graft loss (9.3% vs 11.2%; P = 0.12 in Kaplan-Meier analysis) was not significantly different after 2 years with tacrolimus- vs CsA-ME-based immunosuppression. Biopsy-proven acute rejection was significantly lower (19.6%) with tacrolimus than with CsA-ME (37.3%) during months 0-6 (P<0.0001), but was not significantly different during months 7-12 and 13-24 of follow-up (1.7% and 0.8% with tacrolimus and 4.7% and 0.9% with CsA-ME, respectively). A composite endpoint consisting of graft loss, patient death and biopsy-proven acute rejection occurred significantly more frequently in CsA-ME patients than in tacrolimus patients (42.8% vs 25.9%; P<0.001) during 24 months follow-up. Renal function 2 years post-transplant, measured by serum creatinine concentrations, was significantly better in tacrolimus-based compared with CsA-ME-based immunosuppression (136.9 vs 161.6 micromol/l; P<0.01). Cornerstone immunosuppression remained unchanged in 82.5% and 66.2% of patients treated with tacrolimus and CsA-ME, respectively. At 2 years, more patients in the tacrolimus arm were off steroids and received calcineurin inhibitor monotherapy, and fewer tacrolimus patients remained on a triple immunosuppressive regimen. The cardiovascular risk profile was affected favourably in the tacrolimus arm, with lower cholesterol and triglyceride concentrations (despite less use of cholesterol-lowering drugs); no significant difference in requirement for antidiabetic medication was noted. CONCLUSIONS: The 2 year study results confirm that tacrolimus is a highly efficacious cornerstone immunosuppressant in kidney transplantation. Tacrolimus-based immunosuppression may induce long-term benefits with regard to graft function and graft survival. The overall side-effect profile is considered to be favourable.     

A randomized, prospective, pharmacoeconomic trial of tacrolimus versus cyclosporine in combination with thymoglobulin in renal transplant recipients

BACKGROUND: To date, the clinical trials of tacrolimus (TAC) versus cyclosporine modified (CsA), have not defined which agent is more cost-effective for immunosuppression in renal transplant recipients especially in a quadruple immunosuppressive regimen. METHODS: The objective of this randomized, prospective study was to compare the clinical and economic outcomes of TAC versus CsA, in a regimen that consisted of Thymoglobulin induction, an antimetabolite, and prednisone. Between December 2000 and October 2002, 200 patients were enrolled and randomized in a 2:1 fashion (TAC n=134, CsA n=66). RESULTS: At 1 year, acute rejection (4% TAC vs. 6% CsA), patient survival (TAC 99% vs. CsA 100%), and graft survival (95% TAC versus 100% CsA, P=0.059) were similar. Serum creatinine levels were lower in the TAC group compared with the CsA group (1.3+/-0.3 vs. 1.6+/-0.7 mg/dL, P=0.03). The incidence of CMV infection was similar between the groups and two patients, both in the TAC arm, developed malignancy. Anti-hypertensive requirement (32% TAC vs. 32% CsA) and the incidence of posttransplant diabetes mellitus (4% TAC vs. 2% CsA) were similar. Pretransplant, fewer TAC patients received dyslipidemia treatment (40% TAC vs. 67% CsA, P=0.0005), while more CsA patients were able to discontinue these medications posttransplant (absolute change 25% TAC vs. 47% CsA). Total 12-month medication costs were similar (17,723 +/- 11,647 dollars TAC vs. 16,515 +/- 10,189 dollars CsA). CONCLUSIONS: When combined with Thymoglobulin induction, an antimetabolite, and corticosteroids, TAC and CsA are comparable in safety, efficacy, and cost in renal transplantation.     

Immunosuppression with generic tacrolimus and mycophenolate mofetil in renal transplant recipients: preliminary report in Chile

The association of tacrolimus (TAC) and mycophenolate mofetil (MMF) in renal transplant patients has diminished the incidence of acute rejection. We evaluated the use of generic TAC and MMF as primary immunosuppression in 6 living related (LR) and 11 cadaveric (C) donor renal transplant recipients (9 men, 8 women) of mean age 37 +/- 12 years (range, 17-56 years) between May 2006 and June 2007. From day 0 all patients received TAC, MMF, and prednisone without antibody induction. They were followed for the development of acute rejection, graft loss, side effects, and mortality. Mean follow-up was 7.6 months (range, 2-15 months). No biopsy-proven acute rejection episodes, graft loss, or recipient deaths were observed. Creatinine levels at the end of the study were 1.90 +/- 1.0 mg/dL (range, 0.62-4.25 mg/dL for C recipients and 1.19 +/- 0.15 mg/dL (range, 0.91-1.35 mg/dL) for LR recipients. Mean systolic and diastolic blood pressures were 130/73 mm Hg with 12 patients (70.5%) on antihypertensive therapy with calcium antagonists and beta-blockers. Mean (range) of total cholesterol, triglycerides, and glucose were 172 (110-244) mg/dL, 139 (69-277) mg/dL, and 89 (63-129) mg/dL, respectively. MMF was suspended in 1 patient due to diarrhea and 1 other because of leukopenia. We observed that generic TAC and MMF yielded effective and safe immunosuppression in terms of mortality, biopsy-proven acute rejection, and graft loss with a low incidence of adverse effects during the study period.     

Primary immunosuppression with tacrolimus in kidney transplantation: three-year follow-up in a single center

INTRODUCTION: The 1-year results of the phase III US Multicenter Trial comparing tacrolimus- and cyclosporine (Sandimmun)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. This retrospective, nonrandomized, single-center study represented 3-year data for patient and graft survival and safety in the tacrolimus-treated patients. METHODS: Among 97 consecutive kidney transplant recipients 41 who received tacrolimus and 56 cyclosporine-based immunosuppression were followed for 3 years for patient and graft survivals and for the incidence of acute rejection episodes as well as serious adverse events. RESULTS: The 3-year patient and graft survival rates for tacrolimus and cyclosporine were similar (91.0% vs 90.2%, 96.5% vs 95.0%). However, the incidence of acute rejection episodes was significantly lower in the tacrolimus (17.1%) compared with the cyclosporine group (35.7%, P = .043). There was a higher incidence of headache, posttransplant diabetes, and alopecia reported in the tacrolimus group, whereas hypertension, hypercholesterolemia, and hirsutism were more frequent in the cyclosporine group. The incidences of hand tremor, hyperkalemia, and viral infections were comparable in both groups. Two patients in the tacrolimus group were converted to cyclosporine due to nephrotoxicity and posttransplant diabetes, respectively, whereas 12 patients in the cyclosporine group were converted to tacrolimus as rescue therapy for acute rejection (41.7%), gingival hyperplasia (33.3%), nephrotoxicity (8.3%), neurotoxicity (8.3%), and hirsutism (8.3%), respectively. CONCLUSION: The 3-year results of tacrolimus treatment show excellent efficacy and safety in kidney transplantation. Due to different side-effect profiles, it is necessary to develop individualized immunosuppressive strategies in kidney transplant recipients.     

Cardiovascular risk profile after conversion from cyclosporine A to tacrolimus in stable renal transplant recipients

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in renal recipients. In addition to steroids, cyclosporine A (CsA) has been implicated in contributing to increased cardiovascular risk. Conversion from CsA to tacrolimus (TAC) has been shown to improve hyperlipidemia and hypertension, but little is known about the differential effects of CsA versus TAC on other cardiovascular risk factors. We investigated overall cardiovascular risk profile after conversion from CsA to TAC. METHODS: This was an open-label, single-arm prospective study; 22 adult renal recipients who were receiving CsA-based immunosuppression with serum total cholesterol greater than 200 mg/dL more than 1 year after transplantation were enrolled. CsA was replaced by TAC. Blood pressure, fasting lipid profile, homocysteine, fibrinogen, C-reactive protein, hemoglobin A1c, and creatinine were measured at baseline and at 3 and 6 months after conversion. RESULTS: There was a significant improvement in fibrinogen (366 +/- 81 - 316 +/- 65 mg/dL, P <0.001), total cholesterol (250 +/- 50 - 207 +/- 29 mg/dL, P <0.001), and low-density lipoprotein cholesterol (155 +/- 43 - 121 +/- 24 mg/dL, P <0.001) after conversion. No new onset or worsening of diabetes mellitus was observed after conversion. There were no significant differences in HDL cholesterol, triglycerides, homocysteine, C-reactive protein, hemoglobin A1c levels, serum creatinine, mean blood pressure, and mean number of antihypertensive medications required before and after conversion. CONCLUSIONS: Our results indicate that conversion to low-dose TAC may be preferable over CsA for chronic maintenance immunosuppression because it improves the overall cardiovascular risk profile without any apparent adverse effects.     

Results of a two-center study comparing hepatic fibrosis progression in HCV-positive liver transplant patients receiving cyclosporine or tacrolimus

A 2-center retrospective analysis was performed in 60 patients undergoing liver transplantation for hepatitis C virus (HCV)-related disease (cyclosporine in 20, tacrolimus in 40). Mean (±SEM) follow-up was 23.6 ± 22.5 and 22.3 ± 13.7 months in patients receiving cyclosporine or tacrolimus, respectively. Clinically indicated biopsies were performed in 15/20 cyclosporine patients (75%) and 22/40 tacrolimus patients (55%; P = .17). The Ishak fibrosis score was significantly lower in cyclosporine-treated patients versus tacrolimus-treated patients (mean 1.7 ± 0.4 vs 3.1 ± 0.4; P = .023), as was percentage of fibrosis grade Ishak ≥4 (7% vs 41%; P = .028). The mean time to moderate fibrosis (Ishak score ≥3) was 38.2 ± 15.1 months in cyclosporine patients (4/15) and 23.5 ± 12.6 months in tacrolimus patients (14/22); the difference was not statistically significant (P = .09). This retrospective study suggests that cyclosporine-based immunosuppression is associated with less severe hepatic fibrosis in HCV-positive liver transplant recipients compared with tacrolimus-based regimens, but a larger prospective comparative trial is necessary to confirm these findings.     

Steroid-free immunosuppression in kidney transplant recipients and prograf monotherapy: an interim analysis of a prospective multicenter trial

This report described an interim analysis of a investigator-driven multicenter trial in renal transplant recipients: the Prospective Quality of life Renal Transplantation Switch Study; Tacrolimus-based immunosuppression ("PQRST study"). Patients included in the trial initially treated with cyclosporine-based immunosuppression after renal transplantation who experienced side effects, such as hypertension, hyperlipidemia, hypertrichosis, or other adverse reactions, were converted to a tacrolimus-based immunosuppressive regimen (n = 31). Steroids were subsequently discontinued between 3 and 6 months after the conversion. As of today 19/31 (50%) patients have been successfully weaned off steroids with the remaining patients in this process. In this interim analysis, with a follow-up ranging from 1 to 18 months both patient and graft survivals were 100%. No patient experienced an acute rejection episode; none of the grafts were lost. Blood pressure decreased in 22/31 (71%) of the patients. No patient developed de novo diabetes or other serious side effect related to the conversion. Three patients were withdrawn from the trial because of side effects: bleeding, depression, and proteinuria. However, none of these adverse events were felt to be directly related to the change of the immunosuppressive regimen to tacrolimus monotherapy. In conclusion, conversion from cyclosporine to tacrolimus-based therapy was safe and well tolerated; it may improve the cardiovascular risk profile after kidney transplantation.     

Conversion to low-dose tacrolimus or rapamycin 3 months after kidney transplantation: a prospective, protocol biopsy-guided study

Long-term survival of kidney allografts is primarily limited by a progressive decline in function characterized by the presence of interstitial fibrosis (IF) and tubular atrophy (TA) on biopsy. Since chronic calcineurin-inhibitor (CNI) drug toxicity has been implicated as a significant cause of IF/TA, a major effort in transplantation has been to decrease or eliminate CNI therapy. We now report the clinical and histological consequences of converting renal transplant recipients at 3 months to either very low levels of tacrolimus (TAC; 4-6 ng/mL) or sirolimus (SRL; 6-10 ng/mL) therapy. Fifty-eight enrollees in this prospective randomized trial received low-dose (2.9 ± 0.6 mg/kg) rabbit antithymocyte globulin induction followed by standard doses of TAC (10-15 ng/mL), mycophenolic acid, and low-dose steroids for 3 months. Protocol biopsies were performed at implantation and 3 and 12 months. Six patients had evidence of either borderline changes (n = 5) or grade 1A rejection (n = 1) on the 3-month protocol biopsy and were not randomized. Only one patient had clinically evident rejection that occurred after randomization to SRL. One patient in each group had borderline changes at 12 months. Renal function (estimated glomerular filtration rate) was equivalent in both groups at 12 months (TAC 74 ± 15 vs SRL 66 ± 18 mL/min, P = .22). Chronic allograft damage index scores at 1 year were similar in both groups (TAC 2.8 ± 2.4 vs SRL 2.0 ± 2.7, P = .71). The percentage of patients with IF/TA scores greater than 2 at 1 year was low in both groups (TAC 12% vs SRL 9%, P = .78). Therefore, in a low-risk population defined as having a normal 3-month protocol biopsy, TAC levels can be successfully decreased to very low concentrations. One-year graft function and histology were equally well maintained with either low-dose TAC or SRL immunosuppression.     

Controlled randomized study comparing the cardiovascular profile of everolimus with tacrolimus in renal transplantation

Left ventricular hypertrophy (LVH) regression after kidney transplantation may be influenced by immunosuppression. In a 24‐month open‐label, multicenter, phase‐IV study, 71 kidney allograft recipients without previous acute rejection, showing eGFR >40 ml/min and proteinuria <500 mg/day and between 6 months and 3 years post‐transplantation, were randomized to receive everolimus (EVR) + mycophenolic acid (MPA) or were maintained on tacrolimus (TAC) + MPA. The aim was to assess whether the conversion to EVR could reduce left ventricular mass index (LVMi) at month‐24. LVMi at month‐24 decreased without differences between groups (TAC: 54.0 vs. 48.2 g/m^2.7; EVR: 53.4 vs. 49.4 g/m^2.7). The LVH prevalence at baseline and month‐24 was 59.4% and 40.6% in TAC group and 57.1% and 50.0% in EVR group. EVR conversion was associated with nearly disappearance of concentric LVH and concentric remodeling pattern. The procollagen type I N‐terminal propeptide at month‐24 showed greater reduction in EVR group (51.6 vs. 58.2 mg/l; P = 0.004). Conversion from TAC to EVR was associated with a significant improvement of eGFR (P = 0.0315, ancova ). Adverse events were similar between groups without rejection episode or graft loss. Conversion from TAC to EVR did not further reduce LVMi after 24 months, although its effect on concentric LVH deserves further investigation (NCT01169701).     

Effects of and predictors for tacrolimus rescue therapy among renal transplant patients under cyclosporine-based immunosuppression

BACKGROUND: Though cyclosporine has dramatically decreased rejection rates and improved graft survival rates of renal allografts, there is still a remarkable rate of acute rejection and progressive deterioration of renal function after transplantation. Rescue therapy with tacrolimus has been used for allografts failing under cyclosporine-based treatment in order to get some renal functional recovery or stabilization. The aim was to evaluate tacrolimus rescue therapy for failing allografts under cyclosporine-based immunosuppression for possible prediction factors for success. PATIENTS AND METHODS: Thirty-five renal allograft recipients with failing transplants under cyclosporine-based immunosuppression were enrolled into this study. Renal function was evaluated by reciprocal serum creatinine level (1/Cr) and calculated CCr. The slope of changes in 1/Cr and CCr were calculated before and after tacrolimus therapy. The possible risk factors that affect the outcome of tacrolimus rescue therapy were analyzed. RESULTS: Nineteen patients showed improved renal function (group 1) and 16 patients, persistent deterioration (group 2) after rescue therapy. Group 1 showed positive slopes of changes of 1/Cr and CCr after rescue therapy. Group 2 patients showed persistent negative slopes although less negative than before rescue therapy. Only the posttransplant time was the significant predictive factor for successful tacrolimus therapy (P = .018). CONCLUSION: Tacrolimus rescue therapy improved or stabilized renal function in some patients with failing grafts under cyclosporine-based immunosuppression. To assure a successful rescue effect, it should be given early after transplantation, if there is a tendency toward deterioration of renal function.     

Tacrolimus and cyclosporin doses and blood levels in hepatitis C and alcoholic liver disease patients after liver transplantation.

Hepatitis C virus (HCV)-induced cirrhosis is the most common indication for liver transplantation (LT). However, graft reinfection is nearly universal. The choice of immunosuppression, including the calcineurin inhibitor (CNI), may have some effect on severity of recurrence and graft survival. In addition, HCV recurrence may have some impact on metabolism of immunosuppressive drugs. In this retrospective study, we examined the dose and blood levels of tacrolimus (TAC) and cyclosporin A (CYA) in HCV patients consecutively undergoing transplantation (TAC, n = 44; CYA, n = 60) and surviving 12 months post-LT. In addition, we examined the CNI dose and blood levels in an age- and gender-matched comparison group of patients who were transplanted for alcoholic liver disease (ALD) (TAC, n = 44; CYA, n = 47). During the 12-month period of observation, TAC levels were significantly higher for HCV than for ALD patients (P = 0.002). The dose of TAC decreased over time for both HCV and ALD patients (P < 0.001), but the reduction was greater for HCV patients (P = 0.03). CYA dose decreased over time for both groups (P < 0.001) but a greater reduction was observed for the HCV group (P = 0.007). For both HCV and ALD patients, CYA levels decreased over time (P < 0.001) but there was no significant difference between HCV and ALD patients. Thus, to maintain comparable blood levels, a greater reduction of dose was required for HCV than for ALD patients. In conclusion, our observations demonstrate a likely effect of HCV infection on CNI metabolism, an effect that is not clearly due to graft damage. Physicians need to be alert to this interaction and to the need to respond quickly to changes in CNI levels that may be associated with HCV infection and with HCV clearance during antiviral therapy.     

Tacrolimus as secondary intervention vs. cyclosporine continuation in patients at risk for chronic renal allograft failure

BACKGROUND: Chronic renal allograft failure (CRAF) is the leading cause of graft loss post-renal transplantation. This study evaluated the efficacy and safety of tacrolimus as secondary intervention in cyclosporine-treated kidney transplantation patients with impaired allograft function as indicated by elevated serum creatinine (SCr) levels. METHODS: Patients receiving cyclosporine-based immunosuppression who had an elevated SCr at least 3 months post-renal transplantation were enrolled. Treatment allocation was 2:1 to switch to tacrolimus or continue cyclosporine. This analysis was performed after 2 yr; patients will be followed for an additional 3 yr. RESULTS: There were 186 enrolled and evaluable patients. On baseline biopsy, 90% of patients had chronic allograft nephropathy. Baseline median SCr was 2.5 mg/dL in both treatment groups. For patients with graft function at month 24, SCr had decreased to 2.3 mg/dL in the tacrolimus-treated patients and increased to 2.6 mg/dL in the cyclosporine-treated patients (p = 0.01). Acute rejection occurred in 4.8% of tacrolimus-treated patients and 5.0% of cyclosporine-treated patients during follow-up. Two-year allograft survival was comparable between groups (tacrolimus 69%, cyclosporine 67%; p = 0.70). Tacrolimus-treated patients had significantly lower cholesterol and low-density lipoprotein levels and also had fewer new-onset infections. Cardiac conditions developed in significantly fewer tacrolimus-treated patients (5.6%) than cyclosporine-treated patients (24.3%; p = 0.004). Glucose levels and the incidences of new-onset diabetes and new-onset hyperglycemia did not differ between treatment groups. CONCLUSIONS: Conversion from cyclosporine to tacrolimus results in improved renal function and lipid profiles, and significantly fewer cardiovascular events with no differences in the incidence of acute rejection or new-onset hyperglycemia.     

Comparison of steroid avoidance in tacrolimus/mycophenolate mofetil and tacrolimus/sirolimus combination in kidney transplantation monitored by surveillance biopsy

BACKGROUND: Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation. METHODS: In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored. RESULTS: Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P = 0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P = 0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy. CONCLUSIONS: Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.     

Ethnic disparity in clinical outcome after heart transplantation is abrogated using tacrolimus and mycophenolate mofetil-based immunosuppression

BACKGROUND: Black American heart transplant recipients receiving cyclosporine-based primary immunoprophylaxis suffer higher rates of allograft rejection with hemodynamic compromise, infections, and posttransplant coronary artery disease. We examined the hypothesis that a combination of tacrolimus and mycophenolate mofetil "resurrects" clinical outcome of black Americans to those seen in white heart transplant recipients. METHODS: Sixty-three adult primary heart transplant recipients were included in this study. Twenty black American and 21 white patients who received tacrolimus-based primary immunoprophylaxis were enrolled in this prospective, observational parallel cohort investigation. A separate group of 22 black American patients were randomly allocated to receive cyclosporine-microemulsion-based primary prophylaxis and served as the control population for assessing outcomes in the black American group. Adjunctive immunosuppression included mycophenolate mofetil and corticosteroids. The primary end-point was the freedom from allograft rejection requiring treatment at 1 year. Secondary end-points included rejection with hemodynamic compromise, and patient or graft survival. Adverse events evaluated included development of infections requiring hospitalization and nonimmunological outcomes including hyperlipidemia, hypertension, and diabetes mellitus (new onset or worsened). RESULTS: Tacrolimus-treated black American patients had greater freedom from allograft rejection requiring treatment at 1 year than those treated with cyclosporine (64% vs. 37%, P=0.01). No differences were noted between tacrolimus-treated black Americans and whites in the primary end point (64% and 67% respectively, P=nonsignificant [NS]). Tacrolimus-based immunosuppression was associated with better 1-year survival in black Americans compared with cyclosporine (95% vs. 73%, P=0.04), and this end point was similar to that achieved in tacrolimus-treated white heart transplant recipients (95%). No differences in infection rates were noted among either group. Cyclosporine-treated black Americans suffered more hyperlipidemia and worse hypertension than tacrolimus-treated patients. CONCLUSIONS: Compared with cyclosporine, an immunosuppressive strategy using tacrolimus in black Americans achieves superior efficacy with regard to allograft rejection, higher allograft survival, and similar safety. Furthermore, tacrolimus-based immunosuppression is similar in immunological efficacy and safety in black Americans and in white heart transplant recipients.     

Renal allograft outcomes in African American versus Caucasian transplant recipients in the tacrolimus era

METHODS: Between January 1995 and December 1999, 185 kidney transplants were performed with tacrolimus (TAC)-based immunosuppression including 120 African American (AA, 65%) and 65 Caucasian recipients (C, 35%). Mean follow-up was 34 months. The AA group was characterized by a higher incidence of renal disease due to hypertension (72% AA vs 37% C, P <.001), pretransplant dialysis (95% AA vs 82% C, P =.003), waiting time (1.9 years AA vs 1.1 years C, P =.02), cadaveric donation (88% AA vs 68% C, P =.01), HLA mismatching (mean 3.5 AA vs 2.4 C, P <.001), and delayed graft function (DGF; 50% AA vs 22% C, P =.001). RESULTS: The 5-year actuarial patient and graft survival rates were 96% AA versus 83% C (P = NS) and 83% AA versus 75% C, (P = NS), respectively. The incidence of acute rejection (21% AA vs 12% C, P = NS) and mean time to acute rejection (12 months AA vs 11 months C) were similar. Although the incidence of chronic allograft nephropathy (CAN) was comparable (7% AA vs 5% C), the mean time to CAN was shorter in AA recipients (18 months AA vs 37 months C, P =.03). CONCLUSIONS: These results suggest marked improvement in post-transplant outcomes in the TAC era in patients with multiple immunologic risk factors including AA ethnicity, cadaveric donor source, DGF, and HLA mismatching.     

Predictors of renal function improvement following tacrolimus conversion in cyclosporine-treated kidney transplant recipients

The objective of this study was to evaluate the relationship between variability of cyclosporine (CsA) absorption and tacrolimus (TAC) conversion seeking factors that predict improvement in allograft function after TAC conversion. We performed a retrospective study of 44 adult kidney transplant recipients undergoing conversion from CsA to TAC-based immunosuppression. Before TAC conversion, patients had complete, consecutive, 6 monthly C2 levels and a follow-up duration beyond 6 months after TAC conversion. The patients were divided into 2 groups: one (n=23) with low variability of CsA absorption and one (n=21) with high variability of CsA absorption. At TAC conversion, the estimated glomerular filtration rate (eGFR) was similar in both patient groups. Six months after TAC conversion, eGFR improved in both groups. Stepwise regression analysis revealed the DeltaSCr6 (change in serum creatinine level at 6 months) to be independently associated with the preconversion serum creatinine (SCr; P<.0001) and the percent coefficient of variation (%CV) of SCr (P=.0034). DeltaSCr6 was inversely associated with posttransplantation years (P=.0033), and 6-month TAC blood levels (P=.0053). The DeltaSCr6 was not associated with variability of oral CsA absorption. The cutoff value of baseline SCr at TAC conversion differentiated an increase in or reduction of SCr to be about 1.0 mg/dL. Our study of CsA-treated kidney transplant recipients who underwent TAC conversion showed that a preconversion SCr>1.0 mg/dL, a high variability of SCr, and early TAC conversion predicted greater short-term benefit on graft function.