Substitution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year

BACKGROUND: A new galenic form of cyciosporin A has been developed, basedon microemulsion technology. The bioavailability of the compoundis reiativeiy independent of food intake and bile flow. It wasthe purpose of this prospective clinical trial to study thesafety of the microemulsion form of cyclosporin A. METHODS: Three hundred and two renal transplant patients, stratifiedaccording to transplant age, were switched from the conventionalto the new micro-emulsion formulation of cyclosporin A. A 1:1conversion ratio was used. Measurements included CsA levels,S-creatinine, liver enzymes, uric acid, and blood pressure.Measurements were performed at baseline and on days 4, 8, 15,29 and months 3, 6 and 12 after conversion. Dose adjustmentswere performed to achieve trough levels of 80–120 ng/ml. RESULTS: Within the 12-month observation period the cyclosporin dosewas reduced by 14.7% (from 204±60 mg/day at baselineto 174±51 mg/day after conversion, P<0.001). Acutely,i.e. by day 8, a 1:1 dose conversion resulted in a modest increaseof mean drug trough levels (from 114 ng/ml at baseline to 120ng/ml, P<0.01). This increase was accompanied by an increasein serum creatinine concentration, a decrease in calculatedcreatinine clearance, and an increase in uric acid values (P0.05).Liver enzymes remained unchanged while systolic and mean arterialblood pressure decreased (P<0.05). After 1 month, drug troughlevels had decreased to baseline (112 ng/ml) and remained thereuntil month 6. They were significantly lower after 12 months(102±33 ng/ml, P<0.001). Creatinine clearance valuesincreased to above baseline at 6 and 12 months. Within the 1-yearperiod there occurred 24 (=8%) episodes of biopsy-proven rejectionand seven episodes of cyclosporin-attributed nephrotoxicity. CONCLUSIONS: The 1:1 conversion from conventional cyclosporin A to the microemulsionformulation is efficacious and safe, but an initial dose reductionof 10% is advised in patients with trough levels in the high-normalrange.     

Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac (n=103) or CyA microemulsion (n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baselinecharacteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute re-jection (36.9%) compared with CyA therapy (59.1%) (P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group (P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62±20 ml/min per 1.73 m², n=84) than in the CyA group (56±21 ml/min per 1.73 m², n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences (P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the Tac group and 2 patients in the CyA group. In conclusion, Tac was significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population. The overall safety profiles of the two regimens were comparable. Received: 1 October 2001 / Revised: 25 October 2001 / Accepted: 15 November 2001     

Four-year follow-up of a prospective randomized trial of mycophenolate mofetil with cyclosporine microemulsion or tacrolimus following liver transplantation

BACKGROUND: This is a 4-yr follow-up of a trial using mycophenolate mofetil (MMF) induction in orthotopic liver transplantation (OLT). The goal of this study was to evaluate a multidrug approach that would reduce both early and long-term morbidity related to immunosuppression while maintaining an acceptable freedom from rejection. METHODS: This was a prospective, randomized, intent to treat study designed to compare the primary endpoints of rejection and infection, and secondary endpoints of liver function, renal function, bone marrow function, cardiovascular risk factors, and the recurrence of hepatitis C. Ninety-nine consecutive patients with end stage liver disease who underwent OLT were randomized to receive either cyclosporine microemulsion (N) (50 patients) or tacrolimus (FK) (49 patients) starting on postoperative day 2, with MMF and an identical steroid taper begun preoperatively. RESULTS: Ninety of 99 patients (N 46, FK 44) completed the 4-yr follow-up. The overall 4-yr patient and graft survivals were 93 and 89%, respectively. There was no significant difference in 4-yr patient (N 96% vs. FK 90%, p = ns) or graft (N, 90% vs. FK, 88%, p = ns) survival between groups. The 4-yr rejection rate was not significantly different in either arm (N = 34%, FK = 24%; p = 0.28). There were no differences in infection rates in either arm. The patients with hepatitis C had no differences in the viral titers or Knodell biopsy scores between groups. However, in the hepatitis C subgroup (37 patients), the FK patients had a significantly lower rejection rate (p = 0.0097) and a significantly lower clinically recurrent hepatitis C rate (p = 0.05) than the N patients. No difference was seen in the percent of patients weaned off of steroids after 4 yr (N 51%, FK 49%). There were no differences in the incidences of diabetes mellitus and hypertension. When renal dysfunction was analyzed, a significant difference in the number of patients whose creatinine had increased twofold since transplant was seen (N 63%, FK 38%, p = 0.04). CONCLUSIONS: Use of MMF induction and maintenance following OLT in conjunction with either N or FK and an identical steroid taper, resulted in an acceptable long-term incidence of rejection and infection, without an increase in long-term graft or patient morbidity.     

Efficacy and safety of tacrolimus compared with ciclosporin‐A in renal transplantation: 7‐year observational results

The European Tacrolimus versus Ciclosporin‐A Microemulsion (CsA‐ME) Renal Transplantation Study demonstrated that tacrolimus decreased acute rejection rates at 6 months. Primary endpoints of this investigator‐initiated, observational 7‐year follow‐up study were acute rejection rates, patient and graft survival rates, and a composite endpoint (BPAR, graft loss, and patient death). We analyzed data from the original intent‐to‐treat population (n = 557; 286 tacrolimus, 271 CsA‐ME). A total of 237 tacrolimus and 208 CsA‐ME patients provided data. At 7 years, Kaplan–Meier estimated rates of patients free from BPAR were 77.1% in the tacrolimus arm and 59.9% in the CsA‐ME arm, graft survival rates amounted to 82.6% and 80.6%, and patient survival rates to 89.9% and 88.1%. Estimated combined endpoint‐free survival rates were 60.2% in the tacrolimus arm and 47.0% in the CsA‐ME arm (P = <0.0001). A higher number of patients from the CsA‐ME arm crossed over to tacrolimus during 7 year follow‐up: 19.7% vs. 7.9% (P = <0.002). More patients in the tacrolimus group stopped steroids and received immunosuppressive monotherapy. Significantly, more CsA‐ME patients received lipid‐lowering medication and experienced cosmetic and cardiovascular adverse events. Tacrolimus‐treated renal transplant recipients had significantly higher combined endpoint‐free survival rates mainly driven by lower acute rejection rates despite less immunosuppressive medication at 7 years.     

A case of tacrolimus nephrotoxicity appearing in a second renal transplantation patient

Oka K, Moriyama T, Imai E, Kyo M, Toki K, Tanaka T, Hori M, Kokado Y, Okuyama A, Takahara S. A case of tacrolimus toxicity appearing in a second renal transplantation patient. Clin Transplantation 2001: 15 (Supplement 5): 30–34. ©Munksgaard, 2001
We experienced a case of a second renal trans- plantation patient. With the use of cyclosporin, he lost his first graft because of chronic rejection; with the use of tacrolimus, his second graft suffered from drug nephrotox- icity. On his second renal transplantation, his graft function deteriorated and required haemodialysis with the use of tacrolimus. Repeated biopsies did not reveal the typical characteristics of acute tacrolimus nephrotoxicity and acute rejection. His tacrolimus trough level was not high during the clinical course; however, by reducing tacrolimus dosage, his graft function eventually recovered to mild renal dys- function. This observation was helpful for clinical diagnosis of the functional toxicity of tacrolimus. The case is interest- ing in considering the functional toxicity of tacrolimus and the difference between tacrolimus and cyclosporin in terms of immunosuppressive and nephrotoxic actions.     

Acute effect of cyclosporin on renal function following the initial changeover to a microemulsion formulation in stable kidney transplant patients

Potential differences in the acute effect of cyclosporin on renal function when dosed orally as the current market formulation or following a milligram-to-milligram conversion to a new microemulsion formulation were investigated in 14 stable kidney transplant patients. The study consisted of three sequential periods of 2 weeks duration each. Patients entered (period I) and completed (period III) the investigation with the market formulation and received the microemulsion formulation in period II; individualized cyclosporin doses remained unchanged throughout the study. Over one steady-state dosing interval at the end of each study period, whole blood cyclosprin pharmacokinetic profiles were assessed in parallel with endogenous creatinine clearances over sequential 1-to 2-h intervals. The rate and extent of cyclosporin absorption were significantly greater (P<0.01) from the microemulsion formulation with average increases of 73% in peak concentration and 44% in area under the curve compared to the market formulation. Sequential creatinine clearances exhibited a transient decrease with the nadir occurring on average between 4 and 6h post dose followed by a rapid return to baseline. Specifically in period I on the market formulation, clearances decreased from a baseline of 71.7±20.6 to a minimum of 51.1±17.9 ml/min per 1.73 m² (similar values in period III) and from 76.8±24.8 to 53.5±17.5 ml/min per 1.73 m² in period II on the microemulsion. Neither the baseline nor minimum clearances were significantly different among the study periods. Hence, the pharmacokinetic differences between the formulations did not acutely influence the pattern of glomerular filtration rate following the initial milligramto-milligram changeover in stable renal transplant patients.     

Elective withdrawal of cyclosporin following renal transplantation: A single centre experience

SUMMARY: Withdrawal of cyclosporin in the early post-transplant period may provoke acute graft dysfunction, although the reported incidence is variable. We have reviewed our experience of 212 renal transplant recipients to determine the incidence of early post-withdrawal acute graft dysfunction and examine which factors predict it. Gender, age at initiation of withdrawal, timing and duration of withdrawal, pre-withdrawal immunosuppression, doses of prednisolone and azathioprine at initiation of withdrawal and, during the first 6 months post witfidrawal, episodes of prior acute transplant rejection, human leucocyte antigen match and previous renal transplantation were considered. In classifying acute graft dysfunction, a 50% increase in serum creatinine from baseline was taken as a minimum criterion, and additional evidence (biopsy, fine needle aspirate, response to immunotherapy) was sought for evidence of a link with cyclosporin withdrawal. Acute graft dysfunction was documented in 28 (13.2%) patients, 26 episodes occurring within 4 months of completion of cyclosporin withdrawal. the mean time interval from transplantation to initiation of withdrawal was significantly shorter in this group (239 vs 299 days, P < 0.02). the median withdrawal period was of similar duration in the groups with and without acute dysfunction, but for the subgroup of patients previously on triple therapy (cyclosporin, prednisolone and azathioprine, n = 78), withdrawal had occurred more rapidly in those with dysfunction (25 vs 67 days, P < 0.05). None of the remaining variables that were considered had a significant effect on outcome, although subgroups tended to be small. Cyclosporin withdrawal may be safer if delayed until after the first post-transplant year with gradual dose reduction over a period of months.     

肾移植术后普通环孢素A与环孢素A微乳剂对移植肾功能影响的系统评价

目的评价肾移植术后普通环孢素A与环孢素A微乳剂对受者移植肾功能影响的差异。方法遵循Cochrane肾脏协作组随机对照试验检索策略，检索MEDLINE（1994—2006．3）、EMBASE（1994～2006．3）、中国生物医学文献数据库CBM（1994—2006．3）、Cochrane图书馆（2005年第4期）与肾移植相关的8种中文杂志。采用Revman4．2．7进行Meta分析。结果共有5个随机对照试验纳入研究，包括1671例同种异体尸体肾移植患者。结论肾移植术后使用普通环孢素A与环孢素A微乳剂相比受者移植肾功能无明显差异，但环孢素A微乳剂肾毒性发生率较高。     

Cyclosporin A withdrawal in live related renal transplantation: long-term results

Cyclosporin A (CsA) withdrawal after 1 yr of stable graft function has been shown to be beneficial in cadaveric renal transplantation. This strategy could be even more suitable for 'immunologically advantaged' grafts as in live related renal transplantation. We report the long-term outcome of patients in a live related transplantation programme undergoing early (between 1989 and 1992) and late (1993 onwards) CsA withdrawal as compared with those on long-term low dose CsA (1993 onwards). Two-hundred and fifty-two patients were divided into three groups based on the following immunosuppressive protocol: group ECyW (n=99), early CsA withdrawal (9 months after transplantation); group LCyW (n=44), late CsA withdrawal (median 16 months, range 13--22 months after transplantation); and group LDCy (n=109), long-term low dose CsA. The median period of follow-up was 66 months after transplantation (range 43--84 months). There was no difference in the actuarial 6-yr patient or graft survival among the three groups. Acute rejection episodes were more frequent in ECyW (54.4%) than in LDCy (31.8%) and LCyW (23.8%) (p=0.001). The risk of developing late (> or =9 months) acute rejection was highest in ECyW 32/99 (32.3%) as compared with LCyW 8/44 (18.4%; p=0.08) and LDCy 8/109 (7.3%; p=0.0001). Of the 32 ECyW patients who developed acute rejection episodes after CsA withdrawal, 13 (40.6%) lost their grafts either due to uncontrolled acute rejection or to chronic rejection. Chronic rejection was higher in ECyW (24%) than in LCyW (11%; p=0.04) and LDCy (17%; p=0.17). Antihypertensive requirement was highest in patients maintained on low dose CsA. Graft function, as measured by serum creatinine levels, was significantly better in LCyW (1.24+/-0.4 mg%) as compared with ECyW (1.49+/-0.5 mg%) and LDCy (1.48+/-0.6 mg%). Early CsA withdrawal after live related renal transplantation is associated with a significant risk of acute rejection and subsequent chronic rejection. Slow withdrawal after 1 yr is safe and more economical than the long-term administration of low dose CsA.     

Hyponatraemia and hyperkalaemia are more frequent in renal transplant recipients treated with tacrolimus than with cyclosporin. Further evidence for differences between cyclosporin and tacrolimus nephrotoxicities.

BACKGROUND: This study was designed to examine the hypothesis that the nephrotoxicities caused by cyclosporin and tacrolimus might differ in respect of sodium and potassium handling. METHODS: 125 patients were studied retrospectively for the first 90 days after renal transplantation. Eighty were treated initially with cyclosporin and 45 with tacrolimus. RESULTS: A serum sodium level of <135 mmol/l was present for 542/5171 (10.5%) days under tacrolimus treatment compared with 377/5486 (6.9%) days under cyclosporin treatment (P < 0.0001). Severe hyponatraemia, below 120 mmol/l, was also more prevalent under tacrolimus than cyclosporin treatment, P < 0.025. Nine patients, all receiving tacrolimus, were treated with fludrocortisone for fluid depletion and/or hyponatraemia. Serum potassium levels were higher in tacrolimus-treated patients (P < 0.0001), and subjects with hyponatraemia were more likely to experience hyperkalaemia (P < 0.0001). CONCLUSIONS: Hyponatraemia and hyperkalaemia were more frequent in tacrolimus-treated subjects. Taken together with previous work showing that hyperuricaemia is more frequent with cyclosporin treatment, and hypomagnesaemia with tacrolimus treatment, these findings are consistent with qualitative differences between the nephrotoxicities of cyclosporin and tacrolimus.     

Effect of cyclosporin pharmacokinetics on renal allograft outcome in African-Americans

African-Americans (A-As) experience inferior outcome after transplantation compared with other ethnic groups. Bioavailability of cyclosporin (CsA) has been implicated as a possible contributing factor. This paper describes the outcome of 32 A-A recipients of de novo renal allograft who received CsA-based triple immunotherapy according to individual pharmacokinetic profiles. Patients received CsA-microemulsion q 12 h, dosed initially at 3.5 mg/kg (8 am) and 3.0 mg/kg (8 pm). The am and pm doses were independently adjusted to achieve a 12-h area under the concentration-time curve (AUC0-12) of 6600-7200 nghr/mL and morning trough level (C0) of 250-325 ng/mL, respectively. Mean age was 43 +/- 12 yr, 37% (12) female. Mean AUC0-12 in 1 wk, 1, 3, 6, and 12 months were 7810 +/- 1880 nghr/mL, 9057 +/- 2097 nghr/mL, 7674 +/- 1912 nghr/mL, 7132 +/- 2040 nghr/mL, and 6503 +/- 1410 ngl/h with corresponding C0 of 301 +/- 79 ng/mL, 316 +/- 66 ng/mL, 275 +/- 59 ng/mL, 273 +/- 66 ng/mL, and 224 +/- 49 ng/mL, respectively. Acute rejection occurred in two patients (6%) 1 yr after transplantation. Prospective use of CsA pharmocokinetic profiles improves renal allograft outcome in A-As.     

Misoprostol in renal transplant recipients: a prospective, randomized, controlled study on the prevention of acute rejection episodes and cyclosporin A nephrotoxicity

The aim of this prospective and randomized study was to determinewhether misoprostol, an analogue of PGE1, could decrease theincidence and the number of rejection episodes and could improvethe renal function over a 12-month follow-up, when given at400 µg/day for 12 months in renal transplant patients.Given the known side-effects and the additive cost of misoprostol,a benefit of the therapy should be a decrease of at least 50%in the incidence of rejection episodes in the treated group.Therefore, 60 consecutive renal transplant patients were randomizedto receive misoprostol or to receive aluminium and magnesiumhydroxide. Patients received steroids, azathioprine, antithymocyteglobulins, and cyclosporin A (CsA). CsA was randomly startedon day 0 or on day 8. At 12 months, no difference in the incidenceof rejection episodes was observed: 63.3% in the 30 patientsof the misoprostol + group versus 70.0% in the misoprostol-group(P=0.558 Mantel-Cox). The renal function, assessed by plasmacreatinine, inulin, and para-aminohippuric acid clearances,was not significantly different between misoprostol + and misoprostol-groups.No episode of CsA nephrotoxicity was observed in any patientof group one or group two. At 12 months, the mean dosage ofCsA was 4.9±0.28 mg/kg/day in the misoprostol+group versus4.52 ± 0.23 mg/kg/day in the misoprostol - group andthe trough level was not significantly different between thetwo groups. The graft survival rate at 12 months was 86.7% inthe Misoprostol+ group and 83.33% in the misoprostol- group.The trial failed to demonstrate a significant beneficial effectof misoprostol on the decrease of acute rejection episodes,on the prevention of CsA nephrotoxicity, or on the improvementof renal function over a 12-month period.     

A randomized trial of basiliximab with three different patterns of cyclosporin A initiation in renal transplant from expanded criteria donors and at high risk of delayed graft function

Abstract:  This study assays therapy with basiliximab and different patterns of cyclosporin A (CsA) initiation in renal transplant (RT) recipients from expanded criteria donors (ECD) and at high risk of delayed graft function (DGF). A multicentre six-month open-label randomized trial with three parallel groups treated with basiliximab plus steroids, mycophenolate mofetil and different patterns of CsA initiation: early within 24 h post-RT at 3 mg/kg/d (Group 1; n = 38), and at 5 mg/kg/d (Group 2; n = 40), or delayed after 7–10 d at 5 mg/kg/d (Group 3; n = 36). There were no differences among groups in six months GFR (43.1 ± 12, 48.0 ± 14 and 47.2 ± 17 mL/min, respectively), DGF (Group 1: 31%, Group 2: 37%, Group 3: 42%), nor biopsy-proven acute rejection, although clinically treated and biopsy-proven acute rejection was significantly higher in Group 3 (25%) vs. Group 1 (5.3%, p < 0.05). At six months no differences were observed in death-censored graft survival or patient survival. Induction therapy with basiliximab and three CsA-ME initiation patterns in RT recipients from ECD and at high risk of DGF presented good renal function and graft survival at six months. Late onset group did not achieve improvement in DGF rate and showed a higher incidence of clinically treated and biopsy-proven acute rejection.     

Activation of nuclear factor-kappa B and macrophage invasion in cyclosporin A-and tacrolimus-treated renal transplants

This retrospective study was designed to compare the efficacy of cyclosporin A (CyA) and tacrolimus (FK506) on chronic rejection (CR) associated with nuclear factor-kappa B (NF-kappaB) activation and macrophage invasion. Non-episodic day 50 protocol renal biopsy was performed in 63 consecutive patients with renal transplants from living donors, treated with either CyA or FK506. Southwestern histochemistry for NF-kappaB, immunostaining for CD68, and Banff classification were performed, and these findings were compared with outcome over 34 +/- 13 months. Compared with specimens from FK506-treated patients (n = 20), specimens from CyA-treated patients (n = 43) showed a significant increase in tubulointerstitial CD68-positive cells (1.5 +/- 0.9 vs. 0.9 +/- 0.8, p < 0.01), although no significant differences were observed in NF-kappaB activation. Specimens with Banff acute rejection (AR) grade > or = 1A (n = 20) showed increased macrophages (p < 0.01) compared with specimens with AR < 1A (n = 43). Specimens from patients with clinical AR prior to day 50 biopsy (n = 23) also showed increased macrophage invasion (p < 0.01) compared with specimens from patients without prior clinical AR (n = 40). The cumulative well-functioning (serum creatinine < 1.5 mg/dL) graft survival rate was significantly lower in patients with increased tubulointerstitial CD68-positive cells (n = 63, p < 0.05). Our findings suggest that tacrolimus is more effective than CyA against CR with respect to macrophage invasion and AR.     

Basiliximab plus low-dose cyclosporin vs. OKT3 for induction immunosuppression following renal transplantation

BACKGROUND: Current immunosuppressive therapies are very effective in preventing acute rejection (AR) and graft loss following renal transplantation. Newer agents now make it possible to develop equally efficacious but better tolerated and less toxic strategies. This is especially relevant for our ageing recipients. We now compare the efficacy of basiliximab combined with early low-dose cyclosporin therapy to standard OKT3 induction therapy. METHODS: In this single-centre study, 100 consecutive recipients of cadaveric kidney transplants from November 1998 to August 2000 were treated with basiliximab combined with early low-dose cyclosporin, reduced steroids and mycophenolate mofetil (MMF). Clinical outcomes at 100 d and 1 yr were compared with a group of 26 patients transplanted from March 1995 to November 1998 who received OKT3, delayed full-dose cyclosporin, high-dose steroids and MMF. Amongst basiliximab treated patients, we compared clinical outcomes in those older and younger than 60 yr. RESULTS: Both groups were similar except for a shorter cold ischaemic time in the basiliximab group. Length of stay, number of readmissions, total hospitalization days and cytomegalovirus infections were lower in the basiliximab group. Despite a 40% reduction in steroids, basiliximab-treated patients had fewer biopsy-proven episodes of AR (basiliximab 14% vs. OKT3 35%) and required less antilymphocyte antibody therapy. Clinical outcomes including patient and graft survival were no different between groups. Long-term graft survival for patients over 60 yr was limited primarily by mortality. CONCLUSIONS: Compared with OKT3 induction therapy, the combination of early low-dose cyclosporin and basiliximab is steroid sparing, effective, well tolerated and relatively safe.     

Pre-emptive immunosuppression using tacrolimus monotherapy does not reduce the rate of early acute rejection in renal transplantation from live donors: a comparative cohort study

The planned nature of live donor kidney transplantation allows for immunosuppression to be initiated in the pretransplant period. The aim of this study was to determine the effect of pre-emptive immunosuppression on acute rejection rates after live donor kidney transplantation. In two consecutive cohorts of live donor kidneys transplants, 99 patients received pre-emptive immunosuppression with tacrolimus monotherapy for 2 weeks prior to transplantation (PET group – first era) and 100 patients received tacrolimus-based immunosuppression commencing on the day of transplantation (control group – second era). The main outcome measure was the incidence of biopsy-proven acute rejection (BPAR) in the first 3 months post-transplantation. Tacrolimus levels were significantly higher in the PET group at day 4 post-transplant (PET 9.08 ± 4.57 vs. control 5.92 ± 3.64 ng/ml; P < 0.0001), but there were no significant differences in tacrolimus levels at day 7 (PET 8.22 ± 3.58 vs. control 7.63 ± 3.56 ng/ml; P = 0.2452). BPAR was numerically higher in the PET group, but this difference did not reach statistical significance (PET 13/99 vs. control 6/100; P = 0.097). There were no differences in allograft function measured by serum creatinine at 1 year (PET 130 ± 36 vs. control 142 ± 69 μmol/l; P = 0.6829). Graft survival at 1 year was equivalent in both groups (PET 96.9 vs. control 97.0%; P = 0.9915). This study suggests that there is little role for the use of pre-emptive tacrolimus monotherapy in ABO blood group and HLA-compatible live donor kidney transplantation in patients on triple maintenance immunosuppression.     

Tacrolimus combined with two different corticosteroid-free regimens compared with a standard triple regimen in renal transplantation: one year observational results

Krämer BK, Klinger M, Wlodarczyk Z, Ostrowski M, Midvedt K, Stefoni S, Citterio F, Pietruck F, Squifflet J‐Paul, Segoloni G, Krüger B, Sperschneider H, Banas B, Bäckman L, Weber M, Carmellini M, Perner F, Claesson K, Marcinkowski W, Vítko ?, Senatorski G, Salmela K, Nordström J. Tacrolimus combined with two different corticosteroid‐free regimens compared with a standard triple regimen in renal transplantation: one year observational results.
Clin Transplant 2010: 24: E1–E9. © 2009 John Wiley & Sons A/S. Abstract: Side effects of steroid use have led to efforts to minimize their use in transplantation. Two corticosteroid‐free regimens were compared with a triple immunosuppressive therapy. Data from the original intent‐to‐treat (ITT) population (153 tacrolimus/basiliximab [Tac/Bas], 151 tacrolimus/MMF [Tac/MMF], and 147 tacrolimus/MMF/steroids [control]) were analyzed in a 12‐month follow‐up. Percentage of graft survival were 92.8%, 95.4%, and 95.9% (KM estimates 89.9%, 95.3%, 95.9%), percentage of surviving patients were 98.7%, 98.0%, and 100% (KM estimates 95.9%, 92.8%, and 100%). During months 7–12, graft loss occurred in 3 Tac/Bas, 2 Tac/MMF, and zero control patients, patient deaths in 1 Tac/Bas, 2 Tac/MMF, and zero control, and biopsy‐proven acute rejection episodes in 4 Tac/Bas, 3 Tac/MMF, and zero control. Mean serum creatinine at month 12 was 141.9 ± 69.6 μM, 144.0 ± 82.1 μM, and 134.5 ± 71.2 μM (ns). New‐onset insulin use in previously non‐diabetic patients at month 12 was 1/138, 6/127, and 4/126. Patient and graft survival as well as renal function at 12 months were not different between patient groups, despite considerably higher rates of acute rejection occurring within the first six months after transplantation in both steroid‐free patient groups. Tac/Bas therapy might offer benefits in terms of a trend for a more favorable cardiovascular risk profile.