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。     

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.     

The clinical impact of 1:1 conversion from Neoral to a generic cyclosporine (Gengraf) in renal transplant recipients with stable graft function

The introduction of cyclosporine (CYA) to the immunosuppressive armamentarium has had a significant effect on graft survival. An improvement in the formulation from the oil-based to a microemulsion-based form has resulted in better absorption and more predictable CYA bioavailability. Since the introduction of the first microemulsion form (Neoral), several bioequivalent formulations are now available and are switched in a 1:1 fashion at pharmacies to curtail costs. The purpose of our study was to study the effect of a 1:1 switch from Neoral to Gengraf on CYA trough levels and serum creatinine (SRC) in renal transplant recipients with stable graft function. Eighty-two renal transplant recipients with stable graft function were enrolled in the study, and of these, 73 were switched to Gengraf, whereas nine remained on Neoral. The 13 patients switched to Gengraf required a dosage change after the mean CYA trough levels changed from 234 +/- 96 ng/mL at baseline to 289 +/- 102 ng/mL (p < 0.05) at 2 wk. With the adjustments in dosage, the levels approached the baseline trough concentrations (239 +/- 151 ng/dL). The nine patients who remained on Neoral had no change in the CYA levels or SCR. Nearly 20% of patients who switched to a bioequivalent CYA preparation required a dose adjustment to return to pre-conversion CYA trough levels. Our study raises serious concerns regarding the switchability of generic CYA for Neoral without careful follow-up therapeutic drug monitoring.     

Pharmacokinetics of a new microemulsion formulation of cyclosporin A (Neoral) in young patients after renal transplantation

Pharmacokinetics of the new galenic formulation of cyclosporin A, Neoral, (Sandoz) was examined in 12 stable young patients after renal transplantation. Six of these patients were tested before and 4 weeks after switching from the standard formulation Sandimmun to Neoral. No significant changes were observed in trough levels, t_max, C_max, and AUC_0–12h, but the absorption rate constant (K_a) increased (P=0.003). Glomerular filtration rate, as assessed by inulin clearance, increased by more than 10% in three patients and decreased in two, and was usually associated with a respective drop and rise in C_max and AUC_0–12h of cyclosporin A. The large interindividual variability in the response to the conversion to the new formulation points to a need for close monitoring of cyclosporin A trough levels and renal function after switching from Sandimmun to Neoral in this age group in order to avoid nephrotoxicity.     

Preliminary experience with mycophenolate mofetil for preservation of renal function in cardiac transplant patients with documented cyclosporine nephrotoxicity

BACKGROUND: Cyclosporine (CyA) has positively impacted on the outcome of cardiac transplantation; however, the nephrotoxicity associated with CyA has been a major drawback. METHODS: In an effort to reduce exposure to CyA and possibly alleviate its nephrotoxic effects, we undertook a therapeutic strategy to switch cardiac transplant patients with biopsy-proven CyA nephrotoxicity from azathioprine (AZA) to mycophenolate mofetil (MMF) with subsequent CyA dose reduction or elimination. RESULTS: MMF was substituted for AZA in five cardiac transplant patients (four males; mean age, 60 +/- 6 years old; average time from transplant was 7 +/- 3 years) who had biopsy proven evidence of CyA nephrotoxicity, and in whom CyA dose was reduced (3/5) or discontinued (2/5). At the time of the therapeutic intervention, four patients had an average serum creatinine of 230 +/- 62 micromol/L and one patient had just been started on haemodialysis (HD). During an average follow-up period of 42 months, the slope of the inverse serum creatinine significantly improved in three patients and continued to deteriorate in one patient. The patient on HD could be transiently taken off HD. However, he developed a severe episode of cardiac rejection requiring antirejection therapy and increase in the dose of CyA. The patient was subsequently returned back on HD. CONCLUSION: In this preliminary report, we show that AZA to MMF switch with subsequent CyA dose reduction or discontinuation may slow down the progression of kidney disease in some patients. However, the patients should be followed closely for evidence of cardiac rejection.     

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.     

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.     

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

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

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( ± SD) of C_max, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 ± 9 ng kg/mg ml, 210 ± 70 ng h kg/mg ml and 2.6 ± 0.9 ng kg/mg ml, respectively. For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rejection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/kg–150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mg/kg–100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ng/ml and 700 ng/ml. Received: 1 October 1997 Revised: 20 April 2001 Accepted: 7 June 2001     

Benefits of cyclosporine absorption profiling in nephrotic syndrome: preprandial once-daily administration of cyclosporine microemulsion improves slow absorption and can standardize the absorption profile

AIM: Cyclosporine is known to improve proteinuria in nephrotic syndrome (NS), but is also associated with drug-related renal impairment. In this case series, therapeutic drug monitoring using the absorption profile was applied to adults with NS to investigate the efficacy and safety of once-daily administration of cyclosporine microemulsion (CSAME). METHODS: Twenty patients received CSAME starting at 100-175 mg/day (1.4-3.1 mg/kg per day) once daily after breakfast. The area under the concentration-time curve up to 4 h after administration of cyclosporine (AUC(0-4 h)) was determined in each patient within 1 week after the start of CSAME treatment. Thereafter, the dose of CSAME was adjusted according to the absorption profile. RESULTS: After 6 months, treatment with CSAME improved efficacy test values compared with those prior to treatment, and the severe nephrotic state was eliminated in all patients. No changes in serum creatinine or blood urea nitrogen levels were observed. The dose of CSAME was adjusted so that AUC(0-4 h) and the peak level fell within the range of target values, resulting in a significant decrease in the mean dose of cyclosporine (P = 0.0001). Time of peak level was variable among patients, but when CSAME was administered before breakfast, good absorption was achieved in all patients. CONCLUSION: By monitoring the absorption profile in patients with NS, a once-daily administration of CSAME was used to achieve both efficacy and a reduction in total exposure to the drug. Preprandial administration provided a more stable absorption profile of cyclosporine. The authors hope this method will become standard procedure during cyclosporine treatment in these patients.     

A pharmacokinetic comparison of the corn oil versus microemulsion gelcap formulation of cyclosporin used de novo after renal transplantation

The initial poor absorption of the corn oil-based, gel capsule oral formulation of cyclosporin (CyA) greatly limits its use for inception of immunosuppressive therapy. Insufficient drug concentrations during the early post-transplant period predispose to renal allograft rejection. The present study served to compare the time required to achieve therapeutic CyA concentrations after de novo administration of the corn oil-based gel capsule (CyA-GC; n = 11) versus the microemulsion (CyA-ME; n = 11) formulation of CyA. During the 1st month after renal transplantation, patients underwent serial pharmacokinetic profiling from which we obtained observed and dose-corrected values of several parameters. Although patients in neither the CyA-GC nor the CyA-ME group adequately absorbed the drug during days 0–2, from day 3 to 4 patients in the CyA-ME group showed significantly greater absorption than those in the CyA-GC group (P = 0.041). Patients in the CyA-ME group reached the 1st month target average concentration (C_av) values ( ≥ 550 ng/ml) earlier than those in the CyA-GC group and required significantly lower daily CyA doses (P = 0.018). We conclude that therapeutic CyA levels can be achieved more rapidly and with lower doses of the drug after de novo administration of CyA-ME than with CyA-GC. Received: 13 September 1996 Accepted: 7 January 1997     

心脏死亡器官捐献供者应用血管活性药物对供肝质量及肝移植受者的影响

目的 探讨心脏死亡器官捐献(DCD)供者维护中的血管活性药物应用对肝移植受者及移植物的影响.方法 回顾分析2011年7月至2012年7月间19例DCD供肝移植的临床资料,依据DCD供者在器官切取前是否使用血管活性药物维持血压,将19例DCD供肝移植的供、受者分为血管活性药物组(用药组)和未使用血管活性药物组(未用药组).观察和比较两组供、受者间的临床特征、术后并发症、受者和移植物存活时间等.结果 术后两组受者间肝功能指标均无显著差异.两组受者均未出现与供者相关的胆道并发症、原发性移植物功能不全、门静脉狭窄、肝动脉血栓形成等.用药组受者及移植物的存活时间为(4.2±4.2)个月,未用药组为(6.2±4.2)个月,两组受者及移植物的存活时间基本相同(P＞0.05).结论 在DCD供者的维护中,血管活性药物的应用对肝移植后移植肝功能、胆道并发症、原发性移植物功能不全、门静脉狭窄、肝动脉血栓形成及受者和移植物的存活时间并无明显影响.     

环孢素A转换为他克莫司对慢性移植肾肾病患者的治疗效果

目的 探讨由环孢素A(CsA)转换为他克莫司(Tac)为主的免疫抑制方案对慢性移植肾肾病(CAN)患者的治疗效果.方法 选择接受同种肾移植后发生CAN的患者153例,患者肾移植后均采用CsA、吗替麦考酚酯(MMF)及泼尼松(Pred)的免疫抑制方案.根据是否以Tac替换CsA将患者分为两组.(1)CsA组:45例,进入研究后患者维持原免疫抑制方案.(2)Tac组:108例,进入研究后将CsA转换为Tac,停用CsA后立即开始服用Tac,MMF和Pred的用法同CsA组.对所有患者随访12个月,观察人/移植肾存活率、急性排斥反应发生率、移植肾功能、24 h尿蛋白定量、移植肾穿刺病理学活检及免疫抑制剂的不良反应等指标.结果 随访12个月时,CsA组和Tac组患者存活率均为100%,移植肾存活率分别为86.6%和93.5%(P＜0.05);急性排斥反应发生率分别为4.4%(2/45)和3.7%(4/108)(P＞0.05),6例发生急性排斥反应的患者均经甲泼尼龙冲击治疗3 d后逆转.Tac组患者移植肾功能明显改善,并且出现重度蛋白尿、重度肾间质纤维化和肾小管萎缩的患者比例较CsA组显著减少(P＜0.05).Tac组有13.8%(15例)的患者出现轻度血糖增高,发生率显著高于CsA组的4.4%(2例)(P＜0.05);Tac组有22.2%(24例)的患者发生高血压,发生率显著低于CsA组的55.6%(25例)(P＜0.05);17例因使用CsA而出现牙龈增生和多毛症者,经转换治疗后,症状均明显好转.结论 由CsA转换为Tac为主的免疫抑制方案能够显著改善CAN患者的移植肾功能,延缓CAN的发展,转换过程中未发生严重Tac不良反应并且改善了使用CsA时出现的不良反应.

Abstract：

Objective To investigate the effect of conversion from cyclosporine A (CsA) to tacrolimus (Tac) on chronic allograft nephropathy (CAN). Methods 153 CAN patients undergoing kidney transplantation received CsA, mycophenolate mofetil (MMF) and prednisone (CsA-MMF-Pred) regimen after kidney transplantation, and divided into 2 groups according to whether CsA were maintained in the immunosuppressive regimen: CsA + MMF + Pred group (CsA group, n = 45); Tac + MMF + Pred group (Tac group, n = 108). The patients were followed up with patient/kidney survival rate, acute rejection incidence, renal function, 24-h proteinuria and adverse events of immunosuppressive drugs for 12 months. Results Compared with CsA group, the transplanted kidney survival rate was significantly higher in Tac group (93. 5 % vs 86.6 %, P＜0. 05). Acute rejection (AR) was diagnosed in 4. 4 % (2/45) of recipients in CsA group and 3. 7 % (4/108) in Tac group (P＞0. 05) respectively. Acute rejection (2 cases in CsA group and 4 in Tac group) was reversed by 500 mg of methylprednisolone for consecutive 3 days, and the patients in Tac group showed a significantly lower degree of interstitial fibrosis and tubular atrophy (IF/TA) (P＜0. 05).Renal allograft functions and 24-h proteinuria during a follow-up period of 12 months were significantly improved in Tac group (P ＜ 0. 05). Incidence of mild hyperglycemia in Tac Group (13.8 %, 15/108) was significantly higher than in CsA group (4.4 %, 2/45), and that of hypertension in Tac group (22. 2 %, 24/108) was significantly lower than in CsA group (55.6 %,25/45). CsA-related side effects (such as hirsutism and gingival hypertrophy) in 17 patients were greatly improved after conversion from CsA to Tac treatment. Conclusion The conversion from CsA to Tac on the patients with CAN can improve renal allograft function, retard the progression of renal allograft dysfunction, reduce the incidence of CsA-related side effects and not generate serious adverse effects of Tac.     

Efficacy and safety of conversion from cyclosporine to everolimus in living‐donor kidney transplant recipients: an analysis from the ZEUS study

Conversion of living‐donor kidney transplant patients from calcineurin inhibitor therapy to an mTOR inhibitor is poorly documented. In the prospective, multicentre ZEUS study, 300 kidney transplant recipients without prior rejection (Banff grade >1) and serum creatinine ≤265 μmol/l were randomized to continue cyclosporine or convert to everolimus at 4.5 months post‐transplant. In a post hoc analysis of 80 living‐donor recipients, adjusted estimated GFR (Nankivell) at month 12 (the primary endpoint) was 74.3 (95% CI [70.7, 77.9]) ml/min/1.73 m² with everolimus versus 63.8 (95% CI [60.0, 67.7]) ml/min/1.73 m²) with cyclosporine, a difference of 10.5 ml/min/1.73 m² in favour of everolimus (P < 0.001). From randomization to month 12, adjusted estimated GFR increased by a mean of 9.8 (95% CI [6.2, 13.4]) ml/min/1.73 m² with everolimus versus ?0.7 (95% CI [?4.6, 3.1]) ml/min/1.73 m²) (P < 0.001) with cyclosporine. There were six biopsy‐proven acute rejection episodes in everolimus‐treated patients (five Banff grade I) and one episode in cyclosporine‐treated patients (Banff grade 1). Overall safety profile was similar between groups. Discontinuation due to adverse events occurred in three everolimus patients (7.1%) and five cyclosporine patients (13.2%) between randomization and month 12. Initiation of everolimus with early elimination of calcineurin therapy is associated with a significant renal benefit at 12 months post‐transplant that is observed in both living and deceased‐donor recipients. (clinicaltrials.gov NCT00154310)     

Effect of donor-specific transfusions on the outcome of renal allografts in the cyclosporine era

Despite the introduction of new immunosuppressive agents, a steady decline of functioning renal allografts after living donation is observed. Thus nonpharmacological strategies to prevent graft loss have to be reconsidered, including donor-specific transfusions (DST). We introduced a cyclosporine-based DST protocol for renal allograft recipients from living-related/unrelated donation. From 1993 to 2003, 200 ml of whole blood, or the respective mononuclear cells from the potential living donor were administered twice to all of our 61 recipient candidates. The transplanted subjects were compared with three groups of patients without DST from the Collaborative Transplant Study (Heidelberg, Germany) during a 6-year period. Six patients were sensitized without delay for a subsequent cadaveric kidney. DST patients had less often treatment for rejection and graft survival was superior compared with subjects from the other Swiss transplant centers (n = 513) or from Western Europe (n = 7024). To diminish the probability that superior results reflect patient selection rather than effects of DST, a 'matched-pair' analysis controlling for relevant factors of transplant outcome was performed. Again, this analysis indicated that recipients with DST had better outcome. Thus, our observation suggests that DST improve the outcome of living kidney transplants even when modern immunosuppressive drugs are prescribed.     

Early, abrupt conversion of de novo renal transplant patients from cyclosporine to everolimus: results of a pilot study

Abstract:  In a single-center study, 20 kidney transplant patients without prior rejection were abruptly converted from cyclosporine to everolimus at seven wk post-transplant. All patients received basiliximab induction with maintenance enteric-coated mycophenolate sodium and corticosteroids. Biopsy-proven acute rejection had occurred in three of 20 patients (15.0%) by the end of week seven post-conversion. All episodes were mild and reversible, with subsequent recovery of renal function. Calculated glomerular filtration rate (GFR) improved significantly (51 ± 11 mL/min at time of conversion, 58 ± 12 mL/min at week seven post-conversion, 57 ± 17 mL/min at month six post-conversion; p = 0.001). No patient developed proteinuria in the nephrotic range. Twenty-two adverse events were reported in 10 patients, three of which had a suspected relationship to everolimus. Mean leukocyte and platelet count decreased significantly, and triglyceride level increased. This study suggests that kidney transplant patients without prior rejection can be converted abruptly from cyclosporine to everolimus at seven wk post-transplant, resulting in significantly improved renal function with no apparent increase, in risk of rejection and good tolerability.     

Microemulsion cyclosporin formulation, in contrast to the old formulation, widens the T lymphocyte subsets differences between stable and acute rejection of kidney transplants.

BACKGROUND: The new cyclosporin (CsA) formulation, Neoral, has different pharmacokinetics compared with Sandimmune (SIM). Larger area under the curve (AUC) values with equivalent trough blood values are reached when Neoral is administered at equivalent doses to SIM. Previously, we showed a great diagnostic reliability when using cytofluorometric analysis from fine-needle aspiration biopsy (FNAB) samples. We investigated possible changes brought about by Neoral on lymphocyte subsets and the repercussions on the activation score cut-off for acute rejection, defined under SIM treatment. METHODS: Of 63 patients that received SIM, 40 remained rejection-free and 23 suffered one episode of rejection. Of 52 patients that received Neoral, 38 remained rejection-free. Peripheral blood lymphocytes (PBL) and lymphocytes from FNAB taken on days 7 and 14 post-transplantation and on the first day of acute rejection were analysed by flow cytometry. RESULTS: Trough blood CsA levels were not different between SIM and Neoral treatments. Among rejection-free patients, a significant down-regulation of CD3DR and of CD8DR expression on both graft-infiltrating lymphocytes (GIL) and PBL, and significant up-regulation of na?ve T cells on GIL were observed with Neoral. These changes were followed by a significant down-regulation of the activation score with Neoral. Conversely, within the acute rejection group, the activation score was significantly higher with Neoral than with SIM. The activation score performed equally well in Neoral transplants compared with what we had reported with SIM. CONCLUSIONS: Our study indicates that Neoral elicits stronger immunosuppressive effects in stable patients, which eventually should translate into better clinical efficiency. However, when acute rejection supervenes, the treatment breakthrough seems stronger with Neoral. Cytofluorometric studies from FNAB samples showed that diagnostic reliability was maintained at a high level under Neoral therapy.     

The clinical status of cadaveric renal transplant patients treated for 10 year with cyclosporine therapy

In this paper we assessed the clinical status of 150 cadaveric renal transplant patients who received cyclosporine without interruption for 10 yr. The mean creatinine clearance was 59.2 +/- 15.71 at 1 yr and 55.6 +/- 24.91 mL/min at 10 yr (p = 0.039). Patients were subdivided into four quartiles according to the mean creatinine clearance at 1 yr. The 14 patients with the lowest quartile showed a significant decrease of creatinine clearance from the 1st to 10th year (from 31.5 +/- 5.83 to 24.8 +/- 14.00 mL/min; p = 0.038) while no difference between the mean creatinine clearance at 1 and at 10 yr was found in the other three quartiles. At 10 yr, 84.6% patients needed antihypertensive therapy, a rate similar to that seen at 1 yr (81.4%). The mean plasma cholesterol (253 +/- 57.8 mg/dL) and triglyceride (197 +/- 113.1 mg/dL) at 10 yr were similar to those found at +/- yr (243 +/- 48.2 and 201 +/- 143.0 mg/dL, respectively). Most patients have a high degree of rehabilitation 10 yr after uninterrupted cyclosporine therapy and all patients but 3 were able to work.     

Renal function with delayed or immediate cyclosporine microemulsion in combination with enteric-coated mycophenolate sodium and steroids: results of follow up to 30 months post-transplant

BACKGROUND: In the multicenter, open-label Myriade study, renal transplant patients were randomized to early cyclosporine microemulsion (CsA-ME, day 0) or delayed CsA-ME (day 6) with enteric-coated mycophenolate sodium (EC-MPS), steroids and interleukin-2 receptor induction. One-yr results have been published previously. We now report the results of an extension study in which patients were followed up for a period of three yr post-transplant. METHODS: All patients completing the one-yr core study on-treatment were eligible to enter the extension study. RESULTS: Of the 203 patients, 153 completed the core trial on-treatment; 144 (94%) entered the extension study with a minimum follow-up of one yr (73 early CsA-ME, 71 delayed CsA-ME). In 75% of patients receiving EC-MPS during the extension, the recommended dose was administered (1440 mg/d). Median creatinine clearance remained constant (57 mL/min) at 12, 24 and 30 months post-transplant and was similar in the early and delayed CsA-ME groups as well as in subpopulations with or without delayed graft function. One patient in the early CsA-ME group died. No grafts were lost. The incidence of BPAR from time of transplant to the end of the extension study was 17% (24/139). Seven patients (5%) discontinued the extension study prematurely because of adverse events. CONCLUSION: These results suggest that a regimen of CsA-ME, EC-MPS and steroids results in excellent survival rates with stable renal function over a mean follow-up of 30 months. Immediate introduction of CsA-ME has no deleterious effect on long-term renal function, even among patients with delayed graft function.     

Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases.

BACKGROUND: Therapeutic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using either trough levels (C0) or levels at 2 h post-dose (C2). This analysis assessed changes in C0 and C2 and their relationship to CsA-ME dose over time post-transplant in renal transplant patients. METHODS: Data were obtained from MO2ART, a prospective multicentre trial in which CsA-ME dose was adjusted based on C2 level. All 98 patients in whom C0 and C2 were available at day 5, month 3 and month 12 were included, out of 234 who completed the 12 month study. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was calculated, together with C0/ND, C2/ND and C2/C0. RESULTS: C0/ND and C2/ND both increased between day 5 and month 3: C0/ND from 33+/-15 to 53+/-24 (ng/ml)/(mg/kg) and C2/ND from 161+/-64 to 248+/-80 (ng/ml)/(mg/kg). Between month 3 and month 12, C2/ND remained stable but C0/ND decreased to 42+/-20 (ng/ml)/(mg/kg) while the C2/C0 ratio increased from 5.2+/-1.9 to 6.5+/-2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C0/ND than for C2/ND at 3 months (45 vs 32%, P<0.05) and at 12 months (48 vs 31%, P<0.01). CONCLUSIONS: CsA clearance accelerates between months 3 and 12 post-transplant, resulting in lower C0 levels for a given exposure (as measured by C2). As a consequence, C0 monitoring may progressively underestimate CsA exposure during the first year post-transplant. C2 monitoring contributes to improved individualized CsA-ME treatment in both the de novo phase and beyond month 3.