Optimizing everolimus exposure when combined with calcineurin inhibitors in solid organ transplantation

The mammalian target of rapamycin (mTOR) inhibitor everolimus is a narrow therapeutic index drug for which optimal exposure levels are essential. The consistent pharmacokinetic profile of everolimus allows trough concentration (C₀) measurement to be an appropriate and reliable index for therapeutic drug monitoring (TDM). Exposure-response analyses of data from early fixed-dose trials demonstrated that rates of biopsy-proven acute rejection (BPAR) are significantly higher if everolimus C₀ declines below 3 ng/mL, an observation confirmed in subsequent concentration-controlled trials. Evidence for the most favorable upper limit is less clear but with reduced-exposure calcineurin inhibitor (CNI) therapy, an upper limit of 8 ng/mL appears to balance efficacy and safety outcomes. The recommended C₀ range is 3–8 ng/mL in kidney, liver and heart transplantation patients, based on LC–MS/MS monitoring in whole blood. Randomized clinical trials based on this target range have demonstrated rates of BPAR comparable to a regimen of mycophenolic acid with standard-exposure CNI. Everolimus exhibits moderate intrapatient pharmacokinetic variability, and it can be challenging to maintain stable concentrations within target range in some individuals. Many factors can influence everolimus exposure for a given dose, including hepatic function, activity of the drug efflux pump P-glycoprotein, the rate of everolimus metabolism, drug–drug interactions (predominantly with CYP3A4 and P-glycoprotein inhibitors, including cyclosporine), intake of fatty food, and patient adherence to the prescribed regimen. Trough concentration levels should be monitored 4–5 days after the first dose and after any change in everolimus dose, with additional monitoring in response to any change in concomitant medication or other clinical circumstances which could alter everolimus exposure. Although LC–MS/MS is the gold standard for everolimus monitoring, various immunoassays are widely used due to their relative simplicity and lower cost, and results can show considerable discrepancies with reference methods due to issues such as interassay variability and cross-reactivity. Method standardization will be important in the future to improve the consistency and reproducibility of results between centers. In conclusion, based on an extensive program of clinical trials, the optimal exposure range for everolimus in combination with reduced-exposure CNI therapy has been established and can be achieved in most transplant recipients through careful, planned TDM.     

The CD154-CD40 costimulation pathway in organ transplantation

The CD154-CD40 costimulation pathway is one of the most extensively studied in organ transplantation. However, despite impressive results reported in a number of allograft models, precise mechanisms behind its in vivo blockade remain unclear. Several issues related to its potential clinical application have been addressed, resulting in some intriguing findings, particularly on interaction with conventional immunosuppressive agents and differential effects on T cells under the influence of infections. This review focuses on recent data from rodent studies to provide new insights and builds a cohesive picture of the interlocked immune mechanisms in CD154-CD40 signaling at work in transplant recipients.     

Long-term renal function after liver transplantation is related to calcineurin inhibitors blood levels

BACKGROUND: Renal dysfunction is common after liver transplantation (LT). The aim of our study was to assess the prevalence of renal dysfunction 5 yr after LT and to identify risk factors for the development of this complication. PATIENTS AND METHODS: A total of 134 adult patients underwent LT from 1987 to 1998 and 74.6% of them were alive 5 yr after. Pre-LT, 1 and 5 yr post-LT renal function were calculated by Cockroft and modification of diet in renal disease (MDRD) formula. Since 1987 glomerular filtration rate (GFR) has been measured by radiolabeled tracers clearance (RTC). Risk factors for GFR < 50 mL/min were analyzed using a multivariate logistic regression model. RESULTS: Mean pre-LT GFR was 79 and 85 mL/min with Cockroft and MDRD respectively; 11% of the patients had a GFR or= 150 microg/L or tacrolimus (FK) >or= 10 microg/L at 1 yr and CyA >or= 100 microg/L or FK >or= 8 microg/L at 5 yr. CONCLUSION: 5 yr after LT, patients have lost 26% of their initial GFR and 25% of them have a GFR < 50 mL/min. This complication is predicted by high levels of calcineurin inhibitors (CNI). Therefore CNI levels should be reduced as low as possible and use of alternative drugs should be considered.     

Reversible acute encephalopathy with mutism, induced by calcineurin inhibitors after renal transplantation

The incidence of neurotoxicity from calcineurin inhibitors varies by the organ transplanted. Akinetic mutism is characterized by the inability to perform voluntary movements and express language, without alterations in mental status. This process has been reported in neurotoxicity due to high serum levels of calcineurin inhibitors, but in rare cases, it presents as a form of tacrolimus toxicity after renal transplantation, despite normal serum levels. We report a clinical case of a renal transplant patient in whom reversible acute encephalopathy and akinetic mutism developed. Brain lesions appeared on magnetic resonance imaging, and the condition resolved after the drug was withdrawn.     

CD11b is a novel alternate receptor for CD154 during alloimmunity

Antagonism of the CD154/CD40 pathway is a highly effective means of inducing long‐term graft survival in preclinical models. Using a fully allogeneic murine transplant model, we found that CD154 blockade was more effective in prolonging graft survival than was CD40 blockade, raising the possibility that CD154 binds a second receptor. To test this, we queried the impact of CD154 antagonism in the absence of CD40. Data indicated that anti‐CD154 functioned to reduce graft‐infiltrating CD8⁺ T cells in both WT and CD40^?/? hosts. Because it has recently been reported that CD154 can ligate CD11b, we addressed the impact of blocking CD154‐CD11b interactions during transplantation. We utilized a specific peptide antagonist that prevents CD154 binding of CD11b but has no effect on CD154‐CD40 interactions. CD154:CD11b antagonism significantly increased the efficacy of anti‐CD40 in prolonging allograft survival as compared to anti‐CD40 plus control peptide. Mechanistically, CD154:CD11b antagonism functioned to reduce the frequency of graft‐infiltrating CD8⁺ T cells and innate immune cells. These data therefore demonstrate that blocking CD154 interactions with both CD40 and CD11b is required for optimal inhibition of alloimmunity and provide an explanation for why CD40 blockers may be less efficacious than anti‐CD154 reagents for the inhibition of allograft rejection.     

Long-term mycophenolate mofetil monotherapy in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplantation

BACKGROUND: Calcineurin inhibitors (CNIs) are the first-line immunosuppressive agents administered after liver transplantation, but they cause renal impairment. Two recent randomized trials report cellular rejection and liver graft loss when mycophenolate mofetil (MMF) monotherapy was used as a renal-sparing agent. Our experience with MMF in the same setting but with longer follow-up is described. METHODS: In 45 patients with serum creatinine more than 120 micromol/L or creatinine clearance less than 50 mL/min, 2 g MMF per day was administered (median 29 months, 1-49 months) either as monotherapy (with all other immunosuppression withdrawn in 1 month) in 16 patients (group I) or in combination with low-dose CNI (trough tacrolimus 相似文献   

Effects of sirolimus vs. calcineurin inhibitors on renal dysfunction after orthotopic liver transplantation

Small uncontrolled series have suggested that sirolimus favorably impacts renal function after orthotopic liver transplantation (OLT). We sought to retrospectively compare renal dysfunction between cohorts exposed to sirolimus-based and calcineurin inhibitor-based immunosuppression. We retrospectively studied 79 patients converted to sirolimus-based immunosuppression and 100 control subjects continued on calcineurin inhibitor-based immunosuppression after OLT at our institution from 2000 to 2005. We collected clinical, demographic, and medication history. Renal dysfunction was defined as two or more wk of creatinine > or =2.0 mg/dL. Cohorts were compared using Kaplan-Meier survival analysis and Cox proportional hazards modeling. Patients began sirolimus a median 83 d post-OLT and were followed on the medication for median 359 d. Patients in both the sirolimus and calcineurin inhibitor cohorts had median creatinine 1.2 mg/dL at study entry. Sirolimus-based immunosuppression was associated with a 1.8 (0.8-4.3, p = 0.17) hazards ratio for renal dysfunction. Adjusting for presence of hepatocellular carcinoma, combined kidney/liver transplantation, and age, the hazards ratio was 2.0 (0.8-4.8, p = 0.13). These point estimates were not substantially altered after subgroup analysis of sirolimus as the lone immunosuppressant, duration of exposure, and time between OLT and sirolimus conversion. In conclusion, our retrospective, controlled study showed that conversion to sirolimus after OLT did not protect against renal dysfunction. The effect of sirolimus on renal function will need to be prospectively evaluated in a prospective, randomized trial.     

Monitoring antigenemia is useful in guiding treatment of severe cytomegalovirus disease after organ transplantation

We investigated the value of monitoring CMV antigenemia during and after antiviral therapy for CMV disease. During the study period, 10 out of 214 renal transplant recipients were treated for CMV disease, receiving a total of 14 courses of treatment. Antigenemia decreased within 7 days after onset of treatment in eight of nine courses associated with a rapid clinical recovery. In three courses with a slow or absent response, antigenemia levels initially increased. Monitoring antigenemia was helpful in differentiating persisting CMV disease from other opportunistic infections and rejection. Relapses of CMV disease were preceded by rises in antigenemia. Viral isolation became negative within 3 days after initiation of ganciclovir, irrespective of the clinical response. Antigenemia is a marker of the effect of ganciclovir on CMV replication in vivo, and its monitoring may be valuable in the management of patients with severe CMV disease.     

Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation.

The purpose of the study was to introduce mycophenolate mofetil (MMF) in liver transplant recipients with renal dysfunction to decrease calcineurin inhibitor (CNI) dosages without increasing rejection risk. In this prospective, multicenter, randomized study, chronic CNI-related renal dysfunction was defined by an increase in serum creatinine with values >140 micromol/L and <300 micromol/L. Patients were randomized in 2 groups. Study group: combination of MMF (2 to 3 g/day) and reduced dose of CNI >or=50% of initial dose; control group: no MMF, but with the ability to reduce CNI doses, but not below 75% of initial dose. Fifty-six patients were included, 27 in the study group and 29 in the control group. In the study group, there was a significant decrease in serum creatinine values, from 171.7 +/- 24.2 micromol/L at day 0 to 143.4 +/- 19 micromol/L at month 12 and a significant increase in creatinine clearance, from 42.6 +/- 10.9 mL/min to 51.7 +/- 13.8 mL/min. No rejection episode was observed in the study group. In the control group, there was no improvement of renal function, assessed by the changes in serum creatinine values, from 175.4 +/- 23.4 micromol/L at day 0 to 181.6 +/- 63 micromol/L at month 12, and in creatinine clearance, from 42.8 +/- 12.8 mL/min to 44.8 +/- 19.7 mL/min. The differences between the 2 groups were significant: P = 0.001 for serum creatinine, and P = 0.04 for creatinine clearance. In conclusion, the introduction of MMF combined with the reduction of at least 50% of CNI dose allowed the renal function of liver transplant recipients to significantly improve at 1 year, without any rejection episode and without significant secondary effects.     

Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation

BACKGROUND: The adoption of calcineurin inhibitors (CNI) as the mainstay of immunosuppression has resuited in a significant decrease of acute rejection and improvement of short-term graft survival. However, because of the irreversible nephrotoxicity associated with the chronic use of the CNI, the magnitude of the improvement of long-term graft survival has been more modest. Therefore, an effective immunosuppression regimen that does not rely on CNI may result in improvement of long-term outcome and simplification of the management of transplant recipients. METHODS: Ninety-eight patients of primary cadaver or living donor kidneys at low immunologic risk were enrolled in a CNI avoidance study. The immunosuppression regimen consisted of daclizumab, a humanized monoclonal antibody that binds to the alpha chain of the interleukin-2 receptor (IL-2Ralpha), administered for a total of five doses at biweekly intervals; 3 gm/day mycophenolate mofetil for the first 6 month and 2 gm thereafter; and conventional corticosteroid therapy. Patients who underwent rejection episodes could be started on CNI. The primary efficacy end-point was biopsy-proven rejection during the first 6 months posttransplant. RESULTS: Biopsy-proven rejection was diagnosed in 48% of patients during the first 6 months after transplantation. The majority of rejection episodes were Banff grade I and IIA and were fully reversed with corticosteroid therapy. The median time to the first biopsy-proven rejection among patients who experienced this event during the first 6 months was 39 days. In 22 patients with delayed graft function, the proportion of patients with biopsy-proven rejection was 50% at 6 months. However in the first 2 weeks posttransplant, only 1 of 22 patients with delayed graft function developed biopsy-proven rejection. At 1 year, patient survival was 97% and graft survival was 96%. Only two grafts were lost secondary to rejection. At 1-year posttransplant, 62% of patients had received CNI for more than 7 days. At 1-year posttransplant, the mean serum creatinine in the nonrejectors with no CNI use was 113 micromol/L (95%, confidence interval [CI], 100.7 to 125.3 micromol/L) and in the rejectors or patients with CNI use (more than 7 days) was 154 micromol/L (95% CI, 135.0 to 173.0 micromol/L). In selected patients with rejection, analysis of circulating and intragraft lymphocytes revealed complete IL-2Ralpha saturation. CONCLUSIONS: This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI. However, because complete IL-2Ralpha blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.     

Immunosuppression in liver transplantation: beyond calcineurin inhibitors.

Although calcineurin inhibitors (CNIs) remain the mainstay of immunosuppression in liver transplantation (LTX), their long-term toxicity significantly contributes to morbidity and mortality. The elucidation of mechanisms of alloimmunity and leukocyte migration have provided novel targets for immunosuppression development. The toxicities of these agents differ from that of the CNI and act additively or synergistically. CNI avoidance protocols in LTX have not been achieved routinely; however, pilot trials have begun to delineate the limitations and promises of such approaches. CNI-sparing protocols appear to be much more promising in balancing the early need for minimizing rejection while tapering doses and minimizing long-term toxicity.     

Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation

A majority of kidney transplant recipients receive calcineurin inhibitor‐based immunosuppression. However, some do not tolerate calcineurin inhibitors and require other immunosuppressive strategies. Until recently, alternative approaches have been associated with inferior outcomes, but recent methods have effectively utilized belatacept in calcineurin inhibitor‐intolerant patients. Though promising, belatacept uptake has been limited by higher acute rejection rates, unavailability due to production shortages, and logistical challenges as a result of intravenous infusion requirements. Interestingly, its predecessor abatacept is clinically available in subcutaneous formulation to treat autoimmune disorders but has not been used in clinical transplantation. Here we report on a series of 9 calcineurin inhibitor‐intolerant transplant recipients converted to abatacept early after transplant as rescue immunosuppression during periods of belatacept unavailability. Retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received abatacept for a median duration of 82 months with stable, long‐term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Hence our findings suggest that future clinical studies utilizing abatacept either de novo or as conversion therapy in transplant recipients should be considered.     

Experience with daclizumab in liver transplantation: renal transplant dosing without calcineurin inhibitors is insufficient to prevent acute rejection in liver transplantation

BACKGROUND: Daclizumab is a monoclonal antibody directed against the alpha chain of the interleukin 2 receptor. We review our experience with the use of daclizumab in liver transplant recipients. METHODS: Thirty-two patients were given daclizumab as induction therapy in the setting of hepatic transplantation. Seven of these patients were enrolled in a pilot study to determine the efficacy of daclizumab in conjunction with corticosteroids and mycophenolate mofetil without the initial use of calcineurin inhibitors (CI). The remaining 25 patients received daclizumab, mycophenolate mofetil, and steroids, with the institution of CI generally within the first postoperative week. The majority of these patients (n = 17) had some degree of renal insufficiency. RESULTS: The pilot study was halted after the first seven patients were enrolled because of an unacceptably high rate of rejection (7/7 = 100%). The patients outside of this pilot study, however, had a much lower rate of rejection (36%). The incidence and severity of rejection correlated with the delay in institution of CI. The described dosing schedule resulted in subtherapeutic daclizumab levels in liver transplant recipients. CONCLUSIONS: Daclizumab used in liver transplant recipients without any CI was ineffective and can potentially lead to steroid-resistant rejection. The dosing regimen used in renal transplant recipients is most likely insufficient for liver transplant patients. However, daclizumab can be used safely in patients with preexisting or postoperative renal dysfunction in conjunction with low doses of CI given within the first week postoperatively.     

Rosiglitazone treatment of diabetes mellitus after solid organ transplantation

BACKGROUND: Diabetes mellitus is a common clinical problem after solid organ transplantation. Whether patients have preexisting diabetes or develop posttransplant diabetes, insulin therapy is usually required. Achieving excellent diabetic control is an important target in reducing the incidence of cardiovascular disease after transplantation. METHODS: The authors treated 18 patients with type 2 diabetes after transplantation with rosiglitazone. Eleven patients had preexisting type 2 diabetes and seven patients developed posttransplant diabetes. Rosiglitazone was added to insulin or glyburide to improve elevated hemoglobin Hb A1C levels in patients with preexisting diabetes or was used to try to avoid insulin therapy in posttransplant diabetics. Blood levels of cyclosporine, tacrolimus, creatinine, and HbA1C were followed for a mean of 381 days (range, 133-718 days). RESULTS: The addition of rosiglitazone did not cause any significant changes in serum creatinine, cyclosporine, or tacrolimus. There were no significant changes in cyclosporine or tacrolimus doses. Mean HbA1C improved from 8.1+/-1.5% to 6.9+/-1.3% (P =0.01) in the 18 patients and from 8.6+/-1.5% to 6.7+/-0.5% (P =0.035) in the 7 patients with posttransplant diabetes. All patients with posttransplant diabetes were well controlled without insulin therapy. CONCLUSIONS: Rosiglitazone is a safe and effective oral agent for the treatment of diabetes mellitus after solid organ transplantation. It is the first agent to allow successful oral therapy for patients with posttransplant diabetes, and is a well-tolerated alternative to insulin for these patients.     

器官移植后妊娠

目前国内外报道器官移植后妊娠的病例已很多.本文从病理生理、妊娠条件、临床表现诊断依据及治疗等方面探讨器官移植后妊娠问题.     

实体器官移植术后真菌感染的防治

经过近70年的发展,器官移植已经成为多种终末期疾病的有效治疗手段。但器官移植受者术后需服用免疫抑制剂,导致免疫功能低下,感染的发生率较高,包括病毒、细菌和真菌感染。其中真菌感染发病较隐蔽,早期诊断较困难,假丝酵母、曲霉、隐球菌、肺孢子菌感染是实体器官移植中比较常见的真菌感染。识别实体器官移植术后真菌感染的高危因素,提前预防,术后结合1,3-β-D葡聚糖试验（真菌G试验）、影像学检查和相关体液培养结果,做到早期诊断、早期治疗,对降低实体器官移植术后真菌感染的发生率及相关的病死率具有较大的临床意义。本文就器官移植术后常见的真菌感染进行综述,以期为器官移植术后真菌感染的防治提供参考。