Immunosuppression for long-term maintenance of renal allograft function

The incidence and severity of acute rejection episodes was markedly reduced by the introduction of new immunosuppressive drug regimens for renal transplantation, resulting in improved graft survival at 1 year. However, only modest improvement has been shown in long-term graft function rates.This overview evaluates the efficacy of currently used immunosuppressive drugs and drug combinations for long-term maintenance therapy. Prospective controlled trials rarely extend beyond 5 years; therefore, registry data and retrospective reports have also been employed. From currently available data it may be concluded that the initial beneficial effect of ciclosporin (cyclosporin) is lost 10 years after transplantation. Tacrolimus is an alternative to ciclosporin with a different profile of adverse effects and a higher efficacy in acute rejection treatment. For long-term maintenance, projected half-lives of kidney graft function are in favour of tacrolimus. Mycophenolate mofetil (MMF) has been shown to significantly reduce the incidence of early rejections. However, the improved long-term graft survival reported in retrospective studies has still to be confirmed in controlled trials. There is no convincing evidence for superiority of triple therapy including prednisone (or prednisolone), calcineurin inhibitors and azathioprine/MMF over dual therapy without azathioprine/MMF with respect to long-term outcome. Withdrawal of corticosteroids or calcineurin inhibitors clearly reduces adverse drug effects but carries the risk of acute rejection episodes. Avoidance of corticosteroids by using new immunosuppressive drug combinations may be an option to minimise toxic adverse effects in the future.At present, it seems unjustified to convert renal transplant recipients with stable graft function and tolerable adverse effects from one drug to another solely in expectation of future benefits. Acute early or late rejection episodes and intolerable adverse effects are good reasons for conversions between calcineurin inhibitors or cytotoxic agents. Chronic allograft nephropathy with slowly deteriorating graft function remains an unresolved problem.     

Everolimus: a proliferation signal inhibitor targeting primary causes of allograft dysfunction

Allograft dysfunction remains a major problem for long-term graft survival after kidney and heart transplantation. Current immunosuppressive regimens do not completely address the causes of allograft dysfunction which include acute rejection episodes, complications of immunodeficiency (for example, cytomegalovirus infection), nephrotoxicity from calcineurin inhibitors (cyclosporine and tacrolimus) and vascular remodeling and vasculopathy. Everolimus is a potent immunosuppressor that inhibits growth factor-stimulated proliferation of hematopoietic and nonhematopoietic cells, including vascular smooth muscle. Everolimus is indicated for the prophylaxis of acute rejection in kidney and heart transplant patients in a combined regimen with cyclosporine microemulsion and corticosteroids. Everolimus is formulated as both a tablet and a tablet for oral solution. It is rapidly absorbed and displays dose-proportional, stable pharmacokinetics. Everolimus has equivalent efficacy to mycophenolate mofetil in reducing the incidence of acute rejection after renal transplantation and superior efficacy to azathioprine after heart transplantation. Combination of everolimus with cyclosporine allows dose-reduction of cyclosporine while maintaining efficacy due to the synergistic immunosuppressive effects of the combination. Everolimus reduces intimal thickening of blood vessels to the graft and the incidence of allograft vasculopathy in heart transplantation. In both kidney and heart transplantation, the incidence of cytomegalovirus infection was lower in everolimus-treated patients compared with patients receiving the control treatment. Everolimus-related adverse events include elevated cholesterol and triglycerides, which respond to treatment, and decreased platelet count, which is transient. Nephrotoxicity may result from the combination of everolimus with full-dose cyclosporine but is mitigated by reducing the dose of cyclosporine. Everolimus is initiated at 0.75 mg b.i.d. with dose adjustments guided by therapeutic drug monitoring of predose blood levels. In clinical development trials, everolimus has demonstrated the ability to reduce the incidence of acute rejection episodes, cytomegalovirus infection and cardiac vasculopathy, thus addressing the primary causes of allograft dysfunction.     

Review: metabolism of immunosuppressant drugs

Pharmacokinetic concepts provide a basis for individualization of drug therapy to optimize outcomes of the critical-dose drugs cyclosporine (CsA), tacrolimus (TRL), sirolimus (SRL), and mycophenolate mofetil (MMF). The therapeutic range of a drug-defined as the concentrations at which the desired pharmacologic effect is produced without adverse effects in most patients-is difficult to achieve given the significant inter-and intrapatient variability of the effects of a given concentration of therapeutic agents. Because of the highly variable rates of absorption of immunosuppressive agents and clinical responses to given concentrations in transplant recipients, individualization of drug regimens by using therapeutic drug monitoring (TDM) is essential to optimize pharmacotherapy Assessing proclivity for acute rejection episodes in transplant recipients currently is attempted by estimating drug exposure using the area under the time-concentration curve (AUC) for MMF and the average concentration (Cav, the quotient of the AUC and the dosing interval) for CsA. These studies have revealed that low oral bioavailability was a more important predictor of rejection than was a rapid clearance rate. In addition, the degree of intra-individual variability of AUC values correlated with the development of chronic rejection in renal transplant recipients. Similarly, TDM of MMF requires AUC determinations. Low mycophenolic acid (MPA) exposure, as estimated by the AUC, demonstrates a significant association with an increased risk of an acute renal transplant rejection episode. The AUC0-2 estimate of MPA shows good agreement with the 12-hr AUC estimate from samples obtained during the entire dosing interval. In contrast, trough levels are utilized during treatment with TRL or SRL, potent new immunosuppressive agents that display a pleiotropic array of side effects. Standard body measures, including weight and body mass index, poorly predict the concentration of SRL in whole blood. Large inter- and intra-individual differences displayed in patients also could not be predicted by demographic features or by laboratory parameters. When SRL is given with other immunosuppressive agents such as CsA, which shares with SRL mutual microsomal metabolism by the cytochrome P450 3A system, pharmacokinetic interactions occur, especially when the agents are administered concomitantly. Because of the critical-dose nature of most of the recent generation of immunosuppressive agents, therapeutic drug monitoring is becoming increasingly important in the selection of doses and treatment regimens.     

FTY720 in combination with cyclosporine--an analysis of skin allograft survival and renal function

Acute and chronic nephrotoxicity caused by CsA continuous administration impair kidney allograft survival. Several clinical and experimental protocols have shown benefits to the kidney after decreasing CsA dose, withdrawing the drug or delaying its introduction after transplantation. FTY720 is a new compound that has immunosuppressive characteristics and increase allograft survival in animal models without causing the side effects of calcineurin inhibitors (CNIs). FTY720 described mechanism of action that consists to alter the lymphocyte migration pattern without impairment of the immune system response against pathogens. In our mice model, FTY720 administered alone or in combination with CsA during 21 days increased skin allograft survival in a fully mismatched strain combination and did not cause significant changes in renal function. Moreover, renal structure was normal in all groups suggesting that at low doses (10 mg/kg/day) CsA can be associated during short-term period to other immunosuppressive drugs, i.e. FTY720 without affecting the kidney. Combination of immunosuppressive compounds with FTY720 and/or delayed introduction of low cyclosporine dose could prevent graft rejection and avoid nephrotoxicity.     

肾移植术后应用2种不同剂量环孢素A的临床对照研究

目的:探讨肾移植术后应用环孢素A(CsA)、强的松(Pred)和吗替麦考酚酯(MMF)后是否允许CsA减量而不增加排斥反应发生率,是否可以减少CsA相关副作用以提高疗效。方法:将使用常规剂量CsA的肾移植患者(213例)与使用低剂量CsA患者(176例)进行对照研究。结果:2组肾功能水平、排斥反应发生率及人/肾存活率均无显著性差异,但低剂量CsA组总体疗效稍好,而且不良反应发生率明显减少。结论:肾移植术后患者CsA+MMF+Pred三联用药,在使用足够剂量MMF的情况下,可以允许CsA减量而不增加急性排斥反应的风险。     

FTY720 in combination with cyclosporine—an analysis of skin allograft survival and renal function

Acute and chronic nephrotoxicity caused by CsA continuous administration impair kidney allograft survival. Several clinical and experimental protocols have shown benefits to the kidney after decreasing CsA dose, withdrawing the drug or delaying its introduction after transplantation.FTY720 is a new compound that has immunosuppressive characteristics and increase allograft survival in animal models without causing the side effects of calcineurin inhibitors (CNIs). FTY720 described mechanism of action that consists to alter the lymphocyte migration pattern without impairment of the immune system response against pathogens.In our mice model, FTY720 administered alone or in combination with CsA during 21 days increased skin allograft survival in a fully mismatched strain combination and did not cause significant changes in renal function. Moreover, renal structure was normal in all groups suggesting that at low doses (10 mg/kg/day) CsA can be associated during short-term period to other immunosuppressive drugs, i.e. FTY720 without affecting the kidney.Combination of immunosuppressive compounds with FTY720 and/or delayed introduction of low cyclosporine dose could prevent graft rejection and avoid nephrotoxicity.     

Calcineurin inhibitor-free immunosuppression in pediatric renal transplantation: a viable option?

The introduction, in the mid-1980s, of calcineurin inhibitors - namely ciclosporin (cyclosporine) and later tacrolimus - has significantly improved short-term renal graft survival by lowering acute rejection rates in both adult and pediatric kidney transplantation. Nonetheless, long-term transplant survival is still not satisfactory, with calcineurin inhibitor-induced chronic nephrotoxicity being one of the main causes of progressive nephron loss and declining renal transplant function. Hence, different immunosuppressant regimens have been proposed to avoid or ameliorate calcineurin inhibitor-induced nephrotoxicity. These comprise the use of non-depleting or depleting antibodies for calcineurin inhibitor minimization, calcineurin inhibitor avoidance, or calcineurin inhibitor withdrawal from mycophenolate mofetil-based immunosuppressant protocols. De novo use of a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or conversion from a calcineurin inhibitor to an mTOR inhibitor may constitute another therapeutic option to avoid or reduce calcineurin inhibitor-induced nephrotoxicity. To date, complete calcineurin inhibitor avoidance seems to be inappropriate because other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies are needed for rejection prophylaxis, which are frequently accompanied by a higher incidence of infections and an unacceptably high acute rejection rate under calcineurin inhibitor avoidance. In some studies, calcineurin inhibitor withdrawal in adult and pediatric kidney allograft recipients with stable or declining transplant function has been associated with an amelioration of renal function; however, this is attained at the cost of a higher acute rejection rate in 10-20% of patients. It has been frequently stressed that conversion from a calcineurin inhibitor-based regimen to an mTOR inhibitor-based immunosuppressant regimen should be performed early (e.g. 3 or 6 months post-transplant) in patients with well-preserved renal transplant function without significant proteinuria in order to prevent, or at least limit, calcineurin inhibitor-induced tissue damage and provide long-term benefit. It should be borne in mind though that the use of an mTOR inhibitor carries the risk of potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism. Even though everolimus may be better tolerated than sirolimus, studies on everolimus for calcineurin inhibitor-free immunosuppression in the pediatric kidney transplant patient population are lacking. At present, the safest therapeutic strategy for pediatric renal allograft recipients with chronic calcineurin inhibitor-induced nephrotoxicity appears to be a mycophenolate mofetil-based regimen with low-dose calcineurin inhibitor therapy and corticosteroids; available published data show that dual immunosuppression with mycophenolate mofetil and corticosteroids, as well as an mTOR inhibitor plus mycophenolate mofetil plus corticosteroid-based regimens, are associated with an increased risk of acute rejection episodes. In individual patients with evidenced chronic allograft dysfunction and over-immunosuppression leading to recurrent infections, dual maintenance immunosuppression with mycophenolate mofetil and corticosteroids may be appropriate. As stated in the annual report issued by the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry, currently the most popular immunosuppressant protocol consists of a calcineurin inhibitor combined with mycophenolate mofetil and corticosteroids: 59.1% and 53.2% of patients with a functioning graft receive a calcineurin inhibitor plus mycophenolate mofetil plus corticosteroid-based immunosuppression at 1 and 5 years post-transplant, respectively. 91.4% and 87.8% of patients are administered a calcineurin inhibitor-containing regimen 1 and/or 5 years after transplantation, respectively. Undoubtedly, the use of calcineurin inhibitor-free immunosuppressant regimens with or without antibody induction, plus an mTOR inhibitor and mycophenolate mofetil, requires more comprehensive long-term investigations to determine whether acceptable rejection rates and conservation of renal function can be achieved.     

Immunosuppression for lung transplantation: evidence to date

With the introduction of ciclosporin (cyclosporine) into routine clinical practice 20 years ago, lung transplantation has become an established treatment for patients with advanced lung disease. Most lung transplant recipients routinely continue to receive a triple-drug maintenance immunosuppressive regimen consisting of a calcineurin inhibitor, an antimetabolite and corticosteroids. The use of antibody-based induction therapy remains common, although there has been a shift away from T cell-depleting agents, such as antithymocyte globulin, towards anti-interleukin-2 receptor monoclonal antibodies. Recent years have seen the introduction of sirolimus and everolimus, immunosuppressive drugs that act by blocking growth factor-driven cell proliferation. While the newer immunosuppressive drugs have been rigorously evaluated in large randomised trials in kidney, liver and cardiac transplantation, such studies are lacking in lung transplantation. Despite a shift towards more potent immunosuppressive regimens that incorporate tacrolimus and mycophenolate mofetil, the development of chronic allograft rejection, as manifested by the bronchiolitis obliterans syndrome continues to negatively impact on the long-term survival of lung transplant recipients. This article reviews the evidence for the immunosuppressive regimens used during induction and maintenance of patients undergoing lung transplantation, and discusses current strategies in the management of chronic rejection.     

Pharmacological profiles of mycophenolate mofetil (CellCept), a new immunosuppressive agent

Mycophenolate mofetil (MMF, CellCept), a semisynthetic derivative of mycophenolic acid (MPA) produced by a fungus, is an inhibitor of the inosine monophosphate dehydrogenase (IMPDH) enzyme (IC50 = 25 nM) that catalyzes the synthesis of guanosine monophosphate (GMP) from inosine. GMP is an essential nucleoside for purine synthesis during cell division. As T and B-lymphocytes almost exclusively use the de novo pathway of purine synthesis, these cells are particularly sensitive to the inhibitory action of MMF. It has a mechanism of action distinct from cyclosporine and tacrolimus. Although MMF does not affect cytokine production, by inhibiting the rate-limiting enzyme IMPDH in the de novo synthesis of purines, it inhibits the proliferation of T and B-lymphocytes, the production of antibodies, and the generation of cytotoxic T lymphocytes. Reversal of acute allograft rejection and increased survival of kidney, heart and bone marrow cell allograft has been shown in several animal studies. Moreover, it was suggested that MMF combined with CsA prevented the acute rejection, and approximately half of the animals became long-term survivors. The Ministry of Health and Welfare approved MMF in 1999 for use for rejection treatment in renal transplantation based on several prospective, randomized and blind efficacy trials.     

细辛木脂素抗心脏移植急性排斥反应的实验观察

目的:观察细辛木脂素(Herba Asari Ligini,HAL)对大鼠同种异位心脏移植急性排斥反应的治疗效果,为抗排斥药物的研究提供实验依据。方法:建立大鼠同种异位心脏移植模型,受体自术前1天至术后14天分别给予 CsA10mg/kg/d、CsA2.5mg/kg/d、HAL50mg/kg/d、HAL50MG/kg/d+CsA2.5mg/kg/d 观察移植心存活时间。结果:单用 HAL 组的移植心存活时间比对照组长(P<0.01),但短于 CsA10mg/kg/d 组(P<0.01);CsA2.5mg/kg/d 组与 HAL50mg/kg/d合用组的移植心存活时间与 CsA10mg/kg/d 组相拟(P>0.05)。结论:HAL 具有抗排斥作用,但效果低于治疗量(10mg/kg/d)的 CsA;HAL 与 CsA 抗急性排斥反应具有协同作用。     

Clinical application of population pharmacokinetic methods developed for immunosuppressive drugs

After a brief overview of the relevant exposure indices for cyclosporine (CsA) and mycophenolate mofetil (MMF), as well as of the different steps necessary to develop maximum a posteriori Bayesian estimators (MAP-BE), this paper presents applications of MAP-BE for CsA or MMF to clinical cases and clinical trials. Ina renal transplant patient under CsA, grade I chronic allograft nephropathy was found at the sixth month posttransplantation, with CsA CO slightly above the target range and C2 markedly below; the AUCO0-12 h Bayesian estimate was quite high, at 5.6 mg h/L, as compared with a mean value of 4.3+0.9 mg.h/L in stable renal transplants at this period; the inconsistent C2 level found could be explained by delayed absorption of CsA in this patient, in which case C2 no longer represents the major part of the AUC. The patient was switched to sirolimus, which resulted in a slow and significant improvement of graft function with no acute rejection. In a 50-year-old female renal transplant recipient administered MMF and CsA and with a very favorable outcome otherwise, progressive anemia appeared 8 months posttransplantation. Clinical investigations were negative,but Bayesian estimation showed a rather high MPA AUCO0-12 h (69.8 mg h/L). After MMF dose reduction, hemoglobin level progressively returned to normal, without erythropoietin injection or blood transfusion. Finally, the feasibility of accurate dose adjustment using these MAP-BE is shown through preliminary results from 2 ongoing multicenter clinical trials, 1 evaluating an AUC-controlled cyclosporine-sparing strategy in stable renal transplants, the second evaluating the benefit of MMF therapeutic drug monitoring based on MPA AUCO0-12 h in de novo renal transplant recipients.     

Early steroid withdrawal protocol with basiliximab, cyclosporine and mycophenolate mofetil in renal-transplant recipients

OBJECTIVE: Adverse effects of steroids have led to efforts to minimize their use in recipients of organ transplants. This study evaluated an early steroid withdrawal protocol including basiliximab, cyclosporine (CsA) and mycophenolate mofetil (MMF) in renal-transplant recipients. METHODS: Between January 2001 and April 2005, our early steroid withdrawal protocol was used in 130 patients who underwent renal transplantation. Immunosuppression consisted of CsA (6-8 mg/kg), MMF (2 g/kg) and methylprednisolone (MP); basiliximab was given as induction therapy (steroid withdrawal group). MP was administered in a dose of 500 mg or 250 mg at renal transplantation; thereafter, the dose was rapidly tapered and MP was withdrawn on day 14 post-transplant. RESULTS: The incidence of acute rejection in the steroid withdrawal group was similar to that in the conventional steroid treatment group (without basiliximab) (18% vs. 21%). The severity of rejection episodes was similar in the two groups. Patient and graft survivals were 100% and 97% in the steroid withdrawal group. In 80 of the 130 patients (62%) in the steroid withdrawal group, MP was successfully withdrawn, with good allograft function during follow-up. In the other 50 patients (38%), MP was reinitiated because of acute rejection or other reasons. The success rate of steroid withdrawal 12 months after transplantation in recipients of ABO-compatible grafts was significantly higher than that in recipients of ABO-incompatible grafts (66% vs. 44%). The dose of MMF during the 12 months after renal transplantation was significantly lower in steroid reinitiated group than in the successful withdrawn group (p<0.05). Patients in the successful withdrawn group showed metabolic benefits such as lower cholesterol levels as compared with the steroid reinitiated group. CONCLUSION: Although further follow-up is necessary to confirm our results, our protocol successfully permitted the early withdrawal of steroids in 62% of renal-transplant recipients, with no resumption of steroid treatment during 3 years of follow-up.     

Tacrolimus: a further update of its use in the management of organ transplantation

Extensive clinical use has confirmed that tacrolimus (Prograf) is a key option for immunosuppression after transplantation. In large, prospective, randomised, multicentre trials in adults and children receiving solid organ transplants, tacrolimus was at least as effective or provided better efficacy than cyclosporin microemulsion in terms of patient and graft survival, treatment failure rates and the incidence of biopsy-proven acute and corticosteroid-resistant rejection episodes. Notably, the lower incidence of rejection episodes after renal transplantation in tacrolimus recipients was reflected in improved cost effectiveness. In bone marrow transplant (BMT) recipients, the incidence of tacrolimus grade II-IV graft-versus-host disease was significantly lower with tacrolimus than cyclosporin treatment. Efficacy was maintained in renal and liver transplant recipients after total withdrawal of corticosteroid therapy from tacrolimus-based immunosuppression, with the incidence of acute rejection episodes at up to 2 years' follow-up being similar with or without corticosteroids. Tacrolimus provided effective rescue therapy in transplant recipients with persistent acute or chronic allograft rejection or drug-related toxicity associated with cyclosporin treatment. Typically, conversion to tacrolimus reversed rejection episodes and/or improved the tolerability profile, particularly in terms of reduced hyperlipidaemia. In lung transplant recipients with obliterative bronchiolitis, conversion to tacrolimus reduced the decline in and/or improved lung function in terms of forced expiratory volume in 1 second. Tolerability issues may be a factor when choosing a calcineurin inhibitor. Cyclosporin tends to be associated with a higher incidence of significant hypertension, hyperlipidaemia, hirsutism, gingivitis and gum hyperplasia, whereas the incidence of some types of neurotoxicity, disturbances in glucose metabolism, diarrhoea, pruritus and alopecia may be higher with tacrolimus treatment. Renal function, as assessed by serum creatinine levels and glomerular filtration rates, was better in tacrolimus than cyclosporin recipients at up to 5 years' follow-up. CONCLUSION: Recent well designed trials have consolidated the place of tacrolimus as an important choice for primary immunosuppression in solid organ transplantation and in BMT. Notably, in adults and children receiving transplants, tacrolimus-based primary immunosuppression was at least as effective or provided better efficacy than cyclosporin microemulsion treatment in terms of patient and graft survival, treatment failure and the incidence of acute and corticosteroid-resistant rejection episodes. The reduced incidence of rejection episodes in renal transplant recipients receiving tacrolimus translated into a better cost effectiveness relative to cyclosporin microemulsion treatment. The optimal immunosuppression regimen is ultimately dependent on balancing such factors as the efficacy of the individual drugs, their tolerability, potential for drug interactions and pharmacoeconomic issues.     

高龄患者肾移植126例临床分析

目的 :探讨高龄患者肾移植的临床特点及四联免疫抑制疗法对临床治疗效果的影响。方法 :分析 1990年 1月至 2 0 0 0年 12月 12 5 1例肾移植中 12 6例高龄患者临床资料 ,将术后使用免疫抑制剂为三联疗法 (CsA +Aza +激素 )的 5 5例作组Ⅰ ;而使用四联疗法 (CsA +MMF +激素 +抗T细胞单抗 )的 71例作为组Ⅱ ,组Ⅱ中 4 7例患者术后使用 2周Wu -T3抗排斥治疗 ,另 2 4例应用抗IL- 2R抗体预防急性排斥反应。将两组的术后并发症、急性排斥率及 1年人 /肾存活率相比较 ,并与本院同期非高龄患者相同指标比较。结果 :高龄患者肾移植后心脑血管并发症以及感染发生率均明显高于非高龄患者。组Ⅰ和组Ⅱ患者的术后并发症发生率分别为 74 5 5 %和 38 0 3% ;急性排斥发生率分别为 12 73%和 4 2 3% ;1年人 /肾存活率分别为 81 82 % /78 18%和 97 18% /95 77%。结论 :高龄患者肾移植术后较容易发生心脑血管并发症及感染 ,使用新的四联免疫抑制疗法能有效地降低心脑血管并发症、感染和急性排斥反应的发生率 ,1年人 /肾存活率亦明显提高。     

Mycophenolate mofetil in organ transplantation: focus on metabolism, safety and tolerability

Mycophenolate mofetil (MMF) received its first approval for the prevention of renal allograft rejection in 1995 and has now become the most frequently used antiproliferative agent in maintenance immunosuppressive therapy for kidney, pancreas, liver and heart transplantation. In addition, its use for the treatment of autoimmune diseases steadily increases. This review focuses on the miscellaneous pharmacodynamic properties of the drug, its pharmacokinetics in healthy subjects, recipients of different organ transplants and combination therapy with other pharmaceuticals, as well as its safety profile. The immunosuppressive activity of MMF is thought to derive mainly from the potent and selective inhibition of purine synthesis in both T and B lymphocytes. In contrast to other immunosuppressants on the market, it is metabolised primarily by glucuronidation and lacks nephrotoxicity, cardiovascular toxicity or diabetogenic potential, thus making it a suitable candidate for combination regimens. The most important side effects under MMF include gastrointestinal disorders, of which the underlying mechanisms are not yet fully understood, but seem to be complex and related to both effects of mycophenolic acid and its acyl glucuronide, as well as to decreased -immunity due to general immunosuppression after transplantation.     

A review of interleukin-2 receptor antagonists in solid organ transplantation.

Daclizumab and basiliximab, engineered human IgG monoclonal antibodies to the interleukin-2 (IL-2) receptor alpha-subunit, were approved to prevent acute rejection after renal transplantation. Daclizumab was studied in adult and pediatric renal allograft recipients, liver allograft recipients, and calcineurin-sparing protocols in renal transplant recipients. Basiliximab was studied in renal allograft recipients and subgroups of recipients of living-related and cadaveric transplants, and in patients with diabetes mellitus. Both agents reduced acute rejection and were associated with few adverse effects. However, information regarding their long-term effects on infection, malignancy, chronic rejection, and patient survival must be available before a final decision is made regarding their proper administration. We propose that a likely role the drugs will play in the field of solid organ transplantation is in new protocols that allow sparing of other more toxic immunosuppressive agents.     

Combination therapy with diltiazem plus CsA/MMF/Pred or CsA/Aza/Pred triple immunosuppressive regimens for use in clinical kidney transplantation in Northwestern China

Objective

The effects of diltiazem on 1692 kidney transplant recipients under the immunosuppressive regimen of cyclosporine A (CsA) in combination with either mycophenolate mofetil or azothioprine were assessed. The two treatment groups were compared for blood concentrations of CsA, the extent of acceptable dosage reduction for the maintenance of immunotherapy, potential effects of kidney protection, and promotion of graft function.

Method

We monitored changes of blood concentrations of CsA in the two different patient treatment groups for post-transplant graft function, episodes of acute rejection, and hepatic and renal toxicity in 1640 renal transplant recipients after treatment with diltiazem.

Results

In patients treated with the triple immunosuppressive regimen consisting of CsA, azothioprine, and prednisolone (Pred), the sub-group of patients receiving the diltiazem treatment saw a significantly reduced CsA dosage in comparison to the non-diltiazem group (control group 1) (P?<?0.05), but the blood concentrations of CsA of the diltiazem group were higher than those of control group 1 (P?<?0.01). Of the patients treated with CsA, mycophenolate mofetil, and Pred, the sub-group of patients also treated with diltiazem showed similar effects: CsA dosage was reduced (P?<?0.01) and the blood concentrations of CsA significantly increased (P?<?0.01) in comparison with those of control group 2. In addition, recovery time of graft function decreased to 4.7?±?1.8?days and 3.9?±?1.4?days in the two diltiazem treatment groups, respectively (P?<?0.05), and the rate of acute rejection decreased to 21 (p?<?0.05) and 7.9% (P?<?0.01), respectively.

Conclusion

In our cohort of renal transplantation patients, co-administration of CsA and diltiazem increased CsA blood concentration, thereby resulting in a reduction in its required dosage treatment, which lightened the patients?? economic burden while improving primary and long-term kidney function by promoting the recovery of graft function and decreasing hepatic and renal toxicity. The co-administration of diltiazem may also reduce the rate of acute rejection, especially in patients who also receive the triple immunosuppressive regimen consisting of CsA, mycophenolate mofetil, and Pred.     

Emerging immunosuppressive drugs in kidney transplantation

Calcineurin inhibitors (CNI), a cornerstone of current immunosuppressive therapy, have important cardiovascular and oncogenic side effects and CNI nephrotoxicity contributes to the multifactorial process called "chronic allograft dysfunction", the leading cause of chronic allograft failure among kidney transplant recipients. New drugs, with a different mechanism of action, are being developed focusing on a better balance between drug efficacy and toxicity. These novel compounds interfere with either T-cell mediated or antibody-mediated rejection. In this review, we report on the mechanism of action, pharmacokinetics and preliminary results of clinical trials of these promising new immunosuppressive drugs.     

Mycophenolate mofetil in solid-organ transplantation

This review focuses on the use of mycophenolate mofetil (MMF) as an immunosuppressive agent in solid-organ transplantation. MMF, a non-competitive inhibitor of inosine monophosphate dehydrogenase, blocks de novo purine synthesis in T and B lymphocytes, resulting in the selective inhibition of proliferation of these cells in response to antigenic stimuli. MMF may also promote apoptosis of these cells. The immunosuppressive ability of MMF is thought to derive mainly from the inhibition of inosine monophosphate dehydrogenase. The other effects of MMF include suppression of antibody synthesis by B lymphocytes, inhibition of proliferation of smooth muscle cells in culture and impaired glycosylation of adhesion molecules. MMF may exhibit anti-inflammatory effects resulting from decreased activity of the inducible form of nitric oxide synthase, a consequence of depletion of tetrahydrobiopterin, which leads to decreased generation of peroxynitrite, a pro-inflammatory molecule. The pharmacokinetics, pharmacodynamics and principles underlying therapeutic drug monitoring of MMF are reviewed. The results of the pivotal clinical trials of MMF in kidney and heart transplantation are discussed and a summary of the major studies demonstrating a positive effect of MMF on renal transplantation outcomes is presented. The use of MMF in the context of ABO-incompatible renal transplantation, renal transplantation in highly sensitised and cross-match positive recipients, humoral rejection of renal allografts, chronic allograft nephropathy and steroid/calcineurin inhibitor minimisation in renal transplantation are also discussed.     

Mycophenolate mofetil in solid-organ transplantation

This review focuses on the use of mycophenolate mofetil (MMF) as an immunosuppressive agent in solid-organ transplantation. MMF, a non-competitive inhibitor of inosine monophosphate dehydrogenase, blocks de novo purine synthesis in T and B lymphocytes, resulting in the selective inhibition of proliferation of these cells in response to antigenic stimuli. MMF may also promote apoptosis of these cells. The immunosuppressive ability of MMF is thought to derive mainly from the inhibition of inosine monophosphate dehydrogenase. The other effects of MMF include suppression of antibody synthesis by B lymphocytes, inhibition of proliferation of smooth muscle cells in culture and impaired glycosylation of adhesion molecules. MMF may exhibit anti-inflammatory effects resulting from decreased activity of the inducible form of nitric oxide synthase, a consequence of depletion of tetrahydrobiopterin, which leads to decreased generation of peroxynitrite, a pro-inflammatory molecule. The pharmacokinetics, pharmacodynamics and principles underlying therapeutic drug monitoring of MMF are reviewed. The results of the pivotal clinical trials of MMF in kidney and heart transplantation are discussed and a summary of the major studies demonstrating a positive effect of MMF on renal transplantation outcomes is presented. The use of MMF in the context of ABO-incompatible renal transplantation, renal transplantation in highly sensitised and cross-match positive recipients, humoral rejection of renal allografts, chronic allograft nephropathy and steroid/calcineurin inhibitor minimisation in renal transplantation are also discussed.