Basiliximab: a review of its use as induction therapy in renal transplantation

Basiliximab (Simulect), a chimeric (human/murine) monoclonal antibody, is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents.Basiliximab significantly reduced acute rejection compared with placebo in renal transplant recipients receiving dual- (cyclosporin microemulsion and corticosteroids) or triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and patient survival rates at 12 months were similar. Significantly more basiliximab than placebo recipients were free from the combined endpoint of death, graft loss or acute rejection 3 years, but not 5 years, after transplantation.The incidence of adverse events was similar in basiliximab and placebo recipients, with no increase in the incidence of infection, including cytomegalovirus (CMV) infection. Malignancies or post-transplant lymphoproliferative disorders after treatment with basiliximab were rare, with a similar incidence to that seen with placebo at 12 months or 5 years post-transplantation. Rare cases of hypersensitivity reactions to basiliximab have been reported.The efficacy of basiliximab was similar to that of equine antithymocyte globulin (ATG) and daclizumab, and similar to or greater than that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte globulin (RATG) in patients at relatively low risk of acute rejection, but less effective in high-risk patients. Numerically or significantly fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than ATG or RATG recipients. The incidence of infection, including CMV infection, was similar with basiliximab and ATG or RATG.Basiliximab plus baseline immunosuppression resulted in no significant differences in acute rejection rates compared with baseline immunosuppression with or without ATG or antilymphocyte globulin in retrospective analyses conducted for small numbers of paediatric patients. Limited data from paediatric renal transplant recipients suggest a similar tolerability profile to that in adults. Basiliximab appears to allow the withdrawal of corticosteroids or the use of corticosteroid-free or calcineurin inhibitor-sparing regimens in renal transplant recipients.Basiliximab did not increase the overall costs of therapy in pharmacoeconomic studies.CONCLUSION: Basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, in renal transplant recipients when combined with standard dual- or triple-immunotherapy. The overall incidence of death, graft loss or acute rejection was significantly reduced at 3 years; there was no significant difference for this endpoint 5 years after transplantation. Malignancy was not increased at 5 years. The overall efficacy, tolerability, ease of administration and cost effectiveness of basiliximab make it an attractive option for the prophylaxis of acute renal transplant rejection.     

Impaired prednisolone sensitivities of the endocrine system and peripheral-blood lymphocytes are closely related to clinical incidence in renal transplantation.

Endocrine- and immune-responses to prednisolone and their relation to clinical incidence were assessed in 19 renal transplant recipients. All of the patients were treated with prednisolone and cyclosporin. Response of the hypothalamic-pituitary-adrenal (HPA) system to prednisolone was evaluated by measuring serum cortisol concentration. Cortisol concentration before transplantation was 126.7 +/- 38.6 ng mL-1, while it decreased to 4.1 +/- 2.5 ng mL-1 within the period characterized by a cumulative dose of prednisolone from 300 to 700 mg. A statistically significant high incidence (P less than 0.01) of acute rejections was observed in low HPA responders; (mean cortisol concentration during prednisolone treatment exceeded 3.0 ng mL-1), 6 of 12 with a low HPA response to prednisolone showed signs of rejection, while none of the 7 with a high HPA response showed signs of rejection. The concentrations of prednisolone suppressing the in-vitro response of pretransplant lymphocytes to concanavalin A by 50% (ID50) were determined. Lymphocytes from 8 patients were extremely insensitive (ID50 greater than 500 ng mL-1), and 5 of the 8 showed signs of rejection. Lymphocytes from the other 11 patients showed high sensitivity (ID50 less than 500 ng mL-1), and only one of those showed signs of rejection. Thus, a significantly high incidence of rejection was observed in low lymphocyte-responders to prednisolone (P less than 0.05). The results suggest that an insensitive endocrine response to prednisolone correlates with an impaired lymphocyte response to the steroid, and that both of the indices are related to occurrence of rejection. Evaluation of these pharmacodynamic parameters in combination may serve as a guideline for successful immunosuppressive therapy in renal transplantation.     

Immunosuppressive efficacy of tetrandrine combined with methylprednisolone against mitogen‐activated peripheral blood mononuclear cells of haemodialysis patients

Immunosuppressive therapy for prevention of acute rejection episode occasionally causes serious adverse effects, and thus it is important to develop new therapeutic approach for renal transplant recipients. This study evaluated the immunosuppressive pharmacodynamics of tetrandrine (TET) and/or methylprednisolone (MP) in haemodialysis patients in vitro by using the peripheral blood mononuclear cells (PBMCs) isolated from whole blood of haemodialysis patients. The median (range) of MP IC₅₀ values against the proliferation of patients PBMCs was 7.04 (2.30‐500.00) ng/mL. In contrast, the median (range) of MP IC₅₀ values against the proliferation of healthy PBMCs was 4.44 (3.19‐5.08) ng/mL. The median (range) of TET IC₅₀ values against the proliferation of patients PBMCs was 1.61 (1.04‐4.79) μmol/L. Lower concentrations of TET (0.3‐300 nmol/L) were able to decrease the IC₅₀ values of MP and thus potentiate the MP immunosuppressive effect on patient PBMCs. The median (range) of MP IC₅₀ values in combination with 0.3, 3, 30, and 300 nmol/L TET were 0.92 (0.49‐8.39), 2.10 (0.45‐20.00), 0.35 (0.092‐1.05), and 0.14 (0.05‐6.78) ng/mL, respectively. TET potentiates the MP immunosuppressive pharmacodynamics and thus, it was possible to use the combination of MP and TET to attenuate MP side effects. There were significant correlations between the IC₅₀ values of TET and stimulation indices (P=0.04, r=.58), the IC₅₀ values of TET and the haemodialysis periods (P=0.04, r=.57), or the IC₅₀ values of MP combined with 0.3 nmol/L TET and C‐reactive protein concentrations (P=0.04, r=.64), respectively.     

Review of the proliferation inhibitor everolimus

Everolimus (Certican^?) is being developed for prevention of acute and chronic rejection of solid organ transplants. A novel proliferation inhibitor, everolimus synergies with cyclosporine to prevent and reverse acute rejection in preclinical models of kidney, heart or lung transplantation. The manifestations of chronic rejection that may contribute to graft loss are also inhibited by everolimus in preclinical models. Although everolimus is metabolised by the cytochrome P450 CYP3A isoenzyme, coadministration with cyclosporine does not alter the pharmacokinetics of cyclosporine, but cyclosporine coadministration increases exposure to everolimus. Everolimus interacts with inhibitors and inducers of this system; its clearance is reduced in patients with hepatic impairment. In an immunosuppressive regimen with cyclosporine microemulsion formulation and corticosteroids, transplant recipients treated with everolimus show low rates of acute rejection and, in one heart and one renal trial, lower rates of cytomegalovirus infection. Acute rejection rates are lower than those seen with azathioprine in cardiac transplant recipients and similar to those seen with mycophenolate mofetil in renal transplant recipients. Low rates of acute rejection are maintained when everolimus is given as part of a quadruple immunosuppressive regimen with low-dose cyclosporine in renal transplant recipients, with the added benefit of better renal function compared with full-dose cyclosporine. Use of C₂ monitoring to optimise cyclosporine exposure and enhance efficacy and safety of everolimus is planned in future studies. Hypertriglyceridaemia and hypercholesterolaemia have been associated with everolimus, but these effects are not dose-limiting. There is no clear upper therapeutic limit of everolimus. However, thrombocytopenia occurs at a rate of 17% at everolimus trough serum concentrations above 7.8 ng/ml in renal transplant recipients. There are limited safety data available in patients with trough concentrations > 12 ng/ml. Studies suggest everolimus targets primary causes of chronic rejection by reducing acute rejection, allowing for cyclosporine dose reduction (which may lead to improved renal function relative to full-dose cyclosporine) and by reducing cytomegalovirus infection and inhibiting vascular remodelling.     

Immunosuppression in elderly renal transplant recipients: are current regimens too aggressive?

Renal transplantation is an accepted and successful treatment modality in elderly patients with end-stage renal disease. In comparison with maintenance dialysis, transplantation has been shown to confer a mortality benefit as well as improvements in quality of life in older individuals with end-stage renal disease. Despite this, overall outcomes of renal transplantation in elderly individuals have, in general, been less successful than those of younger renal transplant recipients. Largely, this has been due to the particular vulnerability of elderly patients to the immunosuppressive medications used in renal transplantation. This review article covers these issues in some detail and briefly discusses some of the pharmacokinetic, pharmacodynamic, physiological and immunological differences between younger and older transplant recipients. Elderly renal transplant recipients have both a higher rate of patient death and allograft loss censored for death. Upon multivariate analysis, age of the recipient is strongly associated with allograft loss independent of other known factors. Acute rejections are less frequent in older individuals; however the consequence of a rejection if it occurs is negative for long-term graft survival. On the other hand, death by infection is vastly increased in older versus younger renal transplant recipients. In general, the pharmacokinetics of the immunosuppressive agents are little affected by age, but the tolerance to these agents seems to decrease with increasing age. Elderly renal transplant recipients present a very difficult clinical challenge. As the elderly become an ever-increasing segment of the renal transplant population, new and innovative immunosuppressive strategies will have to be considered and applied.     

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.     

Pharmacodynamic parameters of immunosuppressive drugs are not correlated with age, duration of dialysis, percentage of lymphocytes or lymphocyte stimulation index in renal transplant recipients

The lymphocyte immunosuppressant-sensitivity test (LIST) has been reported extensively as being able to estimate the pharmacological efficacy of immunosuppressive drugs in individual patients. This study measured the IC50 values for 6 drugs, cyclosporine, tacrolimus, methylprednisolone, 6-mercaptopurine, mycophenolic acid, and mizoribine, against mitogen-induced proliferation of peripheral-blood lymphocytes in 29 renal transplant recipients. We also examined relationship between the IC50 values and 4 factors; age, duration of dialysis, percentage of lymphocytes in total white blood cells, and blastogenesis stimulation index by mitogen. There were no significant correlations between the IC50 values and these factors, except that the tacrolimus IC50 value was correlated weakly with the stimulation index (p<0.05, r=-0.429). It was concluded that the pharmacological efficacy of immunosuppressive drugs cannot be inferred from the patient characteristics or their laboratory data. LIST is an effective method to elucidate the pharmacodynamic properties of immunosuppressive agents in individual renal transplant recipients without being influenced by the recipient clinical data.     

Daclizumab: a review of its use in the prevention of acute rejection in renal transplant recipients

The humanised monoclonal antibody daclizumab is an immunosuppressive agent that reduces acute rejection in renal transplant recipients. It is specific for the alpha subunit (Tac/CD25) of the interleukin-2 (IL-2) receptor on activated T cells and achieves immunosuppression by competitive antagonism of IL-2-induced T cell proliferation. Daclizumab has advantages over murine antibodies to the IL-2 receptor, including improved effector function, a low potential for immunogenicity and long elimination half-life. When added to standard cyclosporin-based immunosuppressive therapy with or without azathioprine, daclizumab (1 mg/kg prior to surgery and once every 2 weeks thereafter for a total of 5 doses) significantly reduced the 6-month rate of acute rejection compared with placebo in 2 phase III studies. The mean number of rejection episodes was significantly reduced and the time to first acute rejection significantly increased in daclizumab versus placebo recipients. Patient survival at 1 year after transplantation was significantly higher with daclizumab than placebo in 1 study and showed a trend in favour of the drug in the other study. The 1-year graft survival rate tended to be greater in daclizumab than in placebo recipients in both studies, In a phase II study, acute rejection rates in patients treated with both daclizumab and mycophenolate mofetil (plus standard cyclosporin-based immunosuppression) were lower than those achieved with mycophenolate mofetil alone. Preliminary results indicate that daclizumab is also a useful agent in paediatric renal transplant recipients. Further investigation of the efficacy and tolerability of the drug in this patient group is clearly warranted. Daclizumab does not increase the incidence of adverse events when added to standard cyclosporin-based therapy. The incidence of opportunistic infections, lymphoproliferative disorders and malignancies was not increased above that seen with placebo. CONCLUSIONS: Although the effects of daclizumab on long term graft and patient survival require further investigation, available data indicate that daclizumab is an important advance in renal transplant immunosuppression, reducing acute graft rejection without affecting the tolerability of standard cyclosporin-based immunosuppression.     

The change of immunosuppressive regimen from calcineurin inhibitors to mammalian target of rapamycin (mTOR) inhibitors and its effect on malignancy following heart transplantation

Malignancy is a significant cause of mortality after organ transplantation. There is an increased rate of malignancy following heart transplantation (HTx) compared to the general population and other organ transplant recipients. Post-HTx patients with a history of malignancy are also at a higher risk of developing new malignancies or exacerbation of their existing malignancies. Mammalian target of Rapamycin inhibitors (mTORIs) are newly introduced immunosuppressive drugs with a unique mechanism of action. By changing the immunosuppressive regimen from classic drugs, especially calcineurin inhibitors (CNIs) to mTORIs, the rate of developing de novo malignancies and the relapse of former malignancies is significantly reduced. However, issues like allograft function, total surveillance of patients, and post-transplantation complications should be considered during the conversion of drug regimens utilizing CNIs to drug regimens employing mTORIs. We reviewed different post-heart transplant maintenance immunosuppressive regimens and their effect on post-HTx malignancies with a focus on mTORIs, compared safety against effectiveness, and gathered conclusions based on our review of the literature, which may lead clinicians to make a better evidence-based decision regarding post-HTx maintenance immunosuppressive drug regimens. Overall, CNI to mTORI conversion in post-HTx maintenance immunosuppressive drug regimens was associated with a reduced rate of developing malignancy in post-HTx patients. Furthermore, nephrotoxicity decreased significantly while using mTORIs in combination with lower doses of CNIs and the rejection rate was equivalent to CNI-only regimens. In conclusion, mTORI-based maintenance immunosuppressive drug regimens seem to be safe and beneficial when considering efficacy vs. adverse effects, and all-cause mortality rates are significantly lower in patients switched to mTORIs when compared to CNI recipients.     

Economic implications of the use of basiliximab in addition to triple immunosuppressive therapy in renal allograft recipients: a UK perspective

OBJECTIVE: To compare resource use and costs in renal transplant recipients treated with basiliximab or placebo plus triple immunosuppressive therapy. DESIGN: International randomised, double-blind, placebo-controlled trial; economic evaluation undertaken alongside the efficacy trial. The economic evaluation was performed from a UK National Health Service hospital perspective. SETTING: 31 centres in 12 countries. PARTICIPANTS: 345 renal transplant recipients were enrolled; 340 were randomised (basiliximab 168; placebo 172) and included in the intention-to-treat analysis. INTERVENTION: Treatment with placebo or basiliximab (20mg intravenous bolus) on day 0 and day 4 after transplantation. MAIN OUTCOME MEASURES: Resource utilisation in multiple categories and treatment costs for basiliximab and placebo-treated patients during the 6-month post-transplantation period. RESULTS: No statistically significant differences were found in any of the economically important categories of resource use or in the mean cost of treatment per person across the whole trial. The mean cost of treatment, including the cost of basiliximab, was pound 16 095 for basiliximab recipients and pound 15 864 (1997/1998 costs) for placebo recipients, a mean difference of pound 231 (95% CI: - pound 1983 to pound 2446), which was not significant. Basiliximab treatment led to a significant reduction in acute rejection episodes (basiliximab 20.8%; placebo 34.9%; p = 0.005). CONCLUSIONS: Basiliximab therapy confers a significant clinical benefit to renal transplant recipients without increasing overall treatment costs.     

Review of the proliferation inhibitor everolimus

Everolimus (Certican) is being developed for prevention of acute and chronic rejection of solid organ transplants. A novel proliferation inhibitor, everolimus synergies with cyclosporine to prevent and reverse acute rejection in preclinical models of kidney, heart or lung transplantation. The manifestations of chronic rejection that may contribute to graft loss are also inhibited by everolimus in preclinical models. Although everolimus is metabolised by the cytochrome P450 CYP3A isoenzyme, coadministration with cyclosporine does not alter the pharmacokinetics of cyclosporine, but cyclosporine coadministration increases exposure to everolimus. Everolimus interacts with inhibitors and inducers of this system; its clearance is reduced in patients with hepatic impairment. In an immunosuppressive regimen with cyclosporine microemulsion formulation and corticosteroids, transplant recipients treated with everolimus show low rates of acute rejection and, in one heart and one renal trial, lower rates of cytomegalovirus infection. Acute rejection rates are lower than those seen with azathioprine in cardiac transplant recipients and similar to those seen with mycophenolate mofetil in renal transplant recipients. Low rates of acute rejection are maintained when everolimus is given as part of a quadruple immunosuppressive regimen with low-dose cyclosporine in renal transplant recipients, with the added benefit of better renal function compared with full-dose cyclosporine. Use of C(2) monitoring to optimise cyclosporine exposure and enhance efficacy and safety of everolimus is planned in future studies. Hypertriglyceridaemia and hypercholesterolaemia have been associated with everolimus, but these effects are not dose-limiting. There is no clear upper therapeutic limit of everolimus. However, thrombocytopenia occurs at a rate of 17% at everolimus trough serum concentrations above 7.8 ng/ml in renal transplant recipients. There are limited safety data available in patients with trough concentrations > 12 ng/ml. Studies suggest everolimus targets primary causes of chronic rejection by reducing acute rejection, allowing for cyclosporine dose reduction (which may lead to improved renal function relative to full-dose cyclosporine) and by reducing cytomegalovirus infection and inhibiting vascular remodelling.     

他克莫司在932例肾移植患者中的应用

目的 :评价他克莫司 (FK506)用于肾移植患者免疫抑制治疗的效果与安全性。方法 :对肾移植术后应用FK506的932例患者的资料进行回顾性分析。结果 :肾移植术后即应用FK506的547例患者 ,急性排斥反应发生率低 ;由环孢素A (CsA)改用FK506的385例患者 ,大部分排斥反应缓解 ,肝功能改善。FK506的主要不良反应有血糖升高和神经系统毒性。结论 :FK506是一种强效免疫抑制剂 ,还可用于CsA不能逆转排斥反应的挽救治疗。     

Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update

This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC_0–12) is associated with increased incidence of biopsy-proven acute rejection although AUC_0–12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can be formulated. There is little data on the pharmacology and toxicology of MPA in older and paediatric transplant recipients.     

他克莫司在932例肾移植患者中的应用评价

目的 :评价他克莫司 (FK506)用于肾移植患者免疫抑制治疗的效果与安全性。方法 :对肾移植术后应用FK506的932例患者的资料进行回顾性分析。结果 :肾移植术后即应用FK506的547例患者 ,急性排斥反应发生率低 ;由环孢素A (CsA)改用FK506的385例患者 ,大部分排斥反应缓解 ,肝功能改善。FK506的主要不良反应有血糖升高和神经系统毒性。结论 :FK506是一种强效免疫抑制剂 ,还可用于CsA不能逆转排斥反应的挽救治疗。     

The use of mycophenolate mofetil in transplant recipients

With the development of new immunosuppressive agents, the focus of anti-rejection therapy has shifted from prevention of acute allograft rejection to an emphasis on sufficient immunosuppression with minimal toxicity. Mycophenolate mofetil (MMF) is a recently developed immunosuppressive drug, which acts to inhibit T and B cell proliferation by blocking the production of guanosine nucleotides required for DNA synthesis. It also prevents the glycosylation of adhesion molecules that are involved in attachment of lymphocytes to endothelium and potentially in leukocyte infiltration of an allograft during an immune response. High-quality randomized clinical trials have demonstrated that MMF, when used with cyclosporine (CsA) and steroids, reduces the frequency and severity of acute rejection episodes in kidney and heart transplants, improves patient and graft survival in heart allograft recipients and increases renal allograft survival at 3 years. It has also been effective in reversing acute and resistant rejection episodes in heart, kidney and liver recipients. The ability of MMF to facilitate sparing of other immunosuppressive agents, particularly in CsA-related nephrotoxicity, is also promising. By permitting reduction in CsA doses, MMF may stabilize or improve renal graft function in patients with CsA-related nephrotoxicity or chronic allograft nephropathy. Early results of phase I and II trials evaluating MMF therapy in liver and combined pancreas/kidney transplant recipients are encouraging. The main adverse effects associated with oral or intravenous MMF are gastrointestinal and hematologic in nature. Although the direct costs of using MMF vs. azathioprine (AZA) are higher, the decreased incidence and treatment of acute rejection in patients treated with MMF supports its use as a cost-effective option during the first year following transplantation.Thus, MMF has become an important therapeutic tool in the transplant clinician's armamentarium. Ongoing issues to be resolved in clinical trials include the role of MMF in the absence of other potent agents, e.g., as monotherapy or with a steroid but without calcineurin inhibitor; whether MMF will have an impact on chronic allograft dysfunction; and the cost-effectiveness of treatment following the first year of transplantation.     

Administration of Antithymocyte Globulin (Rabbit) to Treat a Severe,Mixed Rejection Episode in a Pregnant Renal Transplant Recipient

Pregnancy in solid organ transplant recipients carries numerous risks to the mother such as increased risk of rejection, gestational diabetes mellitus, and preeclampsia. The developing fetus is subjected to risks such as birth defects, preterm delivery, and low birth weight. Typically, these risks can be managed through intensive, multidisciplinary prenatal care and a proper immunosuppressive regimen. In the setting of rejection, however, little data are available to suggest safe and effective treatment of acute cellular rejection, antibody‐mediated rejection, or mixed rejection episodes in the pregnant solid organ transplant recipient. We describe the first case, to our knowledge, in which antithymocyte globulin (rabbit) was used to successfully treat a pregnant renal transplant recipient who experienced a mixed rejection episode. A 22‐year‐old, African American woman with stage 6 chronic kidney disease received a deceased donor renal transplant after undergoing hemodialysis for 3 years. Her maintenance immunosuppressive regimen at the time of transplantation consisted of tacrolimus, prednisone, and mycophenolate mofetil. Despite counseling efforts on the importance of having a planned pregnancy after kidney transplantation so that her immunosuppressive medications could be optimized, the patient became pregnant 12 months later; her mycophenolate mofetil was changed to azathioprine to reduce the risk of fetal deformities or death. Three months later, the patient was admitted for biopsy of her transplanted kidney and was evaluated for possible kidney rejection. After confirmation of a mixed 1B acute cellular rejection and antibody‐mediated rejection episode, the patient decided to pursue resolution of her rejection episode and continue the pregnancy despite the potential risks to the fetus. She was treated with high‐dose corticosteroids, intravenous immunoglobulin, plasmapheresis, and antithymocyte globulin (rabbit). Twenty‐nine months after transplantation, the patient was induced and gave birth to a healthy baby boy. Our patient's case offers unique insight into the potential management of a rejection episode requiring aggressive immunosuppressive therapy. Although potent immunosuppressive therapies were successfully used in our patient, further studies are needed to make definitive recommendations regarding the use of such therapies for treatment of rejection episodes in pregnant solid organ transplant recipients. The risks and uncertainties of treating rejection episodes should always be discussed with and understood by the patient before an informed decision is made.     

Statins and solid organ transplantation

Dyslipidaemia is common in solid organ transplant recipients and its presence is associated with chronic rejection and accelerated atherosclerosis, leading to an increased prevalence of cardiovascular disease (CVD). CVD is a major cause of morbidity and mortality in transplant recipients. It is therefore of interest and clinical value to introduce agents that effectively and safely reduce the incidence of this outcome. In the present review we consider the potential benefits of statin administration in adults who have undergone solid organ (mainly renal, heart and liver) transplantation, as well as in paediatric transplant patients. We also briefly review the effects of combination therapy with ezetimibe and statins in this population. Overall, statins are efficient and safe drugs for the management of dyslipidaemias in transplant populations, and in most trials they had a beneficial effect on long-term survival rates, CVD events and rejection rates. The transplanted population is different from other patient groups, mostly due to concomitant immunosuppressive therapy. Statins, at an appropriate dosage, should be prescribed to dyslipidaemic transplanted patients but they should be closely monitored for adverse effects.     

Immune monitoring of kidney transplant recipients: can markers predictive of over-immunosuppression be identified?

While the use of nonspecific immunosuppressive drugs has significantly reduced the incidence of acute graft rejection, the benefits of such therapies on chronic rejection and overall long-term graft survival are uncertain. Persistent excessive immunosuppression after immunosuppressive drug treatment is associated with long-term toxicity including increased incidence of cancers, severe infectious complications and metabolic diseases (for example, diabetes, atherosclerosis). One of our team's aims is to identify immunological factors that can predict such toxicities. We have previously demonstrated that CD4T cell cytopenia was correlated with high risk of cancers and infections as well as atherosclerosis in renal transplant recipients. Now, we are investigating the mechanisms involved in CD4T cell cytopenia. We are also exploring how inflammation and cells from the innate immunity influence the complications associated with kidney transplantation. This was performed through the analysis of gene polymorphism on TLR-4, NOD2/CARD15 receptors and IL-6 promoter and correlation with transplantation outcome. We already correlated IL-6 promoter gene polymorphism at position -174 with new-onset diabetes after transplantation in overweight patients. Identification of gene polymorphisms or factors associated with complications after transplantation may help physicians to determine high-risk recipient profiles and optimize pre- and post-transplantation treatment strategies.     

Immunosuppressive drugs in paediatric liver transplantation

Orthotopic liver transplantation is established treatment for children with acute and chronic liver failure. Despite advances in pre- and postoperative management, innovative surgical techniques and new immunosuppressive drugs, acute and chronic rejection remains a problem. In addition, well established adverse effects of commonly used immunosuppressive drugs are no longer accept able. More potent, but less toxic, immunosuppressive agents have been developed and some novel compounds are now entering routine practice. Cyclosporin was the cornerstone of immunosuppressive therapy until the introduction of its novel pharmaceutical form (Neoral) with improved bioavailability, lower inter- and intraindividual pharmacokinetic variability and improved graft survival. Recently, tacrolimus, a macrolide drug with a similar mode of action, but much higher potency, was introduced and, at present, is the only agent which can successfully replace cyclosporin as a first-line immunosuppressive drug. Mycophenolate mofetil has recently been approved for use in adult and paediatric renal transplant recipients. It has a similar mode of action to cyclosporin and tacrolimus, but acts at a later stage of the T cell activation pathway. Administration with standard immunosuppressive drugs reduces the incidence of acute rejection and enables cyclosporin and tacrolimus dose reduction, thus reducing the risk of associated toxic effects. Phase I and II trials with sirolimus (rapamycin), a macrolide antibiotic, have shown comparable immunosuppressive action, when administered in conjunction with standard immunosuppressants. Further clinical trials need to be carried out to establish efficacy, tolerability and pharmacokinetics in paediatric transplant recipients. Monoclonal antibody therapy (daclizumab and basiliximab) is an exciting new development whereby T cell proliferation is inhibited by selective blockade of interleukin (IL)-2 receptors. Preliminary results, when used in combination with a standard immunosuppressive regimen, are good with respect to incidence of acute graft rejection, host immune response and adverse effects. FTY720 is a novel synthetic immunosuppressive compound which induces a reduction in peripheral blood lymphocyte count through apoptotic T cell death or accelerated trafficking of T cells into lymphatic tissues. Experimental animal studies demonstrated synergistic action in combination with low dose cyclosporin or tacrolimus, potentiating their immunosuppressive effects. Further studies are being carried out to determine its potential for application in organ transplantation. Despite this rapid development of novel compounds, it will take many years before they may become part of standard protocols in paediatric transplantation medicine. Further development and research of efficacy and tolerability of existing drugs is, therefore, vital.     

A pharmacoeconomic comparison of antithymocyte globulin and muromonab CD3 induction therapy in renal transplant recipients

Antithymocyte globulin (ATG) and muromonab CD3 (OKT3) are currently the only antilymphocyte preparations that are commercially available for induction immunosuppressive therapy for renal allograft transplantation in the US. ATG, in the usually prescribed doses, is more expensive than muromonab CD3, but muromonab CD3 is associated with more severe adverse effects that may affect clinical outcome and overall cost. We performed a retrospective study of all adult recipients of a first cadaveric renal allograft, who underwent transplantation between January 1991 and December 1994 who received either ATG (n = 92) or muromonab CD3 (n = 91) for induction therapy at our transplant centre. The average age of recipients was older (50 vs 44 yrs; p = 0.001) and extended donors were more commonly used in the ATG group (41 vs 13%; p = 0.0001) compared with the muromonab CD3 group. Nevertheless, at 1 year post-transplant, the incidence of rejection was lower (34 vs 47%) and graft survival was better (93 vs 85%; p = 0.03) in the ATG group. Patients who received ATG were discharged earlier (9.4 vs 13.3 days; p = 0.0001) and had similar serum creatinine levels on the day of discharge (2.4 +/- 1.5 vs 2.1 +/- 1.1 mg/dl; p = 0.25). Overall, the 1-year hospitalisation costs of transplantation and readmissions were similar [$US39,937 +/- 17,014 vs $US42,850 +/- 20,923 (currency year 1994); p = 0.22]. This is the first comparison of ATG and muromonab CD3 in renal transplant recipients to consider clinical as well as economic outcomes. For renal transplant patients in whom induction therapy is used at our centre, the initial expense of ATG can be justified by improved graft survival, fewer rejection episodes, and shorter hospital stays, which are associated with similar overall transplantation costs.