CME on Transplantation is dedicated to online CME conferences, courses and presentations (slides with voice over) on transplantation, given by local and international experts. Its mission is to keep you up-to-date with the most recent developments on transplantation.
Topic
Immunosuppressive Therapies
In the long and tumultuous history of immunosuppressive therapies, we are now with the help of newer agents and regimens able to fine-tune our therapies to achieve better complication outcomes and better survival rates than seen before. This section will provide you with the latest clinical data allowing you to make informed decisions about which therapy is best suited to your patient's needs.
"Campath-1H in Patients with Delayed Graft Function: Reduced Rejection and Improved Graft Survival" Stuart J. Knechtle (biography) English - 2004-05-18 - 25 minutes
(26 slides)
Summary : Alemtuzumab (Campath®) is a humanized monoclonal antibody against CD52 that is found predominantly on lymphocytes and has recently been approved in the US for the treatment of lymphocytic leukemias. Dr. Knechtle and his team at the University of Wisconsin – Madison are among the few groups who have had some experience with alemtuzumab as induction therapy in renal transplantation in off-label studies.
In this presentation, Dr. Knechtle reviews the origins, structure, and mechanism of action of alemtuzumab. With particular reference to his own group’s work, Dr. Knechtle presents the results of early trials of alemtuzumab-induction. The benefit of alemtuzumab-induction in preventing acute rejection and promoting graft and patient survival, as well as the safety of alemtuzumab-based induction regimens are discussed.
Dr. Knechtle addresses the future place of alemtuzumab within the immunosuppressive armamentarium, with particular reference to steroid- and calcineurin inhibitor-sparing strategies and to certain patient subpopulations.
Learning objectives : After viewing this presentation, participants will be able to discuss:
• The structure and mechanism of action of alemtuzumab (Campath®)
• The results of early studies of alemtuzumab-induction with different maintenance regimens
• How alemtuzumab-induction compares to other induction-regimens
• The potential future role of alemtuzumab in steroid- and calcineurin inhibitor-sparing regimens
• The benefits of alemtuzumab-induction in specific renal transplant subpopulations
"Optimal Monitoring of Neoral - What Do the Data Show?" Dr. Edward H. Cole (biography) English - 2004-02-17 - 43 minutes
(63 slides)
Summary : In this presentation Dr Cole presents the rationale for using C2 or 2-hour post-dose concentration monitoring with Neoral, the microemulsion formulation of cyclosporin A (CsA), and reviews the latest data available on the use of this protocol in de novo and stable kidney transplant recipients, with some data from liver transplantation studies. C2 levels of Neoral were found to correlate well with Cmax (1), which in turn determines drug exposure as measured by the area under the curve (AUC) of cyclosporin levels with time post-dose; and C2 levels of Neoral were shown to reach peak levels in humans at 1-2h post-dose, producing 70-96% calcineurin inhibition (2).
Prospective experience with de novo kidney transplant recipients using cyclosporin microemulsion: Dr Cole describes his experience at the Toronto General Hospital, where all new renal transplant recipients receiving Neoral from August 2000 onwards were monitored with C2 in order to optimize CsA exposure. Results from this and other studies such as MO2ART and CONCERTO are described in terms of rejection rate, renal function, C2 targets and approach to poor absorbers. The distinction is made between poor absorbers (C4 level is still low) and slow absorbers (C4 level is higher than C2).
In a study of 175 stable renal transplant recipients at the Toronto General Hospital, C2 monitoring in these (maintenance) patients was found to be useful in allowing accurate targeting of CsA exposure, and dose reductions in many overexposed patients led to improvements in renal function and blood pressure (3). Also, no acute rejections were observed in this study, with a mean follow-up of 2.5 years.
Outstanding issues in C2 monitoring include the need for more data to determine optimal target levels, the possible influence of co-medications on target levels, and the need for further studies looking at once daily dosing of Neoral with C2 monitoring and its effect on nephrotoxicity.
"Steroid Minimization Protocols" Dr. Edward H. Cole (biography) English - 2004-02-02 - 37 minutes
(58 slides)
Summary : In this presentation Dr Cole presents the latest data available on steroid minimization protocols, in a discussion about their associated risks and benefits; in which patients they may be utilised; and whether steroid avoidance (a short steroid course of 0 to 7 days) is preferable to later steroid withdrawal.
Randomized trials have shown an increase in acute rejection rates with steroid withdrawal (1, 2), although other protocols might achieve better results. Short-term data show steroid avoidance to be safe and effective in low immunologic risk patients, and as having other clinical benefits which will be discussed here.
Learning objectives : The participant will learn about steroid minimization protocols:
Benefits of Steroid Minimization
Steroid Withdrawal versus Avoidance:
- Risks vs benefits
-->Acute rejection
-->Renal function
-->Graft and patient survival
-->Freedom from adverse events
Conclusions
Outstanding Issues
"Rapamune (Sirolimus): A New Option in Kidney Transplantation" Dr. Donald E. Hricik (biography) English - 2003-06-12 - 55 minutes
(60 slides)
Summary : This talk will focus on the de novo uses of Sirolimus in kidney transplantation. Sirolimus (SRL) inhibits TOR to antagonize the cell cycle, whereas calcineurin inhibitors (CIs) block the transcription of IL-2. These 2 mechanisms synergize with each other and because of this have certain advantages and disadvantages when used in combination. For example, when used together, SRL and CIs have lower acute rejection rates, but on the downside enhance nephrotoxicity. SRL on its own is non-nephrotoxic, may be a CI and steroid sparing drug, is effective in high-risk patients, and may be antiatherogenic and antineoplastic. On the downside SRL does cause hyperlipidemia, bone marrow suppression and impaired wound healing. This talk will cover the latest clinical data supporting these conclusions.
Learning objectives : The participant will review a wealth of recent clinical data leading to the following conclusions:
- Sirolimus is potent and synergistic with calcineurin inhibitors.
- Preliminary evidence suggests that sirolimus may facilitate CI or steroid sparing.
- Sirolimus may reduce the frequency of certain malignancies owing to its inherent antineoplastic properties.
- Sirolimus-induced hyperlipidemia must be weighed against the drug’s antiatherogenic effects.
- Further studies are warranted to determine optimal strategies to minimize wound healing problems.
"Calcineurin Inhibitor Drug-Free Kidney Transplantation" Dr. Stuart M. Flechner (biography) English - 2003-05-12 - 50 minutes
(42 slides)
Summary : This talk will focus on current problems in transplantation and offer a novel immunosuppressive solution to some of these problems. First of all there aren’t enough organs available for transplantation, and secondly, not enough is known about diagnosing and treating chronic allograft nephropathy. We’ve seen from North American data that the survival half-life for patients with acute rejection hasn’t changed much in 10 years, whereas that of patients without acute rejection has improved (NEJM 2000. 342: 610). The goal is therefore to not have acute rejection.
Within the last few years we’ve moved towards a standard three-drug regimen of a calcineurin inhibitor, an antiproliferative agent, plus a steroid, which coupled with an induction antibody reduces the rate of acute rejection. Renal function has been studied as a risk factor for chronic renal allograft rejection, with SCr levels > 2 at 6 months found to be associated with increased risk. (Flechner et al. 1996. Transplantation. 61: 1235). Hariharan et al recently demonstrated a stepwise reduction in cadaveric kidney transplant survival with every 0.5mg increase in creatinine (Kidney International. 2002. 62: 311-18).
One of a variety of factors contributing to chronic allograft nephropathy is the use of nephrotoxic drugs. Calcineurin inhibitors like cyclosporin (with tacrolimus) are known to cause vasoconstriction of the pre-glomerular arterioles, leading to diminished renal blood flow and glomerular filtration. Khanna et al have also recently shown the expression of TGF-B and fibrogenic genes in transplant recipients with Tac and CsA nephrotoxicity (Kidney International. 2002. 62: 2257-63). Early evidence of diminished renal function in patients taking CsA was seen 20 years ago, with SCr levels around 2 mg/dl (Flechner et al. 1983.Transplant Proc. 15: 2689).
Sirolimus was originally developed with the intention of use with an early calcineurin inhibitor, and was tested in cyclosporin based regimens. This left much to be desired in terms of acute rejection rates and SCr levels. Hence came the introduction of induction antibodies to a calcineurin inhibitor-free regimen, in order to try to achieve lower acute rejection rates and better renal function. Here we will take a look at the data from recent calcineurin inhibitor –free studies with Sirolimus (SRL+MMF+steroids following Basiliximab) which show improved renal function, and also preliminary data that show the combination of MMF and SRL to prevent renal allograft nephropathy.
Learning objectives : The participant will:
- review the history of immunosuppressive therapies and their performance in terms of acute rejection and renal function.
- review data on calcineurin inhibitor free regimens which show improved renal function; and preliminary data showing a (SRL +MMF) regimen to prevent renal allograft nephropathy.
