Although the technical aspects of renal transplantation were first described in the early 1900’s, immunologic barriers to successful renal allotransplantation remained until the 1950’s and 60’s

Christopher Siegel, MD, PhD and Juan Sanabria, MD, MSc Although the technical aspects of renal transplantation were first described in the early 1900’s, immunologic barriers to successful renal allotransplantation remained until the 1950’s and 60’s. Several attempts at renal allotransplantation and xenotransplantation were made in the United States, Austria and France before the seminal transplant by Drs. Murray and Merrill was performed at the Peter Brent Brigham Hospital in December of 1954 [1-5]. This first successful transplant was performed between identical twins after the recipient was determined to be immunologically non-responsive to the donor[6]. Even with a better understanding of blood and tissue typing, renal transplantation did not become a clinical option for non-identical twins until safe and effective immunosuppressive regimens became available to allow for organ survival. The goal of this chapter is to review the mode of action and side effects of commonly used immunosuppressive agents, and the common drug combinations usually prescribed by transplant physicians to reduce patient morbidity and optimize graft function. Maintenance immunosuppression has continued to evolve over the last 50 years largely as a result of several major serendipitous discoveries involving new classes of immunosuppressants. Major improvements in long term graft survival can be divided into three major eras, the first from, 1954-1982, was based on a drug regimen that included steroids and azathioprine (Imuran). During this time period, early acute rejection was a major obstacle to even short term allograft survival. The introduction of steroids and azathioprine in 1961 provided the first milestone in the ability to control early allograft rejection [7-10]. Although a quantum leap forward, these medications are nonspecific in their ability to immunosuppress and possess significant toxicity. The second era in transplant immunosuppression started in 1982 with FDA approval of cyclosporine. The introduction of cyclosporine (Sandimmune, Neoral), a potent calcineurin inhibitor which selectively acts to block IL-2 production, resulted in markedly improved graft survival and decreased incidence of acute rejection [11]. During the time period from 1982 to 2001, the addition of tacrolimus (Prograf, FK506) a second calcineurin inhibitor as well as the addition of the more selective anti-metabolite medications, mycophenolate mofetil (CellCept) and mycophenolate sodium(Myfortic) resulted in one year patient survival rates in excess of 95% and one year graft survival rates in excess of 90%. Using combinations of these medications, acute graft rejection in low risk, non-sensitized patients is often less than 10%[12] while even in high risk patients the percentage of early acute rejection can be less than 25%[13, 14]. During this time the organ half life of a renal transplant has continued to slowly increase and chronic allograft nephropathy has supplanted acute rejection as the main reason for lost organs and poor long term function in surviving patients (reviewed in [15] ). The most recent era in immunosuppressant history began with the introduction of rapamycin, a new class of drug called a mammalian Target Of Rapamycin (mTOR) inhibitor. In addition to selectively blocking the translation of IL-2, rapamycin is a powerful anti-proliferative agent which blocks both lymphocyte and mesenchymal cell proliferation. The availability of multiple agents to provide adequate immunosuppression has resulted in the opportunity for transplant physicians to combine medications to reduce morbidity and maximize outcome. This has also resulted in significant controversy as to which regimen of immunosuppressive medications may be the most efficacious. One controversy which continues to be debated in the literature is the necessity of steroids to control both acute and chronic rejection [16-22]. Corticosteroids Corticosteroids represent one of the original classes of immunosuppressant used for renal transplantation. Prednisone, and methyprednisolone (Solu-Medrol) are the most common clinically used glucocorticoids. Prednisone an oral prodrug is metabolized to prednisolone, the active glucocorticoid, in the liver. Prednisone has a 70% bioavailability and a half life of approximately one hour. Once converted to prednisolone the molecule is protein bound and has a half life of 2-3 hours. It is excreted by the kidneys. Methyprednisolone is a synthetic glucocorticoid most frequently given intravenously and has half life of 1-3 hours. The metabolism of methylprednisolone is similar to prednisone. The usual dosing for maintenance prednisone is 10 milligams given orally once daily. Although the corticosteroids were one of the first successfully used immunosuppressents in renal transplantation, their mechanism of action continues to be elucidated. The glucocorticords freely diffuse across the cell layer. Glucocorticoid receptors(GR) are present in the cytoplasm and consists of a complex of a 777 amino acid protein, two hsp90 molecules, immunophilins p59, calreticulin and other proteins[23]. When glucocorticoids bind the complex, the unit undergoes a conformational change resulting in translocation of the GR/glucocorticoid unit to the nucleus where it binds to Glucocorticoid Response Elements (GRE) and functions to alter transcription. GRE’s induce positive transcription of several genes which induce immunosuppression in a non-specific manner. In addition, they negatively affect transcription of other genes by both direct DNA binding and by transrepression of DNA transcription factors such as NF-kB, and activator protein-1 (AP-1), proteins important for the expression of inflammatory cytokines(reviewed in [24] ). Glucocorticoids have other abilities to induce immunosuppression. Dexamethasone dependent protein synthesis has been implicated in T-cell apoptosis [25, 26] and blockade of cycle progression of T-cells from G0/G1 cell cycle [27, 28]. These factors combine to reduce T cell proliferation and increase T cell apoptosis[29]. Recent studies have also shown that glucocorticoids have a rapid effect on T-cell signal transduction including impaired phosphorylation of p56lck/p59fyn consensus substrates[30]. The efficacy of these medications is demonstrated by the fact that they continued to be used for transplantation 40 years after their introduction. The benefits are not without consequence and side effects from chronic steroid use are well known. More common problems include hypertension, hyperglycemia, and weight gain. Other less common problems include cataracts, osteoporosis, osteonecrosis, growth retardation, acne, glaucoma and mood alterations. In addition to the significant patient morbidity, complications from chronic steroid use also result in significant costs to the health care system [31]. Multiple studies have been performed utilizing newer immunosuppression regimens in an effort to withdraw or avoid steroid use in renal transplantation [32-34]. Efforts to withdraw steroids in the first week utilizing cyclosporine and imuran resulted in high rates of rejection [35]. Similar trials of withdrawal at 3 months still resulted in episodes of rejection as high as 25% [18, 22]. Randomized trials of steroid withdrawal in patients treated with basilixumab, cyclosporine and mycophenolate mofetil demonstrated no difference in episodes of acute rejection between steroid withdrawal and no withdrawal groups [36]. Further studies to evaluate the efficacy of tacrolimus and MMF in steroid withdrawal have demonstrated that a significant proportion of patients can be withdrawn from steroids with no long term increase in rejection and avoidance of toxicities from steroids [13, 34, 37-39] . One potential problem with steroid avoidance or steroid withdrawal is identification of patients at low risk for rejection. Rejection after renal transplantation has been associated with shorter organ and patient survival and increased incidence of chronic allograft nephropathy. Immunologic monitoring may be one way to try to identify patients which may be at low immunologic risk [15]. Like wise, patients in high risk groups or highly sensitized patients may be at increased risk for a worse long term outcome, and as such, poor candidates for minimization of immunosuppression. Calcineurin Inhibitors The calcineurin inhibitors represent a class of immunosuppressant which functions by interfering with IL-2 transcription. Cyclosporine, FDA approved for use in the US in 1983, and tacrolimus, FDA appoved in 1997 for use in renal transplant, have been the cornerstone of most current immunosuppressant protocols. Although the cytosolic receptor for each of the calcineurin inhibitors is different, the drug and its cytosolic binding protein function by translocation to the nucleus and interference with the transcriptional events in IL-2 expression[40, 41]. Cyclosporine is a cyclic, lipophilic peptide of 11 amino acids produced from the fungus Tolypocladium inflatem Gams. Isolated from a Norwegian soil sample in 1972 and discovered to have immunosuppressant properties, the drug was developed by Sandoz Pharmaceuticals [42]. Because of its lipophilic nature, cyclosporin traverses the cell membrane where it binds cyclophilin, its cytosolic binding protein. The cyclosporin/cyclophilin complex is then translocated across the nuclear membrane and functions to inhibit the effects of calcineurin, a protein phosphatase important in the regulation of Nuclear Factor of Activated T-cells (NF-AT). NF-AT is a family of transcription factors responsible for the regulation of expression of multiple cytokines. The inhibition of cyclosporine/cyclophilin on calcineurin blocks NF-AT dephosphorylation and subsequent induction of IL-2 transcription. Through similar pathways, cyclosporine also induces immune suppression by down regulation of TNF and decrease in expression of adhesion molecules [43, 44]. The original formulation of cyclosporine was an oil based compound called Sandimmune. Initial clinical trials combining Sandimmune and steroids demonstrated significant improvement in both patient and graft survival. In some series, patient survival improved from 80% to 92% at one year when immunosuppression was changed from steroids and azathioprine to steroids and cyclosporine. Graft survival rates similarly increased from 50% and 25% at 1 and 5 years to >80% and 67% respectively [11]. Cyclosporine, although one of the first major improvements in immunosuppression, suffered from poor and erratic absorption from oral administration, significant intra-patient variability, and a narrow therapeutic index. Studies demonstrated that patients with higher bioavailability had fewer episodes of rejection and graft loss when compared with those with lower bioavailability [45, 46]. A second generation microemulsion of cyclosporine, Neoral, was subsequently developed with better absorption and less intra-patient variability. Studies in human volunteers demonstrated 174% to 239% better systemic bioavailability of Neoral compared to Sandimmune [47]. Neoral was subsequently FDA approved for use in the US in 1997. In clinical trials, patients receiving this formulation of cyclosporine demonstrated less rejection and better long term graft function when compared to patients receiving Sandimmune [48, 49]. Drug dosing of cyclosporine was originally based on trough blood levels in order to minimize toxicity and establish therapeutic dosing. Trough levels were used as a surrogate marker for the AUC or area under the curve which is a measure of overall exposure to the drug. Multiple studies have shown the lack of correlation between trough levels and the actual AUC. Recent pharmacokinetic studies have shown a better correlation between the AUC and the two hour post dose concentration known as the C2 level [50]. This has resulted in decreased episodes of rejection, but the effect on improving long term graft survival is still unclear. A generic formulation of cyclosporine was introduced in the US in 2003. Several studies have demonstrated similar efficacy between the generic formulation and Neoral although the bioavailability may be different when taking similar dosages [47]. Patients converted between formulations should have blood cyclosporine levels checked to ensure therapeutic dosing. Target C2 cyclosporine concentrations depend on several factors, such as the length of time the patient is post transplant and whether maintenance immunosuppression also includes a mTOR inhibitor. Target levels of cyclosporine are lower when dosed with rapamycin in order to reduce calcineurin induced toxicity. Common side effects of cyclosporine include nephrotoxicity, hirsutism, gingival hyperplasia, tremor, hypertension and to a lesser frequency liver dysfunction and hyperlipidemia. Tacrolimus (Prograf) is a 23 member macrolide antibiotic derived from the bacterium Streptomyces tsukubaensis. It was first approved by the US FDA for liver transplantation in 1994 and subsequently for renal transplantion in 1997. Tacrolimus binds to FK506 binding protein 12 (FKBP-12) in the cytosol and then translocates to the nucleus where a complex is formed with calcineurin. In a manner similar to cyclosporine, the complex translocates to the nucleus where it inhibits the function of NF-AT decreasing IL-2 production. In trials comparing tacrolimus with cyclosporine, cumulative incidence of biopsy confirmed acute rejection was lower with tacrolimus (26% versus 46%). In addition cumulative incidence of chronic allograft nephropathy was lower in patients treated with tacrolimus (6.6%vs 15.3%) and projected graft half-life favored tacrolimus (15.8 vs 10.8 years) [51]. Studies have also demonstrated superiority of tacrolimus compared to cyclosporine microemulsion in reference to preserved renal function [52]. The bioavailabity of tacrolimus ranges from 15-20% when taken by mouth. Intestinal absorption is slowed with meals and metabolism can be affected by certain drug interaction. Tacrolimus, like cyclosporine, has a narrow therapeutic index and should be monitored by following serum concentrations of the drug in the blood. Therapeutic levels of tacrolimus vary based on the length of time since transplant as well as concominant use of mTOR inhibitors. For the first three months after transplant, most transplant programs target tacrolimus levels between 8-12 ng/ml. If the drug is given with a mTOR inhibitor, levels of 5-8 ng/ml are targeted. When patients are greater than 11 weeks post transplant, many programs will taper tacrolimus to maintain levels of 5-8 ng/ml when used without a mTOR inhibitor or 3-5 ng/ml if rapamycin is included in the immunosuppression regimen. The half life of the tacrolimus can be increased considerably in patients with mild and moderate hepatic impairment. Dose reductions should be considered when starting tacrolimus in this patient population. Frequent monitoring should be performed until a stable blood level has been obtained. While nephrotoxicity remains a common side effect amongst calcineurin inhibitors, not all side effects are similar between cyclosporine and tacrolimus. Studies have indicated the incidence and/or extent of hypertension and hypercholesterolemia may be less severe with tacrolimus-based versus cyclosporine- based immunosuppression [53-55]. For males, the risk of coronary heart disease post renal transplant appeared to be lower than for similar patients on cyclosporine. Studies identifying risk factors for post transplant diabetes mellitus (PTDM) noted African American race, Hispanic ethnicity, body mass index greater than 30 and use of tacrolimus all correlated with a higher risk of hyperglycemia post transplant. The incidence of post transplant diabetes mellitus in renal transplant patients receiving tacrolimus has been reported to be as high as 35% in African American recipients, 29% in Hispanics recipients, and 12% in Caucasion recipients at 1 year post renal transplant. Although initially thought to be more diabetogenic than cyclosporine, newer studies have demonstrated similar rates of PTDM between patients receiving either tacrolimus or cyclosporine microemulsion when controlled for patient population (reviewed in [56]). Side effects of tacrolimus also include nephrotoxicity, hepatotoxicity, alopecia, tremor, headaches, hypertension, and occasionally reversible expressive aphasia. A new long acting formulation has just been introduced which is taken once a Target of Rapamycin (TOR) Inhibitors The mammalian Target of Rapamycin (mTOR) inhibitors are a new class of drug with potent immunosuppressive properties. Currently only two drugs exist in this class, Sirolimus (Wyeth) and Everolimus (Novartis). Sirolimus received FDA approval for use in renal transplantation in 1999. Rapamycin (Sirolimus) is a macrocyclic lactone produced by Streptomyces hygroscopicus[57, 58]. Sirolimus is a lipophilic molecule which traverses the cell membrane and subsequently binds to FKBP-12 in the cytosol. This complex then traverses the nuclear membrane where it functions in the nucleus to inhibit the mTOR proteins. Although the binding protein for sirolimus is the same as that for tacrolimus the nuclear target for rapamycin is different than that of the calcineurin inhibitors. mTOR protein is a regulatory kinase which governs cellular proliferation [59]. The Sirolimus/FKBP-12/mTOR complex functions to prevent cell cycle progression from the G1 to S phase of mitosis. In addition to blockade of proliferation, mTOR inhibitors function to inhibit T-cell triggered growth factors and have been shown in both human and animal studies to enhance T-cell activation induced apoptosis [60, 61] . Rapamycin immunosuppressive effect may also be in part related to its effect on antigen presenting cells. Studies have shown rapamycin impairs antigen uptake in human dendritic cells and may also induce apoptosis [62-64]. Sirolimus is readily absorbed when taken orally and has a long half life of approximately 57-62 hours in normal volunteers. Metalbolism is via the cytochrome P450 and P-glycoprotein pathways [65]. In vitro studies have demonstrated the inhibition of both T and B cell proliferation; in addition, B cell but not T cell activation is also suppressed [59, 66, 67]. mTor inhibitors have been demonstrated to decrease immunoglobulin production of both IgM and IgG in response to antigen in vitro [68]. Because the uptake of cyclosporine and sirolimus is mediated via the same intestinal transport system, dosing to maximize absorption and minimize increases in AUC for these drugs should be staggered by four hours. These changes tend to be more pronounced for Neoral than Sandimmune. For example, simultaneous administration of sirolimus and Neoral will increase the sirolimus AUC by over 200%. Simultaneous administration or sirolimus with Sandimmune will increase the AUC of sirolimus by 50%. Staggering the administration of Neoral and Sirolimus will increase the AUC of sirolimus by 60% or only a third as much when administered together[69, 70]. As with the calcineurin inhibitors, rapamycin blood concentrations and metabolism can be affected by other commonly administered drugs. The AUC for rapamycin is increased by as much as 990% when administered with ketoconazole. Drugs such as diltiazem, cyclosporine, and tacrolimus may also increase the AUC of sirolimus while rifampin coadministration will cause the AUC of rapamycin to decrease. Due to hepatic metabolization of rapamycin, dose adjustments may be needed for patients with hepatic dysfunction. Rapamycin is a drug which also has a narrow therapeutic index and should be monitored based on blood levels. Trough levels of 10 ng/ml are the goal. Loading doses of 15 mg, or three times the average starting dose, were originally suggested; however, when the full loading dose is given soon after surgery, higher incidences of wound complications may occur [71]. Rapamycin is a powerful immunosuppressant for several reasons, 1) it works synergistically with the calcineurin inhibitors to provide adequate immuno- suppression with reduced dose calcineurin inhibitor to lower exposure and toxicity, 2) rapamycin has been effectively used in steroid reduction and steroid elimination protocols, 3) rapamycin has been show to decrease vasculopathy seen which chronic rejection, and 4) rapamycin regimens have a lower incidence of post transplant lymphoproliferative disease, skin tumors or renal cell carcinoma when compared to immunosuppressant regimens which contain calcineurin inhibitors or azathioprine [72, 73]. Studies have demonstrated that rapamycin may extend renal recovery time in patients with delayed graft function [74]. In US phase III sirolimus trials, hypercholesterolemia and hyperlipidemia occured in 38-43% of patients on rapamycin containing regimens It is suggested that prophylaxis against pneumocystis carinii be extended if patients are on rapamycin. Other side effects including anemia, pancytopenia, and interstitial lung disease have also been reported. Antimetabolites The antimetabolite medications are usually used in combination with the calcineuin inhibitors in an attempt to reduce rejection, withdraw steroids, and improve long term graft function. More recently studies have demonstrated the efficacy of a rapamycin and mycophenolate mofetil based protocol to eliminate the need for calcineurin inhibitors [75-78]. One of the original immunosuppressants, azathioprine, was first introduced in 1961. Azathioprine (Imuran) is a purine analog which inhibits both the direct and salvage pathway involved in DNA synthesis. Azathioprine is classified as a human carcinogen and has been associated in epidemiologic studies of renal transplant recipients with an increased incidence of non-Hodgkin’s lymphoma, squamous cell skin cancers, hepatobiliary carcinomas, and mesenchymal tumors. Azathioprine is dosed at 1-2.5 mg/kg/day, then adjusted for toxicity. In the US, mycophenolate mofetil and mycophenolate sodium have largely replaced azathioprine as the antimetabolite of choice in combination immunosuppression therapies. Dosage is reduced based on toxicity, the most common being bone marrow suppression and gastrointestinal disturbances. Azathioprine is metabolized by xanthine oxidase. Its dosage should be reduced if the patient is taking allopurinol [79]. Although the mainstay of transplant protocols for many years, problems with increased cancer formation, lack of selectivity, large intra- and inter-patient variability [80, 81]and the advent of more selective drugs in its class have led to its loss of popularity in current immunosuppressant protocols. Mycophenolate mofetil Mycophenolate mofetil (MMF, CellCept) is the 2 morpholinoethyl ester of mycophenolic acid. The compound is a fermentation product of Penicillium brevicompactum [82], was originally discovered by Gosio in 1893 [83] and demonstrated to inhibit DNA synthesis in 1969 [84]. MMF is a noncompetitive reversible inhibitor of inosine monophosphate dehydrogenase (IMD). The interference of IMD results in obstruction of the de novo pathway of guanine purine synthesis. The effect is more selective for lymphocytes due to the presence of the type II isoform of IMD present in activated T and B lymphocytes as opposed to the type I isoform which is present in most cells. MMF is five fold more active against the type II isoform than against type I [85]. MMF has cytostatic effects on T and B cells, inhibits proliferative responses to antigenic stimulation, suppresses antibody formation and decreases expression of glycosalated adhesion molecules resulting in decreased recruitment of lymphocytes to sites of active inflammation [83]. Oral absorption is rapid and nearly complete. Food delays absorption. Mycophenolic Acid (MPA) is the active metabolite of mycophenolate mofetil and is metabolized to the phenolic glucuronide of MPA (MPAG) which is inactive as an immunosuppressant. MPAG enters the enterohepatic circulation and is reactivated to MPA in the liver resulting in a second peak concentration after initial absorption. This second peak concentration occurs 6-12 hours post dose. The drug is primarily excreted in the urine. Patients with significant renal dysfunction have increased AUC after dosing. AUC levels can vary in patients with hepatic dysfunction depending on the type and extent of liver disease. Studies evaluating the efficacy of MMF demonstrated a significant reduction in deceased-donor transplant rejection at 6 months from 46% to 17% and 13.8 % respectively when MMF at 2grams or 3 grams per day was added to cyclosporine and prednisone [86]. Other studies demonstrated the superiority of MMF over azathioprine when used in conjunction with cyclosporine and steroids [87, 88]. Pooled data from multicenter trials imply that MMF improves graft survival when compared to azathioprine (reviewed in [89]). Trials of MMF with tacrolimus have demonstrated similar results. Newer trials have paired sirolimus and MMF in calcineurin inhibitor sparing protocols involving basiliximab, and steroids [77]. When a regimen utilizing rapamycin and MMF were compared to a regimen of cyclosporine and MMF, there was no difference in rejection but there was improved renal function in the calcineurin inhibitor free arm. Side effects of MMF are dose related and most commonly involve diarrhea, gastrointestinal upset, anemia and thrombocytopenia. Toxicity at the 3 grams per day dose was higher than at 2 grams per day. Mycophenolic acid (Myfortic) is a drug similar to mycophenolate mofetil. This compound, the active metabolite of MMF, is enterically coated so it will not dissolve at acidic pH but will dissolve in the intestines. Pharmacokinetics and metabolism are similar between MMF and Myfortic. In the five years between 1995 and 2000, Tacrolimus, Neoral, Cellcept, Myfortic and sirolimus had all been approved for use as immunosuppressants for renal transplantation. This has resulted in an increasing number of protocols which can be employed to control rejection in renal transplant patients. Controversies exist on whether steroids should be part of optimal regimens, whether calcineurin inhibitors should be minimized or even replaced and whether initial immunosuppression regimens should be the same as those used long term. Immunosuppression regimens in the United States are recorded by the United Network for Organ Sharing (UNOS) and data is available in the scientific registry of transplant recipients (SRTR)( see the OPTN annual report for a complete evaluation of immunosuppression trends nificant decrease in steroid use in renal transplant patients prior to discharge after initial transplant. Reports from the SRTR indicate a decrease in steroid use from 95.6% of recipients in 2000 to 77.5% in 2004. Calcineurin inhibitors remain a cornerstone of immunosuppressant therapy, although there has been a significant shift in the United States from cyclosporine to tacrolimus. In 1995 cyclosporine was used by 81.7% of transplant recipients, this has declined to 21.1% (14.5% Neoral, 5.8%Gengraf, and 0.1% Eon) in 2004. During that same time period tacrolimus use has increased from 6.7% to72.1%. Antimetobolite use in de novo kidney transplant recipients during this time period has remained fairly constant, averaging 82% of patients receiving some type of antimetabolite; however, during the 10 years starting in 1995 Azathioprine use has steadily decreased from 64.6% to 1.3% and MMF use has increased from 12.8% to 82.6%. In 2004, the most common immunosuppression regimen was tacrolimus / mmf / steroids which was used by 46.7% of recipients. When all calcineurin inhibitors were included the number of recipients on this protocol increased to 61%. The most common regimen utilizing rapamycin included sirolimus/tacrolimus/steroids which was used in 3.4% of all kidney transplants. In 2004, (not including steroid withdrawal) regimen changes occurred in 20-50% of kidney transplant patients during the first year post transplant. The most stable regimen appeared to be tacrolimus/MMF with or without steroids. Approximately 75% and 63% of renal transplants which started on this regimen remained on the regimen at one year and two years respectively. Although steroid avoidance has been discussed in the literature for years, only recently has the percentage of patients leaving the hospital after transplant without steroids started to increase. In 2004, 19.8% of deceased donor and 28.1 % of living donor kidney transplant recipients were on steroid free immunosuppressive regimens at discharge, compared to 3-6% of patients from 1996-2000. The majority of patients off steroids were managed on a tacolimus and MMF based protocol. For patients who were discharged in 2002 and 2003 on steroid containing regimens, only 10-13% were withdrawn from steroids over the following 2 years. These rates appear to be slowly increasing and have doubled by comparison to 1999. Since 1954 the transplant community has been trying to reproduce the same immunologic state which Drs Merrill and Murray achieved in the first successful renal transplant, i.e, immunologic tolerance in the recipient or at least long term organ acceptance. The last 10 years has produced an exponential increase in our understanding of immune function and in the number of immunosuppressants which we have at our disposal. From 1994 to 2003 the number of renal transplants had increased over 42% while the incidence of rejection during the first year post transplant has decreased from 31.5% to 13.2% (SRTR Data). While immune tolerance remains the grail of transplant physicians, improvements in maintanence immunosuppression remains the driving force for continued success in organ survival. Unlike the hammer and nail approach of early immunosuppression, the availability of immunosuppressents with unique mechanisms of action and differing side effects will allow for the possibility to design immunosuppression regimens which can be optimized for different patient populations to reduce long term morbidity and improve long term survival of both the graft and more importantly the patient. The beginning of organ transplantation: Emerich Ullmann (1861- 1937). Wien Klin Wochenschr, 2002. 114(4): p. 128-37.
Druml, W. and C. Druml, Emerich Ullmann (1861-1937): not only a pioneer of
kidney transplantation.
J Nephrol, 2004. 17(3): p. 461-6.
Tacrolimus and transplantation: a decade in review. Transplantation, 2004. 77(9 Suppl): p. S41-3.
Guild, W.R., et al., Successful homotransplantation of the kidney in an identical
Trans Am Clin Climatol Assoc, 1955. 67: p. 167-73.
Hume, D.M., et al., Experiences with renal homotransplantation in the human:
report of nine cases.
J Clin Invest, 1955. 34(2): p. 327-82.
Merrill, J.P., et al., Successful homotransplantation of the human kidney between
identical twins.
J Am Med Assoc, 1956. 160(4): p. 277-82.
Progress in clinical renal homotransplantation. Adv Surg, 1966. 2:
Hume, D.M., H.M. Kauffman, and R.J. Cleveland, Renal homotransplantation in
Postgrad Med, 1965. 38(4): p. 421-31.
Zukoski, C.F., H.M. Lee, and D.M. Hume, The prolongation of functional
survival of canine renal homografts by 6-mercaptopurine.
Surg Forum, 1960. 11:
p. 470-2.
Zukoski, C.F., H.M. Lee, and D.M. Hume, The effect of 6-mercaptopurine on
renal homograft survival in the dog.
Surg Gynecol Obstet, 1961. 112: p. 707-14.
Immunosuppressive therapy, 1987. Tex Heart Inst J, 1987. 14(4): p.
Ferguson, R.M., et al., Twenty years of renal transplantation at Ohio State
University: the results of five eras of immunosuppression.
Am J Surg, 2003.
186(3): p. 306-11.
Boardman, R.E., et al., African American renal transplant recipients benefit from
early corticosteroid withdrawal under modern immunosuppression.
Proc, 2005. 37(2): p. 814-6.
Gruber, S.A., et al., Preliminary results with early corticosteroid withdrawal in
African American renal allograft recipients.
Surgery, 2005. 138(4): p. 772-8;
discussion 778-9.
Overcoming barriers to long-term graft survival. Am J Kidney Dis, 2006. 47(4 Suppl 2): p. S52-64.
Steroid withdrawal in renal transplant recipients: pro point of view. Transplant Proc, 1998. 30(4): p. 1380-2.
Hricik, D.E. and J.A. Schulak, Steroid withdrawal from cyclosporine-based
regimens: con--a flawed strategy.
Transplant Proc, 1998. 30(5): p. 1785-7.
Ahsan, N., et al., Prednisone withdrawal in kidney transplant recipients on
cyclosporine and mycophenolate mofetil--a prospective randomized study. Steroid
Withdrawal Study Group.
Transplantation, 1999. 68(12): p. 1865-74.
Steroid withdrawal in renal transplantation. Transplant Proc, 2001. 33(7-8): p. 3261-2.
Kasiske, B.L., et al., A meta-analysis of immunosuppression withdrawal trials in
renal transplantation.
J Am Soc Nephrol, 2000. 11(10): p. 1910-7.
Matas, A.J., et al., Rapid discontinuation of steroids in living donor kidney
transplantation: a pilot study.
Am J Transplant, 2001. 1(3): p. 278-83.
Vanrenterghem, Y., et al., Double-blind comparison of two corticosteroid
regimens plus mycophenolate mofetil and cyclosporine for prevention of acute
renal allograft rejection.
Transplantation, 2000. 70(9): p. 1352-9.
Beato, M., M. Truss, and S. Chavez, Control of transcription by steroid
Ann N Y Acad Sci, 1996. 784: p. 93-123.
Molecular mechanisms of glucocorticoid action: what is important? Thorax, 2000. 55(7): p. 603-13.
Brewer, J.A., et al., Thymocyte apoptosis induced by T cell activation is mediated
by glucocorticoids in vivo.
J Immunol, 2002. 169(4): p. 1837-43.
Malone, M.H., Z. Wang, and C.W. Distelhorst, The glucocorticoid-induced gene
tdag8 encodes a pro-apoptotic G protein-coupled receptor whose activation
promotes glucocorticoid-induced apoptosis.
J Biol Chem, 2004. 279(51): p.
Reisman, D. and E.A. Thompson, Glucocorticoid regulation of cyclin D3 gene
transcription and mRNA stability in lymphoid cells.
Mol Endocrinol, 1995. 9(11):
p. 1500-9.
Rhee, K., et al., Glucocorticoid regulation of G1 cyclin-dependent kinase genes in
lymphoid cells.
Cell Growth Differ, 1995. 6(6): p. 691-8.
Cidlowski, J.A., et al., The biochemistry and molecular biology of glucocorticoid-
induced apoptosis in the immune system.
Recent Prog Horm Res, 1996. 51: p.
457-90; discussion 490-1.
Lowenberg, M., et al., Rapid immunosuppressive effects of glucocorticoids
mediated through Lck and Fyn.
Blood, 2005. 106(5): p. 1703-10.
Veenstra, D.L., et al., Incidence and long-term cost of steroid-related side effects
after renal transplantation.
Am J Kidney Dis, 1999. 33(5): p. 829-39.
Pascual, J., et al., Three-year observational follow-up of a multicenter,
randomized trial on tacrolimus-based therapy with withdrawal of steroids or
mycophenolate mofetil after renal transplant.
Transplantation, 2006. 82(1): p. 55-
Rostaing, L., et al., Corticosteroid-free immunosuppression with tacrolimus,
mycophenolate mofetil, and daclizumab induction in renal transplantation.

Transplantation, 2005. 79(7): p. 807-14.
Vanrenterghem, Y., et al., Minimization of immunosuppressive therapy after renal
transplantation: results of a randomized controlled trial.
Am J Transplant, 2005.
5(1): p. 87-95.
Schulak, J.A., et al., A prospective randomized trial of prednisone versus no
prednisone maintenance therapy in cyclosporine-treated and azathioprine-treated
renal transplant patients.
Transplantation, 1990. 49(2): p. 327-32.
Kato, Y., et al., Early steroid withdrawal protocol with basiliximab, cyclosporine
and mycophenolate mofetil in renal-transplant recipients.
Int Immunopharmacol,
2006. 6(13-14): p. 1984-92.
Borrows, R., et al., Steroid sparing with tacrolimus and mycophenolate mofetil in
renal transplantation.
Am J Transplant, 2004. 4(11): p. 1845-51.
Hricik, D.E., et al., Withdrawal of steroid therapy in African American kidney
transplant recipients receiving sirolimus and tacrolimus.
Transplantation, 2003.
76(6): p. 938-42.
Sola, E., et al., Low-dose and rapid steroid withdrawal in renal transplant
patients treated with tacrolimus and mycophenolate mofetil.
Transplant Proc,
2002. 34(5): p. 1689-90.
Emmel, E.A., et al., Cyclosporin A specifically inhibits function of nuclear
proteins involved in T cell activation.
Science, 1989. 246(4937): p. 1617-20.
Matsuda, S. and S. Koyasu, Mechanisms of action of cyclosporine.
Immunopharmacology, 2000. 47(2-3): p. 119-25.
History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr, 2002. 114(12): p. 433-7.
Frishberg, Y., C.M. Meyers, and C.J. Kelly, Cyclosporine A regulates T cell-
epithelial cell adhesion by altering LFA-1 and ICAM-1 expression.
Kidney Int,
1996. 50(1): p. 45-53.
Soriano-Izquierdo, A., et al., Effect of cyclosporin A on cell adhesion molecules
and leukocyte-endothelial cell interactions in experimental colitis.
Bowel Dis, 2004. 10(6): p. 789-800.
Waiser, J., et al., Impact of the variability of cyclosporin A trough levels on long-
term renal allograft function.
Nephrol Dial Transplant, 2002. 17(7): p. 1310-7.
Kahan, B.D., et al., Low intraindividual variability of cyclosporin A exposure
reduces chronic rejection incidence and health care costs.
J Am Soc Nephrol,
2000. 11(6): p. 1122-31.
Generic cyclosporine: a word of caution. J Nephrol, 2004. 17
Suppl 8: p. S20-4.
Goel, M., et al., The effect of two different cyclosporine formulations on the long-
term progression to chronic rejection in renal allograft recipients.
Transplant, 2002. 16(6): p. 442-9.
Medina-Pestana, J.O., et al., Long-term kidney transplant outcomes in patients
receiving oil-based or microemulsion formulations of cyclosporine.
Proc, 2004. 36(2 Suppl): p. 74S-79S.
Randomized, international study of cyclosporine microemulsion absorption
profiling in renal transplantation with basiliximab immunoprophylaxis.
Am J
Transplant, 2002. 2(2): p. 157-66.
Mayer, A.D., et al., Multicenter randomized trial comparing tacrolimus (FK506)
and cyclosporine in the prevention of renal allograft rejection: a report of the
European Tacrolimus Multicenter Renal Study Group.
Transplantation, 1997.
64(3): p. 436-43.
Kaplan, B., J.D. Schold, and H.U. Meier-Kriesche, Long-term graft survival with
neoral and tacrolimus: a paired kidney analysis.
J Am Soc Nephrol, 2003.
14(11): p. 2980-4.
Friemann, S., et al., Conversion to tacrolimus in hyperlipidemic patients.
Transplant Proc, 1999. 31(7A): p. 41S-43S.
Margreiter, R., et al., Open prospective multicenter study of conversion to
tacrolimus therapy in renal transplant patients experiencing ciclosporin-related
Transpl Int, 2005. 18(7): p. 816-23.
McCune, T.R., et al., Effects of tacrolimus on hyperlipidemia after successful
renal transplantation: a Southeastern Organ Procurement Foundation
multicenter clinical study.
Transplantation, 1998. 65(1): p. 87-92.
Tacrolimus based immunosuppression. J Nephrol, 2004. 17 Suppl 8:
Sehgal, S.N., H. Baker, and C. Vezina, Rapamycin (AY-22,989), a new antifungal
antibiotic. II. Fermentation, isolation and characterization.
J Antibiot (Tokyo),
1975. 28(10): p. 727-32.
Vezina, C., A. Kudelski, and S.N. Sehgal, Rapamycin (AY-22,989), a new
antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of
the active principle.
J Antibiot (Tokyo), 1975. 28(10): p. 721-6.
Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol,
1998. 10(3): p. 330-6.
Takahashi, K., et al., Augmentation of T-cell apoptosis by immunosuppressive
Clin Transplant, 2004. 18 Suppl 12: p. 72-5.
Tian, L., et al., Acceleration of apoptosis in CD4+CD8+ thymocytes by
rapamycin accompanied by increased CD4+CD25+ T cells in the periphery.

Transplantation, 2004. 77(2): p. 183-9.
Hackstein, H., et al., Rapamycin inhibits IL-4--induced dendritic cell maturation
in vitro and dendritic cell mobilization and function in vivo.
Blood, 2003.
101(11): p. 4457-63.
Ishizuka, T., et al., Rapamycin potentiates dexamethasone-induced apoptosis and
inhibits JNK activity in lymphoblastoid cells.
Biochem Biophys Res Commun,
1997. 230(2): p. 386-91.
Monti, P., et al., Rapamycin impairs antigen uptake of human dendritic cells.
Transplantation, 2003. 75(1): p. 137-45.
Center for Drug Evaluation and Research (CDER), NDA 21-083. Aagaard-Tillery, K.M. and D.F. Jelinek, Inhibition of human B lymphocyte cell
cycle progression and differentiation by rapamycin.
Cell Immunol, 1994. 156(2):
p. 493-507.
Kimball, P.M., R.H. Kerman, and B.D. Kahan, Production of synergistic but
nonidentical mechanisms of immunosuppression by rapamycin and cyclosporine.

Transplantation, 1991. 51(2): p. 486-90.
Yoshimura, N., et al., The direct effect of FK506 and rapamycin on interleukin
1(beta) and immunoglobulin production in vitro.
Transplantation, 1994. 57(12): p.
Kaplan, B., et al., The effects of relative timing of sirolimus and cyclosporine
microemulsion formulation coadministration on the pharmacokinetics of each
Clin Pharmacol Ther, 1998. 63(1): p. 48-53.
Zimmerman, J.J. and B.D. Kahan, Pharmacokinetics of sirolimus in stable renal
transplant patients after multiple oral dose administration.
J Clin Pharmacol,
1997. 37(5): p. 405-15.
Valente, J.F., et al., Comparison of sirolimus vs. mycophenolate mofetil on
surgical complications and wound healing in adult kidney transplantation.
Am J
Transplant, 2003. 3(9): p. 1128-34.
Transplantation, 2006. 82(1 Suppl 2): p. 412.
Efficacy and safety of conversion from calcineurin inhibitors to sirolimus versus
continued use of calcineurin inhibitors in renal allograft recipients: 18-month
results from a randomized, open-label comparative trial.
Transplantation, 2006.
82(1 Suppl 2): p. 412-3.
Boratynska, M., et al., Sirolimus delays recovery from posttransplant renal failure
in kidney graft recipients.
Transplant Proc, 2005. 37(2): p. 839-42.
Minimizing calcineurin inhibitor drugs in renal transplantation. Transplant Proc, 2003. 35(3 Suppl): p. 118S-121S.
Flechner, S.M., et al., Alemtuzumab induction and sirolimus plus mycophenolate
mofetil maintenance for CNI and steroid-free kidney transplant
Am J Transplant, 2005. 5(12): p. 3009-14.
Flechner, S.M., et al., Kidney transplantation without calcineurin inhibitor drugs:
a prospective, randomized trial of sirolimus versus cyclosporine.
2002. 74(8): p. 1070-6.
Land, W. and F. Vincenti, Toxicity-sparing protocols using mycophenolate
mofetil in renal transplantation.
Transplantation, 2005. 80(2 Suppl): p. S221-34.
Chan, G.L., D.M. Canafax, and C.A. Johnson, The therapeutic use of azathioprine
in renal transplantation.
Pharmacotherapy, 1987. 7(5): p. 165-77.
Chan, G.L., et al., Pharmacokinetics of 6-thiouric acid and 6-mercaptopurine in
renal allograft recipients after oral administration of azathioprine.
Eur J Clin
Pharmacol, 1989. 36(3): p. 265-71.
Ohlman, S., F. Albertioni, and C. Peterson, Day-to-day variability in azathioprine
pharmacokinetics in renal transplant recipients.
Clin Transplant, 1994. 8(3 Pt 1):
p. 217-23.
Eugui, E.M., et al., Lymphocyte-selective cytostatic and immunosuppressive
effects of mycophenolic acid in vitro: role of deoxyguanosine nucleotide
Scand J Immunol, 1991. 33(2): p. 161-73.
Allison, A.C. and E.M. Eugui, Mechanisms of action of mycophenolate mofetil in
preventing acute and chronic allograft rejection.
Transplantation, 2005. 80(2
Suppl): p. S181-90.
Franklin, T.J. and J.M. Cook, The inhibition of nucleic acid synthesis by
mycophenolic acid.
Biochem J, 1969. 113(3): p. 515-24.
Carr, S.F., et al., Characterization of human type I and type II IMP
J Biol Chem, 1993. 268(36): p. 27286-90.
Placebo-controlled study of mycophenolate mofetil combined with cyclosporin
and corticosteroids for prevention of acute rejection. European Mycophenolate
Mofetil Cooperative Study Group.
Lancet, 1995. 345(8961): p. 1321-5.
A blinded, randomized clinical trial of mycophenolate mofetil for the prevention
of acute rejection in cadaveric renal transplantation. The Tricontinental
Mycophenolate Mofetil Renal Transplantation Study Group.
1996. 61(7): p. 1029-37.
A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years.
Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group.

Transplantation, 1998. 65(11): p. 1450-4.
Ciancio, G., J. Miller, and T.A. Gonwa, Review of major clinical trials with
mycophenolate mofetil in renal transplantation.
Transplantation, 2005. 80(2
Suppl): p. S191-200.


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