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Background: Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens.Methods: We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival.Results: The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%).Conclusions: A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Background: Between April 1995 and November 2005, 500 liver transplantations were performed in 476 patients of age from 3, till 70, at the Transplantation center of the Institute of Clinical and Experimental Medicine (IKEM) in Prague. The most common indications for liver transplantation were alcoholic liver cirrhosis (23%), hepatitis C cirrhosis (17%), and cholestatic cirrhosis (PBC and PSC, 9% each). Mean MELD score of recipients at the transplantation was 15-18 for each year of transplantation. Ten-years patient survival was 79.1 +/- 2.2%, and graft survival 74.1 +/- 2.1% respectively. Best patient and graft survival was achieved among patients transplanted for autoimmune liver diseases, the worst in group of patients with alcoholic cirrhosis. Malignancies were the most common cause of death during the period of follow-up (17 patients)., Methods and Results: Patients were followed longitudinally at the Department of hepatogastroenterology IKEM according to prospective protocol included protocol biopsies. Hypertension (in 71% of recipients), and overweight or obesity (in 56.3%), were the most prevalent medical complications among long-term survivors. Diabetes was found in 28.6%, of which 14.7% was de-nove diabetes after transplantation. Renal insufficiency (S-creatinin > 150 micromol/l) was present in 61 of 348 (17.6%) survivors. Out of these, 16 needed chronic hemodialysis, and 12 underwent kidney transplantation subsequently. Protocol biopsy at 5 years after transplantation was evaluated in a sample of 102 unselected liver transplant recipients. Normal liver was found in 4% of recipients, minor non-specific changes in 36% of them. Disease recurrence was present in all of 16 recipients transplanted for HCV cirrhosis, in one third of them graft cirrhosis was already present. Disease recurrence was found in patients transplanted for autoimmune disease frequently, PBC in 40%, PSC in 25%, and autoimmune hepatitis in 60% of recipients. Graft steatosis greater than 33% was present in 13% of recipients., Conclusions: Liver transplantation is highly effective method of treatment of end stage liver disease. Despite frequent medical complications, and disease recurrence on histological examination almost 80% of recipients transplanted in the liver transplantation program in IKEM survived more than 10 years after procedure. The survival achieved was far above that of the European liver transplant registry.

Background: Kidney transplantation represents the method of choice of end stage renal disease., Methods and Results: The program of kidney transplantation was established in 1966 in our centre. In recent years, roughly 200 patients have undergone kidney transplantation annually, and 20-30 of them have received a graft from the living donor. Triple immunosuppressive regimen based on tacrolimus, MMF and steroids is given to majority of patients, in a case of high rejection risk; patients have received the induction protocols with polyclonal or monoclonal antilymphocyte globulins. Acute rejection is not a frequent finding in recent years and has occurred in 15% of cases in the first 3 months, the use of induction immunosuppression has decreased the rejection risk. Valgancyclovir has been used as prophylactic agent to prevent and treat cytomegalovirus infection. The usage of this strategy reduced the incidence of CMV infection below 10%. Kidney transplant recipients suffer from similar comorbidities as other renal patients in the long term, as cardiovascular complications, infections and malignancies. Anemia is a frequent complication in patients with graft dysfunction and erythropoesis stimulating agents have been used in its therapy. The median kidney graft survival is 8 years., Conclusions: Kidney transplantation is associated with better long-term results when compared with dialysis therapy and thus this method should be offered to all of suitable end stage renal disease patients.

The Symphony study assessed whether mycophenolate mofetil (MMF)-based regimens containing reduced doses of adjunct immunosuppressants could reduce toxicity while maintaining efficacy. Here, we examined the impact of acute rejection and associated risk factors. The incidence of biopsy-proven acute rejection in the low-dose tacrolimus group was approximately half that of the standard-dose cyclosporine and low-dose cyclosporine groups, and a third of that in the low-dose sirolimus group. The low-dose cyclosporine group had more severe rejection episodes (≥grade II) compared with other groups. Acute rejection was associated with a 10 mL/min glomerular filtration rate (GFR) reduction and a 5.3% absolute increase in graft loss at 12 months. Overall, the highest GFR was found in both rejecters and non-rejecters receiving low-dose tacrolimus, both in an intent-to-treat analysis and in patients successfully treated according to the protocol. In Cox regression models, human leukocyte antigen (HLA) mismatches and expanded criteria donors increased the acute rejection risk, while recipient age, living related donor, and MMF dose were associated with a reduced risk. Acute rejection was associated with worse outcome but did not entirely explain the differences among the treatment groups. The 2 g MMF plus low-dose tacrolimus combination appears to be the most efficient of all regimens examined regardless of acute rejection., (© 2009 John Wiley & Sons A/S.)

The cost of immunosuppression following transplantation can be reduced by using generic ciclosporin (for example, Equoral) rather than innovator ciclosporin drugs such as Neoral. Thus, this study aims to evaluate the interchangeability, safety, and tolerability of Equoral, a generic ciclosporin, with Neoral in stable adult renal transplant recipients. This was a multicenter, randomized, open-label, parallel-group clinical trial in stable renal transplant patients, comparing 6 months of treatment with Equoral with the same treatment period on Neoral. The primary end point was the between-treatment comparison of the total daily ciclosporin dose at the end of the study. A total of 99 patients were enrolled and constituted the full analysis/safety population, and 78 patients forming the per-protocol population were assessed for efficacy. Equoral was found to be equivalent to Neoral with regard to the primary end point of daily dose at the end of the study. This was supported by comparable serum ciclosporin levels at the end of the study. There were no renal transplant rejection incidents, but there was one death (in the Neoral group). Drug tolerability and incidence of adverse events were comparable between the treatment groups. In conclusion, Equoral and Neoral are interchangeable in stable renal transplant patients, and both drugs are associated with a similar safety and tolerability profile.

Side effects of steroid use have led to efforts to minimize their use in transplantation. Two corticosteroid-free regimens were compared with a triple immunosuppressive therapy. Data from the original intent-to-treat (ITT) population (153 tacrolimus/basiliximab [Tac/Bas], 151 tacrolimus/MMF [Tac/MMF], and 147 tacrolimus/MMF/steroids [control]) were analyzed in a 12-month follow-up. Percentage of graft survival were 92.8%, 95.4%, and 95.9% (KM estimates 89.9%, 95.3%, 95.9%), percentage of surviving patients were 98.7%, 98.0%, and 100% (KM estimates 95.9%, 92.8%, and 100%). During months 7-12, graft loss occurred in 3 Tac/Bas, 2 Tac/MMF, and zero control patients, patient deaths in 1 Tac/Bas, 2 Tac/MMF, and zero control, and biopsy-proven acute rejection episodes in 4 Tac/Bas, 3 Tac/MMF, and zero control. Mean serum creatinine at month 12 was 141.9 +/- 69.6 microM, 144.0 +/- 82.1 microM, and 134.5 +/- 71.2 microM (ns). New-onset insulin use in previously non-diabetic patients at month 12 was 1/138, 6/127, and 4/126. Patient and graft survival as well as renal function at 12 months were not different between patient groups, despite considerably higher rates of acute rejection occurring within the first six months after transplantation in both steroid-free patient groups. Tac/Bas therapy might offer benefits in terms of a trend for a more favorable cardiovascular risk profile.

Despite the increasing demand for organs for transplantation, the number of cadaveric donors remains stable and waiting time for transplantation is gradually getting longer. In addition to the options of using kidneys from living donors and those of non heart-beating donors (NHBD), an alternative approach is transplantation of both kidneys from adult marginal donors who would otherwise be considered unsuitable for single-kidney donation. Dual kidney transplantation involves the use of both kidneys from a marginal donor for a single recipient without the recipient having to cope with the drawbacks of a limited number of functioning nephrons. Normally. these kidneys would be excluded from the transplantation program and remain unused. The submitted presentation provides information on donor and recipient selection criteria and describes the course of the first dual kidney transplantation in an adult recipient in the Czech Republic.

Long-term renal allograft survival has not improved significantly in recent years and only a minority of grafts survives for more than 15 years. To evaluate the association between HSPA1A G(190)C, HSPA1B A(1267)G and TLR4 A(299)G polymorphisms and allograft survival we analyzed DNA of patients with long-term renal graft function over 15 years (Tx15), consecutively transplanted recipients (Tx), patients with acute rejection and healthy controls. HSPA1B (1267)AA was less prevalent in Tx versus Tx15 (P = 0.02) and versus controls (P = 0.004). HSPA1B (1267)GG was more frequent in Tx versus Tx15 (P = 0.005) and versus controls (P = 0.002). HSPA1B (1267)G allele occurred more often in Tx versus Tx15 (P = 0.03), and versus controls (P = 0.02). TLR4 (299)AG genotype prevalence was increased in Tx15 versus Tx (P = 0.02), while TLR4 (299)G allele was more frequent in Tx15 versus Tx (P = 0.02). The increased frequency of HSPA1B (1267)AA and TLR4 (299)AG genotypes in Tx15 group indicates that better cytoprotective functions in HSPA1B (1267)AA and reduced proinflammatory response in TLR4 (299)AG carriers might have improved renal allograft survival.

Background: The side effects associated with corticosteroids have led to efforts to minimize their use in renal transplant patients. In this study we compared two corticosteroid-free tacrolimus-based regimens with a standard triple therapy., Methods: This was a 6-month, phase III, open-label, parallel-group, multicenter study. The total analysis set comprised 451 patients, randomized (1:1:1) to receive tacrolimus (Tac) monotherapy following basiliximab (Bas) administration (n=153), Tac/mycophenolate mofetil (MMF) (n=151), or, Tac/MMF/corticosteroids triple therapy as a control (n=147)., Results: The study was completed by 91.2% (triple therapy), 94.7% (Tac/MMF), and 82.4% (Bas/Tac) of patients. Patient baseline characteristics were similar in all groups. The incidences of biopsy-proven acute rejection were 8.2% (triple therapy), 30.5% (Tac/MMF), and 26.1% (Bas/Tac), p<0.001 (multiple test for comparison with triple therapy); Bas/Tac vs. Tac/MMF, p=ns. The incidences of corticosteroid-resistant acute rejection were 2.0%, 4.0%, and 5.2%, p=ns. Graft survival (95.9%, 96.7%, and 94.7%, p=ns) and patient survival (100%, 99.3%, and 99.3%, p=ns) were similar in all groups. Median serum creatinine at month 6 was 123.0 micromol/L (triple therapy), 134.7 micromol/L (Tac/MMF) and 135.8 micromol/L (Bas/Tac). The overall safety profiles were similar; differences (p<0.05) were reported for anaemia (24.5% vs. 12.6% vs. 14.5%), diarrhoea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple therapy, Tac/MMF, and Bas/Tac group, respectively. The incidences of new-onset diabetes mellitus were 4.6%, 7.1%, and 1.4%, respectively., Conclusion: Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.

Everolimus 1.5 or 3 mg/day was compared with mycophenolate mofetil (MMF) 2 g/day in a randomized, multicenter 36-month trial in de novo renal allograft recipients (n = 588) receiving cyclosporine microemulsion (CsA) and corticosteroids. The study was double-blind until all patients had completed 12 months, then open-label. By 36 months, graft loss occurred in 7.2, 16.7 and 10.7% of patients in the everolimus 1.5, 3 mg/day, and MMF groups, respectively (p = 0.0048 for everolimus 1.5 mg/day vs. 3 mg/day); efficacy failure (biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up) occurred in 33.0, 38.9 and 37.2% of patients (p = 0.455 overall), respectively. Mortality and incidence of BPAR were comparable in all groups. Creatinine values were higher in everolimus groups, requiring a protocol amendment that recommended lower CsA exposure. Diarrhea, lymphocele, peripheral edema and hyperlipidemia were more common among everolimus-treated patients, whereas viral infections, particularly cytomegalovirus infection, increased in the MMF group. Overall safety and tolerability were better with MMF and everolimus 1.5 mg/day than with everolimus 3 mg/day. In conclusion, at 36 months, an immunosuppressive regimen containing everolimus 1.5 mg/day had equivalent patient, and graft survival and rejection rates compared with MMF in de novo renal transplant recipients, whereas everolimus 3 mg/day had inferior graft survival. Renal dysfunction in everolimus cohorts necessitates close monitoring.

Objective: To inform about the first own experiences and to present opinion on leading pregnancy and delivery after a combined pancreas and kidney transplantation., Design: Case report and review article., Setting: Department of Obstetric and Gynecology, 1st Medical Faculty of the Charles University and General Faculty Hospital, Prague., Results and Conclusions: Pregnancies and deliveries after the transplantation of solid organs are not common. Mostly there are experiences with women after kidney transplantation, smaller or no experiences are with women after transplantation of other solid organs. About 25 pancreas transplantation per year are performed in the Czech republic. Two women after the combined kidney and pancreas transplantation were the first in Czech republic to get pregnant spontaneously and delivered by using a chronic immunosupressive. therapy (Prograf, Imuran, Prednison) in 2002 and 2003. These single pregnancies were led as a high-risk pregnancy in Regional Perinatology Center in collaboration with Transplant and Diabetic Center. Both pregnancies were termined from the obstetrical indication before the term by cesarean section. Both children were healthy. The pregnancy of both patients has not affected the function of the transplanted organs and development of both children has been normal.

Transforming growth factor (TGF)-beta1 is a key profibrogenic cytokine associated with the pathogenesis of chronic allograft nephropathy (CAN). The primary aim of this study was to evaluate TGF-beta1 expression in protocol kidney graft biopsy in patients treated with different immunosuppressive regimens. Protocol kidney graft biopsies were carried out in 77 patients with stable graft function at 1 year after kidney transplantation, treated with a triple-drug regimen based on cyclosporin A (CyA; n = 49) or tacrolimus (TAC; n = 28). Morphological findings were assessed using the Banff 97 classification. TGF-beta1 expression was analysed using immunochemistry, and semiquantitatively scored in different renal structures (total score 0-18). Clinical data were analysed at the time of biopsy, and 12 months thereafter. No significant relation was found between the used immunosuppressive regimen and the histomorphological picture in the graft. TGF-beta1 expression within graft tissue was significantly higher in patients treated with CyA when compared with TAC (9.94 +/- 4.2 vs. 5.0 +/- 3.2; P < 0.001). Serum creatinine and glomerular filtration rate (GFR; Cockroft-Gault calculation) were comparable in both groups but, in the course of the next 12 months, GFR significantly decreased only in the CyA-treated group (from 1.03 +/- 0.33 to 0.96 +/- 0.37 ml/s) while not changing in the TAC-treated group. Patients treated with TAC had significantly lower diastolic blood pressure and serum cholesterol. The significantly lower TGF-beta1 expression in 1-year protocol kidney graft biopsy in TAC-treated patients with stable renal function, and the different development of graft function in both groups suggest a possible benefit of TAC for long-term graft acceptance.

Background: Everolimus is a proliferation inhibitor designed to target chronic rejection, including prevention of acute rejection. Everolimus blocks growth factor-mediated transduction signals, preventing organ rejection by a mechanism different than that of calcineurin inhibitors and of mycophenolate mofetil (MMF). METHODS.: Everolimus (1.5 mg or 3 mg daily) was compared with MMF (2 g daily) in a randomized, multicenter, multinational, 12-month double-blind, double-dummy and 2-year open-label, phase 3 trial in de novo renal allograft recipients (n = 588) who also received cyclosporine and corticosteroids as part of a triple immunosuppressive regimen., Results: At 12 months, there were no statistically significant differences between doses of 1.5 and 3 mg/day everolimus and MMF (2 g/day) in incidence of biopsy-proven acute rejection (23.2%, 19.7%, and 24.0%, respectively), graft loss (4.6%, 10.6%, and 9.2%), or death (5.2%, 4.0%, and 2.6%), respectively. Everolimus 1.5 mg/day and MMF were generally equally well tolerated. Both were better tolerated than everolimus 3 mg/day. The incidence of cytomegalovirus infection was significantly lower in patients receiving either 1.5 or 3 mg/day everolimus than in those receiving MMF (5.2% and 7.6% vs. 19.4%, respectively) (P = .001)., Conclusions: Everolimus is effective in preventing acute rejection and graft loss in de novo renal allograft recipients receiving a triple immunosuppressive regimen. Prevention of acute rejection, along with reduction in cytomegalovirus infection, addresses two factors known to contribute to chronic rejection in such patients.