Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.

OBJECTIVE: To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. DESIGN: Systematic review and meta-analysis of individual patient data. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013. ELIGIBILITY: Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. RESULTS: The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. CONCLUSIONS: Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

Tacrolimus-based, steroid-free regimens in renal transplantation: 3-year follow-up of the ATLAS trial.

BACKGROUND: Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. METHODS: This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. RESULTS: Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. CONCLUSION: Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation.

There is increasing interest in tacrolimus-minimization regimens. ASSET was an open-label, randomized, 12-month study of everolimus plus tacrolimus in de-novo renal-transplant recipients. Everolimus trough targets were 3-8 ng/ml throughout the study. Tacrolimus trough targets were 4-7 ng/ml during the first 3 months and 1.5-3 ng/ml (n = 107) or 4-7 ng/ml (n = 117) from Month 4. All patients received basiliximab induction and corticosteroids. The primary objective was to demonstrate superior estimated glomerular filtration rate (eGFR; MDRD-4) at Month 12 in the tacrolimus 1.5-3 ng/ml versus the 4-7 ng/ml group. Secondary endpoints included incidence of biopsy-proven acute rejection (BPAR; Months 4-12) and serious adverse events (SAEs; Months 0-12). Statistical significance was not achieved for the primary endpoint (mean eGFR: 57.1 vs. 51.7 ml/min/1.73 m(2)), potentially due to overlapping of achieved tacrolimus exposure levels (Month 12 mean ± SD, tacrolimus 1.5-3 ng/ml: 3.4 ± 1.4; tacrolimus 4-7 ng/ml: 5.5 ± 2.0 ng/ml). BPAR (months 4-12) and SAE rates were comparable between groups (2.7% vs. 1.1% and 58.7% vs. 51.3%; respectively). Everolimus-facilitated tacrolimus minimization, to levels lower than previously investigated, achieved good renal function, low BPAR and graft-loss rates, and an acceptable safety profile in renal transplantation over 12 months although statistically superior renal function of the 1.5-3 ng/ml tacrolimus group was not achieved.

Belatacept-versus cyclosporine-based immunosuppression in renal transplant recipients with pre-existing diabetes.

BACKGROUND AND OBJECTIVES: Renal transplant recipients with pre-existing diabetes (PD) have reduced graft survival and increased risk of mortality and ischemic heart disease compared with nondiabetic transplant recipients. To assess the effect of belatacept in this high-risk group, we evaluated outcomes of the subpopulation with PD from previously published BENEFIT and BENEFIT-EXT trials. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis evaluated pooled data from BENEFIT (living donors or standard criteria donors) and BENEFIT-EXT (extended criteria donors). Patients were randomized to receive cyclosporine or a more intensive (MI) or less intensive (LI) belatacept regimen. RESULTS: Of 1209 intent-to-treat patients, 336 had PD. At 12 months, the belatacept LI arm demonstrated a numerically higher rate of patients surviving with a functioning graft (90.4% MI [103 of 114], 92.8% LI [90 of 97], and 80.8% cyclosporine [101 of 125]), and fewer serious adverse events than cyclosporine or MI patients. Three cases of posttransplant lymphoproliferative disorder were reported in LI patients, one involving the central nervous system. Higher rates (% [95% confidence interval]: 22.8% MI [15.1 to 30.5]; 20.6% LI [12.6 to 28.7]; 14.4% cyclosporine (8.2 to 20.6]) and grades of acute rejection were observed with belatacept. Measured GFR (ml/min per 1.73 m(2), 59.8 MI; 62.5 LI; 45.4 cyclosporine), and cardiovascular risk profile were better for belatacept versus cyclosporine. CONCLUSIONS: In post hoc analysis of patients with PD, patient/graft survival and renal function at 12 months were numerically higher with belatacept versus cyclosporine, but not statistically significant. Further study is necessary to confirm the benefits belatacept may provide in these patients.

[Kidney transplantation at the Institute for Clinical and Experimental Medicine]. / Transplantace ledviny v IKEM.

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.

[Long-term follow-up of the first 500 liver transplant recipients transplanted at the Institute for Clinical and Experimental Medicine in Prague]. / Výsledky dlouhodobého sledování prvních 500 pacientu po transplantaci jater provedených v institutu klinické a experimentální medicíny v Praze.

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.

Primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry.

The principal aim of this study was to compare the probability of and potential risk factors for death and graft loss after primary adult and pediatric liver transplantation in patients undergoing transplantation for autoimmune hepatitis (AIH) to those in patients undergoing transplantation for primary biliary cirrhosis (PBC; used as the reference group) or alcoholic cirrhosis (used as an example of a nonautoimmune liver disease). The 5-year survival of patients undergoing transplantation for AIH (n = 827) was 0.73 [95% confidence interval (CI) = 0.67-0.77]. This was similar to that of patients undergoing transplantation for alcoholic cirrhosis (0.74, 95% CI = 0.72-0.76, n = 6424) but significantly worse than that of patients undergoing transplantation for PBC (0.83, 95% CI = 0.80-0.85, n = 1588). Fatal infectious complications occurred at an increased rate in patients with AIH (hazard ratio = 1.8, P = 0.002 with PBC as the reference). The outcome of pediatric AIH patients was similar to that of adult patients undergoing transplantation up to the age of 50 years. However, the survival of AIH patients undergoing transplantation beyond the age of 50 years (0.61 at 5 years, 95% CI = 0.51-0.70) was significantly reduced in comparison with the survival of young adult AIH patients (0.78 at 18-34 years, 95% CI = 0.70-0.86) and in comparison with the survival of patients of the same age group with PBC or alcoholic cirrhosis. In conclusion, age significantly affects patient survival after liver transplantation for AIH. The increased risk of dying of infectious complications in the early postoperative period, especially above the age of 50 years, should be acknowledged in the management of AIH patients with advanced-stage liver disease who are listed for liver transplantation. It should be noted that not all risk factors relevant to patient and graft survival could be analyzed with the European Liver Transplant Registry database.

Interchangeability of ciclosporin formulations in stable adult renal transplant recipients: comparison of Equoral and Neoral capsules in an international, multicenter, randomized, open-label trial.

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.

Tacrolimus combined with two different corticosteroid-free regimens compared with a standard triple regimen in renal transplantation: one year observational results.

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.

Acute rejection in low-toxicity regimens: clinical impact and risk factors in the Symphony study.

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.

Conversion to sirolimus of patients with chronic allograft nephropathy--a retrospective analysis of outcome and influencing factors.

PURPOSE: The purpose of this study was to analyse the outcome and its influencing factors in patients whose therapy was converted from calcineurin inhibitors (CNI) to sirolimus (SRL) due to chronic allograft nephropathy (CAN). MATERIALS AND METHODS: Therapies of 78 patients (44 men) with CAN from three European transplant centres were converted from CNI therapy to SRL and followed 24 months. Slopes for creatinine clearance before and after conversion were calculated. Influencing factors were analysed by a multivariance analysis. RESULTS: The slope of the creatinine clearance improved significantly (-0.90 vs. -0.34 ml min(-1) month(-1); p < 0.01). In patients whose therapy was converted from cyclosporine A (CyA) to SRL, the slope improved significantly, whereas conversion from Tacrolimus (Tac) to SRL did not affect the slope. The benefit was more pronounced in (1) patients with low or moderate baseline creatinine clearance, (2) patients receiving SRL after conversion without additional mycophenolate mofetil and (3) patients with low or moderate proteinuria. CONCLUSION: Conversion from CyA to SRL but not from Tac to CRL is associated with a reduced loss of renal allograft function in patients with CAN.

Asymmetric dimethylarginine in obesity after renal transplantation.

OBJECTIVE: We have assessed in obese renal transplant recipients a course of selected proinflammatory factors liable to influence the long-term outcome of transplant patients and kidney grafts. DESIGN AND PATIENTS: In a prospective cohort study, we examined a total of 68 obese renal transplant recipients (body mass index [BMI] >or= 30 kg/m(2)) for a period of 12 months (Group I). A control group consisted of 72 comparable non-obese renal transplant recipients (Group II). RESULTS: Significant differences were found in plasma 12 months after renal transplantation (Group I versus Group II) in asymmetric dimethylarginine (ADMA; 3.68 micromol/L +/- 0.42 micromol/L vs 2.10 micromol/L +/- 0.34 micromol/L; P < .01), adiponectin (ADPN; 15.1 microg/mL +/- 6.0 microg/mL vs 22.80 microg/mL +/- 7.2 microg/mL; P < .01), leptin (50.4 ng/L +/- 10.2 ng/L vs 22.0 ng/L +/- 8.4 ng/L; P < .01), solubile leptin receptor (ObRe; 23.6 U/mL +/- 7.4 U/mL vs 47.2 U/mL +/- 10.7 U/mL; P < .01), resistin (21.2 microg/mL +/- 10.2 microg/mL vs 15.0 microg/mL +/- 6.2 microg/mL; P < .025) and triglycerides (3.9 mmol/L +/- 1.6 mmol/L vs 2.8 mmol/L +/- 1.6 mmol/L; P < .01). There were significant correlations between ADMA and BMI (r = 0.525, P < .001), ADPN and BMI (r = -0.574, P < .001), and ADMA and ADPN in visceral fat (r = -0.510, P < .001). Correlation between ADMA and Cin was weak, but significant (r = -0.190, P < .05). CONCLUSION: The results indicate that obesity after renal transplantation was associated with increased plasma ADMA and decreased ADPN in plasma and in fat tissue and may represent a risk factor for renal transplant recipients.

Early bone mineral density loss after renal transplantation and pre-transplant PTH: a prospective study.

BACKGROUND: Post-transplant osteopathy is a known complication of kidney transplantation (KTx). The aim of this study was to assess bone mineral density (BMD) in a large cohort of patients with treatment depending on pre-transplant parathormone (PTH) and baseline BMD. PATIENTS AND METHODS: 347 consecutive KTx recipients (222 M, 125 F) finished all follow-up measurements of BMD at lumbar spine, femur and radius using DEXA Lunar (at baseline and at 6 and 18 months). RESULTS: Bone loss with a T-score below -2.5 affected 37.2% of patients before KTx. A negative correlation between baseline PTH and BMD was found (p < 0.01). Patients with high levels of PTH had more bone loss than patients with low PTH values (p < 0.01). In the lumbar spine, a decline of BMD was found in the first 6 months, and after 18 months an improvement was found in all subgroups (p < 0.001). In femur, significant changes were found only in low-PTH patients after 6 months (p < 0.001); the others did not reach significant results. There was no improvement after 18 months in low-PTH patients. In radius, bone loss was not found. CONCLUSION: A relationship between differences in progression of BMD after transplantation and PTH level at baseline was found.

Asymmetric dimethylarginine and adiponectin after renal transplantation: role of obesity.

BACKGROUND: In obese renal transplant recipients, we assessed the course of selected proinflammatory factors liable to influence long-term outcomes of transplant patients and kidney grafts. METHODS: In a prospective cohort study, we examined a total of 140 renal transplant recipients for a period of 12 months. Based on body mass index (BMI), patients were divided into Group I (BMI > or = 30 kg/m2, 68 patients) and Group II (BMI < or = 30 kg/m2, 72 patients). RESULTS: Twelve months after renal transplantation, significant differences were found between Group I versus Group II in plasma levels of asymmetric dimethylarginine (ADMA) (3.65 [SD +/- 0.47 micromol/L] versus 2.01 [SD +/- 0.36 micromol/L], P < .01), adiponectin (ADPN) (15.4 [SD +/- 6.6 microg/mL] versus 22.3 [SD +/- 8.2 microg/mL], P < .01), leptin (51.3 [SD +/- 11.2 ng/L] versus 21.3 [SD +/- 9.2 ng/L], P < .01), soluble leptin receptor (24.6 [SD +/- 8.4 U/mL] versus 46.1 [SD +/- 11.4 U/mL], P < .01), resistin (20.8 [SD +/- 10.1 microg/mL] versus 14.6 [SD +/- 6.4 microg/mL], P < .025), and triglycerides (3.9 [SD +/- 1.6] versus mmol/L 2.8 [SD +/- 1.6 mmol/L], P < .01). There were significant correlations between ADMA and BMI (r = 0.520; P < .001), and ADPN and BMI (r = -0.570, P < .001). The correlation between ADMA and inulin clearance (Cin) was weak (r = -0.185, P < .05). CONCLUSIONS: Obesity after renal transplantation is associated with increased ADMA and decreased ADPN in plasma, and this may represent a risk factor for renal transplant recipients.

Ischaemic heart disease is a risk factor for renal failure after heart transplantation.

BACKGROUND: The improvement of a long-term outcomes of heart transplantation (HTx) has resulted in a new phenomenon; specifically, the development of renal dysfunction secondary to calcineurin inhibitor toxicity. This study was designed to assess the participation of risk factors in the development of renal dysfunction in HTx. METHODS: Data from 310 patients undergoing HTx in our center between 1988-1998 with a post-operation survival period for minimum 5 years (n=155) were analyzed retrospectively. Study cohort was divided into two groups according to renal function estimated by serum creatinine in the fifth year (Group I n=72; serum creatinine > or = 150 micromol/l, Group II: n=83, serum creatinine < 150 micromol/l). RESULTS: We noted that patients with serum creatinine > or = 150 micromol/l at 5 years post-HTx had renal function significantly worse as early as 1 month (p<0.01), and 1 year post-HTx (p<0.001). The risk for developing renal dysfunction after HTx was doubled in patients with a history of coronary artery disease (CAD), and 2.5 times higher in those with small body weight gain. End stage renal disease developed in 16 patients (10.3%) and renal transplantation was performed in 13 (8.4%) of them. CONCLUSION: Our data documented that a history of CAD and limited weight gain is a major risk factor for development of renal dysfunction after HTx. Aggressive modification of risk factors for CAD may reduce the occurrence of this complication.

Reduced exposure to calcineurin inhibitors in renal transplantation.

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].).

Intrarenal cytokine and chemokine gene expression and kidney graft outcome.

AIMS: Proinflammatory cytokines are thought to play an important role in various kidney graft diseases resulting in interstitial fibrosis and tubular atrophy frequently found in case biopsies. To explore the role of various cytokines and chemokines in the long-term graft outcome, the transcription patterns of their genes in kidney allograft biopsies were evaluated. METHODS: The real-time RT-PCR was used to identify intragraft mRNA expression of cytokines and chemokines in 74 kidney graft recipients and the results were correlated with histological and clinical parameters and long-term graft outcome. RESULTS: We observed up-regulated IL-10 (p < 0.001), TGF-beta1, IL-6, MCP-1, RANTES (p < 0.01) and TNF-alpha (p < 0.05) mRNA expression in patients with chronic allograft nephropathy (CAN) as compared to controls. There were positive correlations between the mRNA expression of IL-6 (p < 0.001), IL-10 (p < 0.01), TNF-alpha, MCP-1 (p < 0.05) and the proteinuria. The up-regulation of intrarenal MCP-1 in patients with CAN increased the risk for the graft failure within the next 42 months (OR 5.1, p < 0.05). Kaplan-Meier survival analysis revealed that proteinuria and higher intragraft expression of TGF-beta1 and MCP-1 predict a poor kidney graft outcome. CONCLUSION: Expression patterns of intrarenal proinflammatory genes might discriminate patients at a higher risk for the earlier allograft failure.

Soluble CD30 in patients with antibody-mediated rejection of the kidney allograft.

UNLABELLED: The aim of our retrospective study was to evaluate the clinical significance of measurement of the soluble CD30 (sCD30) molecule for the prediction of antibody-mediated (humoral) rejection (HR). Sixty-two kidney transplant recipients (thirty-one C4d-positive and thirty-one C4d-negative patients) were included into the study. Soluble CD30 levels were evaluated before transplantation and during periods of graft function deterioration. The median concentrations of the sCD30 molecule were identical in C4d-positive and C4d-negative patients before and after transplantation (65.5 vs. 65.0 and 28.2 vs. 36.0 U/ml, respectively). C4d+ patients who developed DSA de novo had a tendency to have higher sCD30 levels before transplantation (80.7+/-53.6 U/ml, n=8) compared with C4d-negative patients (65.0+/-33.4 U/ml, n=15). Soluble CD30 levels were evaluated as positive and negative (>or=100 U/ml and <100 U/ml respectively) and the sensitivity, specificity and accuracy of sCD30 estimation with regard to finding C4d deposits in peritubular capillaries were determined. The sensitivity of sCD30+ testing was generally below 40%, while the specificity of the test, i.e. the likelihood that if sCD30 testing is negative, C4d deposits would be absent, was 82%. C4d+ patients who developed DSA de novo were evaluated separately; the specificity of sCD30 testing for the incidence of HR in this cohort was 86%. CONCLUSION: We could not confirm in our study that high sCD30 levels (>or=100 U/ml) might be predictive for the incidence of HR. Negative sCD30 values might be however helpful for identifying patients with a low risk for development of DSA and antibody-mediated rejection.

12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients.

The proliferation signal inhibitor everolimus (Certican), has demonstrated efficacy with full-dose cyclosporine (CsA) (Neoral). Two multicenter randomized controlled studies were performed to compare 12-month efficacy and safety of everolimus 1.5 and 3.0 mg/day with reduced-dose CsA. Study 1 enrolled 237 de novo renal allograft recipients, randomizing 222 nonblack patients to either everolimus 1.5 or 3.0 mg/day, with the Neoral) dose guided by C(2) (monitoring of CsA concentration 2 h after dosing). Study 2 had a similar protocol, with basiliximab included, enrolling 256 recipients and randomizing 243 nonblack patients. In Study 1, there was a lower incidence of acute rejection in nonblack patients on 3 mg/day (16.4%) compared with 1.5 mg/day (25.9%), P = 0.08. In Study 2, the inclusion of basiliximab lowered the overall incidence of acute rejection; 14.3% of nonblack patients (3 mg/day) and 13.6% of nonblack patients (1.5 mg/day) had acute rejection by 12 months (P =0.891). Renal function was preserved throughout the study, with no differences observed between groups within studies. Everolimus was well tolerated with no significant differences between doses. Everolimus, in combination with reduced-dose Neoral), demonstrated efficacy and was well tolerated. Basiliximab allows for utilization of lower doses of everolimus with reduced dosing of Neoral).