Retrospective studies have demonstrated that patients who are expressors of cytochrome P4503A5 (CYP3A5) require a higher tacrolimus dose to achieve a therapeutic trough concentration (C(0)). The aim of this study was to evaluate this effect prospectively by pretransplantation adaptation. We randomly assigned 280 renal transplant recipients to receive tacrolimus either according to CYP3A5 genotype or according to the standard daily regimen. The primary end point was the proportion of patients within the targeted C(0). Secondary end points included the number of dose modifications and the delay in achieving the targeted C(0). In the group receiving the adapted dose, a higher proportion of patients had values within the targeted C(0) at day 3 after initiation of tacrolimus (43.2% vs. 29.1%; P = 0.03); they required fewer dose modifications, and the targeted C(0) was achieved by 75% of these patients more rapidly. The clinical end points were similar in the two groups. Pharmacogenetic adaptation of the daily dose of tacrolimus is associated with improved achievement of the target C(0). Whether this improvement will affect clinical outcomes requires further evaluation.

Sirolimus (SRL) allows to minimize the use of cyclosporine (CsA), but de novo administration after transplantation is associated with various complications. We report a prospective, open-label, multicenter randomized study to evaluate conversion from a CsAbased regimen to a SRL-based regimen 3 months after transplantation. One hundred ninety-two of a total of 237 patients were eligible at 3 months to be converted to SRL (n = 95) or to continue CsA (n = 97). All patients were also given mycophenolate mofetil (MMF) and oral steroids, planned to be discontinued at month 8. The primary endpoint, the clearance estimated according to Cockcroft and Gault at week 52, was significantly better in the SRL group (68.9 vs. 64.4 mL/min, p = 0.017). Patient and graft survival were not statistically different. The incidence of acute rejection episodes, mainly occurring after withdrawal of steroids, was numerically but not statistically higher in the SRL group (17% vs. 8%, p = 0.071). Sixteen patients discontinued SRL, mainly for adverse events (n = 11), and seven patients discontinued CsA for renal failure or acute rejection. Significantly, more patients in the SRL group reported aphthous, diarrhea, acne and high triglyceride levels. Conversion CsA to SRL 3 months after transplantation combined with MMF is associated with improvement in renal function.

Acute graft rejection remains a major problem in renal transplant recipients, and there is no consensus on the optimal immunosuppressive strategy. Immunoprophylaxis with ThymoglobulinA or basiliximab has significantly reduced the incidence of acute rejection episodes and graft loss following kidney transplantation. This open, randomized, multicenter study investigated the efficacy and tolerability of basiliximab (20 mg day 0-day 4) plus early cyclosporine from day 0 (n Ω 50) compared with Thymoglobulin A plus delayed cyclosporine (n Ω 50) in adult kidney transplant patients. In addition, all patients received steroids and mycophenolate mofetil (MMF) at standard doses from day 0. Patient and graft survival rates at 12 months were 98 and 94% in the basiliximab group, respectively, compared with 100 and 96% in the Thymoglobulin A group. The incidences of biopsy-confirmed acute rejection (8.0% in each group) and treatment failure (14% in the basiliximab group vs. 8% in the Thymoglobulin group) were comparable in the two groups. There was a nonsignificant tendency to more dialysis (14 vs. 6%), and fewer cytomegalovirus (CMV) infections (p Ω0.005) in the basiliximab group, but the percentage of clinical CMV was not different between the two groups (6 vs. 12%). Both strategies give excellent results, despite the differences in patterns, in nonhyperimmunized patients receiving their first cadaveric renal allograft.

To evaluate the efficacy and tolerance of a calcineurin inhibitor (CNI)-free regimen, 145 renal recipients were prospectively randomized to receive either sirolimus (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal antilymphocyte antibodies, mycophenolate mofetil (MMF) and steroids (6 months). The primary endpoint, estimated glomerular filtration rate (eGFR) was not significantly different at 12 months comparing sirolimus-and CsA-treated patients (60 ± 27 vs. 57 ± 21 mL/min). At 12 months, patient and graft survival, incidence of biopsy-proven rejection and rates of steroid withdrawal were not statistically different (97% vs. 97%; 90% vs. 93%; 14.3% vs. 8.6% and 82.8% vs. 84.1%, respectively). Delayed and slow graft function (SGF) was not significantly different (18.6% vs. 12.3% and 11.4% vs. 13.7%, respectively). In patients who remained on treatment according to protocol at 12 months, eGFR was significantly higher with sirolimus (69 ± 19 vs. 60 ± 14 mL/min, p = 0.01). Overall study drug discontinuation rates were 28.2% with sirolimus and 14.9% with CsA. Adverse events (wound complications, mouth ulcers, diarrhea, hypokalemia, bronchopneumonia) and proteinuria >0.5 g/24h (38.8% vs. 5.6%, p < 0.001) were significantly more frequent in sirolimus-treated patients. Cytomegalovirus (CMV) infections were significantly less frequent with sirolimus (6% vs. 23%, p < 0.01). A CNI-free regimen using sirolimus-MMF can achieve excellent renal function, but patients on sirolimus experienced a high rate of adverse events and study drug discontinuation.

Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the haematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC(12).

Acute rejection was significantly lower in the ATG-Tac group compared with the ATG-CsA and Tac triple groups. Significantly more hematologic and infectious adverse events were observed in both ATG induction groups.

Abstract. To date, there is no available treatment of hepatitis C virus (HCV) infection after renal transplantation (RT). Among 55 anti-HCV-positive/HCV RNA-positive hemodialysis patients who were treated with IFN-␣ (9 MU/wk during 6 or 12 mo), 21 of them (38%) had a sustained virologic response. Of these, 16 (76%) underwent RT 38 mo (range, 2 to 57 mo) after ␣-IFN therapy. There were 13 men and 3 women aged 46 yr (range, 27 to 68 yr). At RT, HCV serology was still positive in 15 patients, and HCV viremia was negative in all patients. Immunosuppression relied on anticalcineurin agents with or without steroids and/or antimetabolites; in addition, 12 of them received induction therapy with antithymocyte globulins. At the last follow-up after RT, at 22.5 mo (range, 2 to 88 mo), HCV viremia remained negative in all patients. Moreover, HCV RNA was not present in peripheral blood mononuclear cells when assessed in eight patients. HCV serology was found to be still positive in 13 patients. Three patients presented with acute rejection, one presented with a suppurative lymphocele, one died from a sepsis, and four presented with a cytomegalovirus infection. None of them developed posttransplant diabetes mellitus. In conclusion, hemodialysis patients waiting for a RT need to be treated with ␣-IFN because when HCV RNA clearance occurred, they experienced no relapse after transplantation despite chronic immunosuppressive treatment.Despite the screening of blood donors for hepatitis C virus (HCV) and the use of recombinant erythropoietin for the treatment of anemia in end-stage renal failure, de novo cases of HCV infection still occur that result from nosocomial transmission. Hence, the prevalence of HCV infection in hemodialysis patients and renal transplant recipients remains high. HCV-positive renal transplant recipients' survival is higher than that of HCV-positive hemodialysis patients. Nevertheless, patient and graft survivals are lower in HCV-positive renal transplant patients compared with HCV-negative renal transplant recipients (1). After RT, immunosuppression results in a significant increase in HCV viremia (2). Moreover, there is no efficient and safe treatment of HCV infection in renal transplant recipients. The treatment of HCV-positive renal transplant recipients with IFN-␣ is associated with a low rate of HCV RNA clearance and a high rate of acute rejection (3). Ribavirin monotherapy in renal transplant recipients is associated with an improvement in liver enzymes; however, HCV viremia did not change significantly. In contrast, liver fibrosis progressed significantly after 1 yr of ribavirin monotherapy (4). The treatment of HCV-positive hemodialysis patients with IFN-␣ is associated with a sustained virologic response ranging from 20% to 92% of the cases (5,6). We report on 16 cases of HCV-positive patients who cleared HCV viremia while they were treated with IFN-␣ during hemodialysis, and who did not relapse after renal transplantation (RT).Between 1993 and 1998, 55 anti-HCV-positive/HCV RNApositive hemodial...

Retrospective studies suggest that chronic allograft nephropathy might progress more rapidly in patients with post-transplant anemia, but whether correction of anemia improves renal outcomes is unknown. An open-label, multicenter, randomized controlled trial investigated the effect of epoetin-b to normalize hemoglobin values (13.0-15.0 g/dl, n=63) compared with partial correction of anemia (10.5-11.5 g/dl, n=62) on progression of nephropathy in transplant recipients with hemoglobin ,11.5 g/dl and an estimated creatinine clearance (eCrCl) ,50 ml/min per 1.73 m 2 . After 2 years, the mean hemoglobin was 12.9 and 11.3 g/dl in the normalization and partial correction groups, respectively (P,0.001). From baseline to year 2, the eCrCl decreased by a mean 2.4 ml/min per 1.73 m 2 in the normalization group compared with 5.9 ml/min per 1.73 m 2 in the partial correction group (P=0.03). Furthermore, fewer patients in the normalization group progressed to ESRD (3 versus 13, P,0.01). Cumulative death-censored graft survival was 95% and 80% in the normalization and partial correction groups, respectively (P,0.01). Complete correction was associated with a significant improvement in quality of life at 6 and 12 months. The number of cardiovascular events was low and similar between groups. In conclusion, this prospective study suggests that targeting hemoglobin values $13 g/dl reduces progression of chronic allograft nephropathy in kidney transplant recipients.