Isabelle Etienne

Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation.

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12‐month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration‐controlled doses or fixed‐dose MMF. A novel Bayesian estimator of MPA AUC based on three‐point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration‐controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration‐controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg•h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg•h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.

Efficacy on Renal Function of Early Conversion from Cyclosporine to Sirolimus 3 Months After Renal Transplantation: Concept Study

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 CsA‐based 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.

Immunoprophylaxis with basiliximab compared with antithymocyte globulin in renal transplant patients receiving MMF-containing triple therapy.

Acute graft rejection remains a major problem in renal transplant recipients, and there is no consensus on the optimal immunosuppressive strategy. Immunoprophylaxis with Thymoglobulin® 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 = 50) compared with Thymoglobulin® plus delayed cyclosporine (n = 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® 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 = 0.005) 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.

CYP3A5 and MDR1 Genetic Polymorphisms and Cyclosporine Pharmacokinetics After Renal Transplantation

The immunosuppressive drug cyclosporine (INN, ciclosporin), whose pharmacokinetic characteristics vary greatly among individuals, is a substrate for cytochrome P450 (CYP) 3A and P‐glycoprotein, the product of the multidrug resistance 1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNPs) in these genes are associated with deficient protein expression and reduced in vivo activity. We postulated that, in renal transplant recipients, these SNPs could be associated with interindividual variations in cyclosporine pharmacokinetics.

Efficacy and Safety of Early Cyclosporine Conversion to Sirolimus with Continued MMF—Four-Year Results of the Postconcept Study

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function. We previously reported that conversion from cyclosporine A (CsA) to sirolimus (SRL) 3 months after transplantation significantly improved renal function at 1 year. In the Postconcept trial, 77 patients in the SRL group and 85 in the CsA group were followed for 48 months. Renal function (Cockcroft and Gault) was significantly better at month 48 (M48) in the SRL group both in the intent‐to‐treat population (ITT): 62.6 mL/min/1.73 m2 versus 57.1 mL/min/1.73 m2 (p = 0.013) and in the on‐treatment population (OT): 67.5 mL/min/1.73 m2 versus 57.4 mL/min/1.73 m2 (p = 0.002). Two biopsy proven acute rejection episodes occurred after M12 in each group. Graft and patient survival were comparable (graft survival: 97.4 vs. 100%; patient survival: 97.4 vs. 97.6%, respectively). The incidence of new‐onset diabetes was numerically increased in the SRL group (7 vs. 2). In OT, three cancers occurred in the SRL group versus nine in the CsA group and mean proteinuria was increased in the SRL group (0.42 ± 0.44 vs. 0.26 ± 0.37; p = 0.018). In summary, the renal benefits associated with conversion of CsA to SRL, at 3 months posttransplantation, in combination with MMF were maintained for 4 years posttransplantation.

Hepatosplenic gamma/delta T-cell lymphoma : A report of two cases in immunocompromised patients, associated with isochromosome 7q

Two cases of peripheral T-cell lymphoma, characterized by hepatosplenic presentation and gamma/delta T-cell receptor phenotype on malignant cells, are reported. Little is known about the chromosomal changes in these peculiar lymphomas. We report the cytogenetic analysis of these two patients. Isochromosome 7q and trisomy 8 were observed. These abnormalities were reported previously in five cases of gamma/delta T-cell lymphoma. These two patients had lymphomatous infiltration of the spleen, liver, bone marrow, and (in one case) lymph nodes. These abnormalities occurred in immunocompromised patients (i.e., immunosuppressive therapy for kidney transplantation and chemotherapy for Hodgkins disease), without Epstein-Barr virus infection stigmata in tumor cells.

Interstitial Fibrosis Quantification in Renal Transplant Recipients Randomized to Continue Cyclosporine or Convert to Sirolimus

Conversion from cyclosporine (CsA) to sirolimus at week 12 after kidney transplantation is associated with a significant improvement in renal function. The aim of this analysis was to investigate the effect of this conversion on interstitial fibrosis (IF), a hallmark of chronic allograft injury, in patients taking part in the CONCEPT trial. This multicenter, prospective, trial included 193 renal recipients randomized at week 12 to switch from CsA to sirolimus or to continue CsA, with mycophenolate mofetil. Routine biopsy with automated, quantified assessment of IF by a program of color segmentation was performed at 1 year in 121 patients. At 1 year, renal function was significantly improved in the conversion group as assessed by estimated GFR (MDRD) and measured GFR. Biopsy results, however, showed no between‐group difference in percentage of IF. Calculated GFR at 1 year was significantly associated with the percentage of IF (p = 0.004, R2= 0.07). By multivariate analysis diabetic patients had more fibrosis than non‐diabetic patients. In conclusion, although kidney transplant patients converted from CsA to sirolimus showed significant improvement in renal function, we found no difference of IF on 1‐year biopsies.

Correction of Postkidney Transplant Anemia Reduces Progression of Allograft Nephropathy

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-β 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.

Post-Transplantation Lymphoproliferative Disorder After Kidney Transplantation: Report of a Nationwide French Registry and the Development of a New Prognostic Score

PURPOSE Post-transplantation lymphoproliferative disorder (PTLD) is associated with significant mortality in kidney transplant recipients. We conducted a prospective survey of the occurrence of PTLD in a French nationwide population of adult kidney recipients over 10 years. PATIENTS AND METHODS A French registry was established to cover a nationwide population of transplant recipients and prospectively enroll all adult kidney recipients who developed PTLD between January 1, 1998, and December 31, 2007. Five hundred patient cases of PTLD were referred to the French registry. The prognostic factors for PTLD were investigated using Kaplan-Meier and Cox analyses. RESULTS Patients with PTLD had a 5-year survival rate of 53% and 10-year survival rate of 45%. Multivariable analyses revealed that age > 55 years, serum creatinine level > 133 μmol/L, elevated lactate dehydrogenase levels, disseminated lymphoma, brain localization, invasion of serous membranes, monomorphic PTLD, and T-cell PTLD were independent prognostic indicators of poor survival. Considering five variables at diagnosis (age, serum creatinine, lactate dehydrogenase, PTLD localization, and histology), we constructed a prognostic score that classified patients with PTLD as being at low, moderate, high, or very high risk for death. The 10-year survival rate was 85% for low-, 80% for moderate-, 56% for high-, and 0% for very high-risk recipients. CONCLUSION This nationwide study highlights the prognostic factors for PTLD and enables the development of a new prognostic score. After validation in an independent cohort, the use of this score should allow treatment strategies to be better tailored to individual patients in the future.

Immunosuppressant Regimen Based on Sirolimus Decreases Aortic Stiffness in Renal Transplant Recipients in Comparison to Cyclosporine

Whether or not a cyclosporine A (CsA)‐free immunosuppressant regimen based on sirolimus (SRL) prevents aortic stiffening and improves central hemodynamics in renal recipients remains unknown. Forty‐four patients (48 ± 2 years) enrolled in the CONCEPT trial were randomized at week 12 (W12) to continue CsA or switch to SRL, both associated with mycophenolate mofetil. Carotid systolic blood pressure (cSBP), pulse pressure (cPP), central pressure wave reflection (augmentation index, AIx) and carotid‐to‐femoral pulse‐wave velocity (PWV: aortic stiffness) were blindly assessed at W12, W26 and W52 together with plasma endothelin‐1 (ET‐1), thiobarbituric acid‐reactive substances (TBARS) and superoxide dismutase (SOD) and catalase erythrocyte activities. At W12, there was no difference between groups. At follow‐up, PWV, cSBP, cPP and AIx were lower in the SRL group. The difference in PWV remained significant after adjustment for blood pressure and eGFR. In parallel, ET‐1 decreased in the SRL group, while TBARS, SOD and catalase erythrocyte activities increased in both groups but to a lesser extent in the SRL group. Our results demonstrate that a CsA‐free regimen based on SRL reduces aortic stiffness, plasma endothelin‐1 and oxidative stress in renal recipients suggesting a protective effect on the arterial wall that may be translated into cardiovascular risk reduction.