Cardiac response to early conversion from calcineurin inhibitor to everolimus in renal transplant recipients--a three-yr serial echocardiographic substudy of the randomized controlled CENTRAL trial.

BACKGROUND: In transplant recipients, calcineurin inhibitors (CNIs) are associated with adverse cardiac effects while mTOR inhibitors have been reported to be beneficial. We performed a randomized controlled trial (RCT) in de novo renal transplant recipients examining cardiac responses of everolimus vs. CNI. METHODS: This was a substudy of the three-yr CENTRAL study, an RCT on safety and efficacy of early (week 7 post-engraftment) conversion from cyclosporine A (CsA) to everolimus vs. continued CsA. Thirty-nine recipients [median age 64 yr, (range 31-81)] completed echocardiographic evaluations at baseline, one, and three yr. RESULTS: After three yr, there was no difference between groups in left ventricle (LV) diastolic function, LV systolic function, LV morphology, and blood pressure response. We observed a relevant decrease in LV mass (CsA; 9.6%, p = 0.008, vs. everolimus; 7.0% reduction, p = 0.15), stabilized LV diastolic function, and a trend toward lower systolic blood pressure with 6 mmHg decrease in both arms (CsA, p = 0.08; everolimus, p = 0.14). Diastolic blood pressure was significantly reduced (8 mmHg decrease, p = 0.002) only in everolimus patients. CONCLUSIONS: After three-yr follow-up, no clinically relevant effect on cardiac function of an early conversion from CsA to an everolimus-based immunosuppressive regimen was detected in de novo renal transplant recipients.

Cardiac response to early conversion from calcineurin inhibitor to everolimus in renal transplant recipients: an echocardiographic substudy of the randomized controlled CENTRAL trial.

BACKGROUND: Calcineurin inhibitors are associated with adverse cardiac effects. Mammalian target of rapamycin inhibitors have been reported to have beneficial effects on cardiac function. We used advanced echocardiographic techniques in a randomized controlled trial to examine cardiac responses to an everolimus-based arm versus a calcineurin inhibitor-based arm in de novo kidney transplant recipients. METHODS: This was a substudy of the Certican Nordic Trial in Renal Transplantation study, a randomized controlled trial on safety and efficacy of early (week 7 after renal transplantation) conversion from cyclosporine A (CsA) to everolimus versus continued CsA during 1-year follow-up. A total of 44 patients (66% men; median [range] age, 61 [28-78] years) were included. All participants had a complete echocardiographic evaluation at baseline and at 1-year follow-up. RESULTS: Left ventricular (LV) systolic function, LV mass, left atrial volumes, and blood pressure response did not differ between groups during 1-year follow-up. There was, however, a difference between the groups in change in peak early mitral velocity after 1 year (P=0.02), and E/e' ratio trended higher in the everolimus group (P=0.09). CONCLUSIONS: Early conversion from CsA-based to everolimus-based immunosuppressive treatment in de novo renal transplant recipients caused marginal changes in LV diastolic function but no effect on LV systolic function or LV mass.

Computer-assisted cyclosporine dosing performs better than traditional dosing in renal transplant recipients: results of a pilot study.

Cyclosporine A (CsA) is widely used after organ transplantation. Its narrow therapeutic window and large pharmacokinetic variability makes therapeutic drug monitoring (TDM) demanding and frequent dose adjustments are needed, especially early after transplantation. The aim of the present pilot study was to compare accuracy of CsA TDM by experienced clinicians against a computer-assisted dosing model. Renal transplant recipients on CsA, prednisolone, and mycophenolate were included 2 weeks after transplantation, randomized (1:1) to either computer dosing (MAP-BE) or control (CONTR) and followed for at least 8 weeks. A maximum a posteriori probability Bayesian estimation method, applying a population pharmacokinetic model and the POSTHOC option in nonlinear mixed effects modeling, was used to individualize CsA doses in the MAP-BE group. Forty patients (31 men, 27.5% living donor) between 28 and 80 years were included. A total of 798 CsA concentration measurements and adherent dosing evaluations/adjustments were performed. During the entire study, blood concentrations were on average 10% +/- 5% from the predefined therapeutic target range in the MAP-BE group, as compared with 13% +/- 8% in the CONTR group (P = 0.042). However, there was no significant difference between groups regarding the percentage of CsA concentrations truly within the therapeutic windows [MAP-BE: 37% +/- 17%, CONTR: 33% +/- 15% (P = 0.57)] or in CsA dose [MAP-BE: 3.55 +/- 0.8, CONTR: 3.90 +/- 0.9 mg/kg/d (P = 0.26)]. Acute rejections were present in 4 and 3 patients, respectively (P = 1.00). The computer-assisted TDM-targeted CsA blood concentrations significantly better than experienced transplant physicians. A possible favorable effect on short- and long-term outcome needs to be verified in further, properly powered, clinical trials.

Fabry disease in donor kidneys with 3- and 12-year follow-up after transplantation.

Enzyme replacement therapy (ERT) has been introduced for Fabry disease and has been reported to clear some renal cell types of accumulated glycolipids and to reduce the accumulation in other cell types. We describe two patients without Fabry disease who were transplanted with kidney allografts from a male donor with Fabry disease. Biopsies were taken at transplantation and after 3 years in the first case and after 12 years in the second case. Even though these Fabry kidney allografts for many years had been exposed to normal levels of circulating α-galactosidase A (α-gal-A), the amount of accumulated lysosomal deposits in the podocytes remained unchanged. Additionally, small deposits were also found in tubular cells and glomerular endothelial cells as long as 12 years after transplantation.