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Everolimus versus azathioprine in a cyclosporine and ketoconazole-based immunosuppressive therapy in kidney transplant: 3-year follow-up of an open-label, prospective, cohort, comparative clinical trial.
Gonzalez, F, Espinoza, M, Herrera, P, Rocca, X, Reynolds, E, Lorca, E, Roessler, E, Hidalgo, J, Espinoza, O
Transplantation proceedings. 2010;(1):270-2
Abstract
In cyclosporine-based protocols, everolimus is more effective than azathioprine to reduce acute rejection. Ketoconazole may reduce cyclosporine and everolimus requirements. We compared kidney transplant patients treated with everolimus or azathioprine in a ketoconazole- and cyclosporine-based immunosuppressive regimen. This open-label, prospective trial of low immunologic risk patients. Included one group (n = 11) who received everolimus (target blood level, 3-8 ng/mL) and the other (n = 11) azathioprine (2.0-2.5 mg/kg/d). Both received steroids, ketoconazole, and cyclosporine with C(0) targets (ng/mL) in the everolimus group of 200-250, 100-125, and 50-65 for months 1 and 2 and thereafter and in the azathioprine group of 250-300 in month 1, 200-250 in month 2, 180-200 until month 6, and 100-125 thereafter. Their baseline characteristics were similar. Two biopsy-proven acute rejections occurred in each group. Three-year graft and patient survival in both groups was 100%. Creatinine clearances at months 6, 12, 24, and 36 were 63.7 +/- 25.4, 58.9 +/- 24.9, 56.0 +/- 22.9, and 57.0 +/- 27.6 in the everolimus group versus 72.6 +/- 20, 68.6 +/- 21.3, 71.4 +/- 23.2, and 68.4 +/- 19.2 in the azathioprine group (NS for every comparison). Major complications were rare and similar in both groups. Five patients in the everolimus group received simvastatin versus 4 in the azathioprine cohort (P = .53). The average cyclosporine doses to achieve targets were 0.8-1.2 mg/kg in the everolimus group and 1.6-2.2 mg/kg in the azathioprine group. The average everolimus dose after month 2 was 0.75-0.9 mg/d. We concluded that with cyclosporine, ketoconazole, and steroids, everolimus was as effective and safe as azathioprine. Cyclosporine reduction with everolimus did not influence graft survival or function at 3 years.
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Conversion to enteric-coated mycophenolate sodium from various doses of mycophenolate mofetil: results of a prospective international multicenter trial in maintenance renal transplant patients receiving cyclosporine.
Nashan, B, Suwelack, B, Ivens, K, Arns, W, Lhotta, K, Bourbigot, B, Budde, K, Fischer, W, Pietruck, F, ,
Transplantation proceedings. 2006;(9):2856-9
Abstract
Conversion from mycophenolate mofetil (MMF, CellCept) to enteric-coated mycophenolate sodium (EC-MPS, myfortic) is safe and effective in renal transplant patients treated with the standard dose of 2 g MMF. In this 6-month, international, multicenter, open-label, single-arm trial, a large cohort of maintenance renal transplant patients receiving different doses of MMF were converted under normal clinical conditions to equimolar doses of EC-MPS. Mean calculated creatinine clearance remained stable from the time of study entry (59.6 +/- 19.7 mL/min) to the end of the study (58.3 +/- 19.8 mL/min). Adverse events were reported by 152 patients (67%), with gastrointestinal complications being observed in 45 patients (20%). Thirty-three patients (15%) experienced adverse events or infections with a suspected relation to EC-MPS, including one case of anemia and two cases of leukopenia. Eleven patients (4.9%) required a reduction in EC-MPS dose and seven patients (3.1%) permanently discontinued EC-MPS owing to adverse events. At month 6 after conversion, five patients (2.2%) experienced biopsy-proven acute rejection. There were no graft losses or deaths. These data support earlier findings that stable maintenance renal transplant patients receiving MMF with cyclosporine with or without corticosteroids can be converted to EC-MPS with no compromise in efficacy and tolerability, and no adverse effect on renal function.
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Arterial elasticity measurement in renal transplant patients under anticalcineurin immunosuppression.
Martínez-Castelao, A, Sarrias, X, Bestard, O, Gil-Vernet, S, Serón, D, Cruzado, JM, Moreso, F, Díez-Noguera, A, Grinyó, JM
Transplantation proceedings. 2005;(9):3788-90
Abstract
INTRODUCTION Calcineurin inhibitors may be associated with decreased arterial elasticity and increased vascular risk. We measured pulse wave velocity (PWV) in large or small arteries as an index of elasticity. The aim of our study was to determine aortic and radial arterial elasticity in 30 stable kidney transplant patients treated with calcineurin inhibitor immunosuppression. PATIENTS AND METHODS In stable kidney transplant patients we determined the usual biochemical parameters as well as lipid profiles, 24-hour blood pressure (BP) monitoring (CBPM) using a chronobiological program (Garapa), and PWV with a HDI-PWV CR-2000 monitor. RESULTS Sixteen patients received cyclosporine (CsA, G-1) and 14 tacrolimus (G-2) immunosuppression. There were no baseline differences regarding age (G-1: 56 +/- 12 years, G-2: 56 +/- 14 years), renal transplant follow-up (G-1: 7 +/- 3 years, G-2: 7.5 +/- 3 years), Systolic BP, pulse pressure or plasma creatinine (G-1: 163 +/- 35 umol/L, G-2: 173 +/- 26 umol/L). Patients in the G-1 showed higher diastolic BP (79 +/- 11 vs 74 +/- 8 mm Hg), greater proteinuria (1.26 +/- 0.4 vs 0.6 +/- 0.2 g/d, P < .05), total cholesterol (5.51 +/- 1.2 mmol/L) and low-density lipoprotein (3.08 +/- 0.3 vs 2.99 +/- 0.3 mmol/L, P = NS). Aortic arterial elasticity was decreased in G-1 patients (10.4 +/- 6 vs 14.3 +/- 2 mL/mm Hg x10, P < .05) as well as that in the radial artery (G-1: 5.52 +/- 1 vs 5.57 +/- 1.2 mL/mm Hg x100, P = NS). Almost 100% of the patients presented normal diurnal BP with high nocturnal BP in a nondipper pattern in both groups. CONCLUSION Calcineurin immunosuppression may contribute to arterial stiffness in kidney transplant patients. No differences between CsA or tacrolimus were observed in our study. CBPM and PWV are useful tools to evaluate subclinical atherosclerosis in renal transplant patients.
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Inhibition of plasminogen activator inhibitor-1 by angiotensin II receptor blockers on cyclosporine-treated renal allograft recipients.
Ishikawa, A, Ohta, N, Ozono, S, Kawabe, K, Kitamura, T
Transplantation proceedings. 2005;(2):994-6
Abstract
INTRODUCTION We previously showed that proteinuria from a renal graft was significantly decreased by administration of losartan potassium, an angiotensin II receptor blockers (ARB). To further evaluate the mechanism, we performed another clinical study focusing on the change in plasma plasminogen activator inhibitor-1 (PAI-1) levels among cyclosporine (CyA)-treated renal allograft recipients. METHODS Among 12 hypertensive CyA-treated kidney transplant patients, four received 25 to 50 mg/day of losartan; four, 4 to 8 mg/day of candesartan cilexetil; and another four, 20 to 40 mg/day of nifedipine. Four CyA-treated kidney-transplanted patients without hypertension were selected as a control group. Informed consent was obtained from all participants. PAI-1 and serum creatinine (S-Cr) levels were monitored every 3 months for 1 year. RESULTS Considering the pretreatment of PAI-1 as 100%, the mean percent of PAI-1 at 1 year after the onset of study for losartan, candesartan, nifedipine, and control groups were 78.6 +/- 6.7%, 81.4 +/- 8.0%, 96.7 +/- 7.6%, and 110.4 +/- 9.2%, respectively. The ARB groups demonstrated significant differences from the control group (P < .01), while the nifedipine group did not. S-Cr levels among ARB-administered groups were increased slightly but temporarily. As for S-Cr levels, no significant differences were seen among the four groups. CONCLUSIONS Control of hypertension itself is important for all renal graft recipients; however, PAI-1 reduction by ARBs was thought to be a key for renal preservation. We expect that ARBs will contribute to prolonged renal allograft survival.
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Oral cyclosporine but not tacrolimus reduces renal transplant blood flow.
Nankivell, BJ, Chapman, JR, Bonovas, G, Gruenewald, SM
Transplantation. 2004;(9):1457-9
Abstract
BACKGROUND Calcineurin inhibitors are important immunosuppressive agents, but cause nephrotoxicity. METHODS Instantaneous intra-renal transplant hemodynamics were assessed in 22 patients using quantitative cineloop color Doppler imaging after dosing with microemulsion cyclosporine (CSA) or tacrolimus (TAC). RESULTS CSA dosing resulted in renal hypoperfusion, with a mean relative reduction of 43%+/-20% (range 22-76%) in maximal fractional area (MFA) of color pixels to nadir, compared to baseline. The mean effect occurred 1.1+/-0.9 hr (median 1 hr) after CSA dosing and was abrogated by calcium channel blockers (P <0.05). The main renal artery velocities, resistive index and small vessel perfusion were unchanged, suggestive of medium-sized arteries mediated vasoconstriction. In contrast, TAC did not alter renal vascularity (2.3+/-4.0% absolute reduction of MFA color pixels vs. 10.7+/-6.5% with CSA, P <0.01). CONCLUSION CSA, but not TAC, induces phasic hypoperfusion of variable severity within small to medium sized intra-renal arteries soon after dosing, mitigated by calcium channel blockade.
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Lipid-lowering long-term effects of six different statins in hypercholesterolemic renal transplant patients under cyclosporine immunosuppression.
Martínez-Castelao, A, Grinyó, JM, Gil-Vernet, S, Serón, D, Castiñeiras, MJ, Ramos, R, Alsina, J
Transplantation proceedings. 2002;(1):398-400
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One-center comparison between primary immunosuppression based on neoral cyclosporine and tacrolimus for renal transplantation.
Pascual, J, Marcén, R, Burgos, FJ, Tenorio, MT, Merino, JL, Arambarri, M, Villafruela, JJ, Liaño, F, Mampaso, F, Ortuño, J
Transplantation proceedings. 2002;(1):94-5