Conversion to Mycophenolate Mofetil in Conjunction With Stepwise Withdrawal of Cyclosporine in Stable Renal Transplant Recipients1

Schrama, Yvonne C.; Joles, Jaap A.; Tol, Arie van; Boer, P. de; Koomans, Hein A.; Hené, Ronald J.

doi:10.1097/00007890-200002150-00012

Cited by 67 publications

(48 citation statements)

References 65 publications

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“…A possible contributing factor to the increased incidence of biopsy-proven rejections in our study might be the rapid CsA withdrawal. Although no significant difference was observed in our study between patients with two different withdrawalschedules, lower rejection rates have been described with a longer period of stepwise CsA withdrawal (18,23). Despite the higher incidence of acute rejections after discontinuation of CsA, no detrimental effect on creatinine clearance was noted.…”

Section: Discussioncontrasting

confidence: 72%

“…As a consequence of the intention-to-treat analysis, the effects of discontinuation of CsA are obscured by the proportion of patients in whom this drug was reintroduced (29%). In conversion studies with patients switching from CsA to azathioprine or MMF, beneficial effects on BP and lipid profile were also noted (18,26,29).…”

Section: Discussionmentioning

confidence: 98%

“…MMF has no adverse effect on cardiovascular risk factors. Therefore, discontinuation of either CsA or Pred might positively influence the cardiovascular risk profile, albeit with a small risk of acute rejection or even graft loss (17)(18)(19). The 3-yr follow-up from the European MMF study indicated a modest but not statistically significant effect of the addition of MMF on graft survival, which was attributed solely to the lower incidence of acute rejection (5).…”

Section: Discussionmentioning

confidence: 99%

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Withdrawal of Cyclosporine or Prednisone Six Months after Kidney Transplantation in Patients on Triple Drug Therapy

Gregoor¹,

Sévaux

Ligtenberg

et al. 2002

Journal of the American Society of Nephrology

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141

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ABSTRACT. Uncertainty exists regarding the necessity of continuing triple therapy consisting of mycophenolate mofetil (MMF), cyclosporine (CsA), and prednisone (Pred) after kidney transplantation (RTx). At 6 mo after RTx, 212 patients were randomized to stop CsA (n = 63), stop Pred (n = 76), or continue triple drug therapy (n = 73). The MMF dose was 1000 mg twice daily, target CsA trough levels were 150 ng/ml, and Pred dose was 0.10 mg/kg per d. Follow-up was until 24 mo after RTx. Biopsy-proven acute rejection occurred in 14 (22%) of 63 patients after CsA withdrawal compared with 3 (4%) of 76 in the Pred withdrawal group (P = 0.001) and 1 (1.4%) of 73 in the control group (P = 0.0001). Biopsy-proven chronic rejection was present in one patient in the control group, in nine patients after CsA withdrawal (P = 0.006 versus control group); and in four patients after discontinuation of Pred (NS). Graft loss occurred in two versus one patient after CsA or Pred withdrawal, respectively, and in two patients in the control group (NS). Patients who successfully withdrew CsA had a significantly lower serum creatinine during follow-up. Pred withdrawal resulted in a reduction in mean arterial pressure, and the total cholesterol/HDL ratio increased. In conclusion, rapid CsA withdrawal at 6 mo after RTx results in a significantly increased incidence of biopsy-proven acute and chronic rejection. Pred withdrawal was safe and resulted in a reduction in mean arterial pressure. However, patient and graft survival and renal function 2 yr after RTx were not different among groups.

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Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Withdrawal of Cyclosporine or Prednisone Six Months after Kidney Transplantation in Patients on Triple Drug Therapy

Gregoor¹,

Sévaux

Ligtenberg

et al. 2002

Journal of the American Society of Nephrology

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141

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“…8,9 There are limited data regarding whether different immunosuppressive regimens after heart transplantation may have a significant impact on progression of CAV. 10 It has been shown that the calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506), which cannot prevent CAV, 5,11 can induce endothelial dysfunction and hypertension, 12,13 which has been explained by an increase in vascular reactive oxygen species (ROS) formation. 14, 15 In contrast to this, the inhibitor of inosine monophosphate dehydrogenase (IMPDH), mycophenolate mofetil, or its active metabolite, mycophenolate acid (MPA), have been associated with positive effects on atherosclerosis or hypertension in animal models.…”

mentioning

confidence: 99%

Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

Krötz

Keller²,

Derflinger³

et al. 2007

Hypertension

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Abstract-Endothelial dysfunction precedes hypertension and atherosclerosis and predicts cardiac allograft vasculopathy and death in heart transplant recipients. Endothelial overproduction of reactive oxygen species, such as superoxide anions produced by NAD(P)H oxidase, induces endothelial dysfunction. Because immunosuppressive drugs have been associated with increased reactive oxygen species production and endothelial dysfunction, we sought to elucidate the underlying mechanisms. Reactive oxygen species, release of superoxide anions, and NAD(P)H oxidase activity were studied in human umbilical vein endothelial cells and in polymorphonuclear neutrophils. Gp91ds-tat was used to specifically block NAD(P)H oxidase. Transcriptional activation of different subunits of NAD(P)H oxidase was assessed by real-time RT-PCR. Rac1 subunit translocation and activation were studied by membrane fractionation and pull-down assays. Calcineurin inhibitors significantly increased endothelial superoxide anions production because of NAD(P)H oxidase, whereas mycophenolate acid (MPA) blocked it. MPA also attenuated the respiratory burst induced by neutrophil NAD(P)H oxidase. Because transcriptional activation of NAD(P)H oxidase was not affected, but addition of guanosine restored endothelial superoxide anions formation after MPA treatment, we speculate that the inhibitory effect of MPA was mediated by depletion of cellular guanosine triphosphate content. This prevented activation of Rac1 and, thus, of endothelial NAD(P)H oxidase. Because all heart transplant recipients are at risk for cardiac allograft vasculopathy development, these differential effects of immunosuppressants on endothelial oxidative stress should be considered in the choice of immunosuppressive drugs.

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“…Initially, several authors reported their retrospective experience of the conversion from CsA to MMF in patients who developed CsA nephrotoxicity, showing a significant improvement of renal function without AR after CsA withdrawal (5)(6)(7). In stable renal transplant recipients, CsA withdrawal under MMF was also found to be a safe procedure on the basis of the risk of AR and renal function (8,9), although histologic deterioration was observed in 50% of patients (10). Finally, the incidence of AR after CsA discontinuation under MMF was evaluated in three randomized trials (11)(12)(13).…”

mentioning

confidence: 99%

Predictive Factors of Acute Rejection after Early Cyclosporine Withdrawal in Renal Transplant Recipients Who Receive Mycophenolate Mofetil

Hazzan¹,

Labalette²,

Copin³

et al. 2005

Journal of the American Society of Nephrology

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The aim of this randomized, open-labeled trial was to compare the incidence of acute rejection after an early (3 mo posttransplantation) withdrawal of cyclosporine (CsA) or mycophenolate mofetil (MMF) in renal transplantation. Among 218 eligible recipients, 108 nonsensitized, rejection-free patients who were under a triple drug regimen (CsA-MMF-prednisone) and had received a first kidney from a deceased donor were enrolled. At 3 mo after graft, they were gradually withdrawn from CsA (MMF group, n ‫؍‬ 54) or MMF (CsA group, n ‫؍‬ 54). A graft biopsy and a pharmacokinetic study of CsA and mycophenolic acid were systematically performed before the randomization. At 1 yr, graft and patient survival rates were 100% in each group. Renal function was improved in the MMF group compared with the CsA group (Cockcroft calculated clearance 64.7 ؎ 18.7 versus 56.5 ؎ 18.0 ml/min; P ‫؍‬ 0.023). However, the probability of acute rejection was higher in the MMF group (18.5 versus 5.6%; P ‫؍‬ 0.045). The 10 patients who developed acute rejection after CsA withdrawal had a significantly higher incidence of borderline changes on the randomization biopsy than the 44 rejection-free patients (five of 10 versus eight of 44; P ‫؍‬ 0.034), and they displayed a lower area under the curve of mycophenolic acid (43 ؎ 9 versus 58 ؎ 22 mg/h per L; P ‫؍‬ 0.045). Multivariate analysis confirmed that borderline changes and area under the curve of mycophenolic acid were significant risk factors of acute rejection after CsA discontinuation. It is concluded that a systematic graft biopsy and a pharmacokinetic study of mycophenolic acid are needed to reduce the risk for acute rejection after CsA withdrawal.

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Conversion to Mycophenolate Mofetil in Conjunction With Stepwise Withdrawal of Cyclosporine in Stable Renal Transplant Recipients1

Abstract: The stepwise switch from CsA to MMF was safe and mostly successful, and had beneficial effects on blood pressure, glomerular hemodynamics, and lipid profile. Beneficial trends were already present after partial withdrawal of CsA.

Cited by 67 publications

References 65 publications

Withdrawal of Cyclosporine or Prednisone Six Months after Kidney Transplantation in Patients on Triple Drug Therapy

Withdrawal of Cyclosporine or Prednisone Six Months after Kidney Transplantation in Patients on Triple Drug Therapy

Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

Predictive Factors of Acute Rejection after Early Cyclosporine Withdrawal in Renal Transplant Recipients Who Receive Mycophenolate Mofetil

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