Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the rapamune maintenance regimen study1 2

Oberbauer, Rainer; Kreis, Henri; Johnson, Robert W.; Mota, A.; Claesson, Kerstin; Ruiz, J.C.; Wilczek, H; Jamieson, Neville V.; Henriques, António Castro; Pączek, Leszek; Chapman, Jeremy R.; Burke, James T.

doi:10.1097/01.tp.0000074360.62032.39

Cited by 177 publications

(106 citation statements)

References 14 publications

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“…As a result, the strategy of CNI elimination, which comprised the vast majority of the Withdrawal cohort, may not produce similar outcomes in patients on more standard CNI/MMFbased immunosuppression (28,29). There are other limitations of this study.…”

Section: Discussionmentioning

confidence: 78%

Aggressive Immunosuppression Minimization Reduces Graft Loss Following Diagnosis of BK Virus-Associated Nephropathy

Weiss¹,

Gralla²,

Chan³

et al. 2008

Clinical Journal of the American Society of Nephrology

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Results: Of 910 kidney transplants, 35 (3.8%) cases of BKVAN were diagnosed at a median of 15 months after transplant (range, 5.5 to 90 months after transplant), 16 (46%) of which progressed to graft failure at a median of 11 months (range, 2 to 36 months) after diagnosis. Depleting antibody induction was a significant risk factor for graft loss on univariate analysis, whereas early drug withdrawal (<1 mo following diagnosis) protected against graft loss. On multivariate analysis, these findings were independent predictors of graft outcomes. Additionally, when patients were comanaged by referring nephrologists and the transplant center before the diagnosis of BKVAN, the risk of graft loss was 11-fold higher (P ‫؍‬ 0.03) than if patients were managed solely by the transplant center.Conclusions: Increased awareness and early diagnosis of BKVAN, with aggressive tapering of immunosuppression once established, is critical to preserve kidney graft function. Early drug withdrawal to low-dose two-drug therapy maintenance may be preferable to a general reduction of agents.

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Section: Discussionmentioning

confidence: 78%

Aggressive Immunosuppression Minimization Reduces Graft Loss Following Diagnosis of BK Virus-Associated Nephropathy

Weiss¹,

Gralla²,

Chan³

et al. 2008

Clinical Journal of the American Society of Nephrology

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“…Because of its power to suppress acute rejections, the substance is currently under investigation in calcineurin-inhibitor-sparing regimens after kidney transplantation. Replacement of the nephrotoxic agents by rapamycin might reduce the risk for chronic allograft dysfunction and could thereby lead to an overall improvement of kidney graft survival [3,4]. However, many physicians express their concerns that the withdrawal of calcineurin inhibitors, which have substantially contributed to the success of organ transplantation in general, might put their patients at risk of insufficient immunosuppression.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy

Dittrich¹,

Schmaldienst²,

Soleiman³

et al. 2004

Transplant International

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Rapamycin is a new immunosuppressive agent approved for maintenance therapy after kidney transplantation. It may allow calcineurin-inhibitor-free, nonnephrotoxic immunosuppression. We report, however, on four kidneytransplant recipients who developed post-transplantation glomerulonephritis after conversion from a calcineurin-inhibitor-based immunosuppression to rapamycin. In all four patients nephrotic-range proteinuria occurred 2-9 months after conversion to rapamycin. Renal biopsy confirmed membrano-proliferative glomerulonephritis type 1 in one case, membranous glomerulonephritis in another and IgA-nephropathy in two cases, respectively. Calcineurin-inhibitorbased immunosuppression was reintroduced and resulted in complete remission of proteinuria and in stabilised renal function in all patients. We conclude that in the case of rapamycin-associated post-transplantation glomerulonephritis an attempt should be made to replace rapamycin by a calcineurin inhibitor.

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“…3 This complication was surprisingly not reported in de novo trials using SRL before approval for clinical use, but the reason for that was that this parameter was not evaluated in those trials. Especially the Rapamune Maintenance Regimen (RMR) trial demonstrated a significant improvement in renal function after early cyclosporine (CyA) elimination in a regimen including SRL, a better pathological profile at 3 years postransplant and better graft survival at 4 years postransplant [5][6][7][8] …”

mentioning

confidence: 99%

Early Sirolimus Use With Cyclosporine Elimination Does Not Induce Progressive Proteinuria

Ruiz

Campistol

Fructuoso³

et al. 2007

Transplantation Proceedings

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Proteinuria has been reported in several papers after conversion from calcineurin inhibitors to Sirolimus (SRL), but this complication has not been analyzed in randomized clinical trials using de novo SRL. It is not known whether de novo use of SRL is a risk factor for proteinuria. We analyzed a series of patients included in a big multicenter randomized trial (RMR trial) corresponding to all patients in Spain and Portugal with respect to this issue. We retrospectively evaluated 24-hour proteinuria in all the patients during the study period (5 years postransplant) for comparison between treatment arms group A, continuous cyclosporine (CyA) ϩ SRL and group B SRL with CyA elimination at 3 months postransplant. The elimination of CyA after the third month was not followed by significant changes in proteinuria. Nevertheless, during the last year of follow-up (between 48 and 60 months postransplant) an impressive increase in proteinuria was observed in group A. This surprising finding seemed to be a consequence of a protocol amendment that recommended CyA elimination in patients of group A, due to poorer results in the intermediate analysis of the trial. This fact suggests that the hemodynamic changes induced by elimination of the vasoconstrictor CyA might be responsible for the proteinuria but only in the long term probably when significant pathological lesions are already present. This finding argues for earlier conversion.S IROLIMUS (SRL) conversion after the initial postransplant phase has been frequently associated with increasing proteinuria (PU) in a significant number of patients either in the case of renal transplant recipients or in the recipients of other solid organs. [1][2][3] The mechanism of appearance of this complication is unclear. Various hypotheses have been proposed, namely, a direct tubular toxicity and especially hemodynamic effects derived from calcineurin inhibitor (CNI) elimination, ie. increased glomerular pressure due to afferent vasodilatation. 4 This complication is reversible in most cases and PU returns to preconversion values after SRL elimination and CNI reintroduction. 3 This complication was surprisingly not reported in de novo trials using SRL before approval for clinical use, but the reason for that was that this parameter was not evaluated in those trials. Especially the Rapamune Maintenance Regimen (RMR) trial demonstrated a significant improvement in renal function after early cyclosporine (CyA) elimination in a regimen including SRL, a better pathological profile at 3 years postransplant and better graft survival at 4 years postransplant 5-8 when compared with the control group who maintained CyA treatment. The objective of this work was to analyze the evolution of PU after early CyA withdrawal in a combination of CyA ϩ SRL compared with a control arm with continuous CyA ϩ SRL.

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Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the rapamune maintenance regimen study1 2

Abstract: Data at 2 years confirm that early CsA withdrawal followed by an SRL-ST maintenance regimen results in long-term improvement in both renal function and blood pressure, without increased risk of graft loss or late acute rejection.

Cited by 177 publications

References 14 publications

Aggressive Immunosuppression Minimization Reduces Graft Loss Following Diagnosis of BK Virus-Associated Nephropathy

Aggressive Immunosuppression Minimization Reduces Graft Loss Following Diagnosis of BK Virus-Associated Nephropathy

Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy

Early Sirolimus Use With Cyclosporine Elimination Does Not Induce Progressive Proteinuria

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