Mycophenolate Mofetil versus Azathioprine for Prevention of Chronic Allograft Dysfunction in Renal Transplantation

Remuzzi, Giuseppe; Cravedi, Paolo; Costantini, Marco; Lesti, Mariadomenica; Ganeva, María; Gherardi, Giulia; Ene-Iordache, Bogdan; Gotti, Eliana; Donato, Daniel; Salvadori, Maurizio; Sandrini, Silvio; Segoloni, Giuseppe; Federico, Stefano; Rigotti, Paolo; Sparacino, Vito; Ruggenenti, Piero

doi:10.1681/asn.2006101153

Cited by 103 publications

(68 citation statements)

References 39 publications

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“…But, given current evidence, azathioprine and mycophenolate mofetil appear to be similar in terms of acute rejection rates and long-term allograft survival rates. 35 Our results could be another evidence for this concept.…”

Section: Discussionsupporting

confidence: 57%

Ten-year graft survival of deceased-donor kidney transplantation: a single-center experience

et al. 2010

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Background: Kidney transplantation is the treatment of choice for end-stage renal disease that restores the patients' quality of life and reduces the morbidity and mortality rates induced by renal failure and its complications. However, after transplantation the organ and patient survival rates are important issues of interest in many centers worldwide. Subjects and methods: This is a historical cohort study planned to determine the organ survival rate after kidney transplantation from deceased donor during a period of 10 years (March 1999-March 2009 in Shiraz Transplant Center, Namazi Hospital, Shiraz, Iran. We tried to clarify the probable contributory risk factors implicating in graft loss. Kaplan-Meier method was used to determine the survival rate. Log-rank test was used to compare survival curves, and Cox regression model to define the hazard ratio and for modeling of factors implicating in survival rate. Results: Mean follow-up period was 37.54 ± 28.6 months. Allograft survival rates at 1, 3, 5, and 9 years after kidney transplantation from deceased donor (calculated by Kaplan-Meier method) was found to be 93.7, 89.1, 82.1, and 80.1%, respectively. Duration of dialysis before operation and creatinine level at discharge were showed to be the most important factors influencing survival rate of renal allograft. Conclusion: Overall long-term graft survival in our cohort is satisfactory and comparable with reports from large centers in the world. Duration of dialysis before operation and creatinine level at discharge are the only independent factors that could correlate with long-term graft survival in our cohort.

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Section: Discussionsupporting

confidence: 57%

Ten-year graft survival of deceased-donor kidney transplantation: a single-center experience

et al. 2010

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“…20 At completion of the first 6-mo treatment period, steroid dosage was progressively tapered and eventually discontinued and patients were then followed for up to month 72 posttransplantation, with clinical and laboratory evaluations every 6 mo. 20,33 Genetic data and any other relevant information were retrieved from the study population without interfering with patient management and were handled according to standard regulations for data registration, use, and preservation of patient anonymity and privacy. The study protocol was approved by the Ethical Committee of the Coordinating Center and of all of the Transplant Centers involved in the study.…”

Section: Methodsmentioning

confidence: 99%

ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

Cattaneo

Ruggenenti

Baldelli

et al. 2009

Journal of the American Society of Nephrology

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Cyclosporine A (CsA) is a substrate of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene. Compared with carriers of the wild-type gene, carriers of T allelic variants in exons 21 or 26 have reduced P-glycoprotein activity and, secondarily, increased intracellular concentration of CsA; therefore, carriers of T variants might be at increased risk for CsA-related adverse events. We evaluated the associations between ABCB1 genotypes (in exons 12, 21, and 26) and CsA-related outcomes in 147 renal transplant recipients who were receiving CsA-based immunosuppression and were included in the Mycophenolate Steroids Sparing study. During a median of 65.5 mo follow-up, carriers of T allelic variants in exons 21 or 26 had a three-fold risk for delayed graft function (DGF), a trend to slower recovery of renal function and lower GFR at study end, and significantly higher incidences of new-onset diabetes and cytomegalovirus reactivation compared with carriers of the wild-type genotype. T variants in both exons 21 and 26 were independently associated with 3.8-and 3.5-fold higher risk for DGF, respectively (P ϭ 0.022 and P ϭ 0.034). The incidence of acute rejection and the mean CsA dose and blood levels were comparable in genotype groups. In conclusion, renal transplant recipients with T allelic variants in ABCB1 exons 21 or 26 are at increased risk for CsA-related adverse events. Genetic evaluation may help to identify patients at risk and to modulate CsA therapy to optimize graft and patient outcomes. The introduction of cyclosporine A (CsA) therapy in the early 1980s opened a new era in organ transplantation. Compared with steroid-and azathioprine-based regimens, immunosuppressive protocols including this inhibitor of calcineurin-a key enzyme involved in T cell activation 1 -decreased the incidence of acute rejections from 40% to 50% to 20% to 30% and increased one-year survival rates of the grafts from 60% to between 80% and 90%. 2 Thirty years later, CsA remains a cornerstone of immunosuppressive therapy for recipients of both renal and nonrenal transplants worldwide. However, standard recommended doses are associ-

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“…Nine trials (eight maintenance studies 88,89,92,[110][111][112]122,148 and one study 148 of both induction and maintenance) reported significant baseline between-group differences for key factors, including PRA grade, number of previous transplants, patient age, pretransplant diabetes mellitus, HLA mismatches and ECD donor kidneys. A further six maintenance studies 91,101,130,133,140,155 were rated as 'partial' because they reported a baseline difference in patient sex.…”

Section: Baseline Characteristicsmentioning

confidence: 99%

“…The remaining trials (one induction study 97 and 20 maintenance studies 75,81,85,91,[99][100][101][102]104,109,110,112,114,115,117,[119][120][121][122]127 ) did not report any information about blinding participants to treatment allocation.…”

Section: Treatment Allocation Masked From Participantsmentioning

confidence: 99%

“…Again, four maintenance studies 58,77,143,150 were rated as 'partial' for clinician blinding because blinding occurred for only a limited time, and one induction study 95 was rated as 'unclear' because, although it was a PBO-controlled trial, no further details were reported about blinding. The other 20 maintenance studies 75,81,85,91,[99][100][101][102]104,109,110,112,114,115,117,[119][120][121][122]127 did not report any details about clinician blinding.…”

Section: Treatment Allocation Masked From Cliniciansmentioning

confidence: 99%

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Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

Jones-Hughes

Snowsill

Haasova

et al. 2016

Health Technol Assess

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BackgroundEnd-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival.ObjectivesTo review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect®, Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin®, Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport®, Sandoz; Capexion®, Mylan; Modigraf®, Astellas Pharma; Perixis®, Accord Healthcare; Prograf®, Astellas Pharma; Tacni®, Teva; Vivadex®, Dexcel Pharma), prolonged-release tacrolimus (Advagraf®Astellas Pharma), belatacept (BEL) (Nulojix®, Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip®, Zentiva; CellCept®, Roche Products; Myfenax®, Teva), mycophenolate sodium (MPS) (Myfortic®, Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune®, Pfizer) and everolimus (EVL) (Certican®, Novartis) as maintenance therapy in adult renal transplantation.MethodsClinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association’s electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time–state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.ResultsEighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY.LimitationsFor included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled.Future workHigh-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome.ConclusionOnly a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000–30,000 per QALY.Study registrationThis study is registered as PROSPERO CRD42014013189.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Mycophenolate Mofetil versus Azathioprine for Prevention of Chronic Allograft Dysfunction in Renal Transplantation

Cited by 103 publications

References 39 publications

Ten-year graft survival of deceased-donor kidney transplantation: a single-center experience

Ten-year graft survival of deceased-donor kidney transplantation: a single-center experience

ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

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