To systematically evaluate the clinical consequences of mycophenolate dose reduction in renal transplant recipients on tacrolimus-based regimens.
DATA SOURCES:
PubMed (1949-July 2010), EMBASE (1980-July 2010), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Web of Science were searched using the terms mycophenolate mofetil, tacrolimus, dose reduction, and kidney and/or renal transplant. References from publications identified were reviewed.
STUDY SELECTION AND DATA EXTRACTION:
Studies reporting on rejection rate, allograft survival, or renal function were included and ranked according to the US Preventive Services Task Force classification; excluded were studies that were dose-finding or used cyclosporine only, involved patients on enteric-coated mycophenolate sodium or those with multiorgan transplant, or provided no information on concomitant immunosuppressants. Data extracted were study design, sample size, immunosuppression regimen, type of transplant, and allograft outcomes.
DATA SYNTHESIS:
Of 13 studies included, 1 was level I evidence, 3 were level II-2, 6 were level II-3, and 3 were level III evidence. Three focused on tacrolimus-based regimens, whereas 7 included either cyclosporine or tacrolimus. The only prospective, randomized, multicenter trial demonstrated that early taper of mycophenolate dosage to 1 g/day can be utilized without increased risk of rejection, compared with late tapering, but the rejection rate was high (30–40%). Overall, we found conflicting evidence regarding the impact of mycophenolate dose reduction on rejection rate and allograft loss and that discontinuing mycophenolate led to an increased risk of graft loss as high as 8 fold. Allograft survival was lowest in patients with gastrointestinal complications and those in whom mycophenolate was discontinued, compared with patients with neither gastrointestinal complications nor mycophenolate discontinuation.
CONCLUSIONS:
Weak evidence suggests that mycophenolate dose modifications, either reduction or discontinuation, may increase rejection rate and graft loss; however, this is more apparent in cyclosporine-based regimens. Prospective, well-designed trials are necessary to definitively determine the impact of dose reduction in renal transplant recipients on tacrolimus-based regimens.
HardingerK LKochM JBrennanD C. Current and future immunosuppressive strategies in renal transplantation. Pharmacotherapy2004; 24: 1159–76.
2.
Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection.European Mycophenolate Mofetil Cooperative Study Group. Lancet1995; 345: 1321–5.
3.
A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation.The Tri-continental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation1996; 61: 1029–37.
4.
SollingerH W. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation1995; 60: 225–32.
5.
HalloranPMathewTTomlanovichSGrothCHooftmanLBarkerC.Mycophenolate mofetil in renal allograft recipients: A pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation1997; 63: 39–47.
6.
OjoA OMeier-KriescheH UHansonJ A. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation2000; 69: 2405–9.
7.
GastonR SKaplanBShahT. Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: The Opticept trial. Am J Transplant2009; 9: 1607–19.
8.
Le MeurYBuchlerMThierryA. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant2007; 7: 2496–503.
9.
Van GelderTSilvaH TDe FijterJ W. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: The fixed-dose concentration-controlled trial. Transplantation2008; 86: 1043–51.
10.
HalloranP F. Immunosuppressive drugs for kidney transplantation. N Engl J Med2004; 351: 2715–29.
11.
Meier-KriescheH ULiSGruessnerR W. Immunosuppression: Evolution in practice and trends, 1994–2004. Am J Transplant2006; 6: 1111–31.
12.
KnollG ABellR C. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: Meta-analysis of randomised trials. BMJ1999; 318: 1104–7.
13.
ShapiroRJordanMScantleburyV. FK 506 in clinical kidney transplantation. Transplant Proc1991; 23: 3065–7.
14.
MayerA D. Chronic rejection and graft half-life: Five-year follow-up of the European Tacrolimus Multicenter Renal Study. Transplant Proc2002; 34: 1491–2.
15.
GonwaTJohnsonCAhsanN. Randomized trial of tacrolimus + mycophenolate mofetil or azathioprine versus cyclosporine + mycophenolate mofetil after cadaveric kidney transplantation: Results at three years. Transplantation2003; 75: 2048–53.
16.
KnollG AMacDonaldIKhanAVan WalravenC.Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol2003; 14: 2381–6.
17.
PascualJOcanaJMarcenR. Mycophenolate mofetil tolerability and dose changes in tacrolimus-treated renal allograft recipients. Transplant Proc2006; 38: 2398–9.
18.
PelletierR PAkinBHenryM L. The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant2003; 17: 200–5.
19.
TierceJ CPorterfield-BaxaJPetrillaA AKilburgAFergusonR M. Impact of mycophenolate mofetil (MMF)-related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients. Clin Transplant2005; 19: 779–84.
20.
PietruckFBuddeKSalvadoriM. Efficacy and safety of enteric-coated mycophenolate sodium in renal transplant patients with diabetes mellitus: Post hoc analyses from three clinical trials. Clin Transplant2007; 21: 117–25.
21.
SalvadoriMHolzerHDe MattosA. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant2004; 4: 231–6.
22.
De JongeHNaesensMKuypersD R. New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: Possible consequences for therapeutic drug monitoring in solid organ transplantation. Ther Drug Monit2009; 31: 416–35.
23.
U.S. Preventive Services Task Force. Guide to clinical preventive services: Report of the U.S.Preventive Services Task Force. 2nd ed. Baltimore: Williams & Wilkins, 1996; 861–2.
24.
WalkerRThomasMGoodmanDCampbellSChadbanS.Combination therapy with tacrolimus and mycophenolate mofetil: Effects of early and late minimization of mycophenolate mofetil after renal transplant. Clin Transplant2008; 22: 594–602.
25.
BadowskiMGurk-TurnerCCangroC. The impact of reduced immunosuppression on graft outcomes in elderly renal transplant recipients. Clin Transplant2009; 23: 930–7.
26.
PascualJVan HooffJ PSalmelaKLangPRigottiPBuddeK.Three-year observational follow-up of a multicenter, randomized trial on tacrolimus-based therapy with withdrawal of steroids or mycophenolate mofetil after renal transplant. Transplantation2006; 82: 55–61.
27.
VanrenterghemYVan HooffJ PSquiffletJ P. Minimization of immunosuppressive therapy after renal transplantation: Results of a randomized controlled trial. Am J Transplant2005; 5: 87–95.
28.
BunnapradistSLentineK LBurroughsT E. Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure. Transplantation2006; 82: 102–7.
29.
HardingerK LBrennanD CLowellJSchnitzlerM A. Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil. Transpl Int2004; 17: 609–16.
30.
MachnickiGRicciJ FBrennanD CSchnitzlerM A. Economic impact and long-term graft outcomes of mycophenolate mofetil dosage modifications following gastrointestinal complications in renal transplant recipients. Pharmacoeconomics2008; 26: 951–67.
31.
OpelzGDohlerB.Effect on kidney graft survival of reducing or discontinuing maintenance immunosuppression after the first year posttransplant. Transplantation2008; 86: 371–6.
32.
TakemotoS KPinskyB WSchnitzlerM A. A retrospective analysis of immunosuppression compliance, dose reduction and discontinuation in kidney transplant recipients. Am J Transplant2007; 7: 2704–11.
33.
KahuJKyllonenLSalmelaK.Impact of mycophenolate mofetil intolerance on early results of kidney transplantation. Transplant Proc2005; 37: 3276–9.
34.
ZhuQ GZhaoY KLiuWLuoHQiuYGaoZ Z. Two-year observation of a randomized trial on tacrolimus-based therapy with withdrawal of steroids or mycophenolate mofetil after renal transplantation. Chin Med Sci J2008; 23: 244–8.
35.
KhosroshahiH TNahaliAGojazadehMShojaM M. Comparison of transplanted kidney function in patients on two different doses of mycophenolate mofetil. Transplant Proc2006; 38: 2035–7.
36.
KaushikMKayM DBagulANicholsonM L. Morbidity rates with reduced mycophenolate mofetil dosage: A single-center experience. Transplant Proc2006; 38: 2864–5.
37.
SquiffletJ PBackmanLClaessonK. Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients. Transplantation2001; 72: 63–9.
38.
MillerJMendezRPirschJ DJensikS C. Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant Study Group. Transplantation2000; 69: 875–80.
39.
LamSPartoviNTingL S LEnsomM H H. Corticosteroid interactions with cyclosporine, tacrolimus, mycophenolate, and sirolimus: Fact or fiction?Ann Pharmacother2008; 42: 1037–47. DOI 10.1345/aph.1K628.
40.
CiancioGBurkeG WGaynorJ J. Randomized trial of mycophenolate mofetil versus enteric-coated mycophenolate sodium in primary renal transplant recipients given tacrolimus and daclizumab/thymoglobulin: One year follow-up. Transplantation2008; 86: 67–74.
41.
CooperMDeeringK LSlakeyD P. Comparing outcomes associated with dose manipulations of enteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients. Transplantation2009; 88: 514–20.
42.
SollingerH WSundbergA KLeversonGVossB JPirschJ D. Mycophenolate mofetil versus enteric-coated mycophenolate sodium: A large, single-center comparison of dose adjustments and outcomes in kidney transplant recipients. Transplantation2010; 89: 446–51.
43.
KnightS RMorrisP J. Does the evidence support the use of mycophenolate mofetil therapeutic drug monitoring in clinical practice? A systematic review. Transplantation2008; 85: 1675–85.
44.
ZafraniLTruffautLKreisH. Incidence, risk factors and clinical consequences of neutropenia following kidney transplantation: A retrospective study. Am J Transplant2009; 9: 1816–25.
