In patients undergoing renal transplantation, what is the comparative effectiveness of four immunosuppressive regimens in the maintenance of graft function at 12 months?
Among kidney transplant recipients, immunosuppression with a regimen including low-dose tacrolimus led to higher eGFR, higher rates of graft survival, and lower rates of rejection at 12 months, when compared to three other regimens.
Immunosuppression reduces the incidence of acute allograft rejection among patients who have undergone kidney transplantation. Many immunosuppressive agents are available. Cyclosporine (CsA) and tacrolimus (FK506) are calcineurin inhibitors (CNIs) that are associated with nephrotoxicity, hypertension, and hyperlipidemia. Sirolimus (SRL) is an mTOR inhibitor associated with thrombocytopenia, diarrhea, hyperlipidemia, and delayed wound healing. Mycophenolate mofetil (MMF) is an antimetabolite that inhibits B- and T-cell proliferation and is associated with bone marrow suppression and diarrhea. The optimal immunosuppressive regimen and dose intensity has been up for debate.
Published in 2007, the Efficacy Limiting Toxicity Elimination-Symphony trial (ELITE-Symphony) was an industry-sponsored study designed to test the efficacy and toxicity of low-dose CNIs or a low-dose mTOR inhibitor (SRL). Patients were randomized to standard dose CsA, low-dose CsA, low-dose FK506, or low-dose SRL in an open-label design. All patients were maintained on MMF and all groups except standard dose CsA received induction with daclizumab. (The group providing funding sells both MMF and daclizumab.) Patients treated with low-dose FK506 showed the lowest risk of nephrotoxicity and also had fewer rejection episodes and greater graft survival at 12 months. This group had the highest risk of new-onset diabetes post transplant (NODAT).
This trial was criticized for low enrollment of black patients, uneven loss to follow-up, lack of a FK506 standard dose group, and lack of a duration of follow-up that was clinically meaningful.
KDIGO care of kidney transplant recipients (2009, adapted)
- Maintenance therapy with combination CNI, an antiproliferative agent, +/- corticosteroids (1B)
- Antiproliferative agents include MMF or azathioprine
- Suggest FK506 as first-line CNI (2A)
- Suggest MMF as first-line antiproliferative (2B)
- If an mTOR inhibitor is used, it shouldn't be started until after graft function is established and operative wounds have healed (1B)
- Multicenter, open-label, parallel-group, randomized, controlled trial
- Standard-dose CsA (n=410)
- Low-dose CsA (n=413)
- Low-dose FK506 (n=411)
- Low-dose SRL (n=411)
- Setting: 83 centers in 15 countries
- Enrollment: 2002-2004
- Mean follow-up: 1 year
- Analysis: Intention-to-treat
- Primary outcome: eGFR 12 months following transplantation
- Adults aged 18 to 75 years
- Recipients of either a deceased or living donor renal transplant
- Those with a previous kidney transplant were eligible if they had not lost their previous allograft to acute rejection in the first year post-transplantation
- Multiple organ transplants
- Previous graft lost to acute rejection within the first year
- Need for specific immunosuppression with azathioprine, methotrexate, cyclophosphamide, polyclonal- or monoclonal antibodies, or basiliximab
- Current or historical panel-reactive antibody more than 20%
- Positive cross-match
- Cold-ischemia time more than 30 hours
- Donation after cardiac death transplant
- GI disease preventing medication absorption
- Prior cancer (except non-melanocytic skin cancer)
- Active PUD
- Active liver disease
- Severe leukopenia, anemia, or thrombocytopenia
- Other investigational medication protocol in the prior 3 months
- Demographics: Age 46 years, male sex 65%, white race 93%
- Causes of ESRD:
- Glomerulonephritis: 27%
- Diabetes mellitus: 8%
- Polycystic kidney disease: 13%
- Pyelonephritis/interstitial nephritis: 9%
- Unknown/Other: 43%
- Typer of donor:
- Deceased: 64%
- Living related: 30%
- Living unrelated: 6%
- Expanded criteria donors: 18%
- Donor age: 45 years
- Antigen mismatches (A, B, and DR): 2.95
- Panel-reactive antibodies >0%: 20%
- Cold-ischemia time (hr): 16.4 hours
- CMV mismatch (donor positive, recipient negative): 13%
- Open randomization one of four immunosuppressive treatment groups in a 1:1:1:1 ratio :
- Standard-dose CsA: 3-5 mg/kg BID titrated to a trough of 150-300 ng/ml initially, then 100-200 ng/ml three months post-transplant
- Low-dose CsA: 1-2 mg/kg BID titrated to a trough level of 50-100 ng/ml throughout the study plus daclizumab induction
- Low-dose FK506: 0.05 mg/kg BID titrated to a trough level of 3-7 ng/ml plus daclizumab induction
- Low-dose SRL: 9 mg per day for three days, then 3 mg per day titrated to a trough level of 4-8 ng/ml plus daclizumab induction
- All patients received MMF 2 grams BID and a tapering dose of corticosteroids
Presented as standard dose CsA vs. low-dose CsA vs. low-dose FK506 vs. low-dose SRL. P value is for overall group comparison.
- eGFR at 12 months
- 57.1 vs. 59.4 vs. 65.4 vs. 56.7 mL/min (P<0.001)
- Biopsy-proven acute rejection
- Excluding borderline cases.
- At 6 months: 24.0% vs. 21.9% vs. 11.3% vs. 35.3% (P<0.001)
- At 12 months: 25.8% vs. 24.0% vs 12.3% vs. 37.2% (P<0.001)
- Allograft survival
- Death censored: 91.9% vs. 94.3% vs. 96.4% vs. 91.7% (P=0.02)
- Death uncensored: 89.3% vs. 93.1% vs. 94.2% vs. 89.3% (P=0.02)
- Overall survival
- 96.5% vs. 98.2% vs. 97.2% v. 96.8% (P=0.53)
- Treatment failure
- 22.8% vs. 20.1% vs. 12.2% vs. 35.8% (P<0.001)
An extensive list of adverse events is presented in Table 3 on pages 2572-2574.
- New-onset diabetes after transplantation
- 6.4% vs. 4.7% vs. 10.6% vs. 7.8% (P=0.02)
- 17.9% vs. 14.4% vs. 27.4% vs. 24.0% (P<0.001)
- Lymphocele within 6 months
- 7.0% vs. 6.8% vs. 4.0% vs. 15.8% (P<0.001)
- 33.0% vs. 28.1% vs. 26.3% vs. 26.6% (P=0.03)
- CMV infection
- 15.3% vs. 11.5% vs. 10.2% vs. 6.5% (P=0.003)
- Low diversity, this is particularly a concern as black patients may require higher doses of immunosuppressants
- An interaction between the medications may have meant that those in the tacrolimus group had higher effective levels of MMF, which may have led to greater efficacy
- 1 year follow-up may not be a clinically meaningful endpoint
- Unclear if limiting initial FK506 dose would reduce toxicities and improve long-term outcomes
- The trough levels of SRL may have been to low
- Imbalances in follow-up may have introduced bias in the primary outcome
- There was no FK506 standard dose group without daclizumab induction
- Hoffmann-La Roche, the manufacturer of Zenapax (the brand name of daclizumab) and CellCept (the brand name of MMF)
- Authors with multiple financial conflicts of interest
- Paul LC. "Chronic allograph nephropathy: An update." Kidney International. 1999;56(3):783-793.
- Kreis H, et al. "Sirolimus in association with mycophenolate mofetil induction for prevention of acute graft rejection in renal allograft recipients." Transplantation. 2000;69(7):1252-1260.
- Knight SR, et al. "Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: A systematic review." Transplantation. 2009;87(6):785-794.
- Leichtman AB. "Editorial: Balancing efficacy and toxicity in kidney-transplant immunosuppression." The New England Journal of Medicine. 2007;357:2625-2627.
- Multiple authors. "Correspondence: Reduced exposure to calcineurin inhibitors in renal transplantation." The New England Journal of Medicine. 2008;358:2518-2520.
- Kasiske BL, Zeier MG, et al. "KDIGO clinical practice guidelines for the care of kidney trasnplant recipients." American Journal of Transplantation. 2009;9(supp 3)s1-s155.