30-Year Retrospective on Organ
Transplant Immunosuppression in the
Era of Calcineurin Inhibitors
Herwig-Ulf Meier-Kriesche, MD
Professor of Medicine
Department of Nephrology
University of Florida College of Medicine
Director of Kidney Transplant Program
Department of Transplant Nephrology, Shands
University of Florida
Gainesville, Florida
Sundus Lodhi, MD
Clinical Fellow
Division of Nephrology, Hypertension and Transplantation
University of Florida
Gainesville, Florida
Early Clinical Trial Demonstrating Improved 1-Year
Allograft Survival in Cyclosporine-Treated
Deceased-Donor Kidney Transplant Recipients
Data from Starzl TE, et al. Surg Gynecol Obstet. 1981;153:486-494.
5-Year Comparison of Tacrolimus With
Cyclosporine in Kidney Transplantation
The Kaplan-Meier
estimates of 5-year patient
and allograft survival rates
were equivalent
in the tacrolimus and
cyclosporine treatment
arms.
Data from Vincenti F, et al. Transplantation. 2002;73:775-782.
Chronology of Approval of Maintenance and
Induction Agents for Use in Solid Organ
Transplantation
Trends in the Use of Approved Maintenance
Immunosuppressive Agents in the Modern Era
Organ Procurement Transplantation Network/Scientific Registry of
Transplant Recipients. OPTN/SRTR Annual Report.
Trends in the Use of Approved Induction
Agents in the Modern Era
Organ Procurement Transplantation Network/Scientific Registry of
Transplant Recipients. OPTN/SRTR Annual Report.
Daclizumab vs Placebo
Data from Nashan B, et al. Transplantation. 1999;67:110-115.
Cox Model Hazard Estimates of Relative Risk
for Overall Allograft Loss by Donor Type
Data from Meier-Kriesche HU, et al. Am J Transplant. 2004;4:378-383.
Overall Unadjusted Graft Survival Rates by
Renal Functiona Status After Acute Rejection
aEstimated
glomerular filtration rate
Data from Meier-Kriesche HU, et al. Am J Transplant. 2004;4:378-383.
Survival Trends in Long-term Primary
Deceased-Donor Kidney Transplants
Data from Gjertson DW. Clin Transpl. 1991:225-235.
Overall Allograft Survival in Primary
Deceased-Donor Kidney Transplants
Data from Meier-Kriesche H-U, et al. Am J Transplant. 2004;4:1289-1295.
Overall Allograft Survival Rates by Discharge
Immunosuppressive Regimen for Deceased-Donor
Kidney Transplants
Data from Srinivas TR, et al. Am J Transplant. 2007;7:586-594.
Early Cyclosporine Withdrawal From a
Sirolimus-Based Regimen
Data from Oberbauer R, et al. Transpl Int. 2005;18:22-28.
SYMPHONY Study: Reduced Exposure to
Calcineurin Inhibitors in Kidney Transplantation
SYMPHONY = Efficacy Limiting Toxicity Elimination (ELITE) SYMPHONY
The dashed lines represent the upper and lower limits of the respective
target trough levels.
Data from Ekberg H, et al. N Engl J Med. 2007;357:2562-2575.
SYMPHONY Study Results
Endpoint
Group A
Group B
Group C
eGFR (mL/min) at 12 mo
57.1
59.4
65.4
56.7
P < .001
BPAR (%)
25.8
24.0
12.3
37.2
P < .001
Allograft survival (%)
89.3
93.1
94.2
89.3
P = .02
BPAR = biopsy-proven acute rejection
Ekberg H, et al. N Engl J Med. 2007;357:2562-2575.
Group D P value
Spare-the-Nephron Trial Results*
Aim: Evaluate the efficacy and safety of a maintenance
immunosuppressive regimen of MMF and SRL compared with
MMF and a CNI in kidney allograft recipients
Endpoints
Group A
Group B
P value
BPAR (%)
6.5
7.1
ND
Allograft loss (%)
1.6
2.4
ND
0
2.4
ND
25.8
11.3
ND
Death (%)
Change in GFR (%)
ND = data not provided
*The authors concluded that MMF/SRL maintenance therapy appears to be associated with
improved renal function when compared with MMF/CNI-containing regimens without
increasing the risk for acute rejection and is tolerated in almost 80% of patients.
Pearson TC, et al. Am J Transplant. 2008;8(suppl 2):213.
CONCEPT Study
Aim: Evaluate conversion from a CsA-based regimen to a
SRL-based regimen 3 months after transplantation
Endpoints
Group A
Group B
P value
eGFR (mL/min)
64.4
68.9
P = .017
BPAR
8.2
16.8
NS
Lebranchu Y, et al. Am J Transplant. 2009;9:1115-1123.
CONVERT Trial Resultsa
Aim: Evaluate the efficacy and safety of converting
maintenance
Endpoint
Group A
Group B
P value
GFR (mL/min)
59.9
62.6
P = .009
BPARb
1.6
2.6
NS
Allograft survivalb
98
96.8
NS
99.2
97.8
NS
Patient survivalb
aOn-therapy
patients with baseline GFR > 40 mL/min
b% of patients who met composite and individual safety endpoints at 12 months after
randomization
Note: Enrollment in the 20- to 40-mL/min stratum was halted prematurely due to a
higher incidence of safety endpoints in the SRL conversion arm.
Schena FP, et al. Transplantation. 2009;87:233-242.
CAESAR Trial Results
Aim: Evaluate CNI withdrawal under MMF-based
immunosuppression
Endpoints
Group A Group B Group C P value
Mean eGFR (mL/min/1.73 m2)
50.9
50.9
48.6
NS
Measured GFR at 3 mo
(mL/min/1.73 m2)
49.6
49.0
45.4
NS
Serum creatinine at 12 mo
1.7
1.5
1.6
NS
27.5
P = .027a
P = .040b
BPAR (%) at 12 mo
aGroup
38
A vs Group B
bGroup A vs Group C
Ekberg H, et al. Am J Transplant. 2007;7:560-570.
25.4
Low-Dose Steroid Therapy: The Canadian
Multicentre Transplant Study Group
Data from Sinclair NR. CMAJ. 1992;147:645-657.
Chronic Low-Dose Steroid Therapy
Data from Woodle ES, et al. Ann Surg. 2008;248:564-577.
FREEDOM Study Results
Aim: Demonstrate noninferiority of 12-month GFR in the
steroid-free or steroid-withdrawal groups vs standard steroids
Endpoint
Group A Group B Group C P value
GFR (mL/min/1.73 m2)
58.6
59.1
60.8
NS
Composite endpoint at 3 mo
27.9
--
11.0
P = .032
BPAR at 3 mo
25.2
18.3
7.3
P = .017
Vincenti F, et al. Am J Transplant. 2008;8:307-316.
Emerging Therapy − The BENEFIT Study:
Belatacept-Based Immunosuppression Regimens
vs Cyclosporine in Kidney Transplant Recipients
Data from Vincenti F, et al. Am J Transplant. 2010;10:535-546.
Emerging Therapy − CP-690,550 in Kidney Allograft
Recipients
Data from Busque S, et al. Am J Transplant. 2009;9:1936-1945.