KITxpGL SupplementaryTables

KDIGO CLINICAL PRACTICE GUIDELINE
FOR THE CARE OF

KIDNEY TRANSPLANT RECIPIENTS
SUPPORTING TABLES
November 2009
Supporting Table 1. Evidence Profile Topic 1.2.1: Induction: IL-2 antibody vs. placeboa,b
No. of Total N Methodological Directness of Summary of findings
studies (N on quality of Consistency the evidence Other Quality of
Outcome Importance
and study study studies across studies generalizability/ considerations evidence for Description of effect
design drug) per outcome applicability of outcome
outcome
5 RCTs 584 Some limitations
Not adequately No difference between induction
(High) (300) (–1) No important
No uncertainty powered for the with IL-2 antibody compared to
Mortality inconsistencies Low Critical
(0) outcome no induction/placebo for up to 3
2 SRs Some limitations (0)
2786/1858 (–1) years
(17/8 trials) (–1)

Graft loss inconsistencies Low Critical
2786/1858 (–1) years
(17/8 trials) (–1)
CVD events 0 RCTs Critical

Cancer inconsistencies Low Critical
2786/1858 (–1) years
(17/8 trials) (–1)
5 RCTs 584 Some limitations The incidence of acute rejection
(High) (300) (–1) as well as the incidence of
severe acute rejection is reduced
No important
Acute No uncertainty None in patients treated with IL-2
inconsistencies Moderate High
rejection 2 SRs Some limitations (0) (0) antibody compared to no
2786/1858 (0)
(17/8 trials) (–1) induction/placebo in the first year
after transplantation (but very
limited evidence for children).
No difference between induction
Important
2 RCTs 292 Some limitations Some uncertainty Sparse data with IL-2 antibody compared to
CAN inconsistencies Very low High
(High) (149) (–1) (–1) (–1) no induction/placebo for up to 5
(–1)
years
No important
2 RCTs 292 Some limitations Some uncertainty Sparse data with IL-2 antibody compared to
NODAT inconsistencies Very low High
(High) (149) (–1) (–1) (–1) no induction/placebo for up to 12
(0)
months
studies (N on quality of Consistency the evidence Other Quality of
Outcome Importance
and study study studies across studies generalizability/ considerations evidence for Description of effect
outcome
4 RCTs 476 Some limitations No difference between induction
(High) (248) (–1) with IL-2 antibody compared to
No important
No uncertainty None no induction/placebo for up to 3
Infection inconsistencies Moderate High
2 SRs Some limitations (0) (0) years, especially there is no
2786/1858 (0)
(17/8 trials) (–1) evidence about differences in
CMV-infection
(High) (250) (–1) No important No difference between induction
Delayed graft No uncertainty None
inconsistencies Moderate with IL-2 antibody compared to Moderate
function 1 SR Some limitations (0) (0)
2786 (0) no induction/placebo
(17 trials) (–1)
No important
Kidney 5 RCTs 584 Some limitations No uncertainty None with IL-2 antibody compared to
inconsistencies Moderate Moderate
function (High) (300) (–1) (0) (0) no induction/placebo for up to 12
(0)
months
Serious No important No difference between induction
1 RCT 100 Some uncertainty Sparse data
Proteinuria limitations inconsistencies Very low with IL-2 antibody compared to Moderate
(High) (50) (–1) (–1)
(–2) (0) no induction/placebo
Serious No important No difference between induction
Blood 1 RCT 100 Some uncertainty Sparse data
limitations inconsistencies Very low with IL-2 antibody compared to Moderate
pressure (High) (50) (–1) (–1)
(–2) (0) no induction/placebo
There is no clear evidence that
Adverse 1 RCT 192 induction therapy with an IL-2 Depends on
events (High) (99) antibody is causing more outcome
adverse events than placebo.
Balance of potential benefits and harm: Net benefits Quality of overall evidence:
Treatment with IL-2 antibody is better than placebo for prevention of acute rejection Low (Moderate for acute rejection)
CAN, Chronic allograft nephropathy; CMV, Cytomegalovirus; CNI, Calcineurin inhibitors; CVD, Cardiovascular disease; IL-2, Interleukin-2; N, Number; NODAT, New onset diabetes after transplant; QOL, Quality of life; RCT,
Randomized controlled trials; SR, Systematic review.
Annotations:
a. Overlap with topic 2.5 (steroid avoidance vs. steroid maintenance) and topic 3.1 (CNI low vs. standard dose).
b. References: 1-7
Supporting Table 2. Summary Table Topic 1.2.1: Induction: IL-2 antibody vs. placeboa (categorical outcomes)
No. analyzed (enrolled) Intervention/Control Results
%
Study Concomitant Age Dates of
Outcome Study, year, country deceased P value Quality
duration Arm 1 Arm 2 Arm 1 Arm 2 medication (mean) transplant Arm 1 Arm 2
donor
Mortality
99 93 No Tac/AZA/
6 mo Grenda, 2006,1 EU 6 mo Basiliximab 12 79 2001-04 0% 0% NS fair
(99) (93) Basiliximab Steroids
59 64 CsA-ME/MMF/
12 mo Lawen, 2003,2US, EU 12 mo Basiliximab Placebo 45 73 1998-99 0% 0% NS good
(59) (64) Steroids
50 50 No CsA/AZA/
5y Sheashaa, 2005,3 Egypt 5y Basiliximab 33 0 1998-99 0% 4% NS poor
52 56
12 mo Parrott, 2005,4UK 12 mo Basiliximab Placebo CsA-ME 46 88 <2004 2% 4% NS poor
(52) (56)
40 21 CsA-ME/MMF/
12 mo Pescovitz, 2003,5 US 12 mo Daclizumab Placebo 46 68 <2002 2% 0% NS good
(50) (25) Steroids
Graft loss
99 93 No Tac/AZA/
59 64 CsA-ME/MMF/
12 mo Lawen, 2003,2 US, EU 12 mo Basiliximab Placebo 45 73 1998-99 5% 8% NS good
(59) (64) Steroids
50 50 No CsA/AZA/
5y Sheashaa, 2005,3 Egypt 5y Basiliximab 33 0 1998-99 14% 12% NS poor
52 56
12 mo Parrott, 2005,4 UK 12 mo Basiliximab Placebo CsA-ME 46 88 <2004 12% 12% NS poor
(52) (56)
40 21 CsA-ME/MMF/
(50) (25) Steroids
Cancer
Without PTLD 99 93 No Tac/AZA/ 0% 0% NS fair
Grenda, 2006,1 EU 6 mo Basiliximab 12 79 2001-04
PTLD (99) (93) Basiliximab Steroids 0% 2% NS fair
Without PTLD 59 64 CsA-ME/MMF/ 0% 0% NS good
Lawen, 2003,2 US, EU 12 mo Basiliximab Placebo 45 73 1998-99
PTLD (59) (64) Steroids 0% 0% NS good
50 50 No CsA/AZA/
Kaposi sarcoma Sheashaa, 2005,3 Egypt 5y Basiliximab 33 0 1998-99 2% 4% NS poor
40 21 CsA-ME/MMF/
PTLD Pescovitz, 2003,5 US 12 mo Daclizumab Placebo 46 68 <2002 0% 0% NS good
(50) (25) Steroids
%
donor
Acute rejection
Biopsy-proven 19% 20% NS fair
Severity of AR,
99 93 No Tac/AZA/ 4% 9% nd fair
Banff II or higher Grenda, 2006,1 EU 6 mo Basiliximab 12 79 2001-04
Steroid-resistant 3% 3% NS fair
Time to AR, days 41 43 NS fair
Biopsy-proven
15% 27% NS good
6 mo
Severity of AR,
Banff II or higher 5% 19% nd good
59 64 CsA-ME/MMF/
6 mo Lawen, 2003,2 US, EU 12 mo Basiliximab Placebo 45 73 1998-99
(59) (64) Steroids
Steroid-resistant
5% 16% NS good
6 mo
Time to AR, days <0.01
nd nd fair
4 wk/6 mo <0.05
Acute rejection 36% 62% <0.01
poor
1 y/5 y 54% 72% NS
50 50 No CsA/AZA/
Severity of AR, Sheashaa, 2005,3 Egypt 5y Basiliximab 33 0 1998-99
(50) (50) Basiliximab Steroids 4% 20% <0.01
Banff II or higher poor
6% 22% <0.05
1 y/5 y
52 56
Total Parrott, 2005,4 UK 12 mo Basiliximab Placebo CsA-ME 46 88 <2004 29% 43% NS poor
(52) (56)
Total 40 21 CsA-ME/MMF/ 14% 20% nd fair
Pescovitz, 2003,5 US 12 mo Daclizumab Placebo 46 68 <2002
Biopsy-proven (50) (25) Steroids 14% 16% nd good
Chronic allograft nephropathy and proteinuria
‘Toxic 99 93 No Tac/AZA/
Grenda, 2006,1 EU 6 mo Basiliximab 12 79 2001-04 14% 4% <0.05 fair
nephropathy (99) (93) Basiliximab Steroids
CAN 14% 14% NS poor
CNI-toxicity 50 50 No CsA/AZA/ 6% 8% NS poor
Sheashaa, 2005,3 Egypt 5y Basiliximab 33 0 1998-99
Proteinuria
2% 6% NS poor
>1 g/24 h
NODAT
99 93 No Tac/AZA/
NODAT Grenda, 2006,1 EU 6 mo Basiliximab 12 79 2001-04 5% 2% NS fair
%
donor
50 50 No CsA/AZA/
DM Sheashaa, 2005,3 Egypt 5y Basiliximab 33 0 1998-99 8% 14% NS poor
Infection
Bacterial 32% 32% NS poor
Viral 99 93 No Tac/AZA/ 15% 16% NS poor
UTI (99) (93) Basiliximab Steroids 19% 28% nd fair
CMV 7% 2% NS fair
All 59 64 CsA-ME/MMF/ 63% 70% nd fair
Infection (59) (64) Steroids 14% 19% nd good
UTI 50 50 No CsA/AZA/ 6% 10% NS poor
CMV (50) (50) Basiliximab Steroids 6% 8% NS poor
All 6 mo 20% 16% nd good
40 21 CsA-ME/MMF/
Pescovitz, 2003,5 US 12 mo Daclizumab Placebo 46 68 <2002 8% 0%
CMV 6 mo/12 mo (50) (25) Steroids nd good
18% 0%
Delayed graft function
99 93 No Tac/AZA/
59 64 CsA-ME/MMF/
12 mo Lawen, 2003,2 US, EU 12 mo Basiliximab Placebo 45 73 1998-99 15% 23% NS good
(59) (64) Steroids
52 56
12 mo Parrott, 2005,4 UK 12 mo Basiliximab Placebo CsA-ME 46 88 <2004 19% 38% <0.05 poor
(52) (56)
40 21 CsA-ME/MMF/
(50) (25) Steroids
Kidney function
Scr, µmol/L 99 93 No Tac/AZA/ 91 86 NS fair
eGFR, mL/min (99) (93) Basiliximab Steroids 78 78 NS fair
CrCl, mL/min 59 64 CsA-ME/MMF/ 55 43 <0.05 fair
2 wk/4 wk (59) (64) Steroids nd nd NS poor
Scr, µmol/L 126 128
NS poor
1 y/5 y 50 50 No CsA/AZA/ 152 151
CrCl, mL/min (50) (50) Basiliximab Steroids 75 72
NS poor
1 y/5 y 73 72
%
donor
Scr, µmol/L 40 21 CsA-ME/MMF/

Pescovitz, 2003,5 US 12 mo Daclizumab Placebo 46 68 <2002 133 159 NS good
6 mo (50) (25) Steroids
Hypertension
Hypertension 74% 86% NS poor
50 50 No CsA/AZA/
Blood pressure, Sheashaa, 2005, Egypt 5y Basiliximab 33 0 1998-99
3
(50) (50) Basiliximab Steroids 125/82 125/82 NS poor
mm Hg
Adverse events
99 93 No Tac/AZA/
Anemia Grenda, 2006,1 EU 6 mo Basiliximab 12 79 2001-04 15% 12% NS fair
AE, Adverse events; AR, Acute rejection; AZA, Azathioprine; CAN, Chronic allograft nephropathy; CMV, Cytomegalovirus; CNI, Calcineurin inhibitors; CrCl, Creatinine clearance; CsA, Cyclosporine; CsA-ME, Cyclosporine
microemulsion; DM, Diabetes mellitus; eGFR, Estimated glomerular filtration rate; EU, Europe; GFR, Glomerular filtration rate; IL-2, Interleukin-2; MMF, Mycophenolate mofetil; nd, Not documented; NODAT, New onset diabetes
after transplantation; NS, Not significant; PTLD, Posttransplant lymphoproliferative disease; SCr, Serum creatinine; Tac, Tacrolimus; UK, United Kingdom; US, United States; UTI, Urinary tract infection.
Annotations:
a. Induction: IL-2 antibody vs. Placebo: similar intervention, but categorized in different topics: (A) Topic 2.5 “Steroid avoidance” Rostaing 20058 and terMeulen 2004 9; (B) Topic 3.1 “CNI low vs. standard dose” Ekberg 2007,10
“ELITE Symphony” and Ekberg 2007,11 “CAESAR”
Supporting Table 3. Summary Table Topic 1.2.1: Induction: IL-2 antibody vs. placeboa (continuous outcomes)
No. analyzed
Intervention/Control Results
Study, year, Study (enrolled) Concomitant Age % deceased Dates of P
Outcome Quality
country duration medication (mean) donor transplant Baseline ∆ value
Arm 1 Arm 2 Arm 1 Arm 2
(Control) (Control)
Kidney function
Scr, µmol/L 52 56 150 +9/–9
Parrott, 2005,4 UK 12 mo Basiliximab Placebo CsA-ME 46 88 <2004 nd poor
6 mo/12 mo (52) (56) (234) (–60/–70)
CsA-ME, Cyclosporine microemulsion; IL-2, Interleukin-2; nd, Not documented; SCr, Serum creatinine; UK, United Kingdom.
Annotations:
a. Induction: IL-2 antibody vs. Placebo: similar intervention, but categorized in different topics: (A) Topic 2.5 “Steroid avoidance” Rostaing 20058 and terMeulen 20049; (B) Topic 3.1 “CNI low vs. standard dose” Ekberg 2007,10
“ELITE Symphony” and Ekberg 2007,11“CAESAR”
Supporting Table 4. Summary Table Topic 1.2.1: Induction—Depleting antibody vs. placebo (categorical outcomes)a
Study, year, Study Concomitant Age % deceased Dates of
Outcome P value Quality
country duration Am 1 Arm 2 Arm 1 Arm 2 Medication (mean) donor transplant Arm 1 Arm 2
Mortality
Charpentier 186 185 Tac/AZA/
6 mo 6 mo ATG No ATG 45 100 <2003 2% 3% NS fair
2003,12 EU (186) (185) Steroids
Graft loss
2003,12 EU (186) (185) Steroids
Cancer
All Charpentier 186 185 Tac/AZA/ 1% 0.5% nd fair
6 mo ATG No ATG 45 100 <2003
Lymphoma 2003,12 EU (186) (185) Steroids 0.5% 0% NS fair
Acute rejection
Total 23% 33% <0.01 fair
Biopsy-proven 15% 25% <0.01 fair
Severity of AR, Banff Charpentier 186 185 Tac/AZA/
6 mo ATG No ATG 45 100 <2003 5% 11% NS fair
II or higher 2003,12 EU (186) (185) Steroids
NODAT
2003,12 EU (186) (185) Steroids
Infection
All 68% 58% <0.01 fair
UTI 6 mo ATG No ATG 45 100 <2003 27% 27% NS fair
2003,12 EU (186) (185) Steroids
CMV 24% 16% <0.05 fair
2003,12 EU (186) (185) Steroids
Kidney function
Scr, µmol/L 6 mo ATG No ATG 45 100 <2003 133 132 NS fair
2003,12 EU (186) (185) Steroids
country duration Am 1 Arm 2 Arm 1 Arm 2 Medication (mean) donor transplant Arm 1 Arm 2
Lipids
Hypercholesteremia 6 mo ATG No ATG 45 100 <2003 3% 2% NS poor
2003,12 EU (186) (185) Steroids
Hypertension
Hypertension 6 mo ATG No ATG 45 100 <2003 18% 18% NS poor
2003,12 EU (186) (185) Steroids
Adverse events
Serum sickness 16% 0% <0.001 fair
Anemia Charpentier 186 185 Tac/AZA/ 31% 25% NS fair
6 mo ATG No ATG 45 100 <2003
Leukopenia 2003,12 EU (186) (185) Steroids 39% 9% 0.001 fair
Thrombocytopenia 12% 3% 0.007 fair
AR, Acute rejection; ATG, Antithymocyte globulin; AZA, Azathioprine; CMV, Cytomegalovirus; EU, Europe; nd, Not documented; NS, Not significant; SCr, Serum creatinine; Tac, Tacrolimus; UTI, Urinary tract infection.
Annotations:
a. Overlap with topic 2.2 “early vs. delayed introduction of CNI”.
Supporting Table 5. Evidence Profile Topic 1.2.2: Induction—IL-2 antibody vs. depleting antibody
No. of Total N Methodological Directness of the Summary of findings
studies and (N on quality of Consistency evidence Other Quality of
Outcome Importance
study study studies across studies generalizability/ considerations evidence for Description of effect
outcome
3 RCTs 449 No limitations
Not adequately Moderate
(High) (225) (0) No important No difference between induction with IL-2
No uncertainty powered for the
Mortality inconsistencies antibody compared to induction with a Critical
(0) outcome
1 SR Some limitations (0) depleting antibody for up to 5 years
1264 (–1) Low
(15 trials) (–1)

Graft loss inconsistencies antibody compared to induction with a Critical
(0) outcome
1 SR Some limitations (0) depleting antibody for up to 5 years
1264 (–1) Low
(15 trials) (–1)

Cancer inconsistencies antibody compared to induction with a Critical
(0) outcome
1 SR Some limitations (0) depleting antibody for up to 12 months
1264 (–1) Low
(15 trials) (–1)
Important
inconsistencies There is no clear evidence that induction
(High) (225) (0)
Acute (–1) No uncertainty None with a depleting antibody is superior in
Moderate High
rejection No important (0) (0) reducing the incidence of acute rejection
1 SR Some limitations
1264 inconsistencies to induction therapy with an IL-2 antibody.
(15 trials) (–1)
(0)
No important No difference between induction with IL-2
2 RCTs 171 Some limitations No uncertainty Sparse date
NODAT inconsistencies Low antibody compared to induction with a High
(High) (88) (–1) (0) (–1)
(0) depleting antibody for up to 12 months
No important Based on the systematic review there is
3 RCTs 449 No limitations No uncertainty None
inconsistencies High no significant difference between
(High) (225) (0) (0) (0)
(0) induction therapy with an IL-2 antibody
Infection vs. a depleting antibody. However, the High
Important
1 SR Some limitations No uncertainty None largest trial of good quality showed lower
1264 inconsistencies Low
(15 trials) (–1) (0) (0) incidence of infections (except CMV) in
(–1)
IL-2 treated patients.
studies and (N on quality of Consistency evidence Other Quality of
Outcome Importance
study study studies across studies generalizability/ considerations evidence for Description of effect
outcome
Important Based mainly on the results from the
3 RCTs 449 No limitations systematic review, there is evidence that
inconsistencies
Delayed graft (High) (225) (0) No uncertainty None induction therapy with a depleting
(–1) Moderate Moderate
function No important (0) (0) antibody might reduce the incidence of
1 SR Some limitations delayed graft function when compared to
1264 inconsistencies
(15 trials) (–1) induction therapy with an IL-2 antibody.
(0)
No important No difference between Induction with IL-2
Kidney 3 RCTs 449 No limitations No uncertainty None
inconsistencies High antibody compared to induction with a Moderate
function (High) (225) (0) (0) (0)
(0) depleting antibody
Adverse 1 RCT 278 Depends on
events (High) (137) outcome
Balance of potential benefits and harm: Tradeoffs Quality of overall evidence:
Treatment with a depleting antibody is superior over IL-2 antibody in the prevention of acute rejection, but is associated with a Moderate
higher number of infections.
CMV, Cytomegalovirus; CVD, Cardiovascular disease; IL-2, Interleukin-2; N, Number; NODAT, New onset diabetes after transplant; RCT, Randomized controlled trials; SR, Systematic review; vs, versus
Annotations:
a. References: 6,13-15
Supporting Table 6. Summary Table Topic 1.2.2: Induction—IL-2 antibody vs. depleting antibody (categorical outcomes)a
%
Study, year, Study Concomitant Age Dates of
Outcome deceased P value Quality
country duration Arm 1 Arm 2 Arm 1 Arm 2 medication (mean) transplant Arm 1 Arm 2
donor
Mortality
Brennan, 137 141 CsA-ME/MMF/
12 mo 12 mo Basiliximab ATG 51 100 2000-02 4% 4% NS good
2006,14US, EU (137) (141) Steroids
Kyllonen, 2007,15 58 53
5y 5y Basiliximab ATG CsA/AZA 47 100 1999-2001 3% 8% NS good
Finlandb (58) (53)
Ciancio, 2005,13, 30 30 Tac/MMF/
12 mo 12 mo Daclizumab Thymo 50 100 2002-04 12% 8% NS poor
USc (30) (30) Steroids
Graft loss
Brennan, 2006,14 137 141 CsA-ME/MMF/
US, EU (137) (141) Steroids
Kyllonen, 2007,15 58 53
5y 5y Basiliximab ATG CsA/AZA 47 100 1999-2001 3% 9% nd good
Finlandb (58) (53)
Ciancio, 2005,13 30 30 Tac/MMF/
Cancer
All Brennan, 2006,14 137 141 CsA-ME/MMF/ 1% 4% NS good
12 mo Basiliximab ATG 51 100 2000-02
PTLD US, EU (137) (141) Steroids 0% 3% NS good
Kyllonen, 2007,15 58 53
All 12 mo 5y Basiliximab ATG CsA/AZA 47 100 1999-2001 0% 4% NS good
Finlandb (58) (53)
Acute rejection
Biopsy-proven 26% 16% <0.05 good
Severe AR, 12 mo Basiliximab ATG 51 100 2000-02
US, EU (137) (141) Steroids 8% 1% <0.01 fair
antibody treated
5y 12% 11% NS good
Kyllonen, 2007,15 58 53
Median time to 5y Basiliximab ATG CsA/AZA 47 100 1999-2001
Finlandb (58) (53) 46 13 NS good
AR, days
Biopsy-proven 17% 17% NS poor
Severity of AR, 12 mo Daclizumab Thymo 50 100 2002-04
USc (30) (30) Steroids 3% 10% NS poor
Banff II or higher
NODAT
Kyllonen, 2007,15 58 53
12 mo 5y Basiliximab ATG CsA/AZA 47 100 1999-2001 9% 4% nd fair
Finlandb (58) (53)
%
donor

Infection
All 75% 86% <0.05 good
UTI 27% 39% <0.05 good
CMV US, EU (137) (141) Steroids 18% 8% <0.05 good
Viral other than
12% 21% <0.05 good
CMV
CMV 12 mo Kyllonen, 2007,15 58 53 16% 17% NS good
5y Basiliximab ATG CsA/AZA 47 100 1999-2001
UTI 12 mo Finlandb (58) (53) 12% 1.9% nd good
UTI 0% 3% NS poor
Ciancio, 2005,13, 30 30 Tac/MMF/
CMV 12 mo Daclizumab Thymo 50 100 2002-04 0% 3% NS poor
Polyoma 0% 0% NS poor
Kyllonen, 2007,15 58 53
5y 5y Basiliximab ATG CsA/AZA 47 100 1999-2001 24% 6% 0.025 good
Finlandb (58) (53)
Kidney function
Scr, µmol/L 12 mo Basiliximab ATG 51 100 2000-02 159 177 NS good
Kyllonen, 2007,15 58 53
CrCl, mL/min 5y Basiliximab ATG CsA/AZA 47 100 1999-2001 63 73 NS good
Finlandb (58) (53)
Adverse events
Leukopenia Brennan, 2006,14 137 141 CsA-ME/MMF/ 15% 33% <0.001 good
Thrombocytopenia US, EU (137) (141) Steroids 6% 11% NS good
AR, Acute rejection; ATG, Antithymocyte globulin; AZA, Azathioprine; CMV, Cytomegalovirus; CrCl, Creatinine clearance; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; EU, Europe; IL-2, Interleukin-2; MMF, Mycophenolate
mofetil; nd, Not documented; NS, Not significant; PTLD, Posttransplant lymphoproliferative disease; SCr, Serum creatinine; Ster, Steroids; Tac, Tacrolimus; UTI, Urinary tract infection; US, United States.
Annotations:
a. Overlap with topic 2.2 early vs. delayed introduction of CNI.
b. Kyllonen, 200715 has a third arm of CsA+ AZA without induction.
c. Ciancio 200513: three arm study split: (A) Topic 1.2.2 Induction: IL-2 vs. depleting antibody; (B) Topic 2.5 Steroid avoidance.
Supporting Table 7. Summary Table Topic 1.2.2: Induction—IL-2 antibody vs. depleting antibody (continuous outcomes)a
%
Outcome deceased Baseline ∆ P value Quality
country duration Arm 1 Arm 2 Arm 1 Arm 2 medication (mean) transplant
donor (Control) (Control)
Kidney function
Kyllonen, 2007,15 58 53 129 -8
Scr, µmol/L 12 mo 5y Basiliximab ATG CsA/AZA 47 100 1999-2001 <0.05 good
Finlandb (58) (53) (148) (-30)
108 -4
Scr, µmol/L NS poor
Ciancio, 2005,13 30 30 Tac/MMF/ (111) (+5)
12 mo Daclizumab Thymo 50 100 2002-04
USc (30) (30) Steroids 73 +8
CrCl, mL/min NS poor
(75) (+5)
ATG, Antithymocyte globulin; AZA, Azathioprine; CrCl, Creatinine clearance; CsA, Cyclosporine; IL-2, Interleukin-2; MMF, Mycophenolate mofetil; NS, Not significant; SCr, Serum creatinine; Ster, Steroids; Tac, Tacrolimus; Thymo,
Thymoglobulin; US, United States.
Annotations:
a. Overlap with topic 2.2 early vs. delayed introduction of CNI.
b. Kyllonen, 200715 has a third arm of CsA+ AZA without induction.
c. Ciancio 200513: three arm study split: (A) Topic 1.2.2 Induction: IL-2 vs. depleting antibody; (B) Topic 2.5 Steroid avoidance
Supporting Table 8. Evidence Profile Topic 2.2: Tac vs. CsAa,b
studies (N on quality of Consistency evidence Other Quality of
Outcome Qualitative and quantitative description Importance
and study study studies across studies generalizability/ considerations evidence for
design drug) per outcome applicability of effect of outcome
outcome
(High) (1820) (0) No important Limited duration
No uncertainty
Mortality inconsistencies of follow-up Moderate No difference between Tac and CsA/CsA-ME Critical
(0)
1 SR No limitations (0) (–1)
2604
(14 RCTs) (0)
No important Tac is not significantly better in prolonging
inconsistencies High graft survival when compared mainly to CsA-
(High) (1820) (0)
(0) No uncertainty None ME.
Graft loss Critical
No important (0) (0)
1 SR No limitations Tac is better than CsA/CsA-ME in graft
2604 inconsistencies High
(14 RCTs) (0) survival outcomes.
(0)

(High) (964) (0) No important Limited duration
No uncertainty
Cancer inconsistencies of follow-up Moderate No difference between Tac and CsA/CsA-ME Critical
(0)
1 SR No limitations (0) (–1)
1765
(7 RCTs) (0)
No important Moderate
Acute (High) (1820) (–1) No uncertainty None Tac is better than CsA/CsA-ME in the
inconsistencies High
rejection 1 SR No limitations (0) (0) prevention of acute rejection.
2751 (0) High
(14 RCTs) (0)
Serious
3 RCTs 328
limitations No important Low No difference between Tac and CsA-ME
(High) (163) No uncertainty None
CAN (–2) inconsistencies High
(0) (0)
1 SR No limitations (0) Tac is better than CsA/CsA-ME in the
914 High
(3 RCTs) (0) prevention of CAN.
(High) (1820) (0) No important
No uncertainty None NODAT is more common in Tac-treated
NODAT inconsistencies High High
1 SR No limitations (0) (0) patients compared to CsA/CsA-ME
1956 (0)
(11 RCTs) (0)
Outcome Qualitative and quantitative description Importance
and study study studies across studies generalizability/ considerations evidence for
design drug) per outcome applicability of effect of outcome
outcome
No difference in the incidence of bacterial and
No important viral infections (especially CMV) between Tac
(High) (1583) (0) No uncertainty None
Infection inconsistencies High and CsA/CsA-ME (limited data on BK, but High
(0) (0)
1 SR No limitations (0) there is no clear evidence for differences
1422 between Tac and CsA)
(5 RCTs) (0)
Delayed No important
graft inconsistencies High No difference between Tac and CsA/CsA-ME Moderate
(High) (1633) (0) (0) (0)
function (0)
11 RCTs 3223 No limitations There is some evidence that kidney function in
(High) (1668) (0) Important Tac treated patients is better then in CsA/CsA-
Kidney No uncertainty None
inconsistencies Moderate ME treated patients however, this effect Moderate
function 1 SR No limitations (0) (0)
1216 (–1) seems to be apparent particularly in the first
(8 RCTs) (0) 12 months.
No important There is some evidence that treatment with
4 RCTs 924 Some limitations No uncertainty None
Proteinuria inconsistencies Moderate Tac is causing less proteinuria when Moderate
(High) (465) (–1) (0) (0)
(0) compared to CsA/CsA-ME.
11 RCTs 3223 Some limitations Total cholesterol levels as well as LDL-C
Moderate
(High) (1668) (–1) No important levels are higher in CsA/CsA-ME treated
No uncertainty None
Lipids inconsistencies patients compared to Tac treated patients, Moderate
1 SR No limitations (0) (0)
722 (0) High whereas there is no difference in the effect on
(3 RCTs) (0)
HDL-C levels.
Blood (High) (1421) (–1) No uncertainty None No clear difference between Tac and
inconsistencies Moderate
pressure 1 SR No limitations (0) (0) CsA/CsA-ME
1216 (0) High
(8 RCTs) (0)
5 RCTs 2556 Tac: more tremor and diarrhea (due to higher
Adverse (High) (1288) MPA levels while on the same MMF dose?) Depends on
events 1SR CsA/CsA-ME: more hirsutism, hypertrichosis, outcome
2152
(7 RCTs) gingival hyperplasia
Balance of potential benefits and harm: Net benefit Quality of overall evidence:
Tac is superior to CsA/CsA-ME in the prevention of acute rejection and kidney function. High
Adverse event profiles vary with impaired lipid metabolism in CsA/CsA-ME and a higher incidence of NODAT in
Tac-treated patients.
BK, BK virus; CAN, Chronic Allograft Nephropathy; CMV, Cytomegalovirus; CsA, Cyclosporine A; CsA-ME, Cyclosporine A microemulsion; CVD, Cardiovascular disease; HDL-C, High-density lipoprotein cholesterol; LDL-C, Low-
density lipoprotein cholesterol; MMF, Mycophenolate mofetil; MPA, Mycophenolate acid; N, Number; NODAT, New onset diabetes after transplant; QOL, Quality of life; RCT, Randomized controlled trials; SR, Systematic review;
Tac, Tacrolimus.
Annotations:
a. Systematic review about Tac vs. CsA largely balanced between CsA original formulation and CsA microemulsion (CsA-ME), more recent RCTs mainly about CsA-ME.
b. References: 10,16-32
Supporting Table 9. Summary Table Topic 2.2: Tac vs. CsA (categorical outcomes)
%
donor
Mortality
Hardinger,
Brennan, 134 66 AZA or MMF/
12 mo 12 mo Tac CsA-ME 45 58 2000-02 1% 0% NS good
2005,16,17 (134) (66) Steroids/ATG
US
Kramer, 2003,
200518,19, 6 mo 286/237 271/222 1% 1% NS good
6 mo/24 mo Tac CsA-ME AZA/Steroids 43 97 <2002
Margreiter 2002 20 24 mo (286) (271) 2% 3% <0.05 fair
EU
Murphy, 2003,21 50 52
12 mo 12 mo Tac CsA-ME ±AZA/Steroids 45 84 <2002 4% 0% NS poor
UK (50) (52)
Rowshani, 2006,22 63 63 Tac CsA MMF/Steroids/
12 mo 12 mo nd nd 2000-02 2% 3% NS poor
Netherlandsa (63) (63) (AUC) (AUC) Basiliximab
Vincenti, 2007,23 MMF or EC-
346 336 CsA-ME
6 mo US, Can, EU, Aus, 6 mo Tac MPS Steroids/ 47 68 2003-05 2% 2% NS good
(346) (336) (C2)
Japanb Basiliximab
214 212
12 mo Tac XL CsA-ME 1% 2% NS fair
Silva, 2007,24 US, (214) (212) MMF/Steroids/
12 mo 48 52 <2006
Canada, Brazilc 212 212 Basiliximab
12 mo Tac CsA-ME 4% 2% NS fair
(212) (212)
Ciancio, 2006, 12 mo 50/50 50/50 SRL/Steroids/
12 mo Tac CsA-ME 47 80 2000-01 4% 2% NS good
200425-27 US 36 mo (50) (50) Daclizumab
Gonwa, 2003,28 72 75 MMF/Steroids/
24 mo 36 mo Tac CsA-ME 47 100 <1999 6% 12% NS good
USd (72) (75) ±OKT3
Ekberg, 2007,10
401 399 Tac CsA/ MMF/Steroids/
12 mo EU, Can, Aus, 12 mo 46 64 2002-04 3% 2% NS good
(401) (399) low dose CsA-ME Daclizumab
Brazil, Israele
Artz, 2003, 6 mo 64 60
6 mo Tac CsA-cont. nd 50 nd <1999 2% 3% NS good
200429,30 EUf 24 mo (64) (60)
Hernandez, 80 80 Tac CsA MMF/Steroids/
24 mo 24 mo 47 100 1999-2004 8% 4% NS good
2007,31 Spain (80) (80) low dose low dose Basiliximab
Graft loss
Hardinger,
134 66 AZA or MMF/
Censored for death Brennan, 12 mo Tac CsA-ME 45 58 2000-02 5% 0% NS good
(134) (66) Steroids/ATG
2005,16,17 US
%
donor
Kramer, 2003,
2005,18,19, 6 mo 286/237 271/222 5% 8% NS good
Margreiter 200220 24 mo (286) (271) 9% 11% NS fair
EU
Murphy, 2003,21 50 52
UK (50) (52)
12 mo 12 mo nd nd 2000-02 9% 5% NS poor
346 336 CsA-ME
6 mo US, Can, EU, Aus, 6 mo Tac MPS Steroids/ 47 68 2003-05 3% 2% NS good
(346) (336) (C2)
Japanb Basiliximab
214 212
12 mo 48 52 <2006
(212) (212)
2004, 25-27 US 36 mo (50) (50) Daclizumab
36 mo 36 mo Tac CsA-ME 47 100 <1999 19% 27% NS good
USd (72) (75) ±OKT3
Censored death Ekberg, 2007,10
with a functioning EU, Can, Aus, 12 mo 46 64 2002-04 4% 6% NS good
graft Brazil, Israele
24 mo 24 mo 47 100 1999-2004 18% 10% NS good
Cancer
12 mo Hardinger, 134 66 AZA or MMF/ 2% 0% NS good
Brennan, 12 mo Tac CsA-ME 45 58 2000-02
PTLD (134) (66) Steroids/ATG 0% 0% NS good
2005,16,17 US
Kramer, 2003,
2005,18,19, 6 mo 286/237 271/222 0.3% 0.7% NS good
Margreiter, 24 mo (286) (271) 1% 1% NS fair
2002,20 EU
PTLD 12 mo nd nd 2000-02 nd 2% nd poor
12 mo Ekberg, 2007,10 1% 1% NS good
EU, Can, Aus, 12 mo 46 64 2002-04
PTLD (401) (399) low dose CsA-ME Daclizumab 0% 0% NS good
Brazil, Israele
%
donor
All 24 mo Hernandez, 80 80 Tac CsA MMF/Steroids/ 3% 3% NS good

24 mo 47 100 1999-2004
PTLD 24 mo 2007,31 Spain (80) (80) low dose low dose Basiliximab 0% 0% NS good
Acute rejection
12 mo Hardinger, 4% 6% NS good
134 66 AZA or MMF/
Severity of AR, Brennan, 12 mo Tac CsA-ME 45 58 2000-02
(134) (66) Steroids/ATG 2% 5% nd good
Banff II and higher 2005,16,17 US
20% 37% <0.001 good
6 mo/12 mo/24 mo 22% 42% <0.001 good
Kramer, 2003, 23% 43% <0.001 fair
Severity of AR, 2005,18,19, 6 mo 286/237 271/222
Tac CsA-ME AZA/Steroids 43 97 <2002 12% 25% nd good
Type II and higher Margreiter, 24 mo (286) (271)
14% 27% nd fair
6 mo/24 mo 2002,20 EU
Steroid-resistant 9% 21% <0.001 fair
6 mo/24 mo 9% 22% <0.001 poor
Murphy, 50 52
2003,21UK (50) (52)
Biopsy-proven 7% 16% NS poor
Steroid-resistant Rowshani, 2006,22 63 63 Tac CsA MMF/Steroids/ 2% 6% NS poor
12 mo nd nd 2000-02
Subclinical Netherlandsa (63) (63) (AUC) (AUC) Basiliximab
rejection, Protocol 15% 39% <0.05 poor
Bx 6 mo
Biopsy-proven 7% 10% NS good
Severity of AR, 346 336 CsA-ME
US, Can, EU, Aus, 6 mo Tac MPS, Steroids/ 47 68 2003-05 4% 4% NS good
Banff II or higher (346) (336) (C2)
Japanb Basiliximab
Antibody treated 4% 3% NS fair
12 mo 18% 21% NS fair
Biopsy-proven 214 212 5% 7% NS fair
Tac XL CsA-ME
(214) (212)
Severity of AR,
4% 4% NS fair
Banff II or higher Silva, 2007,24 US, MMF/Steroids/
12 mo 48 52 <2006
12 mo Canada, Brazilc Basiliximab 12% 21% <0.05 fair
Biopsy-proven 212 212 4% 7% NS fair
Tac CsA-ME
(212) (212)
Severity of AR,
2% 4% NS fair
Banff II or higher
%
donor
4% 14%
12 mo/36 mo Ciancio, 2006, 12 mo 50/50 50/50 SRL/Steroids/ nd good
Tac CsA-ME 47 80 2000-01 26% 20%
Severity of AR 2004, 25-27 US 36 mo (50) (50) Daclizumab
6% 6% nd good
Banff II or higher
11% 20%
12 mo/36 mo NS good
Gonwa, 2003,28 72 75 MMF/Steroids/ 17% 25%
36 mo Tac CsA-ME 47 100 <1999
Steroid-resistant USd (72) (75) ±OKT3
6% 12% 0.03 good
12 mo/36 mo
12 mo Ekberg, 2007,10 17% 30% <0.001 fair
Biopsy-proven EU, Can, Aus, 12 mo 46 64 2002-04 12% 24% <0.001 fair
Brazil, Israele
Artz, 2003, 6 mo 64 60
6 mo Tac CsA-cont. nd 50 nd <1999 0% 0% NS fair
2004,29,30 EUf 24 mo (64) (60)
Biopsy-proven
16% 14% NS good
24 mo
Banff I+II Hernandez, 80 80 Tac CsA MMF/Steroids/
24 mo 47 100 1999-2004 14% 13% NS good
24 mo 2007,31 Spain (80) (80) low dose low dose Basiliximab
Steroid-resistant
6% 6% NS good
24 mo
Interstitial
Murphy, 2003,21 50 52
extracellular matrix, 12 mo Tac CsA-ME ±AZA/Steroids 45 84 <2002 16 25 <0.01 poor
UK (50) (52)
mm2
57% 51% NS poor
CAN 6 mo/12 mo
65% 61% NS poor
Rowshani, 2006,22 63 63 Tac CsA MMF/Steroids/ Total 24%, no differences
CNI toxicity 12 mo 12 mo nd nd 2000-02 NS poor
Netherlandsa (63) (63) (AUC) (AUC) Basiliximab between groups
Subclinical rejection
15% 39% <0.05 poor
6 mo
CAN 36 mo Tac CsA-ME 47 80 2000-01 50% 44% NS fair
2004,25-27 US 36 mo (50) (50) Daclizumab
Ekberg, 2007,10
Proteinuria EU, Can, Aus, 12 mo 46 64 2002-04 5% 2% NS fair
Brazil, Israelc
%
donor
NODAT
Hardinger,
134 66 AZA or MMF/
12 mo Brennan, 12 mo Tac CsA-ME 45 58 2000-02 4% 2% NS good
2005,16,17 US
Kramer, 2003,
2005,18,19, 6 mo 286/237 271/222 5% 2% NS good
Margreiter, 24 mo (286) (271) 4% 2% NS fair
2002,20 EU
Murphy, 2003,21 50 52
UK (50) (52)
6 mo Vincenti, 2007,23 MMF or EC- 17% 9% <0.01 good
346 336 CsA-ME
Impaired fasting US, Can, EU, Aus, 6 mo Tac MPS, Steroids/ 47 68 2003-05
(346) (336) (C2) 12% 7% <0.05 good
glucose Japanb Basiliximab
Insulin use ≥30 d 6% 3% NS poor
Oral hypoglycemic 214 212
Tac XL CsA-ME 14% 3% <0.05 poor
use (214) (212)
Fasting glucose
56% 53% NS poor
≥7.0 mmol/L Silva, 2007,24 US, MMF/Steroids/
12 mo 48 52 <2006
Insulin use ≥30 d Canada, Brazilc Basiliximab 6% 3% NS poor
Oral hypoglycemic 212 212
Tac CsA-ME 10% 3% <0.001 poor
use (212) (212)
Fasting glucose
64% 53% NS poor
≥7.0 mmol/L
Ciancio, 2006, 12 mo 41 45 SRL/Steroids/
2004, 25-27 US 36 mo (50) (50) Daclizumab
Gonwa, 200328 46 46 MMF/Steroids/
36 mo 36 mo Tac CsA-ME 47 100 <1999 13% 7% nd fair
USd (72) (75) ±OKT3
Ekberg, 2007,10
12 mo EU, Can, Aus, 12 mo 46 64 2002-04 11% 5% 0.02 fair
Brazil, Israele
Artz, 2003, 6 mo 64 60
6 mo Tac CsA-cont. nd 50 nd <1999 6% 5% NS good
2004,29,30 EUf 24 mo (64) (60)
24 mo 24 mo 47 100 1999-2004 27% 16% NS good
%
donor
Infection
CMV 4% 6% NS good
BK-viruria (DNA) Hardinger, 36% 31% NS good
134 66 AZA or MMF/
Brennan, 12 mo Tac CsA-ME 45 58 2000-02
BK-viremia (DNA) (134) (66) Steroids/ATG 12% 11% NS good
2005,16,17 US
BK nephropathy
0% 0% nd good
(biopsy)
CMV 6 mo Kramer, 2003, 7% 6% NS good
2005,18,19, 6 mo 286/237 271/222
Tac CsA-ME AZA/Steroids 43 97 <2002
UTI 6 mo Margreiter, 24 mo (286) (271) 28% 26% NS good
2002,20 EU
346 336 CsA-ME
CMV US, Can, EU, Aus, 6 mo Tac MPS, Steroids/ 47 68 2003-05 6% 12% <0.01 good
(346) (336) (C2)
Japanb Basiliximab
CMV 7% 8% NS fair
Polyoma 214 212 3% 2% nd fair
Tac XL CsA-ME
Viral (214) (212) 23% 21% NS fair
Bacterial Silva,2007,24
US, MMF/Steroids/ 8% 8% NS fair
12 mo 48 52 <2006
CMV Canada, Brazilc Basiliximab 8% 8% NS fair
Polyoma 212 212 4% 2% nd fair
Tac CsA-ME
Viral (212) (212) 26% 21% NS fair
Bacterial 12% 8% NS fair
24% 20% good
12 mo/36 mo NS
Ciancio, 2006, 12 mo 50/50 50/50 SRL/Steroids/ 32% 30% fair
CMV 36 mo Tac CsA-ME 47 80 2000-01 2% 2% NS fair
2004, 25-27 US 36 mo (50) (50) Daclizumab
BK 36 mo 4% 2% NS fair
CMV Gonwa, 2003,28 72 75 MMF/Steroids/ 14% 11% NS good
36 mo Tac CsA-ME 47 100 <1999
PCP USd (72) (75) ±OKT3 0% 0% NS good
Opportunistic
Ekberg, 2007,10 4% 7% NS fair
infections 401 399 Tac CsA/ MMF/Steroids/
CMV EU, Can, Aus, 12 mo 46 64 2002-04 10% 12% NS fair
Brazil, Israele
UTI 24% 24% NS good
%
donor
24 mo 45% 46% NS good

UTI 24 mo Hernandez, 80 80 Tac CsA MMF/Steroids/ 35% 31% NS good
24 mo 47 100 1999-2004
CMV infection/ 25%/ 20%/ <0.01
good
disease 24 mo 11% 3.7% NS
Hardinger,
134 66 AZA or MMF/
12 mo Brennan, 12 mo Tac CsA-ME 45 58 2000-02 5% 5% NS good
2005,16,17 US
Kramer, 2003,
2005,18,19, 6 mo 286/237 271/222
6 mo Tac CsA-ME AZA/Steroids 43 97 <2002 20% 27% nd good
Margreiter, 24 mo (286) (271)
2002,20 EU
Murphy, 2003,21 50 52
UK (50) (52)
346 336 CsA-ME
6 mo US, Can, EU, Aus, 6 mo Tac MPS, Steroids/ 47 68 2003-05 20% 19% NS good
(346) (336) (C2)
Japanb Basiliximab
214 212
12 mo 48 52 <2006
(212) (212)
2004, 25-27 US 36 mo (50) (50) Daclizumab
36 mo 36 mo Tac CsA-ME 47 100 <1999 36% 28% NS fair
USd (72) (75) ±OKT3
Ekberg, 2007,10
12 mo EU, Can, Aus, 12 mo 46 64 2002-04 36% 32% NS good
(401) (399) low dose CsA-ME³ Daclizumab
Brazil, Israele
Hernandez,
80 80 Tac CsA MMF/Steroids/
24 mo 2007,31 Spain 24 mo 47 100 1999-2004 40% 33% NS good
(80) (80) low dose low dose Basiliximab
Kidney function
Hardinger,
Scr, µmol/L 134 66 AZA or MMF/ 115 132 <0.05
Brennan, 12 mo Tac CsA-ME 45 58 2000-02 good
6 mo/12 mo (134) (66) Steroids/ATG 115 141 <0.05
2005,16,17 US
%
donor
Scr, µmol/L Kramer, 2003, 139 147 NS good

6 mo/24 mo 2005,18,19, 6 mo 286/237 271/222 137 162 <0.01 fair
CrCl, mL/min Margreiter, 24 mo (286) (271) good
2002,20 EU 69 62 nd
24 mo fair
Murphy, 2003,21 50 52
Scr, µmol/L 12 mo Tac CsA-ME ±AZA/Steroids 45 84 <2002 157 170 NS poor
UK (50) (52)
CrCl, mL/min 12 mo nd nd 2000-02 65 64 NS poor
346 336 CsA-ME
CrCl, mL/min US, Can, EU, Aus, 6 mo Tac MPS, Steroids/ 47 68 2003-05 66 64 NS good
(346) (336) (C2)
Japanb Basiliximab
Scr, µmol/L 124 133
NS good
12/36 mo Ciancio, 2006, 12 mo 50/50 50/50 SRL/Steroids/ 124 141
Tac CsA-ME 47 80 2000-01
CrCl, mL/min 2004,25-27 US 36 mo (50) (50) Daclizumab 73 71
NS fair
12/36 mo 73 62
Scr, µmol/L
123 141 NS fair
36 mo Gonwa, 2003,28 72 75 MMF/Steroids/
36 mo Tac CsA-ME 47 100 <1999
CrCl, mL/min USd (72) (75) ±OKT3
59 56 NS fair
36 mo
CrCl, mL/min Ekberg, 2007,10 65 59 0.001 good
GFR, mL/min EU, Can, Aus, 12 mo 46 64 2002-04 70 65 NS fair
Brazil, Israele
eGFR, mL/min 54 50 <0.01 good
Lipids
No. of pts. on lipid-
Ciancio, 2006, 12 mo 49 50 SRL/Steroids/
lowering drug Tac CsA-ME 47 80 2000-01 54% 80% 0.001 fair
2004,25-27 US 36 mo (50) (50) Daclizumab
12 mo
Ekberg, 2007,10
Hypercholesterol- 401 399 Tac CsA/ MMF/Steroids/
EU, Can, Aus, 12 mo 46 64 2002-04 5% 10% nd fair
emia (401) (399) low dose CsA-ME Daclizumab
Brazil, Israele
Hyperlipidemia Hernandez, 80 80 Tac CsA MMF/Steroids/
24 mo 47 100 1999-2004 49% 63% NS fair
Hypertension
Kramer, 2003,
Blood pressure, 200518,19, 6 mo 286/237 271/222
Tac CsA-ME AZA/Steroids 43 97 <2002 136/82 136/81 NS fair
mm Hg 24 mo Margreiter, 24 mo (286) (271)
2002,20 EU
%
donor
No. of
Murphy, 2003,21 50 52
antihypertensive 12 mo Tac CsA-ME ±AZA/Steroids 45 84 <2002 1.7 1.8 NS poor
UK (50) (52)
drugs per pt.
Ekberg, 2007,10
Hypertension EU, Can, Aus, 12 mo 46 64 2002-04 13% 12% nd fair
Brazil, Israele
Hypertension Hernandez, 80 80 Tac CsA MMF/Steroids/
24 mo 47 100 1999-2004 40% 36% NS fair
Adverse events
Kramer, 2003,
Fractures AND
200518,19, 6 mo 286/237 271/222
bone disease Tac CsA-ME AZA/Steroids 43 97 <2002 2% 5% nd poor
Margreiter, 24 mo (286) (271)
24 mo
2002,20 EU
Diarrhea 28% 16% <0.001 good
Tremor Vincenti,
2007,23 MMF or EC- 22% 15% <0.05 good
346 336 CsA-ME
Peripheral edema US, Can, EU, Aus, 6 mo Tac MPS, Steroids/ 47 68 2003-05 15% 23% <0.01 good
(346) (336) (C2)
Japanb Basiliximab
Hirsutism,
1% 9% <0.001 good
Hypertrichosis
Diarrhea 45% 26% <0.001 good
Gingival hyperplasia 1% 5% <0.01 good
214 212
Tremor Tac XL CsA-ME 35% 20% <0.001 good
(214) (212)
Hypertrichosis 0% 3% <0.01 good
Hirsutism Silva,2007,24
US, MMF/Steroids/ 0% 9% <0.001 good
12 mo 48 52 <2006
Diarrhea Canada, Brazilc Basiliximab 44% 26% <0.001 good
Gingival hyperplasia 0% 5% <0.01 good
212 212
Tremor Tac CsA-ME 34% 20% <0.01 good
(212) (212)
Hypertrichosis 0% 3% <0.01 good
Hirsutism 0% 9% <0.001 good
41 45
Lymphocele 12 mo Ciancio, 2006, 16% 14% NS good
12 mo (50) (50) SRL/Steroids/
2004, Ciancio, Tac CsA-ME 47 80 2000-01
Wound infection/ 36 mo 50 50 Daclizumab
200625,26 US 6% 4% NS good
dehiscence 12 mo (50) (50)
%
donor
Diarrhea Ekberg, 2007,10 27% 14% <0.001 good

EU, Can, Aus, 12 mo 46 64 2002-04
Lymphocele (401) (399) low dose CsA-ME Daclizumab 4% 7% NS good
Brazil, Israele
AE, Adverse events; AR, Acute rejection; ATG, Antithymocyte globulin; AUC, Area under the curve; AZA, Azathioprine; Bx, Biopsy; CAN, Chronic allograft nephropathy; CMV, Cytomegalovirus; CNI, Calcineurin inhibitors; cont., Continued; CrCl,
Creatinine clearance; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; DNA, Deoxyribonucleic acid; EC-MPS, Enteric-coated mycophenolate sodium; eGFR, Estimated glomerular filtration rate; EU, Europe; MMF, Mycophenolate
mofetil; nd, Not documented; NODAT, New onset diabetes after transplantation; NS, Not significant; OKT3, Muromonab; PCP, Pneumoystis pneumonia; PTLD, Posttransplant lymphoproliferative disease; SCr, Serum creatinine; SRL, Sirolimus;
Tac, Tacrolimus; Tac-XL, Tacrolimus extended-release formula; UK, United Kingdom; US, United States; UTI, Urinary tract infection
Annotations:
a. Rowshani, 2006 22: Tac and CsA adjusted to AUC within the first 6 weeks, thereafter adjusted to trough levels.
b. Vincenti, 2007 23: CsA-ME adjusted to C2-levels.
c. Silva, 200724: three-arm study split within topic 2.3 Tac vs. CsA.
d. Gonwa, 200328: three-arm study split (A) topic 2.3 Tac vs. CsA, (B) topic 2.4 MMF vs. AZA.
e. Ekberg, 2007 10 “ELITE-Symphony”: four-arm study split: (A) topic 2.3 CsA vs. Tac , (B) topic 3.2 CNI sparing/withdrawal.
f. Artz, 2003, 2004 29,30: conversion of stable patients 1 year after transplant
Supporting Table 10. Summary Table Topic 2.2: Tac vs. CsA (continuous outcomes)
No. analyzed
(enrolled)
country duration medication (mean) donor transplant Baseline ∆
(Control) (Control)
Kidney function
144 -21
Scr, μmol/L <0.05 poor
(148) (–17)
199 193 55 +3.3
CrCl, mL/min Tac XL CsA-ME <0.01 poor
(214) (212) (54) (+1)
53 +5.4
eGFR, mL/min Silva, 2007,24 <0.05 poor
MMF/Steroids/ (52) (+3.5)
US, Canada, 12 mo 48 52 <2006
Basiliximab 143 –17
Scr, μmol/L Brazila NS poor
(148) (–17)
202 193 55 +2.6
CrCl, mL/min Tac CsA-ME <0.05 poor
(212) (212) (54) (+1)
54 +5.6
eGFR, mL/min <0.01 poor
(52) (+3.5)
137 +8
Scr, μmol/L <0.05 good
Artz, 2003, 64 60 (143) (+14)
24 mo Tac CsA-cont. nd 50 nd <1999
2004,29,30 EUb (64) (60) 60 +4
CrCl, mL/min <0.01 good
(59) (–10)
CrCl, mL/min 12 71 +3
<0.05 good
mo (69) (-4)
CrCl, mL/min 24 71 –1
<0.05 good
mo (69) (-3)
eGFR, mL/min/1.73 46 +4
<0.05 good
m² 12 mo Hernandez, 80 80 Tac CsA MMF/Steroids/ (51) (+5)
24 mo 47 100 1999-2004
eGFR, mL/min/1.73 2007,31 Spain (80) (80) low dose low dose Basiliximab 46 +4
0.06 good
m² 24 mo (51) (+5)
eGFR, mL/min/1.73 46 +16
<0.05 good
m² 12 mo (52) (+7)
eGFR, mL/min/1.73 46 +16
<0.05 good
m² 24 mo (52) (+8)
Chronic allograft nephropathy
Chronic injury score 2.1 +1.0
Ciancio, 2006, 12 mo 50/50 50/50 SRL/Steroids/ NS good
12 mo Tac CsA-ME 47 80 2000-01 (1.8) (+1.3)
2004,.25-27 US 36 mo (50) (50) Daclizumab
Proteinuria
No. analyzed
(enrolled)
(Control) (Control)
Proteinuria Artz, 2003, 64 60 0.2 -0.06

6 mo Tac CsA-cont. nd 50 nd <1999 <0.01 good
6 mo 2004,29,30 EUb (64) (60) (0.2) (+0.02)
Proteinuria, mg/d Hernandez, 80 80 Tac CsA MMF/Steroids/ 266 -32 0.06 at
24 mo 47 100 1999-2004 good
24 mo 2007,31 Spain (80) (80) low dose low dose Basiliximab (280) (+37) baseline
Lipids
Hardinger,
No. of pts. on Lipid- 134 66 AZA or MMF/ 40% –10%
Brennan, 12 mo Tac CsA-ME 45 58 2000-02 <0.01 fair
lowering therapy (134) (66) Steroids/ATG (67%) (-32%)
2005 16,17 US
Cholesterol, Kramer, 2003, 5.5 -0.1
<0.001 good
mmol/L 6 mo 200518,19, 6 mo 286/237 271/222 (5.4) (+0.5)
Cholesterol, Margreiter, 24 mo (286) (271) 5.5 -0.3
<0.01 fair
mmol/L 24 mo 2002,20 EU (5.4) (+0.1)
Cholesterol, 5.5 ±0
<0.05 poor
mmol/L Murphy, 50 52 (5.5) (+0.5)
12 mo Tac CsA-ME ±AZA/Steroids 45 84 <2002
2003,21 UK (50) (52) 3.2 ±0
LDL, mmol/L <0.05 poor
(3.5) (+0.5)
Cholesterol, 4.5 +0.3
<0.01 good
mmol/L Vincenti, (4.6) (+0.7)
MMF or EC-
2007,23US, 346 336 CsA-ME 2.4 +0.2
LDL, mmol/L 6 mo Tac MPS, Steroids/ 47 68 2003-05 <0.01 good
Can, EU, Aus, (346) (336) (C2) (2.5) (+0.5)
Basiliximab
No. of pts. on Lipid- Japanc 24% +23%
NS fair
lowering therapy (20%) (+30%)
<0.05 fair
mmol/L (3.7) (+1.5)
180 178 1.1 +0.2
HDL, mmol/L Tac XL CsA-ME NS fair
(214) (212) (1.1) (+0.2)
2.1 +0.6
LDL, mmol/L Silva, 2007,24 <0.05 fair
MMF/Steroids/ (2.1) (+0.9)
US, Canada, 12 mo 48 52 <2006
Cholesterol, Basiliximab 3.7 +1.0
Brazila <0.05 fair
mmol/L (3.7) (+1.5)
182 178 1.2 +0.2
HDL, mmol/L Tac CsA-ME NS fair
(212) (212) (1.1) (+0.2)
2.1 +0.4
LDL, mmol/L <0.05 fair
(2.1) (+0.9)
No. analyzed
(enrolled)
(Control) (Control)

Ciancio, 2006, 12 mo 47 44 SRL/Steroids/ NS fair
mmol/L 12 mo Tac CsA-ME 47 80 2000-01 (4.6) (+0.6)
Triglycerides, 2004,25-27 US 36 mo (50) (50) Daclizumab 2.0 -0.2
NS fair
mmol/L 12 mo (2.1) (-0.1)
<0.05 good
mmol/L 6 mo (5.9) (+1.5)
LDL, mmol/L 2.9 +0.1
Gonwa, 46 46 MMF/Steroids/ <0.05 good
6 mo 36 mo Tac CsA-ME 47 100 <1999 (3.7) (+1.1)
2003,28 USd (72) (75) ± OKT3
No. of pts. on Lipid-
7% +6%
lowering therapy <0.01 good
(5%) (+21%)
6 mo
Cholesterol, 5.8 -0.6
<0.001 fair
mmol/L (5.9) (-0.06)
3.5 -0.4
LDL, mmol/L <0.001 fair
Artz, 2003, 64 60 (3.6) (-0.08)
24 mo Tac CsA-cont. nd 50 nd <1999
2004,29,30 EUb (64) (60) 1.4 -0.06
HDL, mmol/L NS fair
(1.4) (-0.03)
Triglycerides, 2.1 -0.4
<0.01 fair
mmol/L (1.9) (0.17)
Total cholesterol, 5.5 -0.5
NS good
mmol/L 24 mo (5.8) (-0.7)
LDL cholesterol, 3.1 -0.2 0.04 at
good
mmol/L 24 mo Hernandez, 80 80 Tac CsA MMF/Steroids/ (3.6) (-0.4) baseline
24 mo 47 100 1999-2004
HDL cholesterol, 2007,31 Spain (80) (80) low dose low dose Basiliximab 1.7 -0.2
NS good
mmol/L 24 mo (1.6) (0)
Triglycerides, 1.6 0
NS good
mmol/L 24 mo (1.7) (0)
Hypertension
No. of pts. on Hardinger,
134 66 AZA or MMF/ 21% +11%
antihypertensive Brennan, 12 mo Tac CsA-ME 45 58 2000-02 NS fair
(134) (66) Steroids/ATG (24%) (+8%)
drugs 2005,16,17 US
Kramer, 2003, 78% 62%
Hypertension 6 mo <0.05 fair
2005, 6 mo 286/237 271/222 (75%) (52%)
Hypertension Margreiter, 24 mo (286) (271) 78% +1%
NS poor
24 mo 2002,20 EU (75%) (-3%)
No. analyzed
(enrolled)
(Control) (Control)
140 –10
SBP, mm Hg NS good
(140) (–10)
Vincenti,
MMF or EC- 80 ±0
DBP, mm Hg 2007,23 US, 346 336 CsA-ME NS good
6 mo Tac MPS, Steroids / 47 68 2003-05 (85) (-5)
Can, EU, Aus, (346) (336) (C2)
No. of pts. on Basiliximab
Japanc 14% +23%
antihypertensive NS fair
(12%) (+31%)
medication
No. of
2.1 +0.2
antihypertensive NS good
(1.9) (+0.4)
drugs
Artz, 2003, 64 60
24 mo Tac CsA-cont. nd 50 nd <1999 144 -7
SBP, mm Hg 2004,29,30 EUb (64) (60) <0.01 fair
(140) (+1)
84 -4
DBP, mm Hg <0.01 fair
(83) (+1)
Other outcomes
10 y CAD-risk in
13% -3%
males, median Kramer, 2003, <0.01 good
(12%) (+3%)
6 mo 2005,18,19, 6 mo 286/237 271/222
10 y CAD-risk in Margreiter, 24 mo (286) (271)
2002,20 EU 7% -2%
females, median NS good
(8%) (-2%)
6 mo
ATG, Antithymocyte globulin; AZA, Azathioprine; CAD, Coronary artery disease; cont., Continued; CrCl, Creatinine clearance; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; d, Day; DBP, Diastolic blood pressure; EC-MPS, Enteric-
coated mycophenolate sodium; eGFR, Estimated glomerular filtration rate; EU, Europe; HDL, High density lipoprotein; LDL, Low-density lipoprotein; MMF, Mycophenolate mofetil; NS, Not significant; OKT3, Muromonab; pt, Patient; SBP, Systolic
blood pressure; SCr, Serum creatinine; SRL, Sirolimus; Tac, Tacrolimus; Tac-XL, Tacrolimus extended-release formula; UK, United Kingdom; US, United States
Annotations:
a. Silva, 200724: three-arm study split within topic 2.3 Tac vs. CsA.
b. Artz, 2003, 2004 29,30: conversion of stable patients 1 year after transplant.
c. Vincenti, 2007 23: CsA-ME adjusted to C2-levels.
d. Gonwa, 200328: three-arm study split (A) topic 2.3 Tac vs. CsA, (B) topic 2.4 MMF vs. AZA.
Supporting Table 11. Evidence Profile Topic 2.2.1: Early vs. delayed introduction of calcineurin inhibitorsa,b,c
Consistency
studies (N on quality of the evidence Other Quality of
Outcome across Importance
and study study studies generalizability/ considerations evidence for Description of effect
studies of outcome
design drug) per outcome applicability outcome
Not adequately
No important Some No difference between early vs.
5 RCTs 620 No limitations powered for the
Mortality inconsistencies uncertainty Low delayed introduction of CsA for up to 2 Critical
(High) (313) (0) outcome
(0) (–1) years
(–1)
Not adequately
5 RCTs 620 No limitations powered for the
Graft loss inconsistencies uncertainty Low delayed introduction of CsA for up to 2 Critical
(High) (313) (0) outcome
(0) (–1) years
(–1)
Not adequately
powered for the
2 RCTs 222 No limitations outcome, limited
Cancer inconsistencies uncertainty Low delayed introduction of CsA for up to 2 Critical
(High) (111) (0) number of
(0) (–1) years
studies
(–1)
Acute 5 RCTs 620 No limitations None
inconsistencies uncertainty Moderate delayed introduction of CsA for up to 2 High
rejection (High) (313) (0) (0)
(0) (–1) years
No important Some Limited number No difference between early vs.
1 RCT 194 No limitations
CAN inconsistencies uncertainty of studies Low delayed introduction of CsA for up to 2 High
(High) (97) (0)
(0) (–1) (–1) years
There is no clear evidence that the
incidence of infections, in particular
Important Some
5 RCTs 620 Some limitations None CMV, is different between early vs.
Infection inconsistencies uncertainty Very low High
(High) (313) (–1) (0) delayed CsA introduction. Differences
(–1) (–1)
in some trials are probably based on
the use of a depleting antibody.
Delayed No important Some
3 RCTs 338 No limitations None No difference between early vs.
graft inconsistencies uncertainty Moderate Moderate
(High) (167) (0) (0) delayed CsA introduction
function (0) (–1)
Important Some There is no clear evidence that kidney
Kidney 5 RCTs 620 No limitations None
inconsistencies uncertainty Low function is different between early vs. Moderate
function (High) (313) (0) (0)
(–1) (–1) delayed CsA introduction.
Important Some Limited number There is no clear evidence that
Lipids inconsistencies uncertainty of studies Very low hyperlipidemia is different between Moderate
(High) (147) (0)
(–1) (–1) (–1) early vs. delayed CsA introduction.
Consistency
Outcome across Importance
and study study studies generalizability/ considerations evidence for Description of effect
studies of outcome
No important Some Limited number
Blood 2 RCTs 294 No limitations No difference between early vs.
inconsistencies uncertainty of studies Very low Moderate
pressure (High) (147) (0) delayed CsA introduction
(0) (–1) (–1)
There is no clear evidence that the
incidence of adverse events is different
Adverse 1 RCT 278 between early vs. delayed CsA Depends
events (High) (137) introduction. Differences are probably on outcome
based on the use of a depleting
antibody.
Balance of potential benefits and harm: Quality of overall evidence:
No net benefit or harm Low (Moderate for CsA-containing regimens)1
CAN, Chronic allograft nephropathy; CMV, Cytomegalovirus; CNI, Calcineurin inhibitors; CsA, Cyclosporine A; CVD, Cardiovascular disease; EC-MPS, Enteric-coated mycophenolate sodium; IL-2, Interleukin-2; N, Number;
RCT, Randomized controlled trials; SR, Systematic review; Tac, Tacrolimus.
Annotations:
a. Evidence limited to CsA containing regimens, no data about Tac.
b. One RCT testing early vs. late CNI introduction in a Basiliximab/EC-MPS/steroids containing regimen, whereas three RCTs are testing early CNI introduction without induction therapy vs. depleting antibody/delayed CNI
introduction; one RCT tested IL-2 antibody induction/early CsA vs. depleting antibody/delayed CNI introduction.
c. References: 33-37
Supporting Table 12. Summary Table Topic 2.2.1: Early vs. delayed introduction of calcineurin inhibitors (categorical outcomes)a
No. analyzed
(enrolled)
%
country duration medication (mean) transplant
Arm 1 Arm 2 Arm 1 Arm 2 donor Arm 1 Arm 2
Mortality
Kamar, 2006,33 12 mo 97/73 97/71 Early CsA Delayed CsA IL2-AB/EC-
24 mo 48 96 2002-03 4% 1% NS good
Franceb 24 mo (97) (97) (day 0) (day 6) MPS/Steroids
Early CsA ATG/ delayed CsA
Kasiske, 1997,34 50 50
90 d 90 d (day 0)/ (established kidney AZA/Steroids 47 42 1994-96 10% 2% NS good
USc (50) (50)
Diltiazem fct.)
OKT3/ delayed CsA
Henry, 2001,35 49 55 Early CsA 4% 4%
12/24 mo 24 mo (SCr 221-265 MMF/Steroids 47 73 <2001 NS poor
USd (49) (55) (day 0) 6% 5%
µmol/L)
Slakey, 1993,36 60 61 Early CsA ALG/ delayed CsA
32 mo 32 mo AZA/Steroids 47 100 1988-1990 10% 7% NS fair
USe (60) (61) (day 0) (day 6)
Basiliximab/ Thymo/
Lebranchu, 6 mo 51 50
6 mo early CsA delayed CsA MMF/Steroids 45 nd 1998-2000 2% 0% NS good
2002,37 Francef 12 mo (51) (50)
(day 0) (SCr <250µmol/L)
Graft loss
Kamar, 200633 12 mo 97/73 97/71 Early CsA Delayed CsA IL2-AB/EC-
24 mo 48 96 2002-03 4% 3% NS good
Kasiske, 1997,34 50 50
90 d 90 d (day 0)/ (established kidney AZA/Steroids 47 42 1994-96 16% 10% NS good
USc (50) (50)
Diltiazem fct.)
8% 4%
12/24 mo OKT 3/ delayed CsA NS poor
Henry, 2001,35 49 55 Early CsA 14% 7%
24 mo (SCr 221-265 MMF/Steroids 47 73 <2001
Death-censored USd (49) (55) (day 0) 4% 0%
µmol/L) NS poor
12/24 mo 6% 2%
ALG/ 20% 12%
Slakey, 1993,36 60 61 Early CsA
24/36/48 mo 32 mo delayed CsA AZA/Steroids 47 100 1988-1990 22% 20% NS fair
USe (60) (61) (day 0)
(day 6) 27% 20%
Basiliximab/ Thymo/
6 mo early CsA delayed CsA MMF/Steroids 45 nd 1998-2000 4% 0% NS good
2002,37 Francef 12 mo (51) (50)
Cancer
ALG/
Slakey, 1993,36 Mean 60 61 Early CsA
PTLD delayed CsA AZA/Steroids 47 100 1988-1990 0% 0% NS fair
USe 32 mo (60) (61) (day 0)
(day 6)
No. analyzed
(enrolled)
%
12 mo Basiliximab/ Thymo/ 0% 0% NS good

early CsA delayed CsA MMF/Steroids 45 nd 1998-2000
PTLD 12 mo 2002,37 Francef 12 mo (51) (50) 0% 0% NS good
Acute rejection
Biopsy-proven
16% 26% NS good
12 mo
Kamar, 12 mo 97/73 97/71 Early CsA Delayed CsA IL2-AB/EC-
Steroid-resistant, 48 96 2002-03
2006,33Franceb 24 mo (97) (97) (day 0) (day 6) MPS/Steroids
antibody treated 4% 9% NS fair
12 mo
Biopsy-proven Early CsA ATG/ delayed CsA 29% 43% NS good
Kasiske, 1997,34 50 50
Steroid-resistant, 90 d (day 0)/ (established kidney AZA/Steroids 47 42 1994-96
USc (50) (50) 10% 14% NS fair
antibody treated Diltiazem fct.)
OKT 3/
Henry, 2001,35 49 55 Early CsA delayed CsA
24 mo 24 mo MMF/Steroids 47 73 <2001 27% 11% NS poor
USd (49) (55) (day 0) (SCr 221-265
µmol/L)
32 mo ALG/ 51% 49% NS fair
Steroid-resistant, 32 mo delayed CsA AZA/Steroids 47 100 1988-1990
USe (60) (61) (day 0) 30% 28% NS fair
antibody treated (day 6)
Biopsy-proven
Basiliximab/ Thymo/ 8% 8% NS good
6 mo Lebranchu, 6 mo 51 50
Steroid-resistant 2002,37 Francef 12 mo (51) (50)
(day 0) (SCr <250µmol/L) 2% 2% NS good
6 mo
Kamar, 12 mo 97/73 97/71 Early CsA Delayed CsA IL2-AB/EC-
CAN 48 96 2002-03 11% 13% NS good
2006,33Franceb 24 mo (97) (97) (day 0) (day 6) MPS/Steroids
Infections
UTI 48 96 2002-03 33% 25% nd good
CMV
CMV 48 96 2002-03 17% 12% nd good
No. analyzed
(enrolled)
%

Kasiske, 1997,34 50 50
CMV 90 d (day 0)/ (established kidney AZA/Steroids 47 42 1994-96 14% 22% NS fair
USc (50) (50)
Diltiazem fct.)
OKT 3/
Henry, 2001,35 49 55 Early CsA delayed CsA
CMV 24 mo MMF/Steroids 47 73 <2001 16% 20% NS poor
USd (49) (55) (day 0) (SCr 221-265
µmol/L)
Non-CMV
requiring ALG/ 23% 18% NS poor
hospitalization 32 mo delayed CsA AZA/Steroids 47 100 1988-1990
USe (60) (61) (day 0)
(day 6)
CMV 7% 20% <0.05 fair
Any 6 mo Basiliximab/ Thymo/ 65% 86% NS good
CMV 6 mo 2002,37 Francef 12 mo (51) (50) 12% 38% <0.01 good
DGF 27% 23% NS good
Kamar, 2006, 33 12 mo 97/73 97/71 Early CsA Delayed CsA IL2-AB/EC-
Slow graft 48 96 2002-03
Franceb 24 mo (97) (97) (day 0) (day 6) MPS/Steroids 31% 28% NS good
function
Kasiske, 1997,34 50 50
DGF 90 d (day 0)/ (established kidney AZA/Steroids 47 42 1994-96 34% 28% NS good
USc (50) (50)
Diltiazem fct.)
Basiliximab/ Thymo/
Lebranchu, 2002 6 mo 51 50
DGF 37 Francef early CsA delayed CsA MMF/Steroids 45 nd 1998-2000 18% 22% NS good
12 mo (51) (50)
Kidney function
CrCl, mL/min Kamar, 2006,33 12 mo 97/73 97/71 Early CsA Delayed CsA IL2-AB/EC-
48 96 2002-03 51 54 NS good
3 mo Franceb 24 mo (97) (97) (day 0) (day 6) MPS/ Steroids
Kasiske, 1997,34 50 50
Scr, µmol/L 90 d (day 0)/ (established kidney AZA/Steroids 47 42 1994-96 194 203 NS good
USc (50) (50)
Diltiazem fct.)
Hypertension
Hypertension 48 96 2002-03 18% 25% nd fair
No. analyzed
(enrolled)
%

Blood pressure, Kasiske, 1997,34 50 50
90 d (day 0)/ (established kidney AZA/Steroids 47 42 1994-96 135/79 140/80 NS good
mm Hg USc (50) (50)
Diltiazem fct.)
Hyperlipidemia
Hypercholesterol Kamar, 2006,33 12 mo 97/73 97/71 Early CsA Delayed CsA IL2-AB/EC-
48 96 2002-03 6% 13% nd fair
-emia Franceb 24 mo (97) (97) (day 0) (day 6) MPS/Steroids
Total cholesterol,
7.1 6.2 <0.01 good
mmol/L
LDL cholesterol,
Early CsA ATG/ delayed CsA 4.5 3.7 <0.01 good
mmol/L Kasiske, 1997,34 50 50
90 d (day 0)/ (established kidney AZA/Steroids 47 42 1994-96
HDL cholesterol, USc (50) (50)
Diltiazem fct.) 1.6 1.4 NS good
mmol/L
Triglycerides,
2.6 2.5 NS good
mmol/L
Adverse events
Anemia 33% 27% nd fair
Leukopenia Kamar, 2006,33 12 mo 97/73 97/71 Early CsA Delayed CsA IL2-AB/EC- 16% 18% nd fair
48 96 2002-03
Diarrhea Franceb 24 mo (97) (97) (day 0) (day 6) MPS/Steroids 17% 10% nd good
Tremor 15% 14% nd good
Anemia Basiliximab/ Thymo/ 0% 8% NS fair

2002,37 Francef 12 mo (51) (50)
Leukopenia (day 0) (SCr <250 µmol/L) 0% 10% <0.05 fair
AE, Adverse events; ALG, Antilymphocyte globulin; ATG, Antithymocyte globulin; AZA, Azathioprine; CAN, Chronic allograft nephropathy; CMV, Cytomegalovirus; CrCl, Creatinine clearance; CsA, Cyclosporine; DGF, Delayed graft function; EC-
MPS, EC-MPS, Enteric-coated mycophenolate sodium; fct, Function; HDL, High density lipoprotein; IL-2 AB, Interleukin-2 antibody; Ktx, Kidney transplant; LDL, Low-density lipoprotein; MMF, Mycophenolate mofetil; nd, Not documented;
NS, Not significant; OKT3, Muromonab; PTLD, Posttransplant lymphoproliferative disease; SCr, Serum creatinine; Thymo, Thymoglobulin; US, United States; UTI, Urinary tract infection.
Annotations:
a. Overlap with topics 1.2.2 (Induction: IL-2 vs. depleting antibody) and 1.2.1 (depleting antibody vs. placebo).
b. Kamar33: CAN: Grade I-III, Banff 97; delayed graft function: ≥1 dialysis session within the first week post KTx; slow graft function: SCr >264 µmol/L at day 5.
c. Kasiske34: DGF: ≥1 dialysis session within the first week post KTx, detailed information, e.g. number of postoperative dialysis sessions, number of dialysis days, transplant renogram (Tc-99 ).
d. Henry35: “poor”-grade because of exclusion of DGF, which represents an outcome of interest for this guideline-topic, and because of only few safety results reported.
e. Slakey36: “fair”-grade because of exclusion of DGF, which represents an outcome of interest for this guideline-topic.
f. Lebranchu37: Steroid-resistant AR: treated either with antibody or with Tacrolimus; DGF: need for dialysis during first week post KTx and/or SCr > 250 µmol/L in the absence of dialysis.
Supporting Table 13. Summary Table Topic 2.2.1: Early vs. delayed introduction of calcineurin inhibitors (continuous outcomes)a
No. analyzed
(enrolled)
Study, year, Study Concomitant Age % deceased Dates of P
Outcome Quality
(Control) (Control)
Kidney function
CrCl, mL/min 51 +2/ +4
NS good
12/24 mo Kamar, 2006,33 12 mo 97/73 97/71 Early CsA Delayed CsA IL2-AB/EC- (54) (+2/ +3)
48 96 2002-03
Franceb 24 mo (97) (97) (day 0) (day 6) MPS/Steroids 178 -9
Scr, µmol/L 12 mo NS good
(162) (+18)
OKT 3 /
Henry, 2001,35 49 55 Early CsA delayed CsA 177 -20
Scr, µmol/L 12 mo 24 mo MMF/Steroids 47 73 <2001 NS poor
USc (49) (55) (day 0) (SCr 221-265 (171) (–16)
µmol/L)
60 +4
CrCl, mL/min 12 mo ALG/ NS fair
Slakey, 1993,36 Mean 60 61 Early CsA (64) (+4)
delayed CsA AZA/Steroids 47 100 1988-1990
USd 32 mo (60) (61) (day 0) 141 ±0
Scr, µmol/L 12 mo (day 6) NS fair
(141) (+18)
64 +2
CrCl, mL/min 12 mo Basiliximab/ Thymo/ <0.01 good
Lebranchu, 6 mo 51 50 (54) (+6)
2002,37 Francee 12 mo (51) (50) 134 –10
Scr, µmol/L 12 mo (day 0) (SCr <250µmol/L) <0.05 good
(151) (–16)
ALG, Antilymphocyte globulin; AZA, Azathioprine; CAN, Chronic allograft nephropathy; CrCl, Creatinine clearance; CsA, Cyclosporine; DGF, Delayed graft function; IL-2 AB, Interleukin-2 antibody; Ktx, Kidney transplant; MMF, Mycophenolate
mofetil; nd, Not documented; NS, Not significant; OKT3, Muromonab; SCr, Serum creatinine; Thymo, Thymoglobulin; US, United States.
Annotations:
a. Overlap with topics 1.2.2 (Induction: IL-2 vs. depleting antibody) and 1.2.1b (depleting antibody vs. placebo).
b. Kamar33: CAN: Grade I-III, Banff 97; delayed graft function: ≥1 dialysis session within the first week post KTx; slow graft function: SCr >264 µmol/L at day 5.
c. Henry35: “poor”-grade because of exclusion of DGF, which represents an outcome of interest for this guideline-topic, and because of only few safety results reported.
d. Slakey36: “fair”-grade because of exclusion of DGF, which represents an outcome of interest for this guideline-topic.
e. Lebranchu37: Steroid-resistant AR: treated either with antibody or with Tacrolimus; DGF: need for dialysis during first week post KTx and/or SCr > 250 µmol/L in the absence of dialysis.
Supporting Table 14. Evidence Profile Topic 2.3: MMF various doses and MMF vs. placeboa,b
Outcome Qualitative and quantitative Importance
and study study studies per across studies generalizability/ considerations evidence for
design drug) outcome applicability description of effect of outcome
outcome
Not adequately
powered for the
No important
5 RCTs 1871 Some limitations No uncertainty outcome No difference between various doses of
(High) (1233) (–1) (0) (duration of MMF and placebo for up to 36 months
(0)
follow-up)
(–1)
Not adequately
powered for the
Important No statistical significant evidence graft
5 RCTs 1871 Some limitations No uncertainty outcome
Graft loss inconsistencies Very low survival in MMF treated patients is Critical
(High) (1233) (–1) (0) (duration of
(–1) prolonged.
follow-up)
(–1)
Not adequately
powered for the
No important
5 RCTs 1871 Some limitations No uncertainty outcome No difference between various doses of
(High) (1233) (–1) (0) (duration of MMF and placebo for up to 36 months
(0)
follow-up)
(–1)
MMF (2 g or 3 g, not 1 g) is better than
placebo in the prevention of acute
rejection for up to 36 months.
No important MMF 2 g is better than MMF 1 g in the
Acute 5 RCTs 1871 Some limitations No uncertainty None
inconsistencies Moderate prevention of acute rejection for up to 12 High
rejection (High) (1233) (–1) (0) (0)
(0) months.
There is no clear evidence that MMF 3 g
is better than MMF 2 g in the prevention
of acute rejection for up to 36 months.
No statistical significant effect on
No important
2 RCTs 384 Some limitations No uncertainty Sparse data NODAT between MMF and placebo, but
NODAT inconsistencies Low High
(High) (224) (–1) (0) (–1) there might be less NODAT in MMF
(0)
treated patients
There is no statistical significant
No important
Infection 5 RCTs 1871 Some limitations No uncertainty None difference between various doses of
(disease) (High) (1233) (–1) (0) (0) MMF and placebo in the incidence of
(0)
infections.
Outcome Qualitative and quantitative Importance
and study study studies per across studies generalizability/ considerations evidence for
design drug) outcome applicability description of effect of outcome
outcome
No important
Delayed graft 2 RCTs 673 No limitations No uncertainty Sparse data No difference between various doses of
function (High) (455) (0) (0) (–1) MMF
(0)
Kidney function is better in patients
Important
Kidney 4 RCTs 1552 Some limitations No uncertainty None treated with various doses of MMF than
inconsistencies Low Moderate
function (High) (1008) (–1) (0) (0) with placebo. There is no difference
(–1)
between different doses of MMF.
No important
1 RCT 208 Some limitations No uncertainty Sparse data No difference between various doses of
Lipids inconsistencies Low Moderate
(High) (102) (–1) (0) (–1) MMF and placebo, respectively
(0)
No important
Blood 1 RCT 208 Some limitations No uncertainty Sparse data No difference between various doses of
pressure (High) (102) (–1) (0) (–1) MMF and placebo, respectively
(0)
MMF is causing more bone marrow
No important suppression than placebo.
Bone marrow 4 RCTs 1520 Some limitations No uncertainty None
inconsistencies Low There is no statistical significant effect Moderate
suppression (High) (1119) (–1) (0) (0)
(0) between MMF 2 g and MMF 3 g on
leucopenia and anemia.
No statistical significant effect on
No important diarrhea between MMF and placebo.
4 RCTs 1520 Some limitations No uncertainty None
Diarrhea inconsistencies Moderate There might be evidence that higher Moderate
(High) (1119) (–1) (0) (0)
(0) doses of MMF cause more diarrhea than
lower doses of MMF.
MMF (2 g or 3 g, not 1 g) is better than placebo in the prevention of acute rejection Low (Moderate for acute rejection)
AZA, Azathioprine; CVD, Cardiovascular disease; g, grams; MMF, Mycophenolate mofetil; N, Number; NODAT, New onset diabetes after transplant; RCT, Randomized controlled trials; SR, Systematic review.
Annotations:
a. Including information of three RCTs comparing MMF 2 g vs. MMF 3 g listed in the summary table about MMF vs. AZA (topic 2.4).
b. References: 38-42
Supporting Table 15. Summary Table Topic 2.3: MMF various doses and MMF vs. placebo (categorical outcomes)
Outcome Arm Arm Arm P value Quality
country duration Arm 1 Arm 2 Arm 3 Arm 1 Arm 2 Arm 3 medication (mean) donor transplant
1 2 3
Mortality
3% 2% 4%
6 mo/3 y nd fair
6 mo 8% 7% 11%
European MMF 165 166 160
With 12 mo MMF 3 g MMF 2 g Placebo CsA/Steroids 46 100 1992-95
study, 1999,38 EU (165) (166) (160)
functioning 3y 6% 7% 6% nd fair
graft 3 y
Shapiro, 1999,39 106 102 No
15 mo 12 mo — — MMF 2 g Tac/Steroids 51 100 1995-97 — 4% 7% nd fair
US (106) (102) Placebo
Graft loss
6% 4% 9%
6 mo/3 y European MMF 6 mo nd fair
165 166 160 19% 15% 22%
study, 1999,38 12 mo MMF 3 g MMF 2 g Placebo CsA/Steroids 46 100 1992-95
Excluding (165) (166) (160)
EU 3y 13% 9% 16% nd fair
death 3 y
Shapiro, 1999,39, 106 102 No
15 mo 12 mo — — MMF 2 g Tac/Steroids 51 100 1995-97 — 8% 15% nd fair
Cancer
European MMF 6 mo 0% 1% 1%
6 mo/3 y 165 166 160 nd fair
study, 1999,38 12 mo MMF 3 g MMF 2 g Placebo CsA/Steroids 46 100 1992-95 1% 2% 3%
(165) (166) (160)
PTLD 6 mo EU 3y 0% 0% 0% nd fair
Shapiro, 1999,39 106 102 No
PTLD 15 mo 12 mo — — MMF 2 g Tac/Steroids 51 100 1995-97 — 0% 1% nd fair
Acute rejection
6 mo 26% 30% 55% nd fair
Biopsy-proven
14% 17% 46% nd fair
6 mo European MMF 6 mo
Severity of 165 166 160
AR, Banff II or (165) (166) (160) 5% 10% 30% nd fair
EU 3y
higher 6 mo
Steroid-
3% 5% 22% nd fair
resistant 6 mo
15 mo — 27% 44% 0.014 poor
Steroid-
resistant Shapiro, 1999,39 106 102 No — 3% 8% NS fair
15 mo 12 mo — — MMF 2 g Tac/Steroids 51 100 1995-97
Severity of
AR, Banff II or — 7% 19% nd poor
higher 15 mo
Outcome Arm Arm Arm P value Quality
country duration Arm 1 Arm 2 Arm 3 Arm 1 Arm 2 Arm 3 medication (mean) donor transplant
1 2 3
NODAT
Shapiro, 1999,39 106 102 No
12 mo 12 mo — — MMF 2 g Tac/Steroids 51 100 1995-97 — 1% 5% nd poor
Infection
CMV 3 y European MMF 6 mo 165 166 160 23% 19% 16% nd fair
PCP 6 mo (165) (166) (160) 7% 3% 2% nd fair
EU 3y
Shapiro, 1999,39 106 102 No
CMV 15 mo 12 mo — — MMF 2 g Tac/Steroids 51 100 1995-97 — 17% 9% nd fair
Kidney function
6 mo
Scr, µmol/L European MMF 108 126 114
12 mo MMF 3 g MMF 2 g Placebo CsA/Steroids 46 100 1992-95 130 126 142 <0.05 poor
6 mo study, 1999,38 EU (165) (166) (160)
3y
Scr, µmol/L Shapiro, 1999,39 106 102 No
12 mo — — MMF 2 g Tac/Steroids 51 100 1995-97 — 150 141 nd poor
15 mo US (106) (102) Placebo
Lipids
Cholesterol, Shapiro, 1999,39 106 102 No
12 mo — — MMF 2 g Tac/Steroids 51 100 1995-97 — 4.97 5.17 nd fair
mmol/L 15 mo US (106) (102) Placebo
Hypertension
Pts w/o anti-
Shapiro, 1999,39 106 102 No
hypertensive 12 mo — — MMF 2 g Tac/Steroids 51 100 1995-97 — 39% 25% nd poor
drugs 15 mo
Adverse events
Diarrhea 16% 13% 13%
nd fair
6 mo/3 y 26% 21% NA
European MMF 6 mo
Leucopenia 165 166 160 14% 11% 4%
study, 1999,38 12 mo MMF 3 g MMF 2 g Placebo CsA/Steroids 46 100 1992-95 nd fair
6 mo/3 y (165) (166) (160) 20% 14% NA
EU 3y
Anemia 7% 4% 2%
nd fair
6 mo/ 3 y 8% 5% 2%
AE, Adverse events; AR, Acute rejection; CMV, Cytomegalovirus; CsA, Cyclosporine; EU, Europe; MMF, Mycophenolate mofetil; nd, Not documented; NODAT, New onset diabetes after transplantation; NS, Not significant; PCP, Pneumocystis
pneumonia; PTLD, Posttransplant lymphoproliferative disease; pt, Patient; SCr, Serum creatinine; Tac, Tacrolimus; US, United States; w/o, Without.
Supporting Table 16. Evidence Profile Topic 2.3: MMF vs. AZAa
Total N Directness of the Summary of findings
No. of studies Methodological
(N on Consistency evidence Other
Outcome and study quality of studies Quality of evidence Qualitative and quantitative Importance
study across studies generalizability/ considerations
design per outcome for outcome description of effect of outcome
drug) applicability
No limitations for
Not adequately
up to 3 years Moderate
powered for the
(0) No important (<3 y)
6 RCTs 2138 No uncertainty outcome No difference between MMF and AZA for up
Mortality Some limitations inconsistencies Critical
(High) (1356) (0) (duration of to 6 years
for more than 3 (0) Low
follow-up)
years (>3 y)
(–1)
(–1)
No limitations for
Not adequately
up to 3 years Moderate
powered for the
6 RCTs 2138 No uncertainty outcome No difference between MMF and AZA for up
Graft loss Some limitations inconsistencies Critical
(High) (1356) (0) (duration of to 6 years
for more than 3 (0) Low
follow-up)
years (>3 y)
(–1)
(–1)
Not adequately
powered for the
No important
4 RCTs 1514 Some limitations No uncertainty outcome No difference between MMF and AZA for up
(High) (956) (–1) (0) (duration of to 6 years
(0)
follow-up)
(–1)
MMF (2 g or 3 g, not 1 g) might be better than
Dose response:
Important AZA in the prevention of acute rejection within
6 RCTs 2138 No limitations Some uncertainty MMF 2 g better
Acute rejection inconsistencies Moderate the first year after transplantation, one trial High
(High) (1356) (0) (–1) than 1 g
(–1) showed similar acute rejection rates in a CsA-
(+1)
ME based regimen
Sparse data
No important
2 RCTs 323 Some limitations No uncertainty (limited number No difference between MMF and AZA for up
(High) (190) (–1) (0) of studies) to 3 years
(0)
(–1)
Important No difference between MMF and AZA for up
Infection 6 RCTs 2138 Some limitations No uncertainty None
inconsistencies Low to 6 years, higher incidence of CMV infection High
(disease) (High) (1356) (–1) (0) (0)
(–1) in MMF treated patients in 1 trial
No important
Delayed graft 4 RCTs 1162 No limitations No uncertainty None
inconsistencies High No difference between MMF and AZA Moderate
function (High) (695) (0) (0) (0)
(0)
drug) applicability
No limitations for
up to 3 years High
Kidney 5 RCTs 1962 No uncertainty None No difference between MMF and AZA for up
Some limitations inconsistencies Moderate
function (High) (1230) (0) (0) to 6 years
for more than 3 (0) Moderate
years (>3 y)
(–1)
Sparse data
No important
1 RCT 336 Some limitations No uncertainty (limited number
Proteinuria inconsistencies Low No difference between MMF and AZA Moderate
(High) (168) (–1) (0) of studies)
(0)
(–1)
Sparse data
No important
2 RCT 323 Some limitations No uncertainty (limited number No difference between MMF and AZA for up
(High) (190) (–1) (0) of studies) to 3 years
(0)
(–1)
Important
Bone marrow 5 RCTs 1991 No limitations No uncertainty None No statistical significant effect on leucopenia
suppression (High) (1276) (0) (0) (0) and anemia between MMF and AZA
(–1)
No important No statistical significant effect on diarrhea
Diarrhea inconsistencies Moderate between MMF and AZA as reported, but Moderate
(High) (1276) (0) (0) (0)
(0) overall more diarrhea in MMF treated patients
MMF (2 g or 3 g, not 1 g) might be better than AZA in the prevention of acute rejection within the first year after transplantation, Low (Moderate for acute rejection)
but not other outcomes
AZA, Azathioprine, CMV, Cytomegalovirus; CsA-ME, Cyclosporine A microemulsion; CVD, Cardiovascular disease; MMF, Mycophenolate mofetil; N, Number; NODAT, New onset diabetes after transplant; RCT, Randomized controlled trials.
Annotations:
Supporting Table 17. Summary Table Topic 2.3: MMF vs. AZA (categorical outcomes)a,b
%
Concom- Dates of
Study, year, Study Age decea P
Outcome Arm Arm Arm Arm Arm Arm Arm Arm itant trans- Arm Arm Arm Arm Quality
country duration (mean) sed value
1 2 3 4 1 2 3 4 medication plant 1 2 3 4
donor
Mortality
Including Sadek, AZA
MMF
death with 2002,43 158 162 157 MMF 1-2 CsA-ME/
12 mo —
(158) (162) (157)
—
2g
Æ
mg/
44 86 <2001 — 5% 3% 5% NS good
functioning Brazil, EU, AZA² Ster
graft Canadab kg
Mathew,
1998, 6 mo AZA 2% 1% 1%
6 mo/12 164 171 162 MMF MMF 100-
1996,40,44 12 mo (164) (173)
—
(166) 3g 2g
—
150
CsA/Ster 46 100 1992-93 4% 4% — 4% nd good
mo/36 mo
Canada, EU, 36 mo mg 9% 5% 8%
Aus
AZA
Miller, 6 mo 59 59 58 MMF MMF 1.5 Tac/ Ster/
12 mo — — 44 100 1996-98 — 5% 5% 2% NS fair
2000,41 US 12 mo (59) (59) (58) 2g 1g mg/ ±OKT3
kg
Sollinger, AZA
6 mo 166 167 166 MMF MMF 1-2 CsA/Ster 5% 4% 3%
6 mo/36 mo 1995, 199942 (166) (167)
—
(166) 3g 2g
—
mg/
46 100 1992-93 — NS fair
36 mo /±ATG 12% 11% 12%
US kg
Remuzzi, AZA
164/ 164/
6 mo MMF 100- CsA-ME/ 1997- 2% 2% good
6 mo/72 mo 2004, — 124 — 124 — — 44 100 — — NS
72 mo (168) (168)
2g 150 ±Ster 2001 4% 4% fair
2007,47 EU mg
AZA
Gonwa, 72 75 MMF 1.5-2 Tac/Ster/
24 mo 36 mo — — — — 47 100 <1999 — 6% — 4% NS good
2003,28 USa (72) (75) 2g mg/ ±OKT3
kg
Graft loss
Sadek, AZA
MMF
Excluding 2002,43, 158 162 157 MMF 1-2 CsA-ME/
12 mo — — Æ 44 86 <2001 — 10% 9% 10% NS good
death 12 mo Brazil, EU, (158) (162) (157) 2g
AZA²
mg/ Ster
Canadab kg
Mathew,199
8, 6 mo AZA 2% 4% 3%
6 mo/12 164 171 162 MMF MMF 100-
1996,40,44 12 mo (164) (173)
—
(166) 3g 2g
—
150
CsA/Ster 46 100 1992-93 8% 9% — 11% nd good
mo/36 mo
Can, EU, 36 mo mg 15% 18% 20%
Aus
AZA
Excluding Miller, 6 mo 59 59 58 MMF MMF 1.5 Tac/Ster/
— — 44 100 1996-98 — 0% 2% 5% NS fair
death 12 mo 2000,41 US 12 mo (59) (59) (58) 2g 1g mg/ ±OKT3
kg
%
Concom- Dates of
donor
Sollinger, AZA
6 mo 166 167 166 MMF MMF 1-2 CsA/Ster/ 7% 2% 9%
6 mo/36 mo 1995, 199942 — — 46 100 1992-93 — NS fair
36 mo (166) (167) (166) 3g 2g mg/ ±ATG 17% 13% 17%
US kg
Remuzzi, AZA
164/ 164/
6 mo MMF 100- CsA-ME/ 1997- 1% 1% good
6 mo/72 mo 2004, — 124 — 124 — — 44 100 — — NS
72 mo (168) (168)
2g 150 ±Ster 2001 6% 7% fair
2007,47 EU mg
AZA
36 mo 36 mo — — — — 47 100 <1999 — 19% — 20% NS good
2003,28 USa (72) (75) 2g mg/ ±OKT3
kg
Cancer
12 mo/36 Mathew, 8% 11% 7%
6 mo AZA — nd good
mo 1998, 12% 15% 18%
164 171 162 MMF MMF 100-
1996,40,44 12 mo (164) (173)
—
(166) 3g 2g
—
150
CsA/Ster 46 100 1992-93
Lymphoma/L 36 mo
Canada, EU, mg 2% 1% — 1% nd good
PD 36 mo
Aus
AZA
Miller, 6 mo 59 59 58 MMF MMF 1.5 Tac/Steroids
PTLD 12 mo — —
mg/
44 100 1996-98 — 0% 0% 0% NS fair
2000,41 US 12 mo (59) (59) (58) 2g 1g /±OKT3
kg
Sollinger, AZA
PTLD 6 6 mo 166 167 166 MMF MMF 1-2 CsA/Ster/ 1% <1% 0%
1995, 199942 — — 46 100 1992-93 — NS fair
mo/36 mo 36 mo (166) (167) (166) 3g 2g mg/ ±ATG 2% <1% <1%
US kg
72 mo Remuzzi 164/ 164/
AZA — 6% — 10% NS fair
6 mo MMF 100- CsA-ME/ 1997-
2004, — 124 — 124 — — 44 100
PTLD 72 mo 72 mo (168) (168)
2g 150 ±Ster 2001 — 2% — 2% NS fair
2007,47 EU mg
Acute rejection
12 mo — 21% 23% 33% <0.05 good
Sadek, AZA
Biopsy- 2002,43, MMF
CsA-ME/
12 mo —
158 162 157
—
MMF 1-2
44 86 <2001 — 17% 17% 27% <0.05 good
proven Brazil, EU, (158) (162) (157) 2g
Æ
mg/ Ster
Steroid- AZA²
Canadab kg — 7% 6% 15% <0.05 good
resistant
Biopsy-
16% 20% — 36% nd good
proven 6 mo Mathew,1998, AZA
6 mo
Severity of 1996,40,44
12 mo
164 171
—
162 MMF MMF
—
100-
CsA/Ster 46 100 1992-93
AR, Banff II Canada, EU, (164) (173) (166) 3g 2g 150
36 mo 6% 10% — 20% nd good
or higher 6 Aus mg
mo
%
Concom- Dates of
donor
7% 29% 29% <0.01

6 mo/12 mo AZA — fair
Miller, 6 mo 59 59 58 MMF MMF 1.5 Tac/Ster/ 9% 32% 32% <0.01
Time to AR, — — 44 100 1996-98
2000,41 US 12 mo (59) (59) (58) 2g 1g mg/ ±OKT3 98 53 28
days kg — nd fair
129 79 55
6 mo/12 mo
Biopsy-
18% 20% — 38% nd good
proven 6 mo
6 mo 24% 26% — 46% nd good
Steroid- AZA
Sollinger,
resistant 6 mo 166 167 166 MMF MMF 1-2 CsA/Ster/ 5% 10% — 19% nd good
1995, 199942 — — 46 100 1992-93
6 mo 36 mo (166) (167) (166) 3g 2g mg/ ±ATG
US kg
Severity of
AR, Banff II
12% 9% — 20% nd good
or higher 6
mo
34% 35% good
6 mo/72 mo — — NS
46% 52% fair
Biopsy-
— 18% — 23% NS good
proven 6 mo
Remuzzi, AZA
Severity of 164/ 164/
CsA-ME/
6 mo MMF 100- 1997-
AR, Banff II 2004, — 124 — 124 — — 44 100
72 mo (168) (168)
2g 150 ±Ster 2001 — 17% — 23% NS good
or higher 2007,47 EU mg
6 mo
Steroid-
resistant — 5% — 11% NS good
6 mo
36 mo AZA — 17% — 21% NS good
Treated with 36 mo — — — — 47 100 <1999
2003,28 USa (72) (75) 2g mg/ ±OKT3 — 6% — 16% <0.05 good
antibody kg
NODAT
AZA
Miller, 6 mo 59 59 58 MMF MMF 1.5 Tac/Ster/
12 mo — — 44 100 1996-98 — 5% 12% 19% NS fair
2000,41 US 12 mo (59) (59) (58) 2g 1g mg/ ±OKT3
kg
AZA
36 mo 36 mo — — — — 47 100 <1999 — 13% — 19% nd fair
2003,28 USa (72) (75) 2g mg/ ±OKT3
kg
%
Concom- Dates of
donor
Infections
Sadek, AZA
MMF
2002,43, 158 162 157 MMF 1-2 CsA-ME
CMV 12 mo —
(158) (162) (157)
—
2g
Æ
mg/
44 86 <2001 — 20% 22% 11% NS fair
Brazil, EU, AZA² /Ster
Canadab kg
CMV –
viremia + Mathew,
1998, 6 mo AZA 13% 13% — 12% nd good
syndrome 164 171 162 MMF MMF 100-
36 mo 1996,40,44 12 mo (164) (173)
—
(166) 3g 2g
—
150
CsA/Ster 46 100 1992-93
Opportunistic Canada, EU, 36 mo mg
infections Aus 46% 46% — 44% nd good
12 mo
AZA
Miller, 6 mo 59 59 58 MMF MMF 1.5 Tac/Ster/
CMV 12 mo — — 44 100 1996-98 — 7% 7% 5% NS fair
2000,41 US 12 mo (59) (59) (58) 2g 1g mg/ ±OKT3
kg
Opportunistic
infections Sollinger, AZA 47% 45% — 46% NS fair
6 mo 166 167 166 MMF MMF 1-2 CsA/Ster
6 mo 1995, 199942 — — 46 100 1992-93
36 mo (166) (167) (166) 3g 2g mg/ /±ATG
CMV US kg 24% 24% 21% NS
— fair
6 mo/36 mo 27% 26% 22% nd
Remuzzi, AZA
164/ 164/
CMV 6 mo MMF 100- CsA-ME/ 1997- 26% 25% good
2004, — 124 — 124 — — 44 100 — — NS
6 mo/72 mo 72 mo (168) (168)
2g 150 ±Ster 2001 32% 37% fair
2007,47 EU mg
CMV AZA — 14% 4% <0.01 good
36 mo — — — — 47 100 <1999
PCP 2003,28 USa (72) (75) 2g mg/ ±OKT3 — 0% 1% NS good
kg
Mathew,
1998, 6 mo AZA
164 171 162 MMF MMF 100-
6 mo 1996,40,44 12 mo (164) (173)
—
(166) 3g 2g
—
150
CsA/Ster 46 100 1992-93 18% 21% — 13% nd good
Canada, EU, 36 mo mg
Aus
AZA
Miller, 1.5
6 mo 59 59 58 MMF MMF Tac/Ster/
6 mo 2000,41 — — mg/ 44 100 1996-98 — 16% 14% 12% nd fair
12 mo (59) (59) (58) 2g 1g
kg ±OKT3
US
%
Concom- Dates of
donor
Remuzzi AZA
164/ 164/
6 mo MMF 100- CsA-ME / 1997-
6 mo 2004, — 124 — 124 — — 44 100 — 31% — 35% NS good
72 mo (168) (168)
2g 150 ±Ster 2001
2007,47 EU mg
AZA
36 mo 36 mo — — — — 47 100 <1999 — 36% — 33% NS fair
2003,28 USa (72) (75) 2g mg/ ±OKT3
kg
Kidney function
Sadek, AZA
MMF
Scr, µmol/L 2002,43, 158 162 157 MMF 1-2 CsA-ME 140 144 140
12 mo — — Æ 44 86 <2001 — NS good
14 wk/12 mo Brazil, EU, (158) (162) (157) 2g
AZA²
mg/ /Ster 151 146 130
Canadab kg
Mathew,
Scr, µmol/L 1998, 6 mo AZA 123 141 141
164 171 162 MMF MMF 100-
6 mo/12 1996,40,44 12 mo (164) (173)
—
(166) 3g 2g
—
150
CsA/Ster 46 100 1992-93 123 141 — 141 nd good
mo/36 mo Canada, EU, 36 mo mg 141 158 150
Aus
Sollinger, AZA
Scr, µmol/L 6 mo 166 167 166 MMF MMF 1-2 CsA/Ster 150 150 158
1995, 199942 (166) (167)
—
(166) 3g 2g
—
mg/
46 100 1992-93 — NS fair
6 mo/36 mo 36 mo /±ATG 150 150 158
US kg
Scr, µmol/L
AZA — 141 — 132 NS good
6 mo Remuzzi, 164/ 164/
6 mo MMF 100- CsA-ME / 1997-
eGFR, 2004, — 124 — 124 — — 44 100
72 mo (168) (168)
2g 150 ±Ster 2001 62 62 good
mL/min 2007,47 EU mg — — NS
47 50 fair
6 mo/72 mo
Scr, µmol/L AZA — 123 — 123 NS fair
Gonwa, 72 75 MMF 1.5-2 Tac/Ster
CrCl, 36 mo — — — — 47 100 <1999
2003,28 USa (72) (75) 2g mg/ /±OKT3 — 59 — 62 NS fair
mL/min kg
Proteinuria
Proteinuria, Remuzzi, AZA
164/ 164/
6 mo MMF 100- CsA-ME/ 1997-
>0.5 g/d 2004, — 124 — 124 — — 44 100 — 27% — 25% NS fair
72 mo (168) (168)
2g 150 ±Ster 2001
72 mo 2007,47 EU mg
Lipids
Hyperlipid- Miller, 6 mo AZA
Tac/Ster
59 59 58 MMF MMF
emia — — 1.5 44 100 1996-98 — 19% 19% 17% NS poor
2000,41 US 12 mo (59) (59) (58) 2g 1g
mg/ /±OKT3
12 mo
%
Concom- Dates of
donor
Hypercholes- kg
terolemia — 7% 9% 9% NS poor
12 mo
Adverse events
Diarrhea 12
— 17% 13% 8% NS good
mo Sadek, AZA
MMF
Leucopenia 2002,43, 158 162 157 MMF 1-2 CsA-ME/
12 mo — — Æ 44 86 <2001 — 19% 20% 19% NS good
12 mo Brazil, EU, (158) (162) (157) 2g
AZA²
mg/ Ster
Anemia Canadab kg
— 17% 18% 16% NS good
12 mo
Diarrhea
31% 28% 17%
12 — nd good
38% 35% 20%
mo/36 mo Mathew,
1998, 6 mo AZA
Leucopenia
164 171 162 MMF MMF 100- 35% 19% 30%
12 mo/36 1996,40,44 12 mo (164) (173)
—
(166) 3g 2g
—
150
CsA/Ster 46 100 1992-93 — nd good
38% 20% 31%
mo Canada, EU, 36 mo mg
Anemia Aus
9% 15% 10%
12 mo/36 — nd good
12% 16% 10%
mo
Anemia
— 45% 42% 49% NS poor
12 mo AZA
Leukopenia Miller, 6 mo 59 59 58 MMF MMF 1.5 Tac/Ster
— — 44 100 1996-98 — 36% 32% 22% <0.05 poor
12 mo 2000,41 US 12 mo (59) (59) (58) 2g 1g mg/ /±OKT3
Diarrhea 12 kg
— 64% 44% 41% NS fair
mo
Diarrhea 37% 32% 24%
— nd fair
6 mo/36 mo AZA 47% 42% 33%
Sollinger,
Leucopenia 6 mo 166 167 166 MMF MMF 1-2 CsA/Ster
1995, 199942 (166) (167)
—
(166) 3g 2g
—
mg/
46 100 1992-93 37% 29% — 24% nd fair
36 mo 36 mo /±ATG
US kg
Anemia
47% 44% — 43% nd fair
36 mo
Diarrhea 6 AZA
Remuzzi, 164/ 164/ — 2% — 1% NS good
mo 6 mo MMF 100- CsA-ME/ 1997-
2004, — 124 — 124 — — 44 100
Leucopenia 72 mo (168) (168)
2g 150 ±Ster 2001
2007,47 EU mg — 19% — 13% NS good
6 mo
AE, Adverse events; AR, Acute rejection; Aus, Australia; AZA, Azathioprine; CMV, Cytomegalovirus; CrCl, Creatinine clearance; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; EU, Europe; LPD, Lymphoproliferative disorders;
MMF, Mycophenolate mofetil; nd, Not documented; NODAT, New onset diabetes after transplantation; NS, Not significant; OKT3, Muromonab; PCP, Pneumoystis pneumonia; PTLD, Posttransplant lymphoproliferative disease; SCr,
Serum creatinine; SRL, Sirolimus; Ster, Steroids; Tac, Tacrolimus; US, United States.
Annotations:
a. Gonwa, 200328: three-arm study split (A) topic 2.3 Tac vs. CsA, (B) topic 2.4 MMF vs. AZA. b. Sadek, 200243: arm 3: MMF 2 g from d0 to d90, thereafter switch to AZA.
Supporting Table 18. Summary Table Topic 2.3: MMF vs. AZA (continuous outcomes)a
No. analyzed
Intervention/control Results
(enrolled)
%
Outcome Arm 1 deceased P value Quality
country duration Arm 2 medication (mean) transplant Baseline ∆
Arm 1 Arm 2 (interventio donor
(control) (Control) (Control)
n)
Lipids
Total cholesterol, 5.79 +0.62
NS good
mmol/L 6 mo (5.99) (+0.77)
LDL, mmol/L, AZA 2.92 +0.02
Gonwa, 72 75 MMF Tac /Ster/ NS good
6 mo 36 mo 1.5-2 47 100 <1999 (3.54) (+0.55)
2003,28 USa (72) (75) 2g ±OKT3
No. of pts. on mg/kg
7% +6%
lipid-lowering <0.01 fair
(7%) -1.3%
therapy 6 mo
AZA, Azathioprine; LDL, Low-density lipoprotein; MMF, Mycophenolate mofetil; NS, Not significant; OKT3, Muromonab; pt, Patient; Ster, Steroids; Tac, Tacrolimus; US, United States.
Annotations:
a. Gonwa 2003 [619]: three-arm study split (A) topic 2.3 Tac vs. CsA, (B) topic 2.4 MMF vs. AZA.
Supporting Table 19. Evidence Profile Topic 2.4: Steroid avoidance/early withdrawal vs. steroid maintenancea,b
Outcome and study quality of studies Quality of evidence Importance
study across studies generalizability/ considerations Description of effect
design per outcome for outcome of outcome
drug) applicability
Not adequately
No important
4 RCTs 1348 No limitations No uncertainty powered for the No difference between steroid avoidance and
Mortality inconsistencies Moderate Critical
(High) (667) (0) (0) outcome steroid maintenance for up to 5 years
(0)
(–1)
Not adequately
No important
Graft loss inconsistencies Moderate Critical
(0)
(–1)
Not adequately
No important
Cancer inconsistencies Moderate Critical
(0)
(–1)
Higher rate of steroid sensitive acute
rejections in patients treated with induction
antibody with early steroid avoidance
important compared to patients treated with induction
Acute rejection inconsistencies Moderate antibody maintained on steroids. High
(High) (667) (0) (0) (0)
(–1) No difference in acute rejection rates between
steroid avoidance with induction antibody and
steroid maintenance/withdrawal without
induction antibody.
No important
4 RCTs 1348 No limitations No uncertainty None No difference between steroid avoidance and
NODAT inconsistencies High High
(High) (667) (0) (0) (0) steroid maintenance for up to 5 years
(0)
No important
Infection 3 RCTs 984 No limitations No uncertainty None No difference between steroid avoidance and
inconsistencies High High
(disease) (High) (481) (0) (0) (0) steroid maintenance for up to 5 years
(0)
No important There is no clear evidence that there is a
3 RCT 750 No limitations No uncertainty None
Bone fractures inconsistencies High difference between steroid avoidance and High
(High) (377) (0) (0) (0)
(0) steroid maintenance for up 5 years.
No difference between steroid avoidance with
No important
Delayed graft 3 RCTs 962 No limitations No uncertainty None induction antibody and steroid
inconsistencies High Moderate
function (High) (476) (0) (0) (0) maintenance/withdrawal without induction
(0)
antibody
drug) applicability
No important
Kidney 4 RCTs 1348 No limitations No uncertainty None No difference between steroid avoidance and
inconsistencies High Moderate
function (High) (667) (0) (0) (0) steroid maintenance for up to 5 years
(0)
No difference between steroid avoidance with
No important
1 RCT 364 No limitations No uncertainty Sparse data induction antibody and steroid
Proteinuria inconsistencies Moderate Moderate
(High) (186) (0) (0) (–1) maintenance/withdrawal without induction
(0)
antibody for up 12 months
Important No significant difference in lipid profiles
Lipids inconsistencies Moderate between steroid avoidance and steroid Moderate
(High) (637) (0) (0) (0)
(–1) maintenance
No important
3 RCTs 1288 No limitations No uncertainty None No difference between steroid avoidance and
Blood pressure inconsistencies High Moderate
(High) (637) (0) (0) (0) steroid maintenance for up to 5 years
(0)
There is no clear evidence that BMD in
Important patients treated without steroids but with
Bone mineral 2 RCTs 354 Some limitations No uncertainty Sparse data
inconsistencies Very low induction antibody is higher than in patients Moderate
density (High) (183) (–1) (0) (–1)
(–1) with steroids and without induction antibody
for up 12 months
No difference between steroid avoidance and
Important steroid maintenance for up to 5 years in the
Bone marrow 2 RCTs 924 No limitations No uncertainty None
inconsistencies Moderate incidence of anemia Moderate
suppression (High) (451) (0) (0) (0)
(–1) Leukopenia might be more common in
patients without steroid treatment
Tachycardia and dyspnea might be more
frequent in patients treated without steroids
3 RCTs 1288 Depends on
Adverse events but with induction antibody compared to
(High) (637) outcome
patients maintained on with steroids and
without induction antibody
Steroid avoidance/early withdrawal is associated with a higher incidence of steroid-sensitive acute rejections. Moderate
BMD, Bone mineral density; CVD, Cardiovascular disease; NODAT, New onset diabetes after transplant; RCT, Randomized controlled trials.
Annotations:
a. Evidence combined from trials comparing steroid avoidance/early withdrawal vs. steroid maintenance as well as steroid avoidance/early withdrawal with induction therapy vs. steroid maintenance without induction therapy.
b. References: 8,9,13,48,49
Supporting Table 20. Summary Table Topic 2.4: Steroid avoidance/early withdrawal vs. steroid maintenance (categorical outcomes)
No. analyzed
(enrolled)
country duration medication (mean) donor transplant
Arm 1 Arm 2 Arm 1 Arm 2 Arm 1 Arm 2
Mortality
Daclizumab/
Rostaing, 260 278 No Daclizimab
6 mo 6 mo Steroid Tac/MMF 47 nd 2000-02 2% 1% NS good
2005,8 EUa (260) (278) /Steroids
avoidance
ter Meulen, Daclizumab/ No Daclizumab/
186 178
12 mo 2004,9,48 12 mo Steroid Steroid Tac/MMF 49 64 1999-2002 5% 6% NS good
(186) (178)
Netherlandsb avoidance withdrawal
Alemtuzumab/
12 mo Steroid Thymo/Steroids 0% 8% NS poor
Ciancio, 30 30 avoidance
12 mo Tac/MMF 50 100 2002-04
2005,13 USc (30) (30) Alemtuzumab/
Daclizumab/
12 mo Steroid 0% 12% NS poor
Steroids
avoidance
Woodle, 191 195 Steroid Steroid Tac/MMF/IL2 1999-
5y 5y 47 43 6% 7% NS good
2008,49 USd (191) (195) withdrawal4 maintenance or Thymo 2002
Graft loss
Daclizumab/
Rostaing, 260 278 No Daclizimab/
2005,8 EUa (260) (278) Steroids
avoidance
186 178
(186) (178)
Alemtuzumab/
12 mo Tac/MMF 50 100 2002-04
Daclizumab
/Steroids
avoidance
Woodle, 191 195 Steroid Steroid Tac/MMF/IL2 1999-
5y 5y 47 43 6% 4% NS good
2008,49 USd (191) (195) withdrawal maintenance or Thymo 2002
Cancer
Daclizumab/
6 mo 6 mo Steroid Tac/MMF 47 nd 2000-02 0.4% 1% NS fair
2005,8 EUa (260) (278) Steroids
avoidance
Excluding PTLD ter Meulen, Daclizumab/ No Daclizumab/ 3% 1% NS good
186 178
2004,9,48 12 mo Steroid Steroid Tac/MMF 49 64 1999-2002
PTLD (186) (178) 1% 1% NS good
No. analyzed
(enrolled)
5y 11% 11% NS good

PTLD Woodle, 191 195 Steroid Steroid Tac/MMF/IL2 1999- 1% 1% NS good
5y 47 43
Skin cancer, non-
5% 9% NS good
melanoma
Acute rejection
Biopsy-proven 17% 17% NS good
Severity of AR, Daclizumab/
Rostaing, 260 278 No Daclizimab 6% 7% NS good
Banff II or higher 6 mo Steroid Tac/MMF 47 nd 2000-02
2005,8 EUa (260) (278) /Steroids
Time to AR, days avoidance no difference NS fair
Steroid-resistant 5% 4% NS good
12 mo 29% 24% NS good
Biopsy-proven ter Meulen, Daclizumab/ No Daclizumab/ 15% 14% NS good
186 178
Severity of AR, 2004,9,48 12 mo Steroid Steroid Tac/MMF 49 64 1999-2002
(186) (178) 10% 8% NS good
Banff II or higher Netherlandsb avoidance withdrawal
Time to AR, days 11 18 NS good
Biopsy-proven Alemtuzumab/ 17% 17% NS poor
Severity of AR, Steroid Thymo/Steroids
avoidance 7% 10% NS poor
Banff II or higher Ciancio, 30 30
12 mo Tac/MMF 50 100 2002-04
Biopsy-proven 2005,13 US (30) (30) Alemtuzumab/ 17% 17% NS poor
Daclizumab
Severity of AR, Steroid
/Steroids 7% 3% NS poor
Banff II or higher avoidance
Biopsy-proven Woodle, 191 195 Steroid Steroid Tac/MMF/IL2 1999- 18% 11% 0.04 good
5y 47 43
Moderate/severe 2008,49 USd (191) (195) withdrawal maintenance or Thymo 2002 8% 6% NS good
NODAT
Daclizumab/
6 mo 6 mo Steroid Tac/MMF 47 nd 2000-02 0.4% 5% 0.001 good
2005,8 EUa (260) (278) /Steroids
avoidance
186 178
(186) (178)
Alemtuzumab/
Ciancio, 30 30
12 mo avoidance Tac/MMF 50 100 2002-04
2005,13 USc (30) (30)
Alemtuzumab/ Daclizumab
12 mo 11% 14% NS poor
Steroid /Steroids
No. analyzed
(enrolled)
avoidance
Impaired fasting
Woodle, 191 195 Steroid Steroid Tac/MMF/IL2 1999- 22% 21% NS good
glucose, 5 y 5y 47 43
Insulin use, 5 y 4% 12% NS good
Infection
UTI Rostaing, 260 278 Daclizumab/ No Daclizimab/ 25% 30% NS good
6 mo Steroid Tac/MMF 47 nd 2000-02
Pneumonia 2005,8 EUa (260) (278) Steroids 4% 1% <0.05 good
avoidance
UTI Alemtuzumab/ 3% 3% NS poor
CMV Steroid Thymo/Steroids 0% 3% NS poor
avoidance
Polyoma BK Ciancio, 30 30 0% 0% NS poor
12 mo Tac/MMF 50 100 2002-04
UTI 2005,13 USc (30) (30) 3% 0% NS poor
Alemtuzumab/
Daclizumab/
CMV Steroid 0% 0% NS poor
Steroids
avoidance
Polyoma BK 0% 0% NS poor
5y 39% 44% NS good
CMV infection/ 10% 6%
NS good
Tissue invasive Woodle, 191 195 Steroid Steroid Tac/MMF/IL2 1999- 2% 3%
5y 47 43
BK nephropathy, 2008,49 USd (191) (195) withdrawal maintenance or Thymo 2002
4% 3% NS good
Bx confirmed
Fungal infections 7% 10% NS good
Daclizumab/
2005,8 EUa (260) (278) Steroids
avoidance
186 178
(186) (178)
Alemtuzumab
12 mo /Steroid Thymo/Steroids 7% 13% NS poor
12 mo Tac/MMF 50 100 2002-04
Daclizumab/
Steroids
avoidance
Kidney function
No. analyzed
(enrolled)
Scr, µmol/L Rostaing, 260 278 Daclizumab/ No Daclizimab/ 131 125 NS good
CrCl, mL/min 2005,8 EUa (260) (278) Steroids 52 54 NS good
avoidance
No
ter Meulen, Daclizumab/
186 178 Daclizumab/S
CrCl, mL/min 2004,9,48 12 mo Steroid Tac/MMF 49 64 1999-2002 65 62 NS good
(186) (178) teroid
Netherlandsb avoidance
withdrawal
Scr, µmol/L Woodle, 191 195 Steroid Steroid Tac/MMF/IL2 1999- 133 133 NS good
5y 47 43
CrCl, mL/min 2008,49 USd (191) (195) withdrawal maintenance or Thymo 2002 59 60 NS good
Proteinuria
Proteinuria 186 178
2004,9,48 12 mo Steroid Steroid Tac/MMF 49 64 1999-2002 5% 8% NS good
(>1 g/d) (186) (178)
Lipids
Patients on Lipid- 186 178
2004,9,48 12 mo Steroid Steroid Tac/MMF 49 64 1999-2002 9% 7% NS fair
lowering drug (186) (178)
Hypertension
Hypertension 16% 15% NS fair
Daclizumab/
Patients on Rostaing, 260 278 No Daclizimab
hypertensive 2005,8 EUa (260) (278) /Steroids 51% 62% nd fair
avoidance
drugs
Adverse events
Leucopenia 22% 18% NS good
Anemia Daclizumab/ 24% 21% NS good
Tachycardia 2005,8 EUa (260) (278) /Steroids 3% 0.4% <0.05 good
avoidance
Dyspnea 2% 0% <0.05 good
186 178
Rib fractures 2004,9,48 12 mo Steroid Steroid Tac/MMF 49 64 1999-2002 2% 1% NS fair
(186) (178)
Bone fractures Woodle, 5y 191 195 Steroid Steroid Tac/MMF/IL2 47 43 1999- 5% 10% NS good
Avascular 2008,49 USd (191) (195) withdrawal maintenance or Thymo 2002
necrosis + bone 5% 11% 0.04 good
fractures
No. analyzed
(enrolled)
Anemia 4% 2% NS good
Leucopenia 51% 37% <0.01 good
Hyperkalemia 29% 15% <0.01 good
AE, Adverse events; AR, Acute rejection; Bx, Biopsy; CMV, Cytomegalovirus; CrCl, Creatinine clearance; EU, Europe; IL-2, Interleukin-2; MMF, Mycophenolate mofetil; nd, Not documented; NODAT, New onset diabetes
after transplantation; NS, Not significant; PTLD, Posttransplant lymphoproliferative disease; SCr, Serum creatinine; Tac, Tacrolimus; Thymo, Thymoglobulin; US, United States; UTI, Urinary tract infection.
Annotations:
a. Rostaing, 20058: overlap with topic 1 (Induction); both treatment groups received 500 mg Methylprednisolone IV on day 0; Steroid doses in patients without Daclizumab induction therapy were tapered to 5 mg/day until
day 43.
b. ter Meulen, 20049,48: overlap with topic 1 (Induction); both treatment groups received 100 mg Methylprednisolone IV per day from day 0 to day 3; Steroid doses in patients without Daclizumab Induction therapy were
tapered down and withdrawn by month 4.
c. Ciancio, 200513: three arm study split: (A) Induction: IL-2 vs. depleting antibody; (B) Steroid avoidance/withdrawal; overlap with topic 1 (Induction); only treatment groups Dacluzimab and Thymoglobulin received 500 mg
Methylprednisolone IV on day 0 to day 3; Steroid doses were then tapered to 0.15 mg/kg by month 3; Alemtuzumab treated patients did not receive any steroids by protocol.
d. Woodle, 200849: all pts. received unblinded steroids from day 0 to day 7. Thereafter steroids were discontinued (treatment) or tapered to 5 mg/d at day 120 (control). Patients with DGF were excluded.
Supporting Table 21. Summary Table Topic 2.4: Steroid avoidance/early withdrawal vs. steroid maintenance (continuous outcomes)
No. analyzed
(enrolled) %
Study, year, Study Concomitant Age Dates of P
Outcome deceased Quality
country duration medication (mean) transplant Baseline ∆ value
Arm 1 Arm 2 Arm 1 Arm 2 donor
(Control) (Control)
Kidney function
138 –16
Scr, µmol/L Alemtuzumab nd poor
Thymo/ (111) (+5)
/Steroid
Steroids 58 +15
CrCl, mL/min avoidance nd poor
Ciancio, 2005, 30 30 (75) (+5)
13 USa 12 mo Tac/MMF 50 100 2002-04
(30) (30) 138 –16
Scr, µmol/L Alemtuzumab nd poor
Daclizumab (108) (–4)
/Steroid
/Steroids 58 +15
CrCl, mL/min avoidance nd poor
(73) (+8)
Lipids
Total Daclizumab/ No
Rostaing, 260 278 5.12 –0.19
cholesterol, 6 mo Steroid Daclizimab Tac/MMF 47 nd 2000-02 <0.01 good
2005,8EUb (260) (278) (5.06) (+0.19)
mmol/L avoidance /Steroids
Total
No 4.9 +0.3
cholesterol, ter Meulen, Daclizumab/ NS good
186 178 Daclizumab/ (5.4) (–0.1)
mmol/L 2004,9,48 12 mo Steroid Tac/MMF 49 64 1999-2002
(186) (178) Steroid
Netherlandsc avoidance 2.99 +0.13
LDL, mmol/L withdrawal NS good
(3.11) (+0.05)
Treatment of Woodle, 191 195 Steroid Steroid Tac/MMF/IL2 30.4% +31.7% NS
5y 47 43 1999-2002 fair
hyperlipidemia 2008,49 USd (191) (195) withdrawal maintenance or Thymo (28.7%) (+44.8%) (0.06)
Hypertension
Mean arterial
97 +1
pressure, mm No NS good
ter Meulen, Daclizumab/ (101) (–2)
Hg 186 178 Daclizumab/
2004,9,48 12 mo Steroid Tac/MMF 49 64 1999-2002
Number of (186) (178) Steroid
Netherlandsc avoidance 0.9 +0.2
antihypertensive withdrawal NS fair
(1.1) (±0)
drugs
130/78 +8/+1
Blood pressure NS good
(132/79) (+6/+0)
Woodle, 191 195 Steroid Steroid Tac/MMF/IL2
Number of 5y 47 43 1999-2002
2008,49 USd (191) (195) withdrawal maintenance or Thymo 1.6 +0.5
antihypertensive NS fair
(1.9) (+0.2)
drugs
No. analyzed
(enrolled) %
(Control) (Control)
Other outcomes
BMD, T-score
nd –0.15
(total femoral <0.05 poor
Daclizumab/ No (nd) (nd)
region) Rostaing, 48 45
6 mo Steroid Daclizimab Tac/MMF 47 nd 2000-02
BMD, Z-score 2005,8 EUb (260) (278)
avoidance /Steroids nd –0.13
(total femoral <0.05 poor
(nd) (nd)
region)
BMD, lumbar No 1118 +0.9
ter Meulen, Daclizumab/ NS fair
spine, mg/cm2 135 126 Daclizumab/ (1091) (+0.1)
2004,9,48 12 mo Steroid Tac/MMF 49 64 1999-2002
BMD, femoral (186) (178) Steroid 821 –0.6
Netherlandsc avoidance NS fair
neck, mg/cm2 withdrawal (816) (–0.9)
BMD, Bone mineral density; CrCl, Creatinine clearance; EU, Europe; IL-2, Interleukin-2; LDL, Low-density lipoprotein; MMF, Mycophenolate mofetil; mmol, Millimole; mo, Month; nd, Not documented; NS, Not significant; SCr, Serum
creatinine; Tac, Tacrolimus; Thymo, Thymoglobulin; US, United States.
Annotations:
a. Ciancio, 200513: three arm study split: (A) Induction: IL-2 vs. depleting antibody; (B) Steroid avoidance/withdrawal; overlap with topic 1 (Induction); only treatment groups Dacluzimab and Thymoglobulin received 500 mg
Methylprednisolone IV on day 0 to day 3; Steroid doses were then tapered to 0.15 mg/kg by month 3; Alemtuzumab treated patients did not receive any steroids by protocol.
b. Rostaing, 20058: overlap with topic 1 (Induction); both treatment groups received 500 mg Methylprednisolone IV on day 0; Steroid doses in patients without Daclizumab induction therapy were tapered to 5 mg/day until day 43.
c. ter Meulen, 20049,48: overlap with topic 1 (Induction); both treatment groups received 100 mg Methylprednisolone IV per day from day 0 to day 3; Steroid doses in patients without Daclizumab Induction therapy were tapered
down and withdrawn by month 4.
d. Woodle, 200849: all pts. received unblinded steroids from day 0 to day 7. Thereafter steroids were discontinued (treatment) or tapered to 5 mg/d at day 120 (control). Patients with DGF were excluded.
Supporting Table 22. Evidence Profile Topic 2.5: Sirolimus vs. CNI a
Outcome and study quality of studies Quality of evidence Qualitative and quantitative description Importance
design per outcome for outcome of effect (notes) of outcome
drug) applicability

Moderate
(High) (617) (0) No important Not adequately
No uncertainty Overall no difference between sirolimus and
Mortality inconsistencies powered Critical
(0) CNI for mortality outcome
1 SR 631 Some limitations (0) (–1)
Low
(6 trials) (318) (–1)

Moderate
Graft loss inconsistencies powered Critical
(0) CNI for graft loss (censored for death)
Low
(6 trials) (318) (–1)
0 RCTs
CVD events
(cardiac Critical
mortality) 1 SR No important Not adequately
Some limitations No uncertainty No difference between sirolimus and CNI for
(4 trials) 345 inconsistencies powered Low
(–1) (0) cardiac mortality
(High) (0) (–1)
Moderate
Cancer inconsistencies powered Critical
(0) CNI
1 SR 447 Some limitations (0) (–1))
Low
(4 trials) (223) (–1)
No uncertainty None Overall no difference between sirolimus and
Acute rejection inconsistencies Moderate High
1 SR 631 Some limitations (0) (0) CNI
(0)
(6 trials) (318) (–1)
(High) (466) (0) No uncertainty Sparse data Overall no difference between sirolimus and
CAN inconsistencies High
1 SR 123 Some limitations (0) (–1) CNI
(0) Low
(1 trial) (64) (–1)
1 RCT 530 No limitations Sparse data
(High) (215) (0) No important (–1)
Skin cancer inconsistencies Moderate High
1 SR 992 Some limitations (0) None CNI
(0)
(4 trials) (481) (–1) (0)
Outcome and study quality of studies Quality of evidence Qualitative and quantitative description Importance
design per outcome for outcome of effect (notes) of outcome
drug) applicability
No important
(High) (617) (–1) No uncertainty None Overall no difference between sirolimus and
NODAT inconsistencies Moderate High
1 SR 244 Some limitations (0) (0) CNI
(0)
(3 trials) (111) (–1)
(High) (617) (–1) Important Statistically significant higher number of CMV
Infection No uncertainty None
inconsistencies Low infections in the Tac group compared with High
(disease) 1 SR 508 Some limitations (0) (0)
(–1) sirolimus (Consistent)
(5 trials) (254) (–1)
No important
1 RCT 428 Serious limitations No uncertainty Sparse data Significant improvements in some
QOL inconsistencies Very low High
(High) (214) (–2) (0) (–1) components of QoL with CsA withdrawal
(0)
Important
Delayed graft 2 RCTs 932 No limitations No uncertainty Sparse data Overall no difference between sirolimus and
function (High) (466) (0) (0) (–1) CNI
(–1)
(High) (822) (–1) No important Improved kidney function in the sirolimus (CNI
Kidney No uncertainty None
inconsistencies Moderate withdrawal) arm reported in the majority of Moderate
function 1 SR Some limitations (0) (0)
255 (0) trials
(4 trials) (–1)
3 RCTs 439 No limitations Statistically higher proportion of patients in the
Moderate
(High) (218) (0) No important sirolimus group had hyperlipidemia than CNI.
No uncertainty Sparse data
Lipids inconsistencies There were statistically significant increased Moderate
(0) Low mean levels of hypercholesterolemia in the
(2 trials) (81) (–1)
sirolimus arm.
No important
(High (479) (–1) No uncertainty Sparse data Overall no difference between sirolimus and
Blood pressure inconsistencies Low Moderate
1 SR 161 Some limitations (0) (–1) CNI
(0)
(2 trials) (80) (–1)
1 RCT 430 Some limitations
No important Statistically significant increased risk of bone
Bone marrow (High) (215) (–1) No uncertainty None
inconsistencies Moderate marrow suppression was reported in the Moderate
suppression 1 SR 302 Some limitations (0) (0)
(0) sirolimus arm compared with CNI arm.
(4 trials) (152) (–1)
2 RCT 277
Diarrhea: Inconsistent results, favors neither
(High) (138) Depends on
Adverse events Higher drug discontinuation reported in
1 SR 161 outcome
sirolimus arm
(2 trials) (80)
Balance of potential benefits and harm: Net harm Quality of overall evidence:
Treatment with sirolimus is associated with no improved graft or patient outcomes but with increased adverse events. Moderate
CNI toxicity is potentiated with the combined use of SRL and CNI.
CAN, Chronic allograft nephropathy; CMV, Cytomegalovirus; CNI, Calcineurin inhibitors; CsA, Cyclosporine A; CVD, Cardiovascular disease; N, Number; NODAT, New onset diabetes after transplant; QoL, Quality of life; RCT, Randomized
controlled trials; SR, Systematic review; SRL, Sirolimus; Tac, Tacrolimus.
Annotations:
Supporting Table 23. Summary Table Topic 2.5: CNI avoidance in sirolimus-based regimens (categorical outcomes)
No. analyzed
(enrolled)
%
Mortality
Ekberg, MMF 2 g,
399 401 No Tac
At 1 y 2007,10 EU, 1y Taca Ster, 46 64 2002-04 3% 3% NS good
(399) (401) (SRL)
Canada Daclizumab
Hamdy, 67 65 No Tac SRLb, Ster,

At 2 y 2y Tac 32 0 2001-03 0% 3% NS good
2005,50 Egypt (67) (65) (MMF 2 g) Basiliximab
>1 y Larson, 2006,51 80 82 No Tac MMF 1.5 g, 6% 9% NS fair

<3 y Tac 49 17 2001-04
At 1 y US (80) (82) (SRL) Ster, Thymo 2% 4% NS fair
Buchler,
2007,52 71 74 MMF 2 g/d,
1y 12 mo SRL CsA 45 100 2002-03 3% 3% NS fair
(SPIESSER), (71) (74) Ster, ATG
France
Graft loss
Ekberg, MMF 2 g,
399 401 No Tac
At 1 y 2007,10 EU, 1y Tac Ster, 46 64 2002-04 8% 4% <0.01 good
(399) (401) (SRL)
Canada Daclizumab
At 2 y 2y Tac 32 0 2001-03 5% 9% NS good
2005,50Egypt (65) (67) (MMF 2 g) Basiliximab
Larson, 2006,51 80 82 No Tac MMF 1.5 g,
At 1 y <3 y Tac 49 17 2001-04 6% 8% NS fair
US (80) (82) (SRL) Ster, Thymo
At 12 mo Buchler, 10% 7% NS fair
200752 71 74 MMF 2 g/d,
Death-censored at 12 12 mo SRL CsA 45 100 2002-03
(SPIESSER), (71) (74) Ster, ATG 7% 4% NS fair
mo France
Cancer
Any cancer Ekberg, 399 401 No Tac MMF 2 g, 2% 2% NS good
2007,10 EU, 12 mo Tac Ster, 46 64 2002-04
PTLD (399) (401) (SRL) 0.3% 0% NS good
Canada Daclizumab
12 mo
Larson, 2006,51 80 82 MMF 1.5 g,
PTLD mean SRL Tac 49 17 2001-04 3% 1% NS fair
US (80) (82) Ster, Thymo
33 mo
Patients. with any Campistol, 215 215 No
5y CsA-ME SRL, Ster 45 89 1998-99 4% 8% <0.01 good
non–skin cancer 2006, Mota (215) (215) CsA-ME
Any skin cancer 2004, Johnson 7% 9% NS good
2001,53-55 EU,
BCC Canada, 5% 7% NS good
SCC Australia 3% 3% NS good
No. analyzed
(enrolled)
%
Skin cancer, mean

annualized rate 35.8 107.7 <0.01 good
(events/1000 pts per y)
No. of BCC, mean
(events/1000 pts. per y)
No. of SCC, mean
(events/1000 pts. per y)
Time to skin cancer 1126 d 491 d <0.01 good
Time to BCC 1126 d 275 d <0.01 good
Time to SCC 896 d 641 d NS good
Time to any skin
775 d 668 d NS good
cancer
Acute rejection
Any at 2 y 2y Tac 32 0 2001-03 14% 19% NS good
Any at 1 y 19% 14% NS fair
Clinical rejection Larson, 2006,51 80 82 No Tac MMF 1.5 g,
<3 y Tac 49 17 2001-04 10 8 NS fair
episodes at 1 y US (80) (82) (SRL) Ster, Thymo
Subclinical rejection
6 6 NS fair
episodes at 1 y
Any at 1 y 44% 17% <0.01 fair
Ekberg, MMF 2 g,
Biopsy-proven at 1 y 399 401 No Tac 37% 12% <0.01 fair
2007,10 EU, 1y Tac Ster, 46 64 2002-04
(399) (401) (SRL)
Biopsy-proven at 6 Canada Daclizumab
35% 11% <0.01 fair
mo
Chronic allograft nephropathy and Proteinuria
% with proteinuria Hamdy, 67 65 No Tac SRLb, Ster,
2y Tac 32 0 2001-03 30% 14% 0.03 good
≥1 g 2005,50 Egypt (67) (65) (MMF 2 g) Basiliximab
Ekberg, MMF 2 g,
399 401 Tac-low SRL-low
% with proteinuria 2007,10 EU, 12 mo Ster, 46 64 2002-04 5% 5% nd fair
(399) (401) dose dose
Canada Daclizumab
NODAT
1y 2y Tac 32 0 2001-03 19% 28% NS good
Ekberg, MMF 2 g,
399 401 No Tac
1y 2007,10 EU, 12 mo Tac Ster, 46 64 2002-04 8% 11% 0.02 fair
(399) (401) (SRL)
Canada Daclizumab
No. analyzed
(enrolled)
%
1y
1y mean 33 Tac 49 17 2001-04 8% 10% NS poor
mo
Buchler,
200752 71 74 MMF 2 g/d,
1 yc 12 mo SRL CsA 45 100 2002-03 13% 4% 0.07 poor
France
Infection
UTI Ekberg, 399 401 No Tac MMF 2 g, 23% 24% nd good
2007,10 EU, 1y Tac Ster, 46 64 2002-04
CMV (399) (401) (SRL) 7% 10% <0.01 fair
Canada Daclizumab
UTI 1 y 2y Tac 32 0 2001-03 34% 22% 0.01 fair
CMV 1 y <3 y Tac 49 17 2001-04 3% 12% 0.02 poor
Buchler,
200752 71 74 MMF 2 g/d,
CMV 12 mo SRL CsA 45 100 2002-03 6% 23% 0.004 fair
France
QOL
Russ, 200756 NS
163 151 CsA w/dal Physical Favors (treatment
EU, Australia, 3y CsA SRL, Ster 45 88 ≥1998
(~214) (~214) at 3 mo symptoms Neither x time =
Canada
NS)
NS
Favors (treatment
Fatigue
CsA w/dal x time =
0.0005)
NS
Uncertainty- Favors (treatment
KTQ fear Neither x time = poor
NS)
0.03
Favors (treatment
Appearance
CsA w/dal x time =
0.006)
0.03
(treatment
Favors
Emotions x time =
CsA w/dal
0.03)
No. analyzed
(enrolled)
%
NS
Physical Favors (treatment
functioning Neither x time =
NS)
NS
Role- Favors (treatment
physical CsA w/dal x time =
0.049)
NS
Favors (treatment
Bodily pain
Neither x time =
NS)
NS
General Favors (treatment
health CsA w/dal x time =
SF-36 0.01) poor
NS
Favors (treatment
Vitality
CsA w/dal x time =
0.0001)
NS
Social Favors (treatment
functioning CsA w/dal x time =
0.02)
NS
Role- Favors (treatment
emotional Neither x time =
NS)
NS
Mental Favors (treatment
health Neither x time =
NS)
2y 2y Tac 32 0 2001-03 0% 2% NS good
MMF 2 g,
Ekberg,
399 401 No Tac Ster,
1y 2007,10 EU, 1y Tac 46 64 2002-04 21% 36% <0.01 good
(399) (401) (SRL) Daclizumab
Canada
No. analyzed
(enrolled)
%
Lipids
Ekberg, MMF 2 g,
% with 399 401 No Tac
2007,10 EU, 12 mo Tac Ster, 46 64 2002-04 12% 13% nd fair
hypercholesterolemia (399) (401) (SRL)
Canada Daclizumab
% with Hamdy, 67 65 No Tac SRLb, Ster,
24 mo Tac 32 0 2001-03 79% 58% 0.01 fair
hyperlipidemia at 1 y 2005,50 Egypt (67) (65) (MMF 2 g) Basiliximab
12 mo
% on lipid therapy at Larson, 2006,51 80 82 No Tac MMF 1.5 g,
mean 33 Tac 49 17 2001-04 78% 36% <0.01 poor
1y US (80) (82) (SRL) Ster, Thymo
mo
Hypertension
Ekberg, MMF 2 g,
399 401 No Tac
% with HTN 2007,10 EU, 12 mo Tac Ster, 46 64 2002-04 10% 5% nd fair
(399) (401) (SRL)
Canada Daclizumab
12 mo
% on one or more Larson, 2006,51 80 82 No Tac MMF 1.5 g,
mean 33 Tac 49 17 2001-04 79% 66% NS poor
anti-HTN meds US (80) (82) (SRL) Ster, Thymo
mo
Adverse events
Anemia, % Campistol
4.0/13/80 19/11/20
mild/moderate/severe 2006, Mota NS fair
(4.7/12/81) (18/16/17)
1y 2004, Friend 163 184 CsA+SRL+
5y SRL+Ster nd 45 89 1998-99
Anemia, % 2007 53,54,57 (215) (215) Ster
4.0/13/80 16/10/8.5
mild/moderate/severe EU, Canada, <0.01d fair
(4.7/12/81) (20/13/17)
2y Australia
Diarrhea 1 y 24 mo Tac 32 0 2001-03 6% 18% 0.03 fair
Drug withdrawal 2° Buchler,
16% 7% NS fair
AE 200752 71 74 MMF 2 g/d,
12 mo SRL CsA 45 100 2002-03
Diarrhea 1 y 25% 5% 0.01 fair
France
Discontinuation of 12 mo
Larson, 2006,51 80 82 MMF 1.5 g,
drug mean 33 SRL Tac 49 17 2001-04 38% 16% nd poor
US (80) (82) Ster, Thymo
1y mo
2°, Secondary; AE, Adverse events; ATG, Antithymocyte globulin; BCC, Basal cell carcinoma; CMV, Cytomegalovirus; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; EU, Europe; GFR, Glomerular filtration rate; HTN, Hypertension; KTQ,
Kidney Transplant Questionnaire; MMF, Mycophenolate mofetil; nd, Not documented; NODAT, New onset diabetes after transplantation; NS, Not significant; PTLD, Posttransplant lymphoproliferative disease; QOL, Quality of life; SCC, Squamous
cell carcinoma; SF-36, 36-item Medical outcomes Study Short Form Health Survey; SRL, Sirolimus; Ster, Steroids; Tac, Tacrolimus; Thymo, Thymoglobulin; US, United States; UTI, Urinary tract infection; vs, Versus; w/dal, Withdrawal.
Annotations:
a. Low-dose tacrolimus was used for maintenance.
b. Dose was slightly different between groups with regard to target trough level.
c. Not explicitly stated to be new onset after transplant.
d. Consistent statistically significant difference favoring CsA withdrawal in mild, moderate, and severe anemia rates at 3, 4, and 5 years.
Supporting Table 24. Summary Table Topic 2.5: CNI avoidance in sirolimus-based regimens (continuous outcomes)
No. analyzed
(enrolled)
%
country duration medication (mean) transplant Baseline ∆
(Control) (Control)

CADI score Campistol 2006, 1.23 +2.22
NS poor
1y Mota 2004,53,54 215 215 No (1.27) (2.29)
5y CsA-ME SRL, Ster 45 89 1998-99
CADI score EU, Canada, (215) (215) CsA-ME 1.23 +2.36
Australia NS poor
3y (1.27) (3.12)
Hamdy, 2005,50 67 65 No Tac SRLa, Ster 2.69
CADI score 2y Tac 32 0 2001-03 nd NS good
Egypt (67) (65) (MMF 2 g) Basiliximab (2.41)
Kidney function
CrCl, mL/min 93
nd NS good
1y (89)
CrCl, mL/min Hamdy, 2005,50 67 65 No Tac SRLa, Ster 95
24 mo Tac 32 0 2001-03 nd <0.01 good
2y Egypt (67) (65) (MMF 2 g) Basiliximab (80)
Scr μmol/L 104.3
nd NS good
1y (110.5)
Campistol 2006,
GFR, mL/min Mota 2004,53,54 215 215 No 56 +3
5y CsA-ME SRL, Ster 45 89 1998-99 <0.01 fair
3y EU, Canada, (215) (215) CsA-ME (57) (–10)
Australia
eGFR, 56.7
nd <0.01 good
mL/min (65.4)
Ekberg, 2007,10 399 401 No Tac MMF 2 g, Ster,
GFR 12 mo Tac 46 64 2002-04
EU, Can (399) (401) (SRL) Daclizumab 64.4
(measured), nd 0.04 fair
(69.6)
mL/min3
12 mo
GFR, mL/min Larson, 2006,51 70 79 No Tac MMF 1.5 g, 62 -7
mean 33 Tac 49 17 2001–04 NS poor
1y US (80) (82) (SRL) Ster, Thymo (56) (0)
mo
eGFR (ITT), 60
nd NS fair
mL/min Buchler, 200752 (57)
MMF 2 g/d,
eGFR (SPIESSER), 12 mo 71 74 SRL CsA 45 100 2002-03
Ster, ATG 69
(completers), France nd 0.01 fair
(60)
mL/min
Scr, μmol/L 104.3
nd NS good
1y Hamdy, 2005,50 67 65 No Tac SRLa, Ster (10.5)
2y Tac 32 0 2001-03
Scr, μmol/L Egypt (67) (65) (MMF 2 g) Basiliximab 110.5
nd 0.02 good
2y (126.3)
No. analyzed
(enrolled)
%
country duration medication (mean) transplant Baseline ∆
(Control) (Control)
Lipids
Total
Hamdy, 2005,50 No Tac SRLa, Ster 4.16 +1.01
cholesterol 24 mo 67 (67) 65 (65) Tac 32 0 2001-03 0.04 good
Egypt (MMF 2 g) Basiliximab (4.14) (+1.5)
mmol/L 1 y
Total 12 mo
Larson, 2006,51 80 82 No Tac MMF 1.5 g, 4.63 +0.78
cholesterol mean 33 Tac 49 17 2001-04 0.02 fair
US (80) (82) (SRL) Ster, Thymo (4.73) (+0.44)
mmol/L 1 y mo
Total
5.7
cholesterol, nd 0.3 fair
(5.1)
mmol/L
Triglycerides, Buchler, 2007,52 2.3
MMF 2 g/d, nd NS fair
mmol/L (SPIESSER), 12 mo 71 74 SRL CsA 45 100 2002-03 (1.7)
Steroids, ATG
France 1.4
HDL, mmol/L nd NS fair
(1.4)
3.3
LDL, mmol/L nd NS fair
(3.0)
Hypertension
12 mo
Larson, 2006,51 80 82 No Tac MMF 1.5 g, 137/74 +0/-3
1y mean 33 Tac 49 17 2001-04 NS fair
US (80) (82) (SRL) Ster, Thymo (130/73) (+5/+3)
mo
ATG, Antithymocyte globulin; CADI, Chronic allograft damage index; CrCl, Creatinine clearance; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; eGFR, Estimated glomerular filtration rate; EU, Europe; GFR, Glomerular filtration rate; HDL,
High-density lipoprotein; LDL, Low-density lipoprotein; MMF, Mycophenolate mofetil; nd, Not documented; NS, Not significant; SCr, Serum creatinine; SRL, Sirolimus; Ster, Steroids; Tac, Tacrolimus; Thymo, Thymoglobulin; US, United States.
Annotations:
Supporting Table 25. Summary Table Topic 2 (Rationale): MMF vs. EC-MPS (categorical outcomes)
%
donor
Mortality
CsA-ME/
Salvadori, 2003,61 213 210 EC-MPS MMF
12 mo 12 mo Steroids/ 47 83 <2002 1% 2% NS good
US, Canada, EUa (213) (210) 1.44 g 2g
±Induction
Budde, 2003,62 US, 159 163 EC-MPS MMF CsA-ME/
12 mo 12 mo 48 nd <2002 1% 2% NS good
Canada, EUa (159) (163) 1.44 g 2g ±Steroids
Graft loss
CsA-ME/
US, Canada, EUa (213) (210) 1.44 g 2g
±Induction
Budde, 2003,62 US, 159 163 EC-MPS MMF CsA-ME/
12 mo 12 mo 48 nd <2002 0.6% nd nd poor
CsA-ME/
Chronic rejection, Salvadori, 2003,61 213 210 EC-MPS MMF
12 mo Steroids/ 47 83 <2002 3% 6% NS good
Biopsy-proven US, Canada, EUa (213) (210) 1.44 g 2g
±Induction
Chronic rejection, Budde, 2003,62 US, 159 163 EC-MPS MMF CsA-ME/
12 mo 48 nd <2002 4% 5% NS good
Biopsy-proven Canada, EUa (159) (163) 1.44 g 2g ±Steroids
Cancer
12 mo CsA-ME/ 2% 2% NS good
12 mo Steroids/ 47 83 <2002
Lymphoma US, Canada, EUa (213) (210) 1.44 g 2g 1% 1% NS good
±Induction
Budde, US,
2003,62 159 163 EC-MPS MMF CsA-ME/
Lymphoma 12 mo 48 nd <2002 1% nd nd poor
Acute rejection
Biopsy-proven CsA-ME/ 23% 24% NS good
Severity of AR, 12 mo Steroids/ 47 83 <2002
US, Canada, EUa (213) (210) 1.44 g 2g 2% 10% NS good
Banff III ±Induction
Total Budde, 2003,62 US, 159 163 EC-MPS MMF CsA-ME/ 1% 4% NS good
12 mo 48 nd <2002
Biopsy-proven Canada, EUa (159) (163) 1.44 g 2g ±Steroids 1% 3% NS good
%
donor
Infection
All CsA-ME/ 70% 72% NS fair
12 mo Steroids/ 47 83 <2002
CMV US, Canada, EUa (213) (210) 1.44 g 2g 22% 21% NS good
±Induction
All Budde, 2003,62 US, 159 163 EC-MPS MMF CsA-ME/ 59% 59% NS fair
12 mo 48 nd <2002
CMV Canada, EUa (159) (163) 1.44 g 2g ±Steroids 2% 2% NS good
CsA-ME/
US, Canada, EUa (213) (210) 1.44 g 2g
±Induction
Adverse events
GI disorders CsA-ME/ 81% 80% NS good
12 mo Steroids/ 47 83 <2002
Leukopenia US, Canada, EUa (213) (210) 1.44 g 2g 1% 3% NS good
±Induction
GI disorders 26% 21%
NS good
3 mo/12 mo Budde, 2003,62 US, 159 163 EC-MPS MMF CsA-ME/ 30% 25%
12 mo 48 nd <2002
Neutropenia Canada, EUa (159) (163) 1.44 g 2g ±Steroids
1% 3% NS good
3 mo
AE, Adverse events; AR, Acute rejection; CMV, Cytomegalovirus; CsA-ME, Cyclosporine microemulsion; EC-MPS, Enteric-coated mycophenolate sodium; EU, Europe; GI, Gastrointestinal; MMF, Mycophenolate mofetil; nd, Not documented; NS, Not
significant; US, United States.
Annotations:
a. Salvadori, 2003 61: primary immunosuppressive regimen; Budde 200362: change in immunosuppressive regimen in stable patients.
Supporting Table 26. Summary Table Topic 2 (Rationale): MMF vs. EC-MPS (continuous outcomes)
Outcome Baseline ∆ Quality
country duration Arm 1 Arm 2 Arm 1 Arm 2 medication (mean) donor transplant value
(Control) (Control)
Kidney function
Budde, 2003,62 US, 159 163 EC-MPS MMF CsA-ME/ 141 –2

Scr, µmol/L 12 mo 48 nd <2002 NS good
Canada, EUa (159) (163) 1.44 g 2g ±Steroids (138) (0)
CsA-ME, Cyclosporine microemulsion; EC-MPS, Enteric-coated mycophenolate sodium; EU, Europe; MMF, Mycophenolate mofetil; NS, Not significant; SCr, Serum creatinine; US, United States
Annotations:
a. Salvadori, 200361: primary immunosuppressive regimen; Budde 200362: change in immunosuppressive regimen in stable patients
Supporting Table 27. Evidence Profile Topic 3.1: CsA low dose vs. CsA standard dosea
drug) applicability
No important Not adequately
4 RCTs 1584 Some limitations No uncertainty No difference between CsA low dose vs. CsA
Mortality inconsistencies powered Low Critical
(High) (799) (–1) (0) standard dose
(0) (–1)
3 RCTs 1473 Some limitations No uncertainty No difference between CsA low dose vs. CsA
Graft loss inconsistencies powered Low Critical
(High) (746) (–1) (0) standard dose
(0) (–1)
No important
3 RCTs 1256 Some limitations No uncertainty None No difference between CsA low dose vs. CsA
(High) (635) (–1) (0) (0) standard dose
(0)
No important
Acute rejection inconsistencies Moderate High
(0)
No important
1 RCT 111 Some limitations No uncertainty Sparse data No difference between CsA low dose vs. CsA
CAN inconsistencies Low High
(High) (53) (–1) (0) (–1) standard dose
(0)
No important
(0)
No important
Infection 4 RCTs 1584 Some limitations No uncertainty None No difference between CsA low dose vs. CsA
(disease) (High) (799) (–1) (0) (0) standard dose
(0)
No important
Delayed graft 3 RCTs 1473 Some limitations No uncertainty None No difference between CsA low dose vs. CsA
function (High) (746) (–1) (0) (0) standard dose
(0)
No important Kidney function is better in the CsA low dose
Kidney 4 RCTs 1584 Some limitations No uncertainty Sparse data
inconsistencies Low than CsA standard dose in 2 of 3 trials and Moderate
function (High) (799) (–1) (0) (–1)
(0) statistically significantly better in 2 trials.
No important
Proteinuria inconsistencies Low Moderate
(0)
No important
Lipids inconsistencies Moderate Moderate
(0)
No important
2 RCTs 1145 Some limitations No uncertainty Sparse data No difference between CsA low dose vs. CsA
Blood pressure inconsistencies Low Moderate
(0)
drug) applicability
There is no evidence for differences in
1 RCT 328 Depends on
Adverse events adverse event profiles between CsA low dose
vs. CsA standard dose
No net benefit or harm Low
CAN, Chronic allograft nephropathy; CsA, Cyclosporine A; CVD, Cardiovascular disease; N, Number; NODAT, New onset diabetes after transplant; RCT, Randomized controlled trials.
Annotations:
a. References: 10,11,63,64
Supporting Table 28. Summary Table Topic 3.1: CsA low dose vs. CsA standard dose (categorical outcomes)
No. analyzed
(enrolled)
Outcome Quality
country duration mediation (mean) donor transplant value
Mortality
Ekberg, 2007,10 399 390 Low dose CsA Standard
1y 1y MMF/Steroid 47 64 2002-04 2% 4% NS good
EU, Canada (413) (410) (Daclizumab) dose CsA
Basiliximab/
Nashan, 2004,63 53 58 Full dose
3y 36 mo Low dose CsA Everolimus/ 46 77 nd 3% 9% nd fair
US, EU (53) (58) CsA
Steroids
1y 1y MMF/Steroid 48 75 2001-02 2% 3% NS fair
EU, US, Australia (183) (173) (Daclizumab) dose CsA
Basiliximab
Cibrik, 2007,64 66 75 CsA-ME high CsA-ME low
1y 24 mo /EC-MPS/ 48 45 <2006 0% 1% NS poor
Finland (total 164) (total 164) C2 C2
Steroids
Graft loss
Graft loss,
censored death Ekberg, 2007,10 399 390 Low dose CsA Standard
1y MMF/Steroid 47 64 2002-04 6% 8% NS good
w/ functioning EU, Canada (413) (410) (Daclizumab) dose CsA
graft
Censored for Ekberg, 2007,11 183 173 Low dose CsA Standard
1y MMF/Steroid 48 75 2001-02 3% 5% NS fair
patient death EU, US, Australia (183) (173) (Daclizumab) dose CsA
Basiliximab
Graft loss 1 y 24 mo /EC-MPS/ 48 45 <2006 2% 1% NS poor
Steroids
Cancer
Basiliximab/
Cancer over 3 y 3y Low dose CsA Everolimus/ 46 77 nd 5% 4% nd fair
US, EU (53) (58) CsA
Steroids
PTLD 1y MMF/Steroid 47 64 2002-04 0% 0% NS good
Acute rejection (all)
1y Ekberg, 2007,10 399 390 Low dose CsA Standard 30% 33% NS fair
1y MMF/Steroid 47 64 2002-04
AB treated EU, Canada (413) (410) (Daclizumab) dose CsA 5% 6% NS fair
No. analyzed
(enrolled)
Outcome Quality
1y Basiliximab 24% 15% NS poor

Severity of AR, 24 mo /EC-MPS/ 48 45 <2006
Finland (total 164) (total 164) C2 C2 24% 15% NS poor
Banff I+II 1 y Steroids
Acute rejection (Biopsy-proven)
1y Ekberg, 2007,11 183 173 Low dose CsA Standard 25% 28% NS fair
1y MMF/Steroid 48 75 2001-02
6 mo EU US, Australia (183) (173) (Daclizumab) dose CsA 24% 26% NS fair
6 mo Ekberg, 2007,10 399 390 Low dose CsA Standard 22% 24% NS fair
1y MMF/Steroid 47 64 2002-04
1y EU, Canada (413) (410) (Daclizumab) dose CsA 24% 26% NS fair
At 6 mo Basiliximab/ 3% 15% NS fair
At 1 y 3y Low dose CsA Everolimus/ 46 77 nd 7% 17% NS fair
US, EU (53) (58) CsA
At 3 y Steroids 12% 19% NS fair
Basiliximab/
Biopsy-proven Nashan, 2004,63 53 58 Full dose
3y Low dose CsA Everolimus/ 46 77 nd 12% 21% NS fair
CAN US, EU (53) (58) CsA
Steroids
NODAT
NODAT 1y MMF/Steroid 47 64 2002-04 5% 6% NS fair
Infection
Any over 36 mo Basiliximab/ 85% 87% nd fair
CMV 3y Low dose CsA Everolimus/ 46 77 nd 0% 1.9% nd fair
US, EU (53) (58) CsA
PCP Steroids 0% 2% nd fair
CMV Ekberg, 2007,11 183 173 Low dose CsA Standard 3% 4% nd fair
1y MMF/Steroid 48 75 2001-02
UTI EU, US, Australia (183) (173) (Daclizumab) dose CsA 4% 4% nd fair
CMV Ekberg, 2007,10 399 390 Low dose CsA Standard 12% 15% NS fair
1y MMF/Steroid 47 64 2002-04
UTI EU, Canada (413) (410) (Daclizumab) dose CsA 24% 28% nd good
All 1 y Basiliximab 77% 71% NS poor
24 mo /EC-MPS/ 48 45 <2006
UTI 1 y Finland (total 164) (total 164) C2 C2 32% 12% <0.01 poor
Steroids
1y 1y MMF/Steroid 47 64 2002-04 32% 34% NS good
No. analyzed
(enrolled)
Outcome Quality
Basiliximab/
2y 24 mo EC-MPS/ 48 45 <2006 11% 13% NS poor
Steroids
Kidney function
Basiliximab
Scr, µmol/L 24 mo /EC-MPS/ 48 45 <2006 141 132 nd poor
Steroids
Proteinuria
Proteinuria 1y MMF/Steroid 47 64 2002-04 2% 2% nd fair
EU Canada (413) (410) (Daclizumab) dose CsA
Hypertension
No requirement of
antihypertensive 1y MMF/Steroid 48 75 2001-02 83% 82% NS fair
therapy
Hypertension 1y MMF/Steroid 47 64 2002-04 12% 14% NS fair
Lipids
Lipid-lowering Ekberg, 2007,11 183 173 Low dose CsA Standard
1y MMF/Steroid 48 75 2001-02 50% 48% NS fair
meds EU, US, Australia (183) (173) (Daclizumab) dose CsA
Hypercholesterol- Ekberg, 2007,10 399 390 Low dose CsA Standard
1y MMF/Steroid 47 64 2002-04 10% 10% nd fair
emia EU, Canada (413) (410) (Daclizumab) dose CsA
Adverse events
Anemia 12 mo 30% 31% NS poor
Leucopenia 12
Basiliximab 21% 15% NS poor
mo Cibrik, 2007,64 66 75 CsA-ME high CsA-ME low
24 mo /EC-MPS/ 48 45 <2006
Hirsutism 12 mo Finland (total 164) (total 164) C2 C2 11% 15% NS poor
Steroids
Nausea 12 mo 40% 59% <0.05 poor
Diarrhea 12 mo 32% 35% NS poor
Composite endpoints
BPAR, graft loss, Nashan, 2004,63 53 58 Full dose Basiliximab/
death or loss to 3y Low dose CsA Everolimus/ 46 77 nd 3% 15% 0.046 fair
US, EU (53) (58) CsA
follow-up 6 mo, Steroids
No. analyzed
(enrolled)
Outcome Quality
BPAR, graft loss,

death or loss to 9% 28% 0.021 fair
follow-up 1 y.
BPAR, graft loss,
death or loss to 17% 36% 0.032 fair
follow-up 3 y
Graft loss, death
or loss to follow- 2% 2% nd fair
up 6 mo
Graft loss, death
up 1 y
Graft loss, death
up 3 y
Nonfatal serious
78% 85% nd fair
AE over 3 y
Coprimary
efficacy failure ,
composite
7% 19% NS fair
endpoint of death,
graft loss and loss
to follow-up
AE, Adverse events; AR, Acute rejection; BPAR, Biopsy-proven acute rejection; CAN, Chronic allograft nephropathy; CMV, Cytomegalovirus; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; EC-MPS, Enteric-coated mycophenolate sodium;
EU, Europe; MMF, Mycophenolate mofetil; nd, Not documented; NODAT, New onset diabetes after transplantation; NS, Not significant; PCP, Pneumoystis pneumonia; SCr, Serum creatinine; US, United States; UTI, Urinary tract infection
Annotations:
a. Ekberg, 2007,10 Europe, Canada the P-value was calculated from relative risks.
Supporting Table 29. Summary Table Topic 3.1: CsA low dose vs. CsA standard dose (continuous outcomes)
No. analyzed
(enrolled)
%
Study, year Study Concomitant Age Dates of P
(Control) (Control)
Kidney function
Ekberg,
Low dose Standard
GFR, 2007,11 EU, 138 119 49.0 +1.9
12 mo CsA dose MMF/Steroid 48 75 2001-02 NS poor
mL/min US, (183) (173) (45.4) (+3.2)
(Daclizumab) CsA
Australia
CrCl,
42 +17.7
mL/min 0.009 fair
(54) (-2.9)
6 mo
Nashan, Basiliximab/
CrCl, 53 58 Low dose Full dose
2004,63 US, 36 mo Everolimus/ 46 77 nd 42 +17.1
mL/min (53) (58) CsA CsA 0.007 fair
EU Steroids (54) (–0.5)
12 mo
CrCl, 42 +14.6
NS fair
mL/min (54) (+2.3)
eGFR, Final 59.4
Ekberg, Low dose Standard nd nd good
mL/min 399 390 (57.1)
2007,10 EU, 1y CsA dose MMF/Steroid 47 64 2002-04
GFR, (413) (410) Final 65.3
Canada (Daclizumab) CsA nd nd fair
mL/min (63.5)
CrCl,
71.0 +6.6
mL/min <0.05 poor
Cibrik, 66 75 Basiliximab (79.2) (+9.6)
12 mo CsA-ME high CsA-ME
2007,64 24 mo (total (total /EC-MPS/ 48 45 <2006
CrCl, C2 low C2
Finland 164) 164) Steroids 71.5 +7.1
mL/min, nd poor
(79.4) (+ 9.8)
24 mo
CrCl, Creatinine clearance; CsA, Cyclosporine; EC-MPS, Enteric-coated mycophenolate sodium; EU, Europe; GFR, Glomerular filtration rate; MMF, Mycophenolate mofetil; nd, Not documented; NS, Not significant; US, United States
Supporting Table 30. Evidence Profile Topic 3.2: CNI withdrawal in the setting of antimetabolite regimens vs. CNI continuationa
drug) applicability
Not adequately No difference between CsA or CsA-ME
No important
8 RCTs 1891 Some limitations No uncertainty powered for this withdrawal or avoidance with antimetabolite
(High) (1001) (–1) (0) outcome continuation compared to CsA/CsA-ME
(0)
(–1) continuation
No difference between CsA or CsA-ME
No important
8 RCTs 1891 Some limitations No uncertainty None withdrawal or avoidance with antimetabolite
(High) (1001) (–1) (0) (0) continuation compared to CsA/CsA-ME
(0)
continuation
No important
3 RCTs 440 Some limitations No uncertainty Sparse data withdrawal or avoidance with antimetabolite
CVD events inconsistencies Low Critical
(High) (220) (–1) (0) (–1) continuation compared to CsA/CsA-ME
(0)
continuation
No important
5 RCTs 1242 Some limitations No uncertainty None withdrawal or avoidance with antimetabolite
(High) (682) (–1) (0) (0) continuation compared to CsA/CsA-ME
(0)
continuation
An increased rate of acute rejection in
Important
6 RCTs 1547 Some limitations No uncertainty None CsA/CsA-ME withdrawn with antimetabolite
Acute rejection inconsistencies Low High
(High) (839) (–1) (0) (0) continuation trials compared to CsA/CsA-ME
(–1)
continuation trials
No important No difference between CsA or CsA-ME
2 RCTs 433 Some limitations No uncertainty Sparse data
CAN inconsistencies Low withdrawal or avoidance compared with High
(High) (217) (–1) (0) (–1)
(0) continuation
1 RCT 128 Some limitations No uncertainty Sparse data
Skin cancer inconsistencies Low withdrawal or avoidance compared with High
(High) (60) (–1) (0) (–1)
(0) continuation
NODAT inconsistencies Low withdrawal or avoidance compared with High
(High) (358) (–1) (0) (–1)
(0) continuation
Infection 5 RCTs 1330 Some limitations No uncertainty None
inconsistencies Moderate withdrawal or avoidance compared with High
(disease) (High) (724) (–1) (0) (0)
(0) continuation
Delayed graft 1 RCT 352 Some limitations No uncertainty Sparse data
inconsistencies Low withdrawal or avoidance compared with Moderate
function (High) (179) (–1) (0) (–1)
(0) continuation
Improved kidney function in trials of CsA/CsA-
No important
Kidney 7 RCTs 1456 Some limitations No uncertainty None ME withdrawn with antimetabolite
function (High) (784) (–1) (0) (0) continuation compared to CsA/CsA-ME
(0)
continuation trials
drug) applicability
Proteinuria inconsistencies Low withdrawal or avoidance compared with Moderate
(High) (57) (–1) (0) (–1)
(0) continuation
Not adequately
5 RCTs 632 Some limitations No uncertainty powered for this
Lipids inconsistencies Low withdrawal or avoidance compared with Moderate
(High) (306) (–1) (0) outcome
(0) continuation
(–1)
Blood pressure inconsistencies Low withdrawal or avoidance compared with Moderate
(High) (187) (–1) (0) (–1)
(0) continuation
No difference in drug toxicity between CsA or
Adverse events CsA-ME withdrawal or avoidance compared
with continuation at <1 year
Despite a higher incidence of acute rejections associated with complete CNI withdrawal, kidney function is better. However, there is no Moderate
improvement in CAN or long-term graft survival
CAN, Chronic allograft nephropathy; CNI, Calcineurin inhibitors; CsA, Cyclosporine A; CsA-ME, Cyclosporine A microemulsion; CVD, Cardiovascular disease; N, Number; NODAT, New onset diabetes after transplant; RCT, Randomized controlled trials
Annotations:
Supporting Table 31. Summary Table Topic 3.2: CNI withdrawal in the setting of antimetabolite regimens vs. CNI continuation (categorical
outcomes)
No. analyzed
(enrolled)
Outcome Quality
Mortality
Gallagher
2004, Hall 163 162 CsA withdrawn CsA
15 y 10-15 y None 43 100 1983-86 49% 44% NS good
1988,65,66 (165) (166) (AZA, steroid) mono
Australia
Abramowicz, 85 85
9 mo 1% 0% nd good
2002, (85) (85) CsA-ME CsA-ME
5y MMF/Steroids 45 93 <2001
2005,67,68 EU, 74 77 withdrawn continued
5y 7% 5% NS fair
South America (85) (85)
1y Hazzan, 2005, CsA-ME 0% 0% NS good
54 54
2006 69,70 2y withdrawn CsA-ME Steroids/ATG 44 100 <2004
2y (54) (54) 0% 0% NS good
France (MMF)
MacPhee,
Median 102 114 CsA withdrawn
10 y 1998,71 CsA Steroids 41 88 1985-91 21% 23% NS fair
<8 y (102) (114) (AZA)
Scotland
Ekberg,
179 173 CsA withdrawn Standard
1y 2007,11 EU, 1y MMF/Steroids 47 74 2001-02 5% 3% NS fair
(179) (173) (Daclizumab) dose CsA
US, Australia
10 y 27% 28% NS fair
Bakker, 2003,72 60 68 CsA withdrawn CsA No Induction/
15 y 44 nd 1983
15 y Netherlands (60) (68) (AZA) continued Steroid 45% 43% NS fair
CV mortality 23% 21% NS fair
Steroid
5y 0 25% 29% NS fair
Antibody
Gheith, 2007,73 300 175 No CsA
20 y CsA induction for 33 (haploid 1983-88
10 y Egypt (300) (175) (AZA) 40% 42% NS fair
high risk living KTx)
20 y patients 65% 60% NS fair
1y ALG for 2% 2% NS fair
5y Grimbert, 58 59 induction 10% 10% NS fair
12 y No CsA CsA 40 nd 1986-89
2002,74 France (58) (59) AZA
12 y 17% 25% NS fair
Steroid
Graft loss
Abramowicz, 74 77
9 mo 0% 0% nd good
2002, (85) (85) CsA-ME CsA-ME
5y South America 12 % 8% nd good
(85) (85)
No. analyzed
(enrolled)
Outcome Quality
1y Hazzan, 2005, CsA-ME 0% 0% NS good

54 54
2006,69,70 2y withdrawn CsA-ME Steroids/ATG 44 100 <2004
2y (54) (54) 7% 2% NS good
France (MMF)
Gallagher
NS
2004, Hall 10 y (up 163 162 CsA withdrawn CsA
15 y None 43 100 1983-86 41% 56% (p=0.0 good
1988,65,66 to 15 y) (165) (166) (AZA, steroid) mono
6)
Australia
MacPhee,
<8 y (102) (114) (AZA)
Scotland
Ekberg,
Censored for 179 173 CsA withdrawn Standard
2007,11 EU, 1y MMF/Steroids 47 74 2001-02 7% 5% NS fair
patient death (179) (173) (Daclizumab) dose CsA
US, Australia
Graft failure,
censored for
death with a
15% 25% NS fair
functioning
graft 10 y: ITT
Analysis Bakker, 2003,72 60 68 CsA withdrawn CsA No induction
15 y 44 nd 1983
Graft failure, Netherlands (60) (68) (AZA) continued Steroid
censored for
death with a
24% 35% NS fair
functioning
graft: ITT
Analysis
5y Steroid 31% 42% nd fair
10 y Antibody 0 48% 64% nd fair
Gheith, 2007 73 300 175
20 y AZA CsA induction for 33 (haploid 1983-88
Egypt (300) (175)
20 y high risk living KTx) 74% 76% NS fair
patients
1y ALG for 11% 9% NS fair
5y Grimbert, 58 59 induction 25% 18% NS fair
12 y No CsA CsA 40 nd 1986-89
2002,74 France (58) (59) AZA
12 y 44% 41% NS fair
Steroid
CVD
MacPhee,
Median <8 y 1998,71 CsA Steroids 41 88 1985-91 21% 17% NS fair
<8y (102) (114) (AZA)
Scotland
Bakker, 2003,72 60 68 CsA withdrawn CsA No Induction
15 y 15 y 44 nd 1983 36% 42% NS fair
Netherlands (60) (68) (AZA) continued Steroid
No. analyzed
(enrolled)
Outcome Quality
ALG for
Grimbert, 58 59 induction
12 y 12 y No CsA CsA 40 nd 1986-89 12% 14% NS fair
2002,74 France (58) (59) AZA
Steroid
Cancer
Skin cancer Bakker, 2003,72 60 68 CsA withdrawn CsA No Induction 16% 15% NS fair
15 y 44 nd 1983
Other cancers Netherlands (60) (68) (AZA) continued Steroid 18% 10% NS fair
Ekberg,
1y 2007,11 EU, 1y MMF/Steroids 47 74 2001-02 2% 1% nd fair
US, Australia
Abramowicz,
2002, 85/74 85/77 CsA-ME CsA-ME
5y 5y MMF/Steroids 45 93 nd (<2001) 7% 5% nd fair/good
2005,67,68 EU, (85) (85) withdrawn continued
South America
Steroid
Antibody 0
Gheith,2007,73 300 175
20 y 20 y AZA CsA induction for 33 (haploid 1983-88 5% 6% NS fair
Egypt (300) (175)
patients
ALG for
2002,74 France (58) (59) AZA
Steroid
Acute rejection (all)
1y 19% 6% <0.05 good
Hazzan, 2005, CsA-ME
2y 54 54 22% 6% 0.04 good
2006 69,70 2y withdrawn CsA-ME Steroids/ATG 44 100 <2004
C4d positivity (54) (54)
France (MMF) 24% 6% 0.007 good
1y
Abramowicz, 85 85
9 mo 2% 11% nd good
2002, (85) (85) CsA-ME CsA-ME
5y 1% 16% <0.01 fair
South America (85) (85)
Ekberg,
1y 2007,11 EU, 1y MMF/Steroids 47 74 2001-02 44% 35% NS fair
US, Australia
1y Gallagher 69% 67% NS poor
None 43 100 1983-86
10 y 1988,65,66 to 15 y) (165) (166) (AZA, steroid) mono 33% 24% <0.01 poor
Australia
No. analyzed
(enrolled)
Outcome Quality
Steroid
Antibody 0
Number of Gheith,2007,73 300 175
20 y AZA CsA induction for 33 (haploid 1983-88 23% 37% <0.001 fair
episodes Egypt (300) (175)
patients
ALG for
2002,74 France (58) (59) AZA
Steroid
Acute rejection (biopsy-proven)
MacPhee,
<8 y (102) (114) (AZA)
Scotland
Ekberg,
6 mo 179 173 CsA withdrawn Standard 25% 26% NS fair
2007,11 EU, 1y MMF/Steroids 47 74 2001-02
1y US, Australia 38% 28% 0.04 fair
Time to AR, Hazzan, 2005, CsA-ME
54 54
days post Txp 2006,69,70 2y withdrawn CsA-ME Steroids/ATG 44 100 <2004 173 d 149 d nd good
(54) (54)
(1 y) France (MMF)
MacPhee, 4 mo 7 mo
Time to AR 1998,71 CsA Steroids 41 88 1985-91 (2-22 (2-46 <0.001 fair
<8 y (102) (114) (AZA)
Scotland mo) mo)
Proteinuria,
Hazzan, 2005, CsA-ME 11% 4% NS good
>300 mg 1 y 54 54
2006,69,70 2y withdrawn CsA-ME Steroids/ATG 44 100 <2004
Proteinuria, (54) (54)
France (MMF) 13% 13% NS good
>300 mg
Number of
chronic
rejection based
5% 3% nd poor
on numbers of
Gallagher
episodes
12 mo None 43 100 1983-86
1988,65,66 to 15 y) (165) (166) (AZA, steroid) mono
Number of
Australia
chronic
rejection based 36% 34% nd poor
on numbers of
episodes 10 y
No. analyzed
(enrolled)
Outcome Quality
NODAT
Steroid
Antibody 0
Gheith, 2007,73 300 175
20 y 20 y AZA CsA induction for 33 (haploid 1983-88 17% 19% NS fair
Egypt (300) (175)
patients
ALG for
2002,74 France (58) (59) AZA
Steroid
Infection
Abramowicz,
2002, 85 85 CsA-ME CsA-ME
9 mo 5y MMF/Steroids 45 93 <2001 13% 9% nd good
2005,67,68 EU, (85) (85) withdrawn continued
South America
MacPhee,
Any requiring Median 102 114 CsA withdrawn
1998,71 CsA Steroids 41 88 1985-91 31% 37% NS fair
hospitalization <8 y (102) (114) (AZA)
Scotland
CMV Ekberg, 8% 4% nd fair
2007,11 EU, 1y MMF/Steroids 47 74 2001-02
UTI (179) (173) (Daclizumab) dose CsA 5% 4% nd fair
US, Australia
Steroid
Antibody 0
Gheith, 2007,73 300 175
Bacterial 20 y AZA CsA induction for 33 (haploid 1983-88 10% 10% NS fair
Egypt (300) (175)
patients
Severe ALG for
infections Grimbert, 58 59 induction
12 y No CsA CsA 40 nd 1986-1989 19% 21% NS fair
requiring 2002,74 France (58) (59) AZA
hospitalization Steroid
Ekberg,
1y 2007,11 EU, 1y MMF/Steroids 47 74 2001-02 17% 23% nd fair
US, Australia
GFR/Creatinine
Scr >1.5 μmol/L Steroid
11% 12% NS fair
at 1 y Antibody 0
Gheith, 2007,73 300 175
20 y AZA CsA induction for 33 (haploid 1983-88
Scr >1.5 μmol/L Egypt (300) (175)
high risk living KTx) 41% 58% NS fair
at last follow-up
patients
No. analyzed
(enrolled)
Outcome Quality
Proteinuria
% with
57 66
proteinuria 14% 11% NS fair
(60) (68)
≥1 g/d 1 y
% with
46 49
(60) (68)
≥1 g/d 5 y Bakker,2003,72 CsA withdrawn CsA No Induction
15 y 44 nd 1983
% with Netherlands (AZA) continued Steroid
38 37
(60) (68)
≥1 g/d 10 y
% with
17 16
(60) (68)
≥1 g/d
Lipids
Lipid-lowering
therapy 32% 57% NS fair
10/15 y Bakker, 2003,72 60 68 CsA withdrawn CsA No Induction
15 y 44 nd 1983
Lipid-lowering Netherlands (60) (68) (AZA) continued Steroid
therapy 41% 56% NS fair
10/15 y
Ekberg,
Lipid-lowering 179 173 CsA withdrawn Standard
2007,11 EU, 1y MMF/Steroids 47 74 2001-02 50% 48% NS fair
meds (179) (173) (Daclizumab) dose CsA
US, Australia
Blood pressure
No requirement of
antihypertensive MacPhee, 43% 21% <0.005 fair
therapy 1 y Median 102 114 CsA withdrawn
1998,71 CsA Steroids 41 88 1985-91
No requirement of <8 y (102) (114) (AZA)
antihypertensive
Scotland 46% 22 % <0.005 fair
therapy 1 y
Steroid
Antibody 0
Post-txp Gheith, 2007,73 300 175
20 y AZA CsA induction for 33 (haploid 1983-88 69% 75% 0.02 fair
hypertension Egypt (300) (175)
patients
ALG for
HTN Grimbert, 58 59 induction
12 y No CsA CsA 40 nd 1986-89 70% 74% NS fair
prevalence 2002,74 France (58) (59) AZA
Steroid
No. analyzed
(enrolled)
Outcome Quality
Adverse events
Number of drug
Gallagher
toxicity based 10 y
2004, Hall 163 162 CsA withdrawn CsA 15% 16%
on numbers of (up to 15 None 43 100 1983-86 nd poor
1988,65,66 (165) (166) (AZA, steroid) mono 7% 17%
episodes y)
Australia
12 mo/10 y
ALG, Antilymphocyte globulin; AR, Acute rejection; ATG, Antithymocyte globulin, AZA, Azathioprine; CMV, Cytomegalovirus; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; CV, Cardiovascular; CVD, Cardiovascular
disease; EU, Europe; HTN, Hypertension; ITT, Intention to treat; KTx, Kidney transplant; MMF, Mycophenolate mofetil; mo, Month; nd, Not documented; NODAT, New onset diabetes after transplantation; NS, Not significant;
SCr, Serum creatinine; Txp, Transplant; US, United States; UTI, Urinary tract infection.
Supporting Table 32. Summary Table Topic 3.2: CNI withdrawal in the setting of antimetabolite regimens vs. CNI continuation (continuous
outcomes)
No. analyzed
(enrolled)
Outcome Quality
(control) (control)
Kidney function
Scr, µmol/L 102 114 122 –9
MacPhee, CsA <0.05 fair
1y Median (102) (114) (126) (+3)
1998,71 withdrawn CsA Steroids 41 88 1985-91
Scr, µmol/L 93 mo 40 40 122 -1
Scotland (AZA) <0.05 fair
7y (102) (114) (126) (+25)
Scr, µmol/L 114.9 +8.8
NS good
1y (114.9) (+26.5)
eGFR, Hazzan,
CsA-ME Final 49
mL/min 2005, 54 54 nd <0.05 good
2y withdrawn CsA-ME Steroids/ATG 44 100 nd (<2004) (46)
1 y/2 y 2006,69,70 (54) (54)
(MMF)
eGFR, France
Final 40
mL/min nd <0.05 good
(38)
1 y/2 y
Ekberg,
Measured 2007,11 EU, 128 119 CsA Standard MMF 49.6 +1.3
12 mo 47 74 2001-02 NS poor
GFR US, (179) (173) withdrawal dose CsA Steroids (45.4) (+3.2)
Australia
CrCl, Net
85 85
mL/min nd change NS fair
(85) (85)
9 mo Abramowicz, 4.5
CrCl, 2002, 74 77 Net
CsA-ME CsA-ME MMF nd 0.05 fair
mL/min 2005,67,68 5y (85) (85) 45 93 nd (<2001) change 5
withdrawn continued Steroids
Scr, µmol/L EU, South 85 85 136 –1
NS good
9 mo America (85) (85) (132) (–2)
74 77 136 –1
Scr, µmol/L NS good
(85) (85) (132) (+4)
<0.05
GFR, 57 66 53.5 72.9
all fair
mL/min 1 y (60) (68) (56.5) (55.7)
times
<0.05
GFR, 46 50 53.5 71.0
all fair
mL/min 5 y Bakker, (60) (68) CsA (56.5) (56.3)
CsA No Induction times
2003,72 15 y withdrawn 44 nd 1983
GFR, continued Steroid <0.05
Netherlands 38 37 (AZA) 53.5 71.7
mL/min all fair
(60) (68) (56.5) (52.8)
10 y times
<0.05
GFR, 17 15 53.5 71.7
all fair
mL/min (60) (68) (56.5) (56.3)
times
No. analyzed
(enrolled)
Outcome Quality
(control) (control)
Scr, µmol/L ALG for

Grimbert, nd NS poor
12 y 58 59 induction
2002,74 12 y No CsA CsA 40 nd 1986-89
CrCl, (58) (59) AZA
France nd NS poor
mL/min Steroid
Blood pressure
Blood
135/85 +2/–1
pressure NS fair
MacPhee, CsA (135/85) (+3/-1)
1y Median 102 114
1998,71 withdrawn CsA Steroids 41 88 1985-91
Blood 93 mo (102) (114)
Scotland (AZA) 135/85 –3/–3
pressure NS fair
(135/85) (–3/+2)
7y
Abramowicz,
Blood
2002, Final 137/
pressure, 85/74 85/77 CsA-ME MMF
2005,67,68 5y CsA-ME 47 91 nd (<2001) nd 80 NS fair
SBP/DBP (85) (85) withdrawn Steroids
EU, South (133/78)
9 mo/5 y
America
Lipid levels
Cholesterol Abramowicz, 85 85
nd nd 0.02 fair
total 9 mo 2002, (85) (85)
CsA-ME CsA-ME MMF
Cholesterol 2005,67,68 5y 45 93 nd (<2001)
74 77 withdrawn continued Steroids Final 5.23
total, EU, South nd NS good
(85) (85) (5.38)
mmol/L America
Chronic
allograft Hazzan,
CsA-ME
damage 2005, 54 54
2y withdrawn CsA-ME Steroids/ATG 44 100 <2004) 3.3 3.5 NS good
index 2006,69,70 (54) (54)
(MMF)
(CADI) France
1y
Total Bakker, CsA
49 60 CsA No Induction 6.70 7.19
Cholesterol, 2003,72 15 y withdrawn 44 nd 1983 NS fair
(60) (68) continued Steroid (6.59) (7.29)
mmol/L 1 y Netherlands (AZA)
Total
44 46 6.70 6.80
Cholesterol, NS fair
(60) (68) (6.59) (7.01)
mmol/L 5 y
Total
Cholesterol,
38 37 6.70 6.10
mmol/L NS fair
(60) (68) (6.59) (7.45)
10 y
No. analyzed
(enrolled)
Outcome Quality
(control) (control)
Total
Cholesterol, 17 14 6.70 5.69
NS fair
mmol/L (60) (68) (6.59) (5.40)
15 y
Serum
Final 4.8
cholesterol, ALG for nd NS poor
Grimbert, (5.4)
mmol/L 58 59 induction
2002,74 12 y No CsA CsA 40 nd 1986-89
Triglyceride (58) (59) AZA
France Final 1.4
levels, Steroid nd NS poor
(1.8)
mmol/L
ALG, Antilymphocyte globulin; ATG, Antithymocyte globulin, AZA, Azathioprine; CrCl, Creatinine clearance; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; eGFR, Estimated glomerular filtration rate; EU, Europe; GFR,
Glomerular filtration rate; MMF, Mycophenolate mofetil; nd, Not documented; NS, Not significant; SCr, Serum creatinine; Txp, Transplant; US, United States
Supporting Table 33. Evidence Profile Topic 3.3: Steroid withdrawal vs. steroid maintenance in CNI/MMF based regimensa,b,c
drug) applicability
Not adequately
1 SR No important
No limitations Some uncertainty powered for the No difference between steroid withdrawal and
Graft loss (6 RCTs) 1519 inconsistencies Low Critical
(0) (–1) outcome steroid maintenance for up to 24 months
(High) (0)
(–1)
1 SR Important The incidence of acute rejection is higher in
No limitations Some uncertainty None
Acute rejection (6 RCTs) 1519 inconsistencies Low patients withdrawn from steroids compared to High
(0) (–1) (0)
(High) (–1) patients maintained on steroids.
1 SR Important
Kidney No limitations Some uncertainty None No difference between steroid withdrawal and
(6 RCTs) 1519 inconsistencies Low Moderate
function (0) (–1) (0) steroid maintenance for up to 24 months
(High) (–1)
1 SR No Total cholesterol levels are lower in patients
No limitations Some uncertainty None
Lipids (4 RCTs) 1361 inconsistencies Moderate withdrawn from steroids compared to patients Moderate
(0) (–1) (0)
(High) (0) maintained on steroids.
There is no clear evidence that blood
1 SR Important
No limitations Some uncertainty None pressure is lower in patients withdrawn from
Blood pressure (4 RCTs) 1361 inconsistencies Low Moderate
(0) (–1) (0) steroids compared to patients maintained on
(High) (–1)
steroids.
1 SR No limitations Some uncertainty Sparse data Steroid withdrawal is beneficial for BMD. No
Adverse events 500 N/A Low
(1 RCT) (0) (–1) (–1) difference in glucose metabolism
Steroid withdrawal in CNI/MMF based regimens is associated with a higher incidence of acute rejections, no significant impact on graft Lowa
survival. Insufficient evidence on steroid-related adverse effects.
BMD, Bone mineral density; CNI, Calcineurin inhibitors; MMF, Mycophenolate mofetil; N, Number; N/A, Not applicable, RCT, Randomized controlled trials; SR, Systematic review; vs, versus.
Annotations:
a. Evidence based on trials comparing steroid withdrawal vs. steroid maintenance only in CNI/MMF-based regimens
b. Reference: 75
c. This evidence profile is based solely on existing systematic reviews. A de novo systematic review was not conducted.
Supporting Table 34. Evidence Profile Topic 5.1.1: CsA C2 vs. C0 a
Consistency
Outcome across Qualitative and quantitative Importance
and study study studies generalizability/ considerations evidence for
studies description of effect of outcome
Sparse data,
No important Some not adequately
1 RCT 154 Some limitations No significant difference between
Mortality inconsistencies uncertainty powered for the Very low Critical
(High) (74) (–1) CsA C2 vs. C0
(0) (–1) outcome
(–1)
Sparse data,
No important Some not adequately
2 RCTs 358 No limitations No significant difference between
Graft loss inconsistencies uncertainty powered for the Low Critical
(High) (183) (0) CsA C2 vs. C0
(0) (–1) outcome
(–1)
Cancer 0 RCTs Critical
Sparse data
No important Some
Acute 2 RCTs 358 No limitations (limited number No significant difference between
inconsistencies uncertainty Low High
rejection (High) (183) (0) of studies) CsA C2 vs. C0
(0) (–1)
(–1)
Sparse data
No important Some
2 RCTs 240 Some limitations (limited number No significant difference between
CAN inconsistencies uncertainty Very low High
(High) (109+?) (–1) of studies) CsA C2 vs. C0
(0) (–1)
(–1)
No important Some
1 RCT 154 Some limitations Sparse data No significant difference between
NODAT inconsistencies uncertainty Very low High
(High) (74) (–1) (–1) CsA C2 vs. C0
(0) (–1)
No important Some
Infection 2 RCTs 358 No limitations Sparse data No significant difference between
inconsistencies uncertainty Low High
(disease) (High) (183) (0) (–1) CsA C2 vs. C0
(0) (–1)
Delayed No important Some
1 RCT 154 Some limitations Sparse data No significant difference between
graft inconsistencies uncertainty Very low Moderate
(High) (74) (–1) (–1) CsA C2 vs. C0
function (0) (–1)
No important Some
Kidney 2 RCTs 358 No limitations Sparse data No significant difference between
inconsistencies uncertainty Low Moderate
function (High) (183) (0) (–1) CsA C2 vs. C0
(0) (–1)
Adverse 2 RCTs 358 CsA C2 might cause more tremor Depends on
events (High) (183) than C0 monitoring. outcome
Consistency
and study study studies generalizability/ considerations evidence for
Uncertain Very low
C0, 12-hour trough; C2, 2 hour post-dose; CsA, Cyclosporine A; N, Number; RCT, Randomized controlled trials.
Annotations:
a. References: 76,77
Supporting Table 35. Summary Table Topic 5.1.1: CsA C2 vs. C0 (categorical outcomes)a
%
donor
Mortality
Kyllönen, 2006,76 74 80 CsA-ME CsA-ME trough
12 mo 12 mo MMF/Steroids 51 100 2001-04 5% 3% NS fair
Finland (80) (80) (C2) (C0)
Graft loss
Keown, 2002,77 EU, 109 95 CsA-ME AUC CsA-ME trough Steroids/
12 wk 12 wk 46 88 <2001 7% 6% NS good
Canada, Argentinaa (109) (95) (C0+C2±C3) (C0) Basiliximab
12 mo Kyllönen, 2006,76 74 80 CsA-ME CsA-ME trough 5% 8% NS fair
12 mo MMF/Steroids 51 100 2001-04
Censored for death Finland (80) (80) (C2) (C0) 3% 5% NS fair
Acute rejection
12 wk 27% 28% NS good
Severity of AR, 12 wk 46 88 <2001
Canada, Argentinaa (109) (95) (C0+C2±C3) (C0) Basiliximab 14% 29% NS good
Banff II or higher
12 mo 11% 8% NS fair
Severity of AR, Kyllönen, 2006,76 74 80 CsA-ME CsA-ME trough
12 mo MMF/Steroids 51 100 2001-04 0% 3% nd fair
Banff II or higher Finland (80) (80) (C2) (C0)
CsA toxicity or CAN Keown, 2002,77 EU, 109 95 CsA-ME AUC CsA-ME trough Steroids/
12 wk 46 88 <2001 9% 5% NS good
(Bx-proven) Canada, Argentinaa (109) (95) (C0+C2±C3) (C0) Basiliximab
Kyllönen, 2006,76 36 CsA-ME CsA-ME trough
CsA toxicity 12 mo MMF/Steroids 51 100 2001-04 0% 0% NS poor
Finland (160) (C2) (C0)
NODAT
12 mo 12 mo MMF/Steroids 51 100 2001-04 4% 8% NS poor
Finland (80) (80) (C2) (C0)
Infection
12 wk 43% 44% NS good
CMV 12 wk 46 88 <2001 20% 17% NS good
Fungal 4% 3% NS good
Finland (80) (80) (C2) (C0)
Finland (80) (80) (C2) (C0)
%
donor
Kidney function
Scr deterioration
(increase >30% 12 wk 46 88 <2001 58% 54% NS good
above baseline)
Adverse events
Serious AE (urinary,
vascular, 12 wk 46 88 <2001 34% 21% NS good
hematological)
Tremor 12 mo MMF/Steroids 51 100 2001-04 12% 3% <0.05 fair
Finland (80) (80) (C2) (C0)
AE, Adverse events; AR, Acute rejection; AUC, Area under the curve; CAN, Chronic allograft nephropathy; CMV, Cytomegalovirus; CsA, Cyclosporine; CsA-ME, Cyclosporine microemulsion; EU, Europe; MMF, Mycophenolate mofetil; nd, Not
documented; NODAT, New onset diabetes after transplantation; NS, Not significant; SCr, Serum creatinine.
Annotations:
a. Keown, 2002,77 for the International Neoral Renal Transplantation Study Group.
Supporting Table 36. Summary Table Topic 5.1.1: C2 vs. C0 (continuous outcomes)
country duration Arm 1 Arm 2 Arm 1 Arm 2 medication (mean) donor transplant value
(Control) (Control)
Kidney function
Keown, 2002,77
109 95 CsA-ME AUC CsA-ME trough Steroids/ 458 -290
Scr, µmol/L EU, Canada, 12 wk 46 88 <2001 NS good
(109) (95) (C0+C2±C3) (C0) Basiliximab (482) (-315)
Argentinaa
151 –45
Scr , µmol/L nd fair
Kyllönen, 74 80 CsA-ME CsA-ME trough (129) (–29)
12 mo MMF/Steroids 51 100 2001-04
2006,76 Finland (80) (80) (C2) (C0) 68 +11
CrCl, mL/min nd fair
(69) (+10)
AUC, Area under the curve; CrCl, Creatinine clearance; CsA-ME, Cyclosporine microemulsion; EU, Europe; L, Liter; μmol, Micromole; min, Minute; mL, Milliliters; MMF, Mycophenolate mofetil; mo, Month; nd, Not documented; NS, Not
significant; SCr, Serum creatinine; vs, Versus; wk, Week
Annotations:
a. Keown, 2002,77 for the International Neoral Renal Transplantation Study Group.
Supporting Table 37. Summary Table Topic 5.2: MPA monitoring (categorical outcomes)
Study duration
Concomitant
% deceased
Study, year,
medication
transplant
Dates of
country
P value
Quality
(mean)
donor
Age
Outcome
Arm 2
Arm 1
Arm 2
Arm 4
Arm 2
Arm 4
Arm 3
Arm 1
Arm 1
Arm 3
Arm 3
Arm 4
Mortality
MMF- MMF- CsA/
Le Meur, 65 65 2003-
12 mo 12 mo — — — AUC — fixed Steroids/ 49 nd — 2% — 2% nd good
2007,78 Francea (65) (65) 04
(40)b (2 g) IL2-AB
MMF MMF MMF
Hale, 1998,79
51 47 52 low med. high CsA/
6 mo Netherlands, 6 mo — — 48 100 <2001 total group: 1% — nd poor
(51) (47) (52) AUC AUC AUC Steroids
Belgiuma
(16.1)b (32.2)b (60.6)b
CsA or
van Gelder, MMF MMF
12 449 452 Tac/ 2003-
12 mo 2008,80 — — — AUC — fixed (2 45 74 — 3% — 3% NS fair
mo (449) (452) Steroids/ 06
International (45)d g)d
Induction
Graft loss
MMF- MMF- CsA/
Le Meur, 65 65 2003-
12 mo 12 mo — — — AUC — fixed Steroids/ 49 nd — 2% — 0% nd good
2007,78 Francea (65) (65) 04
(40)b (2 g) IL2-AB
MMF MMF MMF
Hale, 1998,79
6 mo Netherlands, 6 mo — — 48 100 <2001 4% 2% 2% — nd good
Belgiuma
(16.1)b (32.2)b (60.6)b
CsA or
van Gelder, MMF MMF
12 449 452 Tac/ 2003-
mo (449) (452) Steroids/ 06
International (45)d g)d
Induction
Cancer
CsA or
van Gelder, MMF MMF
12 449 452 Tac / 2003-
mo (449) (452) Steroids / 06
International (45) d g)d
Induction
Acute rejection
Total — 12% — 31% 0.01 good
MMF- MMF- CsA/
Biopsy-proven Le Meur, 65 65 2003- — 8% — 25% 0.01 good
12 mo — — — AUC — fixed Steroids/ 49 nd
Severity of AR, 2007,78 Francea (65) (65)
(40)b (2 g) IL2-AB
04
— 3% — 11% nd good
Banff II or higher
MMF MMF MMF
Total Hale, 1998,79 31% 17% 13% — nd good
Netherlands, 6 mo — — 48 100 <2001
Biopsy-proven Belgiuma 25% 9% 6% — nd good
(16.1)b (32.2)b (60.6)b
Study duration
Concomitant
% deceased
Study, year,
medication
transplant
Dates of
country
P value
Quality
(mean)
donor
Age
Outcome
Arm 2
Arm 1
Arm 2
Arm 4
Arm 2
Arm 4
Arm 3
Arm 1
Arm 1
Arm 3
Arm 3
Arm 4
Biopsy-proven CsA or — 15% — 16% NS fair
van Gelder, MMF MMF
12 449 452 Tac/ 2003-
Mild/Moderate/S 2008,80 — — — AUC — fixed (2 45 74 10/5/0. NS
mo (449) (452) Steroids/ 06 — 8/6/1% — fair
evere International (45)d g)d 2% (0.06)
Induction
Infections
CMV (viremia) MMF- MMF- CsA/ — 17% — 25% nd good
Le Meur, 65 65 2003-
CMV (tissue 12 mo — — — AUC — fixed Steroids/ 49 nd
2007,78 Francea (65) (65) 04 — 8% — 6% nd good
invasive) (40)b (2 g) IL2-AB
CsA or
Opportunistic van Gelder, MMF MMF
12 449 452 Tac/ 2003-
infection (at 2008,80 — — — AUC — fixed (2 45 74 — 29% — 26% NS poor4
mo (449) (452) Steroids/ 06
least 1) International (45) d g)d
Induction
Kidney function
MMF- MMF- CsA/
Le Meur, 65 65 2003-
Scr, µmol/L 12 mo — — — AUC — fixed Steroids/ 49 nd — 137 — 150 NS good
2007,78 Francea (65) (65) 04
(40)b (2 g) IL2-AB
Adverse events
GI disorders — 25% — 20% nd good
MMF- MMF- CsA/
Leukopenia Le Meur, 65 65 2003- — 40% — 34% nd good
12 mo — — — AUC — fixed Steroids/ 49 nd
Anemia 2007,78 Francea (65) (65) 04 — 66% — 61% nd good
(40)b (2 g) IL2-AB
Proteinuria, mg/d — 190 — 233 nd good
MMF MMF MMF
Hale, 1998,79
Withdrawal due 51 47 52 low med. high CsA/
Netherlands, 6 mo — — 48 100 <2001 6% 17% 38% — nd fair
to AEc (51) (47) (52) AUC AUC AUC Steroids
Belgiuma
(16.1)b (32.2)b (60.6)b
Anemia — 15% — 14% NS fair
Diarrhea CsA or — 25% — 25% NS fair
van Gelder, MMF MMF
Leucopenia 12 449 452 Tac/ 2003- — 18% — 14% NS fair
2008,80 — — — AUC — fixed 45 74
Thrombocyto- mo (449) (452) Steroids/ 06
International (45)d (2 g)d — 5% — 6% NS fair
penia Induction
Weight loss — 2% — 2% NS fair
AE, Adverse events; AR, Acute rejection; AUC, Area under the curve; CMV, Cytomegalovirus; CsA, Cyclosporine; GI, Gastrointestinal; IL2-AB, Interleukin-2 antibody; MMF, Mycophenolate mofetil; mo, Month; MPA, Mycophenolate acid; nd, Not documented;
NS, Not significant; SCr, Serum creatinine; Tac, Tacrolimus
Annotations:
a. Le Meur, 2007 78: MMF AUC versus MMF fixed dose; Hale, 1998 79: 3 different MMF-AUC targets.
b. MMF-AUC: numbers in parentheses describe target AUC in µg x h/mL..
c. AE vaguely reported: diarrhea, nausea, leucopenia, CMV, UTI, abdominal pain: “not significantly different”.
d. The trial failed to achieve separation of groups (AUC in MMF fixed dose and MMF AUC were similar); the trial failed to achieve the target AUC of 45 mg h/L especially in the early post KTx period.
Supporting Table 38. Evidence Profile Topic 6.3.2 OKT3 vs. other antibody for acute rejectiona,b
Directness of the Summary of findings
Consistency evidence Other
Outcome and study Total N quality of studies Quality of evidence Qualitative and quantitative description Importance
across studies generalizability/ considerations
design per outcome for outcome of effect of outcome
applicability
Not adequately
1 SR No important
Some limitations No uncertainty powered for the No difference between treatment of acute
Mortality (3 RCTs) 175 inconsistencies Low Critical
(–1) (0) outcome rejection with an OKT3 and other antibodies
(High) (0)
(–1)
Not adequately
1 SR No important
Some limitations No uncertainty powered for the No difference between treatment of acute
Graft loss (3 RCTs) 136 inconsistencies Low Critical
(–1) (0) outcome rejection with an OKT3 and other antibodies
(High) (0)
(–1)
None, but some
Failure of acute 1 SR No important studies with
Some limitations No uncertainty No difference between treatment of acute
rejection (3 RCTs) 136 inconsistencies small sample Moderate High
(–1) (0) rejection with an OKT3 and other antibodies
reversal (High) (0) size
(0)
1 SR No important
Some limitations No uncertainty Sparse data No difference between treatment of acute
Infection (3 RCTs) 175 inconsistencies Low High
(–1) (0) (–1) rejection with an OKT3 and other antibodies
(High) (0)
1 SR No important
Kidney Some limitations No uncertainty Sparse data No difference between treatment of acute
function (–1) (0) (–1) rejection with an OKT3 and other antibodies
(High) (0)
Fever, chills,
1 SR No important
malaise Some limitations No uncertainty Sparse data No difference between treatment of acute
following drug (–1) (0) (–1) rejection with an OKT3 and other antibodies
(High) (0)
administration
Uncertain Low
OKT3, Muromonab (anti-T cell antibody); N, Number; RCT, Randomized controlled trials; SR, Systematic review.
Annotations:
a. Reference: 81
b. This evidence profile is based solely on existing systematic reviews. A de novo systematic review was not conducted.
Supporting Table 39. Evidence Profile Topic 6.4: Antibody (OKT3, ATG, ALG) vs. steroid alone for acute rejectiona,b
Directness of the Summary of findings
Consistency evidence Other
Outcome and study Total N quality of studies Quality of evidence Qualitative and quantitative Importance
across studies generalizability/ considerations
design per outcome1 for outcome description of effect of outcome
applicability
Not adequately
1 SR No important There is no evidence that treatment of acute
Some limitations No uncertainty powered for the
Mortality (6 RCTs) 318 inconsistencies Low rejection with an antibody is causing more Critical
(–1) (0) outcome
(High) (0) deaths than treatment with steroids alone.
(–1)
Not adequately
1 SR No important Treatment of acute rejection with an antibody
Some limitations No uncertainty powered for the
Graft loss (7 RCTs) 380 inconsistencies Low is associated with less graft loss than Critical
(–1) (0) outcome
(High) (0) treatment with steroids alone.
(–1)
None, but some
Failure of acute 1 SR No important studies with
Some limitations No uncertainty Treatment with an antibody is better than with
rejection (6 RCTs) 334 inconsistencies small sample Moderate High
(–1) (0) steroids alone for treatment of acute rejection.
reversal (High) (0) size
(0)
There is no evidence that treatment of acute
1 SR No important rejection with an antibody is causing more
Some limitations No uncertainty Sparse data
Infection (4 RCTs) 206 inconsistencies Low infections than treatment with steroids alone. High
(–1) (0) (–1)
(High) (0) Data on CMV are very limited due to small
sample size.
None, but some
Fever, chills,
1 SR No important studies with Treatment of acute rejection with an antibody
malaise Some limitations No uncertainty
(3 RCTs) 185 inconsistencies small sample Moderate is associated with more adverse events than Moderate
following drug (–1) (0)
(High) (0) size treatment with steroids alone.
administration
(0)
No net benefit or harm Low
ALG, Antilymphocyte globulin ; ATG, Antithymocyte globulin; CMV, Cytomegalovirus; OKT3, Muromonab (anti-T cell antibody);N, Number; RCT, Randomized controlled trials; SR, Systematic review
a. Reference: 81
Supporting Table 40. Summary Table Topic 6.5: Change in immunosuppression in the setting of acute rejection (categorical outcomes)
Outcome Quality
country duration Arm 1 Arm 2 Arm 1 Arm 2 medication (mean) donor transplant Arm 1 Arm 2 value
Mortality
MMF Rejection
113 108 MMF
3y Group, 2001,82,83 3y AZA CsA/Steroids 44 nd 1991-94 4% 3% NS poor
(113) (108) 3g
US, Canadaa
MMF Refractory
Rejection Group, 77 73 MMF
12 mo 12 mo IV–Steroids CsA/Steroids 39 nd <1996 3% 1% NS poor
1996,84 US, (77) (77) 3g
Canadab
Graft loss
MMF Rejection
Censored for 113 108 MMF
Group, 2001,82,83 3y AZA CsA/Steroids 44 nd 1991-94 6% 12% NS poor
death (113) (108) 3g
US, Canadaa
MMF Refractory
12 mo 12 mo IV–Steroids CsA/Steroids 39 nd <1996 12% 25% nd poor
1996,84US, (77) (77) 3g
Canadab
Immuno-
Böhmig, 2007,85 5 5 No Immuno- Switch to Tac/ 62/30
21 d 21 d adsorption nd 2001-05 0% 80% <0.05 fair
Austriac (5) (5) adsorption MMF Steroids (median)
(Protein A)
Cancer
3y MMF Rejection 113 108 MMF 14% 10% nd poor
Group, 2001,82,83 3y AZA CsA/Steroids 44 nd 1991-94
PTLD (113) (108) 3g 3% 3% NS poor
US, Canadaa
12 mo MMF Refractory 4% 1% NS poor
12 mo IV–Steroids CsA/Steroids 39 nd <1996
PTLD 1996,84 US, (77) (77) 3g 3% 0% NS poor
Canadab
Acute rejection
Subsequent
39% 66% nd poor
AR, total
Subsequent
AR, biopsy-
proven, MMF Rejection
Group, 113 108 MMF Δ27%
censored for 3y AZA CsA/Steroids 44 nd 1991-94
2001,82,83US, (113) (108) 3g 42% 69% (13-40) poor
death, graft
Canadaa 95% CI
loss,
premature
withdrawal
Antibody – 17% 42% <0.001 poor
Outcome Quality
country duration Arm 1 Arm 2 Arm 1 Arm 2 medication (mean) donor transplant Arm 1 Arm 2 value
therapy
12 mo
Subsequent
17% 27% nd poor
AR, total
MMF Refractory
Subsequent
AR, biopsy- 12 mo IV-Steroids CsA/Steroids 39 nd <1996 27% 41% nd poor
1996,84 US, (77) (77) 3g
proven
Canadab
Antibody–
10% 25% nd poor
therapy
Chronic
MMF Rejection
renal 113 108 MMF
Group, 2001,82,83 3y AZA CsA/Steroids 44 nd 1991-94 8% 6% nd poor
allograft (113) (108) 3g
US, Canadaa
dysfunction
Infection
CMV MMF Rejection 113 108 MMF 37% 26% nd poor
Group, 2001,82,83 3y AZA CsA/Steroids 44 nd 1991-94
PCP (113) (108) 3g 1% 1% NS poor
US, Canadaa
CMV MMF Refractory 14% 15% NS poor
12 mo IV–Steroids CsA/Steroids 39 nd <1996
PCP 1996,84 US, (77) (77) 3g 0% 1% NS poor
Canadab
Immuno-
Böhmig, 2007,85 5 5 No Immuno- Switch to Tac/ 62/30
CMV 21 d adsorption nd 2001-05 40% nd nd poor
Austriac (5) (5) adsorption MMF Steroids (median)
(Protein A)
Kidney function
MMF Rejection
CrCl, 113 108 MMF
Group, 2001,82,83 3y AZA CsA/Steroids 44 nd 1991-94 73 69 nd poor
mL/min (113) (108) 3g
US, Canadaa
MMF Refractory
Scr, µmol/L, Rejection Group, 77 73 MMF
12 mo IV–Steroids CsA/Steroids 39 nd <1996 182 218 NS poor
6 mo 1996,84 US, (77) (77) 3g
Canadab
Adverse events
Diarrhea MMF Rejection 50% 39% nd poor
113 108 MMF
Anemia Group, 2001,82,83 3y AZA CsA/Steroids 44 nd 1991-94 47% 41% nd poor
(113) (108) 3g
US, Canadaa
Leucopenia 39% 37% nd poor
AE, Adverse events; AR, Acute rejection; AZA, Azathioprine; CMV, Cytomegalovirus; CrCl, Creatinine clearance; CsA, Cyclosporine; IV, Intravenous; MMF, Mycophenolate mofetil; nd, Not documented; NS, Not significant;
PCP, Pneumoystis pneumonia; PTLD, Posttransplant lymphoproliferative disease; SCr, Serum creatinine; Tac, Tacrolimus; US, United States
Annotations:
a. MMF Rejection Group, 200182,83: treatment of patients with biopsy-proven acute rejection, between day 7 and month 6 after transplantation
b. MMF Refractory Rejection Group, 199684: treatment of patients with biopsy-proven acute rejection, that did NOT respond to treatment with OKT3, ATG or ALG over 7 days or recurred within 7 days.
c. Böhmig, 200785: treatment of patients with acute humoral, C4d positive acute rejection; concomitantly all pts. were switched to Tacrolimus and received treatment for cellular rejection according to Banff histology results
(IV Steroids and/or ATG); trial prematurely stopped because of high efficacy in the treatment group.
Supporting Table 41. Summary Table Topic 6.5: Change in immunosuppression in the setting of acute rejection (continuous outcomes)
No. analyzed
(enrolled) %
(Control) (Control)
Kidney function
MMF Rejection
Scr; µmol/L, 113 108 MMF 269 –125
Group 2001,82,83 3y AZA CsA/Steroids 44 nd 1991-94 <0.05 poor
12 mo (113) (108) 3g (254) (–108)
US, Canadaa
AZA, Azathioprine; CsA, Cyclosporine; MMF, Mycophenolate mofetil; nd, Not documented; SCr, Serum creatinine; US, United States.
Annotations:
a. MMF Rejection Group, 200182,83: treatment of patients with Biopsy-proven acute rejection, between day 7 and month 6 after transplantation.
b. MMF Refractory Rejection Group, 199684: treatment of patients with Biopsy-proven acute rejection, that did NOT respond to treatment with OKT3, ATG or ALG over 7 days or recurred within 7 days.
c. Böhmig, 200785: treatment of patients with acute humoral, C4d positive acute rejection; concomitantly all pts. were switched to Tacrolimus and received treatment for cellular rejection according to Banff histology results
(IV Steroids and/or ATG); trial prematurely stopped because of high efficacy in the treatment group.
Supporting Table 42. Evidence Profile Topic 7.2: CsA withdrawal in the setting of biopsy-proven CANa
drug) applicability
2 RCTs 329 Some limitations No uncertainty No difference between CsA withdrawal vs.
Mortality inconsistencies powered Low Critical
(High) (199) (–1) (0) CsA continuation in biopsy-proven CAN
(0) (–1)
No important Data available
2 RCTs 329 Some limitations No uncertainty No difference between CsA withdrawal vs.
Graft loss inconsistency up to 2 years Low Critical
(High) (199) (–1) (0) CsA continuation in biopsy-proven CAN
(0) (–1)
No important Higher rates of incident CVD events with CsA
CVD events inconsistency Low continuation in biopsy-proven CAN compared Critical
(High) (126) (–1) (0) (–1)
(0) to the withdrawn arm
Cancer 0 RCTs Critical
No important
1 RCT 186 Some limitations No uncertainty Sparse data No difference between CsA withdrawal vs.
Acute rejection inconsistency Low High
(High) (126) (–1) (0) (–1) CsA continuation in biopsy-proven CAN
(0)
No important
NODAT inconsistency Low High
(0)
Important
Infection 2 RCTs 329 Some limitations No uncertainty None No difference between CsA withdrawal vs.
inconsistencies Low High
(disease) (High) (199) (–1) (0) (0) CsA continuation in biopsy-proven CAN
(–1)
No important Kidney function is better in the CsA
Kidney 2 RCTs 329 Some limitations No uncertainty None
inconsistencies Moderate withdrawal compared with CsA continuation in Moderate
function (High) (199) (–1) (0) (0)
(0) biopsy-proven CAN.
Important
2 RCTs 329 Some limitations No uncertainty None No difference between CsA withdrawal vs.
(High) (199) (–1) (0) (0) CsA continuation in biopsy-proven CAN
(–1)
No important
Blood pressure inconsistency Low Moderate
(0)
No difference in drug discontinuation rates
Adverse events between CsA withdrawal vs. CsA continuation
in biopsy-proven CAN
Uncertain Low
CAN, Chronic allograft nephropathy; CsA, Cyclosporine A; CVD, Cardiovascular disease; N, Number; NODAT, New onset diabetes after transplant; RCT, Randomized controlled trials
Annotations:
Supporting Table 43. Summary Table Topic 7.2: CsA withdrawal in the setting of biopsy-proven CAN (categorical outcomes)
No. analyzed
Study, Intervention/Control % Results
Study (enrolled) Concomitant Age* Dates of P
Outcome year, deceased Quality
duration Medications (Mean) transplant value
country Arm 1 Arm 2 Arm 1 Arm 2 donor Arm 1 Arm 2
Mortality
Dudley,
2005,86 Steroids
73 70
12 mo EU, US, 12 mo MMF CsA (AZA for CsA 43 77 nd 4% 0% nd fair
(73) (70)
South group)
America
Shihab,
126 60 MMF
5y 2008,88 5y Tac CsA 45 66 1998-2000 18% 22% NS fair
(126) (60) Steroids
US
Graft loss
Graft survival Dudley,
including 2005,86 Steroids
73 70
death with EU, US, 12 mo MMF CsA (AZA for CsA 43 77 nd 93% 94% nd fair
(73) (70)
functioning South group)
graft America
Shihab,
126 60 MMF
5y 2008,88 5y Tac CsA 45 66 1998-2000 55% 57% NS fair
(126) (60) Steroids
US
CVD events
Shihab,
Incident 123 58 MMF
2008,88 5y Tac CsA 45 66 1998-2000 11% 28% 0.004 fair
events (126) (60) Steroids
US
Acute rejection
Shihab,
126 60 MMF
Biopsy-proven 2008,88 5y Tac CsA 45 66 1998-2000 9% 8% NS fair
(126) (60) Steroids
US
Kidney function
Patients with
improved
73 70
kidney Dudley, 49% 26% 0.006 fair
(73) (70)
function 2005,86 Steroids
6 mo EU, US, 12 mo MMF CsA (AZA for CsA 43 77 nd
Patients with South group)
improved America 62 60
48% 35% NS fair
kidney (73) (70)
function
No. analyzed
Study, Intervention/Control % Results
Study (enrolled) Concomitant Age* Dates of P
Outcome year, deceased Quality
duration Medications (Mean) transplant value
country Arm 1 Arm 2 Arm 1 Arm 2 donor Arm 1 Arm 2
Infection
UTI Dudley, 14% 7% nd fair

2005,86 Steroids
73 70
EU, US, 12 mo MMF CsA (AZA for CsA 43 77 nd
(73) (70)
South group)
12 mo America 22% 7% nd fair
Shihab,
110 50 MMF
5y 2008,88 5y Tac CsA 45 66 1998-2000 22% 26% NS fair
(126) (60) Steroids
US
NODAT
Shihab,
87 43 MMF
5y 2008,88 5y Tac CsA 45 66 1998-2000 13% 14% NS poor
(126) (60) Steroids
US
Adverse events
Shihab,
Discontinued 126 60 MMF
2008,88 5y Tac CsA 45 66 1998-2000 9% 8% NS fair
treatment (126) (60) Steroids
US
AZA, Azathioprine; CAN, Chronic allograft nephropathy; CsA, Cyclosporine; CVD, Cardiovascular disease; EU, Europe; MMF, Mycophenolate mofetil; nd, Not documented; NODAT, New onset diabetes after transplantation;
NS, Not significant; Tac, Tacrolimus; US, United States; UTI, Urinary tract infection.
Supporting Table 44. Summary Table Topic 7.2: CsA withdrawal in the setting of biopsy-proven CAN (continuous outcomes)a
No. analyzed
Study, (enrolled) % P
Outcome year deceased value Quality
duration medications (Mean) transplant Baseline ∆
country Arm 1 Arm 2 Arm 1 Arm 2 donor
(Control) (Control)
Kidney function
CrCl, mL/min Dudley, 61 55 37 +4.5
0.01 poor
6 mo 2005,86 (73) (70) Steroids (37) (–0.9)
South 53 50 group) 37 +5.0
CrCl, mL/min America 0.01 poor
(73) (70) (37) (–0.7)
CrCl, mL/min 34 +1.3

nd
mean (34) (-5.5) poor
CrCl, mL/min Shihab, +1.2
43 19 MMF nd 0.02
median 2008,88 5y Tac CsA 45 66 1998-2000 (-4.1)
Scr, μmol/L (126) (60) Steroids 224 -15
US nd
mean (220) (+42) poor
Scr, μmol/L -18
nd 0.004
median (+35)
Lipids
Serum
47 49 6.02 –0.66
cholesterol, 0.05 poor
(73) (70) (6.02) (0.08)
mmol/L 6 mo
Serum
Dudley, 40 41 6.02 –0.85
cholesterol, 0.01 poor
2005,86 (73) (70) Steroids (6.02) (-0.28)
mmol/L
Serum South group)
46 48 2.18 –0.2
triglycerides, America NS poor
(73) (70) (2.18) (–0.23)
mmol/L 6 mo
Serum
40 39 2.18 –0.33
triglycerides, NS poor
(73) (70) (2.18) (–0.12)
mmol/L
Total Waid,
62 24 MMF 5.59 +1.29
cholesterol, 2005,87 2y Tac CsA 45 nd 1998-2000 0.004 fair
(126) (60) Steroids (5.72) (+0.49)
mmol/L US
a
HDL
55 19 1.2 +0.1
cholesterol, NS fair
(126) (60) (1.1) (–0.1)
mmol/L
LDL
52 19 3.18 +1.03
cholesterol, 0.008 fair
(126) (60) (3.39) (+0.49)
mmol/L
No. analyzed
Study, (enrolled) % P
Outcome year deceased value Quality
duration medications (Mean) transplant Baseline ∆
country Arm 1 Arm 2 Arm 1 Arm 2 donor
(Control) (Control)
Triglycerides, 60 23 2.42 +0.68

NS fair
mmol/L (126) (60) (2.34) (–0.15)
Hypertension
SBP, mm Hg 60 54 146.2 –8.1
NS poor
6 mo (73) (70) (146.2) (–1.7)
Dudley,
52 50 146.2 –6.1
SBP, mm Hg 2005,86 Steroids NS poor
(73) (70) (146.2) (–0.9)
DBP, mm Hg South 60 54 group) 86.0 –3.5
NS poor
6 mo America (73) (70) (86.0) (–0.2)
60 54 86.0 –3.0
DBP, mm Hg NS poor
(73) (70) (86.0) (–1.6)
AZA, Azathioprine; CrCl, Creatinine clearance; CsA, Cyclosporine; DBP, Diastolic blood pressure; EU, Europe; HDL, High density lipoprotein; LDL, Low-density lipoprotein; MMF, Mycophenolate mofetil; nd, Not documented;
NS, Not significant; SBP, Systolic blood pressure; SCr, Serum creatinine; Tac, Tacrolimus; US, United States.
a. The reported 2-year results from the same study as Shihab 2008.
Supporting Table 45. Evidence Profile Topic 9 (Rationale): Protocol biopsya
No. of studies Total N Methodological Directness of the Summary of findings

study across studies generalizability/a considerations
drug) pplicability
No important
281 Some limitations Some uncertainty Sparse data
Mortality 2 RCTs inconsistencies Very Low No difference between the groups Critical
(141) (–1) (–1) (–1)
(0)
No important
Graft loss 2 RCTs inconsistencies Very Low No difference between the groups Critical
(141) (–1) (–1) (–1)
(0)
No important
72 Some limitations Some uncertainty Sparse data Protocol biopsy is better than no protocol
CAN 1 RCT inconsistencies Very Low High
(36) (–1) (–1) (–1) biopsy in identifying CsA nephropathy
(0)
No important
454 Some limitations Some uncertainty None
Acute rejection 4 RCTs inconsistencies Low No difference between the groups High
(229) (–1) (–1) (0)
(0)
No important
61 Some limitations Some uncertainty Sparse data Higher rates of cancers reported in the no
Cancer (others) 1 RCT inconsistencies Very Low High
(30) (–1) (–1) (–1) protocol group
(0)
No important
61 Some limitations Some uncertainty Sparse data Higher rates of CV events reported in the
CV events 1 RCT inconsistencies Very Low High
(30) (–1) (–1) (–1) protocol group
(0)
Kidney function was better in the protocol
No important
Kidney 454 Some limitations Some uncertainty None group in 3 small trials. There was no
4 RCT inconsistencies Low Moderate
function (229) (–1) (–1) (0) difference between the groups in 1 moderate
(0)
sample size trial
No important
Infection 1 RCT inconsistencies Very Low No difference between the groups Moderate
(52) (–1) (–1) (–1)
(0)
Benefit of protocol biopsies for patients treated with a combination of CsA and AZA Very Low
(questionably without induction)
AZA, Azathioprine; CAN, Chronic allograft nephropathy; CsA, Cyclosporine A; CV, Cardiovascular; N, Number; RCT, Randomized controlled trials
Annotations:
a. References: 89-92.
Supporting Table 46. Summary Table Topic 9 (Rationale): Protocol biopsy (categorical outcomes)
Study, Study No. analyzed (enrolled) Intervention/Control IS Age % Dates of Results P
Outcome year deceased Quality
duration Arm 1 Arm 2 Arm 1 Arm 2 regimen (mean) transplant Arm 1 Arm 2 value
country donor
Mortality
Rush,
2007,92 111 107 Tac/MMF/
6 mo 6 mo Biopsy Control 48 nd 2001-04 <1% 0% nd fair
Canada, (111) (107) Steroids
US
Gotti,
30 31 Protocol No CsA/AZA/
36 mo 2003,89 36 mo 43 100 nd 3% 0% nd poor
(30) (31) biopsy biopsy Steroids
Italy
Graft loss
Rush,
2007,92 111 107 Tac/MMF/
6 mo 6 mo Biopsy Control 48 nd 2001-04 1% 2% nd fair
US
Gotti,
36 mo 2003,89 36 mo 43 100 nd 3% 3% nd poor
Italy
CAN
Gotti,
CSA 30 31 Protocol No CsA/AZA/
2003,89 36 mo 43 100 nd 43% nd nd poor
nephropathy (30) (31) biopsy biopsy Steroids
Italy
Acute rejection
6 mo Rush, 9% 7% NS fair
2007,92 111 107 Tac/MMF/
Subclinical 6 mo Biopsy Control 48 nd 2001-04
Canada, (111) (107) Steroids 9% 6% NS fair
rejection
US
Subclinical
rejection 15% 32% NS fair
6 mo
Incidence of
clinical
41% 69% 0.02 fair
rejection
Protocol
2-3 mo Rush, Biopsy
36 36 biopsies CsA/AZA/
Incidence of 1998,91 24 mo at 6 and 41 86 1992-95
(36) (36) 1,2,3,6,12 Steroids
clinical Canada 12 mo
mo 28% 33% NS fair
rejection
4-6 mo
Incidence of
clinical
11% 33% 0.03 fair
rejection
7-12 mo
Study, Study No. analyzed (enrolled) Intervention/Control IS Age % Dates of Results P
Outcome year deceased Quality
duration Arm 1 Arm 2 Arm 1 Arm 2 regimen (mean) transplant Arm 1 Arm 2 value
country donor
CsA or
Kurtkoti,
52 51 Protocol No Tac/MMF
1 mo 2007,90 12 mo 31 0 2004-05 6% 4% nd fair
(52) (51) biopsy biopsy or AZA/
India
Steroids
Gotti,
36 mo 2003,89 36 mo 43 100 nd 63% 0% nd poor
Italy
DGF
Rush,
2007,92 111 107 Tac/MMF/
6 mo 6 mo Biopsy Control 48 nd 2001-04 15.3% 16.8% NS fair
US
Cancer
Gotti,
Neoplasia 2003,89 36 mo 43 100 nd 3% 14% nd poor
Italy
Other outcomes
CV events 13% 3% nd poor
Gotti,
Clinical 30 31 Protocol No CsA/AZA/ Fewer in the steroid
2003,89 36 mo 43 100 nd
outcome (30) (31) biopsy biopsy Steroids withdrawal or CsA nd poor
Italy
events reduction (.06)
CsA or
Kurtkoti,
52 51 Protocol No Tac/MMF
Infection 2007,90 12 mo 31 0 2004-05 10% 12% nd fair
(52) (51) biopsy biopsy or AZA/
India
Steroids
CAN, Chronic allograft nephropathy; CsA, Cyclosporine; CV, Cardiovascular; DGF, Delayed graft function; IS, Immunosuppression; nd, Not documented; NS, Not significant; US, United States
Supporting Table 47. Summary Table Topic 9 (Rationale): Protocol biopsy (continuous outcomes)
Study, No. analyzed (enrolled) Intervention/Control % Results
Study IS Age Dates of P
Outcome year, deceased Baseline ∆ Quality
duration Arm 1 Arm 2 Arm 1 Arm 2 regimen (mean) transplant value
country donor (Control) (Control)
Kidney function
GFR,
70 –5
mL/min/1.73m2 <0.01 fair
(69) (–10)
6 mo
GFR, CsA or
Kurtkoti, 70 –1
mL/min/1.73m2 52 51 Protocol No Tac/MMF <0.01 fair
2007,90 12 mo 31 0 2004-05 (69) (–9)
12 mo (52) (51) biopsy biopsy or AZA/
India
Scr, µmol/L Steroids 104.3 +8.8
<0.01 fair
6 mo (105.2) (+31.8)
Scr, µmol/L 104.3 +1.8
<0.01 fair
12 mo (105.2) (+29.1)
Gotti,
GFR, 30 31 Protocol No CsA/AZA/ 79.3 –3.97
2003,89 36 mo 43 100 nd nd poor
mL/min/1.73m2 (30) (31) biopsy biopsy Steroids (72.3) (–13.3)
Italy
Final 72.9
CrCl, mL/min nd NS fair
(68.9)
Rush, Final
Scr, µmol/L 2007,92 111 107 Tac/MMF/ nd 119.9 NS fair
6 mo Biopsy Control 48 nd 2001-04
Canada, (111) (107) Steroids (124.1)
Sum of chronic US
Final 1.17
score (ci + ct) nd NS fair
(0.79)
≤2
Protocol Biopsy
Rush,
Scr, μmol/L 36 36 biopsies at 6 CsA/AZA/ 133
1998,91 24 mo 41 86 1992-95 nd 0.05 fair
24 mo (36) (36) 1,2,3,6,12 and 12 Steroids (183)
Canada
mo mo
ci, Interstitial score; CrCl, Creatinine clearance; ct, Tubular score; GFR, Glomerular filtration rate; IS, Immunosuppression; nd, Not documented; NS, Not significant; SCr, Serum creatinine; US, United States.
Supporting Table 48. Evidence Profile Topic 13.2: CMV prophylaxisa
No. of Directness of the Summary of findings
Total N Methodological
studies Consistency evidence Other Quality of Qualitative and
Outcome (N on quality of studies Importance
and study across studies generalizability/ considerations evidence for quantitative
Prophylaxis) per outcome of outcome
design applicability outcome description of effect
No important
2 RCTs 217 No limitations No uncertainty Sparse data
Mortality inconsistencies Moderate No difference in mortality Critical
(High) (107) (0) (0) (–1)
(0)
Inconsistent findings
Important
2 RCTs 193 Some limitations No uncertainty Sparse data between studies of benefit of
Graft loss inconsistencies Very Low Critical
(High) (97) (–1) (0) (–1) prophylaxis and of
(–1)
underlying rate of graft loss
Less than half the rate of
1 RCT 69 No limitations No uncertainty Sparse data
Acute rejection NA Moderate biopsy-proven acute High
(High) (33) (0) (0) (–1)
rejection with prophylaxis
Lower rate of CMV infection
Important
Infection 2 RCTs 207 Some limitations No uncertainty Sparse data with ganciclovir prophylaxis,
inconsistencies Very Low High
(disease) (High) (106) (–1) (0) (–1) but not with valacyclovir
(–1)
prophylaxis
No important
Infection 2 RCTs 207 No limitations No uncertainty Sparse data Significantly lower rates of
(asymptomatic) (High) (106) (0) (0) (–1) DNAemia with prophylaxis
(0)
Delayed graft 1 RCT 69 No limitations No uncertainty Sparse data No difference in rate of
NA Moderate Moderate
function (High) (33) (0) (0) (–1) delayed graft function
In one study, a higher rate of
leucopenia, but not
No important
2 RCTs 217 Some limitations No uncertainty Sparse data neutropenia with
Adverse events inconsistencies Low Moderate
(High) (107) (–1) (0) (–1) prophylaxis. No other
(0)
differences in adverse event
rates.
Chemoprophylaxis results in less acute rejection and CMV infection, with no clear evidence of increased adverse events Low for KTR (Moderate based on additional trials in patients
with solid organ transplant b)
CMV, Cytomegalovirus; N, Number; RCT, Randomized controlled trials.
Annotations:
b. Based on a Cochrane systematic review (Hodson EM, et al. Cochrane Database of Systematic Reviews). (2):CD005129, 2007} of 32 trials (high quality of overall evidence) in patients with any solid organ transplant that
chemoprophylaxis significantly reduces all-cause mortality, CMV disease mortality, CMV disease, but not acute rejection or graft loss.
Supporting Table 49. Summary Table Topic 13.2: CMV prophylaxis
Study, year, Study No. analyzed (enrolled) Intervention/Control Age % Dates of Results
country duration Arm 1 Arm 2 Arm 1 Arm 2 (mean) transplant Arm 1 Arm 2
donor
Mortality
Kliem, 2008,93 74 74 Ganciclovir 1 No
12 mo 12 mo 48 nd 2000-02 7% 5% NS good
Germany (74) (74) g 3x/d x 90 d prophylaxis
Reischig,
33 36 Valacyclovir 2 No
12 mo 2008,94 12 mo 48 34 2003-06 3% 0% NS good
(34) (36) g 4x/d x 3 mo prophylaxis
Czech Rep.
Graft outcomes
Allograft loss Kliem, 2008,93 64 60 Ganciclovir 1 No
4y 48 nd 2000-02 8% 22% 0.04 fair
beyond 100 d Germany (74) (74) g 3x/d x 90 d prophylaxis
Allograft loss 9% 3% NS good
Delayed graft Reischig,
33 36 Valacyclovir 2 No 27% 17% NS good
function 2008,94 12 mo 48 34 2003-06
Acute rejection, Czech Rep.
15% 36% 0.03 good
Biopsy-proven
Infection outcomes
CMV disease
7% 18% 0.04 fair
(hospitalization) Kliem, 2008,93 73 65 Ganciclovir 1 No
12 mo 48 nd 2000-02
CMV infection Germany (74) (74) g 3x/d x 90 d prophylaxis
18% 51% <0.0001 good
(DNAemia)
CMV disease
Reischig, 9% 6% NS good
(symptomatic) 33 36 Valacyclovir 2 No
2008,94 12 mo 48 34 2003-06
CMV infection (34) (36) g 4x/d x 3 mo prophylaxis
Czech Rep. 59% 92% <0.001 good
(DNAemia)
Complications
Serious AE
(including CMV-
Kliem, 2008,93 74 74 Ganciclovir 1 No 57% 53% NS
related) 12 mo 48 nd 2000-02 fair
Germany (74) (74) g 3x/d x 90 d prophylaxis [15%/1%] [1% / 0%] [0.004/NS]
[Leukopenia/
Neutropenia]
Reischig,
33 36 Valacyclovir 2 No
Overall 2008,94 12 mo 48 34 2003-06 No significant differences good
Czech Rep.
AE, Adverse events; CMV, Cytomegalovirus; nd, Not documented; NS, Not significant.
Supporting Table 50. Evidence Profile Topic 14.1.1: UTI treatmenta
No. of studies Total N Methodological Directness of the Summary of findings
drug) applicability
Important
1 RCT 80 No limitations No uncertainty Sparse data No difference between ciprofloxacin vs.
(High) (41) (0) (0) (–1) placebo
(–1)
No important
2 RCTs 183 Some limitations No uncertainty None No difference between ciprofloxacin vs. TMP-
(High) (92) (–1) (0) (0) SMZ or placebo
(0)
Antibiotic (ciprofloxacin/TMP-SMZ)
No important
Infection 3 RCTs 315 Some limitations No uncertainty None prophylaxis is better than no antibiotic.
(disease) (High) (159) (–1) (0) (0) Pneumocystis prevented only in patients on
(0)
TMP-SMZ
Antibiotic prophylaxis exceeds harm. Moderate
The use of ciprofloxacin alone runs the risk of pneumocystis infection
N, Number; RCT, Randomized controlled trials; TMP-SMZ, Trimethoprim sulfamethoxazole; UTI, Urinary tract infection.
Annotations:
a. References: 95-97
Supporting Table 51. Summary Table Topic 14.1.1: UTI Treatment
Study, year Study No. analyzed (enrolled) Intervention/Control Age % Dates of Results P
country duration Arm 1 Arm 2 Arm 1 Arm 2 (mean) transplant Arm 1 Arm 2 value
donor
Mortality
Ciprofloxacin
Moyses, 250 mg twice
28 30
6 mo 1997,95 6 mo daily x 10 d Placebo nd 95 1993-95 7% 8% nd fair
(41) (39)
Brazil 250 mg single
dose x 6 mo
Graft outcomes
TMP-SMZ
Allograft Hibberd, 51 52 Ciprofloxacin
9 mo single 44 84 1988-90 8% 2% NS fair
failure 1992,95 US (51) (52) 250 mg
strength
Ciprofloxacin
Moyses, 250 mg twice
41 39
Graft loss 1997,95 6 mo daily x 10 d Placebo nd 95 1993-95 15% 8% nd fair
(41) (39)
Brazil 250 mg single
dose x 6 mo
Infection outcomes
UTI at 6 mo 0% 8% 0.016 fair
TMP-SMZ
UTI or AE Hibberd, 51 52 Ciprofloxacin
9 mo single 44 84 1988-90 0% 15% 0.002 fair
at 9 mo 1992,95 US (51) (52) 250 mg
strength
PCP 14% 0% 0.006 fair
Ciprofloxacin
250 mg twice
Moyses, 28 30
UTI 6 mo daily x 10 d Placebo nd 95 1993-95 15% 49% <0.05 fair
1997,95 Brazil (41) (39)
250 mg single
dose x 6 mo
Overall UTI
N of 24 54 <0.005 good
infections
Catheter-
Fox, 1990,97 66 66 15 18 NS good
related UTI 9 mo TMP-SMZ Placebo 38 61 1984-1985
US (66) (66)
Non–
catheter- 9 36 <0.005 good
related UTI
PCP 0 1 NS good
nd, Not documented; NS, Not significant; PCP, Pneumocystis pneumonia; TMP-SMZ, Trimethoprim sulfamethoxazole; US, United States; UTI, Urinary tract infection.
Supporting Table 52. Evidence Profile Topic 18.6: Skin cancer prevention with oral retinoidsa,b
No. of Total N Directness of the Summary of findings
Methodological
studies and (N on Consistency evidence Other Quality of
Outcome quality of studies Qualitative and quantitative Importance of
study study across studies generalizability/ considerations evidence
per outcome description of effect* outcome
design drug) applicability for outcome
Mortality 0 RCTs None Critical
Acitretin use resulted in less SCC.
1 SR No important
93 No limitations Some uncertaintyc None No significant difference in the number
Skin cancer (3 RCTs) inconsistencies Moderate High
(74) (0) (–1) (0) of SCC lesions on different doses of
(High) (0)
acitretin
Chelitis, alopecia, HA, myalgia,
1 SR No important
Adverse 93 No limitations Some uncertaintyc None photosensitivity, dry eyes, epistaxis all
(3 RCTs) inconsistencies Moderate Moderate
events (74) (0) (–1) (0) common on treatment (with resolution).
(High) (0)
Drug cessation common.
Decrease in SCC rates on drug but QoL-related adverse events common Moderate
BCC, Basal cell carcinoma; HA, Headache; N, Number; RCT, Randomized controlled trials; SCC, Squamous cell carcinoma; SR, Systematic review.
Annotations:
a. Reference: 98
c. All Caucasian, average 10-15 years after transplant, each with different eligibility criteria (any; ≥10 keratotic lesions on hands/forearms; ≥3 SCC/BCC lesions in past 5 years or ≥10 keratoses at enrollment).
Supporting Table 53. Summary Table Topic 21 (Rationale): Bone outcomes on various immunosuppression regimens
No. analyzed (enrolled) Interventions Results
Study, year, Study Age % deceased Dates of P value
country duration Arm 1 Arm 2 Arm 1 Arm 2 (mean) donor transplant (Control)
(Control) (Control)
Bone mineral density
0.966 +0.052 0.006
18 mo poor
(0.961) (–0.074) (<0.001)
27 30 0.966 +0.024
12 mo CsA + Steroids nd poor
(13) (20) (0.961) (–0.069)
0.966 –0.006
6 mo nd poor
Aroldi, (0.961) (–0.057)
18 mo CsA alone 38 79 nd
1997,99 Italy 0.966 +0.052 0.006
18 mo poor
(0.979) (–0.078) (<0.001)
27 32 CsA + Steroids + 0.966 +0.024
12 mo nd poor
(13) (20) AZA (0.979) (–0.077)
0.966 –0.006
6 mo nd poor
(0.979) (–0.051)
<0.01 for L1-
L4, Femoral
Farmer, 44 48 Steroid Steroids Increased Neck; <0.05
∆BMD 12 mo 44 72 nd nd poor
2006,100 UK (32) (34) Withdrawal Maintained (Reduced) for
Trochanter,
Total Femur
BMD, %∆
Z score
+6.4% +0.5% <0.001 poor
lumbar
spine 39 35
12 mo
BMD, %∆ (39) (35)
Z score
+3.1% –0.3% <0.001 poor
femoral
neck Pelletier, Steroid Steroid
45 64 1997-2002
BMD, %∆ 2006,101 USª withdrawal maintenance
Z score,
+7.1% +1.3% 0.004 poor
lumbar
spine 16 18
36 mo
BMD, %∆ (39) (35)
Z score
+1.8% +0.7% NS poor
femoral
neck
BMD, %Δ
ter Meulen,
lumbar 135 126 Dac/Tac/ Tac/MMF/
2004,9,48 12 mo 48 64 1999-2002 Δ–2.3% Δ–1.3% NS fair
spine 3 (186) (178) MMF Steroids (4 mo)
Netherlands
mo
BMD %Δ
femoral
Δ–1.3% Δ–1.4% NS fair
neck
3 mo
No. analyzed (enrolled) Interventions Results
Study, year, Study Age % deceased Dates of P value
country duration Arm 1 Arm 2 Arm 1 Arm 2 (mean) donor transplant (Control)
(Control) (Control)
BMD %Δ
lumbar
Δ+0.1% Δ+0.9% NS fair
spine 12
mo
BMD %Δ
femoral
Δ–0.9% Δ–0.6% NS fair
neck
12 mo
(final)100.3
BMD, L2 nd <0.01 poor
(94.3)
Vanrent- (final)99.5
BMD, L3 nd <0.01 poor
erghem, 252 248 Low/stop Full standard dose (94.3)
12 mo 45 90 nd
BMD, L4 2000,102 (252) (248) dose steroid steroid
and Multipleb
nd nd NS poor
femoral
neck,
Z-Scores
–1.052 +0.506 0.044
Z-Score CsA + Steroids poor
Aroldi, 27 30 (–1.023) (–0.653) (0.02)
18 mo CsA alone 38 79 nd
1997,99 Italy (13) (20) CsA + Steroids + –1.052 +0.506 0.044
Z-Score C
AZA (–0.921) (–0.723) (0.049)
Mean Z-
–0.35 +0.05
Score nd B
(–0.52) (–0.08)
(L1-L4)
Farmer, 44 48 Steroid Steroids
Mean Z- 12 mo 44 72 nd
2006,100 UK (32) (34) Withdrawal Maintained
Score –0.30 +0.09
nd B
(Total (–0.65) (0.00)
Hip)
Fractures
Rib ter Meulen,
135 126 Dac/Tac/ Tac/MMF/
fractures 2004,9,48 12 mo 48 64 1999-2002 0.8% 1.5% NS B
(186) (178) MMF Steroids (4 mo)
(12 mo) Netherlands
AZA, Azathioprine; BMD, Bone mineral density; CsA, Cyclosporine; Dac, Daclizumab; L1, First lumbar vertebrae; L2, Second lumbar vertebrae; L3, Third lumbar vertebrae; L4, Fourth lumbar vertebrae; MMF, Mycophenolate mofetil; nd,
Not documented; NS, Not significant; Tac, Tacrolimus; UK, United Kingdom; US, United States.
Annotations:
a. Z-scores represent percentage changes in Z scores only.
b. No baseline or change was reported; only final values were reported. Unit of measurement not documented.
Supporting Table 54. Summary Table Topic 22.2: Anemia (categorical outcomes)
Study, year Study No. analyzed (enrolled) Intervention/Control Age % deceased Dates of Results P
Outcome Quality
country duration Arm 1 Arm 2 Arm 1 Arm 2 (mean) donor transplant Arm 1 Arm 2 value
Mortality
Linde, 2001,103
32 24 Subnormal
12-18 mo Scandinavian 12-18 mo Normal Hb 52 94 nd 9% 12% NS poor
(32) (24) Hb
countries
Graft outcomes
Early kidney
VanLoo,
graft 14 15 0% 7% NS poor
1996,104 2 mo Epoetin beta Non EPO 47 nd 1993-94
dysfunction (14) (15)
Belgium
Acute rejection 64% 60% NS poor
Linde, 2001,103
32 24 Subnormal
Acute rejection Scandinavian 12-18 mo Normal Hb 52 94 nd 38% 42% NS poor
(32) (24) Hb
countries
Topic outcomes
Correction of
Moore, 12 12 Fe fumarate No 100% 63% <0.05 fair
anemia 6 mo 40 76% 1991-92
1994,105 US (12) (12) 66 mg Fe treatment
Polycythemia 33% 0% <0.05 fair
Van Biesen,
Anemia 22 18
2005,106 3 mo RhuEPO 100U/kg Non EPO 44 nd nd 35% nd poor
(Hb <125 g/L) (22) (18)
Belgium
EPO, Erythropoietin; Fe, Iron; Hb, Hemoglobin; nd, Not documented; NS, Not significant; RhuEPO, Recombinant erythropoietin; SCr ,Serum creatinine; U, Units; US, United States.
Supporting Table 55. Summary Table Topic 22.2: Anemia (continuous outcomes)
Intervention used
No. analyzed (enrolled) Results
Study, year, Study Control used Age % deceased Dates of P
Outcome Quality
country duration (mean) donor transplant Baseline* ∆ value
(Control) (Control)
Kidney outcomes
Moore, 12 12 Fe fumarate No 327 –221
Scr, µmol/L 6 mo 40 76 1991-92 NS fair
1994,105 US (12) (12) 66 mg Fe treatment (389) (–212)
Topic outcomes
0.27 +0.17
Hct, L <0.05 fair
Moore, 12 12 Fe fumarate No (0.25) (+0.11)
6 mo 40 76 1991-92
1994,105 US (12) (12) 66 mg Fe treatment 88.2 –45.7
EPO, mU/mL NS fair
(53.9) (–30.2)
Hb, g/L 84 –2
Van Biesen, NS poor
day 15 22 18 RhuEPO (92) (–7)
2005,105 3 mo Non EPO 44 nd nd
Hb, g/L (22) (18) 100 U/kg 84 +42
Belgium NS poor
3 mo (92) (+29)
EPO, Erythropoietin; Fe, Iron; Hb, Hemoglobin; nd, Not documented; NS, Not significant; RhuEPO, Recombinant erythropoietin SCr ,Serum creatinine; U, Units; US, United States.
Supporting Table 56. Evidence Profile Topic 22.4: Erythrocytosis treatment
Consistency
and study study studies per generalizability/ considerations evidence for
design drug) outcome applicability outcome
Mortality 0 RCTs Critical
Graft loss 0 RCTs Critical
Enalapril better than placebo, but: NS
No important
Kidney 3 RCTs 66 No limitations No uncertainty Sparse data Enalapril vs. losartan: NS
function (High) (39) (0) (0) (–1) Theophylline better than fosinopril,
(0)
but: NS
No important Enalapril better than placebo
Hematological 3 RCTs 66 No limitations No uncertainty Sparse data
inconsistencies Moderate Enalapril vs. losartan: NS Moderate
outcomes (High) (39) (0) (0) (–1)
(0) Fosinopril better than theophylline
ACE inhibitor better than placebo or theophylline for hematocrit, kidney function unclear Low
N, Number; NS, Not significant; RCT, Randomized controlled trials.
Annotations
a. References: 107-109
Supporting Table 57. Summary Table Topic 22.4: Erythrocytosis treatment (categorical outcomes)
Study, year, Study No. analyzed (enrolled) Intervention/Control Age % deceased Dates of Results P
Outcome Quality
country duration Arm 1 Arm 2 Arm 1 Arm 2 (mean) donor transplant Arm 1 Arm 2 value
Topic outcomes
Hb response Yildiz, 2001,107 15 12 Losartan
2 mo Enalapril 10 mg 32 27% <1996 80% 75% NS fair
(>10 g/L) Turkey (15) (12) 50 mg
Hb, Hemoglobin; NS, Not significant.
Supporting Table 58. Summary Table Topic 22.4: Erythrocytosis treatment (continuous outcomes)
Study, year, Study Age % deceased Dates of P
country duration Arm 1 Arm 2 Arm 1 Arm 2 (mean) donor transplant value
(Control) (Control)
Kidney outcomes
Yildiz, 2001,107 15 12 Enalapril Losartan 114 –5
Scr, μmol/L 2 mo 32 27 <1996 NS fair
Turkey (15) (12) 10 mg 50 mg (121) (+5)
Beckingham
15 10 Enalapril 59.0 –4.1
GFR, mL/min 1995,108 4 mo Placebo nd nd nd NS fair
(15) (10) 2.5 mg/day (65.1) (+1.7)
England, UK
Theophylline
Trivedi, 9 5 Fosinopril up to 141 0
Scr, μmol/L 3 mo up to 8 55 78 nd NS poor
2003,109 US (9) (5) 20 mg/d (124) (+17)
mg/kg/d
Topic outcomes
174 –25
Hb, g/L NS fair
Yildiz, 2001,107 15 12 Enalapril Losartan (171) (–12)
2 mo 32 27 <1996
Turkey (15) (12) 10 mg 50 mg 54.1 –4.3
Hct, % NS fair
(53.4) (–2.5)
163 –12
Hb, g/L Beckingham NS fair
15 10 Enalapril (167) (–7)
1995,108 4 mo Placebo nd nd nd
(15) (10) 2.5 mg/day 52.7 –6.6
Hct, % England, UK 0.004 fair
(52.4) (–1.3)
Theophylline
Trivedi, 9 5 Fosinopril up to 51.3 –7.6
Hct, % 3 mo up to 8 55 78 nd nd poor
2003,109 US (9) (5) 20 mg/d (52.4) (–2.3)
mg/kg/d
GFR, Glomerular filtration rate; Hb, Hemoglobin; Hct, Hematocrit; nd, Not documented; NS, Not significant; SCr, Serum creatinine; UK, United Kingdom; US, United States
Supporting Table 59. Evidence Profile Topic 24.2: Growth hormone treatmenta
Consistency
and study study studies per generalizability/ considerations evidence for
design drug) outcome applicability outcome
Mortality 0 Critical
Graft loss 0 Critical
1 SR “Frequently
317
(9 RCTs) suboptimal” No important
Graft (184) No uncertainty None
(High) (–1) inconsistencies Moderate No difference in change in CrCl or SCr Moderate
function (0) (0)
1 RCT 27 No limitations (0)
(High) (13) (0)
Different
doses
“Frequently No important
rhGH 117 No uncertainty Sparse data
suboptimal” inconsistencies
1 SR (117) (0) (–1)
(–1) (0)
(4 RCTs)
rhGH much better than placebo
(High) Moderate
Growth and (+2.3 cm/y) (95% CI 1.4-3.2)).
rhGH vs. (Low for Moderate
development 28 IU/m2/wk better than 14 IU (3 RCTs)
placebo “Frequently doses)
331 and no different than 56 IU (single RCT)
1 SR suboptimal” No important
(197) No uncertainty None
(9 RCTs) (–1) inconsistencies
(0) (0)
(High) (0)
1 RCT 27 No limitations
(High) (13) (0)
Inadequate
1 SR “Frequently Lack of No effect on glucose tolerance (3 RCTs)
Adverse 433 No uncertainty reporting,
(9 RCTs) suboptimal” consistency Very Low Possible important adverse event included Moderate
events (287) (0) standardization
(High) (–1) (–1) asthma/wheezing (1 RCT)
(–2)
rhGH better than placebo for increasing growth. No evident harm, though data inadequate. Moderate
CI: Confidence interval; CrCl, Creatinine clearance; IU, International units; N, Number; RCT, Randomized controlled trials; rhGH; Recombinant human growth hormone, SCr, Serum creatinine; SR, Systematic reviews.
Annotations:
Supporting Table 60. Summary Table Topic 24.2: Growth hormone treatment (categorical outcomes)
Study, year Study No. analyzed (enrolled) Intervention/Control Age % Dates of Results P
country duration Arm 1 Arm 2 Arm 1 Arm 2 (mean) transplant Arm 1 Arm 2 value
donor
Deflazacort Methylprednisone
Acute Ferraris, 2000,110 13 14
12 mo (mean 0.3 (mean 0.23 9 0 nd 0% 7% NS fair
rejection Argentina (13) (14)
mg/kg/d) mg/kg/d)
nd, Not documented; NS, Not significant.
Supporting Table 61. Summary Table Topic 24.2: Growth hormone treatment (continuous outcomes)
Study, No. analyzed (enrolled) Intervention/Control Results
Study Age % deceased Dates of
Outcome year, Baseline ∆ P value Quality
duration Arm 1 Arm 2 Arm 1 Arm 2 (mean) donor transplant
country (Control) (Control)
Kidney outcomes
CrCl, 68.6 –3.1 NS
Ferraris, Deflazacort Methylprednisone fair
mL/min/1.73 m2 13 14 (66.3) (–8.0) (implied)
2000,110 12 mo (mean 0.3 (mean 0.23 9 0 nd
(13) (14) 85 +12 NS
Scr, μmol/L Argentina mg/kg/d) mg/kg/d) fair
(87) (+19) (implied)
Topic outcomes
901 +29
BMC, g/m2 <0.05 fair
(875) (–48)
1.2 +0.3
HDL, mmol/L <0.05 fair
(1.4) (+0.1)
–2.3 +0.1
Height (SDS) <0.01 fair
(–2.9) (–0.2)
Height Velocity –3.2 +2.7
<0.005 fair
(SDS, unitless) (–2.0) (–1.3)
Ferraris, Deflazacort Methylprednisone 3.49 –0.1
LDL, mmol/L 13 14 <0.025 fair
2000,110 12 mo (mean 0.3 (mean 0.23 9 0 nd (3.54) (+0.44)
(13) (14)
LS BMD, g/cm2 Argentina mg/kg/d) mg/kg/d) 0.734 –0.0489
NS fair
per m2 (0.749) (–0.0723)
1.92 –0.2
Tg, mmol/L NS fair
(2.00) (–0.29)
TSk BMD, 0.939 –0.018
NS fair
g/cm2 per m2 (0.976) (–0.067)
Weight/Height
22.1 –7.1
(%, exceeded <0.005 fair
(15.9) (6.6)
50th %ile)
BMC, Bone mineral content; BMD, Bone mineral density; CrCl, Creatinine clearance; HDL, High density lipoprotein; LDL, Low-density lipoprotein; nd, Not documented; NS, Not significant; SCr, Serum creatinine; SDS, Standard deviation
score; Tg, Triglycerides; TSk BMD, Total skeleton bone mineral density.
Supporting Table 62. The Conference on Guideline Standardization (COGS)
Checklist for Reporting Clinical Practice Guidelinesa
Topic Description Discussed in KDIGO Transplant Guideline
1. Overview material Provide a structured abstract that includes the guideline’s
See Abstract and Appendix: Methods for Guideline
release date, status (original, revised, updated), and print and
Development.
electronic sources.
2. Focus Describe the primary disease/condition and
intervention/service/technology that the guideline addresses.
Indicate any alternative preventative, diagnostic, or This is addressed in the Guideline Scope section.
therapeutic interventions that were considered during
development.
3. Goal Describe the goal that following the guideline is expected to This clinical practice guideline is intended to assist the
achieve, including the rationale for development of a practitioner caring for KTRs in their prevention and
guideline on this topic. treatment of complication that occur after kidney
transplantation to improve patient survival and quality of
life.
4. User/setting Describe the intended users of the guideline (e.g., provider All Transplant Care Providers: Nurses, coordinators,
types, patients) and the settings in which the guideline is pharmacists, doctors, and other medical professionals
intended to be used. that directly or indirectly care for KTRs.
Patients: All KTRs and their relatives and friends.
Policy Makers: Those in related health fields.

5. Target population Describe the patient population eligible for guideline
All KTRs, adult and pediatric.
recommendations and list any exclusion criteria.
6. Developer Identify the organization(s) responsible for guideline Organization: KDIGO.
development and the names/credentials/potential conflicts of
interest of individuals involved in the guideline’s Names/credentials/potential conflicts of interest of
development. individuals involved in the guideline’s development are
disclosed in section Biographic and Disclosure
Information.
7. Funding source/sponsor Identify the funding source/sponsor and describe its role in KDIGO is supported by a consortium of sponsors
developing and/or reporting the guideline. Disclose potential including Abbott, Amgen, Belo Foundation, Coca-Cola
conflict of interest. Company, Dole Food Company, Genzyme, Hoffmann-
LaRoche, JC Penney, NATCO-The Organization for
Transplant Professionals, National Kidney Foundation-
Board of Directors, Novartis, Robert and Jane Cizik
Foundation, Shire, Transwestern Commercial Services,
and Wyeth.
No funding is accepted for the development of specific

guidelines.
Stakeholders could participate in the public review.

8. Evidence collection Describe the methods used to search the scientific literature, The MEDLINE, Cochrane Central Registry for trials and
including the range of dates and databases searched, and Cochrane database of systematic reviews were
criteria applied to filter the retrieved evidence. searched by the ERT to capture all citations relevant to
the topic of kidney transplantation including original
articles, systematic reviews, and previous guidelines.
The Cochrane Renal Group ran parallel searches in
their Renal Registry database and these supplemented
the primary ERT searches. The search was updated
through February 2008 and supplemented by articles
identified by Work Group members through November,
2008.
9. Recommendation Describe the criteria used to rate the quality of evidence that Quality of individual studies was graded in a three-
grading criteria supports the recommendations and the system for describing tiered grading system (see Table 35 in the Appendix:
the strength of the recommendations. Methods for Guideline Development).
Recommendation strength communicates the importance if Quality of evidence and strength of recommendations
adherence to a recommendation and is based on both the were graded following the GRADE approach (Tables
quality of the evidence and the magnitude of anticipated 37-41 in the Appendix: Methods for Guideline
benefits and harm. Development).
The Work Group could provide general guidance in

ungraded statements.
10. Method for Describe how evidence was used to create 1) Topics were triaged either to a) systematic review, b)
synthesizing evidence recommendations, e.g., evidence tables, meta-analysis, systematic search followed by narrative summary, or c)
decision analysis. narrative summary. For systematic review topics,
summary tables and evidence profiles were generated.
2) For recommendations on treatment interventions, the

steps outlined by GRADE were followed.
11. Prerelease review Describe how the guideline developer reviewed and/or tested
The guideline will undergo internal and external review.
the guidelines prior to release.
12. Update plan State whether or not there is a plan to update the guideline There is no date set yet for updating. The updating of
and, if applicable, expiration date for this version of the the guideline will depend on the publication of new
guideline. evidence that would change the quality of the evidence
or the estimates for effect sizes. Results from registered
ongoing studies and other publications will be reviewed
periodically to evaluate their potential to impact on the
recommendations in this guideline.
13. Definitions Define unfamiliar terms and those critical to correct
application of the guideline that might be subject to See Abbreviations and Acronyms.
misinterpretation.
14. Recommendations and State the recommended action precisely and the specific Recommendations are provided in Section I,
rationale circumstances under which to perform it. Justify each Immunosuppression; Section II, Graft Monitoring and
recommendation by describing the linkage between the Infections; Section III, Cardiovascular Disease; Section
recommendation and its supporting evidence. Indicate the IV, Malignancy; and Section V, Other Complications.
quality of evidence and the recommendation strength, based
on the criteria described in 9. Each recommendation builds on a supporting rationale
with evidence tables if available. The strength of the
recommendation and the quality of evidence is provided
in parenthesis within each recommendation.
15. Potential benefits and Describe anticipated benefits and potential risks associated The benefits and harm for each intervention are
harm with implementation of guideline recommendations. provided in summary tables and summarized in
evidence profiles. The estimated balance between
potential benefits and harm was considered when
formulating the recommendations.
16. Patient preferences Describe the role of patient preferences when a Level 2 recommendations inherently indicate a greater
recommendation involves a substantial element of personal need to help each patient arrive at a management
choice or values. decision consistent with her or his values and
preferences.
17. Algorithm Provide (when appropriate) a graphical description of the These were not provided in the guideline, but may be
stages and decisions in clinical care described by the developed later as implementation tools by Kidney
guideline. Learning Solutions™.
18. Implementation Describe anticipated barriers to application of the
These recommendations are global. Review Criteria
considerations recommendations. Provide reference to any auxiliary
were not suggested because implementation with
documents for providers or patients that are intended to
prioritization and development of review criteria has to
facilitate implementation. Suggest review criteria for
proceed locally. Suggestions were provided for future
measuring changes in care when the guideline is
research.
implemented.
ERT. Evidence review team; GRADE, Grading of Recommendations Assessment, Development and Evaluation; KDIGO, Kidney Disease Improving Global Outcomes;
KTR, Kidney transplant recipients
Annotations:
a. Reference: 112
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KDIGO CLINICAL PRACTICE GUIDELINE

FOR THE CARE OF

5 RCTs 584 Some limitations

CVD events 0 RCTs Critical

4 RCTs 476 Some limitations

Scr, µmol/L 40 21 CsA-ME/MMF/

3 RCTs 449 No limitations

CVD events 0 RCTs Critical

2 RCTs 389 No limitations

Ciancio, 2005,13 30 30 Tac/MMF/

CVD events 0 RCTs Critical

5 RCTs 1843 No limitations

All 24 mo Hernandez, 80 80 Tac CsA MMF/Steroids/ 3% 3% NS good

24 mo 45% 46% NS good

Scr, µmol/L Kramer, 2003, 139 147 NS good

Diarrhea Ekberg, 2007,10 27% 14% <0.001 good

Proteinuria Artz, 2003, 64 60 0.2 -0.06

Cholesterol, 4.7 +0.5

CVD events 0 RCTs Critical

12 mo Basiliximab/ Thymo/ 0% 0% NS good

Early CsA ATG/ delayed CsA

Early CsA ATG/ delayed CsA

Anemia Basiliximab/ Thymo/ 0% 8% NS fair

CVD events 0 RCTs Critical

7% 29% 29% <0.01

CVD events 0 RCTs Critical

5y 11% 11% NS good

4 RCTs 1239 No limitations

4 RCTs 1239 No limitations

Hamdy, 67 65 No Tac SRLb, Ster,

>1 y Larson, 2006,51 80 82 No Tac MMF 1.5 g, 6% 9% NS fair

Skin cancer, mean

Chronic allograft nephropathy

Budde, 2003,62 US, 159 163 EC-MPS MMF CsA-ME/ 141 –2

CVD events 0 RCTs Critical

1y Basiliximab 24% 15% NS poor

BPAR, graft loss,

1y Hazzan, 2005, CsA-ME 0% 0% NS good

Scr, µmol/L ALG for

CVD events 0 RCTs Critical

Cancer 0 RCTs Critical

Cancer 0 RCTs Critical

UTI Dudley, 14% 7% nd fair

CrCl, mL/min 34 +1.3

Triglycerides, 60 23 2.42 +0.68

No. of studies Total N Methodological Directness of the Summary of findings

Patients: All KTRs and their relatives and friends.

Policy Makers: Those in related health fields.

No funding is accepted for the development of specific

Stakeholders could participate in the public review.

The Work Group could provide general guidance in

2) For recommendations on treatment interventions, the

1. Grenda R, Watson A, Vondrak K, et al. A prospective, randomized, multicenter trial of tacrolimus-based

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