2008 ASN Highlights: Kidney Transplantation Donald E. Hricik, M.D. Professor of Medicine, Chief...
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Transcript of 2008 ASN Highlights: Kidney Transplantation Donald E. Hricik, M.D. Professor of Medicine, Chief...
2008 ASN Highlights:2008 ASN Highlights:Kidney TransplantationKidney Transplantation
Donald E. Hricik, M.D.Professor of Medicine, Chief Division of Nephrology
and HypertensionUniversity Hospitals Case Medical Center
Cleveland, OhioPostgraduate Education Director, AST
2009 Renal Weekend Transplant Team: Donald Hricik, David Roth, Connie Davis
ASN Renal Weekends 2009
Overview
• Immunosuppression, including clinical trials• Desensitization protocols• Complications
– Malignancy– Anemia– Proteinuria
• The failed transplant/retransplantation
ASN Renal Weekends 2009
Calcineurin Inhibitor Calcineurin Inhibitor Sparing Protocols:Sparing Protocols:
Is There Evidence that Is There Evidence that
They Work?They Work?
Henrik EkbergHenrik Ekberg
Lund University, Lund University,
Malmö, SwedenMalmö, Sweden
ASN Renal Weekends 2009
Longitudinal assessment by protocol biopsy:
CNI nephrotoxicity and subclinical rejection
0 3 12 mo. 2 3 4 5 6 7 8 9 10 years
Timeline of biopsy protocol
• 961 protocol kidney biopsies • 120 kidney/pancreas recipients• Young donors
NEJM 2003; 349: 2326-33
Brian Nankivell
ASN Renal Weekends 2009
Histological features of Cyclosporine Nephrotoxicity
ASN Renal Weekends 2009
The objectives of CNI sparing protocols:
To reduce CNI nephrotoxicity and chronic graft injury: and thereby– improve renal graft function– reduce overall toxicity– improve long-term graft survival
But maintain efficacy in terms of
acute and subclinical rejection
ASN Renal Weekends 2009ASN Renal Weekends 2009
CNI sparing strategies
CNI avoidance CNI withdrawal CNI dose reduction CNI replacement using mToR
inhibitors
ASN Renal Weekends 2009
6 mo.
2°
12 mo.
Tx
Daclizumab
MMF
Steroids
1°
3g/day
2g/day
21
CNI avoidance Daclizumab + CsA + MMF + CS
n = 98
Vincenti F et al. Transplantation 2001; 71:1282–7.
Excellent Renal Function 53 % Acute rejection
at 12 mo.
ASN Renal Weekends 2009
DaclizumabLow-CsA w/dMMFSteroids
Standard CsAMMFSteroids
0 6 12 mo
DaclizumabLow-CsAMMFSteroids
CAESAR study design
Low CsA w/d
Stand CsA
Low CsA
Ekberg H et al. Am J Transplant 2007; 7 (3): 560.
50-100 ng/mL
150-300 ng/mL, 4 mo.: 100-200
50-100 ng/mLWithdrawal 4-6 mo.
ASN Renal Weekends 2009
CAESAR studyRenal function at 12 months
Two values for GFR > 200 ml/min/1.73 m2 excluded
0
10
20
30
40
50
60
70
80
90
100
12 months post-Tx
GF
R (
Co
ckcr
oft
Gau
lt)
[ml/m
in]
A Low CsA w/d
B Low CsA
C Standard CsA
No significant difference
Ekberg H et al. Am J Transplant 2007; 7 (3): 560.
No improvement in GFR by dose-reduction or w/d of CsA
ASN Renal Weekends 2009
CAESAR studyBPAR at 6 and 12 months
0
10
20
30
40
50
6 months post-Tx
BP
AR
[%
of
pa
tie
nts
]
A Low CsA w/d
B Low CsA
C Standard CsA
0
10
20
30
40
50
12 months post-Tx
BP
AR
[%
of
pat
ien
ts] A Low CsA w/d
B Low CsA
C Stand CsA
25 % Acute Rejection
at 6 mo.
38 % Acute Rejection
at 12 mo.
after w/d
Ekberg H et al. Am J Transplant 2007, 7 (3): 560.
ASN Renal Weekends 2009
CNI sparing strategies
So: CNI avoidance – did not work CNI withdrawal (at 4-6 mo.) – did not
work CsA dose reduction …
ASN Renal Weekends 2009
SYMPHONYSYMPHONY Study Design Study Design1645 patients at 83 sites in 15 countries1645 patients at 83 sites in 15 countries
Transplantation 6 months 12 months
Standard-dose CsA
Low-dose CsADaclizumab
MMFSteroids
B50–100ng/mL
Steroids
Low-dose SRLDMMF
Daclizumab4–8ng/mL
Low-dose TACMMFSteroids
Daclizumab3–7ng/mLC
150–300ng/mL for 3 months100–200ng/mL thereafter
MMFSteroids
A
Ekberg H, et al. NEJM 2007;357:2562–75
ASN Renal Weekends 2009
00
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
12 months post-Tx12 months post-Tx
GF
R (
Co
ck
cro
ft G
au
lt)
(ml/m
in)
GF
R (
Co
ck
cro
ft G
au
lt)
(ml/m
in)
Graft function was superior with Graft function was superior with Low-dose TacLow-dose TacCalculated GFR Cockcroft-GaultCalculated GFR Cockcroft-Gault
pp<0.0001<0.0001pp=0.0014=0.0014
pp<0.0001<0.0001
5757 59596565
5757
Standard-dose CsAStandard-dose CsA
Low-dose CsALow-dose CsA
Low-dose TACLow-dose TAC
Low-dose SRLLow-dose SRL
No significant difference between CsA and Low-CsA
Ekberg H et al NEJM 2007; 357: 2562.
ASN Renal Weekends 2009
Graft Survival was superior Graft Survival was superior with Low-dose Tacwith Low-dose Tac
Low-dose TACLow-dose TAC Low-dose SRLLow-dose SRL
pp=0.0147=0.0147pp=0.0143=0.0143
89%89%
93%93% 94%94%
89%89%
7070
8080
9090
100100
12 months post-Tx12 months post-Tx
Gra
ft s
urv
iva
l (%
)G
raft
su
rviv
al (
%)
7070
8080
9090
100100
12 months post-Tx12 months post-Tx
Pa
tie
nt
surv
ival
(%
)P
ati
en
t su
rviv
al (
%)
pp = NS = NS
97%97%98%98% 97%97% 97%97%
Standard-dose CsAStandard-dose CsA Low-dose CsALow-dose CsA
ASN Renal Weekends 2009
Less Biopsy Proven Acute RejectionLess Biopsy Proven Acute Rejectionwith Low-dose Tac with Low-dose Tac (ITT, Excluding Borderline)(ITT, Excluding Borderline)
26%26%24%24%
12%12%
37%37%
p<0.0001p<0.0001
p<0.0001p<0.0001
00
1010
2020
3030
4040
5050
12 months post-Tx12 months post-Tx
BP
AR
(%
of
pa
tien
ts)
BP
AR
(%
of
pa
tien
ts)
Standard-dose CsAStandard-dose CsA
Low-dose CsALow-dose CsA
Low-dose TACLow-dose TAC
Low-dose SRLLow-dose SRL
No significant difference between CsA and Low-CsA;about 25%
Ekberg H et al NEJM 2007; 357: 2562.
ASN Renal Weekends 2009
The CNI-free alternative:The CNI-free alternative:
Was the target 4-8 ng/ml for Was the target 4-8 ng/ml for Low-dose SRL too low?Low-dose SRL too low?
Daclizumab + MMF + CSDaclizumab + MMF + CS
No CNI / No SRLNo CNI / No SRL
Vincenti et al.Vincenti et al.
Acute Rejection 53%Acute Rejection 53%
Low-SRLLow-SRL
SYMPHONYSYMPHONY
Acute Rejection 37%Acute Rejection 37%
+ + + lymphocele+ + + lymphocele
+ + + delayed wound healing+ + + delayed wound healing
+ + + hyperlipidaemia+ + + hyperlipidaemia
Similar overall rates of infectionSimilar overall rates of infection
Low-SRL was Low-SRL was notnot efficient enough, efficient enough, but still but still notnot without toxicity without toxicity
Vincenti F et al. Vincenti F et al. TransplantationTransplantation 2001; 71:1282. 2001; 71:1282.
Ekberg H et al NEJM 2007; 357: 2562.
-16%-16%
ASN Renal Weekends 2009
CyclosporineCyclosporine
Low-TacLow-Tac
05
1015
2025
30
0
.05
.10
.15
.20
.25
.30
.35
Low-SRLLow-SRL
Pro
bab
ilit
y o
f O
ne-
year
AR
0
500300
400600 700
800
100200
0106 8 12 14 18
2 416
Values indicate average 1-month trough levels
Probability of One-Year Acute Rejection Probability of One-Year Acute Rejection by Drug Exposure at 1 month by Drug Exposure at 1 month
ASN Renal Weekends 2009
3-year Follow-up Study3-year Follow-up Study
Core study (12 months)Core study (12 months)
Enrolled:Enrolled:
Safety (Safety (received Rx):received Rx):
ITT ITT (received Rx, transplanted):(received Rx, transplanted):
16451645
16021602
15891589
Follow-up study (data at 36 months)Follow-up study (data at 36 months)
FU-Enrolled:FU-Enrolled:
FU-Safety:FU-Safety:
FU-ITT:FU-ITT:
955955
954954
954954
Approx. 60% of patientsApprox. 60% of patients
ASN Renal Weekends 2009
Many patients switched treatments Many patients switched treatments during the 1st yearduring the 1st year
Switches from SRL to TacSwitches from SRL to Tacoccurred due to treatment failure, mainly ARoccurred due to treatment failure, mainly AR
25 2534 1750 470
10
20
30
40
50
60
CsA Tac SRL
Pa
tie
nts
(%
)
- 3%- 3%
+ 9%+ 9%
- 8%- 8%
Dotted bars: Day 0Dotted bars: Day 0Striped bars: Month 12Striped bars: Month 12
ASN Renal Weekends 2009
Incidence of BPAR remained lowestIncidence of BPAR remained lowestin Low-Tac group at 3 yearsin Low-Tac group at 3 years
391427 270
5
10
15
20
25
30
35
40
Standard-CsA
Low-CsA Low-Tac Low-SRL
BP
AR
(%
of
pat
ien
ts)
BP
AR
(%
of
pat
ien
ts) p<0.0001
p<0.0001p<0.0001
ASN Renal Weekends 2009
Graft survival* remained superiorGraft survival* remained superior in Low-Tac group at 3 yearsin Low-Tac group at 3 years
13 11 10 150
2
4
6
8
10
12
14
Standard-CsA
Low-CsA Low-Tac Low-SRLGra
ft l
oss
(%
of
pat
ien
ts)
Gra
ft l
oss
(%
of
pat
ien
ts)
p>0.05
* Graft survival not censored for patient death
ASN Renal Weekends 2009
InterimInterim 1-Year Outcomes of the 1-Year Outcomes of the Spare-the-Nephron (STN) Trial: An Spare-the-Nephron (STN) Trial: An MMF-Based Regimen Combined MMF-Based Regimen Combined
With Sirolimus to Spare With Sirolimus to Spare Renal FunctionRenal Function
Roberto Kalil, MD
University of Iowa Hospitals and Clinics, Iowa City, Iowa
T. C. Pearson, S. Mulgaonkar, A. Patel, H. Shidban, M. Weir, D. Patel, and J. Scandling
ASN Renal Weekends 2009
Trial DesignTrial Design
MMF + MMF + tacrolimustacrolimus
MMF + cyclosporineMMF + cyclosporine
MMF + tacrolimusMMF + tacrolimus
MMF + cyclosporineMMF + cyclosporine
MMF + sirolimusMMF + sirolimus
MMF + sirolimusMMF + sirolimus
Post-randomizationPost-randomization
Patient screening Patient screening and enrollment and enrollment
1 year1 year 2 years2 years
30 – 18030 – 180
DDAAYYSS
PPOOSSTT--TTXX
Pre-randomization*Pre-randomization*
*Randomization pre-stratified by CNI type at screening*Randomization pre-stratified by CNI type at screening
Target population = 305 single-organ renal allograft recipients
ASN Renal Weekends 2009
Randomized Randomized N=298N=298
Patient Allocation (Intent-to-Treat)*Patient Allocation (Intent-to-Treat)*
MMF/CNIMMF/CNIN=150N=150
MMF/SRLMMF/SRLN=148 N=148
TacrolimusTacrolimusWithdrawalWithdrawal
N=122N=122
CyclosporineCyclosporineWithdrawalWithdrawal
N=26N=26
TacrolimusTacrolimusN=119N=119
CyclosporineCyclosporineN=31N=31
*81% received tacrolimus and 19% received cyclosporine
ASN Renal Weekends 2009
MMF/CNIMMF/CNI
MMF/SRL*MMF/SRL*N=148N=148
Total*Total*N=150N=150
MMF/TACMMF/TACN=119N=119
Biopsy-proven acuteBiopsy-proven acute rejectionrejection 10 (7%)10 (7%) 9 (6%)9 (6%) 7 (6%)7 (6%)
DeathDeath 0 (0%)0 (0%) 3 (2%)3 (2%) 2 (2%)2 (2%)
Graft lossGraft loss 3 (2%)3 (2%) 4 (3%)4 (3%) 3 (3%)3 (3%)
African AmericansAfrican Americans N=48*N=48* N=50*N=50* N=40N=40
Biopsy-proven acuteBiopsy-proven acute rejectionrejection 4 (8%)4 (8%) 4 (8%)4 (8%) 4 (10%)4 (10%)
Efficacy Outcomes, n (%)Efficacy Outcomes, n (%)
*P = NS for MMF/SRL vs. MMF/CNI.
ASN Renal Weekends 2009
MMF/CNIMMF/CNI
MMF/SRLMMF/SRLN=148N=148
TotalTotalN=150N=150
MMF/TACMMF/TACN=119N=119
Treatment failure*Treatment failure* 44 (30%)44 (30%) 35 (23%)35 (23%) 30 (25%)30 (25%)
Reason for treatment failureReason for treatment failure
Death Death 0 (0%)0 (0%) 2 (1%)2 (1%) 1 (1%)1 (1%)
Withdrawal due to AEWithdrawal due to AE 23 (16%)23 (16%) 10 (7%)10 (7%) 8 (7%)8 (7%)
Need to resume CNINeed to resume CNI 5 (3%)5 (3%) 0 (0%)0 (0%) 0 (0%)0 (0%)
Need to withdraw therapyNeed to withdraw therapy 5 (3%)5 (3%) 11 (7%)11 (7%) 11 (9%)11 (9%)
Lost to follow-upLost to follow-up 10 (7%)10 (7%) 12 (8%)12 (8%) 10 (8%)10 (8%)
Withdrew consentWithdrew consent 1 (1%)1 (1%) 0 (0%)0 (0%) 0 (0%)0 (0%)
Treatment Failure, n (%)Treatment Failure, n (%)
Events are mutually exclusive; only the first event counted per patient.*P = NS for MMF/SRL vs. MMF/CNI.
ASN Renal Weekends 2009
Mean % Change in Measured GFR Mean % Change in Measured GFR
Baseline to Month 12Baseline to Month 12
N = 118 N = 109
0
5
10
15
20
25
30
35
Mea
n P
erce
nt
Ch
ang
e ±
SE
M
MMF/SRL
MMF/CNI
7.8
Baseline GFR(mL/min/1.7 m2) SEM 59.5 2.0 58.7 2.2
-5
P=0.013
25.7
ASN Renal Weekends 2009
Urinary Protein/Creatinine RatioUrinary Protein/Creatinine Ratio
MMF/SRL MMF/SRL MMF/CNIMMF/CNI
All Patients*All Patients* TotalTotal TAC WDTAC WD TotalTotal MMF/TACMMF/TAC
Baseline, medianBaseline, median 2525thth, 75, 75th th percentiles (n)percentiles (n)
0.10.10.1, 0.2 (123) 0.1, 0.2 (123)
0.2 0.2 0.1, 0.2 (104) 0.1, 0.2 (104)
0.2 0.2 0.1, 0.2 (129)0.1, 0.2 (129)
0.2 0.2 0.1, 0.2 (102)0.1, 0.2 (102)
12 Months, median12 Months, median 2525thth, 75, 75th th percentiles (n)percentiles (n)
0.20.20.1, 0.4 (106)0.1, 0.4 (106)
0.2 0.2 0.1, 0.4 (87)0.1, 0.4 (87)
0.1 0.1 0.1, 0.3 (110)0.1, 0.3 (110)
0.10.10.1, 0.2 (88)0.1, 0.2 (88)
African Americans**African Americans**
Baseline, medianBaseline, median 2525thth, 75, 75th th percentiles (n)percentiles (n)
0.10.10.1, 0.2 (40) 0.1, 0.2 (40)
0.1 0.1 0.1, 0.2 (37) 0.1, 0.2 (37)
0.1 0.1 0.1, 0.3 (44)0.1, 0.3 (44)
0.2 0.2 0.1, 0.3 (35)0.1, 0.3 (35)
12 Months, median12 Months, median 2525thth, 75, 75th th percentiles (n)percentiles (n)
0.20.20.1, 0.6 (34)0.1, 0.6 (34)
0.2 0.2 0.1, 0.6 (29)0.1, 0.6 (29)
0.1 0.1 0.1, 0.3 (40)0.1, 0.3 (40)
0.10.10.1, 0.2 (33)0.1, 0.2 (33)
MMF/SRL vs. MMF/CNI: baseline, P=NS; 12 months, *P=0.096; **P=0.043.
ASN Renal Weekends 2009
Desensitization Protocols
ASN Renal Weekends 2009
Approaches to DesensitizationApproaches to Desensitization
Mark D. Stegall, M.D.
Mayo Clinic, Rochester, MN
ASN Renal Week November 7, 2008
Mark D. Stegall, M.D.
Mayo Clinic, Rochester, MN
ASN Renal Week November 7, 2008
ASN Renal Weekends 2009
DesensitizationDesensitizationWhat is it?
• Removing or blocking donor specific antibody (almost always anti-HLA)
• High Dose IVIG versus low dose IVIG and plasmapheresis with or without rituximab
Goal?
Prevention of:
• Hyperacute rejection
• Acute humoral rejection
• Transplant glomerulopathy (chronic damage)
Efficacy?
• Few comparative studies of different approaches
What is it?
• Removing or blocking donor specific antibody (almost always anti-HLA)
• High Dose IVIG versus low dose IVIG and plasmapheresis with or without rituximab
Goal?
Prevention of:
• Hyperacute rejection
• Acute humoral rejection
• Transplant glomerulopathy (chronic damage)
Efficacy?
• Few comparative studies of different approaches
ASN Renal Weekends 2009
IVIG + Rituximab Protocol Vo et al NEJM 2008;359:242-51
IVIG + Rituximab Protocol Vo et al NEJM 2008;359:242-51
• 20 sensitized patients underwent IVIG desensitization
• IVIG 2 g/kg day 0, 30 and Rituximab 1g on day 7 and 22)
• Required a T cell AHG – at 1:2 and a T flow crossmatch <250.
• 18 transplanted (8 deceased donor and 10 living donor)
• Alemtuzumab, Tacrolimus, MMF, Pred
• 20 sensitized patients underwent IVIG desensitization
• IVIG 2 g/kg day 0, 30 and Rituximab 1g on day 7 and 22)
• Required a T cell AHG – at 1:2 and a T flow crossmatch <250.
• 18 transplanted (8 deceased donor and 10 living donor)
• Alemtuzumab, Tacrolimus, MMF, Pred
ASN Renal Weekends 2009
IVIG and Acute RejectionIVIG and Acute Rejection
• Acute rejection
• 50%
• 31% C4d+ AMR
• Treatment
• Banff I or II: methylprednisolone, IVIG (2 g/kg) and rituximab (375 mg/BSA)
• Banff III: Plasmapheresis (3-5 sessions) IVIG and rituximab (375 mg/BSA)
• Acute rejection
• 50%
• 31% C4d+ AMR
• Treatment
• Banff I or II: methylprednisolone, IVIG (2 g/kg) and rituximab (375 mg/BSA)
• Banff III: Plasmapheresis (3-5 sessions) IVIG and rituximab (375 mg/BSA)
ASN Renal Weekends 2009
ASN Renal Weekends 2009
ASN Renal Weekends 2009
RATIONAL DESENSITIZATION PROTOCOLS: TREATMENT ACCORDING TO MEDIAN FLUORESCENCE INTENSITY VALUES OF LUMINEX FLOW BEADS
Akalin E, Dinavahi R, de Boccardo G, Schroppel B, Sehgal V, Murphy B, and Bromberg JS
Mount Sinai School of MedicineRenal DivisionRecanati/Miller Transplantation InstituteNew York, NYNO. I HAVE NOTHING TO DISCLOSE.
ASN Renal Weekends 2009
CLINICAL OUTCOMES PER LUMINEX MFI VALUES
IVIG only IVIG only IVIG/PP____ DSA MFI < 6,000 DSA MFI > 6,000 DSA
MFI>6,000(n=33) (n=17) (n=20)
______________________________________________________________________Median F/U (mos) 30 (4-80) 40 (14-53) 16
(12-28)Patient survival 100% 100% 90%Graft survival 97% 65% 75%
Living 100% 67% 88%Deceased-donor 88% 64% 67%
Acute rejection 0% 59% 20% AMR 0% 47% 15% ACR 0% 12% 5%Biopsy proven CAN 6% 36% 20%Transplant glomerulopathy 6% 12% 10%Median Cr (mg/dl) 1.1 (0.6-3.1) 1.2 (1.0-3.1) 1.4 (0.8-1.9)Patients with Cr < 1.4 81% 73% 87%DSA loss during F/U 77% 31% 36%
ASN Renal Weekends 2009
• IVIg and Plasmapheresis:• “The azathioprine and prednisone
of desensitization”:
• Major Problem: Current protocols do not control antibody production
• Solution: We need to understand antibody production better
• New Paradigms• Prevent antibody production• Prevent the impact of antibody
(complement inhibition)
• IVIg and Plasmapheresis:• “The azathioprine and prednisone
of desensitization”:
• Major Problem: Current protocols do not control antibody production
• Solution: We need to understand antibody production better
• New Paradigms• Prevent antibody production• Prevent the impact of antibody
(complement inhibition)
ASN Renal Weekends 2009
Proteasome InhibitionProteasome Inhibition
• Proteasome is a group of enzymes that “recycles” proteins in eukaryotic cells
• Very active in highly-secretory cells
• Velcade (bortezomib)—FDA approved proteasome inhibitor approved for treatment of resistant myeloma
• Kills by apoptosis
• Proteasome is a group of enzymes that “recycles” proteins in eukaryotic cells
• Very active in highly-secretory cells
• Velcade (bortezomib)—FDA approved proteasome inhibitor approved for treatment of resistant myeloma
• Kills by apoptosis
ASN Renal Weekends 2009
DAPI staining demonstrating apoptosis of Velcade treated cells
DAPI staining demonstrating apoptosis of Velcade treated cells
Control Velcade
ASN Renal Weekends 2009
Classical PathwayAntigen/Antibody Complexes
Lectin PathwayCarbohydrate Structures
Alternative PathwayM/O and Mammalian
Cell Membranes
Activated C1
C3
C3a
C4b2a
C3 Convertase
C3bBb
C3b C5
C3bBb3b
C4b2a3b
C5b-9
C6 C7 C8 C9
Weak Anaphylatoxin
Immune Complex Microbial Opsonization
C5 Convertase
C5 ConvertaseC3 Convertase
Potent AnaphylatoxinChemotaxis
Cell Activation
C3H20Tickover
Cell ActivationNeisseria Clearance
RBC Lysis
The Complement Cascade: Targeted InhibitionThe Complement Cascade: Targeted InhibitionThe Complement Cascade: Targeted InhibitionThe Complement Cascade: Targeted Inhibition
Activated MBL
C4+C2
Factor B+D
C3b
C5a
C5bXX
EculizumabTarget
ASN Renal Weekends 2009
Anti-C5 AntibodyEculizumab
Anti-C5 AntibodyEculizumab
• Humanized monoclonal antibody
• FDA approved for treatment of paroxysmal nocturnal hemoglobinuria
• Blocks formation of C5a and C5b-9
• May also decrease more proximal complement activation via feedback loop inhibition
• ½ life = ??
• Partially removed by plasmapheresis
• Humanized monoclonal antibody
• FDA approved for treatment of paroxysmal nocturnal hemoglobinuria
• Blocks formation of C5a and C5b-9
• May also decrease more proximal complement activation via feedback loop inhibition
• ½ life = ??
• Partially removed by plasmapheresis
ASN Renal Weekends 2009
Anti-C5 Study Anti-C5 Study • Combine anti-C5 Ab with current
protocol
• Goal: Decrease incidence of AHR compared to historical untreated controls
• Expected Findings:
• High antibody levels (and C4d+) without histologic injury/graft dysfunction
• Combine anti-C5 Ab with current protocol
• Goal: Decrease incidence of AHR compared to historical untreated controls
• Expected Findings:
• High antibody levels (and C4d+) without histologic injury/graft dysfunction
ASN Renal Weekends 2009
Kidney Transplantation:Complications
ASN Renal Weekends 2009
Immunosuppression Management in the Patient with
Cancer: Role of Sirolimus
Bertrand Kasiske
University of Minnesota
ASN Renal Weekends 2009
Sirolimus for Kaposi’s Sarcoma
Stallone G, et al. New Engl J Med 2005;352:1317
15 kidney transplant recipients Biopsy-proven Kaposi’s Sarcoma Treatment:
CsA was discontinued Sirolimus was begun
Outcome: No lesions at 3 months Confirmed by biopsy
Before After
ASN Renal Weekends 2009
Everolimus in Advanced Renal Cell Carcinoma: A Double Blind RCT
Motzer RJ, et al. Lancet 2008;372:449
N=272N=138
Progression-Free Survival(Everolimus dose =10 mg/day)
ASN Renal Weekends 2009
1.00 1.05 0.74 0.68 0.940.00
0.20
0.40
0.60
0.80
1.00
1.20
mTOR Inhibitors and Non-Skin Cancers in Kidney Recipients: OPTN Data
1Kauffman HM, et al. Transplantation 2005;80:8832Wida SC, et al. American Transplant Congress, June 2008 Abstract #294
1.00 0.400.00
0.20
0.40
0.60
0.80
1.00
1.20
Transplanted 1996-20011 Transplanted 2000-20052
P=0.0002
RE
FE
RE
NC
E
RE
FE
RE
NC
E
Rel
ativ
e R
isk
Rel
ativ
e R
isk
CsA/Tac SRL/EVL Tac CsA SRL SRL+CsA SRL+TacN= 30,424 2,825 37,829 18,783 2,257 2,664 4,659
ASN Renal Weekends 2009
Rel
ativ
e R
isk
Rel
ativ
e R
isk
CNI mTOR Antimetabolite mTOR 4 Trials (N=447) 6 Trials (N=2,944)
1.00 0.830.00
0.50
1.00
1.50
2.00
Webster AC, et al. Am J Transplant 2006;81:1234
1.00 0.660.00
0.50
1.00
1.50
2.00
CNIs v. mTOR Antimetabolites v. mTOR
mTOR Inhibitors and Malignancies: A Meta-Analysis of RCTs
ASN Renal Weekends 2009
Rel
ativ
e R
isk
Rel
ativ
e R
isk
CNI mTOR Antimetabolite mTOR 5 Trials (N=447) 3 Trials (N=1,616)
1.00 2.030.00
2.00
4.00
6.00
8.00
10.00
Webster AC, et al. Am J Transplant 2006;81:1234
1.00 1.610.00
2.00
4.00
6.00
8.00
10.00
mTOR Inhibitors and PTLD: A Meta-Analysis of RCTs
CNIs v. mTOR Antimetabolites v. mTOR
ASN Renal Weekends 2009
Shapiro RJ, et al. Am J Transplant 2008; 8 (Suppl 2):523
Sirolimus Conversion for Skin Cancer in 30 Kidney Transplant Recipients
Immunosuppression:•20 triple therapy• 9 double therapy• 1 CsA alone
Cancers: 5.4 per ptGraft function:
•eGFR = 46.414.8
Immunosuppression:•17 SRL + Prednisone•Levels 6.8-7.7 ng/mL•4 stopped SRL (AEs)
Cancers: 1.6 per ptGraft function:
•eGFR = 44.819.3•No acute rejections
AfterBefore
ASN Renal Weekends 2009
Dr Catherine Harwood MD PhD
Senior Lecturer and Consultant Dermatologist
Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK
Management of skin cancer in transplant patients
Management of skin cancer in transplant patients
ASN Renal Weekends 2009
ASN Renal Weekends 2009
GeneticsGenetics
UVRUVR VirusesViruses
DrugsDrugs
Aetiology of transplant skin cancerASN Renal Weekends 2009
Cyclosporin - reduces repair of UV-induced DNA damage Herman 2001; Sugie 2002; Yarosh, 2005
- Promotes progression - TGF- production Hojo, Nature 1999;397:530-4
Azathioprine- reduces repair of UV-induced DNA damage Kelly, 1987; de Graaf, 2007
- generates mutagenic oxidative damage with UVA O’Donovan, Science, 2005
- photosensitises human skin to UV-A radiation in vivo. Perrett. BJD 2008 - signature mutation associated with azathioprine Harwood, BJC, 2008
Rapamycin (Sirolimus) - inhibits rather than promotes cancers Campistol, 2006; Kauffman, 2005; Mathew, 2004
Immunosuppressive drugs as direct carcinogens
Immunosuppressive drugs
Triple therapy > dual therapy Glover. Lancet 1997; Jensen JAAD 1999
High dose > standard dose cyclosporin Dantal, Lancet, 1998
Association with CD4 count
Intensity of immunosuppression
ASN Renal Weekends 2009
Does sunscreen use post-transplantation lead to a reduction in skin (pre)malignancies?
ASN Renal Weekends 2009
Prevention of UV-induced malignant skin diseases in OTR by regular use of a liposomal sunscreen.
60 OTR: 20 renal, 20 cardiac, 20 liver
Randomised to intensive sunscreen (SPF>50, high UVA; 2mg/cm’) versus not.
24 months: reduction in AK; no new SCC (vs 8), 2 new BCC (vs 9)
Ulrich et al, Nephrol Dial Transpl 2008
Cosmesis; Cost
Concerns re vitamin D deficiency
ASN Renal Weekends 2009
Significance and Management of Significance and Management of Proteinuria in the Transplant Recipient: Proteinuria in the Transplant Recipient:
Evidence-Based PracticeEvidence-Based Practice
Greg Knoll MD MScGreg Knoll MD MScAssociate Professor of MedicineAssociate Professor of Medicine
Medical Director, Kidney TransplantationMedical Director, Kidney TransplantationUniversity of Ottawa and The Ottawa HospitalUniversity of Ottawa and The Ottawa Hospital
Allograft Function: The New End-Point in Transplantation
Saturday November 8, 2008
ASN Renal Weekends 2009
Prevalence of Proteinuria in Prevalence of Proteinuria in Kidney TransplantationKidney Transplantation
Study Definition of
Proteinuria Time Post-
Transplantation Prevalence of
Proteinuria
Roodnat, 2001 (n=722)
>0.2 g/L 12 months 31.0%
Fernandez, 2002
(n=532) >0.5 g/day >12 months 36.4%
Halimi, 2005
(n=484) >0.5 g/day 12 months 35.2%
Sancho, 2007
(n=337) >0.5 g/day >3 months 20.2%
Ibis, 2007 (n=130)
>0.3 g/day 12 months 34.3%
Amer, 2007
(n=613) >0.15 g/day 12 months 45.0%
ASN Renal Weekends 2009
Proteinuria: Is it from the Native Proteinuria: Is it from the Native Kidneys or the Transplanted Kidneys or the Transplanted
Kidney?Kidney?
ASN Renal Weekends 2009
All patients had urine Pr/Cr ratio < 0.2
Occurred on average 4.5 weeks post-Tx but took up to 10 weeks
D’Cunha PT et al, Am J Transplant; 5:351-355, 2005
n=14
ASN Renal Weekends 2009
DTPA Scan one week pre-Tx and 3 weeks post-Tx
D’Cunha et al, Am J Transplant; 5, 2005
ASN Renal Weekends 2009
3650±3702 550±918 472±1116
Only 10% had >1500 mg/day at 3 wks
Myslak M et al, Am J of Transplant; 6:1660-65 2006
n=115
ASN Renal Weekends 2009
These 5 all had glomerular lesions on allograft biopsy
Myslak et al, Am J of Transplant; 6, 2006
ASN Renal Weekends 2009
Proteinuria: What is the Proteinuria: What is the Allograft Pathology?Allograft Pathology?
ASN Renal Weekends 2009
613 patients transplanted between 1998 and 613 patients transplanted between 1998 and 20042004
All had 24 hour urine collection and All had 24 hour urine collection and protocol Bx at 1-yearprotocol Bx at 1-year
Amer et al, Am J Transplant; 7: 2748, 2007
ASN Renal Weekends 2009
<150 mg/day
150-500 mg/day
500-1500 mg/day
>1500 mg/day
Proteinuria >1.5 g/day is Associated with Proteinuria >1.5 g/day is Associated with Glomerular PathologyGlomerular Pathology
80% of patients with proteinuria > 1500 mg/day had glomerular disease on biopsy
Amer et al, Am J Transplant; 7: 2748, 2007
ASN Renal Weekends 2009
Does Proteinuria have any Impact on Does Proteinuria have any Impact on Patient or Graft Survival?Patient or Graft Survival?
ASN Renal Weekends 2009
Roodnat et al, Transplantation 72: 438, 2001
Multivariate HR 2.03 (1.50-2.76) P<0.0001
N=722 Tx recipients 1971-1995Tx function at 1 year
Proteinuria is Associated with Proteinuria is Associated with Graft Survival Graft Survival
Proteinuria: >0.2 g/L
ASN Renal Weekends 2009
Proteinuria is Associated with Proteinuria is Associated with Patient SurvivalPatient Survival
Multivariate HR 1.98 (1.44-2.72) P<0.0001
Roodnat et al, Transplantation 72: 438, 2001
ASN Renal Weekends 2009
Proteinuria is Associated with Proteinuria is Associated with Cardiovascular DiseaseCardiovascular Disease
CVD defined as :CVD defined as : Angina, MI, TIA, stroke, PVDAngina, MI, TIA, stroke, PVD
Proteinuria associated with:Proteinuria associated with: RR of CVD RR of CVD 2.452.45 (1.66-3.62) (1.66-3.62)
Risk increased with increasing amounts of Risk increased with increasing amounts of proteinuriaproteinuria
Pr 0.5-1.0 g/day: RR of CVD Pr 0.5-1.0 g/day: RR of CVD 1.451.45 (0.85-2.45) (0.85-2.45)
Pr 1.0-3.0 g/day: RR of CVD Pr 1.0-3.0 g/day: RR of CVD 1.85 1.85 (1.1-2.96)(1.1-2.96)
Pr >3 g/day: RR of CVD Pr >3 g/day: RR of CVD 2.882.88 (1.47-5.61) (1.47-5.61)
Fernandez et al, Transplantation 73: 1345, 2002
ASN Renal Weekends 2009
Management of Proteinuria in the Management of Proteinuria in the Kidney Transplant RecipientKidney Transplant Recipient
ASN Renal Weekends 2009
Management of Proteinuria in the Management of Proteinuria in the Kidney Transplant RecipientKidney Transplant Recipient
In the In the non-transplantnon-transplant patient, the goals of patient, the goals of proteinuria reduction include:proteinuria reduction include: Symptom management (e.g. edema)Symptom management (e.g. edema)
Prevention of complications from heavy proteinuria (e.g. Prevention of complications from heavy proteinuria (e.g. hyperlipidemia, thrombosis etc)hyperlipidemia, thrombosis etc)
Prevention of Progressive CKD or ESRDPrevention of Progressive CKD or ESRD
Prevention of CV eventsPrevention of CV events
ACE-Inhibitors in Kidney ACE-Inhibitors in Kidney TransplantationTransplantation
Heinze et al, J Am Soc Nephrol 17: 889, 2006n=2031
ASN Renal Weekends 2009
No Effect of ACE-Inhibitors in No Effect of ACE-Inhibitors in Kidney TransplantationKidney Transplantation
Opelz et al, J Am Soc Nephrol 17: 3257–3262, 2006
n=17,209
ASN Renal Weekends 2009
Randomized Trials of ACE-I in Randomized Trials of ACE-I in Kidney TransplantationKidney Transplantation
Systematic review and meta-analyses Systematic review and meta-analyses
Search yielded Search yielded 11531153 articles articles
2121 Randomized trials (n= Randomized trials (n=15491549 patients) patients)
Comparator groups included the following:Comparator groups included the following:
DHP CCB (n=9)DHP CCB (n=9)
usual care (n=5)usual care (n=5)
placebo (n=5)placebo (n=5)
other drug (n=2)other drug (n=2)
Hiremath et al, Am J Transplant 7: 2350, 2007
ASN Renal Weekends 2009
Renin Angiotensin System Blockade in Renin Angiotensin System Blockade in Kidney TransplantationKidney Transplantation
Data from Data from Randomized TrialsRandomized Trials shows the shows the following:following: Patients on ACE-I:Patients on ACE-I:
Change in proteinuria was 470 mg/day lower than Change in proteinuria was 470 mg/day lower than control groupcontrol group
Change in GFR 6 ml/min lower than control with Change in GFR 6 ml/min lower than control with median follow-up of 27 monthsmedian follow-up of 27 months
No data on patient or graft survivalNo data on patient or graft survival
Hiremath et al, Am J Transplant 7: 2350, 2007
ASN Renal Weekends 2009
Renin Angiotensin System Renin Angiotensin System Blockade in Kidney Blockade in Kidney
TransplantationTransplantation
Knoll et al, Nephrol Dial Transplant 23: 354, 2008
ASN Renal Weekends 2009
10 sites now actively recruiting10 sites now actively recruiting
128 patients consented as of October 16, 128 patients consented as of October 16, 20082008
Target sample size n=528Target sample size n=528
ASN Renal Weekends 2009
Anemia Correction Improves Quality of Life of Renal Transplant Recipients:
Results of the CAPRIT Study
Gabriel Choukroun, Lionel Rostaing, Bertrand Dussol, Isabelle Etienne, Elisabeth Cassuto-Viguier, Olivier Toupance, Christian Noël, Bruno Hurault de Ligny, Bruno Moulin, Yvon Lebranchu, Guy
Touchard, Yannick LeMeur, Anne-Elisabeth Heng, Philippe Lang, Pierre Merville, and Frank Martinez for the CAPRIT study investigators
American Society of Nephrology - Philadelphia, PA - 2008
ASN Renal Weekends 2009
Investigate the effect of suboptimal anemia correction in kidney transplant
recipients with chronic allograph nephropathy (stage 3 to 4 CKD) and
anemia on the rate of progression of kidney dysfunction, quality of life,
and left ventricular remodeling
Tx > 12 monthseClcr 50 - 20 ml/minHb < 115 g/Ln = 125
R
Groupe A : Hb 130 - 150 g/L
Groupe B : Hb 105 - 115 g/L
QoL QoL QoL
eGFR eGFR eGFR eGFR eGFR
NeoRecormon SC
Goals and design of the studyASN Renal Weekends 2009
Group A130 - 150 g/L
Group B105 - 115 g/L
n 62 63
Hb at inclusion (g/L) 103 ± 9 106 ± 7
Scr (µmol/L) 182 ± 50 192 ± 56
eClCr (ml/min/1.73 m2) 43.0 ± 13.0 40.7 ± 12.9
Nankivell (ml/min) 39.7 ± 12.2 41.0 ± 13.4
eDFG - MDRD 4 (ml/min/1.73 m2) 33.9 ± 9.9 33.0 ± 9.9
Proteinuria (g/d) 0.15 ± 0.33 0.21 ± 0.42
Renal function at inclusion Renal function at inclusionASN Renal Weekends 2009
Renal function at inclusion Evolution of Hb level during the study
Follow-up
150
140
110
100
90
80
120
70
130
Hém
oglo
bin
e (g
/l)
B 4630 ± 4130 UI/s
T0 M1 M3 M6M2 M12
A 7330 ± 5200 UI/s
ASN Renal Weekends 2009
Renal function at inclusion Quality of Life at 1 year SF-36 Questionnaire
40
30
0
- 10
10
20
RPPF BP GH VT RESF MH
50 Group A (130 - 150 g/l)Group B (105 - 115 g/l)
* p < 0.05
*
* *
*
*
*
Physical General HealthSocial, Emotional,
Mental
Var
iati
on f
rom
bas
elin
e (%
)
ASN Renal Weekends 2009
Renal function at inclusion Quality of Life at 1 year KTQ-25 Questionnaire
20
15
0
-5
-10
5
10
Fatigue Fear Appearence Emotion
Group A (130 - 150 g/l)Group B (105 - 115 g/l)V
aria
tion
fro
m b
asel
ine
(%)
*
ASN Renal Weekends 2009
Retransplantation- Current Status and Candidate
Selection.Panduranga S Rao MD DNB MS
University of Michigan, Ann ArborAmerican Society of Nephrology
Philadelphia, PANovember 7, 2008
ASN Renal Weekends 2009
Patients returning to dialysis after a failed kidney transplant
0
2000
4000
6000
1992 1994 1996 1998 2000 2002 2004 2006
Years
Nu
mb
er o
f P
atie
nts
USRDS ADR 2008
ASN Renal Weekends 2009
01,000
2,0003,000
4,0005,000
6,0007,000
8,0009,000
10,000
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Year
Nu
mb
er o
f P
ts.
Failed Transplants on Waitlist
ASN Renal Weekends 2009
Mortality risk on dialysis after graft failure - first year
Rao et al AJKD 2007
ASN Renal Weekends 2009
Do all returning patients have the same mortality risk?
Ojo et al Transplantation 1998
ASN Renal Weekends 2009
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 Year 3 Years 5 Years
Years Since Transplant
Su
rviv
al (
%)
First Transplant Second Transplant
Unadjusted Deceased Donor Graft Survival for First and Second Kidney Transplants, 2000-
2005
Source: SRTR Analysis, May 2006
ASN Renal Weekends 2009
Survival benefit of retransplantation – US experience: Type 1 diabetes
ASN Renal Weekends 2009
Ojo et al. Transplantation 1998
Survival benefit : non-diabetics ASN Renal Weekends 2009
Donor Selection for the Retransplant Candidate: Living vs. Standard vs.
Expanded Criteria Donors
Akinlolu Ojo
ASN Renal Weekends 2009
Deceased Donor Types: SCD, DCD, ECD & DCD-ECD
Heart-beating (primary brain death)
1. SCD: Standard Criteria Donor● Heart-beating donors● Less than 60 years of age and not
2. ECD: Expanded Criteria Donor
● Heart-beating donors over 60 years of age or those between age 50 and 59 year plus two of the following three conditions: died of a stroke, had a history of hypertension, or had a terminal serum creatinine of greater than 1.5
Non-heart beating (cardiac standstill precedes/simultaneous with brain death)
3. DCD: Donation After Cardiac Death
ASN Renal Weekends 2009
ECD and non-ECD vs. “Standard Therapy” for Retransplant Candidates
TreatmentAdjusted
Mortality Ratio* (95% CI) p
Standard
Therapy
1
(reference)-- --
ECD 0.98 (0.76, 1.26) 0.88
Non-ECD 0.44 (0.39, 0.51) <0.0001
*Adjusted for age, gender,race,primary renal diagnosis, calender period,time on dialysis prior to transplant, donor source, region,PRA,time between primary transplant and graft failure, time between graft failure and relisting
ASN Renal Weekends 2009
Adjusted Recipient Survival ECD vs. Standard Therapy
0.5
0.6
0.7
0.8
0.9
1
0 1 2 3 4 5 6
Time (years)
Su
rviv
al P
rob
abil
ity
ECD
ST
ASN Renal Weekends 2009
Adjusted Recipient Survival Non-ECD vs. Standard Therapy
0.5
0.6
0.7
0.8
0.9
1
0 1 2 3 4 5 6 7
Time (years)
Sur
viva
l Pro
babi
lity
non-ECD
ST
ASN Renal Weekends 2009
Retransplant vs. Standard Therapy by TimeBetween First Transplant and 1st Graft Loss
Comparison
Time Until
1st Graft Loss RR of Death (95% CI) P
ECD vs. ST 0-4 years 1.22 (0.92, 1.62) 0.17
ECD vs. ST 4+ years 0.55 (0.32, 0.96) 0.03
ASN Renal Weekends 2009