Transcript 2008 ASN Highlights: Kidney Transplantation

ASN Renal Weekends 2009
2008 ASN Highlights:
Kidney Transplantation
Donald E. Hricik, M.D.
Professor of Medicine, Chief Division of Nephrology
and Hypertension
University Hospitals Case Medical Center
Cleveland, Ohio
Postgraduate 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
Sparing Protocols:
Is There Evidence that
They Work?
Henrik Ekberg
Lund University,
Malmö, Sweden
ASN Renal Weekends 2009
Brian Nankivell
Longitudinal assessment by
protocol biopsy:
CNI nephrotoxicity and
subclinical rejection
Timeline of biopsy protocol
0 3 12 mo. 2 3
4
5
6
7
• 961 protocol kidney biopsies
• 120 kidney/pancreas recipients
• Young donors
NEJM 2003; 349: 2326-33
8
9
10 years
ASN Renal Weekends 2009
Histological
features of Cyclosporine
0
0 .1 0 .2 5 0 .5
1
2
3
4
5
6
7
8
9
10
Nephrotoxicity
Percentage affected
1 00
75
50
Arteriola r hya linosis
Striped fibros is
25
Tubular c alcifica tion
0
0
2
4
6
Years after transplantation
8
10
ASN Renal Weekends 2009
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 2009
CNI sparing strategies




CNI avoidance
CNI withdrawal
CNI dose reduction
CNI replacement using mToR inhibitors
ASN Renal Weekends 2009
CNI avoidance
Daclizumab + CsA + MMF + CS
Excellent Renal Function1°
2
Daclizumab
MMF
53 %
2°
Acute rejection
at 12 mo.
1
3g/day
2g/day
Steroids
n = 98
Tx
6 mo.
12 mo.
Vincenti F et al. Transplantation 2001; 71:1282–7.
ASN Renal Weekends 2009
CAESAR study design
50-100 ng/mL
Withdrawal 4-6 mo.
Low CsA
w/d
Daclizumab
Low-CsA w/d
MMF
Steroids
50-100 ng/mL
Daclizumab
Low-CsA
MMF
Steroids
Low CsA
150-300 ng/mL, 4 mo.: 100-200
Standard CsA
MMF
Steroids
Stand CsA
0
6
12 mo
Ekberg H et al. Am J Transplant 2007; 7 (3): 560.
CAESAR study
Renal function at 12 months
ASN Renal Weekends 2009
GFR (Cockcroft Gault) [ml/min]
100
90
No significant difference
80
70
A Low Cs A w /d
B Low Cs A
C Standard Cs A
60
50
40
30
20
10
0
12 m onths post-Tx
Twoimprovement
values for GFRin
> 200
ml/min/1.73
m2 excludedor w/d of CsA
No
GFR
by dose-reduction
Ekberg H et al. Am J Transplant 2007; 7 (3): 560.
CAESAR study
BPAR at 6 and 12 months
25 %
38 %
Acute Rejection
at 6 mo.
Acute Rejection
at 12 mo.
40
50
BPAR [% of patients]
BPAR [% of patients]
50
ASN Renal Weekends 2009
30
20
10
40
after w/d
A Low Cs A w /d
B Low Cs A
C Standard Cs A
30
A Low Cs A w /d
B Low Cs A
C Stand Cs A
20
10
0
0
6 m onths post-Tx
12 m onths post-Tx
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 …
SYMPHONY Study Design
ASN Renal Weekends 2009
1645 patients at 83 sites in 15 countries
150–300ng/mL for 3 months
100–200ng/mL thereafter
A
Standard-dose CsA
MMF
Steroids
50–100ng/mL
Daclizumab
Low-dose CsA
MMF
Steroids
3–7ng/mL
Daclizumab
Low-dose TAC
MMF
Steroids
4–8ng/mL
Daclizumab
Low-dose SRL
MMF
Steroids
B
C
D
Transplantation
6 months
12 months
Ekberg H, et al. NEJM 2007;357:2562–75
ASN Renal Weekends 2009
Graft function was superior with
Low-dose Tac
GFR (Cockcroft Gault) (ml/min)
Calculated GFR Cockcroft-Gault
100
90
p=0.0014
p<0.0001
p<0.0001
80
70
60
Standard-dose CsA
65
57
59
57
Low-dose CsA
Low-dose TAC
50
Low-dose SRL
40
30
No significant
difference between
CsA and Low-CsA
20
10
0
12 months post-Tx
Ekberg H et al NEJM 2007; 357: 2562.
Graft Survival was superior
with Low-dose Tac
ASN Renal Weekends 2009
p = NS
p=0.0143
p=0.0147
Graft survival (%)
93% 94%
89%
90
89%
80
100
Patient survival (%)
100
98% 97%
97%
97%
90
80
70
70
12 months post-Tx
Standard-dose CsA
Low-dose CsA
12 months post-Tx
Low-dose TAC
Low-dose SRL
ASN Renal Weekends 2009
Less Biopsy Proven Acute Rejection
with Low-dose Tac
BPAR (% of patients)
(ITT, Excluding Borderline)
50
p<0.0001
40
p<0.0001
30
26%
37%
Standard-dose CsA
Low-dose CsA
24%
Low-dose TAC
Low-dose SRL
20
12%
10
0
12 months post-Tx
No significant
difference between
CsA and Low-CsA;
about 25%
Ekberg H et al NEJM 2007; 357: 2562.
The CNI-free alternative:
ASN Renal Weekends 2009
Was the target 4-8 ng/ml for
Low-dose SRL too low?
Daclizumab + MMF + CS
No CNI / No SRL
Vincenti et al.
Acute Rejection 53%
Low-SRL
SYMPHONY
Acute Rejection 37%
+ + + lymphocele
+ + + delayed wound healing
+ + + hyperlipidaemia
Similar overall rates of infection
-16%
Low-SRL was not efficient enough, but still not without toxicity
Vincenti F et al. Transplantation 2001; 71:1282.
Ekberg H et al NEJM 2007; 357: 2562.
ASN Renal Weekends 2009
Probability of One-Year Acute Rejection
by Drug Exposure at 1 month
.35
Low-SRL
0
5
Probability of One-year AR
.30
10
15
20
25
30
.25
.20
.15
0
Cyclosporine
100
200
300
400
500
.10
600
700
800
Low-Tac
.05
0
2
4
6
8
10
12
14
0
Values indicate average 1-month trough levels
16
18
ASN Renal Weekends 2009
3-year Follow-up Study
Core study (12 months)
Enrolled:
1645
Safety (received Rx):
1602
ITT (received Rx, transplanted):
1589
Approx. 60% of patients
Follow-up study (data at 36 months)
FU-Enrolled:
955
FU-Safety:
954
FU-ITT:
954
ASN Renal Weekends 2009
Many patients switched treatments
during the 1st year
60
- 3%
Patients (%)
50
Dotted bars: Day 0
Striped bars: Month 12
+ 9%
40
- 8%
30
20
10
0
50
47
CsA
25
34
Tac
25
17
SRL
Switches from SRL to Tac
occurred due to treatment failure, mainly AR
ASN Renal Weekends 2009
Incidence of BPAR remained lowest
in Low-Tac group at 3 years
p<0.0001
BPAR (% of patients)
p<0.0001
40
35
30
25
20
15
10
5
0
27
StandardCsA
p<0.0001
27
Low-CsA
14
Low-Tac
39
Low-SRL
ASN Renal Weekends 2009
Graft survival* remained superior
in Low-Tac group at 3 years
Graft loss (% of patients)
p>0.05
14
12
10
8
6
4
2
0
13
StandardCsA
11
Low-CsA
10
Low-Tac
15
Low-SRL
* Graft survival not censored for patient death
ASN Renal Weekends 2009
Interim 1-Year Outcomes of the
Spare-the-Nephron (STN) Trial: An
MMF-Based Regimen Combined
With Sirolimus to Spare
Renal 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 Design
Pre-randomization*
Post-randomization
30 – 180
MMF + tacrolimus
MMF + cyclosporine
D
A
Y
S
P
O
S
T
T
X
MMF + tacrolimus
MMF + sirolimus
MMF + cyclosporine
MMF + sirolimus
Patient screening
and enrollment
1 year
*Randomization pre-stratified by CNI type at screening
Target population = 305 single-organ renal allograft recipients
2 years
ASN Renal Weekends 2009
Patient Allocation (Intent-to-Treat)*
Randomized
N=298
MMF/SRL
N=148
Tacrolimus
Withdrawal
N=122
Cyclosporine
Withdrawal
N=26
MMF/CNI
N=150
Tacrolimus
N=119
Cyclosporine
N=31
*81% received tacrolimus and 19% received cyclosporine
ASN Renal Weekends 2009
Efficacy Outcomes, n (%)
MMF/SRL*
N=148
MMF/CNI
MMF/TAC
Total*
N=119
N=150
Biopsy-proven acute
rejection
10 (7%)
9 (6%)
7 (6%)
Death
0 (0%)
3 (2%)
2 (2%)
Graft loss
3 (2%)
4 (3%)
3 (3%)
African Americans
N=48*
N=50*
N=40
Biopsy-proven acute
rejection
4 (8%)
4 (8%)
4 (10%)
*P = NS for MMF/SRL vs. MMF/CNI.
ASN Renal Weekends 2009
Treatment Failure, n (%)
MMF/SRL
N=148
Treatment failure*
MMF/CNI
MMF/TAC
Total
N=119
N=150
44 (30%)
35 (23%)
30 (25%)
0 (0%)
2 (1%)
1 (1%)
23 (16%)
10 (7%)
8 (7%)
Need to resume CNI
5 (3%)
0 (0%)
0 (0%)
Need to withdraw therapy
5 (3%)
11 (7%)
11 (9%)
Lost to follow-up
10 (7%)
12 (8%)
10 (8%)
Withdrew consent
1 (1%)
0 (0%)
0 (0%)
Reason for treatment failure
Death
Withdrawal due to AE
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
Baseline to Month 12
P=0.013
Mean Percent Change
± SEM
35
MMF/SRL
30
25
MMF/CNI
25.7
20
15
10
7.8
5
0
-5
Baseline GFR
(mL/min/1.7 m2)  SEM
N = 118
N = 109
59.5  2.0
58.7  2.2
ASN Renal Weekends 2009
Urinary Protein/Creatinine Ratio
MMF/SRL
All Patients*
Total
TAC WD
MMF/CNI
Total
MMF/TAC
Baseline, median
0.1
0.2
0.2
0.2
25th, 75th percentiles (n) 0.1, 0.2 (123) 0.1, 0.2 (104) 0.1, 0.2 (129) 0.1, 0.2 (102)
12 Months, median
0.2
0.2
0.1
0.1
25th, 75th percentiles (n) 0.1, 0.4 (106) 0.1, 0.4 (87) 0.1, 0.3 (110) 0.1, 0.2 (88)
African Americans**
Baseline, median
0.1
25th, 75th percentiles (n) 0.1, 0.2 (40)
12 Months, median
0.2
25th, 75th percentiles (n) 0.1, 0.6 (34)
0.1
0.1, 0.2 (37)
0.2
0.1, 0.6 (29)
0.1
0.1, 0.3 (44)
0.1
0.1, 0.3 (40)
MMF/SRL vs. MMF/CNI: baseline, P=NS; 12 months, *P=0.096; **P=0.043.
0.2
0.1, 0.3 (35)
0.1
0.1, 0.2 (33)
ASN Renal Weekends 2009
Desensitization Protocols
ASN Renal Weekends 2009
Approaches to Desensitization
Mark D. Stegall, M.D.
Mayo Clinic, Rochester, MN
ASN Renal Week November 7, 2008
ASN Renal Weekends 2009
Desensitization
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
• 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 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)
ASN Renal Weekends 2009
ASN Renal Weekends 2009
RATIONAL DESENSITIZATION
PROTOCOLS: TREATMENT
ACCORDING TO MEDIAN
FLUORESCENCE INTENSITY VALUES
OF LUMINEX FLOW BEADS
ASN Renal Weekends 2009
Akalin E, Dinavahi R, de Boccardo G,
Schroppel B, Sehgal V, Murphy B, and
Bromberg JS
Mount Sinai School of Medicine
Renal Division
Recanati/Miller Transplantation Institute
New York, NY
NO. I HAVE NOTHING TO DISCLOSE.
CLINICAL OUTCOMES PER
LUMINEX MFI VALUES
ASN Renal Weekends 2009
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)
Patient survival
Graft survival
Living
Deceased-donor
Acute rejection
AMR
ACR
Biopsy proven CAN
Transplant glomerulopathy
Median Cr (mg/dl)
Patients with Cr < 1.4
DSA loss during F/U
30 (4-80)
100%
97%
100%
88%
0%
0%
0%
6%
6%
1.1 (0.6-3.1)
81%
77%
40 (14-53)
100%
65%
67%
64%
59%
47%
12%
36%
12%
1.2 (1.0-3.1)
73%
31%
16 (12-28)
90%
75%
88%
67%
20%
15%
5%
20%
10%
1.4 (0.8-1.9)
87%
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)
ASN Renal Weekends 2009
Proteasome 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
ASN Renal Weekends 2009
DAPI staining demonstrating
apoptosis of Velcade treated cells
Control
Velcade
The Complement Cascade: Targeted Inhibition
Classical Pathway
ASN Renal Weekends 2009
Antigen/Antibody Complexes
Lectin Pathway
Activated C1
Carbohydrate Structures
C4+C2
C3 Convertase
C5 Convertase
C4b2a
C4b2a3b
Activated MBL
Weak
Anaphylatoxin
Potent Anaphylatoxin
Chemotaxis
Cell Activation
Cell Activation
Neisseria Clearance
C5a
RBC Lysis
C3a
Immune Complex
Microbial Opsonization
C3
C3b
C5
X
C5b
C5b-9
C6 C7 C8 C9
Alternative Pathway
M/O and Mammalian
Cell Membranes
C3b
C3bBb
C3bBb3b
C3 Convertase
C5 Convertase
Factor B+D
C3H20
Tickover
Eculizumab
Target
ASN Renal Weekends 2009
Anti-C5 Antibody
Eculizumab
• 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
• 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
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
Stallone G, et al. New Engl J Med 2005;352:1317
After
ASN Renal Weekends 2009
Everolimus in Advanced Renal Cell
Carcinoma: A Double Blind RCT
Progression-Free Survival
(Everolimus dose =10 mg/day)
N=272
N=138
Motzer RJ, et al. Lancet 2008;372:449
ASN Renal Weekends 2009
mTOR Inhibitors and Non-Skin Cancers
in Kidney Recipients: OPTN Data
Transplanted 2000-20052
Transplanted 1996-20011
1.20
1.20
1.00
1.00
0.80
P=0.0002
0.80
0.60
0.60
0.40
0.40
0.20
0.20
1.00
0.40
0.00
CsA/Tac SRL/EVL
N= 30,424
2,825
1Kauffman
1.00
1.05
Tac
37,829
CsA
18,783
0.74
0.68
0.94
0.00
SRL SRL+CsA SRL+Tac
2,257
2,664
4,659
HM, et al. Transplantation 2005;80:883
2Wida SC, et al. American Transplant Congress, June 2008 Abstract #294
ASN Renal Weekends 2009
mTOR Inhibitors and Malignancies:
A Meta-Analysis of RCTs
CNIs v. mTOR
Antimetabolites v. mTOR
2.00
2.00
1.50
1.50
1.00
1.00
0.50
0.50
1.00
0.66
0.00
1.00
0.83
0.00
CNI
mTOR
4 Trials (N=447)
Antimetabolite mTOR
6 Trials (N=2,944)
Webster AC, et al. Am J Transplant 2006;81:1234
ASN Renal Weekends 2009
mTOR Inhibitors and PTLD:
A Meta-Analysis of RCTs
CNIs v. mTOR
Antimetabolites v. mTOR
10.00
10.00
8.00
8.00
6.00
6.00
4.00
4.00
2.00
2.00
1.00
1.61
0.00
1.00
2.03
0.00
CNI
mTOR
5 Trials (N=447)
Antimetabolite mTOR
3 Trials (N=1,616)
Webster AC, et al. Am J Transplant 2006;81:1234
ASN Renal Weekends 2009
Sirolimus Conversion for Skin Cancer
in 30 Kidney Transplant Recipients
Before
After
Immunosuppression:
Immunosuppression:
•20 triple therapy
• 9 double therapy
• 1 CsA alone
Cancers: 5.4 per pt
Graft function:
•eGFR = 46.414.8
•17 SRL + Prednisone
•Levels 6.8-7.7 ng/mL
•4 stopped SRL (AEs)
Cancers: 1.6 per pt
Graft function:
•eGFR = 44.819.3
•No acute rejections
Shapiro RJ, et al. Am J Transplant 2008; 8 (Suppl 2):523
ASN Renal Weekends 2009
Management of skin cancer
in transplant patients
Dr Catherine Harwood MD PhD
Senior Lecturer and Consultant Dermatologist
Barts and the London School of Medicine and Dentistry,
Mary University of London, UK
Queen
ASN Renal Weekends 2009
ASN Renal Weekends 2009
Aetiology of transplant skin cancer
UVR
Drugs
Viruses
Genetics
Immunosuppressive drugs
ASN Renal Weekends 2009
Intensity of immunosuppression
Triple therapy > dual therapy Glover. Lancet 1997; Jensen JAAD 1999
High dose > standard dose cyclosporin Dantal, Lancet, 1998
Association with CD4 count
Immunosuppressive drugs as direct carcinogens
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
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
Proteinuria in the Transplant Recipient:
Evidence-Based Practice
Greg Knoll MD MSc
Associate Professor of Medicine
Medical Director, Kidney Transplantation
University of Ottawa and The Ottawa Hospital
Allograft Function: The New EndPoint in Transplantation
Saturday November 8, 2008
ASN Renal Weekends 2009
Prevalence of Proteinuria in
Kidney Transplantation
Study
Definition of
Proteinuria
Time PostTransplantation
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
Kidneys or the Transplanted
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
n=14
D’Cunha PT et al, Am J Transplant; 5:351-355, 2005
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
Only 10% had
>1500 mg/day
at 3 wks
n=115
3650±3702
550±918
472±1116
Myslak M et al, Am J of Transplant; 6:1660-65 2006
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
Allograft Pathology?
ASN Renal Weekends 2009
 613
patients transplanted between 1998 and
2004
 All
had 24 hour urine collection and
protocol Bx at 1-year
Amer et al, Am J Transplant; 7: 2748, 2007
ASN Renal Weekends 2009
Proteinuria >1.5 g/day is Associated with
Glomerular Pathology
<150 mg/day
150-500 mg/day
500-1500 mg/day
>1500 mg/day
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
Patient or Graft Survival?
ASN Renal Weekends 2009
Proteinuria is Associated with
Graft Survival
N=722
Tx recipients 1971-1995
Tx function at 1 year
Proteinuria: >0.2 g/L
Multivariate HR 2.03
(1.50-2.76)
P<0.0001
Roodnat et al, Transplantation 72: 438, 2001
ASN Renal Weekends 2009
Proteinuria is Associated with
Patient 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
Cardiovascular Disease

CVD defined as :


Proteinuria associated with:


Angina, MI, TIA, stroke, PVD
RR of CVD 2.45 (1.66-3.62)
Risk increased with increasing amounts of
proteinuria

Pr 0.5-1.0 g/day: RR of CVD 1.45 (0.85-2.45)

Pr 1.0-3.0 g/day: RR of CVD 1.85 (1.1-2.96)

Pr >3 g/day: RR of CVD 2.88 (1.47-5.61)
Fernandez et al, Transplantation 73: 1345, 2002
ASN Renal Weekends 2009
Management of Proteinuria in the
Kidney Transplant Recipient
Management of Proteinuria in the
Kidney Transplant Recipient
 In
the non-transplant patient, the goals of
proteinuria reduction include:

Symptom management (e.g. edema)

Prevention of complications from heavy proteinuria (e.g.
hyperlipidemia, thrombosis etc)

Prevention of Progressive CKD or ESRD

Prevention of CV events
ASN Renal Weekends 2009
ACE-Inhibitors in Kidney
Transplantation
n=2031
Heinze et al, J Am Soc Nephrol 17: 889, 2006
ASN Renal Weekends 2009
No Effect of ACE-Inhibitors in
Kidney Transplantation
n=17,209
Opelz et al, J Am Soc Nephrol 17: 3257–3262, 2006
ASN Renal Weekends 2009
Randomized Trials of ACE-I in
Kidney Transplantation

Systematic review and meta-analyses

Search yielded 1153 articles
 21

Randomized trials (n=1549 patients)
Comparator groups included the following:
 DHP
CCB (n=9)
 usual
care (n=5)
 placebo

(n=5)
other drug (n=2)
Hiremath et al, Am J Transplant 7: 2350, 2007
ASN Renal Weekends 2009
Renin Angiotensin System Blockade in
Kidney Transplantation
 Data
from Randomized Trials shows the
following:
 Patients
on ACE-I:
 Change
in proteinuria was 470 mg/day lower than
control group
 Change in GFR 6 ml/min lower than control with
median follow-up of 27 months
 No
data on patient or graft survival
Hiremath et al, Am J Transplant 7: 2350, 2007
ASN Renal Weekends 2009
Renin Angiotensin System
Blockade in Kidney
Transplantation
Knoll et al, Nephrol Dial Transplant 23: 354, 2008
ASN Renal Weekends 2009

10 sites now actively recruiting

128 patients consented as of October 16,
2008

Target sample size n=528
American Society of Nephrology - Philadelphia, PA - 2008
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
ASN Renal Weekends 2009
Goals and design of the study
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
Groupe A : Hb 130 - 150 g/L
R
NeoRecormon SC
Tx > 12 months
eClcr 50 - 20 ml/min
Hb < 115 g/L
n = 125
Groupe B : Hb 105 - 115 g/L
QoL
eGFR
QoL
eGFR
QoL
eGFR
eGFR
eGFR
function
at inclusion
RenalRenal
function
at inclusion
ASN Renal Weekends 2009
Group A
Group B
130 - 150 g/L
105 - 115 g/L
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
n
Renal
function
at inclusion
Evolution
of Hb
level during
the study
ASN Renal Weekends 2009
150
A 7330 ± 5200 UI/s
Hémoglobine (g/l)
140
130
120
110
B 4630 ± 4130 UI/s
100
90
80
70
T0
M1
M2
M3
M6
Follow-up
M12
Quality
of Life
at 1 yearat inclusion
Renal
function
ASN Renal Weekends 2009
SF-36 Questionnaire
Variation from baseline (%)
50
40
Group A (130 - 150 g/l)
Group B (105 - 115 g/l)
*
30
20
*
*
*
10
0
- 10
PF
RP
Physical
* p < 0.05
*
*
BP
GH
VT
General Health
SF
RE
MH
Social, Emotional,
Mental
Quality
of Life
at 1 yearat inclusion
Renal
function
ASN Renal Weekends 2009
Variation from baseline (%)
KTQ-25 Questionnaire
20
Fatigue
Fear
Appearence
Emotion
*
15
10
5
0
-5
-10
Group A (130 - 150 g/l)
Group B (105 - 115 g/l)
ASN Renal Weekends 2009
Retransplantation- Current
Status and Candidate
Selection.
Panduranga S Rao MD DNB MS
University of Michigan, Ann Arbor
American Society of Nephrology
Philadelphia, PA
November 7, 2008
ASN Renal Weekends 2009
Patients returning to dialysis after a
failed kidney transplant
Number of Patients
6000
4000
2000
0
1992
1994
1996
1998
2000
Years
USRDS ADR 2008
2002
2004
2006
ASN Renal Weekends 2009
Number of Pts.
Failed Transplants on Waitlist
10,000
9,000
8,000
7,000
6,000
5,000
4,000
3,000
2,000
1,000
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Year
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
Unadjusted Deceased Donor Graft Survival
for First and Second Kidney Transplants,
2000-2005
100%
First Transplant
90%
Second Transplant
Survival (%)
80%
70%
60%
50%
40%
30%
20%
10%
0%
1 Year
3 Years
Years Since Transplant
Source: SRTR Analysis, May 2006
5 Years
ASN Renal Weekends 2009
Survival benefit of retransplantation –
US experience: Type 1 diabetes
Survival benefit : non-diabetics
Ojo et al. Transplantation 1998
ASN Renal Weekends 2009
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
Treatment
Adjusted
Mortality Ratio*
Standard
Therapy
(95% CI)
p
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
Survival Probability
1
0.9
0.8
ECD
ST
0.7
0.6
0.5
0
1
2
3
Time (years)
4
5
6
ASN Renal Weekends 2009
Adjusted Recipient Survival
Non-ECD vs. Standard Therapy
Survival Probability
1
0.9
0.8
non-ECD
ST
0.7
0.6
0.5
0
1
2
3
4
Time (years)
5
6
7
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