2008 ASN Highlights: Kidney Transplantation Donald E. Hricik, M.D. Professor of Medicine, Chief Division of Nephrology and Hypertension University Hospitals

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


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


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


Histological features of Cyclosporine Nephrotoxicity


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


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.


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.


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


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.


CNI sparing strategies

So: CNI avoidance – did not work CNI withdrawal (at 4-6 mo.) – did not

work CsA dose reduction …


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


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.


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


Gra

ft s

urv

iva

l (%

)G

raft

su

rviv

al (

%)

7070

8080

9090

100100


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


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


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%



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.


-16%-16%


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


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


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


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


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


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


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


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


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.


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.


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


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.


Desensitization Protocols


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


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


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


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)




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.


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%


• 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)


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


DAPI staining demonstrating apoptosis of Velcade treated cells

DAPI staining demonstrating apoptosis of Velcade treated cells

Control Velcade


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


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


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


Kidney Transplantation:Complications


Immunosuppression Management in the Patient with

Cancer: Role of Sirolimus

Bertrand Kasiske

University of Minnesota


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


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)


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


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


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


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


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



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


Does sunscreen use post-transplantation lead to a reduction in skin (pre)malignancies?


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


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


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%


Proteinuria: Is it from the Native Proteinuria: Is it from the Native Kidneys or the Transplanted Kidneys or the Transplanted

Kidney?Kidney?


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


DTPA Scan one week pre-Tx and 3 weeks post-Tx

D’Cunha et al, Am J Transplant; 5, 2005


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


These 5 all had glomerular lesions on allograft biopsy

Myslak et al, Am J of Transplant; 6, 2006


Proteinuria: What is the Proteinuria: What is the Allograft Pathology?Allograft Pathology?


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


<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


Does Proteinuria have any Impact on Does Proteinuria have any Impact on Patient or Graft Survival?Patient or Graft Survival?


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


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


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


Management of Proteinuria in the Management of Proteinuria in the Kidney Transplant RecipientKidney Transplant Recipient


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


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


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


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


Renin Angiotensin System Renin Angiotensin System Blockade in Kidney Blockade in Kidney

TransplantationTransplantation

Knoll et al, Nephrol Dial Transplant 23: 354, 2008


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


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


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


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 (%

)


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

(%)

*


Retransplantation- Current Status and Candidate

Selection.Panduranga S Rao MD DNB MS

University of Michigan, Ann ArborAmerican Society of Nephrology

Philadelphia, PANovember 7, 2008


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


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


Mortality risk on dialysis after graft failure - first year

Rao et al AJKD 2007


Do all returning patients have the same mortality risk?

Ojo et al Transplantation 1998


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


Survival benefit of retransplantation – US experience: Type 1 diabetes


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


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


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


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


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


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


Documents

2008 ASN Highlights: Kidney Transplantation Donald E. Hricik, M.D. Professor of Medicine, Chief Division of Nephrology and Hypertension University Hospitals