1 2013-11-23 Halle CNI free - Nierentransplantation

Wolfgang ArnsTransplant Center CologneCologne Merheim Medical Center

[email protected]

CNI-freie Immunsuppression :Modell für die Zukunft?

Langzeitergebnisse und Sicherheit innovativerImmunsuppression nach Nierentransplantation

Disclosures

● Dr. Arns and his institution have received scientific grants and consultation honoraria from Novartis, Astellas, Roche, BMS and Pfizer.

Contents

● What have we learned from recent studies?

● The DSA concept

● The immunological and non-immunological risk

● The comorbidity concept

3

1960

Year of transplant

Acu

te r

ejec

tion/

graf

t su

rviv

al (

%)

80–90%

40–50%

5–20%

~60%

Azathioprine Prednisone

CsA

MMF

Basiliximab

Tacrolimus

Sirolimus

Acute rejection80

100

60

20

40

2005 1965 1970 1975 1980 1985 1990 1995 2000 2010

0

ATG

Considerable improvements have been made in acute rejection and short-term graft survival

but…

1-year graft survival

Everolimus

CsA, cyclosporine; ATG, anti-thymocyte globulin; MMF, mycophenolate mofetil.1. Morris PJ. N Engl J Med. 2004;351:2678−80; 2. Sayegh MH, et al. N Engl J Med. 2004;351:2761−6; 3. Khurana A, Brennan D. Current concepts of immunosuppression and side effects in Pathology of Solid Organ Transplantation, 2011 4

... long -term renal allograft survival has not improved…

0

1

2

3

4

5

6

7

8

9

10

1998 1999 2000 2001 2002 2003 2004 2005

Yea

rs to

ove

rall

graf

t su

rviv

al h

alf-

life

Year of transplant

8.3 8.8

Deceased donor kidney transplant attrition rates in the USA (n=164,480)

. Lamb KE, et al. Am J Transplant. 2011;11:450–462.

20

0

4

8

12

16

1994 1999 2004 20091989

0−−−−1yr

5−−−−10 yrs

1−−−−3 yrs

3−−−−5 yrs

5

Cumulative graft t½ by transplant year (forecasted Kaplan-Meier estimates)

... neither has long -term patient survival

0

10

20

30

40

50

60

70

80

90

100

1994–1995 1996–1997 1998–1999 2000–2001 2002–2003 2004–2005 2006–2007

Rec

ipie

nt s

urvi

val,

%

86%

Patient 5-year survival 1994–2007Recipients of a first deceased-donor kidney

Year of transplant

ANZDATA registry 2012 report. Available at: http://www.anzdata.org.au/anzdata/AnzdataReport/35thReport/2012c08_transplants_v1.pdf. Accessed 17 June 2013.

88%

6

Cardiovascular disease and malignancy are the leadi ng causes of death with functioning graft

65%

Malignancy, 31% CVD,

34%

Infection, 19%Miscellaneous, 10%

Social, 7%

CVD34%

aData from 2007–2011; n=1071 patients in Australia; bData from 2007–2011; n=852 patients in AustraliaANZDATA registry 2012 report. Available at: http://www.anzdata.org.au/anzdata/AnzdataReport/35thReport/2012c08_transplants_v1.pdf. Accessed 17 June 2013. 7

Causes of death with functioning graft according to the ANZDATA registry 2007–2011b

Kidney function at Month 12 is associated independently with graft failure

Relationship between eGFR and graft failure over 10 -years of follow-up(Cox proportional hazard adjusted for multiple cova riates)

0.5

1.0

2.0

4.0

8.0

16.0

32.0H

azar

d R

atio

by

eGF

R D

eclin

e

0 20 40 60 80 100 120

12-month eGFR, mL/min/1.73m 2

0.0

0.5

1.0

1.5

2.0

2.5

3.0

12-M

onth

eG

FR

dis

trib

utio

n, %

Hazard ratio (95% Confidence Interval)eGFR distribution

eGFR <50 mL/min/1.73m2 was associated with proportionally lower graft survival, death-

censored graft failure and death with function

eGFR, estimated glomerular filtration rate.Kasiske B, et al. Am J Kidney Dis. 2011;57:466–75. 8

Patients with eGFR levels <45 mL/min/1.73m 2

have an increased risk of CVD and mortality

0,5 1 1,5 2 2,5 3 3,5

Hazard ratio (95% CI)

Increased risk of CVD/death

<30

30−−−−45

45−−−−60

≥≥≥≥75

Reference

1.041.07

Reference

0.881.02

1.391.34

1.852.05

60–74

Reduced risk of CVD/death

CVDMortality

eGF

R, m

L/m

in/1

.73m

2

Hazard ratios of CVD and mortality (n=3676)

CI, confidence interval; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate.Weiner DE, et al. Am J Transplant. 2012;12:2437−45. 9

Follow-up, years

Even patients with high 1-year eGFR can have progressive graft failure

No difference in between the mean 1-year eGFRMDRD of the High-NP† and High-P groups

eGFR, estimated glomerular filtration rate; NP, non-progressor; P, progressor.Park WD, et al. Transplantation. 2012;94:931–39.

Gra

ft su

rviv

al

P<0.0001

1-ye

ar e

GF

RM

DR

D

High-NP High-P

Graft failureGroup n % # High-NP* 553 1% 7

Low** 113 19% 22

High-P † 122 34% 41

140

120

100

80

60

40

20

Graft failure rate was higher among the high-eGFR progressorsthan the low eGFR group (34% vs 19%, P<0.0021)

This analysis excluded allografts that failed befor e 2.5 years posttransplant*Patients with high 1-year GFR (>40 mL/min) with increasing or stable eGFRMDMD.**Patients with low 1-year eGFR (<40 mL/min).†Patients with high 1-year eGFR (>40 mL/min) with strongly negative eGFRMDRD slope.

Individual transplantGroup mean value

1.0

0.9

0.8

0.7

0.6

0.52 3 4 65 8 9 107

10

Halloran PF, NEJM 2004; 351(26): 2715-2729

CNIs seem to be the most effective drugs forinhibition of antigen triggering T cells

Donor antigen (presented via MHC on donor-derived

or recipient APC)

T cells 1

activation

Effector T cells

Regulatory T cells

Dendritic cells/macrophage

differentiation

activation

Donor antigens in allograft trigger complex immune response involving T-cells, B -cells and complement

Activation of the classic complement cascade with graft

1. Nankivell BJ, et al. N Engl J Med. 2010;363:1451–1462; 2. Stegall MD, et al. Am J Transplant. 2009;9:998–1005.

B cells 2

Plasmablasts Plasma cells

Low-affinityantibodies

High-affinityantibodies

proliferation

germinal center reaction

activation

Memory B cells

Activation of intragraft APC and T cells

Complement 1

Helper T cells

recruitment

12

Chronic low-level DSAs may have no detrimental effect, may have even protective effect3, some have

been implicated in AMR1

DSA can be preformed or arise de novo at anytime after Tx

AMR, antibody-mediated rejection; DSA, donor-specific antibody; HLA, human leukocyte antigen.1. Loupy A, et al. Nat Rev Nephrol. 2012;8:348–357; 2. Nankivell BJ, et al. N Engl J Med. 2010;363:145114–62; 3. Turgeon NA, et al. Transplant Rev. 2009;23:25–33; 4. Colvin RB. J Am Soc Nephrol. 2007;18:1046–1056.

Tran

spla

ntat

ion

Development of anti-HLA DSA due to:1,2

• Pregnancy• Blood product transfusion • Previous transplantation

Increased risk of acute or chronic AMR1

Development of DSA hypothesized to be related to inadequate immunosuppression and may appear any time after transplantation at varying levels1

Preformed DSA de novo DSA

TimeAcute AMR Chronic AMR

Often associated with antibodies against

HLA class II4

Often associated with antibodies against

HLA class I and/or II4

13

DSAs are poorly characterized with low prevalence in renal transplant recipients

� The exact prevalence of donor-specific antibodies ( DSAs) in kidney transplant patients is difficult to ascertain given that there is no stand ardized test for measuring DSA 1

� One study in 1043 kidney transplant recipients foun d ~10% of patients had DSA within 4 years of transplantation 2

� A separate study reported that among patients with out detectable DSA at the time of transplantation, ~11% will have detectable DSA at 1 year and ~20% over the next 4 years

� Antibodies may also be classified according to thei r activity against HLA 2,4

– In a study of 1229 kidney transplant patients, 17% had anti-HLA antibodies, one third of which had anti-HLA DSA4

DSA, donor-specific antibody; HLA, human leukocyte antigen; MMF, mycophenolate mofetil.1. Archdeacon P, et al. Am J Transplant. 2011;11:896–906; 2. Lachmann N, et al. Clin Transpl. 2006:171–199; 3. Everly MJ, et al. Transplantation. 2013;95:410–417; 4. Hourmant M, et al. J Am Soc Nephrol. 2005;16:2804–2812.

No anti-HLA antibodies, 83.0%

DSA, 8.6%

Non-DSA, 19.8%No antibodies,

71.6%

Anti-HLA non-DSA Anti-HLA DSA

11.3% 5.5%

14

Adapted from Loupy, A. et al. (2012) The impact of donor-specific anti-HLA antibodies on late kidney allograft failure; Nat. Rev. Nephrol. doi:10.1038/nrneph.2012.81

Transplantation

Time

Antibody Mediated Deterioration of Allograft:

Donor-specific anti-HLA Antibodies after transplant ation may be complement dependent or independent

Loupy A et al. N Engl J Med 2013;369:1215-1226

Consensus for clinical management of DSA

Tait BD et al, TP 2013, 95, 19-47

screening***de novo DSA

protocolbiopsy

immunologicalrisk

DSA-* 3-12 monthde novoDSA+

low

DSAactual-DSAhistorical+

<1 monthde novoDSA+

intermediate

DSA+** <3 month <3 month high/very high

*in case of PRA0% (CDC) und DSA- allocation XM not mandatory.

Cave: actual XM- is still mandatory

**even in case of desensitization therapy

***at leat 1x / in given period

Σ 126 patients[median 1059 d]

65 CSA [median 991 d] 61 EVR [median 551 d]

7 DSAs (10.8%) 14 DSAs (23,0%)

2 AMR 8 AMR

0 graft loss 4 graft loss

Cyclosporine vs. everolimus

Single center experience from the ZEUS and HERAKLES study

Liefeldt L et al. Am J Transplant. 2012;12:1192–8

Results:

No difference in incidence of DSAs oranti-HLA antibodies between bothgroups.

Figure and Tab modified from Kamar et al., Clin.Transplant 2013 27:455-462

Incidence of de novo DSAs in KTx patients followingconversion to an Everolimus-based CNI-free regimen

Kamar et al., Clin.Transplant 2013: 27: 455-462

Scheme of drug weaning andde novo DSAs

Hoshino J, Transplantation 2012; 93:1173-78

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.500.0

0.2

0.4

0.6

0.8

1.0

CsA/MPS/P

Cert/MPS/P

A2:2500B13:3900DR7:100

A2:4000B13:900DR7:100

A2:1400B13:100DR7:100

A2:1200B13:100DR7:100DQ8:400

A2:100B13:100DR7:100DQ8:100

Jahre post Op

1/K

reat

inin

Translating in to clinical praxisRenal function slope and DSAs

A2309 post-hoc study: Safety events that met the criteria for further analysis

*Increased as CsA exposure increased across most everolimus ranges**No clear correlation with everolimus levelsAE, adverse event; CsA, cyclosporine A; EVR, everolimus; NODM, new onset diabetes mellitus; T, testosteroneShihab FS, et al. Clin Transplant. 2013;27:217−226. 22

Adverse eventsWound

healing*

Proteinuria

Edema*

NODM*,**

Stomatitis*,**Lipid disorders*

Low T in men**

Lowest rates of AEs observed when EVR=3–8 ng/mL and

CsA<100 ng/mL

Lowest rate of proteinuria was observed with EVR<3–8 ng/mL

Inhibition of mTOR and the podocyte: Hypothetical mechanisms

Hypothetical model: mTOR complexed to Rictor forms mTORC2, which phosphorylates Akt at Ser473

ALB, albumin; HMW, high molecular weight; LMW, low molecular weight; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor; WT, wild type.Letavernier E, et al. Nephrol Dial Transplant. 2009;24:630–38.

Sirolimus

Akt Akt

VEGF

?

mTORC2 complex

mTOR

Akt Podocytes survival and differentiation

Podocytes survival and adhesion

Podocytes integrity and differentiation

P

VEGF-R

VEGF

WT1

23

TAC/MPS/P

RAD/MPS/P

TAC/MPS/P

0

100

200

300

400

500

600

700

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0 1 2 3 4 5 6

Alb

umin

iU

1/K

rea

Jahre

1/Krea Aging (2%) Albumin iU

Case study

24RAD, everolimus; MPS, mycophenolate sodium; P, prednisone; TAC, tacrolimus.

completely de novo

SMART12-3 Weeks

CONCEPT3,4

HERAKLES3 Months

Spare the Nephron21-6 Months

A2309ORION, ELITE, Symphony

ZEUS5,64.5 MonthsAPOLLO; CONVERT7> 6 Months

Over the last decade many trials investigated the potenti al of mTORinhibitors to replace CNIs at different time points post -transplant.

1. Guba M et al. Transpl Int 2012; 25: 416-232. Weir MR et al. Kidney Int 2011; 79: 897-907 3. Lebranchu Y et al. Am J Transplant 2009; 9: 1115-1123

4. Lebranchu Y et al. Am J Transplant 2011;11: 1665-75 5. Budde K, et al. Lancet 2011; 377: 837-8476. Budde K, et al. AJT2012; 12(6):1528-407. Schena FP, et al. Transplantation 2009; 87: 233-242

De novo conversion to mTORi and CNI withdrawal orminimization

Study Patients Length of published FU Time of conversion

Early Conversion:Early Conversion:Early Conversion:Early Conversion:

SMART1 141 3 years 10–24 days

CENTRAL2 202 1 year 7 weeks

CONCEPT3,4 192 4 years 3 Mo

Spare The Nephron5 299 2 years 30–180 days(mean 3.8 Mo)

A230910 822 2 years de novo

HeraklesHeraklesHeraklesHerakles 499 2 year data now available 3 Mo

ZEUS6,9 3005 year data

now available 4.5 Mo

Late Conversion:Late Conversion:Late Conversion:Late Conversion:

CONVERT7 830 2 years 6–120 Mo(mean 3.3 years)

ASCERTAIN8 394 2 years >6 Mo(mean 5.6 years)

1. Guba M et al. Transpl Int 2012; 25: 416-23 ; 2. Mjörnstedt L et al. Am J Transplant 2012;12: 2744-53; 3. Lebranchu Y et al. Am J Transplant 2009; 9: 1115-1123; 4. LebranchuY et al. Am J Transplant 2011;11: 1665-75; 5. Weir MR et al. Kidney Int 2011; 79: 897-9076. Budde K, et al. Lancet 2011; 377: 837-847; 7. Schena FP, et al. Transplantation 2009; 87: 233-242 8. Holdaas H, et al. Transplantation 2011; 92: 410-418 9. Budde K, et al. AJT 2012; 12(6):1528-40.;10. Cibrik D, et al. Transplantation 2013; 95(7):933-42.

De novo conversion to mTORi and CNI withdrawal orminimization

Multiple clinical trials have examined the differen t regimens for using everolimus in

kidney transplantation

27*everolimus is not approved for CNI elimination in kidney transplantation BPAR, biopsy proven acute rejection; BKV, BK virus; CNI, calcineurin inhibitor; CMV, cytomegalovirus.

1998 20131998 2013

Late conversionNo renal function benefit

CMV + BKV benefits (when used de novo )

CNI minimization

Improved renal function

Better on severe BPAR

Practical challenges

Risk of acute rejectionTolerability issues

Improved renal function

CNI elimination*

Less neoplasia

1960 1970 1980 1990 201520102000

AZA

STEROIDS

CsA-ME

ALG Campath

EculizumabBortezomib

Rituximab

IvIg

?

Immunosuppressive drug development in organ transplantation

28

OKT3 ATG

BasiliximabDaclizumab

Belatacept

CsACsA SRLSRLMMFMMFTACTAC MPAMPA EVREVR

FTYFK778AlefaceptSotrastaurinTofacitinib?

ATG, anti-thymocyte globulin; ALG, Anti-lymphocyte globulin; AZA, azathioprine; CsA, cyclosporine; CsA-ME, cyclosporine microemulsion; EVR, everolimus; MMF, mycophenolate mofetil; TAC, tacrolimus; MPA, mycophenolic acid, SRL, sirolimus.

Next decade will probably focus on refinement of known drug treatments

Long -term renal allograft survival has not improved

29

aKaplan-Meier estimates of cumulative graft half-lives by transplant year: 1st deceased-donor transplants 1989–2000.MMF, mycophenolate mofetil; Pred, prednisone; TAC, tacrolimus. 1. Lamb KE, et al. Am J Transplant. 2011;11:450–62; 2. Lodhi SA, Meier-Kriesche HU. Nephrol Dial Transplant. 2011;26:15−7.

80% TAC-MMF-Pred

0

12

16

20

1–3 years

1989 1999 2004 20091994

% A

ttriti

on

Transplant Year

8

4

Decreased donor kidney transplant attrition rates i n the US (n=164,480)

0–1 year 3–5 years 5–10 years

Poor renal function after transplantation has been shown to have multiple consequences

CAN / IFTA1 Graft failure2 Increased risk of mortality3

Increased health care costs4

Increased CVD risk5

CAN, chronic allograft nephropathy; CVD, cardiovascular disease; IFTA, interstitial fibrosis and tubular atrophy.1. Pascual J, et al. Transplant Rev (Orlando). 2012;26:280–90; 2. Park WD, et al. Transplantation. 2012;94:931–39; 3. Moranne O, et al. Am J Transplant. 2013;13:695–706; 4. Schnitzler MA et al. J Med Econ. 2013;16:75−84; 5. Weiner DE, et al. Am J Transplant. 2012;12:2437−45. 30

mTOR inhibitors (everolimus) are central in several pathways relevant to post-transplant management

Graft failure Mortality

Effectively preventsrejection when used in combination with reduced-dose CNIs

Tumor cell proliferation

Angiogenesis

Viral replication

CVD, cardiovascular disease; HIF-1α, hypoxia inducible factor 1 alpha; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; NFkB, nuclear factor kappa B; SREBP1, sterol regulator element binding protein 1.Johnson SC, et al. Nature. 2013;493:338–345; Populo H, et al. Int J Mol Sci. 2012;13:1886–1918; Buchkovich NJ, et al. Nature Reviews Microbiology 2008;6:266–275; Farsetti S, et al. Transplant Proc. 2010;42:1381–1382.

P13-K

Akt-PKB

S6K

eIF4EeIF4G

eIF4A

MuK1

mTORC2

4EBPs

mTORC1

Everolimus

CVD CAN/IFTA

Cardiac hypertrophy Endothelial cell proliferation

Homocysteine

Oxidative stress

Efficacy at 12 months after kidney transplantTedesco-Silva. Transplant Res. and Risk Manag., 2011

De novo everolimus with low CNI provides protection against acute rejection in kidney transplantation

A23091

CSAr+EVR 0.75A23091

CSAs+MPA

5

10

15

25

20

BPAR (%)

16.217.0

CSA100-200 ng/mL M0-M275-150 ng/mL M2-M450-100 ng/mL M4-M625-50 ng/mL M6-M12

N=277

CSA200-300 ng/mL M0-M2100-250 ng/mL M2-M12

N=277

ASSET2

TACvl+EVR 1.5

18.7

TAC4-7 ng/mL M0-M3

1.5-3 ng/mL M4-M12N=107

ASSET2

TACr+EVR 1.5

7.7

TAC4-7 ng/mL M0-M12

N=117

US093

TACr+EVR 0.75

14.0ǂ

TAC4-7 ng/mL M0-M33-6 ng/mL M4-M6

N=49

US093

TACs+EVR 0.75

14.0ǂ


N=43

ǂResults at 6-mEverolimus is not approved for use in combination with tacrolimus in kidney transplantation.CsA, cyclosporine; eGFR, estimated glomerular filtration rate; EVR, everolimus; MPA, mycophenolate acid; TAC, tacrolimus1. Tedesco Silva H et al. Am J Transplant. 2010;10:1401–13; 2. Langer RM, et al. Transpl Int. 2012;25:592-602; 3. Chan L, et al. Transplantation. 2008;85:821-6; 4. Ekberg H, et al. Am J Transplant. 2009;9:1876−85.

15.4

SYMPHONY4

TACr

TAC3–7 ng/mLM0-M12

N=401

32

De novo everolimus with CNI minimization provides renal benefits in kidney transplantation

A23091

CSAr+EVR 0.75A23091

CSAs+MPA

68.8 67.9

CSA100-200 ng/mL M0-M275-150 ng/mL M2-M450-100 ng/mL M4-M625-50 ng/mL M6-M12

N=277

CSA200-300 ng/mL M0-M2100-250 ng/mL M2-M12

N=277

ASSET2

TACvl+EVR 1.5

67.1

TAC4-7 ng/mL M0-M3

1.5-3 ng/mL M4-M12N=107

ASSET2

TACr+EVR 1.5

61.1

TAC4-7 ng/mL M0-M12

N=117

US093

TACr+EVR 0.75

82.8ǂ


N=49

US093

TACs+EVR 0.75

77.2ǂ


N=43

Efficacy at 12 months after kidney transplantTedesco-Silva. Transplant Res. and Risk Manag., 2011

ǂResults at 6-mEverolimus is not approved for use in combination with tacrolimus in kidney transplantation.CsA, cyclosporine; eGFR, estimated glomerular filtration rate; EVR, everolimus; MPA, mycophenolate acid; TAC, tacrolimus1. Tedesco Silva H et al. Am J Transplant. 2010;10:1401–13; 2. Langer RM, et al. Transpl Int. 2012;25:592-602; 3. Chan L, et al. Transplantation. 2008;85:821-6; 4. Ekberg H, et al. Am J Transplant. 2009;9:1876−85.

SYMPHONY4

TACr

TAC3–7 ng/mLM0-M12

N=401

10

20

30

50

60

80

100

40

90

70

eGFRmL/min(C-G)

70.3

33

● To meet the increasing need for kidney transplants, the criteria for the use of deceased kidneys has been expanded1

ECD transplantation – expands the number of transplants but comes with additional problems

● Created a category of donors termed ‘expanded criteria donors (ECD)’1

– Allografts are at risk for diminished post-transplant function1

92,384,5

68

94,6 90,679,9

0

20

40

60

80

100

3 months 1 year 3 yearsG

raft

surv

ival

, %Years since transplantation

ECD non-ECD

0

20

40

60

80

100

98 00 02 04 06 08 10

Accept ECD kidney 2

No data prior

to 2003

ECD = All donors aged over 60, and donors aged 50–5 9 plus ≥ two additional risk factors (cerebrovascular accident as a cause of death, hist ory of hypertension, and

serum creatinine >1.5 mg/dl prior to transplantatio n)

ECD = All donors aged over 60, and donors aged 50–5 9 plus ≥ two additional risk factors (cerebrovascular accident as a cause of death, hist ory of hypertension, and

serum creatinine >1.5 mg/dl prior to transplantatio n)

Pat

ient

s, %

ECD, extended criteria donor.1. Audard V, et al. Transpl Int. 2008;21:11−7; 2. OPTN/SRTR Annual report 2011. Available at: http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/01_kidney_12.pdf. Accessed: May 30, 2013. 34

Graft survival with CNI minimization (17 trials, n= 4131)

Study or subgroup CNI sparing CNI Odds Ratio

Events Total Events Total Weight M-H, Fixed, 95% CI

Andres 2008 7 36 4 38 1.9% 2.05 (0.55, 7.72)

Budde 2010 0 66 0 76 Not estimable

Chan 2008 0 49 1 43 1.0% 0.29 (0.01, 7.21)

Chan 2009 (A) 2 82 2 41 1.6% 0.49 (0.07, 3.59)

Ciancio 2005 0 30 3 30 2.1% 0.13 (0.01, 2.61)

De Sevaux 2001 11 152 19 161 10.4% 0.58 (0.27, 1.27)

Ekberg 2007 10 183 14 173 8.3% 0.66 (0.28, 1.52)

Ekberg-3 2007 30 399 46 390 26.2% 0.61 (0.38, 0.99)

Gaston 2009 5 243 4 237 2.4% 1.22 (0.32, 4.61)

Hernandez 2007 9 80 9 80 4.9% 1.00 (0.38, 2.67)

Kandaswamy 2005 5 82 4 72 2.4% 1.10 (0.28, 4.28)

Nashan 2004 1 58 4 53 2.5% 0.21 (0.02, 1.99)

Russ 2003 3 33 1 31 0.6% 3.00 (0.30, 30.50)

Salvadori 2006 24 224 26 219 14.3% 0.89 (0.49, 1.61)

Salvadori 2009 5 142 16 143 9.4% 0.29 (0.10, 0.81)

Tedesco-Silva 2006 20 231 21 224 11.8% 0.92 (0.48, 1.74)

Vathsala 2005 3 20 0 10 0.3% 4.20 (0.20, 89.61)

Total (95% CI) 2110 2021 100% 0.73 (0.58, 0.92)

Total events 135 174

Heterogeneity Chi2=14.20, df=15 (P=0.51); I2=0%

Test for overall effect Z=2.62 (P=0.009) 0.01 0.1 1 10 100Favours CNI sparing Favours CNI

CNI minimization, compared with standard exposure CNI, was associated with:- reduced overall graft failure (OR 0.73, P=0.009) - reduced death-censored graft failure (OR 0.73, P=0.03)- no difference in graft failure secondary to rejection (OR 0.67 [95% CI, 0.34–1.31], P=0.24)

CNI minimization is associated with reduced overall graft failure and death-censored graft failure

CNI, calcineurin inhibitor; CI, confidence interval; df, degrees of freedom; OR, odds ratio. Sharif A, et al. J Am Soc Nephrol. 2011;22:2107–18. 35

CAN, CVD and malignancy are the leading causes of graft failure and death with a functioning graft

aData from 2007–2011; n=1071 patients in Australia; bData from 2007–2011; n=852 patients in Australia.CAN, chronic allograft nephropathy; CVD, cardiovascular disease; IFTA, interstitial fibrosis and tubular atrophy.ANZDATA registry 2012 report. Available at: http://www.anzdata.org.au/anzdata/AnzdataReport/35thReport/2012c08_transplants_v1.pdf. Accessed 22 July 2013.

Other, 9%

Glomerulonephritis, 6%

Vascular, 5%

Acute rejection, 5%

Noncompliance, 4%

Technical problems, 1%

CAN, 69%

Causes of kidney graft failure a

65%


34%


Social, 7%

Causes of death with functioning graft b

ANZDATA registry data 2007 −−−−20111

EVR allows for CNI minimization2

EVR reduces LVMi3

EVR results in fewer malignancies vs. SoC4

36

CI, confidence interval; CsA, cyclosporine A; eGFR, estimated glomerular filtration rate; EVR, everolimus; sCsA, standard CsA; tBPAR, treated biopsy-proven acute rejectionNovartis data on file

0-5-10-15-20-25 +5

- 9.7

- 14.1

- 4.3

A2309: 12-month analysisRisk Difference (%) and 95% CI

eGFR≤40 or tBPAR

eGFR≤50 or tBPAR

eGFR≤60 or tBPAR

In favor of MPA + sCsAIn favor of EVR + low CsA

An endpoint designed to assess the clinical balance between rejection and renal function

37

EVR: a multifaceted drug with the potential to improve long -term outcomes

CNI, calcineurin inhibitor; CMV, cytomegalovirus. EVR, everolimus.1. Pascual J. Transplantation. 2005;79(Suppl 9):S76–S79; 2. Eisen H, et al. N Engl J Med. 2003;349:847–858; 3. Vitko S, et al. Am J Transplant. 2005;5:2521–2530; 4. Tedesco-Silva H, et al. Transpl Int. 2007;20:27–36; 5. Nashan B, et al. Transplantation. 2004;78:1332–1340; 6. Nashan B. Transplant Proc. 2001;33:3215–3220; 7. Majewski M, et al. Transplantation. 2003;75:1710–1717; 8. Schuler W, et al. Transplantation.1997;64:36–42; 9. Viklicky O, et al. Transplantation. 2000;96:497–502; 10. Koch M, et al. Transplantation. 2007;83:498–505; 11. Andrés V, et al. Nephrol Dial Transplant. 2006;21(Suppl 3):iii14–17; 12. Pascual J, et al. Nephrol Dial Transplant. 2006;21(Suppl 3):iii38–41.

EVRCould help protect

against CMV infection2,3

Reduced exposure to CNI prevents

nephrotoxicity6

Low incidence ofacute rejection1,2,4,5

Can inhibit vascular remodelling2,6

Potentialcardiovascular

benefits11,12

May help preventgraft fibrosis9,10

Potential antimalignancy

effects7

Antiproliferativeaction7,8

38

Wolfgang ArnsTransplant Center CologneCologne Merheim Medical Center

[email protected]

CNI-Minimierung :Das Modell der Zukunft!

Summary

● Despite advances in acute rejection and 1-year graft survival over the past decade, long-term graft survival in kidney transplantation remains poor

● Declining posttransplant renal function is predictive of poor graft survival, patient mortality and is associated with:

– Increased risk of CV disease and mortality

– Increased healthcare cost

● EVR has the potential to improve long-term outcomes compared with standard CNI regimens

● EVR plus low-dose CNI has been shown to be:

– Effective in preventing acute rejections in recipients of kidney transplantation

– Associated with improved renal function at Month 12 and 24

● TRANSFORM is a superiority trial comparing EVR 1.5 mg plus low dose CNI with MPA plus standard dose CNI, which utilizes a novel and innovative primary endpoint comparing tBPAR and eGFR

– Designed to assess the clinical balance between rejection and renal function (graft outcome)

40CNI, calcineurin inhibitor; CV, cardiovascular; eGFR, estimated glomerular filtration rate; EVR, everolimus; tBPAR, treated biopsy-proven acute rejection.

BACK UP SLIDES

41

Renal transplantation: pre-CNI era

CNI, calcineurin inhibitor.1. Watson CJE and Dark JH. British J Anaesthesia 2012;108:i29–i42;2. Najarian JS, et al. Ann Surg. 1982;196:442–452; 3. Myburgh JA, et al. Transplant Proceedings 1991;23:2033–2034. 42

The first successful kidney transplant was performed between identical twins to avoid the immune-response related graft/patient survival1

Minimal success has been observed with the use of total body irradiation for immunosuppression.2,3

Disadvantages: 1. Cannot be quickly reversed 2. Does not have a long-lasting impact

0

1960

Year of transplant

Acu

te r

ejec

tion/

graf

t sur

viva

l, %

40–50%

80–90%

~60%

5–20%

MMF

Basiliximab

Acute rejection

80

100

60

20

40

2005 1965 1970 1975 1980 1985 1990 1995 2000 2010

Azathioprine Prednisone

CsA Tacrolimus

Sirolimus

Considerable improvements have been made in acute rejection and short-term graft survival but…

1-year graft survival

EVR

ATG, anti-thymocyte globulin; CsA, cyclosporine; EVR, everolimus; MMF, mycophenolate mofetil.1. Morris PJ. N Engl J Med. 2004;351:2678−80; 2. Sayegh MH, et al. N Engl J Med. 2004;351:2761−6; 3. Khurana A, Brennan D. Current concepts of immunosuppression and side effects in Pathology of Solid Organ Transplantation; 2011. 43

ATG

… and neither has long -term patient survival

0102030405060708090

100

Rec

ipie

nt s

urvi

val,

%

84%89%

ANZDATA registry 2011 report. Available at: http://www.anzdata.org.au/anzdata/AnzdataReport/34thReport/2011c08_transplantation_v1.7.pdf. Accessed 21 March 2013.

Primary deceased donor recipient 5-year survival 1991 −−−−2006

Year of transplant

44

... long -term renal allograft survival has not improved…

.

Deceased donor kidney transplant attrition rates (n=164,480) 2

45

20

0

4

8

12

16

1994 1999 2004 20091989

0−−−−1 year

5−−−−10 years

1−−−−3 years

3−−−−5 years

Attr

ition

, %

aKaplan-Meier estimates of cumulative graft half-lives by transplant year: 1st deceased-donor transplants 1989–2000. 1. Lamb KE, et al. Am J Transplant. 2011;11:450–62; 2. Lodhi SA, Meier-Kriesche HU. Nephrol Dial Transplant. 2011;26:15−7.

CAN is the leading cause of graft failureCVD and malignancy are the leading causes of death in

patients with a functioning graft

5

68

16

27

38

0

10

20

30

40

50

60

70

80

Gra

ft fa

ilure

a , %

Acuterejection

CAN Hyperacuterejection

Vascular Technicalproblems

Glomerulo-nephritis

Non-compliance

Other

aData from 2006–2010; n=1029 patients in Australia; bData from 2006–2010; n=772 patients in AustraliaCAN, chronic allograft nephropathy; CVD, cardiovascular disease.ANZDATA registry 2011 report. Available at: http://www.anzdata.org.au/anzdata/AnzdataReport/34thReport/2011c08_transplantation_v1.7.pdf. Accessed August 2013.

Causes of death with a functioning graft b

Malignancies

Cardiac and vascular

31%

37% 68%

Infections 18%

Social 6%

Miscellaneous 8%

Causes of graft failure a

46

CVD, malignancy and infection are the major cause of death in patients with a functioning graft

aData from 2006–2010; n=772 patients in AustraliaCVD, cardiovascular disease.Clayton P et al. ANZDATA registry 2011 report. Available at: http://www.anzdata.org.au/anzdata/AnzdataReport/34thReport/2011c08_transplantation_v1.7.pdf . Accessed May 30, 2013.

Causes of death with a functioning graft a

Malignancies


31%

37%

Infections 18%

Social 6%

Miscellaneous 8%

47

0,1 1 10

Transplant patients with diabetes and high cholesterol have a higher risk of associated IHD

FHS, Framingham Heart Study; HDL, high-density lipoprotein; IHD, ischemic heart disease. Kasiske BL, et al. J Am Soc Nephrol. 2000;11:1735–43.

200–239

240–279

>280

<35

35–44

45–49

50–59

≥60

Cholesterol

(mg/dL)

Male transplant population (n=634)

Relative risk of IHD in renal transplant patients c ompared with FHS database

Cigarette use (Y/N)

Male FHS population (n=2491)

Higher risk of IHDLower risk of IHD

Diabetes mellitus (Y/N)

48

HDL (mg/dL)

Improvement in renal function after early conversion from a CNI- to an EVR -based

immunosuppression regimen

CNI, calcineurine inhibitor; CsA, cyclosporine; EVR, everolimus; ITT, intent to treat; mGFR, measured glomerular filtration rate.Mjornstedt L, et al. Am J Transplant 2012;12:2744–2753.

An open-label, multicenter trial for de novo kidneytransplant recipients: CENTRAL study

ITT population Per patient population

46,2 47,8

51,2

47,8

0

10

20

30

40

50

60

EVR CsA

mG

FR

(mL/

min

)

4448,2

52,70

47,70

0

10

20

30

40

50

60

EVR CsA

mG

FR

(mL/

min

)

Control (baseline)EVR (baseline)

49

EVR (Month 12) Control (Month 12)

EVR has the potential to improve key long-term outcomes for kidney transplant patients

5

68

16

27

38

0

10

20

30

40

50

60

70

80

Gra

ft fa

ilure

, %

Acuterejection

CAN Hyperacuterejection

Vascular Technicalproblems

Glomerulo-nephritis

Non-compliance

Other

Causes of death with a functioning graft b

Malignancies


31%

37% 68%

Infections 18%

Social 6%

Miscellaneous 8%

50

EVR allows for CNI minimization2

EVR reduces LVMi3

EVR results in fewer malignancies vs. SoC4

CAN, chronic allograft nephropathy; CNI, Calcineurin inhibitor; CVD, cardiovascular disease; EVR, everolimus;IFTA, interstitial fibrosis and tubular atrophy; LVMi, left ventricular mass index; SoC, standard of care1. ANZDATA registry 2011 report. Available at: http://www.anzdata.org.au/anzdata/AnzdataReport/34thReport/2011c08_transplantation_v1.7.pdf. Accessed 21 March 2013; 2. Tedesco Silva H Jr, et al. Am J Transplant. 2010;10:1401–1413; 3. Paoletti E, et al. Transplantation. 2012;93:503–508; 4. Kauffman HM, et al. Transplantation. 2005; 80:883–889.

Causes of graft failure

De novo everolimus with CNI minimization resulted in reduced incidence of CMV and BKV

infections at Month 12 and 24

1-year

2-year

CMV infection 1,2

EVR 1.5 mg

0

2

4

8

6

1.1%

10

1.5%

MPA

8.4%

6.2%

% of patients

BKV infection 1,2

EVR 1.5 mg

0.7% 0.7%

MPA

4%

4.8%

0

2

4

8

6

10

% of patients

BKV, BK virus; CMV, cytomegalovirus; EVR, everolimus; MPA, mycophenolate acid.1. Tedesco Silva H et al. Am J Transplant. 2010;10:1401–13; 2. Cibrik D et al. Transplantation. 2013;95:933-942. 51

CMV infection is associated with reduced long -term survival in renal transplant patients

aHigh-risk group includes patients with nephrosclerosis, diabetic nephropathy and amyloidosis.CMV, cytomegalovirus.Sagedal S, et al. Clin Transplant 2007;21:309–313.

Prospective analysis of long-term survival of 471 k idney transplant recipients transplanted between 1994 and 1997

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0Probability of long-term patient survival

1000 2000 3000

Time posttransplant (days)

Low mortality risk, CMV–

Low mortality risk, CMV+

High mortality risk a, CMV–High mortality risk a, CMV+

0

52

CMV infection in renal transplant recipients is associated with impaired survival

2000 30001000

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Days posttransplantation

Long

-ter

m p

atie

nt s

urvi

val

Low-risk* group/CMV −

Low-risk* group/CMV +

High-risk† group/CMV −

High-risk† group/CMV +

Kaplan Meier analysis of overall recipient survivalbeyond 100 days posttransplantation

*Low risk of mortality: All other patients.†High risk of mortality: Transplanted patients with a kidney diagnosis of nephrosclerosis, diabetic nephropathy and amyloidosis.CMV, cytomegalovirus.Sagedal S, et al. Clin Transplant. 2007;21:309−313.

CMV infection during the first 100 days after kidney transplantation is associated with overall long-term mortality both in patients with a high or low risk of mortality

53

The risk of cancer is 3-fold higher in kidney transplant recipients than in general population

aNon-melanoma skin cancer, in situ lesions and lip cancer not includedANZDATA, Australia and New Zealand Dialysis and Transplant Registry data; CI, confidence interval; RTx, renal transplant; SRR, standard rate ratioWebster AC et al. Am J Transplant 2007;7:2140–51

200S

RR

120805030

1510

5

1

8075706560555045403530252015105Age at cancer diagnosis (years)

FemaleMale

95% CI95% CI

SRR 3.2 (2.94–3.45)SRR 2.6 (2.40–2.78)

ANZDATA (1980–2002)n=12,633; RTx, ≥1 cancer 10.5%

Cancer risk a in kidney transplant recipients versus the general population

54

A2309 (N=833)B201 (N=588)B251 (N=583)

Less CMV infections with everolimus than with MPA in KT: Pooled analysis of RCTs

100%

90%

80%

% o

f rec

ipie

nts

free

from

CM

V e

vent 95.5%

93.5%

85.2%

EVR 1.5 mg

EVR 3.0 mg

MPA

Time (days)

0 60 120 180 240 300 360 420 480 540 600 680 720 780

EVR 1.5 mg vs. MPA: P=0.0006

EVR 3.0 mg vs. MPA: P<0.0001

EVR, everolimus; MPA, mycophenolic acid; CMV, cytomegalovirus.Brennan DC, et al. Am J Transplant. 2011;11;2453–62. 55

Incidence of neoplasms (AE) 1,2

De novo everolimus with CNI minimization resulted in fewer neoplasms

AE, adverse event; CNI, calcineurin inhibitor; EVR, everolimus; KTx, kidney transplant; MPA, mycophenolate acid.1. Tedesco Silva H et al. Am J Transplant. 2010;10:1401–13; 2. Cibrik D et al. Transplantation. 2013;95:933-942.

1 year

2 years

EVR 1.5 mg

0

2

4

8

6

3.3% 3.3%2.9%

2.5%

5.9%

4.8%

EVR 3.0 mg MPA

% of patients

56

Group 1: CNI minimization (n=1,020)Low CNI + EVR (C0 3–8 ng/mL)

Group 2: Standard of care (n=1,020)Standard CNI + MPA

M60D1D0 M12

Main AnalysisGraft Outcome

M24

End of StudyGraft Outcome

Extension Study:

Malignancies, CV, LTGF

SCR Tx RDN‡

Induction

Opportunity for local & regional sub-studies

57

De novo EVR: TRANSFORM study designSimple trial design and clinically relevant

*Induction with basiliximab or ATG**Stratified randomization within 12 hours for CsA or tacrolimus and donor type (living donors, deceased standard criteria donors, and deceased expanded criteria donors).ATG, antithymocyte globulin; CNI, calcineurin Inhibitor; CV, cardiovascular; D, day; EVR, everolimus; LTGF, long-term graft function; MPA, mycophenolate acid; M, month; RDN, randomization; SCR, screening; Tx, transplantation.Pascual J, et al. Poster presented at: 16th Congress of the European Society of Organ Transplantation (ESOT); September 8−11, 2013; Vienna, Austria.

tBPAR or eGFR* < 50 mL/min/1.73 m 2 at M12

♦ Typical primary composite endpoint in transplantation registration trials includes death, graft loss, lost of follow up and tBPAR

♦ tBPAR is the largest contributor in the composite endpoint

♦ tBPAR is the only component that provides information about acute rejection relevant to require treatment

♦ Acute rejection (tBPAR) at 1-y has been associated with graft outcomes

♦ Best estimate of renal function beyond mGFR

♦ eGFR or renal function at 1-y post-transplant has been associated with graft survival, all-cause mortality and CV risk*

♦ eGFR<50 represents a moderate level of renal dysfunction expected to be sensitive to the effects of acute and chronic rejection and nephrotoxic effects of immunosuppressants

♦ eGFR<50 may represent a surrogate for long-term survival

tBPAR eGFR

An innovative and novel endpoint based on current recommendations and latest thinking

*(eGFR by MDRD4 formula) CV, cardiovascular; eGFR, estimated glomerular filtration rate; tBPAR, treated biopsy-proven acute rejection.Wu J, et al. Clin. Transplant. 2010;24:862–868; Kasiske B, et al. Am J Kidney Dis. 2011;57:466–475; Park WD, et al. Transplantation2012;94:931–939; Fellström B, et al. Am J Transplant. 2005;5:1986–1991; Weiner DE, et al. Am J Transplant, 2012;12:2437–2445;Moranne O, et al. Am J Transplant. 2013;13:695–706. 58

Two-step hypothesis for chronic AMR (1): A complement-dependent step

� The first step of the two-step hypothesis is largely similar to the hypothesis for the mechanism of acute AMR

2. C4 degrades to C4d, which binds and remains covalently attached to the endothelium

1. DSAs activate complement C1 complex and form complement activation products including C4

3. C3a and C5a act as potent chemotactic factors and promote proinflammatory cell infiltration

AMR, antibody-mediated rejection; DSA, donor-specific antibody; Ig, immunoglobulin; HLA, human leukocyte antigen.Figure adapted from Stegall MD, et al. Nat Rev Nephrol. 2012;8:670–678 and Colvin RB. J Am Soc Nephrol. 2007;18:1046–1056. 59

Two-step hypothesis for chronic AMR (2): A complement-independent step

� Progression to graft loss may be due to inflammatory cell infiltration and prothrombotic factor expression independent of continued complement activation

Maintenance of cellular injury leads to transplant

glomerulopathy subsequently resulting in graft loss

Persistent expression of prothrombotic factors

AMR, antibody-mediated rejection; NK, natural killer.Figure adapted from Stegall MD, et al. Nat Rev Nephrol. 2012;8:670–678 and Colvin RB. J Am Soc Nephrol. 2007;18:1046–1056.

Persistent infiltration of inflammatory cells

60

Primarily complement-independenthypothesis for chronic AMR

1. Intermittent or low-level activation of DSA

2. Complement activation leading to formation of C3a without C4d deposition

3. Chemotaxis of C3a causes infiltration of inflammatory cells

4. Development of transplant glomerulopathy subsequently leading to graft loss

AMR, antibody-mediated rejection; DSA, donor-specific antibody; HLA, human leukocyte antigen; NK, natural killer.Figure adapted from Stegall MD, et al. Nat Rev Nephrol. 2012;8:670–678. 61

Complement-independent hypothesis for chronic AMR

1. DSAs directly activate endothelial cells

2. Development of transplant glomerulopathy subsequently leading to graft loss

AMR, antibody-mediated rejection; DSA, donor-specific antibody; HLA, human leukocyte antigen; MAC, membrane attack complex.Figure adapted from Stegall MD, et al. Nat Rev Nephrol. 2012;8:670–678. 62

� DSA bind HLA- or other donor antigen on endothelial cell

� Monocytes adhere to endothelium and infiltrate tissue

� Activation of mTOR-pathway -> proteinsynthesis and proliferation ofendothelial and smooth muscle cells of vessels

� ⇒ subclinic vascular remodelling = antibody mediated accelerated arteriosclerosis

Complement-independent pathway of antibodymediated rejection (AMR)

Aus: “Blickpunkt Medizin, Klinik und Praxis; Donorspezifische Antikörper (DSA) bei Nierentransplantation”, Advisory Boards FFM/Berlin 2013; Thieme; Sonderpuplikation in der DMW, 2013


Single center experience from the ZEUS and HERAKLES study

Σ 126 patients[median 1059 d]

65 CSA [median 991 d] 61 RAD [median 551 d]

7 DSAs (10.8%) 14 DSAs (23,0%)


Never skip CNIs In frequent relapsing glomeruloneph ritis!

The rate in our center was max. 50%!

We never skip steroids in CNI withdrawal patients!



Effect on everolimus PK Effect on EC-MPS PK

CsAwithdrawal1

36% lower everolimusexposure

69% increase in MPA exposure

Tacrolimus withdrawal2

8% lower everolimus exposure

6% increase in MPA exposure only

Combination of EC -MPS and everolimus

1. Budde K et al. Transplantation. 2006;82(Suppl 3):999;2. Arns W et al. Transplantation. 2006;82(Suppl 3):488

Liefeldt L et al. Am J Transplant 2012;12:1192–8

CNI-elimination regimens

● Early CNI elimination* offers a long-term perspective on preserved renal function, but

– Is not suitable immediately post-transplantation

– Requires adequate dosing/TDM of the remaining drug

– Exclusion of subclinical inflammation requires protocol biopsies

– There is a risk of additional acute rejection episodes

● CNI-elimination regimens can be difficult to implement in the clinic

● Requiring additional safety and dose-finding visits

● May introduce additional/new drug-related adverse events

● Ongoing trials (MECANO, ELEVATE) will provide additional insights into the benefit/risk equation of early CNI elimination

*Everolimus is not approved for CNI elimination in kidney transplantationCNI, calcineurin inhibitor; TDM, therapeutic drug monitoring. 67

The challenge is to improve long -term outcomes

90,6 91,1 88,7

7771,3

62,556,5

45,7

33,7

0

10

20

30

40

50

60

70

80

90

100

Category 1 Category 2 Category 3

1-year5-year10-year

68CTS, Collaborative Transplant Study; UNOS, United Network for Organ Sharing.Gondos A, et al. Transplantation. 2013;95:267−274.

CTS Europe UNOS White American

UNOS African American

Period estimates of 1-, 5-, and 10-year graft survi val in recipients of deceased-donor transplants between 20 05−−−−2008

Gra

ft su

rviv

alra

tes,

%

CAN is characterized by a progressive decrease in GFR, generally associated with proteinuria and

arterial hypertension

Changes in SCr levels and proteinuria may not accura tely represent the underlying renal damage. Deterioration of renal function over time, determined

through slope analysis, is a more accurate indicato r of CRAI

Etiology Typical morphological changes

Nonimmune damage

Interstitial fibrosis and tubular atrophy due to CNI nephrotoxicity

Arteriolar hyalinosis with peripheral hyaline nodules and/or progressive increase in the absence of hypertension or diabetes. Tubular cellular damage with isometric vacuolization

Interstitial fibrosis and tubular atrophy due to arterial hypertension Fibrointimal enlargement with elastica reduplication, usually with hyaline arteriolar changes

Chronic urinary tract obstruction Marked tubular dilatation. Tamm–Horsfall protein casts with interstitial and/or lymphatic extravasation

Viral nephropathy (especially BK virus nephropathy)

Viral inclusions in histology and immunohistology and/or electronic microscopy, variable degrees of tubulointerstitial inflammation and chronic nephritis

Bacterial pyelonephritis Intratubular and peritubular neutrophils, with follicular lymphoid formation

Immune damage

Antibody-mediated chronic rejection C4d deposits in PTC, with combinations of PTC basal membrane multilayering, glomerular basal membrane duplication (transplant glomerulopathy) or fibrointimal arterial enlargement without internal elastica duplicationOther findings: inflammatory mononuclear cells in PTC, glomerulitis, interstitial plasmocytic infiltrate

T-cell mediated chronic rejection Arterial intimal fibrosis with mononuclear infiltration in fibrotic areas with neointima formation

Causes of chronic allograft injury and morphologica l correlation

CAN, chronic allograft nephropathy; CNI, calcineurin inhibitor; CRAI, chronic renal allograft injury; GFR, glomerular filtration rate; PTC, peritubular capillaries; SCr, serum creatinine.Pascual J, et al. Transplant Rev (Orlando). 2012;26:280–90. 69

Sur

vivi

ng g

raft

Low eGFR one year after transplantation is predictive of graft failure in subsequent years

Graft survival trends from 1 year after transplanta tion for patients with different levels of eGFR by MDRD (n=896)*

*US data.eGFR, estimated glomerular filtration rate; MDRD, modified diet in renal disease.Park WD, et al. Transplantation. 2012;94:931–39.

Sur

vivi

ng g

raft

1

0.91.0

0.80.70.60.5

0.30.20.10.0

0.4

5 6 7 9842 3 10

Follow-up, years

<40 mL/min

≥≥≥≥40 mL/min

P<0.0001

0.91.0

0.80.7

0.6

0.50.4

0.30.2

0.10.0

Follow-up, years

1 5 6 7 9 10842 3

>60 mL/min50−−−−59 mL/min40−−−−49 mL/min

<40 mL/min

Patients with eGFR <40 mL/min 1 year after transplant have significantly lower graft survival (P<0.001)

70

Early renal function is a strong predictor of 5-year graft failure

Adjusted hazard ratio of 5-year all-cause graft fai lureby 1-year eGFR (mL/min/1.73 m 2)

0

4

8

16

12

<15 15–29 30–44 45–59 90+60–89

Haz

ard

ratio

for

graf

t fai

lure

eGFR (mL/min/1.73m 2) at 1-year post transplant

Kidney-only transplant recipients, aged >18 years. eGFR, estimated glomerular filtration rate (using the Modification of Diet in Renal Disease equation).United States Renal Data System Annual Report 2010, vol. 2, ch. 7, http://www.usrds.org/atlas.aspx 71

1-year eGFR predicts early graft failure

Graft survival trends from 1 year after transplanta tion for patients with different levels of eGFR by MDRD (N=896)

Sur

vivi

ng g

raft

1

0.91.0

0.80.70.60.5

0.30.20.10.0

0.4

5 6 7 9842 3 10

Follow-up (Years)

<40 mL/min

>40 mL/min

P<0.0001

0.91.0

0.80.70.60.50.4

0.30.2

0.10.0

Sur

vivi

ng g

raft

Follow-up (Years)

1 5 6 7 9 10842 3

>60 mL/min50−−−−59 mL/min40−−−−49 mL/min

<40 mL/min

Patients with eGFR <40 mL/min experienced significa ntly poorer graft survival

Park WD, et al. Transplantation. 2012;94:931–39 72



Conversion to an Everolimus-based CNI-free immunosuppressive regimen has beenassociated with significantly better renal function maintained for 5 years1 as well asbetter outcome on de novo malignancies and BKV viremia2.

However, it is still under debate whether Everolimus and CNI have different impact on DSA development.

Kamar et al3 performed a retrospective case-control study to compare the incidenceof de novo DSAs in patients after conversion to an Everolimus-based, CNI-freeimmunosuppressive regimen (n=61) with (age, gender, induction therapy, date of Tx-) matched control group on standard CNI therapy (n=61).

Methods:

� Stepwise conversion to Everolimus, median time after Tx= 22 (0.5-224) months

� Conversion for reasons of: IFTA or CNI-nephrotoxicity (n=26), participation in a clinical trial (n=26), BK-virus nephropathy (n=3)

� Biopsie proven that no features of cellular or humoral rejection had occurred

� HLA-antibody screening (Luminex) negative before conversion

1 Budde et al, ATC 2013; 2 Moscarelli et al., Clin Transplant. 2013 Jul;27(4):546-54. 3Kamar et al., Clin.Transplant 2013: 27: 455-462

74

Results:

No difference in incidence of DSAs or anti-HLA antibodies between both groups. Onlythe rate of increase in DSA within the everolimus group from 0% at baseline to 9.8% at last follow-up was significant but not within control group with 5% at last follow-up. However, no difference of any parameter was found between boths groups.

Tab from Kamar et al., Clin.Transplant 2013 27:455-462



75

Results:

No difference in incidence of DSAs or anti-HLA antibodies between both groups. Onlythe rate of increase in DSA within the everolimus group from 0% at baseline to 9.8% at last follow-up was significant but not within control group with 5% at last follow-up. However, no difference of any parameter was found between boths groups.




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Conclusion from this retrospective case-control study:

� Both groups showed incidence of de novo DSAs at last follow-up (FU)

� The incidence of DSAs was similar between both groups at last FU

� The increased incidence of DSAs between baseline and last FU was significantwithin the everolimus group (from 0% to 9.8%) but not within control group (0% to5%). No significant inter-group difference.

� The incidence of AMR tended to be higher in the everolimus group.

� Low number of events makes interpretation difficult

� Multivariate modeling for factors associated with DSA occurence did not identifyeverolimus regimen as risk factor for DSAs.

� Only younger recipient age was identified as factor associated with de novo DSA development.

=> Younger recipient age is well known risk factor for non-compliance.




CAN, CVD and malignancy are the leading causes of graft failure and death with a functioning graft

aData from 2007–2011; n=1071 patients in Australia; bData from 2007–2011; n=852 patients in Australia.CAN, chronic allograft nephropathy; CVD, cardiovascular disease; IFTA, interstitial fibrosis and tubular atrophy.ANZDATA registry 2012 report. Available at: http://www.anzdata.org.au/anzdata/AnzdataReport/35thReport/2012c08_transplants_v1.pdf. Accessed 22 July 2013.

Other, 9%

Glomerulonephritis, 6%

Vascular, 5%

Acute rejection, 5%

Noncompliance, 4%

Technical problems, 1%

CAN, 69%

Causes of kidney graft failure a

65%


34%


Social, 7%

Causes of death with functioning graft b

ANZDATA registry data 2007 −−−−20111

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Striking a balance between EVR exposure, tBPAR , and eGFR

CsA, cyclosporine; eGFR, estimated glomerular filtration rate; EVR, everolimus; tBPAR, treated biopsy-proven acute rejection.Shihab FS, et al. Clin Transplant. 2013;27:217−226.

Estimated probability of tBPAR at Month 1 from Cox proportional hazards model based on data to Day 45 in A2309 study

Probability of tBPAR Mean change in eGFR

*Time normalized

78

56,2

8,3

13,6

3,94,3

5,0

6,3

3,5 3,7 4,0 4,5

0

2

4

6

8

10

12

14

16

200 ng/ml 150 ng/ml 100 ng/ml 50 ng/ml

Est

imat

ed p

roba

bilit

y of

trea

ted

BP

AR

, %

14,38

11,46

7,34

0,3

9,71

7,76

5,01

0,32

7,77

6,22

4,05

0,330

2

4

6

8

10

12

14

16

200 ng/ml 150 ng/ml 100 ng/ml 50 ng/ml

Neg

ativ

e ch

ange

in e

GF

R fr

om

Mon

th 1

to M

onth

12,

m

L/m

in/1

.73

m2

Time normalized CsA trough concentration to day 45

Everolimus 6 ng/mL Everolimus 8 ng/mLEverolimus 3 ng/mL

Time-normalized CsA trough concentration to Day 45 Tim e-normalized CsA trough concentration (12-months on-treatment)

EVR plus reduced CsA is associated with LVH regression in renal transplant recipients

1-year follow-upBaseline

60

55

50

45

40

35

Mea

n le

ft ve

ntric

ular

mas

s in

dex,

g/m

2

*Randomized controlled single-center trial in kidney transplant patients.CsA, cyclosporine; EVR, everolimus; LVH, left ventricular hypertrophy.1. Rigatto C, et al. J Am Soc Nephrol 2003; 14:462–468; 2. Paoletti E, et al. Transplantation. 2012;93:503–508.

Left ventricular hypertrophy 1 year after kidney tr ansplantation is associated with reduced long-term survival and increased risk of de novo heart failure 1

LVMi was significantly lower in the EVR plus low CsA group than in controls*2

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Standard CsA

EVR plus low CsA vs baseline P=0.0016

The risk of cancer is 3-fold higher in kidney transplant recipients than in general population

CI, confidence interval; RTx, renal transplant; SRR, standard rate ratio.Webster AC, et al. Am J Transplant. 2007;7:2140–2151.

200S

RR

120805030

1510

5

1

8075706560555045403530252015105Age at cancer diagnosis, years

FemaleMale

95% CI95% CI

SRR 3.2 (2.94–3.45)SRR 2.6 (2.40–2.78)

ANZDATA (1980–2002)n=12,633; RTx, ≥1 cancer 10.5%

Cancer risk a in kidney transplant recipients versus the general population

aNon-melanoma skin cancer, in situ lesions and lip cancer not included.

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In the presence of mTOR inhibitors, the TORC1 dependant stages of viral replication are blocked

81

CMV, cytomegalovirus; mTOR, mammalian target of rapamycin; TORC, target of rapamycin complex.Clippinger AJ, et al. J Virol. 2011;85:3930–3939; Brennan DC, et al. Rev Med Virol. 2013;23:97–125;Nashan B, et al. Transplantation. 2012;93:1075–1085.

Nucleus

Replication ReplicationmTORi

1. Normal viralreplication

Early viral protein synthesis:mTORC1 - independent

Early viral protein synthesis:mTORC1 - independent

Early viral protein synthesis: IE-1

Late viral protein synthesis: pUL-44, pp65

Cell membrane

Human myeloid cell

Late viral protein synthesis:mTORC1 - dependent

Late viral protein synthesis:mTORC1 - dependent

2. In the presence of mTORimTORC1-dependent stages are blocked, reducing viral replication

Recent studies conclude that while CMV protein synthesis is reliant on mTOR kinase during early

infection, CMV replication appears to be mTOR kinase independent in later stages

Chronic viral (opportunistic) infection associated malignancies have the most increased incidence

Brain

-1

Can

cer s

ite /

type

1 10 100 1000

Standardized incidence ratio

ProstateBreastOvaryTestis

Colon and rectumTrachea, bronchus and lung

MelanomaLeukaemia

BladderMultiple myeloma

ThyroidKidneyLarynx

EsophagusEye

Non-melanoma skin Lip

Cervix uteriOral cavity and pharynx

AnusPenis

Vulva and vaginaStomach

LiverHodgkin’s lymphoma

Non-Hodgkin’s lymphomaKaposi’s sarcoma HHV8

EBV

HBV / HCVHelicobacter pylori

HPV

PossibleHPV

EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV8, human herpesvirus 8; HPV, human papilloma virus.Vajdic CM et al. Int J Cancer 2009;125:1747–1754. 82

Practical challenges associated with CNI elimination regimens

CNI, calcineurin inhibitor. 83

ChallengesChallenges

Treatment regimen change

in stable transplant recipients

Treatment regimen change

in stable transplant recipients

Period with more frequent monitoring for acute rejection required

Period with more frequent monitoring for acute rejection required

Risk of introducing additional/new adverse

events

Risk of introducing additional/new adverse

events

Additional hospital

visits

Additional hospital

visits

1 2013-11-23 Halle CNI free - Nierentransplantation

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