Risk Factors in Long Term Immunosuppressive Use

and Advagraf

Daniel Serón

Nephrology department

Hospital Universitari Vall d’Hebron

Progressivewell defineddiseases

ABMRGN Polyoma

Non-specificFindings

FibrosisInflammation

Non-specificFindings

FibrosisInflammation

1st year > 1 year

Time dependency of histological diagnosis

Sellares J et al. Am J Transplant 2012; 12: 388

ABMR is the main cause of graft failure

Early

Late

0

10

20

30

40

50

60

70

Torres IB et al. Unpubliished observation

Before 6 mAfter 6m

Inflammation a driving force for fibrosis

Prevention of early inflammation and progression of fibrosis

Providing an adequate immunosuppression

Inflammation a driving force for fibrosis

Prevention of early inflammation and progression of fibrosis

Providing an adequate immunosuppression

Temporal evolution of histologic lesions120 patients with DM1, receiving a kidney-pancreas transplant, 961 biopsies

Nankivell B et al N Engl J Med 2003; 349: 2236

Glomerulosclerosis

Subclinical inflammation

IF/TA

Fibrosis is measured with an ordinal scale

10%

25%

50%

100%

0%

3

2

1

0

Inflammation and progression of IF/TA in paired biopsies

n=598 Bx, (no SCR 462, SCRB 102, SCRA 34)

Nankivell BJ et al, Transplantation 2004; 78:242

* p<0.05***p<0.001

Classification of inflammation and fibrosis

Normal (no inflammation no fibrosis)

Inflammation and fibrosis

Inflammation (no fibrosis)

Fibrosis (no inflammation)

i-IF/TA

Shishido et al, JASN 2003; 14: 1046Cosio FG et al, Am J Transplant 2005; 5: 2464, Moreso F et al Am J Transplant 2006; 6:747Gago M et al. Am J Transplant 2012; 12: 1199

.25

.5

.75

1

0 50 100 150 200 months

Normal=186i=74

IF/TA=110

i=IF/TA=65

Surveillance biopsies < 6 m

Inflammation at 1m/4m and IF/TA and i-IF/TA at 1 y Induction + TAC+MMF+P (500, 250,125,60,30)

No inflammation 172, Borderline 50, acute rejection 19

0

10

20

30

40

50

60

i-IF/TA

i-IF/TA0

10

20

30

40

50

60

IF/TA ≥ 2

IF/TA ≥ 2

Heilman RL et al. Am J Transplant 2010; 10: 563

Inflammation IF/TA and i-IF/TA at 1year

Inflammation

IF/TA

i-IF/TA

(p=0.003)

Acute score

Inflammation at 4 m and risk of late AMR 1988-2006

Moreso F et al. Transplantation 2012; 93: 41

Late AMR 44IF/TA nos 42Recurrence 11De novo GN 7Acute rejection 4Polyoma 1

SurveillanceBxn = 517

IndicationBxn = 109

7y

CHR, IF/TA and outcome

Moreso F et al. Transplantation 2012; 93: 41

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

DSA No DSA

i

ptc

Wiebe C et al. Am J Transplant 2012; 12: 1157

Surveillance Bx at 6m, de novo DSA and late AMR n=315 (DSA=47, no DSA=268)Time of DSA detection 4.6±3.0

Wiebe C et al. Am J Transplant 2012; 12: 1157

Graft survival and DSA

AR during 1st year in DSA neg pts and 1y protocol Bx

n=797 pts (1998-2010), DSA pre Tx neg

El Ters M et al. Am J Transplant 2013: 13: 2334

% normal histology at 1 y

% class II DSA at 1 y

Inflammation

IF/TA

i-IF/TA

CHR+IF/TA

What does early inflammation mean?

a.) Injury repairinnate immunity

a.) Alloimmune responseaquired immune response againstdonor antigens

N=60 pts Elispot and protocol biopsy at 6 months (SRL 22 and TAC 38)

Anti-donor cellular reactivity & subclinicalinflammation

Bestard O et al. Kidney Int 2013; 84: 1126

Injury/repair after kidney transplantation

TissueDamage

Inflammation

ApoptosisNecrosis

MBL

Complement

Failure to repair injury and inflammation:Mannose binding lectin

Ibernon M et al. Transpl Immunol 2014; 31: 152

• Ibernon M et al. Transpl Immunol 2014; 31: 152

p=0.044

0

0,5

1

1,5

2

2,5

3

3,5

MBL T1 MBL T2+T3

v

t

i

g

InflammationApoptotic cells

Ibernon M et al. Transpl Immunol 2014; 31: 152

Low MBL and increased inflammation and apoptosis

Inflammation

IF/TA

i-IF/TA

CHR

Alloimmunity

Injury/repair

Inflammation a driving force for fibrosis

Prevention of early inflammation and progression of fibrosis

Providing an adequate immunosuppression

Treatment of SCR with steroid boluses(n=72; 36 pts per group)

CsA+AZA+PN

1 2 3 6 12

Biopsy group

Control group

Randomization

Biopsy group Control group_______________________________________________________________chronic score at 6m 0.50 0.13 1.02 0.31 nsci + ct score at 6m 0.21 0.09 0.62 0.18 0.05_______________________________________________________________

Rush D et al, J Am Soc Nephrol 1998; 9: 2129

Inflammation > 50 (%)

Treatment of SCR in p<tients treatedwith TAC+MMF+PProspective, multicentric study (12 centres)

Protocol Bx Control(n=121) (n=119)

____________________________________________6m IF/TA>2 (%) 35 2024m IF/TA>2 (%) 48 3924 m CrCl (ml/min) 7627 72 18_____________________________________________

1 2 3 6 24

Biopsy group

Control group

Randomization

Rush D et al Am J T ransplant2007; 7: 2538

5 7 0 9 0

6 2

TAC vs CsA: a case control studyall treated with MMF and P

n=98

Moreso F et al Transplantation 2004; 78: 1064

borderline

AR I

AR II

Tac versus CsA: 4m immunophenotype

Serón D et al. Transplantation 2007;83:649–652

p<0.01

p<0.01 p<0.05ns

Tacrolimus (n=44) vs ciclosporina (n=22)

NUMBER OF INTERSTITIAL INFILTRATING CELLS ACCORDING TO TACROLIMUS TROUGH LEVELS AT BIOPSY

(median TAC levels at Bx = 9.3 ng/mL) n=90 pts

P=0.122

P=0.020

P=0.004

P = 0.0031

Torres IB. 2015 unpublished observation

CNI+MMF vs CNI +SRLProspective randomized study (jun 2000-oct 2004)

Basiliximab + stop steroids at 2 days

Kumar A et al. Transpl Immunol 2008; 20:32

Lesión CsA + MMF

50

CSA + SRL

50

TAC + MMF

50

TAC + SRL

50

BPAR % (1a) 18 8 14 4

SCR% (1a) 22 8 16 6

IF/TA % (5a) 54 16 38 14

CNI +MMF vs CNI +EVR6 m protocol Bx

historical cohort 2002-2006 (N=51), experimental cohort 2006-2009 (N=28)

0

5

10

15

20

25

CNI +MMF

CNI +EVR

SCR

0

10

20

30

40

50

CNI +MMF

CNI +EVR

IF/TA

Kanzelmeyer NK et al. Clin Transplant 2013; 27:319

54

56

58

60

62

64

66

68

70

CNI + MMF CNI + EVR

eGFR

ml/min/1.73m2

CsA minimisation & progression of IF/TAN=155 patients & 310 biopsies

Serón D et al. Kidney Int 2002;61:727

0 4m 1y

No progression

(n=104)

Progression

(n=51)

P

Donor age (years) 35 ± 18 37 ± 15 NS

DGF (%) 19 16 NS

AR (%) 21 20 NS

Mean CsA levels (1st

biopsy)

218 72 217 74 NS

Mean CsA levels (2nd

biopsy)

165 ± 50 149 ± 41 0.04

Tac Exposure and Evolution of Histology in the First Year After Transplantation

(n=61 pairs of biopsies)

Naesens M et al. AJT 2007;7:2114–2123

Tacrolimus minimisation and withdrawal after 1 year

is associated with poor graft survival

Withdrawal (n=296)

Continuation (n=1,736)Dose reduction (n=352)

Tacrolimus:

Kidney graft survival (serum creatinine <260µmol/L); both comparisons

Cu

mu

lati

ve s

urv

ival

0 1 5 7

0

100

65

80

85

90

32 4 6

70

75

95

Years post-transplantation

Opelz G et al. Transplantation 2008;86:371

Thierry A et al. AJT 2011; 11: 2153

Inflammation and CNI free regimens1y subclinical inflammation:CONCEPT trial

n=121 pts CsA+MMF+P: continuation vs conversion to SRL at 3 m

SRL CsA p

N 61 60

______________________________

SCI (%) 45.2 15.3 <0.01

______________________________

CNI-free regimens are associated with an increased risk of DSA and antibody-

mediated rejectionn=127 patients (Zeus and Crad001); CsA (n=66),

everolimus (n=61)

Cum

ula

tive

incid

en

ce o

f D

SA

Cum

ula

tive

incid

en

ce o

f A

bM

R

Time after transplantation

(months)

Time after transplantation

(months)

Liefeldt L et al. Am J Transplant 2012;12:1192–1198.

EVR

CsA

EVR

CsA

Inflammation a driving force for fibrosis

Prevention of early inflammation and progression of fibrosis

Providing an adequate immunosuppression

Adherence in children and graft survival > 6m Medicacation possesion ratio

Tx 1995-2000 4080

CNI based IS 4009

Graft survival > 6m 3908

36 m follow up 3856

36m claims database 877

Crisholm-Burns MA et al. Am J Transplant 2009; 9: 2497

Upper quartile

1-3 quartiles

Cause of graft failure and non adherence

Sellares J et al. Am J Transplant 2012; 12: 388-399.

Non-adherence is associated with poor graft survival in kidney transplantation

Kaplan-Meier graft survival. The non-adherent group consisted of 19 patients (3 graft failures) and the adherent group consisted of 94 patients (2 graft failures)

Tielen M et al. Am J Transplant 2014;Article 675301.

∕∕

Non adherence

Fine et al. Am J Transplant 2009; 9: 35

Evaluation of non adherence

Morisky scale yes (0) and no (1)

MMAS-4

Do you ever forget to take your medicine?

Are you careless at times about taking your medicine?

Sometimes when you feel worse when you take the medicine, do you stop taking it?

When you feel better do you sometimes stop taking your medicine?

Couzi et al et al. Transplantation 2013; 95: 326

Factors associated with non-adherenceN=312 pts: Morisky scale > 0

0

5

10

15

20

25

30

35

40

3m 6m 12m 24m

% NA

Non adherence18 y73 %males87 % cadaveric87 % first TxN=63%

SMAQ 27 %

BAASIS 30.2 %

Prospective randomized study: adherence contract vs conventional follow up

Chisholm-Burns MA et al. Am J Transplant 2013; 13: 2364.

Adherence (pharmacy refill records) Probability (%) NOT to be hospitalized

High variability in tacrolimus exposure is associated with increased incidence of rejection

100

80

60

40

20

0

No rejection

(n=36)

CV

% o

f ta

cro

lim

us l

evels

Rejection (n=10)

CV% >41%

OR=9.7, P=0.005

Hsiau M et al. Transplantation2011;92:918

Varaibility of TAC and outcomeoutcome variable: late AR, TG, graft loss

Sapir-Pichhadze T et al. Kidney Int 2013; 85: 1404

Variability of TAC levels and inflammation

Variable Tac CV (<26,7) n =

28

Tac CV (26,7-43,8) n =

29

Tac CV >43,8 n=28 p-value

E GFR 57± 16 57± 13 53±17 ns

g-score 0.06± 0.24 0.11 ± 0.32 0.13±0.33 ns

i-score 0.17 ± 0.4 0.28± 0.5 0.57±0.6 0.0161

Total i score 0.22±0.5 0.36±0.7 0.7±0.8 0.0027

CD45 17.2±22 11.9±8 25±18 0.034

IB Torres et al Manuscript in preparation

Moreso F et al. (in press)

Factors associated with non-adherence

Socio-economic factorsfinancial difficulties / lack of transportation

Health organization barriers limited amount of time/patient, staff rotation

Disease related factorsdepression and anxiety

Therapy related factors side effects of drugs, complex dose regimens

Patient related factorscommunication barriers, healt attitudeshealth beliefs and literacy

Improvements in correct dosing after

conversion from TAC to ADV (n=219 pts)

Kuypers et al. Transplantation 2013; 95: 333

p= 0.0009

Non adherence is more commonin the evening dose

Kuypers et al. Transplantation 2013; 95: 333

Conversion from TAC to ADVn=1832 pts

Conv 1:1 and 1 to 1.1 in pts with through levels < 6 ng(ml

Guirado L et al. Am J Transplant 2011; 11: 1965

Var AUC 0-24 after conversion from TAC BID toTAC QD

AUC 5 times before and 5 times after conversion (n=40)

0

2

4

6

8

10

12

14

16

Var coeficient %14,1

TAC

ADV

P =0.012

Stifft F et al. Transplantation 2014;97: 775

Treatment

inflammation

+

IF-TA

i-IFTA

Chronic humoral rejection

Summary

+

Under-immunosuppression as a cause of chronic rejection and graft loss

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