Risk Factors in Long Term Immunosuppressive Use and Advagraf. Daniel Serón Nephrology department Hospital Universitari Vall d Hebron

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1 Risk Factors in Long Term Immunosuppressive Use and Advagraf Daniel Serón Nephrology department Hospital Universitari Vall d Hebron

2 Progressive well defined diseases ABMR GN Polyoma Non-specific Findings Fibrosis Inflammation Non-specific Findings Fibrosis Inflammation 1 st year > 1 year

3 Time dependency of histological diagnosis Sellares J et al. Am J Transplant 2012; 12: 388

4 ABMR is the main cause of graft failure Late Early Before 6 m After 6m Torres IB et al. Unpubliished observation

5 Inflammation a driving force for fibrosis Prevention of early inflammation and progression of fibrosis Providing an adequate immunosuppression

6 Inflammation a driving force for fibrosis Prevention of early inflammation and progression of fibrosis Providing an adequate immunosuppression

7 Temporal evolution of histologic lesions 120 patients with DM1, receiving a kidney-pancreas transplant, 961 biopsies Subclinical inflammation IF/TA Glomerulosclerosis Nankivell B et al N Engl J Med 2003; 349: 2236

8 Fibrosis is measured with an ordinal scale 100% 50% 3 25% 10% 0% 2 1 0

9 Inflammation and progression of IF/TA in paired biopsies n=598 Bx, (no SCR 462, SCRB 102, SCRA 34) * p<0.05 ***p<0.001 Nankivell BJ et al, Transplantation 2004; 78:242

10 Classification of inflammation and fibrosis Normal (no inflammation no fibrosis) Inflammation (no fibrosis) Fibrosis (no inflammation) Inflammation and fibrosis

11 i-if/ta Surveillance biopsies < 6 m 1.75 Normal=186 i=74 IF/TA=110.5 i=if/ta= months Shishido et al, JASN 2003; 14: 1046 Cosio FG et al, Am J Transplant 2005; 5: 2464, Moreso F et al Am J Transplant 2006; 6:747 Gago M et al. Am J Transplant 2012; 12: 1199

12 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 IF/TA 2 IF/TA i-if/ta i-if/ta Heilman RL et al. Am J Transplant 2010; 10: 563

13 Inflammation IF/TA and i-if/ta at 1year IF/TA Inflammation i-if/ta

14 Moreso F et al. Transplantation 2012; 93: 41 Inflammation at 4 m and risk of late AMR Surveillance Bx n = 517 7y Late AMR 44 IF/TA nos 42 Recurrence 11 De novo GN 7 Acute rejection 4 Polyoma 1 Acute score (p=0.003) Indication Bx n = 109

15 CHR, IF/TA and outcome Moreso F et al. Transplantation 2012; 93: 41

16 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 0,7 0,6 0,5 0,4 0,3 i ptc 0,2 0,1 0 DSA No DSA Wiebe C et al. Am J Transplant 2012; 12: 1157

17 Graft survival and DSA Wiebe C et al. Am J Transplant 2012; 12: 1157

18 AR during 1st year in DSA neg pts and 1y % normal histology at 1 y protocol Bx n=797 pts ( ), DSA pre Tx neg % class II DSA at 1 y El Ters M et al. Am J Transplant 2013: 13: 2334

19 IF/TA Inflammation i-if/ta CHR+IF/TA

20 What does early inflammation mean? a.) Injury repair innate immunity a.) Alloimmune response aquired immune response against donor antigens

21 Anti-donor cellular reactivity & subclinical inflammation Bestard O et al. Kidney Int 2013; 84: 1126 N=60 pts Elispot and protocol biopsy at 6 months (SRL 22 and TAC 38)

22 Injury/repair after kidney transplantation Tissue Damage Complement Apoptosis Necrosis Inflammation MBL

23 Failure to repair injury and inflammation: Mannose binding lectin Ibernon M et al. Transpl Immunol 2014; 31: 152

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

25 Ibernon M et al. Transpl Immunol 2014; 31: 152 Low MBL and increased inflammation and apoptosis Apoptotic cells Inflammation 3,5 3 p= ,5 2 1,5 1 v t i g 0,5 0 MBL T1 MBL T2+T3

26 Alloimmunity IF/TA Inflammation i-if/ta Injury/repair CHR

27 Inflammation a driving force for fibrosis Prevention of early inflammation and progression of fibrosis Providing an adequate immunosuppression

28 Treatment of SCR with steroid boluses (n=72; 36 pts per group) CsA+AZA+PN Inflammation > 50 (%) Biopsy group Randomization Control group Biopsy group Control group chronic score at 6m ns ci + ct score at 6m Rush D et al, J Am Soc Nephrol 1998; 9: 2129

29 Treatment of SCR in p<tients treated with TAC+MMF+P Prospective, multicentric study (12 centres) Randomization Biopsy group Control group Protocol Bx (n=121) Control (n=119) 6m IF/TA>2 (%) m IF/TA>2 (%) m CrCl (ml/min) Rush D et al Am J T ransplant2007; 7: 2538

30 TAC vs CsA: a case control study all treated with MMF and P n=98 borderline AR I AR II Moreso F et al Transplantation 2004; 78: 1064

31 Serón D et al. Transplantation 2007;83: Tac versus CsA: 4m immunophenotype Tacrolimus (n=44) vs ciclosporina (n=22) p<0.01 p<0.01 ns p<0.05

32 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 = P=0.122 P=0.020 P=0.004 Torres IB unpublished observation

33 CNI+MMF vs CNI +SRL Prospective randomized study (jun 2000-oct 2004) Basiliximab + stop steroids at 2 days Lesión CsA + MMF 50 CSA + SRL 50 TAC + MMF 50 TAC + SRL 50 BPAR % (1a) SCR% (1a) IF/TA % (5a) Kumar A et al. Transpl Immunol 2008; 20:32

34 CNI +MMF vs CNI +EVR 6 m protocol Bx historical cohort (N=51), experimental cohort (N=28) SCR ml/min/1.73m CNI + MMF CNI + EVR IF/TA CNI + MMF CNI + EVR egfr 0 CNI + MMF CNI + EVR Kanzelmeyer NK et al. Clin Transplant 2013; 27:319

35 Serón D et al. Kidney Int 2002;61:727 CsA minimisation & progression of IF/TA N=155 patients & 310 biopsies 0 4m 1y No progression (n=104) Progression (n=51) Donor age (years) 35 ± ± 15 NS DGF (%) NS AR (%) NS Mean CsA levels (1 st biopsy) Mean CsA levels (2 nd biopsy) NS 165 ± ± P

36 Tac Exposure and Evolution of Histology in the First Year After Transplantation (n=61 pairs of biopsies) Naesens M et al. AJT 2007;7:

37 Cumulative survival Tacrolimus minimisation and withdrawal after 1 year is associated with poor graft survival Kidney graft survival (serum creatinine <260µmol/L); both comparisons Years post-transplantation Tacrolimus: Continuation (n=1,736) Dose reduction (n=352) Withdrawal (n=296) Opelz G et al. Transplantation 2008;86:371

38 Inflammation and CNI free regimens 1y subclinical inflammation:concept trial n=121 pts CsA+MMF+P: continuation vs conversion to SRL at 3 m SRL CsA p N SCI (%) <0.01 Thierry A et al. AJT 2011; 11: 2153

39 Cumulative incidence of DSA Cumulative incidence of AbMR Liefeldt L et al. Am J Transplant 2012;12: CNI-free regimens are associated with an increased risk of DSA and antibodymediated rejection n=127 patients (Zeus and Crad001); CsA (n=66), everolimus (n=61) EVR CsA EVR CsA Time after transplantation (months) Time after transplantation (months)

40 Inflammation a driving force for fibrosis Prevention of early inflammation and progression of fibrosis Providing an adequate immunosuppression

41

42 Adherence in children and graft survival > 6m Medicacation possesion ratio Tx CNI based IS 4009 Graft survival > 6m 3908 Upper quartile 36 m follow up quartiles 36m claims database 877 Crisholm-Burns MA et al. Am J Transplant 2009; 9: 2497

43 Cause of graft failure and non adherence Sellares J et al. Am J Transplant 2012; 12:

44 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

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

46 Evaluation of non adherence

47 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?

48 Factors associated with non-adherence N=312 pts: Morisky scale > m 6m 12m 24m % NA Couzi et al et al. Transplantation 2013; 95: 326

49 Non adherence 18 y 73 %males 87 % cadaveric 87 % first Tx N=63% SMAQ 27 % BAASIS 30.2 %

50 Prospective randomized study: adherence contract vs conventional follow up Adherence (pharmacy refill records) Probability (%) NOT to be hospitalized Chisholm-Burns MA et al. Am J Transplant 2013; 13: 2364.

51 High variability in tacrolimus exposure is associated with increased incidence of rejection CV% of tacrolimus levels 100 CV% >41% OR=9.7, P= No rejection (n=36) Rejection (n=10) Hsiau M et al. Transplantation2011;92:918

52 Varaibility of TAC and outcome outcome variable: late AR, TG, graft loss Sapir-Pichhadze T et al. Kidney Int 2013; 85: 1404

53 Variability of TAC levels and inflammation Variable Tac CV (<26,7) n = Tac CV (26,7-43,8) n = Tac CV >43,8 n=28 p-value E GFR 57± 16 57± 13 53±17 ns g-score 0.06± ± ±0.33 ns i-score 0.17 ± ± ± Total i score 0.22± ± ± CD ± ±8 25± IB Torres et al Manuscript in preparation

54 Factors associated with non-adherence Socio-economic factors financial difficulties / lack of transportation Health organization barriers limited amount of time/patient, staff rotation Disease related factors depression and anxiety Therapy related factors side effects of drugs, complex dose regimens Patient related factors communication barriers, healt attitudes health beliefs and literacy Moreso F et al. (in press)

55 Improvements in correct dosing after conversion from TAC to ADV (n=219 pts) p= Kuypers et al. Transplantation 2013; 95: 333

56 Non adherence is more commonin the evening dose Kuypers et al. Transplantation 2013; 95: 333

57 Conversion from TAC to ADV n=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

58 Var AUC 0-24 after conversion from TAC BID to TAC QD AUC 5 times before and 5 times after conversion (n=40) P =0.012 TAC ADV Var coeficient %14,1 Stifft F et al. Transplantation 2014;97: 775

59 Summary + inflammation Treatment + IF-TA i-ifta Chronic humoral rejection

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

61 61