sample

European Society of Organ

Transplantation (ESOT) Congress 2017

Our abstracts : part 2


Tuesday September 26, 2017


15/ COMPLEMENT-ACTIVATING ANTI-HLA ANTIBODIES: IDENTIFICATION OF SPECIFIC HISTO-MOLECULAR PHENOTYPE OF REJECTION FOR COMPLEMENT-TARGETING THERAPY

Session : « ABMR : from diagnosis to treatment » (11:10 to 12:40) 

Location : Room 123 – 11:31 

C Lefaucheur, B Sis, D Viglietti, O Aubert, D Glotz, C Legendre, A Zeevi, P Halloran, A Loupy

Background: 

We investigated whether circulating complement-binding donor-specific anti-HLA antibodies (DSA) induce specific rejection phenotype and influence response to complement-targeting treatment.

Methods: 

We prospectively enrolled 931 kidney recipients transplanted between 2011 and 2014, with systematic screening for circulating DSA in the first year post-transplantation. All patients underwent allograft biopsy at the time post-transplant DSA detection. The allograft rejection phenotypes were assessed by histopathology, immunochemistry and allograft gene expression (microarray). A model of fully MHC-mismatched male CBA (H-2k) kidneys transplanted into B6.RAG1-/- (H-2b) immunodeficient mice with adoptive transfer of complement and non-complement-activating DSA was studied. The effect of complement inhibition therapy (Eculizumab) on allograft injury phenotype was assessed in two prospective studies (N=116).

Results: 

The histo-molecular phenotype of C1q-binding DSA allograft rejection (N=44) was characterized by increased microvascular infiltration by NK cells (P<0.001), monocyte/macrophages (P<0.001), greater prevalence of complement deposition (P<0.001), and selective changes in gene expression including interferon-gamma and endothelial activation (CXCL11, CCL4, MS4A6A, MS4A7, GBP1; P<0.01) as compared with patients with non-C1q-binding DSA (N=113). This phenotype was distinct from that of patients with non-C1q-binding DSA and without DSA in unsupervised principal component analysis. Mice receiving complement-binding DSA reproduced the human complement-activating antibody-mediated histo-molecular rejection phenotype. Eculizumab specifically abrogated the histo-molecular phenotype induced by C1q-binding DSAs and showed no effect on allograft injury in patients with non-C1q-binding DSA.

Conclusion: 

Circulating complement-binding DSA induce a specific histo-molecular phenotype of kidney allograft rejection that can be reversed by complement inhibition.  

16/ COMPOSITE PROGNOSTIC SCORE IMPROVES CLINICAL BENEFIT IN KIDNEY RECIPIENTS RECEIVING STANDARD OF CARE THERAPY FOR ANTIBODY-MEDIATED REJECTION

Session : « ABMR : from diagnosis to treatment » (11:10 to 12:40) 

Location : Room 123 – 12:13 

D Viglietti, A Loupy, O Aubert, C Legendre, D Glotz, C Lefaucheur

Background: 

There is a substantial heterogeneity in antibody-mediated rejection (AMR) patients’ prognosis after standard of care (SOC) including plasma exchange (PE) and intravenous immunoglobulin (IVIG). We investigated whether the use of a prognostic score in kidney recipients receiving AMR SOC therapy improves clinical-decision making.

Methods: 

We prospectively enrolled 2666 kidney recipients transplanted between 2004 and 2012 and included those diagnosed with active AMR who received standardized treatment with PE (x4) and high-dose IVIG (2 g/kg every 3 weeks x3). Patients were assessed at diagnosis and 3 months post-treatment for clinical and histological characteristics, and donor-specific anti-HLA antibodies (DSA) by SAB. An AMR prognostic score was derived from the multivariate Cox model for allograft loss. The net clinical benefit of the prognostic score was assessed by decision curve analysis.

Results: 

We included 284 patients with biopsy-proven active AMR who received SOC treatment. The independent predictors of graft loss were: GFR (HR, 0.93; 95%CI, 0.90-0.95; P<0.001) and presence of IF/TA (HR, 2.44; 1.36-4.37; P=0.003) at AMR diagnosis, and change in GFR (HR, 0.24; 95%CI, 0.16-0.35; P<0.001), ptc Banff score (HR, 1.50; 95%CI, 1.16-1.93; P=0.002) and DSA level after treatment (HR,1.30; 95%CI, 1.11-1.52; P=0.001). The AMR prognostic score showed good discrimination (C-statistic, 0.84). Decision-making after AMR SOC based on the prognostic score provided greater net clinical benefit than considering patients on the same risk level. The initiation of a second-line therapy based on the prognostic score would lead to treat 11 patients who will lose their graft in the absence of clinical intervention per 100 patients receiving SOC while not treating patients who will not lose their graft.

Conclusion: 

The use of an accurate composite prognostic score based on clinical, histological and immunological parameters in kidney recipients receiving SOC therapy for AMR improved clinical decision-making.  

17/ LONG-TERM OUTCOME OF ANTIBODY-MEDIATED REJECTION DUE TO PRE-EXISTING VS. DE NOVO DSA IN KIDNEY ALLOGRAFT RECIPIENTS.

Session : « ABMR : from diagnosis to treatment » (11:10 to 12:40) 

Location : Room 123 – 12:27

O Aubert, C Lefaucheur, S Higgins, L Hidalgo, J-P Duong van Huyen, D Viglietti, X Jouven, D Glotz, C Legendre, P Halloran and A Loupy.

Background: 

Antibody-mediated rejection (ABMR) can occur in patients with pre-existing anti-HLA donor-specific antibodies (DSA) or in patients who develop de novo DSA. However, how these processes compare in terms of kidney allograft outcome has not been addressed. 

Methods: 

From a cohort of 771 kidney biopsies, we included all patients with a diagnosis of ABMR. We used an integrative analysis strategy comprising a systematic assessment of clinical-biological parameters, transplant characteristics, histopathology, immunohistochemistry, type of treatment and circulating DSA assessment.

Results: 

Among the 205 patients with ABMR, 103 were related to pre-existing DSA while 102 were related to de novo DSA. ABMR due to de novo DSA displayed increased proteinuria and transplant glomerulopathy lesions, lower glomerulitis, but similar peritubular-capillaritis Banff scores and C4d-deposition than patients with ABMR due to pre-existing DSA. Graft survival was superior in patients with pre-existing DSA ABMR compared to patients with de novo DSA ABMR (graft survival at 8 years post ABMR of 63% vs 35% respectively, p<0.001). We identified de novo DSA ABMR (HR=1.82 compared to pre-existing DSA ABMR); low (<30mL/min/1.73m2) eGFR at diagnosis (HR=3.27; p<0.001); ≥0.30g/g proteinuria/creatinine ratio (HR=2.44; p<0.001); and presence of cg-lesions (HR=2.25; p=0.002) as the main determinants of allograft loss independently of type of treatment, time of diagnosis and degree of allograft injury and atrophy scarring at the time of diagnosis.

Conclusion: 

We found that these diseases have distinct prognosis with an acceptable and superior allograft survival in patients with preexisting/persisting DSA related ABMR. This supports the transplantation of highly-sensitized patients but also encouraging efforts to monitor patients for de novo DSA and avoidance of minimization strategies. 


18/ ABSENCE OF INDEPENDENT AND ADDITIONAL PREDICTIVE ABILITY OF PREIMPLANTATION KIDNEY ALLOGRAFT BIOPSIES FOR LONG-TERM OUTCOME: POPULATION BASED STUDY

Session : « Deceased donor risk and kidney allocation» (17:05 to 18:35) 

Location : Room 116 – 17:47

O Aubert, D Viglietti, C Loheac, M Rabant, C Gosset, J-P Duong van Huyen, D Glotz, C Legendre, C Lefaucheur and A Loupy.

Background: 

A significant number of kidneys are discarded worldwide. The mean cause is the result of the preimplantation biopsy without clear evidence that its results are associated with long-term allograft survival. 

Methods: 

We included patients who underwent kidney transplantations from a deceased donor in 2 French referral centers between 2004 and 2011 where preimplantation are routinely performed. All the patients with preimplantation biopsy were included. A systematic assessment of donor, recipient, and transplant clinical characteristics, a preimplantation biopsy and an evaluation of baseline circulating donor-specific anti-HLA antibody (DSA) levels were performed. 

Results: 

A total of 882 patients were included in the study. A total of 352/882 (40%) transplantations were performed using ECD kidneys and a total of 143/882 (16%) had an anti-HLA DSA at the day of transplantation. The mean follow-up time after transplantation was 6.56 ± 2.37 years. After adjusting for donor, recipient, and transplant characteristics as well as for preimplantation biopsy findings (including the atrophy-fibrosis, percentage of sclerotic glomeruli, arteriosclerosis and arteriolar hyalinosis scores) and baseline immunological parameters, we identified the KDRI score (HR=2.17; p=0.002) and the presence of circulating anti-HLA DSA on the day of transplantation (HR=2.89p<0.0001) as the main independent determinants of long-term allograft loss. None of the preimplantation biopsy findings showed independent association with the kidney allograft survival. 

Conclusion: 

Preimplantation biopsy assessment does not provide independent and additional predictive ability for long-term allograft outcome at a population level in deceased donor program. The current practice of discarding kidneys based on preimplantation biopsy findings may not be optimal for decision-making and is a barrier to the decrease in the rate of discarded kidneys.  


19/ GENE EXPRESSION PROFILING FOR THE IDENTIFICATION AND CLASSIFICATION OF ANTIBODY-MEDIATED HEART REJECTION 

Session : « Challenges in heart transplantation» (17:05 to 18:35) 

Location : Room 124 – 17:05

A Loupy, JP Duong Van Huyen, L Hidalgo, J Reeve, M Racapé, O Aubert, D Viglietti, P Bruneval, C Lefaucheur, PF Halloran 

Background: 

The specific effects of anti-HLA antibodies on heart allograft injury have not been addressed at a population level.

Methods: 

We prospectively monitored 617 heart recipients referred from 4 French heart transplant centers (2006 - 2011) for antibody-mediated rejection (AMR). We compared AMR patients (n=50) to a matched control group of 50 patients without AMR. We characterized all patients using histopathology (ISHLT 2013), immunostaining, gene expression assessments of allografts (microarray) and circulating anti-HLA DSA at the time of biopsy. We studied an external validation cohort of 98 heart recipients transplanted in Edmonton (Canada) including 27 pAMR cases and 71 controls.

Results: 

240 heart transplant EMB were assessed. AMR showed a distinct pattern of injury characterized by microcirculation inflammation by monocytes/macrophages and NK cells, and very selective changes in endothelial/angiogenesis and NK cell transcripts. The AMR selective gene sets discriminated patients with AMR from those without and included NK (AUC=0.87), endothelial activation (AUC=0.80), macrophage (AUC=0.86) and IFNG transcripts (AUC=0.84, p<0.0001 for all comparisons). These 4 gene sets showed increased expression with increasing AMR ISHLT grades (p<0.001), association with DSA levels and chronic allograft vasculopathy. The unsupervised PCA analysis demonstrated a high proportion of molecular inactive pAMRI+ compared with a significant molecular overlap between pAMR1H+ and pAMR2-3 reclassifying 25% of AMR cases. The molecular architecture and selective AMR transcripts, and the gene set discrimination capacity for AMR were highly conserved in the external validation cohort.

Conclusion: 

Antibody-mediated heart rejection is mainly driven by NK burden, endothelial activation, macrophage burden and IFNG effects. Molecular intragraft measurements for these specific pathogenesis-based transcripts classify AMR with great accuracy and correlate with the degree of injury and disease activity. 


20/ A NEW DIAGNOSTIC SCORE OF INTRAVASCULAR ACTIVATED MONONUCLEAR CELLS IN ANTIBODY-MEDIATED REJECTION IN HEART TRANSPLANTATION 

Session : « Challenges in heart transplantation» (17:05 to 18:35) 

Location : Room 124 – 17:12

A Loupy, X Jouven, M Racapé 

Background

The ISHLT classification defines Intravascular Activated Mononuclear Cells (IAMC) as one of the histopathologic features of Antibody-Mediated Rejection (pAMR) in heart transplantation. However, no accurate grading of IAMC correlating with pAMR diagnosis has been proposed. The aim of this study was to develop a score to grade the extent and the pattern of the IAMC in endomyocardial biopsies (EMB) with AMR.

Methods

This case-control study included heart transplant patients from five French referral centers with biopsy-proven AMR (pAMR1-3) (n=64) and a matched control group of 44 patients without rejection (pAMR0). IAMC on EMBs was graded blind of pAMR grades by two skilled pathologists according to the percentage of the area with IAMC in capillaries and to the maximum number of IAMC in the most affected capillary on a 0 to 3 scale and a positivity defined by a grade ≥ 1. The score was compared to the gene expression profile in EMBs by microarray using the ABMR molecular score and pathogenesis-based transcripts reflecting endothelial activation (ENDAT), DSA (DSAST), macrophage burden (QCMAT), gamma-interferon response (GRIT) and NK-cell burden (NKB) (http://atagc.med.ualberta.ca).

Results

100% of control EMBs were graded as IAMC score 0. All pAMR1(I+) EMBs and none of the pAMR1(H+) and pAMR2-3 were graded as IAMC score 0. The highest IAMC score 3 was mainly distributed in pAMR2-3 (Fischer's exact=0.000). Increase in the IAMC score was associated with an increase in the proportion of C4d and CD68 (macrophage marker) positive EMBs, and a higher proportion of DSA positive at EMB. It was also associated with an increase in the expression of ENDAT, DSAST, GRIT, NKB and QCMAT transcripts (All Kruskal-Wallis<0.001).

Conclusion

The IAMC score is associated with molecular activation in grafted myocardial tissue. The IAMC score could help pathologists for AMR diagnosis, emphasizing the value of IAMC in AMR detection.


21/ DETERMINANTS AND OUTCOMES OF CARDIAC ALLOGRAFT VASCULOPATHY / MAJOR ROLE OF DONOR-SPECIFIC ANTIBODY 

Session : « Challenges in heart transplantation» (17:05 to 18:35) 

Location : Room 124 – 17:47

M Racapé, G Bonnet, MC Bories, S Varnous P. Rouvier, R. Guillemain, P. Bruneval, JL Taupin, C Lefaucheur, A. Loupy

Background

The role of circulating DSA in addition to traditional cardiovascular risk factors in the development of CAV has not been demonstrated.

Methods

This observational, prospective cohort study included 723 heart transplant patients from 2 centers between 2004 and 2011. Participants were screened for traditional cardiovascular risk factors, circulating anti-HLA antibodies (specificity, HLA class, strength). All patients underwent prospective heart allograft biopsies and angiogram with assessment of CAV lesions. We assessed the independent determinants of CAV at 3 years after transplantation.

Results

A total of 145 patients (20.1%) had circulating DSA at transplantation. 170 patients (23.5%) experienced acute rejection in the first 3 years post-transplant with 128 cases (17.7%) of grade 2R ACR and 83 cases (11.5%) of antibody-mediated rejection (ISHLT pAMR+). At 3 years post transplant, 29.7% of patients had CAV (20.8%, 7.4% and 1.5% with CAV scores of 1, 2 and 3 respectively). After adjusting on traditional risk factors (recipient age, primary heart disease, gender, hypertension, tobacco use, dyslipidemia, diabetes mellitus, BMI), donor factors (age, gender, BMI, cause of death), transplant characteristics (cold ischemia time, center, emergency heart transplantation), immunological parameters (circulating DSA at transplantation and acute rejection), and CMV disease occurence, the independent determinants of CAV at 3 years were: donor age (RR=1.05; 95%CI=1.03-1.08), recipient dyslipidemia (RR=2.1; 95%CI=1.02-4.29), presence of circulating DSA at transplantation (RR=2.45 95%CI=1.45-4.12). Occurrence of pAMR2 post-transplant was also a strong and independent factor associated with CAV at 3 years post-transplant (RR=3.51, IC95%=1.84-6.69). This group showed decreased patient survival (HR=1.8 p=0.01).

Conclusion

Circulating DSA are major determinants of severe arteriosclerosis, independent of traditional cardiovascular risk factors. Antibody-mediated CAV is associated with reduced patient survival. 



A propos de Carmen Lefaucheur


Carmen Lefaucheur is Doctor in the Renal Transplant department in Saint-Louis Hospital

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