Transcript Acute cellular rejection

Acute rejection after kidney
transplantation
Pr Lionel ROSTAING
Département de Néphrologie et Transplantation d’Organes (DNTO)
CHU Toulouse-Rangueil, France
[email protected]
Tbilisi, April 8th2016
Prevalence of acute rejection: 10 to 20%
[acute cellular rejection : 90%
antibody-mediated rejection: 10%]
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Hyperacute rejection
• It is mediated by preformed circulating antibodies that do bind
complement : they can be directed against
 Donor HLA antigens
 ABO antigens (in the setting of ABO incompatible kidney transplantation)
 Xeno-antigens.
 Complement activation results in platelet aggegation and
ultimately vascular thrombosis
 organ necrosis
 This type of acute rejection should NEVER be observed
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Homoral/vascular rejection
• It is mediated by alloantibody (ies) already present at transplantation but
however, at very low titer : thereby the cross-match
(microlymphocytotoxicity) is negative. Conversely, these alloantibody (ies)
can be synthetized at posttransplant anamnestic response).
 Anti-HLA alloantibody
 Anti-endothelial cell antibody
 Mostly observed in patients transfused in the past or in women (pregnancy,
miscarriage)
• Histology :
 Vascular lesions (endarteritis ; C4d deposits on vascular walls)
 Withoit specific treatment results in organ necrosis
 This type of rejection represents less than 10% of acute
rejections.
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Acute cellular rejection
•
Acute cellular rejection : this is the most frequent acute
rejection type
•
This is a T-cell mediated process
 Differed process (a few days to a few months)
 If no treatment is implemented, this will result in
organ destruction
 Acute cellular rejection occurs in 10 to 15% of kidney
transplant patients
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Targets of acute rejection
• Kidney  tubular cells, endothelium (glomeruli)
 Prevalence of acute cellular rejection : 10 to 15%
 Prevalence of acute humoral rejection : a few %
• What are the mediators of acute rejection?
 T activated cytotoxic lymphocytes (CD8+, CD45 RO+, DR+, Perforine+,
granzyme B+, Fas L+)
 Donor-specific alloantibodies (DSA); complement activation.
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Rejection description according to
Banff classification
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Banff 07 diagnostic categories for renal
allograft biopsies (1); revised in 2013
T-cell-mediated rejection (TCMR)
 Acute T-cell-mediated rejection (Type/Grade:)
 IA. Cases with significant interstitial infiltration (>25% of parenchyma
affected, i2 or i3) and foci of moderate tubulitis (t2)
 IB. Cases with significant interstitial infiltration (>25% of parenchyma
affected, i2 or i3) and foci of severe tubulitis (t3)
 IIA. Cases with mild-to-moderate intimal arteritis (v1)
 IIB. Cases with severe intimal arteritis comprising >25% of the
luminal area (v2)
 III. Cases with ‘transmural’ arteritis and/or arterial fibrinoid change
and necrosis of medial smooth muscle cells with accompanying
lymphocytic inflammation (v3)
 Chronic active T-cell-mediated rejection
 ‘chronic allograft arteriopathy’ (arterial intimal fibrosis with
mononuclear cell infiltration in fibrosis, formation of neo-intima)
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Solez K et al. Am J Transplant 2008;8:753-760
Banff 07 diagnostic categories for renal
allograft biopsies (2); revised in 2013
Borderline changes: ‘Suspicious’ for acute T-cellmediated rejection
 This category is used when no intimal arteritis is present, but
there are foci of tubulitis (t1, t2 or t3) with minor interstitial
infiltration (i0 or i1) or interstitial infiltration (i2, i3) with mild (t1)
tubulitis
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Solez K et al. Am J Transplant 2008;8:753-760
Banff 07 diagnostic categories for renal
allograft biopsies (3); revised in 2013
Acute/active AMR; all three features must be present for diagnosis
1. Histologic evidence of acute tissue injury, including one or more of the following:
 Microvascular inflammation (g > 0 and/or ptc > 0)
 Intimal or transmural arteritis (v > 0)
 Acute thrombotic microangiopathy, in the absence of any other cause
 Acute tubular injury, in the absence of any other apparent cause
2. Evidence of current/recent antibody interaction with vascular endothelium, including
at least one of the following:
 Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen
sections, or C4d > 0 by IHC on paraffin sections)
 At least moderate microvascular inflammation ([g + ptc] ≥ 2)
 Increased expression of gene transcripts in the biopsy tissue indicative of
endothelial injury, if thoroughly validated
3. Serologic evidence of donor-specific antibodies (DSAs) (HLA or other antigens)
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Haas M et al. Am J Transplant 2014;14:272-283
Banff 07 diagnostic categories for renal
allograft biopsies (4); revised in 2013
Chronic, active AMR; all three features must be present for diagnosis
1. Morphologic evidence of chronic tissue injury, including one or more of the following :
 Transplant glomerulopathy (TG) (cg > 0), if no evidence of chronic thrombotic
microangiopathy> 0)
 Severe peritubular capillary basement membrane multilayering (requires EM)
 Arterial intimal fibrosis of new onset, excluding other causes
2. Evidence of current/recent antibody interaction with vascular endothelium, including
at least one of the following:
 Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen
sections, or C4d > 0 by IHC on paraffin sections)
 At least moderate microvascular inflammation ([g + ptc] ≥ 2)
 Increased expression of gene transcripts in the biopsy tissue indicative of
endothelial injury, if thoroughly validated
3. Serologic evidence of DSAs (HLA or other antigens)
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Haas M et al. Am J Transplant 2014;14:272-283
Banff 07 diagnostic categories for renal
allograft biopsies (5); revised in 2013
Interstitial fibrosis and tubular atrophy, no evidence of
any specific etiology
(may include nonspecific vascular and glomerular sclerosis, but
severity graded by tubulointerstitial features)
 Grade :
I. Mild interstitial fibrosis and tubular atrophy (<25% of cortical
area)
II. Moderate interstitial fibrosis and tubular atrophy (26–50% of
cortical area)
III. Severe interstitial fibrosis and tubular atrophy/loss (>50% of
cortical area)
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Solez K et al. Am J Transplant 2008;8:753-760
Antibody-mediated vascular rejection of kidney
allografts : a population-based study (1)
Identification of four distinct rejection patterns according to clinical, histological, and immunological variables
The unsupervised principal component analysis examined kidney recipients with acute biopsy-proven rejection with seven variables:
glomerulitis, peritubular capillaritis, donor-specific anti-HLA antibodies, C4d deposition, interstitial inflammation, tubulitis, and
endarteritis. The horizontal axis opposes cellular rejection (interstitial inflammation and tubulitis) and antibody-mediated rejection
(donor-specific anti-HLA antibodies, glomerulitis, peritubular capillaritis and C4d), as recognised by the international Banff
classification. The vertical axis defines the presence or absence of lesions of endarteritis (appendix).
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Lefaucheur C. et al.The Lancet 2013;381:313-319
Antibody-mediated vascular rejection of kidney
allografts : a population-based study (2)
Comparison of morphological and
immunological variables in the four
rejection patterns
Bars represent SD. NS=not significant.
TCMR/V– =T cell-mediated rejection
without vasculitis.
TCMR/V+ =T cell-mediated vascular
rejection.
ABMR/V+ =antibody-mediated vascular
rejection.
ABMR/V– =antibody-mediated rejection
without vasculitis.
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Lefaucheur C. et al.The Lancet 2013;381:313-319
Antibody-mediated vascular rejection of kidney
allografts : a population-based study (3)
Kaplan-Meier curves for kidney graft survival by acute rejection phenotype
Initial diagnoses as per (A) Banff classifications and (B) our new approach. Graft survival in patients
without rejection is purely illustrative; graft survival in these individuals starts at time of transplantation.
TCMR/V– =T cell-mediated rejection without vasculitis.
TCMR/V+ =T cell-mediated vascular rejection.
ABMR/V– =antibody-mediated rejection without vasculitis.
ABMR/V+ =antibody-mediated vascular rejection.
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Lefaucheur C et al.The Lancet 2013;381:313-319
Antibody-mediated vascular rejection of kidney
allografts : a population-based study (4)
Multivariate analysis of factors associated with graft loss in patients with antibodymediated vascular rejection,
Number of
patients
Numbers of
events
Hazard ratio
(95% CI)
P value
3
32
7
1
…
>3
32
14
4.33 (1.5-12.1)
0.005
<3
52
15
1
…
3
12
6
5.17 (1.8-14.6)
0.002
<3000
41
9
1
…
3000
23
12
3.88 (1.5-9.8)
0.004
Steroids and intravenous immune globulin
13
7
1
…
Steroids plus munomonab-CD3 or rabbit antithymocyte globulin
29
11
0.4 (0.2-1.3)
0.1
Steroids, plasmapheresis, intravenous immune globulin, and rituximab
22
3
0.16 (0.04-0.66)
0.01
Intersistial inflammation and tubulitis score*
Endarteritis score
DSAmax MFI
Treatment strategy
Hazard ratios were estimated in a single Cox proportional hazards model. DSAmax MFI=maximum mean intensity of fluorescence of donor-specific
anti-HLA antibodies.
*Interstitial inflammation and tubulitis score was defined as the sum of interstitial inflammation and tubulitis, and was graded from 0 to 6.
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Lefaucheur C et al.The Lancet 2013;381:313-319
Influence of acute rejection type upon kidney
allograft survival
cellulaire
P < 0,001
humoral
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Everly MJ & al. Am J Transplant. 2009;9:1063-1071
Influence of de novo DSA on kidney allograft
•
De novo DSA at the time of acute rejection :
  graft survival
•
Rapid decrease in DSA
 Improvement of allograft survival
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Everly MJ & al. Am J Transplant. 2009;9:1063-1071
Influence of de novo DSA at the time of acute
rejection on allograft survival
p= 0,001
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Everly MJ & al. Am J Transplant. 2009;9:1063-1071
Diagnosis of acute rejection (1)
• Two situations: early posttransplant, and after a few weeks:
 Immediately posttransplant acuet rejection has to be ruled out in the
following settings:
 Prolonged acute tubular necrosis (> 5 days), specially in the
setting of living kidney transplant
 A rapid drop in urine outpout
 A stable but impaired serum creatinine(i,e, above the level at which
it should be)
 An increase in serum creatinine above its baseline value
 Otherwise, we have to rule out acute rejection wherever there is an
unexplained rise in serum creatinine.
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Diagnosis of acute rejection (2)
• Positive diagnosis:
 To rule-out other causes of allograft dysfunction, such as obstruction of
urinary tract, or ureteral leaking, or acute pyelonephritis, or vascular
thrombosis (artery or vein), or toxic levels of ciclosporin /tacrolimus
 Kidney allograft biopsy :
 Lymphocytic interstitial infiltrate (CD3 +); apply Banff classification
C4d deposits?
 Endarteritis ? Glomerulitis? Interstitial haemorrhage and/or
interstitial edema?
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Elementary lesions
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Elementary lesions
•
•
•
•
•
Acute
Glomerulitis
Inflammatory infiltrate
Tubulitis
Capillaritis
Vasculitis
•
•
•
•
•
Chronic
Chronic allograft
nephropathy
Interstitial fibrosis
Tubular atrophy
Allograft vasculopathy
Arteriolar hyalinosis
Others :
• Edema
• Interstitial hemorraghae
C4d
Acute lesions
CD3
C4d
Diagnosis
Tubulitis +
inflammatory infiltrate
Borderline acute rejection
Grade I acute rejection (mild)
Capillaritis +
glomerulitis +
edema + C4d (+)
Humoral
rejection
Arteritis
Moderate acute
rejection (grade II)
Severe AR (grade III)
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Differential diagnosis
• Infection :
 Acute pyelonephritis
 BK-virus infection
• Vascular problem :
 Arterial stenosis
 Venous stenosis
• Lymphoproliferative disorder
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Treatment of acute rejection
• Treatment :
 First line therapy: IV Methylprednisolone:
 10 mg/kg/d for 3 consecutive days = proapoptotic effect
 In case of steroid-resistant acute rejection (less tha 10% of
cases): antilymphocyte preparations (Thymoglobulines®)
 In case of humoral rejection: plasmapheresis +/- IVIg +/- Rituximab
(anti-CD20 monoclonal antibody)
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How to prevent acute rejection? (1)
• To perform pretransplant a cross-match
(microlymphocytotoxicity and when possible by flow
cytometry) in order to rule-out donor-specific alloantibody
(ies)
 T-cell cross-match (assess anti-class I antibodies)
 B-cell cross-match (assess anti-class I and anti-class II antibodies)
 Dithiotrietol (DTT) which enables to get rid out of IgM alloantibodies
(i,e, they are not pathogenic)
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How to prevent acute rejection? (2)
• How to perform the cross-match?
 By micro-lymphocytotoxicity (CDC cross-match)
 lymphocytes + serum + complement --> Patient’s T-cell lysis? If yes -->
positive cross-match
 Flow cytometry
 Results :
 If T-cell cross-match is positive : NO kidney transpalntation
If B-cell cross-match is positive:
* transplant day serum: NO transplantation
* on historical serums only: kidney transplantation IS possible
but high risk of antibody-mediated rejection
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