Update in acute humoral rejection

Christophe Legendre
Hpital Necker
Universit Paris Descartes
Pars

Definitions of rejection

PF Halloran et al, Kidney Int 2014

Clinical acute cellular

rejection (TCMR)
1. Acute renal dysfunction
2. Histologic features:
IA. Significant interstitial infiltration (>25% i2 or i3) and foci
of moderate tubulitis (t2),
IB. Significant interstitial infiltration (>25% i2 or i3) and foci of
severe tubulitis (t3)
IIA. Mild-to-moderate intimal arteritis (v1)
IIB. Severe intimal arteritis comprising (>25%, V2) III.
III. Cases with transmural arteritis and/or arterial fibrinoid
change and necrosis
C4d -

3. Absence of donor specific antibodies

Solez K et al, Am J Transplantation 2007

Acute cellular rejection

(TCMR)

TCMR = 12% of LIR, 7% of all patients

JM Chemouny et al, Transplantation (In press)

TCMR and de novo DSAs

21%
TCMR = 12% of LIR, 7%
of all patients
JM Chemouny et al, Transplantation (In press)

TCMR and de novo DSAs:

prognosis

Post-TCMR de novo DSAs

Post-TCMR de novo DSAs

and acute rejection
JM Chemouny et al, Transplantation (In press)

Acute antibody-mediated
rejection (ABMR)
Subclinical antibodymediated rejection

1. Acute renal dysfunction

2. Histologic features:

Vascular lesions as
severity index

ATN-like minimal inflammation (I)

Capillary and/or glomerular
inflammation
(ptc/g>0) and/or thromboses (II)
C4d negative antibodymediated rejection
Arterial v3 (III)
C4d positivity as severity index
C4d+

3. Donor specific antibodies (Anti-HLA

or not)

Ant-HLA C DSAs
Anti-HLA DSAs of UO
Non anti-HLA DSAs

K Solez et al, Am J Transplantation 2007

Acute antibody-mediated
rejection (ABMR)
Subclinical antibodymediated rejection

1. Acute renal dysfunction

2. Histologic features:
ATN-like minimal inflammation (I)
Capillary and/or glomerular
inflammation
(ptc/g>0) and/or thromboses (II)
Arterial v3 (III)
C4d+

3. Donor specific antibodies (Anti-HLA

or not)
K Solez et al, Am J Transplantation 2007

Necker: initial experience

with DSA+ recipients

D Anglicheau et al, Am J Transplant 2007

Necker: initial experience

with DSA+ recipients

D Anglicheau et al, Am J Transplant 2007

Acute lesions of AMR

A Loupy et al, Am J Transplant 2009

Chronic lesions of AMR

A Loupy et al, Am J Transplant 2009

G Hill et al, J Am Soc Nephrol 2011

Subclinical antibodymediated rejection

1. No or mild renal dysfunction
2. Histologic features (acute and chronic):
Microvascular inflammation
Glomerular double contours and/or
Peritubular capillary basement
+membrane multilayering and/or
IF/TA
Fibrous intimal thickening in arteries,
C4d+

3. Donor specific antibodies (Anti-HLA or

M Haas et al, Am J Transplant 2007
not)

A Loupy et al, Am J Transplant 2009

14%

Necker experience:
1Y screening biopsy
(n = 1001 patients)

A Loupy et al, J Am Soc Nephrol (In press)

A Loupy et al, J Am Soc Nephrol (In press)

Risk of graft loss:

multivariate analysis

A Loupy et al, J Am Soc Nephrol (In press)

Acute antibody-mediated
rejection (ABMR)
1. Acute renal dysfunction
2. Histologic features:
ATN-like minimal inflammation (I)
Capillary and/or glomerular
inflammation
(ptc/g>0) and/or thromboses (II)
Arterial v3 (III)
C4d+

Vascular lesions as
severity index

3. Donor specific antibodies (Anti-HLA

or not)
K Solez et al, Am J Transplantation 2007

Ttulo
Subttulo

A methodology to discriminate
relevant rejection patterns
2062 Kidney recipients
302 with clinical rejection

1.
2.
3.
4.
5.
6.
7.

Interstitium (i)
Tubules (t)
Arteries (v)
Capillaries (ptc)
Glomeruli (g)
Circulating DSA (DSA)
Complement (C4d)
C Lefaucheur, A Loupy et al, Lancet 2013

C Lefaucheur, A Loupy et al, Lancet 2013

C Lefaucheur, A Loupy et al, Lancet 2013

C Lefaucheur, A Loupy et al, Lancet 2013

C Lefaucheur, A Loupy et al, Lancet 2013

Acute antibody-mediated
rejection (ABMR)
1. Acute renal dysfunction
2. Histologic features:
ATN-like minimal inflammation (I)
Capillary and/or glomerular
inflammation
(ptc/g>0) and/or thromboses (II)
C4d negative antibodymediated rejection
Arterial v3 (III)
C4d positivity as severity index
C4d+

3. Donor specific antibodies (Anti-HLA

or not)
K Solez et al, Am J Transplantation 2007

A Loupy et al, Am J Transplant 2011

A Loupy et al, Am J Transplant 2011

A Loupy et al, Am J Transplant 2011

Acute antibody-mediated
rejection (ABMR)
1. Acute renal dysfunction
2. Histologic features:
ATN-like minimal inflammation (I)
Capillary and/or glomerular
inflammation
(ptc/g>0) and/or thromboses (II)
Arterial v3 (III)
C4d+

3. Donor specific antibodies (Anti-HLA

or not)

Ant-HLA C DSAs
Anti-HLA DSAs of UO
Non anti-HLA DSAs

K Solez et al, Am J Transplantation 2007

Anti C-DSA

27% AMR

O Aubert et al, Am J Transplant 2014

Acute antibody-mediated
rejection (Banff 2013)
1. Acute renal dysfunction
2. Histologic evidence of:
- Acute tissue injury ( 1):
- Microvascular inflammation (g or cpt > 0),
- Intimal or transmural arteritis (v > 0),
- Thrombotic microangiopathy,
- ATN without other evidence,

- Interaction Ab endothelium (1):

- Linear staining of C4d,
- At least [g + cpt] > 2)
- Increased expression of gene transcripts
in tissue

3. Serologic evidence of DSA (HLA, nonM Haas et al, Am J Transplantation 2014

HLA)

Acute ABMR

Chronic ABMR

Subclinical
ABMR

Electron microscopy

Endothelial-associated transcripts

A Loupy et al, Clin J Am Soc Nephrol 2011

Chronic antibody-mediated
rejection
1. Renal dysfunction (creat, HTA, Pu)
2. Histologic evidence of:
- Chronic tissue injury (1):
- Transplant glomerulopathy (g > 0),
- Ptc basal membrane multilayering (EM) ,
- Arterial intimal fibrosis of new onset,,

- Interaction Ab endothelium (1) :

- Linear staining of C4d,
- At least [g + cpt] > 2)
- Increased expression of gene
transcripts in tissue

3. Serologic evidence of DSA (HLA, nonHLA)

M Haas et al, Am J Transplantation 2014

Conclusions
Clinical and subclinical acute cellular rejection
occur in 10-15% of cases and have a good long-term
prognostic impact (except when de novo DSAs).
The definition of clinical acute humoral rejection
has changed: microcirculation inflammation is
nowdays the major feature.
Subclinical acute humoral rejection is present at
one year in 10-15% of cases mainly in preformed
DSA+ patients, should probably be treated (but
how!) and has clearly a deleterious long-term
prognostic impact.
Referencia en caso de materiales originales